H LEE MOFFITT CANCER CENTER Nonprofit Org. & RESEARCH INSTITUTE INC 12902 Magnolia Drive PAID Tampa FL 33612-9416 Jacksonville, FL

Permit No. 4390

Index Medicus/MEDLINE Index

is included in included is Control Cancer

Alexis Cruz-Chacon, MD, John Mathews, MD, and Ernesto Ayala, MD Ayala, Ernesto and MD, Mathews, John MD, Cruz-Chacon, Alexis

Histiocytic Disorders Histiocytic

and Lymphoproliferative Rare in Transplantation

Nanette Grana, MD Grana, Nanette

Langerhans Cell Histiocytosis Histiocytosis Cell Langerhans

Samir Dalia, MD, Elizabeth Sagatys, MD, Lubomir Sokol, MD, PhD, et al et PhD, MD, Sokol, Lubomir MD, Sagatys, Elizabeth MD, Dalia, Samir

Pathology, and Treatment and Pathology,

Rosai–Dorfman Disease: Tumor Biology, Clinical Features, Features, Clinical Biology, Tumor Disease: Rosai–Dorfman

Darcie Deaver, PhD, Pedro Horna, MD, Hernani Cualing, MD, et al et MD, Cualing, Hernani MD, Horna, Pedro PhD, Deaver, Darcie

Kikuchi–Fujimoto Disease Kikuchi–Fujimoto

of Management and Diagnosis, Pathogenesis,

Ling Zhang, MD, Jun Zhou, MD, and Lubomir Sokol, MD, PhD MD, Sokol, Lubomir and MD, Zhou, Jun MD, Zhang, Ling

Lymphohistiocytosis Lymphohistiocytosis

Hemophagocytic Acquired and Hereditary

Samir Dalia, MD, Haipeng Shao, MD, PhD, Elizabeth Sagatys, MD, et al et MD, Sagatys, Elizabeth PhD, MD, Shao, Haipeng MD, Dalia, Samir

Biology, Diagnosis, and Treatment Treatment and Diagnosis, Biology,

Neoplasms: Histiocytic and Cell Dendritic

Wasif Riaz, MD, Ling Zhang, MD, Pedro Horna, MD, et al et MD, Horna, Pedro MD, Zhang, Ling MD, Riaz, Wasif

Update on Molecular Biology, Diagnosis, and Therapy and Diagnosis, Biology, Molecular on Update

Neoplasm: Cell Dendritic Plasmacytoid Blastic

and Jeremy S. Abramson, MD Abramson, S. Jeremy and

MD, Sohani, R. Aliyah MD, Soumerai, D. Jacob

Diagnosis and Management of Castleman Disease Disease Castleman of Management and Diagnosis

H. LEE MOFFITT CANCER CENTER & RESEARCH INSTITUTE, AN NCI COMPREHENSIVE CANCER CENTER CANCER COMPREHENSIVE NCI AN INSTITUTE, RESEARCH & CENTER CANCER MOFFITT LEE H.

Vol. 21, No. 4, October 2014 October 4, No. 21, Vol. cancercontroljournal.org advances in the management of multiple

Save the Date!

presents Advances in the Management of Multiple Myeloma March 6–7, 2015 Loews Don Cesar Hotel St. Petersburg Beach, Florida

Course Directors: Melissa Alsina, MD, Rachid Baz, MD, and Kenneth H. Shain, MD, PhD Moffitt Cancer Center, Tampa, Florida

Conference Overview: Advances in the Management of Multiple Myeloma conference is designed to foster the exchange of the most recent advances in the biology and treatment of multiple myeloma. National and international leading experts in the field will present in a format promoting discussion and interaction with participants.

Target Audience: This educational program is directed toward hematologists, medical and surgical oncologists, and BMT physicians who diagnose, treat, and manage multiple myeloma. Other health care professionals who are interested in the diagnosis, treatment, and care of patients with multiple myeloma are also invited to attend.

To be added to the conference mailing list, contact: Moffitt Cancer Center | Marsha Moyer, MBA | 813-745-2286 | [email protected] Editorial Board Members

Editor: Rami Komrokji, MD Production Staff: Associate Member Lodovico Balducci, MD Veronica Nemeth Malignant Hematology Senior Member Editorial Coordinator Conor C. Lynch, PhD Program Leader, Senior Adult Oncology Program Don Buchanan Assistant Member Moffitt Cancer Center Graphic Designer Tumor Biology Deputy Editor: Amit Mahipal, MD, MPH Consultant: Julio M. Pow-Sang, MD Assistant Member Clinical Research Unit Sherri Damlo Senior Member Medical Copy Editor Chair, Department of Genitourinary Oncology Gastrointestinal Oncology Director of Moffitt Robotics Program Kristen J. Otto, MD Associate Editor of Moffitt Cancer Center Assistant Member Head & Neck Oncology Educational Projects Editor Emeritus: Michael A. Poch, MD John M. York, PharmD Akita Biomedical Consulting John Horton, MB, ChB Assistant Member 1111 Bailey Drive Professor Emeritus of Medicine & Oncology Genitourinary Oncology Paso Robles, CA 93446 Jeffery S. Russell, MD, PhD Phone: 805-238-2485 Moffitt Cancer Center Assistant Member Fax: 949-203-6115 Journal Advisory Committee: Endocrine Tumor Oncology E-mail: [email protected] Aliyah Baluch, MD Elizabeth M. Sagatys, MD Assistant Member Assistant Member For Consumer and Infectious Diseases Pathology - Clinical General Advertising Dung-Tsa Chen, PhD Jose E. Sarria, MD Information: Associate Member Assistant Member Veronica Nemeth Biostatistics Anesthesiology Editorial Coordinator Hey Sook Chon, MD Saïd M. Sebti, PhD Cancer Control: Assistant Member Senior Member Journal of the Moffitt Cancer Center Gynecological Oncology Drug Discovery 12902 Magnolia Drive – MBC-JRNL Tampa, FL 33612 Jasreman Dhillon, MD Bijal D. Shah, MD Phone: 813-745-1348 Assistant Member Assistant Member Fax: 813-449-8680 Pathology - Anatomic Malignant Hematology E-mail: [email protected] Jennifer S. Drukteinis, MD Lubomir Sokol, MD, PhD Associate Member Senior Member Diagnostic Radiology Hematology/Oncology Timothy J. George, PharmD Hatem H. Soliman, MD Pharmacy Residency Director Assistant Member Clinical Pharmacist - Malignant Hematology Breast Oncology Clement K. Gwede, PhD Jonathan R. Strosberg, MD Associate Member Assistant Member Health Outcomes & Behavior Gastrointestinal Oncology Sarah E. Hoffe, MD Sarah W. Thirlwell, RN Associate Member Nurse Director Radiation Oncology Supportive Care Medicine Program Cancer Control is a member of John V. Kiluk, MD Eric M. Toloza, MD, PhD the Medscape Publishers’ Circle®, Associate Member Assistant Member an alliance of leading medical Breast Oncology Thoracic Oncology publishers whose content is Richard D. Kim, MD Nam D. Tran, MD featured on Medscape Associate Member Assistant Member (www.medscape.com). Gastrointestinal Oncology Neuro-Oncology Bela Kis, MD, PhD Jonathan S. Zager, MD Most issues and supplements of Assistant Member Associate Member Cancer Control are available at Diagnostic Radiology Sarcoma and Cutaneous Oncology cancercontroljournal.org

CANCER CONTROL: JOURNAL OF THE MOFFITT CANCER CENTER (ISSN 1073-2748) is published by H. Lee Moffitt Cancer Center & Research Institute, 12902 Magnolia Drive, Tampa, FL 33612. Telephone: 813-745-1348. Fax: 813-449-8680. E-mail: [email protected]. Internet address: cancercontroljournal.org. Cancer Control is included in Index Medicus ®/MEDLINE® and EM- BASE®/Excerpta Medica, Thomson Reuters Science Citation Index Expanded (SciSearch®) and Journal Citation Reports/Science Edition. Send subscription requests to the publisher. Single copy: $10 US, $15 Canada and foreign. Subscription rates: nonqualified individuals $60 per year US, $75 per year outside US, institutions/libraries $120 per year US ($135 per year foreign). Send change of address to the publisher with old address label and new address. Publisher is not responsible for undelivered copies. Copyright 2014 by H. Lee Moffitt Cancer Center & Research Institute. All rights reserved. Printed on acid-free paper. Cancer Control: Journal of the Moffitt Cancer Center is a peer-reviewed journal that is published to enhance the knowledge needed by professionals in oncology to help them minimize the impact of human malignancy. Each issue emphasizes a specific theme relating to the detection or management of cancer. The objectives of Cancer Control are to define the current state of cancer care, to integrate recently generated information with historical practice patterns, and to enlighten readers through critical reviews, commentaries, and analyses of recent research studies. DISCLAIMER: All articles published in this journal, including editorials and letters, represent the opinions of the author(s) and do not necessarily reflect the opinions of the editorial board, the H. Lee Moffitt Cancer Center & Research Institute, Inc, or the institutions with which the authors are affiliated unless clearly specified. The reader is advised to independently verify the effectiveness of all methods of treatment and the accuracy of all drug names, dosages, and schedules. Dosages and methods of administration of pharmaceutical products may not be those listed in the package insert and solely reflect the experience of the author(s) and/or clinical investigator(s).

October 2014, Vol. 21, No. 4 Cancer Control 257 Table of Contents

Editorial

Hope for Orphan Lymphoproliferative and Histocytic Diseases on the Horizon? 260 Lubomir Sokol, MD, PhD

Articles

Diagnosis and Management of Castleman Disease 266 Jacob D. Soumerai, MD, Aliyah R. Sohani, MD, and Jeremy S. Abramson, MD

Blastic Plasmacytoid Dendritic Cell Neoplasm: 279 Update on Molecular Biology, Diagnosis, and Therapy Wasif Riaz, MD, Ling Zhang, MD, Pedro Horna, MD, and Lubomir Sokol, MD, PhD

Dendritic Cell and Histiocytic Neoplasms: 290 Biology, Diagnosis, and Treatment Samir Dalia, MD, Haipeng Shao, MD, PhD, Elizabeth Sagatys, MD, Hernani Cualing, MD, and Lubomir Sokol, MD, PhD

Hereditary and Acquired Hemophagocytic Lymphohistiocytosis 301 Ling Zhang, MD, Jun Zhou, MD, and Lubomir Sokol, MD, PhD

Pathogenesis, Diagnosis, and Management of 313 Kikuchi–Fujimoto Disease Darcie Deaver, PhD, Pedro Horna, MD, Hernani Cualing, MD, and Lubomir Sokol, MD, PhD

Rosai–Dorfman Disease: Tumor Biology, Clinical Features, 322 Pathology, and Treatment Samir Dalia, MD, Elizabeth Sagatys, MD, Lubomir Sokol, MD, PhD, and Timothy Kubal, MD

258 Cancer Control October 2014, Vol. 21, No. 4 Table of Contents

Langerhans Cell Histiocytosis 328 Nanette Grana, MD

Transplantation in Rare Lymphoproliferative and 335 Histiocytic Disorders Alexis Cruz-Chacon, MD, John Mathews, MD, and Ernesto Ayala, MD

Departments

Special Report: Social Determinants of Racial and Ethnic Disparities in 343 Cutaneous Melanoma Outcomes Valerie M. Harvey, MD, Hitesh Patel, MS, MBA, Sophia Sandhu, MD, Sherrie Flynt Wallington, PhD, and Ginette Hinds, MD

Special Report: Fruit and Vegetable Intake Among Jordanians: 350 Results From a Case-Control Study of Colorectal Cancer Reema F. Tayyem, PhD, Ihab Shehadah, MD, Suhad S. Abu-Mweis, PhD, Hiba A. Bawadi, PhD, Kamal E. Bani-Hani, MD, PhD, Tareq Al-Jaberi, MD, PhD, Majed Al-Nusairr, MD, and Dennis D. Heath, MS

Ten Best Readings Relating to Rare Lymphoproliferative and Histiocytic Diseases 361

Index for 2014, Volume 21 362

Peer Reviewers, 2014 365

About the art in this issue: Sherri Damlo has been a professional medical editor for nearly a decade. Currently, she runs Damlo Edits, a small editing business, and is the medical copy editor for Cancer Control. She became interested in photography as a hobby when she moved to the Pacific Northwest in 2008. Ever since she was a young girl she has always had her nose pointed toward the ground to discover the specimens of nature that many people tend to overlook. Her collection in this issue reflects this same ecological obsession, including photographs of fungi, gastropods, and insects. She also is intrigued about the way in which nature reclaims objects, so she has always been attracted to ruins and places lost to time. Sherri loves to travel, and she never leaves home without her camera. More of her work can be seen at www.flickr.com/sdamlo, www.damloshots.com, and on the stock image site, Getty Images. Cover: Cupped Mushrooms Pages: 258-259 Gum Drop Mushrooms Eye of a Dandelion Mushroom Biome Snail on Moss Net-Wing Beetle Eight-Spotted Skimmer White Butterfly Mottled Star

October 2014, Vol. 21, No. 4 Cancer Control 259 Editorial

Hope for Orphan Lymphoproliferative and Histiocytic Diseases on the Horizon?

Orphan diseases are conditions with low prevalences mass. However, the standard of care has not been in the population, and the rarity of these diseases has established for patients with disseminated disease; been a major obstacle for experimental and clinical in- therefore, such patients should be referred to tertiary vestigations. The recent advent of new high-through- centers for diagnostic confirmation and for the design put molecular biology techniques (eg, next-generation of a therapeutic plan. sequencing) has accelerated our understanding of Dr Zhang and colleagues review hemophagocytic these diseases as well as the identification of new lymphohistiocytosis in the next article. Within the last target molecules, which have substantially facilitated decade significant progress has been made in the di- drug discovery. Although our understanding of the agnosis and management of familial hemophagocytic pathobiology of these rare diseases is far from sat- lymphohistiocytosis. Several causative germinal mu- isfactory, progress has been made in the diagnosis tations have been identified in families with this dis- and management of several rare lymphoproliferative order. Patient outcomes have improved following the and histiocytic disorders discussed in this issue of introduction of allogeneic stem cell transplantation; Cancer Control. however, patients with secondary hemophagocytic The first article in this issue is by Dr Soumerai and lymphohistiocytosis due to malignancies, viral infec- colleagues and is devoted to Castleman disease. The tion, or autoimmune diseases have a worse prognosis. majority of patients with the unicentric, hyaline-vas- The mortality rate is high, particularly in patients cular subtype of Castleman disease can be cured with who develop multiple organ failure; therefore, early complete surgical resection of the enlarged lymph diagnosis is essential for better outcomes. nodes; by contrast, the multicentric plasma cell variant Dr Deaver and others discuss Kikuchi–Fujimoto of Castleman disease typically has a more aggressive disease, which is a rare histiocytic disorder. This idio- course of disease. Results from a recent, randomized pathic condition frequently manifests with the rapid phase 3 study of an anti-interleukin 6 monoclonal and painful enlargement of cervical lymph nodes and antibody led the US Food and Drug Administration systemic B symptoms in young women of Asian de- to approve the agent as a therapeutic option for the scent. Clinical symptomatology and high fluorodeoxy- multicentric plasma cell variant of Castleman disease glucose uptake using positron emission tomography/ in patients negative for both HIV and human herpes- computed tomography may clinically mimic malig- virus 8 infections. nant lymphoma. Typically, excisional or core needle Dr Riaz and others discuss a rare aggressive ma- biopsy of the enlarged lymph nodes and a careful lignancy called blastic plasmacytoid dendritic cell histology and immunohistochemistry evaluation by neoplasm, a disease initially believed to arise from an experienced hematopathologist are sufficient for immature natural killer cells; however, more recently, diagnosis. The disease is self-limiting and rarely re- a plasmacytoid dendritic cell origin has been suggest- quires treatment. ed. Whole genome sequencing revealed somatic gene In their article, Dr Dalia and colleagues describe mutations similar to those identified in myelodys- Rosai–Dorfman disease, a rare histiocytic disorder plastic syndrome, acute myeloid leukemia, and some that involves various organs and systems (eg, central lymphoproliferative disorders. The strong expression nervous system, skin, lymph nodes). Surgical resection of interleukin 3α receptor (CD123) on blastic plasma- of the tumor mass in patients with localized disease cytoid dendritic cell neoplasm cells became a target is considered the most effective frontline therapy, al- for novel biological therapy. Recent data from an early though some patients with more advanced or unre- phase 1/2 study of an anti-CD123 antibody conjugate sectable disease can benefit from radiation therapy. are very promising. The use of systemic chemotherapy or immunotherapy Dr Dalia and coauthors review rare dendritic and is based on case reports alone. histiocytic cell sarcomas, which make up a clinical- Dr Grana reviews the diagnosis and manage- ly and histopathologically heterogeneous group of ment of Langerhans cell histiocytosis in children and malignant diseases derived from mature dendritic adults. This disease can aggressively manifest in in- cells or histiocytes. Patients with localized disease fants and young children as Letter–Siwe disease or can benefit from a complete resection of the tumor Hand–Schüller–Christian disease, respectively, and

260 Cancer Control October 2014, Vol. 21, No. 4 may require intensive systemic therapy. A less acute course of the disease is often observed in adults who present with localized eosinophilic granuloma that commonly involves the bones and the lungs. Smoking has been implicated in the pathogenesis of Langer- hans cell histiocytosis when the lungs are involved. Smoking cessation can result in the spontaneous re- gression of the disease. The discovery of the BRAF V600E gene mutation in patients with Langerhans cell histiocytosis has offered the possibility of novel targeted therapy using BRAF inhibitors. Dr Cruz-Chacon and coauthors provide a com- prehensive review about the utility of hematopoietic stem cell transplantation in patients with rare lymph- oproliferative and histiocytic disorders. Some of these diseases are aggressive and have short-lived responses to conventional chemotherapy regimens. Consolida- tion with high-dose chemotherapy followed by he- matopoietic stem cell transplantation during the first remission or in patients with chemosensitive disease can be curative in selected patients. In 2 Special Reports included in this issue, Dr Harvey and coauthors review the medical litera- ture dealing with the social determinants of racial and ethnic disparities in cutaneous melanoma outcomes, and Dr Tayyem and colleagues compare fruit and vegetable intake between 2 groups of Jordanians in a case-control study of colorectal cancer. I hope that our series of articles dealing with rare lymphoproliferative and histiocytic disorders as well as the Special Reports in this issue will be useful for busy hematology practitioners and other medical professionals interested in this field.

Lubomir Sokol, MD, PhD Senior Member Head, Section of Lymphoma Department of Malignant Hematology H. Lee Moffitt Cancer Center & Research Institute Tampa, Florida [email protected]

October 2014, Vol. 21, No. 4 Cancer Control 261 Department of Malignant Hematology H. Lee Moffitt Cancer Center & Research Institute Eduardo M. Sotomayor, MD, Chair

The Department of Malignant Hematology specializes in the evaluation, treatment, and comprehensive care of patients with lymphoma, leukemia, multiple myeloma, myelodysplastic syndrome (MDS), and myeloproliferative syndrome. The department is recognized as a Center of Excellence by the Myelodysplasia Foundation and is 1 of 4 founding institutions of the Bone Marrow Failure (BMF) Consortium funded by the National Institutes of Health. All patients with MDS, large granular lymphocytic leukemia, aplastic anemia, or other rare causes of bone marrow failure are registered in the Consortium’s national database, which was developed and is maintained at the H. Lee Moffitt Cancer Center & Research Institute. The BMF Consortium is the first and only co-operative network developed by the National Institutes of Health for the study of the biology and development of novel therapeutics for these disorders. Although chemotherapy remains an integral component of the treatment for most hematological malignancies, the development of disease-specific or targeted therapeutics represents the research goal of Moffitt investiga- tors who treat patients with lymphoma, leukemias, and multiple myeloma. Marrow or stem cell transplantation often is indicated for the treatment of hematological malignancies. The treatment protocols of the Department of Malignant Hematology are integrated with those of the Blood and Marrow Transplant Program. The Cancer Center has state-of-the-art facilities for both inpatient and outpatient administration of chemotherapy.

SECTIONS OF THE DEPARTMENT OF MALIGNANT HEMATOLOGY

PHARMACY AND LEUKEMIA/MDS LYMPHOMA MYELOMA IMMUNOTHERAPY SUPPORTIVE CARE Jeffrey E. Lancet, MD Lubomir Sokol, MD, PhD Rachid Baz, MD Javier Pinilla-Ibarz, MD, PhD Viet Q. Ho, PharmD Section Head Section Head Section Head Section Head Section Head

Clinical Specialists Clinical Specialists Clinical Specialists Clinical Specialists Clinical Specialists Rami S. Komrokji, MD Celeste Bello, MD Melissa Alsina, MD Julie Yin Djeu, PhD Sheetal A. Desai, PharmD Timothy Kubal, MD Julio C. Chavez, MD William S. Dalton, MD, PhD Chih-Chi Andrew Hu, PhD Timothy J. George, PharmD Alan F. List, MD Paul A. Chervenick, MD Benjamin Djulbegovic, MD, PhD Jeffrey E. Lancet, MD Van D. Hoang, PharmD (MDS) Benjamin Djulbegovic, MD, PhD John M. Koomen, PhD Lubomir Sokol, MD, PhD Rod E. Quilitz, PharmD Lynn C. Moscinski, MD L. Frank Glass, MD (Pathology) Eduardo M. Sotomayor, MD Dana A. Spears, PharmD Eric Padron, MD (Dermatologist/Cutaneous Mojdeh Naghashpour, MD, PhD Alejandro Villagra, PhD Javier Pinilla-Ibarz, MD, PhD Lymphomas) (Pathology) (CML) Michael Montejo, MD Kenneth H. Shain, MD, PhD Haipeng Shao, MD, PhD (Radiation Oncology) Kendra Sweet, MD Javier Pinilla-Ibarz, MD, PhD (CLL) Ling Zhang, MD Bijal D. Shah, MD Kenneth S. Zuckerman, MD Eduardo M. Sotomayor, MD

Scientific Collaborators Scientific Collaborators Scientific Collaborators Scientific Collaborators Pearlie K. Burnette, PharmD, PhD Sophie Dessureault, MD, PhD Lori A. Hazlehurst, PhD Scott J. Antonia, MD, PhD Lori A. Hazlehurst, PhD Pedro Horna, MD Saïd M. Sebti, PhD Pearlie K. Burnette, PharmD, PhD Lynn C. Moscinski, MD Chih-Chi Andrew Hu, PhD Kenneth H. Shain, MD, PhD Sophie Dessureault, MD, PhD Gary W. Reuther, PhD Elizabeth Sagatys, MD Ariosto S. Silva, PhD Lori A. Hazlehurst, PhD Sheng Wei, MD Michael J. Schell, PhD Daniel Sullivan, MD Sheng Wei, MD Edward Seto, PhD Kenneth L. Wright, PhD Jianguo Tao, MD, PhD Kenneth L. Wright, PhD

These specialists are complemented by physician extenders, nurses, dietitians, social workers, data managers, and administrative support. Education and training are also heavily emphasized, with programs ranging from medical student courses to fellowship training and international education.

262 Cancer Control October 2014, Vol. 21, No. 4 Selected Active Clinical Trials Relating to Malignant Hematology at Moffitt Cancer Center

Acute Lymphoblastic Leukemia

MCC 15625 Phase 1/2 Study of Sequential Idarubicin + Cytarabine, Followed by Lenalidomide, in Patients With Myelodysplastic Syndrome (RAEB-2) or With Previously Untreated Acute Myeloid Leukemia

MCC 16434 Study of the Anti-EphA3 Monoclonal Antibody KB004 in Subjects With EphA3-Expressing Hematologic Malignancies

MCC 16548 Phase 3, Randomized, Controlled, Double-Blind, Multinational Clinical Study of the Efficacy and Safety of Vosaroxin and Cytarabine Versus Placebo and Cytarabine in Patients With First Relapsed or Refractory Acute Myeloid Leukemia (VALOR)

MCC 17208 Phase 1, Open-Label, Dose-Escalation Study of SGN-CD19A in Patients With B-Lineage Acute Lymphoblastic Leuke- mia and Highly Aggressive Lymphomas

MCC 17409 Open-Label, Randomized Phase 3 Study of Inotuzumab Ozogamicin Compared to a Defined Investigators Choice in Adult Patients With Relapsed or Refractory CD22-Positive Acute Lymphoblastic Leukemia (ALL)

Acute Myelogenous Leukemia

MCC 17061 Phase 1B/2 Study to Evaluate the Safety and Efficacy of PF-04449913, an Oral Hedgehog Inhibitor, in Combination With Intensive Chemotherapy, Low Dose ARA-C or Decitabine in Patients With Acute Myeloid Leukemia or High-Risk Myelodysplastic Syndrome

MCC 17088 Phase 1 Study of the Safety, Pharmacokinetics and Pharmacodynamics of Escalating Doses of the Selective Inhibitor of Nuclear Export (SINE) KPT-330 in Patients With Advanced Hematological Malignancies

MCC 17234 Phase 3, Multicenter, Randomized, Trial of CPX-351 (Cytarabine:Daunorubicin) Liposome Injection Versus Cytara- bine and Daunorubicin in Patients 60-75 Years of Age With Untreated High Risk (Secondary) AML

MCC 17576 Phase 1 Trial of SGN-CD33A in Patients With CD33-Positive Acute Myeloid Leukemia

Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma

MCC 16002 Phase 1/2 Study of MEDI-551, a Humanized Monoclonal Antibody-Directed Against CD19, in Adult Subjects With Relapsed or Refractory Advanced B-Cell Malignancies

MCC 16622 Phase 2 Study of Ofatumumab in Combination With High Dose Methylprednisolone Followed by Ofatumumab and Lenalidomide Consolidative Therapy for the Treatment of Untreated CLL/SLL: The HiLOG Trial

MCC 16631 Phase 2 Study of Ofatumumab in Combination With High Dose Methylprednisolone Followed by Ofatumumab and Lenalidomide Consolidative Therapy for the Treatment of Relapsed or Refractory CLL/SLL: The HiLOG Trial

MCC 17180 Brentuximab Vedotin Plus AVD in Non-Bulky Limited Stage Hodgkin Lymphoma

Chronic Myeloid Leukemia

MCC 17114 Phase 1/2 Study of Ruxolitinib in Combination With Nilotinib in CML Patients With Evidence of Molecular Disease

MCC 17396 Single-Arm, Multicenter, Nilotinib Treatment-Free Remission Study in Patients With BCR-ABL1 Positive Chronic Myelogenous Leukemia in Chronic Phase Who Have Achieved Durable Minimal Residual Disease (MRD) Status on First Line Nilotinib Treatment

MCC 17577 Phase 2 Randomized, Multicenter Study of Treatment-Free Remission in Chronic Myeloid Leukemia in Chronic Phase (CML-CP) Patients Who Achieve and Sustain MR4.5 After Switching to Nilotinib

continues on page 264

October 2014, Vol. 21, No. 4 Cancer Control 263 Selected Active Clinical Trials Relating to Malignant Hematology at Moffitt Cancer Center

Chronic Myelomonocytic Leukemia

MCC 17182 Open-Label, Randomized Phase 2, Parallel, Dose-Ranging, Multicenter Study of Sotatercept for the Treatment of Patients With Anemia and Low or Intermediate-1 Risk Myelodysplastic Syndromes or Non-Proliferative Chronic Myelomonocytic Leukemia (CMML)

MCC 17259 Sequential Two-Stage Dose Escalation Study to Evaluate the Safety and Efficacy of Ruxolitinib for the Treatment of Chronic Myelomonocytic Leukemia (CMML)

Lymphoma

MCC 16434 Study of the Anti-EphA3 Monoclonal Antibody KB004 in Subjects With EphA3-Expressing Hematologic Malignancies

MCC 17088 Phase 1 Study of the Safety, Pharmacokinetics and Pharmacodynamics of Escalating Doses of the Selective Inhibitor of Nuclear Export (SINE) KPT-330 in Patients With Advanced Hematological Malignancies

Mantle Cell Lymphoma

MCC 16002 Phase 1/2 Study of MEDI-551, a Humanized Monoclonal Antibody-Directed Against CD19, in Adult Subjects With Relapsed or Refractory Advanced B-Cell Malignancies

MCC 17303 A Phase 1, Open-Label, Dose-Escalation Study of SGN-CD19A in Patients With Relapsed or Refractory B-Lineage Non-Hodgkin Lymphoma

Multiple Myeloma

MCC 16434 Study of the Anti-EphA3 Monoclonal Antibody KB004 in Subjects With EphA3-Expressing Hematologic Malignancies

MCC 16659 Phase 1b, Open-Label, Multicenter Study of BMS-936564 in Combination With Lenalidomide (Revlimid®) Plus Low- Dose Dexamethasone, or With Bortezomib (Velcade®) Plus Dexamethasone in Subjects With Lapsed or Refractory Multiple Myeloma

MCC 17088 Phase 1 Study of the Safety, Pharmacokinetics and Pharmacodynamics of Escalating Doses of the Selective Inhibitor of Nuclear Export (SINE) KPT-330 in Patients With Advanced Hematological Malignancies

MCC 17155 Phase 1/2 Trial of Combination Plerixafor (AMD3100), Bortezomib and Dexamethasone in Relapsed or Relapsed/ Refractory Multiple Myeloma

MCC 17223 Phase 1/2 Open-Label Study to Assess the Safety, Tolerability and Preliminary Efficacy of TH-302, a Hypoxia-Ac- tivated Prodrug, and Dexamethasone With or Without Bortezomib in Subjects With Relapsed/Refractory Multiple Myeloma

MCC 17419 Phase 1b/2, Multicenter, Open-Label Study of Oprozomib and Dexamethasone in Patients With Relapsed and/or Refractory Multiple Myeloma

Myelodysplastic Syndrome

MCC 15445 Randomized Phase 3 Trial Comparing the Frequency of Major Erythroid Response (MER) to Treatment With Lenalid- omide (Revlimid) Alone and in Combination With Epoetin Alfa (Procrit) in Subjects With Low- or Intermediate-1 Risk MDS and Symptomatic Anemia

MCC 15625 Phase 1/2 Study of Sequential Idarubicin + Cytarabine, Followed by Lenalidomide, in Patients With Myelodysplastic Syndrome (RAEB-2) or With Previously Untreated Acute Myeloid Leukemia

MCC 16434 Study of the Anti-EphA3 Monoclonal Antibody KB004 in Subjects With EphA3-Expressing Hematologic Malignancies

continues on page 265

264 Cancer Control October 2014, Vol. 21, No. 4 Selected Active Clinical Trials Relating to Malignant Hematology at Moffitt Cancer Center

Myelodysplastic Syndrome (continued)

MCC 16523 Sequential Two-Stage Dose Escalation Study to Evaluate the Safety and Efficacy of Eltrombopag in Myelodysplastic Syndrome (MDS) Patients With Thrombocytopenia Who Progressed or Are Resistant to Hypomethylating Agents

MCC 17061 Phase 1B/2 Study to Evaluate the Safety and Efficacy of PF-04449913, an Oral Hedgehog Inhibitor, in Combination With Intensive Chemotherapy, Low Dose ARA-C or Decitabine in Patients With Acute Myeloid Leukemia or High-Risk Myelodysplastic Syndrome

MCC 17182 Open-Label, Randomized Phase 2, Parallel, Dose-Ranging, Multicenter Study of Sotatercept for the Treatment of Patients With Anemia and Low- or Intermediate-1 Risk Myelodysplastic Syndromes or Non-Proliferative Chronic Myelomonocytic Leukemia (CMML)

MCC 17302 Phase 2 Study Evaluating the Oral Smoothened Inhibitor PF-04449913 in Patients With Myelodysplastic Syndrome

Non-Hodgkin Lymphoma

MCC 16002 Phase 1/2 Study of MEDI-551, a Humanized Monoclonal Antibody-Directed Against CD19, in Adult Subjects With Relapsed or Refractory Advanced B-Cell Malignancies

MCC 17303 Phase 1, Open-Label, Dose-Escalation Study of SGN-CD19A in Patients With Relapsed or Refractory B-Lineage Non-Hodgkin Lymphoma

MCC 17344 Phase 3, Randomized, Double-Blind, Placebo-Controlled Study Evaluating the Efficacy and Safety of Idelalisib (GS- 1101) in Combination With Rituximab for Previously Treated Indolent Non-Hodgkin Lymphomas

MCC 17682 Phase 1B, Multi-Center, Open-Label Study of Novel Combinations of CC-122, CC-223, CC-292, and Rituximab in Diffuse Large B-Cell Lymphoma

T-Cell Lymphoma

MCC 17006 Phase 3 Randomized Two-Arm Open-Label Multicenter International Trial of Alisertib (MLN8237) or Investigators Choice (Selected Single Agent) in Patients With Relapsed or Refractory Peripheral T-Cell Lymphoma

MCC 17215 Open-Label, Multi-Center, Randomized Study of Anti-CCR4 Monoclonal Antibody KW-0761 (Mogamulizumab) Versus Vorinostat in Subjects With Previously Treated Cutaneous T-Cell Lymphoma

MCC 17343 Pilot Study of Brentuximab Vedotin in Relapsed/Refractory Peripheral T-Cell Lymphoma Expressing CD30 Receptor

To schedule a patient appointment with a physician in the Department of Malignant Hematology, call the New Patient Appointment Center at (813) 745-3980 or 1-888-860-2778 (during normal business hours).

For information about clinical trials, please call Cheryl Maker in the Clinical Research Department at (813) 745-4106 or e-mail [email protected] or check the Department of Malignant Hematology’s Web page at www.MOFFITT.org.

October 2014, Vol. 21, No. 4 Cancer Control 265 Castleman disease is an uncommon and

heterogeneous lymphoproliferative disorder

for which management is rapidly evolving.

Gum Drop Mushrooms. Photograph courtesy of Sherri Damlo. www.damloedits.com.

Diagnosis and Management of Castleman Disease Jacob D. Soumerai, MD, Aliyah R. Sohani, MD, and Jeremy S. Abramson, MD

Background: Castleman disease is an uncommon lymphoproliferative disorder characterized as either unicentric or multicentric. Unicentric Castleman disease (UCD) is localized and carries an excellent prognosis, whereas multicentric Castleman disease (MCD) is a systemic disease occurring most commonly in the setting of HIV infection and is associated with human herpesvirus 8. MCD has been associated with considerable morbidity and mortality, and the therapeutic landscape for its management continues to evolve. Methods: The available medical literature on UCD and MCD was reviewed. The clinical presentation and pathological diagnosis of Castleman disease was reviewed, along with associated disorders such as certain malignancies and autoimmune complications. Results: Surgical resection remains the standard therapy for UCD, while systemic therapies are required for the management of MCD. Rituximab monotherapy is the mainstay of therapy; however, novel therapies targeting interleukin 6 may represent a treatment option in the near future. Antiviral strategies as well as single-agent and combination chemotherapy with glucocorticoids are established systemic therapies. The management of Castleman disease also requires careful attention to potential concomitant infections, malignancies, and associated syndromes. Conclusions: UCD and MCD constitute uncommon but well-defined clinicopathologic entities. Although UCD is typically well controlled with local therapy, MCD continues to pose formidable challenges in management. We address historical chemotherapy-based approaches to this disease as well as recently developed targeted therapies, including rituximab and siltuximab, that have improved the outcome for newly diagnosed patients. Ongoing research into the management of MCD is needed.

Introduction From the Center for Lymphoma at the Massachusetts General Hospital Cancer Center (JDS, JSA), Harvard Medical School (JDS, Castleman disease, also known as angiofollicular ARS, JSA), and the Department of Pathology (ARS) at the Massa- lymph node hyperplasia, is an uncommon lymph- chusetts General Hospital, Boston, Massachusetts. oproliferative disorder originally described in a case Submitted March 31, 2014; accepted June 18, 2014. published in 1954.1 The patient from that case was Address correspondence to Jeremy S. Abramson, MD, Center for a man aged 42 years who presented with high fe- Lymphoma, Massachusetts General Hospital Cancer Center, 55 Fruit Street, Yawkey 9A, Boston, MA 02114; E-mail: jabramson@mgh. vers, sweats, fatigue, and a nonproductive cough. harvard.edu He was found to have an anterior mediastinal mass No significant relationships exist between the authors and the com- with anemia and an elevated sedimentation rate. The panies/organizations whose products or services may be referenced treating physician suspected tuberculosis and empir- in this article. ical streptomycin was administered prior to complete The authors have disclosed that this article discusses unlabeled/ unapproved uses of the drug tocilizumab for the treatment of surgical resection. The discussants favored a diag- Castleman disease. nosis of teratoma or dermoid cyst, also considering

266 Cancer Control October 2014, Vol. 21, No. 4 mediastinal tuberculoma, thymoma, and Hodgkin get in Castleman disease based on its critical role in disease. Castleman presented the surgical pathology pathogenesis and driving of symptomatology. and described a new syndrome characterized by hy- HIV-associated MCD is uniformly associated with perplasia of mediastinal lymph nodes with regressed HHV-8 infection, although its prevalence in HIV-nega- germinal centers.1 The disease did not recur in this tive MCD varies by the local prevalence rate of HHV-8. patient following surgical resection. This case, fol- Plasma levels of HHV-8 DNA correlate with clinical lowed 2 years later by a case series,2 described what symptoms and predict relapse rates in HIV-associ- is now known as unicentric Castleman disease (UCD), ated MCD.13 In patients with HHV-8-positive MCD, which is distinct from multicentric Castleman disease HHV-8-infected vascular and lymphoid cells express (MCD), a condition with unique clinical and patho- a viral analog of IL-6 (vIL-6), which likely contrib- logical features. utes to the pathogenesis of this significant subset of Histologically, Castleman disease may be classified Castleman disease. Both human IL-6 and vIL-6 are as either the hyaline-vascular or plasma cell variant, sufficient to induce disease flares in HIV-associated with occasional cases demonstrating mixed features.3 MCD and promote the expression of proinflammatory The hyaline-vascular histology accounts for most UCD cytokines during disease flares.12,14-16 cases and the plasma cell type characterizes most cases of MCD. UCD is typically localized, associated Pathological Diagnosis with minimal symptoms, and treated with local ther- Castleman disease is a pathological diagnosis made apy alone. However, MCD is a systemic disease that by excisional biopsy of affected lymph node tissue. commonly occurs in the setting of HIV infection and is In cases of deeper or less accessible disease, core clinically characterized by diffuse lymphadenopathy, needle biopsy is preferred to fine needle aspiration, splenomegaly, anemia, and systemic inflammatory because fine needle aspirations are insensitive for symptoms.4 Accordingly, MCD is primarily treated both UCD and MCD. with systemic therapies. Most cases of UCD are histologically classified as Although Castleman disease is not a malignant the hyaline-vascular variant, which is characterized by condition, the condition has been associated with increased numbers of small, hyalinized blood vessels an increased risk of developing certain malignancies within and between follicles with obliteration of the and other diseases, most notably large B-cell lym- medullary sinuses.3 Lymphoid follicles are increased phomas, along with polyneuropathy, organomegaly, in number and exhibit features of “regression,” a endocrinopathy, monoclonal gammopathy and skin term referring to a predominance of dendritic cells abnormality (POEMS) syndrome, follicular dendritic within germinal centers with a relative paucity of cell sarcomas, and paraneoplastic pemphigus.5-7 Kapo- lymphocytes and a consequent broadening of mantle si sarcoma is also commonly diagnosed concurrently zones. The small lymphocytes of the mantle zones or sequentially with MCD because the 2 entities share are frequently arranged in concentric rings around a common viral pathogenesis. the germinal center (“onion-skinning”), and follicles may be radially penetrated by a blood vessel (“lolli- Pathogenesis pop” follicle; Fig 1). Plasma cells may be found in the The pathogenesis of Castleman disease is not fully interfollicular region, but they are typically few and understood; however, the central roles of interleukin present in small clusters. Cases with abundant plasma (IL) 6 in UCD and both IL-6 and human herpesvi- cells likely reflect examples of UCD with “mixed” or rus (HHV) 8 in MCD have been well described.8-12 “transitional” features between the hyaline-vascular Dysregulated and overproduced IL-6, particularly in and plasma cell histological variants.17 patients with MCD, stimulates the production of acute By contrast to hyaline-vascular Castleman disease, phase reactants in the liver, resulting in constitutional cases of plasma cell variant Castleman disease typi- symptoms, including fever, sweats, and fatigue, and cally show greater retention of the nodal architecture laboratory abnormalities, such as anemia, elevated with hyperplastic follicles of varying sizes and focally inflammatory markers, hypergammaglobulinemia, and patent medullary sinuses. The interfollicular region hypoalbuminemia. IL-6 also stimulates B-cell prolif- may be mildly hypervascular and characteristically eration and induces the expression of vascular en- contains sheets of mature-appearing plasma cells, dothelial growth factor and increased angiogenesis. which show monotypic immunoglobulin (Ig) G or The activation of the IL-6 receptor further results in IgA λ restriction in up to 50% of cases (Fig 2).17 Cases the activation of the Janus kinase–mediated activation positive for HHV-8 show distinctive histological fea- of the signal transducers and the activation of tran- tures with greater interfollicular vascularity, blurring scription pathway and the mitogen-activated protein of the germinal center-mantle zone boundary, and kinase cascade, which enhances B-cell proliferation scattered plasmacytoid immunoblasts, or plasmablasts and survival. IL-6 has emerged as a therapeutic tar- present within the mantle zones (Fig 3), giving rise

October 2014, Vol. 21, No. 4 Cancer Control 267 A B

C D Fig 1. — Hyaline-vascular Castleman disease. (A) Low power view of an involved lymph node shows increased numbers of lymphoid follicles with small, regressed germinal centers and broad mantle zones. The interfollicular areas demonstrate increased vascularity with obliteration of medullary sinuses (H & E, × 40). (B–D) Higher magnification reveals typical features of the follicles, including an increased proportion of follicular dendritic cells relative to lymphocytes within germinal centers, known as follicle regression; concentric arrangement of mantle zone lymphocytes in an “onion skin” pattern; and hypervascularity of follicles, some of which are radially penetrated by a hyalinized blood vessel, resembling a lollipop (B–C: H & E, × 200; D: H & E, × 400). Note the sharp demarcation between the germinal center and mantle zone in images B to D, a feature unlike that seen in HIV-associated multicentric Castleman disease. H & E = hematoxylin and eosin.

A B Fig 2. — Plasma cell variant of Castleman disease negative for human herpesvirus 8. (A) Low power view shows hyperplastic follicles of varying sizes with mildly increased interfollicular vascularity and focally patent medullary sinuses; they are best seen in the lower right-hand portion of the image. Some follicles contain more than 1 germinal center, a feature that may also be seen in the hyaline-vascular variant (H & E, × 25). (B) Higher magnification of the interfollicular areas shows sheets of mature plasma cells with eccentric nuclei and clumped chromatin (H & E, × 400). H & E = hematoxylin and eosin.

268 Cancer Control October 2014, Vol. 21, No. 4 A B

C D

E F Fig 3. — HIV-associated plasmablastic Castleman disease with concurrent nodal involvement by Kaposi sarcoma. (A) Follicles are regressed with a paucity of lymphocytes, hypervascularity, and an indistinct border between the germinal center and surrounding mantle zone, which contains scattered, large, atypical plasmablasts (arrows) with vesicular chromatin, prominent nucleoli, and scant to moderate pink cytoplasm (H & E, × 400). (B) In this case, further examination revealed an atypical spindled cell proliferation consisting of plump endothelial cells with small nucleoli and prominent red blood cell extravasation extending from the lymph node capsule to the subcapsular region, consistent with nodal involvement by Kaposi sarcoma (H & E, × 400). (C) Plasmablasts within the mantle zones showed λ light-chain restriction (Λ-mRNA in situ hybridization, × 400). (D) K-mRNA in situ hybridization showed staining of mature polytypic plasma cells outside of follicles (× 200). (E) Plasmablasts were also positive for immunoglobulin M heavy chain (anti-µ immunohistochemical stain, × 400). (F) Immunohistochemistry with an antibody specific for human herpesvirus 8 latency-associated nuclear antigen 1 showed finely stippled nuclear staining of the plasmablasts (× 1000); a similar staining pattern with this antibody was seen in the endothelial cells of the vascular proliferation (not shown), confirming the concurrent diagnoses of Castleman disease and Kaposi sarcoma involving the same lymph node. H & E = hematoxylin and eosin.

October 2014, Vol. 21, No. 4 Cancer Control 269 to the term “plasmablastic variant” of Castleman dis- or syphilitic (luetic) lymphadenitis due to overlap- ease.18 Immunohistochemistry demonstrates positivity ping features of follicular hyperplasia and increased of plasmablasts for HHV-8 latency-associated nuclear interfollicular plasma cells. In addition, lymphade- antigen 1; these cells express monotypic IgM λ, but nopathy associated with IgG4-related disease may they have been shown to be polyclonal. In some cas- show features that overlap with Castleman disease. es, the atypical plasmablasts coalesce to form micro- The diagnosis of rheumatoid arthritis, syphilis, or scopic nodules adjacent to or replacing some follicles, IgG4-related disease can be readily established based an early stage of large B-cell lymphoma arising in on clinical and laboratory features. In addition, Cas- HHV-8-associated MCD; cases of frank lymphoma are tleman disease lacks the histiocytic inflammation and characterized by complete effacement of the lymph inflamed vasculature seen in syphilis in which spiro- node architecture by sheets of atypical plasmablasts chetes can be identified using special histochemical expressing HHV-8 latency-associated nuclear antigen stains or antitreponemal immunohistochemistry.17,20-22 1.19 Foci of Kaposi sarcoma may be present in some Perhaps the most challenging histological distinction cases, and a diagnosis of Kaposi sarcoma must also be in the pathological diagnosis of MCD is with that of excluded in cases positive for HHV-8; in such cases, HIV-related generalized lymphadenopathy, which is the atypical endothelial cells also show staining for characterized by plasmacytosis, vascular prominence, HHV-8 latency-associated nuclear antigen 1 (see Fig 3). and hyperplastic or regressive changes in the follicles From a pathological standpoint, Castleman dis- of involved lymph nodes depending on their stage ease is a diagnosis of exclusion and its varied histolog- of evolution. However, HIV-related lymphadenopathy ical features give rise to a broad differential diagnosis should not contain plasmablasts positive for HHV-8 that includes both benign and neoplastic entities, most that characterize HIV-associated MCD. For the diag- of which can be excluded on the basis of careful nosis of other subtypes of Castleman disease in the histological examination, immunohistochemical, or setting of HIV infection, one should adhere to strict other ancillary studies (eg, flow cytometry, molecu- morphological criteria given the known histological lar genetics) and correlation with clinical, laboratory, overlap between these entities.17 and radiological findings. Angioimmunoblastic T-cell lymphoma and rare cases of early interfollicular Hod- Staging gkin lymphoma may be associated with Castleman Once Castleman disease is confirmed and the histo- disease–like changes, including the regression of re- logical subtype has been identified, clinical staging sidual germinal centers and hypervascularity. Howev- guides treatment decisions and prognosis. The goals of er, Castleman disease lacks an atypical interfollicular the staging and pretreatment evaluation in Castleman population of neoplastic T cells or Reed–Sternberg disease are to (1) determine whether the patient has cells. The appearance of the follicles in hyaline-vas- unicentric or multicentric disease, (2) identify patients cular Castleman disease may raise the possibility of with systemic inflammatory manifestations of Castle- early nodal involvement by follicular lymphoma in man disease, and (3) assess for the presence of HIV, which atypical follicles can show variable degrees of as well as associated conditions and malignancies. hyalinization. The prominence of the mantle zones in The initial laboratory evaluation of patients with hyaline-vascular Castleman disease may also raise the Castleman disease includes a complete blood count, possibility of early mantle cell lymphoma. Finally, the inflammatory markers (erythrocyte sedimentation rate plasma cell variant of Castleman disease may mimic and C-reactive protein), complete metabolic panel, and lymphoplasmacytic lymphoma (Waldenström macro- albumin. HIV testing should be performed in all pa- globulinemia) due to the large number of interfollic- tients. Plasma HHV-8 DNA levels should be obtained, ular plasma cells; this distinction may be particularly because these levels correlate with symptomatic dis- challenging in cases showing λ light chain restriction. ease and may serve as a helpful biomarker, both to In all of these scenarios, the diagnosis of Castleman support the diagnosis of MCD and to monitor disease disease can be made based on the lack of additional activity and response to therapy. Although levels of histological features supporting a diagnosis of lym- cytokines, most notably IL-6 and IL-10, are important in phoma and the absence of a clonal B-cell population the pathogenesis of Castleman disease and have been with a characteristic immunophenotype. In addition, used as surrogate markers of disease activity in clinical lymphoplasmacytic lymphoma commonly expresses studies, we do not recommend routinely measuring IgM heavy chain and may not show λ light chain them. Serum protein electrophoresis with immuno- restriction, unlike IgG or IgA λ-restricted plasma cell fixation should be obtained when POEMS syndrome variant Castleman disease.17 is suspected. In patients with HIV-associated MCD, a Among non-neoplastic conditions, the plasma thorough skin examination should be performed to as- cell variant of Castleman disease may mimic lymph sess for previously undiagnosed Kaposi sarcoma given nodes biopsied in the setting of rheumatoid arthritis the common concurrent presentation of these entities.

270 Cancer Control October 2014, Vol. 21, No. 4 Computed tomography of the chest, abdomen, ease, partial resection followed by clinical observation and pelvis should be obtained at the time of diagno- alone may result in lengthy remissions; however, such sis to assess for adenopathy and splenomegaly. This treatment warrants careful attention to local progres- imaging modality also helps inform the question of sion. Select patients who are asymptomatic with a low resectability in patients with UCD. A role for routine disease burden who cannot be treated with either sur- positron emission tomography has not been estab- gery or radiation may be closely followed, given the lished in the setting of Castleman disease, although in- often indolent nature of the disease. Systemic options volved nodes in MCD are quite fludeoxyglucose-avid. for MCD, as necessary, should be considered for pa- tients with symptomatic local disease who cannot be Unicentric Castleman Disease treated with surgery or radiation or for those whose Epidemiology disease fails to respond to such treatment. UCD most commonly presents in the third and fourth decade of life, with the mean age of diagnosis being Multicentric Castleman Disease 34 years (range, 2–84 years); UCD also has a slight Epidemiology female predominance (1.4:1).23 No association with MCD commonly presents in the sixth decade of life, HIV or HHV-8 infection exists and epidemiological although patients with HIV infection tend to present risk factors have not been established. at a younger age.4,25,32 A slight male predominance is seen in MCD. HIV infection is an important risk Clinical Presentation factor for MCD, and all patients with HIV-associated UCD may be asymptomatic at diagnosis and be inci- MCD are coinfected with HHV-8. HHV-8 infection is dentally discovered on chest or abdominal imaging present in approximately 50% of HIV-negative cases performed for other reasons. Other patients may pres- of MCD and varies with the HHV-8 seroprevalence ent with painless lymphadenopathy or local anatom- of the population. ical symptoms varying by location. Common sites of Large population studies have revealed an in- presentation in UCD include the chest (30%), neck creased incidence of HIV-associated MCD since the (23%), abdomen (20%), retroperitoneum (17%), and, introduction of antiretroviral therapy, which is in con- rarely, the axilla (5%), groin (3%), or pelvis (2%).23 trast to the marked decline in incidence of HIV-as- Intrathoracic disease is frequently found along the sociated Kaposi sarcoma.33 The mechanism of this tracheobronchial tree or lung hila. Thoracic disease increase is unclear, but such an increase may reflect may present with cough, hemoptysis, dyspnea, or improved survival rates, longstanding immune dys- chest discomfort. Abdominal, retroperitoneal, and regulation associated with long-term HIV infection, or pelvic disease may present with abdominal or back an increased awareness of the disease among health discomfort.2 Bowel and ureteral obstruction have care professionals. been described as presenting symptoms, but they are rare.24 Disease confined to the peripheral lymph Clinical Presentation node chains, including the neck, axilla, or groin, may Systemic inflammatory manifestations characterize present with nontender lymphadenopathy. Systemic the vast majority of patients with MCD who present manifestations, including B symptoms (fevers, drench- with fevers, night sweats, weight loss, and fatigue.4,25,32 ing night sweats, and weight loss) and laboratory ab- Physical examination is typically notable for general- normalities (anemia, elevated inflammatory markers, ized lymphadenopathy and hepatosplenomegaly, and hypergammaglobulinemia, and hypoalbuminemia) many patients have evidence of fluid retention with are uncommon in unicentric disease, but such symp- lower extremity edema, pleural and pericardial effu- toms are observed frequently among patients with sions, and abdominal ascites. Common hematological the plasma cell variant. abnormalities include anemia, elevated inflammato- ry markers, hypergammaglobulinemia, and hypoal- Management buminemia. Systemic symptoms and hematological The optimal therapy for UCD is surgical resection, abnormalities have been shown to correspond to which is usually curative if the disease is amena- elevated inflammatory markers and cytokine levels, ble to complete resection.3,23 For disease that can- particularly IL-6 and IL-10. not be completely excised, radiation therapy is an The natural history of MCD is variable. Some option due to its high rates of objective response, patients may present with indolent disease and very including complete responses in nearly one-half of slow progression over months to years, while others reported cases.25-31 will experience a relapsing-remitting course or an For select patients who are not candidates for acute and fulminant disease that can be fatal within surgical excision, but who are also not candidates for weeks; the latter courses are more common in pa- radiation therapy based on the location of the dis- tients with HIV-associated MCD.34,35 HIV-associated

October 2014, Vol. 21, No. 4 Cancer Control 271 MCD may also concurrently or sequentially present patients.4,32,37-42 None of these reported cases were with other concomitant malignancies, including Ka- known to be positive for HIV. Given the delayed posi sarcoma or primary effusion lymphoma, each response to rituximab monotherapy, glucocorticoid of which share an HHV-8–mediated pathogenesis. pulses may be helpful as an initial adjunct for acutely Kaposi sarcoma may be identified in 72% of HIV-re- symptomatic disease. In these patients, prednisone lated MCD cases at diagnosis and may be seen in 1 mg/kg daily or its equivalent may be added to rit- HIV-negative MCD, although at a far lower rate.33 uximab until systemic inflammatory symptoms are Patients are also at significant risk for diffuse large adequately controlled and then tapered off. B-cell lymphoma, which may arise directly out of Cytotoxic Chemotherapy: Various agents have HHV-8–positive MCD; therefore, one must consider been used as single-agent chemotherapy in the the possibility of a second malignancy at the time treatment of MCD, although data are limited to few of diagnosis and perform a thorough skin exam- case reports and small case series. These include ination for cutaneous Kaposi sarcoma, as well as oral etoposide,5 vinblastine,43 cyclophosphamide,32 consider biopsying bulky or visceral locations seen cladribine,44,45 chlorambucil,32 and liposomal doxoru- on imaging studies for staging that may constitute bicin.46,47 Responses following these agents are often a distinct histology from Castleman disease. Repeat short-lived and symptoms may rapidly recur following biopsy should also be considered at progression or the completion of therapy. Single-agent chemother- relapse to evaluate for lymphomatous transformation. apies are often administered at doses and schedules Patients with HIV-associated MCD will often present routinely used to treat patients with lymphoma. Etopo- with a low CD4 count, so concomitant opportunistic side may be administered at a dose of 50 or 100 mg infections must also be considered at diagnosis and by mouth daily on days 1 through 7 of a 14-day cycle during the course of illness, including Pneumocystis until maximal response, or 100 mg/m2 intravenously jiroveci, Toxoplasma gondii, cytomegalovirus, and once weekly for 4 weeks, and can be used with a mycobacterial infections, among others. maintenance schedule to prolong remission duration. Vinblastine may be administered at a dose of 4 to Treatment 6 mg/m2 every 2 weeks until maximal response, and Treatment options for MCD are based on few non- it can be used with a maintenance schedule in the randomized prospective studies, small case series, absence of significant toxicity. and expert opinion; therefore, the body of evidence Combination chemotherapy with cyclophospha- must be interpreted with caution. Available treatments mide/doxorubicin/vincristine/prednisone (CHOP) include glucocorticoids, single-agent and combination or cyclophosphamide/vincristine/prednisone (CVP) chemotherapy, antiviral strategies, and monoclonal without rituximab have produced durable remissions antibody therapies targeting CD20 or IL-6. in small case series of patients with MCD,4,25,32,46,48,49 Antiretroviral Therapy: All patients with HIV although many patients will progress or experience infection and MCD should be initiated on combination infectious toxicities. These data are primarily from be- antiretroviral therapy if they are not already taking fore the introduction of rituximab, and the impact of it, although antiretroviral therapy alone is unlikely to rituximab in combination with chemotherapy in these independently result in a Castleman disease response. patients is unknown. Our practice is to include ritux- The risk of developing MCD is not influenced by the imab for most patients and to administer chemother- use of combination antiretroviral therapy or by the CD4 apy at doses and schedules typical for patients with count at the time of diagnosis.33 However, independent lymphoma, but infectious risk is increased; therefore, of MCD, the initiation of combination antiretroviral caution and attention to supportive care are required, therapy can prevent further consequences of poorly particularly in patients with low CD4 counts. controlled HIV, including opportunistic infections and Dose reductions may be necessary on the basis of malignancies, and allows for the safe administration interactions with antiretroviral therapy, because pro- of chemotherapy due to immune reconstitution. Pa- tease inhibitors and non-nucleoside reverse transcrip- tients should be monitored for immune reconstitution tase inhibitors are metabolized by the CYP450 system, inflammatory syndrome, including an exacerbation of which is either induced or inhibited by many che- MCD and concurrent Kaposi sarcoma.36 motherapeutic agents, including cyclophosphamide, Glucocorticoids: Glucocorticoids have activity doxorubicin, etoposide, vinblastine, and vincristine. as monotherapy in MCD and may offer short-term Rituximab: Rituximab is highly active as mono- control of symptoms, but complete remissions are therapy in MCD. Its role in HIV-associated MCD is rare and are generally short-lived. Twenty-one cases supported by prospective and retrospective trials of MCD treated with glucocorticoids alone have been demonstrating sustained remissions.34,50-55 Small case described in case reports and small case series, and series have also demonstrated activity in patients with responses were observed in approximately 80% of MCD who are HIV negative.56-59

272 Cancer Control October 2014, Vol. 21, No. 4 A prospective study enrolled 24 patients with che- HHV-8 negative MCD.62 Patients were randomized motherapy-dependent, HIV-associated MCD.50 Patients 2:1 to siltuximab or placebo administered once every had received single-agent chemotherapy (etoposide, 3 weeks. Patients receiving placebo were permitted vinblastine, or liposomal doxorubicin) for a medi- to cross over to open-label siltuximab at progression. an of 13 months and all patients had failed at least Of the 79 randomized patients, 53 received siltux- 1 attempt to discontinue chemotherapy. All patients re- imab and 26 received placebo. The median age was ceived concurrent combination antiretroviral therapy. 48 years and a 2:1 male predominance was seen.62 After 4 weekly infusions of rituximab at a dose of Hyaline-vascular, plasma cell, and mixed pathologies 375 mg/m2, 22 of 24 patients (92%) achieved the pri- were observed in 33%, 23%, and 44% of patients, mary endpoint of sustained remission at 60 days off respectively.62 A total of 58% had received prior ther- treatment, and 17 patients (71%) were alive and in re- apy and 30% were on corticosteroids at enrollment.62 mission at 1 year.51 A second prospective trial enrolled The primary endpoint was durable radiological and 21 patients with previously untreated HIV-associat- symptomatic responses (improvement or stabilization ed MCD and treated with 4 weekly rituximab infu- of symptoms) lasting at least 18 weeks. Treatment sions.51 Clinical and radiological responses occurred in with siltuximab was associated with a higher rate of 20 (95%) and 14 (67%) patients, respectively, and the achieving the primary endpoint (34% vs 0%).62 Ra- 2-year progression-free survival rate was 79%.51 diographic tumor response rates were seen in 38% These small prospective studies are also support- and 4% of patients, favoring the siltuximab arm, and ed by a retrospective analysis of 49 patients naive to symptomatic response rates were 57% and 19%.62 treatment with HIV-associated MCD who were given Complete symptom resolution was observed in those rituximab with or without etoposide.34 Combination receiving siltuximab (25% vs 0%).62 Patients receiv- therapy with rituximab/etoposide was reserved for ing siltuximab also had improvements in anemia and patients with a poor performance status or evidence of hypoalbuminemia, and a decrease in inflammatory end-organ involvement. For the entire cohort, 5-year markers (erythrocyte sedimentation rate, C-reactive progression-free and overall survival rates were 61% protein, and fibrinogen) relative to patients receiving and 90%, respectively.34 No difference was seen in placebo. These data demonstrate that siltuximab is outcomes between the 2 treatment arms; however, highly active in MCD with durable disease control the 2 arms included distinct patient populations by and improvement in clinically relevant outcomes. design, and it is unknown whether patients treated However, an important caveat is that patients with with combination therapy would have performed as HIV and HHV-8-associated MCD were excluded from well if treated with rituximab alone. This does add to this study. Siltuximab was also compared against a a body of literature demonstrating favorable progres- placebo rather than rituximab. sion-free and overall survival rates in patients treated The anti-IL-6R humanized monoclonal antibody with rituximab therapy.34 tocilizumab is also active in MCD. Twenty-eight pa- Patients with concomitant MCD and Kaposi sar- tients with symptomatic MCD were enrolled in a coma require vigilance for Kaposi sarcoma flareups phase 2 trial,63 all of whom were HIV negative and during rituximab therapy. Exacerbations of Kaposi only 2 of whom were positive for HHV-8. All pa- sarcoma during rituximab treatment was observed in tients had pathological findings consistent with the all trials of rituximab in HIV-associated MCD, occur- plasma cell variant. Patients received tocilizumab ev- ring in 36% to 67% of reported patients.34,50,51 ery 2 weeks for 16 weeks and the study drug was Anti-Interleukin 6 Therapy: Siltuximab and to- continued thereafter at the discretion of the treating cilizumab are monoclonal antibodies targeting IL-6 investigator. The alleviation of systemic inflammatory and its receptor (IL-6R), respectively. The US Food and symptoms was universal and weight gain occurred Drug Administration (FDA) has approved siltuximab in all patients. Laboratory abnormalities, including for the treatment of patients with HIV negative, HHV-8 anemia, hypoalbuminemia, and elevated C-reactive negative MCD, where it shows significant clinical ac- protein, all improved with therapy, as did lymphade- tivity, resulting in control of IL-6–dependent systemic nopathy. Eleven of the 15 (73%) patients receiving symptoms and laboratory abnormalities.60,61 A phase corticosteroids at enrollment were able to decrease 2 study that included 19 patients with HIV negative or discontinue concomitant corticosteroid therapy.63 and HHV-8 negative MCD reported 8 radiological re- It is worth noting, however, that tocilizumab is cur- sponses, including 1 complete response.61 At a me- rently FDA approved only for rheumatoid arthritis and dian follow-up of 5.1 years (range, 3.4–7.2 years), all systemic or polyarticular juvenile idiopathic arthritis. 19 patients taking siltuximab therapy were still alive.61 Monoclonal antibodies targeting IL-6 remain large- The data from those studies prompted a multi- ly unevaluated in patients with HIV and HHV-8-asso- center, randomized, double-blind, placebo-controlled ciated MCD. It is not known whether targeting IL-6 trial of siltuximab in patients with HIV negative, is similarly effective in this population, yet several

October 2014, Vol. 21, No. 4 Cancer Control 273 features make these patients appealing candidates Treatment involves 4 weekly doses at 375 mg/m2 that for therapies targeting IL-6. Although vIL-6 is impli- can be repeated as necessary for subsequent flareups cated in the pathogenesis of HHV-8-associated MCD in patients who previously responded favorably to and is not targeted by the current monoclonal anti- therapy.55,77 bodies, human IL-6 is also elevated in the majority In patients who are negative for HIV but who of patients with HIV-associated MCD and likely re- have failed to respond to, or relapse rapidly following mains a significant contributor to disease activity and rituximab monotherapy, siltuximab monotherapy is symptomatology.12 Three cases in the literature have recommended. For patients who progress following demonstrated activity of IL-6 targeted therapy in HIV treatment with siltuximab, single-agent chemotherapy and HHV-8-associated MCD,64,65 speaking to the need can be utilized with etoposide,5 vinblastine,43 or lipo- for prospective clinical trials in these patients. somal doxorubicin47 with or without rituximab. Com- Antiherpesvirus Therapy: Antiherpesvirus bination chemotherapy regimens such as rituximab agents have been explored as therapy for HIV-associ- plus CHOP (R-CHOP) and rituximab plus CVP (R-CVP) ated MCD given the pathogenetic link with HHV-8.66-68 are options for patients with resistant or rapidly pro- Lytic replication of HHV-8 is common in MCD and gressive disease. In patients with HIV-associated MCD may be important in its pathogenesis, as opposed to who fail to respond to or relapse rapidly following Kaposi sarcoma in which HHV-8 infection most often rituximab monotherapy, the use of either single-agent remains latent. Many HHV-8–derived gene products, chemotherapy with or without rituximab or antiher- including vIL-6, are expressed during the lytic cycle of pesvirus therapy with high-dose zidovudine and val- HHV-8 replication.69 Therefore, MCD is potentially tar- ganciclovir is recommended.67 Given the increased getable with antiviral therapy, particularly in patients toxicity in patients with HIV infection and MCD, com- with detectable HHV-8 viral loads. An early report bination therapy with R-CHOP or R-CVP should be of 3 patients with MCD treated with intravenous or reserved for select patients with treatment-resistant, oral ganciclovir was promising.70 Two patients expe- rapidly progressive, or fulminant disease. rienced flares of symptomatic disease less frequently In cases of progression following second-line and a third patient had prolonged remission.70 This therapy, the use of alternative single-agent or com- report prompted a prospective study evaluating the bination chemotherapies with or without rituximab, use of high-dose zidovudine (600 mg orally every bortezomib, antiherpesvirus therapies, or IL-6-directed 6 hours) and valganciclovir (900 mg orally every therapy with siltuximab or tocilizumab should be con- 12 hours) given for 1 out of every 3 weeks.67,68 Four- sidered. Siltuximab or tocilizumab should be consid- teen patients with symptomatic HIV-associated, ered for use in patients positive for HIV in the context HHV-8 positive MCD were enrolled and demonstrated of a clinical trial. Corticosteroid pulses may be helpful overall clinical and complete response rates of 86% for acutely symptomatic disease; however, steroids and 50%, respectively. The overall radiographic re- alone are unlikely to induce lengthy remissions, so sponse rate was lower at 36%, with 29% of patients they should be reserved for short-term symptomat- experiencing a complete radiographic response. ic control.3,32,37-42 The emerging IL-6 and its receptor Three patients who achieved a complete clinical and antibodies appear highly active in clinical trials, al- radiographic response remained in sustained remis- though they have not been studied in HIV-associated sion at a median of 29 months after the completion MCD.60-62,65,79,80 A recommended treatment algorithm of therapy.68 Antiherpesvirus agents have not been is provided in Fig 4. studied in patients who were HIV negative in whom HHV-8 is often present but whose role in patho- Associated Conditions and Malignancy Risk genesis is less clearly defined. Among small reports, Kaposi Sarcoma success has not been observed with cidofovir.71 HHV-8 plays a critical role in the pathogenesis of both Bortezomib: Bortezomib is a proteasome inhibi- MCD and Kaposi sarcoma, and the clinical association tor active in plasma cell neoplasms by multiple mech- of these diseases was noted prior to the identification anisms; it also decreases the production of IL-6 via the of HHV-8 as a common underlying viral pathogen. NFκB blockade.72 Anecdotal reports of durable clinical Patients with HIV-associated MCD have a 72% risk of and radiographic responses in MCD warrant further being diagnosed with Kaposi sarcoma, either concur- study in the context of clinical trials.73-76 rently or sequentially, and the 2 diseases may coexist Summary of Treatment Approaches: For initial in the same pathological specimen (see Fig 3).33 The systemic therapy, rituximab monotherapy has been association is lower with Kaposi sarcoma negative for recommended based on encouraging efficacy and safe- HIV, where the dual incidence is reported at 0% to ty results, with a high likelihood of initial response 13%.33,81 Exacerbations of Kaposi sarcoma have been and associated long-term, progression-free survival observed with rituximab therapy34,50,51; therefore, vig- rates reported to be between 60% and 79%.34,50-57,59,77,78 ilance for flareups of Kaposi sarcoma is necessary

274 Cancer Control October 2014, Vol. 21, No. 4 when using treatments containing rituximab in a pa- the most common lymphoma subtype. Patients with tient with both diseases. MCD are also at increased risk for primary effusion lymphoma, which shares a common HHV-8-mediat- Lymphoma ed pathogenesis. Patients infected with HIV may also Patients with Castleman disease are at increased risk for develop other HIV-associated lymphomas not directly lymphoma. Non-Hodgkin lymphoma has been reported related to MCD, including plasmablastic lymphoma, in approximately 20% of patients with MCD, as well Hodgkin lymphoma, and primary lymphoma of the as in patients with UCD.18,32,38,82,83 Among these, large central nervous system. Amyloidosis has also been B-cell lymphoma arising in HHV-8-associated MCD is reported in association with both UCD and MCD.84-88

Diagnosis and Staging

UCD MCD

Complete surgical resection For HIV‐associated MCD, ensure patient is on antiretroviral therapy and appropriate prophylaxis

If not amenable to resection or not a candidate for surgery

Rituximab If not a candidate ± prednisone Radiation therapy for resection or radio- ± valgancyclovir/gancyclovir therapy, go to MCD if HHV-8 positive

If progression after or within If relapse after initial 6 months of completing rituximab favorable response

Rituximab ± prednisone HIV positive HIV negative If relapse/refractory (may repeat without limit until patient is refractory)

If relapse/refractory If fulminant or rapidly progressive Siltuximab

Single‐agent chemotherapy Combination chemotherapy If fulminant or (etoposide, vinblastine, (R-CHOP, R-­CVP, or If relapse/refractory rapidly progressive liposomal doxorubicin) rituximab/IV etoposide) ± rituximab or high-­dose zidovudine/valgancyclovir Single-­agent chemotherapy Combination chemotherapy (etoposide, vinblastine, (R‐CHOP, R­‐CVP, or liposomal doxorubicin) rituximab/IV etoposide) ± rituximab

If relapse/refractory If relapse/refractory

Consider alternative single-­agent or combination chemotherapy, Consider alternative single‐agent or bortezomib, valgancyclovir ± zidovudine, or interleukin 6 therapy combination chemotherapy, bortezomib, with siltuximab or tocilizumab (in the context of a clinical trial) siltuximab, or tocilizumab

Fig 4. — Recommended treatment algorithm for Castleman disease. IV = intravenous, MCD = multicentric Castleman disease, R-CHOP = rituximab/ cyclophosphamide/doxorubicin/vincristine/prednisone, R-CVP = rituximab/cyclophosphamide/vincristine/prednisone, UCD = unicentric Castleman disease.

October 2014, Vol. 21, No. 4 Cancer Control 275 Although most cases of lymphoma arising in MCD occur agement of multicentric disease continues to evolve. in patients with HIV or HHV-8 infection, patients with Rituximab monotherapy is the current mainstay of MCD in the absence of HIV or HHV-8 infection are also therapy, and novel agents targeting interleukin 6 repre- at increased risk of lymphoma to a lesser degree.82,89 sent exciting new additions to the treatment armamen- tarium. Single-agent and combination chemotherapies POEMS Syndrome as well as antiviral therapy provide adjunctive support, POEMS syndrome is characterized by a λ light chain particularly in the setting of relapsed or refractory dis- restricted monoclonal gammopathy and a progres- ease. The ongoing exploration of antiviral and novel sive polyneuropathy with early sensory symptoms strategies, such as proteasome inhibition, is warranted. and later more severe motor symptoms, resembling The management of Castleman disease also requires a chronic inflammatory demyelinating polyneurop- careful attention to potential concomitant infections, athy.90,91 MCD is present in 15% to 25% of patients malignancies, and associated syndromes. with POEMS syndrome and is included as a major criterion for the diagnosis of POEMS syndrome.7,92 References Other common features include osteosclerotic bone 1. Castleman B, Towne V. CASE records of the Massachusetts Gener- lesions, elevated levels of vascular endothelial growth al Hospital weekly clinicopathological exercises: case 40011. N Engl J Med. 1954;250(1):26-30. factor, hepatosplenomegaly, lymphadenopathy, en- 2. Castleman B, Iverson L, Menendez VP. Localized mediastinal lymph- docrinopathy, skin changes, and elevated protein in node hyperplasia resembling thymoma. Cancer. 1956;9(4):822-830. 3. Keller AR, Hochholzer L, Castleman B. Hyaline-vascular and plas- the cerebrospinal fluid. Treatment is directed at the ma-cell types of giant lymph node hyperplasia of the mediastinum and other plasma cell clone and includes dexamethasone, lena- locations. Cancer. 1972;29(3):670-683. 4. Herrada J, Cabanillas F, Rice L, et al. The clinical behavior of localized lidomide, and alkylator-based therapy, with high-dose and multicentric Castleman disease. Ann Intern Med. 1998;128(8):657-662. chemotherapy and autologous stem cell transplanta- 5. Scott D, Cabral L, Harrington WJ Jr. Treatment of HIV-associat- ed multicentric Castleman’s disease with oral etoposide. Am J Hematol. tion reserved for select cases. 2001;66(2):148-150. 6. Oksenhendler E, Boulanger E, Galicier L, et al. High incidence of Kaposi sarcoma-associated herpesvirus-related non-Hodgkin lymphoma in patients Follicular Dendritic Cell Sarcoma with HIV infection and multicentric Castleman disease. Blood. 2002;99(7):2331- Follicular dendritic cell sarcoma is a rare malignancy 2336. 7. B élec L, Mohamed AS, Authier FJ, et al. Human herpesvirus 8 infec- that frequently occurs in lymph nodes, although it tion in patients with POEMS syndrome-associated multicentric Castleman’s may also involve extranodal sites. Follicular dendritic disease. Blood. 1999;93(11):3643-3653. 8. Chang Y, Cesarman E, Pessin MS, et al. Identification of herpesvi- cell sarcoma has been associated with UCD; in such rus-like DNA sequences in AIDS-associated Kaposi’s sarcoma. Science. cases, follicular dendritic cell sarcoma is diagnosed 1994;266(5192):1865-1869. 9. Soulier J, Grollet L, Oksenhendler E, et al. Kaposi’s sarcoma-associated either concurrently with or following the diagnosis herpesvirus-like DNA sequences in multicentric Castleman’s disease. Blood. of UCD.93-100 Optimal therapy is surgical resection, 1995;86(4):1276-1280. 10. An J, Lichtenstein AK, Brent G, et al. The Kaposi sarcoma-associated with or without adjuvant radiation therapy or chemo- herpesvirus (KSHV) induces cellular interleukin 6 expression: role of the KSHV therapy, although data to guide chemotherapy in this latency-associated nuclear antigen and the AP1 response element. Blood. 2002;99(2):649-654. population are scant given the rarity of the disease. 11. Keller SA, Hernandez-Hopkins D, Vider J, et al. NF-kappaB is essential for the progression of KSHV- and EBV-infected lymphomas in vivo. Blood. 2006;107(8):3295-3302. Paraneoplastic Pemphigus 12. Polizzotto MN, Uldrick TS, Wang V, et al. Human and viral interleukin-6 Paraneoplastic pemphigus is an autoimmune muco- and other cytokines in Kaposi sarcoma herpesvirus-associated multicentric Castleman disease. Blood. 2013;122(26):4189-4198. cutaneous blistering disease associated with localized 13. Stebbing J, Adams C, Sanitt A, et al. Plasma HHV8 DNA predicts Castleman disease in 18% of cases and can be a dev- relapse in individuals with HIV-associated multicentric Castleman disease. 101 Blood. 2011;118(2):271-275. astating disease with a high mortality rate. Approxi- 14. Newsom-Davis T, Bower M, Wildfire A, et al. Resolution of AIDS-related mately two-thirds of patients with paraneoplastic pem- Castleman’s disease with anti-CD20 monoclonal antibodies is associated with declining IL-6 and TNF-alpha levels. Leuk Lymphoma. 2004;45(9):1939-1941. phigus have either UCD or an associated malignancy 15. Bower M, Veraitch O, Szydlo R, et al. Cytokine changes during rit- (eg, B-cell lymphoma, lymphoplasmacytic lymphoma, uximab therapy in HIV-associated multicentric Castleman disease. Blood. 2009;113(19):4521-4524. chronic lymphocytic leukemia) at the time of diagno- 16. Carbone A, De Paoli P, Gloghini A, et al. KSHV-associated multicentric sis.102 The disease precedes the diagnosis of UCD or Castleman disease: A tangle of different entities requiring multitarget treatment strategies. Int J Cancer. 2014. [Epub ahead of print]. cancer in the remaining cases. UCD should be sus- 17. Ferry J, Harris N. Atlas of Lymphoid Hyperplasia and Lymphoma. pected in any young patient with paraneoplastic pem- Philadelphia: WB Saunders; 1997. 18. Dupin N, Diss TL, Kellam P, et al. HHV-8 is associated with a plasmab- phigus. Complete resection of UCD results in clinical lastic variant of Castleman disease that is linked to HHV-8-positive plasmab- improvement or complete remission in most patients. lastic lymphoma. Blood. 2000;95(4):1406-1412. 19. Isaacson P, Campo E, Harris N. Large B-cell lymphoma arising in HHV8-associated multicentric Castleman disease. In: Swerlow S, Campo E, Conclusions Harris N, et al, eds. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. Lyon, France: IARC; 2008:258. Castleman disease is an uncommon lymphoprolifera- 20. Chan JK. Newly available antibodies with practical applications in sur- tive disorder that continues to pose clinical challenges. gical pathology. Int J Surg Pathol. 2013;21(6):553-572. 21. Sato Y, Kojima M, Takata K, et al. Systemic IgG4-related lymphadenop- Although surgical resection remains the standard ther- athy: a clinical and pathologic comparison to multicentric Castleman’s disease. apy for unicentric disease, the landscape for the man- Mod Pathol. 2009;22(4):589-599.

276 Cancer Control October 2014, Vol. 21, No. 4 22. Cheuk W, Chan JK. Lymphadenopathy of IgG4-related disease: an imab in HIV-associated multicentric Castleman disease. Ann Intern Med. underdiagnosed and overdiagnosed entity. Semin Diagn Pathol. 2012;29(4): 2007;147(12):836-839. 226-234. 52. Hoffmann C, Schmid H, Muller M, et al. Improved outcome with ritux- 23. Talat N, Belgaumkar AP, Schulte KM. Surgery in Castleman’s disease: imab in patients with HIV-associated multicentric Castleman disease. Blood. a systematic review of 404 published cases. Ann Surg. 2012;255(4):677-684. 2011;118(13):3499-3503. 24. Pietra G. Castleman’s angio-plasma-cellular lymph-node hyperpla- 53. Marcelin AG, Aaron L, Mateus C, et al. Rituximab therapy for HIV-as- sia in roentgenograms [in German]. Fortschr Geb Rontgenstr Nuklearmed. sociated Castleman disease. Blood. 2003;102(8):2786-2788. 1964;101:665-667. 54. Marrache F, Larroche C, Memain N, et al. Prolonged remission of 25. Chronowski GM, Ha CS, Wilder RB, et al. Treatment of unicentric HIV-associated multicentric castelman’s disease with an anti-CD20 monoclonal and multicentric Castleman disease and the role of radiotherapy. Cancer. antibody as primary therapy. AIDS. 2003;17(9):1409-1410. 2001;92(3):670-676. 55. Powles T, Stebbing J, Montoto S, et al. Rituximab as retreatment for 26. de Vries IA, van Acht MM, Demeyere T, et al. Neoadjuvant radiotherapy rituximab pretreated HIV-associated multicentric Castleman disease. Blood. of primary irresectable unicentric Castleman’s disease: a case report and 2007;110(12):4132-4133. review of the literature. Radiat Oncol. 2010;5:7. 56. Cervera Grau JM, Galiana Esquerdo G, Llorca Ferrandiz C, et al. 27. Li YM, Liu PH, Zhang YH, et al. Radiotherapy of unicentric mediastinal Complete remission in a pancytopenic HIV negative, HHV-8 positive patient Castleman’s disease. Chin J Cancer. 2011;30(5):351-356. with multicentric Castleman’s disease induced with anti-CD20. Clin Transl 28. Matthiesen C, Ramgopol R, Seavey J, et al. Intensity modulated ra- Oncol. 2006;8(7):540-541. diation therapy (IMRT) for the treatment of unicentric Castlemans disease: 57. Nicoli P, Familiari U, Bosa M, et al. HHV8-positive, HIV-negative mul- a case report and review of the use of radiotherapy in the literature. Radiol ticentric Castleman’s disease: early and sustained complete remission with Oncol. 2012;46(3):265-270. rituximab therapy without reactivation of Kaposi sarcoma. Int J Hematol. 29. Miranda FA, Faria VH, Arruda GV, et al. Radiation therapy in the treat- 2009;90(3):392-396. ment of unicentric Castleman’s disease. J Bras Pneumol. 2013;39(1):116-118. 58. Law AB, Ryan G, Lade S, et al. Development of Kaposi’s sarcoma after 30. Neuhof D, Debus J. Outcome and late complications of radiotherapy in complete remission of multicentric Castlemans disease with rituximab therapy patients with unicentric Castleman disease. Acta Oncol. 2006;45(8):1126-1131. in a HHV8-positive, HIV-negative patient. Int J Hematol. 2010;91(2):347-349. 31. Noh OK, Lee SW, Lee JW, et al. Cases report of unicentric Castleman’s 59. Ide M, Kawachi Y, Izumi Y, et al. Long-term remission in HIV-negative disease: revisit of radiotherapy role. Radiat Oncol J. 2013;31(1):48-54. patients with multicentric Castleman’s disease using rituximab. Eur J Haematol. 32. Frizzera G, Peterson BA, Bayrd ED, et al. A systemic lymphoproliferative 2006;76(2):119-123. disorder with morphologic features of Castleman’s disease: clinical findings 60. Kurzrock R, Voorhees PM, Casper C, et al. A phase I, open-label study and clinicopathologic correlations in 15 patients. J Clin Oncol. 1985;3(9): of siltuximab, an anti-IL-6 monoclonal antibody, in patients with B-cell non-hod- 1202-1216. gkin lymphoma, multiple myeloma, or Castleman disease. Clin Cancer Res. 33. Mylona EE, Baraboutis IG, Lekakis LJ, et al. Multicentric Castleman’s 2013;19(13):3659-3670. disease in HIV infection: a systematic review of the literature. AIDS Rev. 61. Casper C, Voorhees PM, Fayad LE, et al. An open-label, phase 2, 2008;10(1):25-35. multicenter study of the safety of long-term treatment with siltuximab (an an- 34. Bower M, Newsom-Davis T, Naresh K, et al. Clinical features and ti-interleukin-6 monoclonal antibody) in patients with multicentric Castleman’s outcome in HIV-associated multicentric Castleman’s disease. J Clin Oncol. disease. Blood. 2013;122(21):1806-1806. 2011;29(18):2481-2486. 62. Casper C, Munshi N, Ke X, et al. A multicenter, randomized, dou- 35. Bower M. How I treat HIV-associated multicentric Castleman disease. ble-blind, placebo-controlled study of the efficacy and safety of siltuximab, an Blood. 2010;116(22):4415-4421. anti-interleukin-6 monoclonal antibody, in patients with multicentric Castleman’s 36. Zietz C, Bogner JR, Goebel FD, et al. An unusual cluster of cases disease. Blood. 2013;122(21):505-505. of Castleman’s disease during highly active antiretroviral therapy for AIDS. 63. Nishimoto N, Kanakura Y, Aozasa K, et al. Humanized anti-interleu- N Engl J Med. 1999;340(24):1923-1924. kin-6 receptor antibody treatment of multicentric Castleman disease. Blood. 37. Summerfield GP, Taylor W, Bellingham AJ, et al. Hyaline-vascular variant 2005;106(8):2627-2632. of angiofollicular lymph node hyperplasia with systemic manifestations and 64. Muzes G, Sipos F, Csomor J, et al. Successful tocilizumab treatment response to corticosteroids. J Clin Pathol. 1983;36(9):1005-1011. in a patient with human herpesvirus 8-positive and human immunodeficiency 38. Weisenburger DD, Nathwani BN, Winberg CD, et al. Multicentric an- virus-negative multicentric Castleman’s disease of plasma cell type nonre- giofollicular lymph node hyperplasia: a clinicopathologic study of 16 cases. sponsive to rituximab-CVP therapy. APMIS. 2013;121(7):668-674. Hum Pathol. 1985;16(2):162-172. 65. Nagao A, Nakazawa S, Hanabusa H. Short-term efficacy of the IL6 39. Stanley MW, Frizzera G, Dehner LP. Castleman’s disease, plasma-cell receptor antibody tocilizumab in patients with HIV-associated multicentric type. Diagnosis of central nervous system involvement by cerebrospinal fluid Castleman disease: report of two cases. J Hematol Oncol. 2014;7(1): cytology. Acta Cytol. 1986;30(5):481-486. 10-8722-7-10. 40. Donaghy M, Hall P, Gawler J, et al. Peripheral neuropathy associated 66. Bottieau E, Colebunders R, Schroyens W, et al. Multicentric Castleman’s with Castleman’s disease. J Neurol Sci. 1989;89(2-3):253-267. disease in 2 patients with HIV infection, unresponsive to antiviral therapy. Acta 41. Bowne WB, Lewis JJ, Filippa DA, et al. The management of unicentric Clin Belg. 2000;55(2):97-101. and multicentric Castleman’s disease: a report of 16 cases and a review of 67. Uldrick TS, Polizzotto MN, Aleman K, et al. High-dose zidovudine the literature. Cancer. 1999;85(3):706-717. plus valganciclovir for kaposi sarcoma herpesvirus-associated multicentric 42. Park JB, Hwang JH, Kim H, et al. Castleman disease presenting with Castleman disease: a pilot study of virus-activated cytotoxic therapy. Blood. jaundice: a case with the multicentric hyaline vascular variant. Korean J Intern 2011;117(26):6977-6986. Med. 2007;22(2):113-117. 68. Senanayake S, Kelly J, Lloyd A, et al. Multicentric Castleman’s disease 43. Oksenhendler E, Duarte M, Soulier J, et al. Multicentric Castleman’s treated with antivirals and immunosuppressants. J Med Virol. 2003;71(3): disease in HIV infection: a clinical and pathological study of 20 patients. AIDS. 399-403. 1996;10(1):61-67. 69. Schulte KM, Talat N. Castleman’s disease--a two compartment model 44. Colleoni GW, Duarte LC, Kerbauy FR, et al. 2-chloro-deoxyadenosine of HHV8 infection. Nat Rev Clin Oncol. 2010;7(9):533-543. induces durable complete remission in Castleman’s disease but may accelerate 70. Casper C, Nichols WG, Huang ML, et al. Remission of HHV-8 and its transformation to non-hodgkin’s lymphoma. Acta Oncol. 2003;42(7):784-787. HIV-associated multicentric Castleman disease with ganciclovir treatment. 45. Bordeleau L, Bredeson C, Markman S. 2-chloro-deoxyadenosine ther- Blood. 2004;103(5):1632-1634. apy for giant lymph node hyperplasia. Br J Haematol. 1995;91(3):668-670. 71. Berezne A, Agbalika F, Oksenhendler E. Failure of cidofovir in HIV-as- 46. Loi S, Goldstein D, Clezy K, et al. Castleman’s disease and HIV infection sociated multicentric Castleman disease. Blood. 2004;103(11):4368-4369. in Australia. HIV Med. 2004;5(3):157-162. 72. Rajkumar SV, Richardson PG, Hideshima T, et al. Proteasome inhibi- 47. Uldrick TS, Polizzotto MN, O’Mahony D, et al. Rituximab combined tion as a novel therapeutic target in human cancer. J Clin Oncol. 2005;23(3): with liposomal doxorubicin (R-Dox) in HIV-infected patients with severe Kaposi 630-639. sarcoma-associated herpes virus (KSHV) associated multicentric Castleman 73. Hess G, Wagner V, Kreft A, et al. Effects of bortezomib on pro-inflamma- disease (MCD). Infect Agent Cancer. 2010;5(suppl 1):A72. tory cytokine levels and transfusion dependency in a patient with multicentric 48. Seo HY, Kim EB, Kim JW, et al. Complete remission in a patient with Castleman disease. Br J Haematol. 2006;134(5):544-545. human herpes virus-8 negative multicentric Castleman disease using CHOP 74. Khan AA, Siraj F, Bhargava M, et al. Successful treatment of multicentric chemotherapy. Cancer Res Treat. 2009;41(2):104-107. Castleman’s disease accompanying myeloma with bortezomib. BMJ Case 49. Lee JH, Kwon KA, Lee S, et al. Multicentric Castleman disease com- Rep. 2012;2012:10.1136/bcr-2012-007646. plicated by tumor lysis syndrome after systemic chemotherapy. Leuk Res. 75. Sobas MA, Alonso Vence N, Diaz Arias J, et al. Efficacy of bortezomib 2010;34(1):e42-e45. in refractory form of multicentric Castleman disease associated to poems 50. Gerard L, Berezne A, Galicier L, et al. Prospective study of rituximab syndrome (MCD-POEMS variant). Ann Hematol. 2010;89(2):217-219. in chemotherapy-dependent human immunodeficiency virus associated 76. Yuan ZG, Dun XY, Li YH, et al. Treatment of multicentric Castleman’s multicentric Castleman’s disease: ANRS 117 CastlemaB trial. J Clin Oncol. disease accompanying multiple myeloma with bortezomib: a case report. 2007;25(22):3350-3356. J Hematol Oncol. 2009;2:19-8722-2-19. 51. Bower M, Powles T, Williams S, et al. Brief communication: ritux- 77. Casquero A, Barroso A, Fernandez Guerrero ML, et al. Use of rituximab

October 2014, Vol. 21, No. 4 Cancer Control 277 as a salvage therapy for HIV-associated multicentric Castleman disease. Ann Hematol. 2006;85(3):185-187. 78. Corbellino M, Bestetti G, Scalamogna C, et al. Long-term remission of kaposi sarcoma-associated herpesvirus-related multicentric Castleman disease with anti-CD20 monoclonal antibody therapy. Blood. 2001;98(12): 3473-3475. 79. Turcotte LM, Correll CK, Reed RC, et al. Sustained remission of se- vere multicentric Castleman disease following multiagent chemotherapy and tocilizumab maintenance. Pediatr Blood Cancer. 2014;61(4):737-739. 80. Song SN, Tomosugi N, Kawabata H, et al. Down-regulation of hepcidin resulting from long-term treatment with an anti-IL-6 receptor antibody (tocili- zumab) improves anemia of inflammation in multicentric Castleman disease. Blood. 2010;116(18):3627-3634. 81. Peterson BA, Frizzera G. Multicentric Castleman’s disease. Semin Oncol. 1993;20(6):636-647. 82. Larroche C, Cacoub P, Soulier J, et al. Castleman’s disease and lym- phoma: report of eight cases in HIV-negative patients and literature review. Am J Hematol. 2002;69(2):119-126. 83. Kessler E. Multicentric giant lymph node hyperplasia. A report of seven cases. Cancer. 1985;56(10):2446-2451. 84. Abdel-Reheim FA, Koss W, Rappaport ES, et al. Coexistence of Hod- gkin’s disease and giant lymph node hyperplasia of the plasma-cell type (Cas- tleman’s disease). Arch Pathol Lab Med. 1996;120(1):91-96. 85. Drut R, Larregina A. Angiofollicular lymph node transformation in Hod- gkin’s lymphoma. Pediatr Pathol. 1991;11(6):903-908. 86. McAloon EJ. Hodgkin’s disease in a patient with Castleman’s disease. N Engl J Med. 1985;313(12):758. 87. Saletti P, Ghielmini M, Scali G, et al. Hodgkin’s and Castleman’s disease in a patient with systemic mastocytosis. Ann Hematol. 1999;78(2):97-100. 88. Zarate-Osorno A, Medeiros LJ, Danon AD, et al. Hodgkin’s disease with coexistent Castleman-like histologic features. A report of three cases. Arch Pathol Lab Med. 1994;118(3):270-274. 89. Parravicini C, Corbellino M, Paulli M, et al. Expression of a virus-derived cytokine, KSHV vIL-6, in HIV-seronegative Castleman’s disease. Am J Pathol. 1997;151(6):1517-1522. 90. Andhavarapu S, Jiang L. POEMS syndrome and Castleman disease. Blood. 2013;122(2):159. 91. Dispenzieri A. POEMS syndrome: 2011 update on diagnosis, risk-strat- ification, and management. Am J Hematol. 2011;86(7):591-601. 92. Bélec L, Authier FJ, Mohamed AS, et al. Antibodies to human herpes- virus 8 in POEMS (polyneuropathy, organomegaly, endocrinopathy, M protein, skin changes) syndrome with multicentric Castleman’s disease. Clin Infect Dis. 1999;28(3):678-679. 93. Andriko JW, Kaldjian EP, Tsokos M, et al. Reticulum cell neoplasms of lymph nodes: a clinicopathologic study of 11 cases with recognition of a new subtype derived from fibroblastic reticular cells. Am J Surg Pathol. 1998;22(9):1048-1058. 94. Chan AC, Chan KW, Chan JK, et al. Development of follicular den- dritic cell sarcoma in hyaline-vascular Castleman’s disease of the nasophar- ynx: tracing its evolution by sequential biopsies. Histopathology. 2001;38(6): 510-518. 95. Chan JK, Fletcher CD, Nayler SJ, et al. Follicular dendritic cell sarcoma. clinicopathologic analysis of 17 cases suggesting a malignant potential higher than currently recognized. Cancer. 1997;79(2):294-313. 96. Chan JK, Tsang WY, Ng CS. Follicular dendritic cell tumor and vascular neoplasm complicating hyaline-vascular Castleman’s disease. Am J Surg Pathol. 1994;18(5):517-525. 97. Fornelli A, Mureden A, Eusebi V. Follicular dendritic cell tumor and unusual vascular lesion in lymph node with Castleman’s disease. Description of a case. Pathologica. 1998;90(2):146-151. 98. Katano H, Kaneko K, Shimizu S, et al. Follicular dendritic cell sarcoma complicated by hyaline-vascular type Castleman’s disease in a schizophrenic patient. Pathol Int. 1997;47(10):703-706. 99. Lee IJ, Kim SC, Kim HS, et al. Paraneoplastic pemphigus associated with follicular dendritic cell sarcoma arising from Castleman’s tumor. J Am Acad Dermatol. 1999;40(2 Pt 2):294-297. 100. Lin O, Frizzera G. Angiomyoid and follicular dendritic cell proliferative lesions in Castleman’s disease of hyaline-vascular type: a study of 10 cases. Am J Surg Pathol. 1997;21(11):1295-1306. 101. Kaplan I, Hodak E, Ackerman L, et al. Neoplasms associated with paraneoplastic pemphigus: a review with emphasis on non-hematologic ma- lignancy and oral mucosal manifestations. Oral Oncol. 2004;40(6):553-562. 102. Sehgal VN, Srivastava G. Paraneoplastic pemphigus/paraneoplastic autoimmune multiorgan syndrome. Int J Dermatol. 2009;48(2):162-169.

278 Cancer Control October 2014, Vol. 21, No. 4 BPDCN is a rare but aggressive

hematological malignancy with

a poor prognosis.

Eye of a Dandelion. Photograph courtesy of Sherri Damlo. www.damloedits.com.

Blastic Plasmacytoid Dendritic Cell Neoplasm: Update on Molecular Biology, Diagnosis, and Therapy Wasif Riaz, MD, Ling Zhang, MD, Pedro Horna, MD, and Lubomir Sokol, MD, PhD

Background: Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare hematological malignancy with an aggressive clinical course. Most patients with BPDCN have skin lesions and simultaneous involvement of the peripheral blood, bone marrow, and lymph nodes. Methods: A search of PubMed and Medline was conducted for English-written articles relating to BPDCN, CD4+CD56+ hematodermic neoplasm, and blastic natural killer cell lymphoma. Data regarding diagnosis, prognosis, and treatment were analyzed. Results: BPDCN is derived from precursor plasmacytoid dendritic cells. The diagnosis of BPDCN is based on the characteristic cytology and immunophenotype of malignant cells coexpressing CD4, CD56, CD123, blood dendritic cell antigens 2 and 4, and CD2AP markers. Multiple chromosomal abnormalities and gene mutations previously reported in patients with myeloid and selected lymphoid neoplasms were identified in approximately 60% of patients with BPDCN. Prospectively controlled studies to guide treatment decisions are lacking. The over- all response rate with aggressive acute lymphoblastic leukemia–type induction regimens was as high as 90%, but the durability of response was short. Median survival rates ranged between 12 and 16 months. Patients with relapsed disease may respond to L-asparaginase–containing regimens. Allogeneic hematopoietic stem cell transplantation, particularly when performed during the first remission, may produce durable remissions in selected adults. Conclusions: BPDCN is a rare aggressive disease that typically affects elderly patients. The most commonly affected nonhematopoietic organ is the skin. Although BPDCN is initially sensitive to conventional chemotherapy regimens, this response is relatively short and long-term prognosis is poor. In the near future, novel targeted therapies may improve outcomes for patients with BPDCN.

From the Hematology/Oncology Fellowship Program (WR) of the Drive, FOB-3 HEM PROG, Tampa, Florida 33612. E-mail: Lubomir. Department of Internal Medicine at the University of South Flor- [email protected] ida Morsani College of Medicine, and the Departments of Hema- No significant relationships exist between the authors and the com- topathology and Laboratory Medicine (LZ, PH) and Malignant panies/organizations whose products or services may be referenced Hematology (LS) at the H. Lee Moffitt Cancer Center & Research in this article. Institute, Tampa, Florida. The US Food and Drug Administration has not approved the agents Submitted March 14, 2014; accepted July 1, 2014. described in this article for the treatment of BPDCN; therefore, the Address correspondence to Lubomir Sokol, MD, PhD, Department use of such agents is considered to be off-label due to the rarity of Malignant Hematology, Moffitt Cancer Center, 12902 Magnolia of BPDCN.

October 2014, Vol. 21, No. 4 Cancer Control 279 Introduction eage-specific markers and CD56 expression, BPDCN Blastic plasmacytoid dendritic cell neoplasm (BPDCN) was initially believed to have arisen from immature is a rare and aggressive hematological neoplasm de- NK cells6; however, subsequent studies identified a rived from the precursor of plasmacytoid dendrit- malignant cell counterpart in plasmacytoid mono- ic cells (pDCs).1 The nomenclature of BPDCN has cytes.5,17 It is believed that BPDCN arises from pre- evolved over the last 20 years; the disease is classified cursor pDCs, with normal pDCs accounting for fewer under acute myeloid leukemia (AML) and related pre- than 0.4% of peripheral blood mononuclear cells.1 A cursor neoplasms in the 2008 World Health Organi- small proportion of these cells reside in primary and zation classification of tumors of hematopoietic and secondary lymphoid organs.16,18 Nonmalignant pDCs lymphoid tissues.1 It was initially described in the can accumulate in various pathological conditions mid-1990s as agranular CD4+ natural killer (NK) cell such as autoimmune diseases, classical Hodgkin lym- leukemia due to its unique agranular morphology phoma, and carcinomas.19 and phenotype (CD4+, CD56+, CD15+, and CD3–).2,3 pDCs are characterized by a lineage (Lin) negative It has also been termed blastic NK cell lymphoma4,5 human leukocyte antigen (HLA)-DR+ CD56– CD123+ due to its expression of NK-cell marker CD56, blastic CD11c– immunophenotype, which is distinct from the NK cell leukemia/lymphoma, as well as CD4+ CD56+ immunophenotype seen in malignant cells of BPDCN. hematodermic neoplasm/tumor based on morphol- Functionally, pDCs belong to a group of type 1 inter- ogy, immunophenotype, and tropism for the skin.5,6 feron–producing cells implicated in innate adaptive immune responses such as sensing nucleic acids of Epidemiology viruses and bacteria via the Toll-like receptors 7 and BPDCN can occur at any age and any geographical 9 expressed on the surface of pDCs.19-21 area; however, most patients are older adults with a An analysis of subsets of dendritic cells in nor- median age of 67 years (range, 8–103 years), and the mal healthy individuals identified a potential normal male:female ratio is 2.2–3.0:1.0.7,8 Although the exact counterpart of BPDCN.22,23 A search for cells with the incidence of BPDCN is unknown, it represents 0.44% Lin– HLA-DR+ CD56+ immunophenotype revealed a of all hematological malignancies, less than 1% of minor cell population comprising 0.03% of peripheral acute leukemias, 0.7% of cutaneous lymphoma cases, blood mononuclear cells among the healthy volun- and 6.3% of the NK-cell lineage malignancies in Ja- teers. These plasmacytoid dendritic-like cells (pDLCs) pan.5,9-12 In 2005, an estimated 100 cases were reported were functionally distinct from more abundant nor- since its first description, 13 and, since then, more than mal pDCs expressing the Lin HLA-DR+ CD56– CD123+ 100 new cases have been described in the literature. CD11c– immunophenotype.23 The ratio of pDLC:pDC was higher in bone marrow than in peripheral blood, Etiology and pDLC also expressed BDCA2, BDCA4, myeloid The etiology of BPDCN is unknown, with no evidence antigens, and Toll-like receptors, yet produced less suggesting an association with Epstein-Barr virus.1 interferon α after stimulation. These data demonstrate A single case of BPDCN has been reported in a carrier that pDLCs are a distinct subpopulation with an im- of human T-cell lymphotropic virus 1, favoring a ran- munophenotype similar to BPDCNs. dom coincidence over causative relation.14 In a series of 43 patients with BPDCN, 10 patients (23%) were Molecular Biology diagnosed with secondary leukemia.8 In 4 patients Approximately two-thirds of patients with BPDCN (9%), myelodysplastic syndrome (MDS) preceded have multiple karyotypic abnormalities (Table).1,24-32 BPDCN and had a median latency time of 3.5 years Leroux et al24 reported 6 recurrent cytogenetic abnor- (range, 1–4 years); 6 patients (14%) presented with malities, including chromosomes 5q (72%), 12p (64%), therapy-related leukemia following chemotherapy for 13q (64%), 6q (50%), 15q (43%), and monosomy 9 the first neoplasm. The median time of latency between (28%) in 21 patients; however, none were specific chemotherapy exposure and diagnosis of BPDCN was or diagnostic. Lucioni et al25 employed array-based 5 years (range, 1–15 years).8 These observations sup- comparative genomic hybridization and found the 4 port a hypothesis that exposure to prior chemotherapy most commonly deleted regions involved 9p21.3 (CD- is an important pathogenic factor, and the association KN2A/CDKN2B), 13q13.1-q14.3 (RB1), 12p13.2-p13.1 with myeloid neoplasms suggests that a putative initi- (CDKN1B), and 13q11-q12 (LATS2), with biallelic loss ating mutation might reside in hematopoietic stem cells or multiple heterozygous deletions of these genes in or a common myeloid/lymphoid progenitor.15 more than 90% of cases. The biallelic loss of 9p21.3 was associated with poor prognosis. Cell of Origin Wiesner at al26 analyzed skin samples from Normal pDCs can originate from common myeloid or 14 patients using high-resolution, array-based com- common lymphoid progenitors.16 Due to a lack of lin- parative genomic hybridization and immunostaining

280 Cancer Control October 2014, Vol. 21, No. 4 and found that the most frequent chromosomal ab- detected and confirmed by immunohistochemistry. errations were the losses of chromosomes 9, 12, 13, Both the proteasome inhibitor bortezomib and a se- and 15. A loss of the CDKN1B locus was identified in lective inhibitor of IkB kinase-b induced cell cycle 64% of tumors, and the cell-cycle inhibitor p27 (KIP1), arrest and apoptosis in BPDCN cells. which is encoded by CDKN1B, was weakly expressed Dijkman et al29 identified the overexpression of in the nuclei of tumor cells. A loss of the CDKN2A/ the oncogenes HES6, RUNX2, and FLT3 without the ARF/CDKN2B locus occurred in 50% of patients.26 The associated genomic amplification as well as the high cell-cycle inhibitor p16 (INK4a), which is encoded by expression of various pDC-related genes. Alayed et al30 CDKN2A, was not expressed in tumor cells, suggesting also studied 16 patients with BPDCN, 5 of whom (31%) a complete loss of function. The loss of chromosome had myelodysplastic changes in their marrow. Conven- 13, including RB1, was observed in 43% of tumors.26 tional cytogenetics revealed the abnormal karyotype The results of this study suggested that the loss of in 6 of the 13 (46%) patients. Targeted next-generation multiple cell-cycle checkpoints that control proteins sequencing was performed on 5 patient samples and might play a role in the malignant transformation and showed TET2 mutations but no other MDS/AML- the aggressive biological behavior of BPDCN. associated mutations. Tokuda et al27 reported on an infant with congeni- Menezes et al31 performed whole-exome sequenc- tal BPDCN with clinically manifested hemophagocytic ing on samples of BPDCN. Based on these data, the lymphohistiocytosis. An analysis of the peripheral blood researchers designed a custom panel of 38 genes for leukocytes revealed a t(2;17;8)(p23;q23;p23) translo- a targeted resequencing of 25 samples. Their data re- cation with a CLTC-ALK fusion gene. This translocat- vealed mutations in TET2 (36%), ASXL1 (32%), NPM1 ed fusion gene was identified in cells of myeloid and (20%), NRAS (20%), IKZF1 (20%), IKZF1-3 (20%), ZEB2 T-cell lineages, suggesting that the chromosomal defect (16%), HOXB9 (4%), and UBE2G2 (4%).31 A total of occurred in a common myeloid/lymphoid progenitor. 48% of patients with gene mutations in the methyla- Sapienza et al28 studied gene expression profiling tion pathways had significantly worse overall surviv- in 27 samples of BPDCN and 8 samples of non-neo- al rates than patients without these gene mutations plastic resting pDCs. The up regulation of the nucle- (11 months vs 79 months).31 ar factor (NF)-kB pathway concurrently with the up Taylor et al32 reported on the next-generation regulation of 2 NF-kB targets (BCL2 and IRF4) was sequencing of all exons of 219 genes known to be

Table. — Genetic Abnormalities in Blastic Plasmacytoid Dendritic Cell Neoplasm

Reference No. of Methods Chromosome Abnormality Gene Defect GEP Patients

Leroux et al24 21 Cytogenetics 5q, 12p, 13q, 6q, 15q, NA NA monosomy 9

Lucioni et al25 21 aCGH Deletions of 9p21.3, CDKN2A/CDKN2B, RB1, NA 13q13.1-q14.3, 12p13.2-p13.1, CDKN1B, LATS2 13q11-q12

Wiesner et al26 14 aCGH Losses of chromosomes 9, CDKN1B, CDKN2A/ARF/ NA 12, 13, 15 CDKN2B, RB1

Tokuda et al27 1 Cytogenetics t(2; 17; 8) (p23; q23; p23) Fusion protein CLTC-ALK

Sapienza et al28 27 GEP NA NA IRF4, NFkB, BCL2

Dijkman et al29 13 GEP NA NA HES6, RUNX2, FLT3

Alayed et al30 16 NGS TET2 NA

Menezes et al31 3 WES/TS NA TET2, ASXL1 NPM1, NRAS, NA IKZF1, IKZF1–3, ZEB2, HOXB9, UBE2G2

Taylor et al32 7 NGS NA TET2, TP53, ASXL1, IDH2, NA KRAS, ABL1, ARID1A, GNA13, U2AF1, SRSF2, IRF8, ZRSR2

aCGH = array-based comparative genomic hybridization, GEP = gene expression profiling, NA = not applicable, NGS = next-generation sequencing, TS = target sequencing, WES = whole-exome sequencing.

October 2014, Vol. 21, No. 4 Cancer Control 281 recurrently mutated in hematological malignancies. A to characteristic morphology, a demonstration of a discovery gene cohort was sequenced in 7 patients specific immunophenotype either by immunohisto- with BPDCN. Many mutations in genes previously chemistry or flow cytometry is required for diagnosis. described in various hematological malignancies, such Skin biopsy typically demonstrates a diffuse, as TET2 (57%), TP53 (14%), and ASXL1 (28%), were monomorphic infiltrate of medium-sized blast cells confirmed, along with multiple loss-of-function muta- with irregular nuclei, fine chromatin, and at least tions in the splicing factor ZRSR2 (57% of patients).32 1 small nucleolus. Typically, malignant cells do not The mutations were also more frequently present in infiltrate the epidermis (Fig 3). The cytoplasm is scant older men. Altogether, these molecular data demon- and agranular. Mitoses are variable in number and strate that BPDCN cells can carry multiple mutations angioinvasion and coagulative necrosis are absent.1 that overlap with the genetic abnormalities of myeloid Bone marrow is involved in the majority of patients. and lymphoid neoplasms, leading to the dysregula- Findings on bone marrow biopsy may range from tion of multiple pathways that may serve as targets small interstitial infiltrates detectable by immunohis- for agents (eg, proteasome and anaplastic lymphoma tochemistry or flow cytometry to diffuse bone mar- kinase inhibitors). row involvement (Fig 4). Dysplastic changes may also be present in residual hematopoietic tissue, particu- Clinical Manifestations Most patients present with nonpruritic cutaneous lesions, blood, bone marrow, and lymph node in- Cutaneous Lesion volvement,1,8 although patients with cutaneous dis- (nodule, bruise-like infiltrate, or plaque) ease alone have also been described.33-35 Cutaneous With or Without Lymphadenopathy, Hepatosplenomegaly, and Cytopenias lesions are variable in size, shape, and color and can present as tumors, nodules, bruise-like infiltrates, or plaques (Fig 1).1,7 In a large registry study, the ma- jority of patients manifested with skin nodules (73%) and, less frequently, with bruise-like lesions (12%).7 Skin Biopsy Splenomegaly, hepatomegaly, and cytopenias due to bone marrow involvement can be present at diagnosis or may occur with disease progression.1 Involvement of other sites, including soft tissues, the lungs, and the central nervous system, has been also reported.1,25 Immunophenotype Morphology Less frequently, patients with BPDCN can present with in the leukemic phase without skin involvement.8,36 CD4+, CD43+, Diffuse, monomorphous CD45RA+, CD56+, infiltrate of medium-sized CD123+, TCL1+, blast cells with irregular Diagnosis CLA+, CD2AP+, nuclei and fine chromatin The diagnosis of BPDCN is pathological (Fig 2). BP- BDCA 2+, BDCA 4+ with ≥ 1 nucleoli. DCN should be suspected in older patients with non- Scant and agranular specific persistent skin lesions refractory to treatment; cytoplasm, angioinvasion, and coagulation necrosis these patients should undergo skin biopsy. In addition absent

BPDCN

Staging and Pretreatment Evaluation CBC, CMP, LDH, peripheral blood flow cytometry, bone marrow aspiration and biopsy, and computed tomography scan of thorax, abdomen, and pelvis

Fig 2. — Diagnostic algorithm for BPDCN. BPDCN = blastic plasmacytoid Fig 1. — Skin involvement with bruise-like infiltrate of blastic plasmacytoid dendritic cell neoplasm, CBC = complete blood count, CMP = comprehensive dendritic cell neoplasm. metabolic panel, LDH = lactate dehydrogenase.

282 Cancer Control October 2014, Vol. 21, No. 4 larly in megakaryocytes.13 BPDCN exhibits a specif- ers (CD19, CD20, CD79a) are not expressed. Typically, ic immunophenotype and coexpresses CD4, CD43, lysozyme and myeloperoxidase are negative. Rarely, CD45RA, and CD56 as well as pDC-related antigens, CD56 can be negative; in such cases, BPDCN can be including CD123 (interleukin 3α chain receptor), T-cell diagnosed based on morphology and complete im- leukemia 1 (TCL1), cutaneous lymphocyte-associat- munophenotypic profile. ed antigen, blood dendritic cell antigen (BDCA) 2 Garnache-Ottou et al44 proposed a diagnostic al- (CD303), BDCA4/CD304, CD2AP, Spi-B transcription gorithm for BPDCN. They determined that the coex- factor, and platelet endothelial cell adhesion molecule pressions of CD4+, CD56+/–, CD123+, BDCA2+, and/or (CD31).5,11,37-43 Terminal deoxynucleotidyl transferase BDCA4+ and an absence of CD3–, CD11c–, MPO–, and (TdT) is expressed in approximately one-third of cases. CD79a– are diagnostic for BPDCN. If CD123 expres- Stem cell markers, including CD34 and CD117, and sion is negative or dim, or when CD123 is positive Epstein–Barr virus-encoded small RNAs are negative.1 but cells do not express BDCA2 or BDCA4, then a The immunophenotype of BPDCN overlaps with pDC, diagnosis of BPDCN should not be considered. Julia occurring in reactive lymph nodes except the expres- et al7 analyzed 91 patients with BPDCN and identi- sion of CD56 and TdT.1,16,18 CD7 and CD33 expression fied that the 5 most characteristic immunophenotypic is common. T-cell markers (CD3, CD5) and B-cell mark- markers are CD4, CD56, CD123, CD303, and TCL1.

A B

CD4 CD56

CD123 TdT

C

Fig 3. — (A) Punch biopsy of a skin lesion showing blastic plasmacytoid dendritic cell neoplasm (H & E, × 40) and (inset) medium-sized malignant cells spare the epidermis (H & E, × 1000). (B) Immunohistochemical staining demonstrates the coexpression of CD4, CD56, CD123, and (immunoperoxidase, × 200). (C) Flow cytometry identified an atypical lymphoid population (areas in red) expressing CD45 and CD56 that was negative for T-cell markers (CD3, CD8). H & E = hematoxylin and eosin, TdT = terminal deoxynucleotidyl transferase..

October 2014, Vol. 21, No. 4 Cancer Control 283 Simultaneous expression of all markers was observed TCL1. Two of the 3 novel markers (CD162 and CD303) in 46% of patients, but the expression of 4 markers showed a poor predictive value for differentiating was sufficient for a reliable diagnosis.7 BPDCN from EMS.45 Patients with cutaneous T-cell lymphoma fre- Differential Diagnosis quently present with skin lesions and blood involve- BPDCN must be differentiated from several distinct ment, but the disease can be differentiated from myeloid and dendritic cell neoplasms and from cu- BPDCN based on morphology, disproportionate epi- taneous involvement with T-cell and NK-cell malig- dermotropism, and mature T-cell immunophenotype nancies exhibiting the CD4+ or CD56+ immunophe- with a lack of CD56 expression.46 Extranodal NK/ notype.1 Extramedullary myeloid sarcoma (EMS) may T-cell lymphoma can manifest with skin lesions and be difficult to differentiate from BPDCN because im- the expression of the CD4+/CD56+ immunophenotype. munophenotypic overlap exists among these 2 dis- This rare aggressive malignancy can be differentiated eases and both diseases frequently manifest with skin from BPDCN by demonstrating Epstein–Barr virus infiltration. positivity via in situ hybridization using Epstein–Barr Sangle et al45 studied the clinical utility of 3 novel virus-encoded small ribonucleic acids.1,47 markers previously described in BPDCN (myxovirus Vitte et al48 identified 42 patients from a French A, CD162/cutaneous lymphocyte-associated antigen, database who had cutaneous involvement of ma- and CD303/BDCA2) on 23 paraffin samples of EMS lignant myeloid and dendritic cell neoplasms. Four and 17 samples with BPDCN. The results of this study distinct clinicopathologic groups were identified, the suggested that BPDCN is associated with the posi- first of which included myelomonocytic cell tumors tive coexpression of CD56, TdT, or TCL1 or negative (n = 18) positive for CD68, myeloperoxidase, or both staining for lysozyme. The EMS samples also showed but negative for dendritic cell markers. The second positive staining for lysozyme or myeloperoxidase group consisted of mature pDC tumors (n = 16) coex- or negative staining for CD56, CD123, myxovirus, or pressing CD123, TCL1, and CD303 but missing CD56,

A B

C D E F Fig 4. — Bone marrow involved with BPDCN. (A) Bone marrow aspirate containing plasmacytoid neoplastic cells with fine chromatin, 1 or more prom- inent small nucleoli, and light basophilic cytoplasm consistent with BPDCN (Wright–Giemsa stain, × 1000). (B) Bone marrow core biopsy showing dif- fuse infiltrate by BPDCN (hematoxylin and eosin stain, × 600). (C–F) Neoplastic cells stained positive for CD4 (C, strong), CD56 (D, variable), TCL1 (E, strong), and CD123 (F, moderate to strong; immunoperoxidase, × 600). BPDCN = blastic plasmacytoid dendritic cell neoplasm, TCL1 = T-cell leukemia 1.

284 Cancer Control October 2014, Vol. 21, No. 4 CD1a, and S100 markers. The third group was com- doxorubicin/dexamethasone [hyper-CVAD] alternat- posed of blastic pDC tumors (n = 4) consisting of ing with methotrexate and cytarabine), and AML.51-53 medium-sized blasts positive for CD4, CD56, CD123, Feuillard et al51 treated 23 patients with CHOP- and TCL1 but negative for CD1a and S100. The fourth like regimens and reported a complete response (CR) group included blastic indeterminate dendritic cell rate of 86%; however, responses were short lived, tumors (n = 4) that coexpressed monocytic and den- with a median time to relapse of 9 months. Three dritic cell markers. A different prognosis was observed patients had isolated cutaneous lesions at diagno- among these disease entities. A minimal diagnostic sis and demonstrated bone marrow involvement at panel for stratification of all 4 entities included CD68, relapse, and 5 patients had central nervous system CD1a, S100, langerin, and CD123. relapse. Overall survival was 25% after 24 months Assaf et al49 studied a heterogeneous group of of follow-up.51 More intensive, ALL-like treatment re- cutaneous malignancies expressing the CD56 marker, gimes (eg, hyper-CVAD) yielded higher response rates. including hematodermic neoplasm, AML, NK/T-cell Pemmaraju et al52 reported a CR of 90% in 10 patients lymphoma, and cutaneous T-cell lymphoma. Patients treated with hyper-CVAD, reporting a median dura- without a diagnosis of cutaneous T-cell lymphoma tion of response of 20 months and a median overall had a poor prognosis and a median survival rate of survival rate of 29 months. 11 months. Altogether, these data underline the com- AML-like treatment regimens have also been used plexity and difficulty of diagnosing cutaneous myeloid as initial therapy. Dietrich et al53 reported a CR rate of and dendritic cell neoplasms, which frequently require 83% in 6 patients treated with an AML-like regimen. An the expertise of dermatopathology and hematopathol- et al54 reported a single institutional experience with ogy consultants at a tertiary center. 6 patients treated with multiagent chemotherapy as first-line treatment and 1 patient treated with radiation Therapy therapy. The median progression-free survival rate was Typically, patients with BPDCN have poor outcomes. 8.6 months (range, 2.6–28.9 months) and the overall Prospective data are lacking, with retrospective case survival rate was 15 months (range, 4.4–60.0 months), reports, case series, and disease registry reviews alone with a median follow-up of 13.8 months (range, 1.9– available to guide treatment decisions. Reported me- 29.9).54 Four patients with cutaneous involvement sur- dian overall survival rates in most of the studies re- vived, which is in contrast to the patient without skin viewed ranged from 12 to 16 months.7,13,50 involvement who died of disease.54 Gills et al55 treated 11 patients with BPDCN, with 6 receiving high-dose Induction Therapy methotrexate followed by L-asparaginase. All 6 patients BPDCN can be initially limited to skin without obvious (55%) who received the combination therapy achieved systemic involvement. Skin-directed therapies with fo- CR, while 5 patients treated with an alkylating agent cal radiation therapy, systemic glucocorticosteroids, or as frontline therapy achieved only a partial response nonintensive chemotherapy regimens can be initially (PR). Nine patients (82%) died of disease progression effective and may lead to the complete resolution of (median survival, 9 months).55 cutaneous lesions, but such approaches do not appear Pagano et al8 reported the outcomes of 43 patients to provide a long-term benefit.33-35 Nearly all patients with BPDCN who were diagnosed in Italy between relapse within several months after such treatment; 2005 and 2011. Forty-one of these patients received however, because patients with isolated cutaneous induction therapy, with 26 and 15 receiving AML-like lesions may have better prognoses, the skin-directed and ALL-like regimens, respectively. Seventeen (41%) therapeutic approach can be a reasonable palliative patients achieved a CR (7 in the AML-like group and option for patients who have a poor performance 10 in the ALL-like group), with a statistically signifi- status due to underlying comorbidities and who are cant advantage for ALL-like chemotherapy (P = .02). unable to tolerate systemic intensive chemotherapy.35 Of the 17 patients who achieved a CR, 6 (35%) subse- Standard frontline therapy has not been estab- quently relapsed. Three patients had a central nervous lished for patients with advanced-stage BPDCN; thus, system relapse. None received central nervous sys- participation in a clinical trial should be encouraged tem prophylaxis.8 Although prospective, randomized (Fig 5). Clinical practice varies based on institution- studies have not compared ALL-like with AML-like al preference. Patients with BPDCN may have been induction regimens, data from retrospective studies treated with regimens derived from the management have suggested a higher response rate with ALL-like of more common hematological malignancies, includ- regimens.8,55 Due to a high risk of central nervous ing non-Hodgkin lymphoma (cyclophosphamide/ system involvement, particularly among patients who hydroxydaunomycin/vincristine/prednisone [CHOP] have relapsed, central nervous system prophylaxis or CHOP-like), acute lymphoblastic leukemia (ALL; should be considered, as the incidence of central ner- hyperfractionated/cyclophosphamide/vincristine/ vous system involvement is between 9% and 26%.8

October 2014, Vol. 21, No. 4 Cancer Control 285 Relapse Management and Maintenance Therapy of skin tumors after being treated with weekly pra- Gruson et al56 treated 7 patients with an L-asparagi- latrexate. Using low-dose etoposide therapy, Hatano nase–containing regimen (L-asparaginase/methotrex- et al58 maintained a long-term remission in a patient ate/dexamethasone) and reported good tolerance in with relapsed BPDCN. These data suggest that less both the untreated and relapsed patients. The ob- intensive regimens containing L-asparaginase and jective response rate was 71% (4 CR and 1 PR), and monochemotherapy may be used in relapsed disease overall survival rates ranged from 6 to 34 months.56 or as maintenance in patients not eligible for hema- However, only patients who received consolidation topoietic stem cell transplantation (HSCT). with allogeneic stem cell transplantation were alive at the time of the report. Leitenberger et al57 report- Hematopoietic Stem Cell Transplantation ed on a patient with relapsed BPDCN following Despite a favorable response to initial induction ther- 2 cycles of CHOP who demonstrated a regression apy in most patients, responses are typically short-

Clinical Trial Is Preferred Choice for Initial Therapy/Relapsed Disease

Age > 70 y and significant Age > 70 y, excellent performance status, Age ≤ 70 y and no significant medical comorbidities and no significant medical comorbiditiesa medical comorbidities

Isolated cutaneous L-asparaginase–based regimen Systemic disease involvement or CHOP-like regimen

Skin-directed Palliative ALL-like regimen (hyper-CVAD) therapy chemotherapy (radiation, low-dose ± maintenance chemotherapy) Response to treatment

Ye s No

Candidate for transplantation AML-like regimen

No Ye s Response to treatment Ye s No

Allogeneic hematopoietic Best supportive Observation stem cell transplantation care

Fig 5. — Treatment algorithm for blastic plasmacytoid dendritic cell neoplasm. aSelected patients may be considered for consolidation with reduced-intensity conditioning allogeneic stem cell transplantation during the first remission. ALL = acute lymphocytic leukemia, AML = acute myeloid leukemia, CHOP = cyclophosphamide/hydroxydaunomycin/vincristine/prednisone, hyper-CVAD = hyperfractionated cyclophosphamide/vincristine/doxorubicin/dexamethasone.

286 Cancer Control October 2014, Vol. 21, No. 4 lived, suggesting that induction therapy alone is not icant improvement in survival among patients treat- sufficient to maintain durable remissions. The role of ed with HSCT compared with conventional therapy. maintenance or consolidative therapy has not been However, the numbers of patients were too small to well defined, and no randomized controlled trials de- draw any definitive conclusions. Unteregger et al65 fine the role of HSCT. In most HSCT reports, because treated 5 patients with allogeneic HSCT during the of the small number of patients, statistical power could first or subsequent remission. Four patients received not be shown regarding whether a difference could be reduced intensity conditioning and 2 umbilical cord seen among patients undergoing transplantation and blood transplantations. No graft-vs-host disease was those who did not.59 In a literature review of HSCT in observed in patients who received umbilical cord patients with BPDCN, 76 patients were identified who blood transplantation, but both of these patients devel- underwent consolidation with allogeneic HSCT and oped post-transplantation lymphoproliferative disease. 13 patients with autologous HSCT.60 Because younger Four patients were in complete remission at the time patients typically have a better performance status of the report, with progression-free survival and over- and a good response to induction chemotherapy than all survival rates of 17 and 21 months, respectively.65 older patients, younger people are typically selected Jegalian et al66 retrospectively reviewed the cases for HSCT; therefore, the better outcomes seen in some of 25 pediatric patients with BPDCN who underwent reports among patients undergoing HSCT could be induction therapy with intensive high-risk, ALL-type due to a selection bias. chemotherapy regimens. The event-free survival rate Autologous HSCT has been utilized as consolida- was 64%, and 9 of the 25 patients (36%) were alive tive therapy in patients with BPDCN. Suzuki et al61 5 years after diagnosis.66 Three patients underwent reported on the outcomes of 6 patients who received HSCT. Among those who did not manifest cutaneous high-dose chemotherapy followed by autologous involvement, the survival rate was 100%; by contrast, HSCT. Two patients had a CR, 1 patient had a PR, the survival rate was 61% in patients with cutaneous another patient had a second PR, 1 patient was treat- disease.66 The overall survival rate was 72% with a ed at the time of the first relapse, and 1 patient had median follow-up of 30 months.66 This study sug- primary refractory disease. Three patients died after gested that a prognosis of BPDCN might be better disease progression and 3 patients were alive at 11, 22, in pediatric patients; thus, consolidation with HSCT and 37 months following autologous HSCT. Reimer et should be reserved for pediatric patients in cases of al62 reported disease relapse in 3 of 4 patients studied relapse during complete remission. following autologous HSCT; the median survival rate was 13 months. Due to limited data and a high re- Targeted Therapy lapse rate, only selected patients with chemosensitive No specifically targeted agents are currently approved disease and no available donor for allogeneic HSCT for patients with BPDCN. However, advances in the should be referred for autologous HSCT. understanding of the pathobiology of BPDCN, as well Allogeneic HSCT offers durable disease control as the results of early clinical studies, have revealed and possible cure, particularly if it is performed during novel targets and potentially effective agents. FLT3-ITD the first complete remission.59,60,62 Roos-Weil et al63 mutations were detected in 3 patients among 14 ex- analyzed 34 patients (median age, 41 years) in the amined cases of BPDCN8; none of these 3 patients had European Group for Blood and Marrow Transplanta- previous MDS or myeloproliferative neoplasm. If these tion registry who underwent allogeneic HSCT between results are confirmed in a larger cohort of patients, 2003 and 2009. Eleven patients received a transplant then these findings could lead to a potential novel from siblings, 23 patients received a transplant from therapy with FMS-like tyrosine kinase-3 inhibitors.8 unrelated donors, and 19 (56%) patients underwent Agliano et al67 demonstrated the ex vivo efficacy transplantation during their first remission. The 3-year of lenalidomide against BPDCN cells in a xenograft cumulative incidences of relapse, disease-free survival, mouse model; thus, the activity of lenalidomide should and overall survival rates were 32%, 33%, and 41%, be further explored in clinical studies of patients with respectively.63 In a univariate analysis, allogeneic HSCT BPDCN. Laribi et al68 reported on 2 patients with at first remission was associated with improved surviv- BPDCN who underwent frontline therapy with 5-azacyt- al rates.63 In a single institutional report, 6 of the 19 idine and achieved a resolution of their skin lesions and patients (32%) studied underwent consolidation with a stabilization of their hematological parameters. This autologous (3 patients), allogeneic (2 patients), and therapy could be effective, particularly among patients cord blood (1 patient) transplantation.64 The median with BPDCN and concurrent myelodysplastic changes overall survival rate for patients undergoing trans- or myeloid malignancy (eg, MDS, AML). plantation was 31 months vs 29 months for those Several groups of investigators have reported not receiving transplantation (n = 13; P = .82).64 The the results of preclinical and early clinical data with results of this study suggested no statistically signif- SL-401, a recombinant human interleukin 3α protein

October 2014, Vol. 21, No. 4 Cancer Control 287 conjugated with truncated diphtheria α-toxin, a po- kemia–like induction chemotherapy regimens are as- tent inhibitor of protein synthesis.69-71 In a preclini- sociated with relatively high response rates, although cal study, SL-401 revealed antitumor activity against with a short duration in adult patients. Available data BPDCN cell lines with the half maximal inhibitory suggest that allogeneic hematopoietic stem cell trans- concentration in the femtomolar range.70 Frankel et plantation, particularly if performed during the first al71 reported on data from a phase 1/2 study in which complete response, offers the best chance of durable 11 patients with BPDCN received a single daily course remission. Although it is difficult to conduct random- of SL-401 at 12.5 mcg/kg for 5 days. Of those pa- ized trials in this rare disease entity, prospective stud- tients, 2 were not evaluable for a response; however, ies using novel targeted agents could establish more 7 patients (78%) achieved major responses (5 CRs, effective and tolerable therapies in the near future. 2 PRs).71 Complete remissions included the elimina- tion of malignant cells from all compartments, includ- References ing the skin, bone marrow, peripheral blood, spleen, 1. Swerdlow SH, Campo E, Harris NL, et al, eds. WHO Classification and lymph nodes.71 The median duration of response of Tumours of Haematopoietic and Lymphoid Tissues. 4th ed. Lyon, France: IARC Press; 2008. was 5 months (range, 1–20+ months). The most com- 2. Adachi M, Maeda K, Takekawa M, et al. High expression of CD56 mon adverse events seen in these patients were fever, (N-CAM) in a patient with cutaneous CD4-positive lymphoma. Am J Hematol. 1994;47(4):278-282. chills, hypotension, hypoalbuminemia, peripheral ede- 3. Brody JP, Allen S, Schulman P, et al. Acute agranular CD4-positive ma, thrombocytopenia, and the transient elevation of natural killer cell leukemia. Comprehensive clinicopathologic studies including virologic and in vitro culture with inducing agents. Cancer 1995;75(10):2474- liver transaminases. These encouraging results suggest 2483. that targeted therapy has the potential for improving 4. DiGiuseppe JA, Louie DC, Williams JE, et al. Blastic natural kill- er cell leukemia/lymphoma: a clinicopathologic study. Am J Surg Pathol. patient outcomes. 1997;21(10):1223-1230. 5. Petrella T, Comeau MR, Maynadié M, et al. ‘Agranular CD4+ CD56+ hematodermic neoplasm’ (blastic NK-cell lymphoma) originates from a popu- Prognosis lation of CD56+ precursor cells related to plasmacytoid monocytes. Am J Surg The long-term prognosis of patients with BPDCN is Pathol. 2002;26(7):852-862. 6. Jaffe ES HN, Stein H, et al, eds. Pathology and Genetics. Tumours poor due to the aggressive behavior of the disease, of the Haematopoietic and Lymphoid Tissues. 3rd ed. Lyon, France: IARC the advanced age of most patients, and an absence of Press; 2001. 1,7,8 7. Julia F, Dalle S, Duru G, et al. Blastic plasmacytoid dendritic cell neo- effective targeted therapy with low toxicity rates. plasms: clinico-immunohistochemical correlations in a series of 91 patients. Due to the limited number of patients in retrospective Am J Surg Pathol. 2014;38(5):673-680. 8. Pagano L, Valentini CG, Pulsoni A, et al. Blastic plasmacytoid dendritic reports, validated prognostic and predictive markers cell neoplasm with leukemic presentation: an Italian multicenter study. Hae- are lacking. Analyses of small case series suggest that matologica. 2013;98(2):239-246. 9. Bueno C, Almeida J, Lucio P, et al. Incidence and characteristics of adult patients with skin involvement at presentation CD4(+)/HLA DRhi dendritic cell malignancies. Haematologica. 2004;89(1):58-69. have better prognoses than their counterparts.24,25,54 By 10. Ng AP, Lade S, Rutherford T, et al. Primary cutaneous CD4+/CD56+ hematodermic neoplasm (blastic NK-cell lymphoma): a report of five cases. contrast, in 1 study, patients with the leukemic form Haematologica. 2006;91(1):143-144. of BPDCN had a median survival rate of 8.7 months, 11. Jacob MC, Chaperot L, Mossuz P, et al. CD4+ CD56+ lineage nega- tive malignancies: a new entity developed from malignant early plasmacytoid which is shorter than the 12 months reported for all dendritic cells. Haematologica. 2003;88(8)941-955. patients together.8 12. Oshimi K, Kawa K, Nakamura S, et al. NK-cell neoplasms in Japan. Hematology. 2005;10(3):237-245. In a large, retrospective, national registry study, 13. Petrella T, Bagot M, Willemze R, et al. Blastic NK-cell lymphomas the expression levels of CD303 and high Ki-67 prolif- (agranular CD4+CD56+ hematodermic neoplasms): a review. Am J Clin Pathol. 2005;123(5):662-675. erative index were significantly associated with longer 14. Uchida Y, Kawai K, Kubo H, et al. Blastic plasmacytoid dendritic cell survival rates.7 The biallelic loss of 9p21.3 and the mu- neoplasm in a human T-cell lymphotropic virus type I (HTLV-1) carrier: a co- incidental association? Eur J Dermatol. 2013;23(2):250-251. tations in the methylation pathway genes have been 15. Khoury JD, Medeiros LJ, Manning JT, et al. CD56(+) TdT(+) blastic associated with an unfavorable prognosis.25 Pediatric natural killer cell tumor of the skin: a primitive systemic malignancy related to myelomonocytic leukemia. Cancer. 2002;94(9):2401-2408. patients with BPDCN treated with high-risk, ALL-like 16. Li HS, Watowich SS. Diversification of dendritic cell subsets: emerging induction regimens had better prognoses than their roles of STAT proteins. JAKSTAT. 2013;2(4):e25112. 17. Chaperot L, Bendriss N, Manches O, et al. Identification of a leukemic adult counterparts, and most of these patients did not counterpart of the plasmacytoid dendritic cells. Blood. 2001;97(10):3210-3217. require consolidation with allogeneic HSCT during 18. Tversky JR, Le TV, Bieneman AP, et al. Human blood dendritic cells 66 from allergic subjects have impaired capacity to produce interferon-alpha via their first remission. Toll-like receptor 9. Clin Exp Allergy. 2008;38(5):781-788. 19. Jegalian AG, Facchetti F, Jaffe ES. Plasmacytoid dendritic cells: phys- iologic roles and pathologic states. Adv Anat Pathol. 2009;16(6):392-404. Conclusions 20. Vermi W, Facchetti F, Rosati S et al. Nodal and extranodal tumor-forming Blastic plasmacytoid dendritic cell neoplasm is a rare accumulation of plasmacytoid monocytes/interferon-producing cells associated with myeloid disorders. Am J Surg Pathol. 2004;28(5):585-595. but aggressive hematological malignancy with a poor 21. Reizis B, Bunin A, Ghosh HS, et al. Plasmacytoid dendritic cells: recent prognosis. Prognosis for pediatric patients appears progress and open questions. Annu Rev Immunol. 2011;29:163-183. 22. MacDonald KP, Munster DJ, Clark GJ, et al. Characterization of human to be better than for adults. No established standard blood dendritic cell subsets. Blood. 2002;100(13):4512-4520. frontline treatment regimen exists for patients with 23. Osaki Y, Yokohama A, Saito A, et al. Characterization of CD56+ den- dritic-like cells: a normal counterpart of blastic plasmacytoid dendritic cell blastic plasmacytoid dendritic cell neoplasm. Acute neoplasm? PLoS One. 2013;8(11):e81722. lymphoblastic leukemia–like and acute myeloid leu- 24. Leroux D, Mugneret F, Callanan M, et al. CD4(+), CD56(+) DC2 acute

288 Cancer Control October 2014, Vol. 21, No. 4 leukemia is characterized by recurrent clonal chromosomal changes affecting 50. Piccaluga PP, Paolini S, Sapienza MR, et al. Blastic plasmacytoid 6 major targets: a study of 21 cases by the Groupe Français de Cytogénétique dendritic cell neoplasm: is it time to redefine the standard of care? Expert Hématologique. Blood. 2002;99(11):4154-4159. Rev Hematol. 2012;5(4):353-355. 25. Lucioni M, Novara F, Fiandrino G, et al. Twenty-one cases of blastic 51. Feuillard J, Jacob MC, Valensi F, et al. Clinical and biologic features plasmacytoid dendritic cell neoplasm: focus on biallelic locus 9p21.3 deletion. of CD4(+)CD56(+) malignancies. Blood. 2002;99(5):1556-1563. Blood. 2011;118(17):4591-4594. 52. Pemmaraju N, Deborah A. Kantarijan H, et al. Analysis of outcomes 26. Wiesner T, Obenauf AC, Cota C, et al. Alterations of the cell-cycle of patients (pts) with blastic plasmacytoid dendritic cell neoplasm (BPDCN) inhibitors p27(KIP1) and p16(INK4a) are frequent in blastic plasmacytoid [Abstract]. J Clin Oncol. 2010;30(suppl):6578. dendritic cell neoplasms. J Invest Dermatol. 2010;130(4):1152-1157. 53. Dietrich S, Andrulis M, Hegenbart U, et al. Blastic plasmacytoid den- 27. Tokuda K, Eguchi-Ishimae M, Yagi C, et al. CLTC-ALK fusion as a pri- dritic cell neoplasia (BPDC) in elderly patients: results of a treatment algorithm mary event in congenital blastic plasmacytoid dendritic cell neoplasm. Genes employing allogeneic stem cell transplantation with moderately reduced con- Chromosomes Cancer. 2014;53(1):78-89. ditioning intensity. Biol Blood Marrow Transplant. 2011;17(8):1250-1254. 28. Sapienza MR, Fuligni F, Agostinelli C, et al. Molecular profiling of blastic 54. An HJ, Yoon DH, Kim S, et al. Blastic plasmacytoid dendritic cell neo- plasmacytoid dendritic cell neoplasm reveals a unique pattern and suggests plasm: a single-center experience. Ann Hematol. 2013;92(3):351-356. selective sensitivity to NF-KB pathway inhibition. Leukemia. 2014;28(8):1606- 55. Gills L, Lebras L, Bouafia-Sauvy F, et al. Sequential combination of high 1616. dose methotrexate and L-asparaginase followed by allogeneic transplant: a 29. Dijkman R, van Doorn R, Szuhai K, et al. Gene-expression profiling first-line strategy for CD4+/CD56+ hematodermic neoplasm. Leuk Lymphoma. and array-based CGH classify CD4+CD56+ hematodermic neoplasm and 2012;53(8):1633-1637. cutaneous myelomonocytic leukemia as distinct disease entities. Blood. 56. Gruson B, Vaida I, Merlusca L, et al. L-asparaginase with methotrexate 2007;109(4):1720-1727. and dexamethasone is an effective treatment combination in blastic plasma- 30. Alayed K, Patel KP, Konoplev S, et al. TET2 mutations, myelodysplastic cytoid dendritic cell neoplasm. Br J Haematol. 2013;163(4):543-545. features, and a distinct immunoprofile characterize blastic plasmacytoid den- 57. Leitenberger JJ, Berthelot CN, Polder KD, et al. CD4+ CD56+ hemato- dritic cell neoplasm in the bone marrow. Am J Hematol. 2013;88(12):1055-1061. dermic/plasmacytoid dendritic cell tumor with response to pralatrexate. J Am 31. Menezes J, Acquadro F, Wiseman M, et al. Exome sequencing reveals Acad Dermatol. 2008;58(3):480-484. novel and recurrent mutations with clinical impact in blastic plasmacytoid 58. Hatano Y, Ogata M, Ohishi M, et al. Maintenance of long-term re- dendritic cell neoplasm. Leukemia. 2014;28(4):823-829. mission using oral administration of low-dose etoposide in a patient demon- 32. Taylor J, Kim SS, Stevenson KE, et al. Loss-of-function mutations in strating a relapse of blastic natural killer-cell lymphoma. Clin Exp Dermatol. the splicing factor ZRSR2 are common in blastic plasmacytoid dendritic cell 2007;32(1):96-97. neoplasm and have male predominance. Blood. 2013;122(21):741. 59. Dalle S, Beylot-Barry M, Bagot M, et al. Blastic plasmacytoid dendritic 33. Sugimoto KJ, Shimada A, Yamaguchi N, et al. Sustained complete cell neoplasm: is transplantation the treatment of choice? Br J Dermatol. remission of a limited-stage blastic plasmacytoid dendritic cell neoplasm fol- 2010;162(1):74-79. lowed by a simultaneous combination of low-dose DeVIC therapy and radia- 60. Kharfan-Dabaja MA, Lazarus HM, Nishihori T, et al. Diagnostic and tion therapy: a case report and review of the literature. Int J Clin Exp Pathol. therapeutic advances in blastic plasmacytoid dendritic cell neoplasm: a fo- 2013;6(11):2603-2608. cus on hematopoietic cell transplantation. Biol Blood Marrow Transplant. 34. Li Y, Li Z, Lin HL, et al. Primary cutaneous blastic plasmacytoid dendritic 2013;19(7):1006-1012. cell neoplasm without extracutaneous manifestation: case report and review 61. Suzuki R, Suzumiya J, Nakamura S, et al. Hematopoietic stem cell of the literature. Pathol Res Pract. 2011;207(1):55-59. transplantation for natural killer-cell lineage neoplasms. Bone Marrow Trans- 35. Pileri A, Delfino C, Grandi V, et al. Blastic plasmacytoid dendritic cell plant. 2006;37(4):425-431. + + neoplasm (BPDCN): the cutaneous sanctuary. G Ital Dermatol Venereol. 62. Reimer P, Rüdiger T, Kraemer D, et al. What is CD4 CD56 malignancy 2012;147(6):603-608 and how should it be treated? Bone Marrow Transplant. 2003;32(7):637-646. 36. Rauh MJ, Rahman F, Good D, et al. Blastic plasmacytoid dendritic cell 63. Roos-Weil D, Dietrich S, Boumendil A, et al. Stem cell transplantation neoplasm with leukemic presentation, lacking cutaneous involvement: case can provide durable disease control in blastic plasmacytoid dendritic cell series and literature review. Leuk Res. 2012;36(1):81-86. neoplasm: a retrospective study from the European Group for Blood and 37. Herling M, Teitell MA, Shen RR, et al. TCL1 expression in plasmacytoid Marrow Transplantation. Blood. 2013;121(3):440-446. dendritic cells (DC2s) and the related CD4+ CD56+ blastic tumors of skin. 64. Pemmaraju N, Thomas D, Kantarjian HM, et al. Analysis of outcomes of Blood. 2003;101(12):5007-5009. patients with blastic plasmacytoid dendritic cell neoplasm. https://ash.confex. 38. Petrella T, Meijer CJ, Dalac S, et al. TCL1 and CLA expression in com/ash/2012/webprogram/Paper53971.html. Accessed July 28, 2014. agranular CD4/CD56 hematodermic neoplasms (blastic NK-cell lymphomas) 65. Unteregger M, Valentin A, Zinke-Cerwenka W, et al. Unrelated SCT and leukemia cutis. Am J Clin Pathol. 2004;122(2):307-313. induces long-term remission in patients with blastic plasmacytoid dendritic 39. Pilichowska ME, Fleming MD, Pinkus JL, et al. CD4+/CD56+ hema- cell neoplasm. Bone Marrow Transplant. 2013;48(6):799-802. todermic neoplasm (“blastic natural killer cell lymphoma”): neoplastic cells 66. Jegalian AG, Buxbaum NP, Facchetti F, et al. Blastic plasmacytoid express the immature dendritic cell marker BDCA2 and produce interferon. dendritic cell neoplasm in children: diagnostic features and clinical implications. Am J Clin Pathol. 2007;128(3):445-453. Haematologica. 2010;95(11):1873-1879. 40. Reichard KK, Burks EJ, Foucar MK, et al. CD4(+) CD56(+) lineage-neg- 67. Agliano A, Martin-Padura I, Marighetti P, et al. Therapeutic effect of ative malignancies are rare tumors of plasmacytoid dendritic cells. Am J Surg lenalidomide in a novel xenograft mouse model of human blastic NK cell Pathol. 2005;29(10):1274-1283. lymphoma/blastic plasmacytoid dendritic cell neoplasm. Clin Cancer Res. 41. Marafioti T, Paterson JC, Ballabio E, et al. Novel markers of normal and 2011;17(19):6163-6173. neoplastic human plasmacytoid dendritic cells. Blood. 2008;111(7):3778-3792. 68. Laribi K, Denizon N, Ghnaya H, et al. Blastic plasmacytoid dendritic cell 42. Montes-Moreno S, Ramos-Medina R, Martínez-López A, et al. SPIB, a neoplasm: the first report of 2 cases treated by 5-azacytidine. Eur J Haematol. novel immunohistochemical marker for human blastic plasmacytoid dendritic 2014;93(1):81-85. 69. Frankel AE, McCubrey JA, Miller MS, et al. Diphtheria toxin fused to cell neoplasms: characterization of its expression in major hematolymphoid human interleukin-3 is toxic to blasts from patients with myeloid leukemias. neoplasms. Blood. 2013;121(4):643-647. Leukemia. 2000;14(4):576-585. 43. Salva KA, Haemel AK, Pincus LB, et al. Expression of CD31/PECAM-1 70. Angelot-Delettre F, Frankel AE, Liu JS, et al. The IL-3R -targeted drug (platelet endothelial cell adhesion molecule 1) by blastic plasmacytoid dendritic a SL-401 selectively kills blastic plasmacytoid dendritic cell neoplasm cells. cell neoplasms. JAMA Dermatol. 2014;150(1):73-76. https://ash.confex.com/ash/2011/webprogram/Paper37851.html. Accessed 44. Garnache-Ottou F, Feuillard J, Ferrand C, et al. Extended diag- July 28, 2014. nostic criteria for plasmacytoid dendritic cell leukaemia. Br J Haematol. 71. Frankel AE, Woo JH, Ahn C, et al. Activity of SL-401, a targeted ther- 2009;145(5):624-636. apy directed to interleukin-3 receptor, in blastic plasmacytoid dendritic cell 45. Sangle NA, Schmidt RL, Patel JL, et al. Optimized immunohistochem- neoplasm patients. Blood. 2014;124(3):385-392. ical panel to differentiate myeloid sarcoma from blastic plasmacytoid dendritic cell neoplasm. Mod Pathol. 2014;27(8):1137-1143. 46. Song SX, Willemze R, Swerdlow SH, et al. Mycosis fungoides: report of the 2011 Society for Hematopathology/European Association for Haema- topathology workshop. Am J Clin Pathol. 2013;139(4):466-490. 47. Liang X, Graham DK. Natural killer cell neoplasms. Cancer. 2008;112(7):1425-1436. 48. Vitte F, Fabiani B, Bénet C, et al. Specific skin lesions in chronic my- elomonocytic leukemia: a spectrum of myelomonocytic and dendritic cell proliferations: a study of 42 cases. Am J Surg Pathol. 2012;36(9):1302-1316. 49. Assaf C, Gellrich S, Whittaker S, et al. CD56-positive haematological neoplasms of the skin: a multicentre study of the Cutaneous Lymphoma Project Group of the European Organisation for Research and Treatment of Cancer. J Clin Pathol. 2007;60(9):981-989.

October 2014, Vol. 21, No. 4 Cancer Control 289 Immunohistochemistry remains the

mainstay of diagnosing rare dendritic cell

and histiocytic neoplasms. Collaborative

efforts are needed to better treat patients

with these rare disorders.

Mushroom Biome. Photograph courtesy of Sherri Damlo. www.damloedits.com.

Dendritic Cell and Histiocytic Neoplasms: Biology, Diagnosis, and Treatment Samir Dalia, MD, Haipeng Shao, MD, PhD, Elizabeth Sagatys, MD, Hernani Cualing, MD, and Lubomir Sokol, MD, PhD

Background: Dendritic and histiocytic cell neoplasms are rare malignancies that make up less than 1% of all neoplasms arising in lymph nodes or soft tissues. These disorders have distinctive disease biology, clinical presentations, pathology, and unique treatment options. Morphology and immunohistochemistry evaluation by a hematopathologist remains key for differentiating between these neoplasms. In this review, we describe tumor biology, clinical features, pathology, and treatment of follicular dendritic cell sarcoma, interdigitating dendritic cell sarcoma, indeterminate dendritic cell sarcoma, histiocytic sarcoma, fibroblastic reticular cell tumors, and disseminated juvenile xanthogranuloma. Methods: A literature search for articles published between 1990 and 2013 was undertaken. Articles are reviewed and salient findings are systematically described. Results: Patients with dendritic cell and histiocytic neoplasms have distinct but variable clinical presentations; however, because many tumors have recently been recognized, their true incidence is uncertain. Although the clinical features can present in many organs, most occur in the lymph nodes or skin. Most cases are unifocal and solitary presentations have good prognoses with surgical resection. The role of adjuvant therapy in these disorders remains unclear. In cases with disseminated disease, prognosis is poor and data on treatment options are limited, although chemotherapy and referral to a tertiary care center should be considered. Excisional biopsy is the preferred method of specimen collection for tissue diagnosis, and immunohistochemistry is the most important diagnostic method for differentiating these disorders from other entities. Conclusions: Dendritic cell and histiocytic cell neoplasms are rare hematological disorders with variable clinical presentations and prognoses. Immunohistochemistry remains important for diagnosis. Larger pooled analyses or clinical trials are needed to better understand optimal treatment options in these rare disorders. Whenever possible, patients should be referred to a tertiary care center for disease management.

From the Departments of Medical Oncology (SD), Hematopathology Submitted December 20, 2013; accepted May 1, 2014. and Laboratory Medicine (HS, ES), and Malignant Hematology (LS) at Address correspondence to Samir Dalia, MD, Mercy Clinic Oncol- the H. Lee Moffitt Cancer Center & Research Institute, Tampa, Florida, ogy-Hematology, 3001 McClelland Boulevard, Joplin, MO 64804. the University of South Florida Morsani College of Medicine (SD, HS), E-mail: [email protected] Tampa, Florida, and IHCFLOW (HC), Lutz, Florida. No significant relationships exist between the authors and the com- Dr Dalia is now affiliated with Mercy Clinic Oncology-Hematology, panies/organizations whose products or services may be referenced Joplin, Missouri. in this article.

290 Cancer Control October 2014, Vol. 21, No. 4 Introduction nodes or the extranodal ectopic lymphoid tissue, Dendritic and histiocytic neoplasms are rare hema- including lymphoid nodules in the bone marrow. tological malignancies that involve common immune Through the formation of immune complexes, these accessory or mesenchymal cells. These tumors are cells store and retain antigens and serve as a nidus typically placed into 2 main groups based on their for B-cell proliferation and differentiation, along with derivation from either bone marrow precursors or help from T cells.5-7 FDCs are mesenchymal in origin mesenchymal cells. Histiocytic sarcoma (HS), Lang- and similar to myofibroblasts. Although FDCs are not erhans cell histiocytosis (LCH), and interdigitating derived from bone marrow progenitors, they express dendritic cell sarcoma (IDCS) are derived from bone antigens related to bone marrow stroma. Hence, these marrow precursors, while follicular dendritic cell sar- cells typically express markers of FDC differentiation, coma (FDCS), indeterminate dendritic cell sarcoma including CD21, CD23, and CD35.8 (INDCS), fibroblastic reticular cell tumors (FRCTs), Although FDCS is mesenchymal in origin, it is and disseminated juvenile xanthogranuloma (DJX) clonally related to follicular lymphoma, possibly are histogenetically of stromal-derived dendritic cells through transdifferentiation of the follicular lympho- or mesenchymal in origin.1,2 Divergent differentiation ma clone.3 The disease has also been associated with from marrow precursors is the normal histogenesis, Castleman disease, paraneoplastic pemphigus, and although hybrid or transdifferentiation from neoplas- myasthenia gravis.9-13 FDCS may arise in lymph nodes tic lymphoid clones has also been proposed in IDCS, that harbor dysplastic FDCs in Castleman disease, with HS, or FDCS.2-4 Together, dendritic and histiocytic neo- some studies reporting clonal expansion of FDCs in plasms make up less than 1% of neoplasms presenting these patients.14,15 FDCS and non-neoplastic FDCs of in the lymph nodes or soft tissues. Castleman disease express epidermal growth factor re- The rarity of these tumors makes them difficult ceptor, which may promote FDC persistence and allow to accurately diagnose and treat, and they are often for mutations that may result in FDCS.16 In addition, mistaken as non-Hodgkin lymphoma or other lymph- a correlation exists between FDCS and the presence oproliferative disorders. Patients with suspected den- of Epstein–Barr virus (EBV).17 Because FDCs express dritic and histiocytic neoplasms require hematopathol- CD21 (acting as a receptor for EBV), the virus could ogy consultation and should be referred to a tertiary gain entry into these cells.18-20 The differential diagno- care cancer center when possible. The diagnosis of sis of FDCS remains broad and includes B- and T-cell these rare disorders is based on differential features lymphomas, myeloid sarcomas, melanoma, carcino- in morphology and immunohistochemistry. Recent mas, and other dendritic and histiocytic disorders, such advances in immunohistochemistry have helped in a as blastic plasmacytoid dendritic cell neoplasms and better classification of dendritic cell and histiocytic LCH (Table 1). Rarely, peripheral nerve sheath tumors neoplasms and have improved our knowledge of their and malignant fibrous histiocytoma are mistaken for tumor biology and histogenesis, which may be helpful FDCS; immunohistochemistry might help in the diag- in the management of these rare diseases. The aim of nosis of these entities.21,22 this review is to provide clinicians with the current scientific framework to better understand the tumor Clinical Features biology, clinical features, pathology, and treatment of FDCS presents in a wide range of ages, but it shows FDCS, IDCS, INDCS, HS, FRCT, and DJX. adult predominance (mean age, 44 years).23,24 Local- We performed a literature search for articles pub- ized FDCS has a benign course, a median survival lished between January 1, 1990, and December 1, 2013, rate of 168 months (range, 2–360 months), and risks to find research related to tumor biology, clinical fea- of local recurrence and distant metastasis of 27% to tures, pathology, and treatments for each of these rare 28%, respectively.10 Larger tumor size (≥ 6 cm), the disorders. We referred to the text and references of the presence of coagulative necrosis, high mitotic count fourth edition of the WHO Classification of Tumours (≥ 5 per 10 HPF), and cytological atypia are associated of Haematopoietic and Lymphoid Tissues1 as a basis to with a poor prognosis.8,10,25 Stage did not significantly comprehensively cover these disorders. Although LCH impact overall survival rates in patients with FDCS.10 is integral in understanding these entities, it has been Saygin et al10 reported that 2-year survival rates for separately reviewed by Dr Grana on page 328 of this early, locally advanced, and distant metastatic disease issue and will not be covered here. were 84.2%, 80%, and 42.8%, respectively. In the majority of cases, FDCS presents as a Follicular Dendritic Cell Sarcoma slow-growing mass, usually with the most frequent Tumor Biology location in the head and neck or abdominal lymph FDCS is a very rare clonal neoplasm of follicular nodes. Approximately one-half of patients will present dendritic cells (FDCs). FDCs are stromal-derived cells with a local cervical and intra-abdominal mass.10,26 normally found in the germinal centers of lymph Although rare, most extranodal involvement occurs

October 2014, Vol. 21, No. 4 Cancer Control 291 Table 1. — Differential Diagnosis of Dendritic Cell Sarcomas

FDCS and IDCS FRCT HS INDCS JXG

Anaplastic large cell lymphoma FDCS Anaplastic large cell LCH Dermatofibroma IDCS (for FDCS) or FDCS IDCS lymphoma Pityriasis rosea Eruptive xanthomas (for IDCS) INDCS Diffuse large B-cell Scabies LCH Inflammatory pseudotumors lymphoma Palisaded T-cell lymphomas Mastocytoma Intranodal myofibroblastoma Hemophagocytic myofibroblastoma (cutaneous T-cell hyperplasia, Papular xanthoma LCH lymphohistiocytosis mycosis fungoides) Sarcoma Spitz nevus Non-Hodgkin lymphoma LCH Tuberous xanthoma Peripheral nerve sheath tumors Lymphoma Xanthoma disseminatum True histiocytic lymphomas Metastatic carcinoma or melanoma

FDCS = follicular dendritic cell sarcoma, FRCT = fibroblastic reticular cell tumor, HS = histiocytic sarcoma, IDCS = interdigitating dendritic cell sarco- ma, INDCS = indeterminate dendritic cell sarcoma, JXG = juvenile xanthogranuloma, LCH = Langerhans cell histiocytosis. in the liver, lungs, tonsils, or spleen.10 Workup for pression of CD68 can be seen.5,8,28 Clusterin is strong- patients with FDCS should include computed tomog- ly positive in FDCS and is negative or weakly posi- raphy (CT) scans with contrast from the neck to the tive in other dendritic cell tumors.21,29 Desmoplakin, pelvis to evaluate other sites of disease, complete vimentin, fascin, epidermal growth factor receptor, blood counts, bone marrow aspiration, and biopsy. CD45, and HLA-DR can be variably positive.5,16,28,30 In certain patients, HIV, EBV, and hepatitis testing can Immunoglobulin and T-cell receptor genes are in a be considered to exclude concurrent viral infection. germline configuration.30 Cytogenetic data in patients Core needle biopsy or excisional biopsy (preferred) with FDCS are limited and do not aid in diagnosis.31 of the tumor mass is necessary for an accurate diag- The major clinical and pathological findings for nosis of FDCS. Fine needle aspiration biopsy should FDCS are outlined in Table 2. be avoided. Treatment Pathology Surgical resection remains the mainstay of treatment in Cytomorphology of a biopsied/resected lesion is FDCS. A Surveillance, Epidemiology, and End Results characterized as spindled to ovoid cells that form database study reported that 94% of patients with fascicles, whorls, diffuse sheets, or nodules (Fig 1). localized disease had surgical resection as the initial Individual cells generally show indistinct cell borders and a moderate amount of eo- sinophilic cytoplasm. Nuclear pseudoinclusions are common and binucleated, and multinu- cleated tumor cells are seen.1 Long cytoplasmic projections and desmosomal junctions are seen on electron microscopy; Birbeck granules and numer- ous lysosomes are not present.5 Lymphoplasmacytic infiltration is present in more than 90% of cases.10 Rarely, Reed-Sternberg– like cells can lead to a mistaken diagnosis of Hodgkin disease.27 Immunohistochemistry is the most important work- up to help differentiate FDCS Fig 1. — Follicular dendritic cell sarcoma. This spindle cell proliferation was identified on a retroperitoneal from other histiocytic tumors. mass in a 79-year-old man. The spindle cells form fascicles with occasional whorls. Several mitotic figures In FDCS, CD21, CD23, CD35, were seen (lower right panel), which, in combination with the intra-abdominal location and large size of the mass, suggested an increased risk for recurrence. A few small lymphocytes are seen in the background, which R4/23, Ki-FDC1p, and KiM4 is typical for this entity. By immunohistochemistry the spindle cells were positive for CD21, CD23, CD68, and are positive and a variable ex- D2-40. The cells were negative for CD117 (c-kit), S100, desmin, cytokeratin, and CD34.

292 Cancer Control October 2014, Vol. 21, No. 4 treatment.26 The benefit of adjuvant therapy for fully tation in FDCS is unclear. One study reported relapses resected lesions in patients with limited stage disease within 1 year in 2 patients treated with allogeneic is debatable. Two large analyses both reported no ben- transplantation for FDCS.32 efit for adjuvant radiation therapy in patients with lo- calized FDCS.10,26 Soriano et al32 reported in a series of Interdigitating Dendritic Cell Sarcoma 14 cases with FDCS that 3 patients treated with surgery Tumor Biology followed by adjuvant chemotherapy and radiotherapy Normal interdigitating dendritic cells (IDCs) are anti- had complete remission, while 3 patients given che- gen-processing cells usually located in the lymph node motherapy alone showed no complete response. The paracortex, a major T-cell region. These cells present role of adjuvant chemotherapy or radiation therapy antigens to T cells and regulate cellular immune re- in localized FDCS remains controversial and should sponse.10,34-38 IDCs originate from marrow hematopoi- be considered on a case-by-case basis. etic precursors through the conversion of Langerhans In patients with extensive disease, Saygin et al10 cells as they travel to the lymph node.10,34,39-41 Malignant reported that 23 patients treated with combined che- IDCs result in IDCS and are usually positive for S100 motherapy and radiotherapy had excellent survival and vimentin and negative for CD1a and langerin.1 rates, with only 2 deaths due to disease. These data Unlike FDCS, they do not express CD21 or CD35. suggest the importance of combined modality in ad- IDCS have been reported in association with vanced FDCS, although no prospective randomized other hematological and solid tumor malignancies, trial data exist. Regimens designed to manage ag- including B-cell neoplasms, mycosis fungoides, and gressive lymphomas, such as cyclophosphamide/vin- neoplasms of the skin, liver, stomach, colon, breast, cristine/doxorubicin/prednisone (CHOP), ifosfamide/ and brain.10 A clonal relationship between IDCS and carboplatin/etoposide (ICE), and doxorubicin/bleomy- low-grade B-cell lymphomas has been reported and cin/vincristine/dacarbazine (ABVD), have been used may be due to the transdifferentiation of the lympho- with variable success.5,10,32,33 Currently, lymphoma-type ma clones.2-4 In one series of 7 patients with chronic chemotherapy remains the mainstay of treatment for lymphocytic leukemia/small lymphocytic leukemia, disseminated FDCS. The role of allogeneic transplan- 4 patients had features suggestive of IDCS. In these

Table 2. — Clinical and Pathological Findings of Dendritic Cell Sarcomas

FDCS IDCS INDCS HS FRCT JXG

Clinical Findings Slow growing Asymptomatic Papules, nodules, Solitary mass Asymptomatic Small solitary (usual presentation) mass, usually a solitary lymph or plaques on the with systemic mass papule lymph node node mass skin symptoms Can have skin le- sions (rash-like)

Cytomorphology Spindle to Spindle to Resembles Large and round Spindle to Small and oval ovoid cells ovoid cells Langerhans cells to oval shape ovoid cells with a bland with whorls with whorls with irregular with focal areas with whorls round to oval nuclear grooves of spindling in paracortical nucleus without and clefts areas grooves

Immunophenotypical CD4 (+) CD4 (+) CD1a (–) CD163 (+) Vimentin (+) Vimentin (+) Markers CD21 (+) CD45 (+/–) CD4 (+) CD68 (+) Desmin (+) sCD14(+) CD34 (–) CD68 (+) Fascin (+) Lysozyme (+) Smooth muscle CD68 (+) CD35 (+) Fascin (+) S100 (+) CD1a (–) actin (+) Stabilin-1 (+) CD68 (+/–) S100 (+) CD68 (+/–) CD21 (–) Factor XIIIa (+) CD163 (+) Fascin (+) Birbeck granules (–) CD35 (–) CD21 (–) Factor XIIIa (+) CD33(–) CD35 (–) CD1a (–) S100 (–) CD1a (–)

Treatment for Surgical resec- Surgical Surgical excision Surgical Surgical None needed Limited Disease tion ± adjuvant resection resection resection for localized chemotherapy or RT ± RT ± RT asymptomatic or RT lesion

Treatment for Lymphoma-type Lymphoma-type Multimodality Lymphoma-type Participation Langerhans Disseminated chemotherapy chemotherapy chemotherapy in a clinical trial histiocytosis– Disease based treatment

FDCS = follicular dendritic cell sarcoma, FRCT = fibroblastic reticular cell tumor, HS = histiocytic sarcoma, IDCS = interdigitating dendritic cell sarcoma, INDCS = indeterminate dendritic cell sarcoma, JXG = juvenile xanthogranuloma, RT = radiation therapy.

October 2014, Vol. 21, No. 4 Cancer Control 293 cases, identical clonal IGH or IGK was found, along Pathology with chromosome 17p deletion by fluorescence in situ Cytomorphology typically reveals large spindle to hybridization, suggesting a common clonal origin.2 ovoid cells with the formation of whorls. Cells may Another series of 3 cases showed an identical V-J have coarse nuclear chromatin with moderate to abun- junction sequences and trisomy 12 in both chronic dant cytoplasm resembling histiocytes.28 The presence lymphocytic leukemia and IDCS tumors, suggesting of small lymphocytes intermingling with the large transdifferentiation of the lymphoma clones.4 histiocytic cell population is a key diagnostic feature Unlike FDCS, a viral etiology for IDCS has not less typical of carcinomas and sarcomas (Fig 2A).28 been demonstrated. Most cases of IDCS are negative Immunophenotype will show cells negative for for EBV and the human herpesvirus 8 genome.10 IDCS CD1a, positive for S100 and CD45, and have variable has also been reported following the use of calci- positivity for CD68 (Fig 2B).24,45 Some cases of IDCS are neurin inhibitors, which may be due to their effect positive for vimentin, HLA-DR, and fascin.35 Lysozyme by dampening the responses of T cells to which IDCs can also be positive, although this is uncommon.45 present antigens.10,42,43 The differential diagnosis for B-cell markers such as CD20 and T-cell markers such IDCS is presented in Table 1. With advances in immu- as CD3 and CD5 are usually negative. Cytokeratin, nohistochemistry and molecular diagnosis, IDCS has myeloperoxidase, CD1a, CD21, CD23, CD30, CD35, become less difficult to diagnose; however, a recent clusterin, langerin, CD34, CD79a, BCL2, and BCL6 are report reclassified malignant fibrous histiocytoma as negative.1,24,45,46 A distinguishing feature of IDCS is the IDCS, highlighting the importance of accurate diag- absence of Birbeck granules on electron microsco- nosis in these rare neoplasms.44 py.24,45 Immunoglobulin and T-cell receptor genes are in a germline configuration.48 Table 2 illustrates the Clinical Features clinical and pathological findings associated with IDCS. IDCS is an extremely rare disease with a pooled analysis of 462 cases of dendritic cell sarcomas, of Treatment which 100 were cases of IDCS. Another Surveillance, Historically, the mainstay of treatment of IDCS has been Epidemiology, and End Results database study of surgical resection. One report suggests that surgical 74 DCS cases included 20 IDCS cases.10,26 Median age at resection is associated with improved overall survival diagnosis is 56.5 years (range, 21 months to 88 years), rates (P = .04).26 Conversely, another study reported no and the disease has a male:female ratio of 1.38:1.10 difference in overall survival rates between surgery and Prognosis varies in patients with IDCS, from a benign nonsurgical modalities of treatment such as radiation course to rapidly progressive lethal disease in patients treatment for localized IDCS.10 Until further conclu- with disseminated disease. Patients who are younger sive evidence is available, either surgical resection or and those who have a higher stage as well as intra-ab- radiation therapy is recommended as initial therapy dominal involvement have a worse prognosis than their for localized IDCS. In disseminated disease, chemo- counterparts.10,26 Median survival rates for patients with therapy such as CHOP, ICE, and ABVD has been used disseminated disease are between 9 and 10 months; with variable success.10,43,46 Although chemotherapy is according to 2 reported series, those with localized dis- usually considered for patients with disseminated IDCS, ease did not reach median survival.10,26 Saygin et al10 re- surgical resection may still play a role, with 1 study ported 1- and 2-year survival rates of 84.8% and 68.1%, reporting a trend toward improved overall survival respectively, while patients with metastatic disease had in patients who underwent surgery followed by che- 1- and 2-year survival rates that dropped to 38.5% and motherapy.10 Currently, no consensus exists on opti- 15.8%, respectively. mal treatment in patients with disseminated disease; Patients normally present with a solitary lymph participation in a clinical trial or referral to a tertiary node mass, but cases with skin and soft-tissue involve- care center is optimal. No data have been published ment have been described.1,28,35,45-47 Patients are usually on hematopoietic stem-cell transplantation in IDCS; asymptomatic, but fatigue, fever, and night sweats may therefore, the procedure cannot be recommended. be present. Similar to FDCS, staging includes CT scans with contrast from the neck to the pelvis to evaluate Indeterminate Dendritic Cell Sarcoma other sites of disease, complete blood counts, bone Tumor Biology marrow aspiration, and biopsy. Because viral etiology INDCS, also known as indeterminate cell histiocytosis, has not been implicated in patients with IDCS, test- is a rare neoplastic proliferation of normal dendritic ing for HIV infection and hepatitis is not indicated accessory cells, which are usually found in the der- in most cases. Core needle biopsy or excisional bi- mis. Because indeterminate cells share morphological opsy (preferred) of the tumor mass is necessary for and immunophenotypical features with Langerhans an accurate diagnosis; fine needle aspiration biopsy cells (except the presence of Birbeck granules on should be avoided. electron microscopy), some authors speculate that

294 Cancer Control October 2014, Vol. 21, No. 4 A B S100 CD21

Clusterin Langerin

Fig 2. — Interdigitating dendritic cell sarcoma. (A) Paracortical infiltrate by large neoplastic cells with oval to elongated nuclei, abundant eosinophilic cyto- plasm, and indistinct cell border. (B) Neoplastic cells positive for S100 and negative for CD21, clusterin, and langerin. Note the positive stain for CD21 and cluster on follicular dendritic cells in the residual germinal centers. indeterminate cells may represent a mature form of and CD34 are both negative, unlike xanthogranulo- Langerhans cells.49-52 Neoplasms of indeterminate cells mas and dermatofibrosarcoma protuberance, respec- are extremely rare and little is known of the natural tively.59,61 Variable positivity is seen for CD45, CD68, history of INDCS. Associations between the prolif- lysozyme, and CD4.62 One case report indicates that eration of indeterminate cells and nodular scabies, INDCS may be clonal by the human androgen receptor pityriasis rosea, and low-grade B-cell lymphomas have gene assay.62 The clinical and pathological character- been reported.53-57 Immunophenotypical markers are istics for INDCS are summarized in Table 2. similar to IDCS, which show cells positive for S100 and CD1a; on an ultrastructural examination, Birbeck Treatment granules will be absent. The differential diagnosis for Due to the rarity of INDCS, little is known about the INDCS is presented in Table 1. natural history or treatment of this disease. Most le- sions are indolent or self-limited.58 New lesions may Clinical Features develop, and the spontaneous regression of lesions INDCS has been reported in case reports alone; thus, has been reported.53 Currently, the resection of le- no data exist on median age, sex, or race predilection sions, if present, remains the therapy of choice. The among those with INDCS. Most patients present with roles of chemotherapy and radiation therapy remain 1 or more papules, nodules, or plaques on the trunk, unclear in INDCS. In rare cases of disseminated dis- face, neck, or extremities.58,59 Generalized distribu- ease, multimodality treatment can be considered. tion has rarely been reported.60 Diagnosis is usually made by skin biopsy and systemic workup, including Histiocytic Sarcoma CT scans and bone marrow biopsy. Other testing is Tumor Biology typically not indicated in localized cases. HS is a rare non-Langerhans histiocyte disorder of ma- ture tissue histiocytes. The etiology of this disorder Pathology remains unknown, but some cases have occurred in Microscopy evaluation shows that these dermal le- patients with mediastinal germ cell tumor, suggesting sions are diffusely infiltrating and are composed of that HS may arise from pluripotential germ cells.63 As- cells with irregular nuclear grooves and clefts that sociations between HS and follicular lymphoma, myel- resemble Langerhans cells.59 Cytoplasm is abundant, odysplastic syndrome, and acute lymphoblastic leuke- pale, and eosinophilic. Multinucleated giant cells may mia have also been made.2,24,64,65 A study has reported be seen and the spindling or dendritic formation of transdifferentiation in patients with HS and follicular some cells may be present (Fig 3A, B). These cells lymphoma and reported the presence of t(14;18) and lack Birbeck granules on electron microscopy and IGH gene rearrangements in all of the patients, suggest- desmosomes are lacking; however, interdigitating cell ing a common clonal origin of follicular lymphoma and processes may be present.1,58 HS.3 Another study reported that 2 patients with HS had Immunophenotype shows that INDCS cells are a clonal immunoglobulin rearrangement, suggesting a positive for S100 and CD1a (Fig 3C–E).58 These cells clonal evolution of HS from chronic lymphocytic leu- are negative for specific B- and T-cell markers, CD30, kemia/small lymphocytic leukemia.2 Further research CD163, CD21, CD23, CD35, and langerin. Factor XIIIa is needed to confirm these findings.

October 2014, Vol. 21, No. 4 Cancer Control 295 Expert morphology review and immunohisto- nucleoli (Fig 4A). On occasion, the cells may have a chemistry remain important in the diagnosis of HS. xanthomatous appearance.1,24,64 Immunohistochemical markers in patients with HS Immunochemistry is positive for histiocytic mark- include positivity for CD163, CD68, and lysozyme. The ers, including CD163, CD68, and lysozyme. CD1a, differential diagnosis for HS is presented in Table 1. CD21, CD35, and CD33 markers are all negative. S100 can be positive but is usually weak or focal (Fig 4B). Clinical Features Ki67 is variable (see Table 2).24,64 HS has been reported in all age groups but is more commonly seen in adults (median age, Treatment 46–55 years).24,64,66 Male predilection has been found The rarity of HS makes it difficult to assess the ben- in 2 reports but has not been confirmed in others.24,64,66 efits of multimodality treatment in these patients. In The disease usually presents with single or multifocal unifocal extranodal disease, a study of 14 patients extranodal tumors, most commonly in the intestines, gave insights into different treatment modalities.64 skin, or soft tissue.24,64 Rarely, cases have been de- In this series, 5 patients were treated with surgical scribed with diffuse lymphadenopathy and multiple resection alone, 3 patients with surgical resection sites of involvement, and those with multifocal disease and adjuvant radiation therapy, and 6 patients were have a worse outcome.64,66,67 Systemic symptoms such treated with surgical resection followed by adjuvant as fever and weight loss are common, and symptoms chemotherapy. The 2 patients treated with surgery from the compression of a vital organ (eg, small bowel alone went on to develop distant disease within obstruction) can occur. Skin involvement can include 6 months, while 1 recurred at 6 months and was rash to innumerable tumors in multiple areas of the alive 11 years after repeat resection and adjuvant body.1 Cytopenias are seen in 30% of cases.24 Because radiation therapy. Two patients treated with surgery patients with unifocal disease have better outcomes, alone did not have evidence of recurrence. In the we recommend that patients receive full staging, in- 3 patients initially treated with surgical resection cluding CT scans and bone marrow biopsy, to rule out and adjuvant radiation therapy, no local recurrences multifocal disease. Excisional biopsy is the preferred were seen; however, 1 patient had distal recurrence diagnostic method in these cases. and was treated with repeat resection. The most common chemotherapy regimen in the 6 patients Pathology receiving adjuvant chemotherapy was CHOP. Two Microscopic evaluation can show a noncohesive pro- patients had distant spread within weeks and re- liferation of large cells twice the size of small lym- ceived salvage chemotherapy, and 2 patients were phocytes that may have focal spindling.24 The eosin- alive and disease free at a median follow-up of ophilic cytoplasm can contain vacuoles. Nuclei are 16 months.64 From this series we can conclude that pleomorphic and can be eccentric and have 1 or more the mainstay of treatment in patients with HS re-

A B C

D E

Fig 3. — Indeterminate dendritic cell sarcoma presenting as a rapidly growing scalp nodule. (A) Low power view showing a deep tumor nodule extending to the subcutis. (B) High power view shows the dermal histiocytic infiltrate with spindly to dendritic to polygonal histiocytic cells with oval nuclei, abundant pink cytoplasm with distinct cell borders, and grooved nuclei. (C) These cells are diffusely positive for CD1a. (D) High power oil magnification view of CD68 histiocytic marker highlights the grooved or clefted nuclear folds. (E) These are typically S100 positive, similar to Langerhans cells, but are also character- istically negative for factor XIIIa, a dermal dendrocyte marker. Birbeck granules are not present on electron microscopy.

296 Cancer Control October 2014, Vol. 21, No. 4 A mains surgical resection. Adjuvant radiation thera- py may help reduce local recurrence rates, but the role of adjuvant chemotherapy remains unclear and should only be used in cases of disseminated dis- ease in which surgical resection is not possible. The optimal chemotherapy regimen remains unclear, and patients should be referred for clinical trials or treat- ment at tertiary care centers.

Fibroblastic Reticular Cell Tumor Tumor Biology FRCT is a rare neoplasm of fibroblastic reticular cells. Fibroblastic reticular cells are stromal support cells located in the parafollicular areas and the deep cortex of lymph nodes where they are associated B CD68 with the nodal reticular network.68,69 These cells are also thought to be crucial to the interaction between IDCs and T cells in the primary immune response.68 The entity previously reported as cytokeratin-pos- itive interstitial reticulum cell tumor is likely the same as FRCT, and both entities usually present together in a series.1,10 In general, FRCT presents in the lymph nodes but can occur in the spleen, lung, liver, and soft tissue.10,70 Although smoking, drug abuse, and viral illnesses have been reported with FRCT, these associations are controversial.10,70 FRCT is differentiated from IDCS and FDCS based on immunohistochemistry. FRCTs are immunoreactive CD163 with vimentin, smooth-muscle actin, factor XIIIa, and desmin, but they are negative for CD21, CD35, and CD1a. The differential diagnosis for FRCT is presented in Table 1.

Clinical Features Clinical information about FRCT generally comes from a pooled analysis of 19 cases.10 In this analysis, Say- gin et al10 reported the median age of patients to be 61 years with a male predominance. Sixteen of the 19 patients presented with nodal disease, with the cervical and mediastinal lymph nodes being the most commonly involved. Extranodal sites included the liv- S100 er, spleen, lung, kidney, adrenal, bone, and soft tissue. Univariate analysis of the prognostic variable did not show a statistically significant prognostic marker in patients with FRCT but did show that patients with higher-stage disease have a significantly shorter sur- vival rate than their counterparts. Patients with local disease had a 2-year survival rate of 85.7%; median survival was not reached.10 Patients with distant dis- ease died in 2 years and had a median survival rate of 13 months.10 Most patients present with a newly diagnosed asymptomatic mass that is surgically excised.10,70 The value of CT scans, bone marrow biopsy, and other Fig 4. — Histiocytic sarcoma. (A) Diffuse infiltrate by large atypical neo- plastic cells with pleomorphic nuclei and moderate to abundant cytoplasm. staging work in single nodal disease is unknown and (B) Neoplastic cells positive for CD68 and CD163 and negative for S100. should be considered in patients with multiple en-

October 2014, Vol. 21, No. 4 Cancer Control 297 larged lymph nodes. Excisional biopsy is the preferred These disorders have been associated with type 1 diagnostic method for FRCT. neurofibromatosis and juvenile myelomonocytic leu- kemia.1,72 Patients with both LCH and JXG have also Pathology been reported, suggesting a clonal relationship of Morphologically, FBRC presents as spindle to ovoid these disorders.1 The differential diagnosis for DJX is cells with whorls in the paracortical areas associated presented in Table 1. with abundant reticulin staining fibers. Immunohis- tochemistry is positive for vimentin, desmin factor Clinical Features XIIIa, and smooth muscle actin. CD45RB, CD21, DJX usually occurs by 10 years of age, with one-half CD35, S100, CD65, and CD1a are negative.1,68 Ul- of reported cases occurring in the first year of life.72 trastructural evaluation reveals peripherally located Skin and soft-tissue presentations are the most com- fusiform densities, long cytoplasmic extensions, and mon sites of involvement and can include the muco- desmosomal-like intercellular attachments. sal surfaces of the upper airway. These lesions are commonly solitary, papular, and small, and multiple Treatment lesions can be present. Although rare, the central Surgery is the treatment of choice for patients with nervous system, eyes, liver, lungs, lymph nodes, and localized disease. Limited data exist on the role of bone marrow can all be involved.72 Lesions of the adjuvant radiation therapy, and chemotherapy has no central nervous system can cause diabetes insipidus, role in localized disease.10,70 Not enough data exist seizures, hydrocephalus, and changes in mental sta- to offer treatment recommendations for distal FRCT. tus.72 The workup in patients with suspected DJX Patients should be encouraged to participate in clin- should include excisional biopsy of the lesion with ical trials, referred to tertiary care centers for treat- an immunopathological review. The role of staging ment recommendations, or both. CT scans and bone marrow biopsy remains unclear.

Disseminated Juvenile Xanthogranuloma Pathology Tumor Biology Morphologically, the JXG cell is small and oval with DJX is a proliferation of histiocytes similar to that a bland, round to oval nucleus and pink cytoplasm seen in dermal juvenile xanthogranuloma (JXG). (Fig 5A). Touton cells are seen at dermal sites but are Solitary dermal JXG is common and does not progress less common in nondermal sites. The cells become to more disseminated forms. Skin lesions normally xanthomatous and inflammatory components can regress, but lesions have been reported in the brain, be seen.1 Immunohistochemistry reveals cells that soft tissue, or, rarely, with disseminated disease.71,72 express vimentin, lysozyme, CD14, CD68, CD163,

A B C

D E

Fig 5. — Disseminated juvenile xanthogranuloma presenting as a recently growing yellowish nodule in the lower leg associated with a spinal compressive mass. (A) Dermal histiocytic infiltrate by xanthomatous and spindle to scalloped histiocytic cells with oval to elongated nuclei and abundant foamy cytoplasm with an indistinct cell border. (B) These cells are diffusely positive for factor XIIIa and (C) CD68 in a coarse granular pattern as well as (D) lysozyme. (E) These cells are typically negative for S100 with focal variable staining (usually < 10%) and characteristically negative for CD1a. Vascular and myofibro- blastic markers for dermatofibrosarcoma, such as CD34, are negative. Note the inflammatory component of eosinophils, lymphocytes, and few plasma cells. Touton giant cells are usually transient and not present in all cases.

298 Cancer Control October 2014, Vol. 21, No. 4 stabilin-1, and factor XIIIa (Fig 5B–D). CD1a is nega- and accessory activity in initiation of memory IgG responses in vitro. J Immunol. 1996;157(8):3404-3411. tive and S100 is usually negative but can be variably 8. Chan JK, Fletcher CD, Nayler SJ, et al. Follicular dendritic cell sarcoma. weak and focally positive in some cases (Fig 5E; Clinicopathologic analysis of 17 cases suggesting a malignant potential higher 1,72 than currently recognized. Cancer. 1997;79(2):294-313. see Table 2). Despite this multifocal presentation, 9. Lee IJ, Kim SC, Kim HS, et al. Paraneoplastic pemphigus associated which simulates lymphoma in some cases, immuno- with follicular dendritic cell sarcoma arising from Castleman’s tumor. J Am Acad Dermatol. 1999;40(2 pt 2):294-297. globulin and T-cell receptor genes are present in a 10. Saygin C, Uzunaslan D, Ozguroglu M, et al. Dendritic cell sarcoma: a germline configuration.73 pooled analysis including 462 cases with presentation of our case series. Crit Rev Oncol Hematol. 2013;88(2):253-271. 11. Meijs M, Mekkes J, van Noesel C, et al. Paraneoplastic pemphigus Treatment associated with follicular dendritic cell sarcoma without Castleman’s disease: treatment with rituximab. Int J Dermatol. 2008;47(6):632-634. In patients with cutaneous, subcutaneous, and soft-tis- 12. Wang J, Bu DF, Li T, et al. Autoantibody production from a thymoma and sue JXG, no treatment is indicated because many of a follicular dendritic cell sarcoma associated with paraneoplastic pemphigus. the lesions may spontaneously regress. Patients with Br J Dermatol. 2005;153(3):558-564. 13. Chan JK, Tsang WY, Ng CS. Follicular dendritic cell tumor and vascular symptomatic DJX or central nervous system involve- neoplasm complicating hyaline-vascular Castleman’s disease. Am J Surg ment require referral to a tertiary care center and Pathol. 1994;18(5):517-525. 14. Pauwels P, Dal Cin P, Vlasveld LT, et al. A chromosomal abnormality chemotherapy. Variable responses have been seen in hyaline vascular Castleman’s disease: evidence for clonal proliferation of with LCH-based treatments with agents such as vin- dysplastic stromal cells. Am J Surg Pathol. 2000;24(6):882-888. 15. Cokelaere K, Debiec-Rychter M, De Wolf-Peeters C, et al. Hyaline blastine, prednisone, and methotrexate; when possi- vascular Castleman’s disease with HMGIC rearrangement in follicular dendritic ble, the patient should be encouraged to participate cells: molecular evidence of mesenchymal tumorigenesis. Am J Surg Pathol. 2002;26(5):662-669. 71,73-75 in a clinical trial. 16. Sun X, Chang KC, Abruzzo LV, et al. Epidermal growth factor receptor expression in follicular dendritic cells: a shared feature of follicular dendritic cell sarcoma and Castleman’s disease. Hum Pathol. 2003;34(9):835-840. Conclusions 17. Arber DA, Weiss LM, Chang KL. Detection of Epstein-Barr virus in Dendritic and histiocytic neoplasms are rare neo- inflammatory pseudotumor. Semin Diagn Pathol. 1998;15(2):155-160. 18. Cheuk W, Chan JK, Shek TW, et al. Inflammatory pseudotumor-like plasms that represent less than 1% of all the neo- follicular dendritic cell tumor: a distinctive low-grade malignant intra-abdominal plasms seen in the lymph nodes or soft tissues. An neoplasm with consistent Epstein-Barr virus association. Am J Surg Pathol. 2001;25(6):721-731. accurate diagnosis, with the help of an experienced 19. Lewis JT, Gaffney RL, Casey MB, et al. Inflammatory pseudotumor of hematopathologist, a morphology review, and immu- the spleen associated with a clonal Epstein-Barr virus genome. Case report and review of the literature. Am J Clin Pathol. 2003;120(1):56-61. nohistochemistry studies, will help differentiate these 20. Lindhout E, Lakeman A, Mevissen ML, et al. Functionally active Ep- disorders from other malignancies. When possible, stein-Barr virus-transformed follicular dendritic cell-like cell lines. J Exp Med. 1994;179(4):1173-1184. patients should be referred to a tertiary care center for 21. Grogg KL, Macon WR, Kurtin PJ, et al. A survey of clusterin and fas- diagnosis and treatment. The mainstay of treatment of cin expression in sarcomas and spindle cell neoplasms: strong clusterin im- munostaining is highly specific for follicular dendritic cell tumor. Mod Pathol. localized disease continues to be surgery. The role of 2005;18(2):260-266. adjuvant therapies remains controversial and must be 22. Hashimoto K, Pritzker MS. Electron microscopic study of reticulohis- tiocytoma. An unusual case of congenital, self-healing reticulohistiocytosis. studied in larger pooled analyses or in the context of Arch Dermatol. 1973;107(2):263-270. a clinical trial. In patients with disseminated disease, 23. Nguyen TT, Schwartz EJ, West RB, et al. Expression of CD163 (he- moglobin scavenger receptor) in normal tissues, lymphomas, carcinomas, the mainstay of treatment remains chemotherapy, al- and sarcomas is largely restricted to the monocyte/macrophage lineage. Am though participation in a clinical trial is preferred. The J Surg Pathol. 2005;29(5):617-624. 24. Pileri SA, Grogan TM, Harris NL, et al. Tumours of histiocytes and role of bone marrow transplantation remains unclear accessory dendritic cells: an immunohistochemical approach to classification in this group of disorders. Collaborative efforts are from the International Lymphoma Study Group based on 61 cases. Histopa- thology. 2002;41(1):1-29. needed to better understand tumor biology, clinical 25. Shia J, Chen W, Tang LH, et al. Extranodal follicular dendritic cell sarco- features, associations with other malignancies, and ma: clinical, pathologic, and histogenetic characteristics of an underrecognized disease entity. Virchows Arch. 2006;449(2):148-158. treatments in these rare diseases. 26. Perkins SM, Shinohara ET. Interdigitating and follicular dendritic cell sarcomas: a SEER analysis. Am J Clin Oncol. 2013;36(4):395-398. 27. Mohanty SK, Dey P, Vashishta RK, et al. Cytologic diagnosis of follicular References dendritic cell tumor: a diagnostic dilemma. Diagn Cytopathol. 2003;29(6): 1. World Heath Organization. WHO Classification of Tumours of Hae- 368-369. matopoietic and Lymphoid Tissues. Lyon, France: International Agency for 28. Ylagan LR, Bartlett NL, Kraus M. Interdigitating dendritic reticulum cell Research on Cancer; 2008. tumor of lymph nodes: case report with differential diagnostic considerations. 2. Shao H, Xi L, Raffeld M, et al. Clonally related histiocytic/dendritic cell Diagn Cytopathol. 2003;28(5):278-281. sarcoma and chronic lymphocytic leukemia/small lymphocytic lymphoma: a 29. Grogg KL, Lae ME, Kurtin PJ, et al. Clusterin expression distinguishes study of seven cases. Mod Pathol. 2011;24(11):1421-1432. follicular dendritic cell tumors from other dendritic cell neoplasms: report of a 3. Feldman AL, Arber DA, Pittaluga S, et al. Clonally related follicular novel follicular dendritic cell marker and clinicopathologic data on 12 additional lymphomas and histiocytic/dendritic cell sarcomas: evidence for transdiffer- follicular dendritic cell tumors and 6 additional interdigitating dendritic cell entiation of the follicular lymphoma clone. Blood. 2008;111(12):5433-5439. tumors. Am J Surg Pathol. 2004;28(8):988-998. 4. Fraser CR, Wang W, Gomez M, et al. Transformation of chronic lym- 30. Chan J, Chan J. Proliferative lesions of follicular dendritic cells: an phocytic leukemia/small lymphocytic lymphoma to interdigitating dendritic cell overview, including a detailed account of follicular dendritic cell sarcoma, a sarcoma: evidence for transdifferentiation of the lymphoma clone. Am J Clin neoplasm with many faces and uncommon etiologic associations. Adv Anat Pathol. 2009;132(6):928-939. Pathol. 1997;4:387-411. 5. Fonseca R, Yamakawa M, Nakamura S, et al. Follicular dendritic cell 31. Sander B, Middel P, Gunawan B, et al. Follicular dendritic cell sarcoma sarcoma and interdigitating reticulum cell sarcoma: a review. Am J Hematol. of the spleen. Hum Pathol. 2007;38(4):668-672. 1998;59(2):161-167. 32. Soriano AO, Thompson MA, Admirand JH, et al. Follicular dendritic cell 6. Tew JG, Kosco MH, Burton GF, et al. Follicular dendritic cells as ac- sarcoma: a report of 14 cases and a review of the literature. Am J Hematol. cessory cells. Immunol Rev. 1990;117:185-211. 2007;82(8):725-728. 7. Wu J, Qin D, Burton GF, et al. Follicular dendritic cell-derived antigen 33. Li L, Shi YH, Guo ZJ, et al. Clinicopathological features and prognosis

October 2014, Vol. 21, No. 4 Cancer Control 299 assessment of extranodal follicular dendritic cell sarcoma. World J Gastroen- sociation with later occurrence of acute myeloblastic leukaemia. Br J Dermatol. terol. 2010;16(20):2504-2519. 2007;156(6):1357-1361. 34. Steinman RM, Pack M, Inaba K. Dendritic cells in the T-cell areas of 63. deMent SH. Association between mediastinal germ cell tumors and lymphoid organs. Immunol Rev. 1997;156:25-37. hematologic malignancies: an update. Hum Pathol. 1990;21(7):699-703. 35. Maeda K, Takahashi T, Saitoh C, et al. Interdigitating cell sarcoma: 64. Hornick JL, Jaffe ES, Fletcher CD. Extranodal histiocytic sarcoma: a report of an autopsy case and literature review. J Clin Exp Hematopathol. clinicopathologic analysis of 14 cases of a rare epithelioid malignancy. Am J 2005;45:37-44. Surg Pathol. 2004;28(9):1133-1144. 36. Imai Y, Yamakawa M, Kasajima T. The lymphocyte-dendritic cell system. 65. Zeng W, Meck J, Cheson BD, et al. Histiocytic sarcoma transdiffer- Histol Histopathol. 1998;13(2):469-510. entiated from follicular lymphoma presenting as a cutaneous tumor. J Cutan 37. Steinman RM. Some interfaces of dendritic cell biology. APMIS. Pathol. 2011;38(12):999-1003. 2003;111(7-8):675-697. 66. Vos JA, Abbondanzo SL, Barekman CL, et al. Histiocytic sarcoma: 38. Chung NP, Chen Y, Chan VS, et al. Dendritic cells: sentinels against a study of five cases including the histiocyte marker CD163. Mod Pathol. pathogens. Histol Histopathol. 2004;19(1):317-324. 2005;18(5):693-704. 39. Wu L, Liu YJ. Development of dendritic-cell lineages. Immunity. 67. Gianotti F, Caputo R. Histiocytic syndromes: a review. J Am Acad Der- 2007;26(6):741-750. matol. 1985;13(3):383-404. 40. Wood GS, Turner RR, Shiurba RA, et al. Human dendritic cells and 68. Andriko JW, Kaldjian EP, Tsokos M, et al. Reticulum cell neoplasms macrophages. In situ immunophenotypic definition of subsets that exhibit of lymph nodes: a clinicopathologic study of 11 cases with recognition of specific morphologic and microenvironmental characteristics. Am J Pathol. a new subtype derived from fibroblastic reticular cells. Am J Surg Pathol. 1985;119(1):73-82. 1998;22(9):1048-1058. 41. Rosenzweig M, Canque B, Gluckman J. Human dendritic cell differentiation 69. Gloghini A, Carbone A. The nonlymphoid microenvironment of reactive pathway from CD34+ hematopoietic percursor cells. Blood. 1996;87:535-544. follicles and lymphomas of follicular origin as defined by immunohistology on 42. Gordon MK, Kraus M, van Besien K. Interdigitating dendritic cell tumors paraffin-embedded tissues. Hum Pathol. 1993;24(1):67-76. in two patients exposed to topical calcineurin inhibitors. Leuk Lymphoma. 70. Martel M, Sarli D, Colecchia M, et al. Fibroblastic reticular cell tu- 2007;48(4):816-818. mor of the spleen: report of a case and review of the entity. Hum Pathol. 43. Wu Q, Liu C, Lei L, et al. Interdigitating dendritic cell sarcoma involv- 2003;34(9):954-957. ing bone marrow in a liver transplant recipient. Transplant Proc. 2010;42(5): 71. Asarch A, Thiele JJ, Ashby-Richardson H, et al. Cutaneous dissemi- 1963-1966. nated xanthogranuloma in an adult: case report and review of the literature. 44. Romeo S, Bovee JV, Kroon HM, et al. Malignant fibrous histiocytoma Cutis. 2009;83(5):243-249. and fibrosarcoma of bone: a re-assessment in the light of currently employed 72. Janssen D, Harms D. Juvenile xanthogranuloma in childhood and ad- morphological, immunohistochemical and molecular approaches. Virchows olescence: a clinicopathologic study of 129 patients from the kiel pediatric Arch. 2012;461(5):561-570. tumor registry. Am J Surg Pathol. 2005;29(1):21-28. 45. Gaertner EM, Tsokos M, Derringer GA, et al. Interdigitating dendritic 73. Maly E, Przyborska M, Rybczynska A, et al. Juvenile xanthogranu- cell sarcoma. A report of four cases and review of the literature. Am J Clin loma with clonal proliferation in the bone marrow. J Pediatr Hematol Oncol. Pathol. 2001;115(4):589-597. 2012;34(3):222-225. 46. Jiang YZ, Dong NZ, Wu DP, et al. Interdigitating dendritic cell sarcoma 74. Meshkini A, Shahzadi S, Zali A, et al. Systemic juvenile xanthogran- presenting simultaneously with acute myelomonocytic leukemia: report of a uloma with multiple central nervous system lesions. J Cancer Res Ther. rare case and literature review. Int J Hematol. 2013;97(5):657-666. 2012;8(2):311-313. 47. Lee JC, Christensen T, O’Hara CJ. Metastatic interdigitating dendritic 75. Patel P, Vyas R, Blickman J, et al. Multi-modality imaging findings of cell sarcoma masquerading as a skin primary tumor: a case report and review disseminated juvenile xanthogranuloma with renal involvement in an infant. of the literature. Am J Dermatopathol. 2009;31(1):88-93. Pediatr Radiol. 2010;40(suppl 1):S6-10. 48. Weiss LM, Berry GJ, Dorfman RF, et al. Spindle cell neoplasms of lymph nodes of probable reticulum cell lineage. True reticulum cell sarcoma? Am J Surg Pathol. 1990;14(5):405-414. 49. Chu A, Eisinger M, Lee JS, et al. Immunoelectron microscopic identi- fication of Langerhans cells using a new antigenic marker. J Invest Dermatol. 1982;78(2):177-180. 50. Romani N, Lenz A, Glassel H, et al. Cultured human Langerhans cells resemble lymphoid dendritic cells in phenotype and function. J Invest Dermatol. 1989;93(5):600-609. 51. Teunissen MB, Wormmeester J, Krieg SR, et al. Human epidermal Langerhans cells undergo profound morphologic and phenotypical changes during in vitro culture. J Invest Dermatol. 1990;94(2):166-173. 52. Weiss T, Weber L, Scharffetter-Kochanek K, et al. Solitary cutaneous dendritic cell tumor in a child: role of dendritic cell markers for the diagnosis of skin Langerhans cell histiocytosis. J Am Acad Dermatol. 2005;53(5):838-844. 53. Ratzinger G, Burgdorf WH, Metze D, et al. Indeterminate cell histiocy- tosis: fact or fiction? J Cutan Pathol. 2005;32(8):552-560. 54. Hashimoto K, Fujiwara K, Punwaney J, et al. Post-scabetic nod- ules: a lymphohistiocytic reaction rich in indeterminate cells. J Dermatol. 2000;27(3):181-194. 55. Wollenberg A, Burgdorf WH, Schaller M, et al. Long-lasting “Christmas tree rash” in an adolescent: isotopic response of indeterminate cell histiocytosis in pityriasis rosea? Acta Derm Venereol. 2002;82(4):288-291. 56. Vasef MA, Zaatari GS, Chan WC, et al. Dendritic cell tumors associated with low-grade B-cell malignancies. Report of three cases. Am J Clin Pathol. 1995;104(6):696-701. 57. Segal GH, Mesa MV, Fishleder AJ, et al. Precursor Langerhans cell histiocytosis. An unusual histiocytic proliferation in a patient with persistent non-Hodgkin lymphoma and terminal acute monocytic leukemia. Cancer. 1992;70(2):547-553. 58. Ferran M, Toll A, Gilaberte M, et al. Acquired mucosal indeterminate cell histiocytoma. Pediatr Dermatol. 2007;24(3):253-256. 59. Rosenberg AS, Morgan MB. Cutaneous indeterminate cell histiocytosis: a new spindle cell variant resembling dendritic cell sarcoma. J Cutan Pathol. 2001;28(10):531-537. 60. Sidoroff A, Zelger B, Steiner H, et al. Indeterminate cell histiocytosis--a clinicopathological entity with features of both X- and non-X histiocytosis. Br J Dermatol. 1996;134(3):525-532. 61. Favara BE, Feller AC, Pauli M, et al. Contemporary classification of histiocytic disorders. The WHO Committee On Histiocytic/Reticulum Cell Prolif- erations. Reclassification Working Group of the Histiocyte Society. Med Pediatr Oncol. 1997;29(3):157-166. 62. Vener C, Soligo D, Berti E, et al. Indeterminate cell histiocytosis in as-

300 Cancer Control October 2014, Vol. 21, No. 4 Secondary hemophagocytic lymphohistiocytosis

has a high mortality rate among adults despite

recent advances in treatment.

Snail on Moss. Photograph courtesy of Sherri Damlo. www.damloedits.com.

Hereditary and Acquired Hemophagocytic Lymphohistiocytosis Ling Zhang, MD, Jun Zhou, MD, and Lubomir Sokol, MD, PhD

Background: Hemophagocytic lymphohistiocytosis (HLH) is a rare but life-threatening hyperinflammatory/ hypercytokinemia syndrome clinicopathologically manifested by fever, hepatosplenomegaly, cytopenias, liver dysfunction, and hemophagocytosis. Methods: We searched the medical literature for English-written articles and analyzed data regarding the diagnosis, pathoetiology, prognosis, and management of HLH. Results: HLH can be subcategorized into primary/genetic (PHLH) or secondary/acquired (SHLH) according to etiology. PHLH, including familial HLH and inherited immune deficiency syndromes, typically occurs in children harboring underlying genetic defects, whereas SHLH frequently manifests in adults and is associated with infection, autoimmunity, immune suppression, or malignancy. The pathogenesis of HLH is still elusive. Its known mechanisms include somatic mutations in gene coding for proteins implicated in the cytotoxic pathways of cytotoxic T or natural killer cells. The impaired ability of these cells to kill target cells leads to an uncontrolled hypercytokinemia and hyperinflammatory process, triggering hemophagocytosis and multiorgan failure. Corticosteroids, chemotherapy, and immunotherapy are the mainstay therapeutic strategies. The consolidation with allogeneic hematopoietic stem cell transplantation is a potentially curative option for PHLH and refractory or relapsed SHLH. Conclusions: Understanding of the pathophysiology of HLH has improved in the last decade. The establishment of diagnostic and treatment guidelines for PHLH and SHLH has resulted in earlier diagnoses and the rapid initiation of therapy, both of which are associated with favorable outcomes.

Introduction Hemophagocytic lymphohistiocytosis (HLH) is clinical syndrome characterized by a hyperinflammatory con- dition caused by increased levels of circulating inflam- From the Departments of Hematopathology and Laboratory Medi- matory cytokines due to a highly stimulated but inef- cine (LZ, JZ) and Malignant Hematology (LS) at the H. Lee Moffitt Cancer Center & Research Institute, Tampa, Florida. fective immune process, and it is uniformly manifested Submitted January 15, 2014; accepted June 2, 2014. by an abnormal proliferation of histiocytes throughout Address correspondence to Ling Zhang, MD, Department of the reticuloendothelial system with the engulfment of Hematopathology and Laboratory Medicine, Moffitt Cancer Cen- hematopoietic cells (hemophagocytosis).1-3 The first ter, 12902 Magnolia Drive, MCC-LAB, Tampa, FL 33612. E-mail: case of HLH was described by Scott and Robb-Smith4 [email protected] in 1939 as histiocytic medullary reticulosis in light of No significant relationships exist between the authors and the com- panies/organizations whose products or services may be referenced poorly controlled histiocytic proliferation; later, the in this article. term was changed to HLH and macrophage activation

October 2014, Vol. 21, No. 4 Cancer Control 301 syndrome.5 Familial HLH (FHLH) was first described infection, autoimmunity, immune suppression, and in 1952 as an autosomal recessive immune dysregu- malignancies (Table).1,7-10 Clinically, it is most often lation disorder of childhood.6 characterized by prolonged and persistent fevers, HLH can be subcategorized as primary/genetic hepatomegaly, splenomegaly, hemophagocytosis, bi- (PHLH) or secondary/reactive (SHLH) forms. PHLH lineage or trilineage cytopenias, hypertriglyceridemia, includes both FHLH and inherited immune defi- and/or hypofibrinogenemia. Neurological symptoms ciency syndromes, whereas SHLH is associated with and multiorgan failures may be predominant in the be- ginning of the disease, or they Table. — Classification of Hemophagocytic Syndrome may develop during the clinical course.7,11 Our understanding Primary or Genetic Hemophagocytic Syndrome of the pathophysiology of HLH, Familial Hemophagocytic Lymphohistiocytosis Immune Deficiency Syndrome particularly PHLH, has signifi- Type 1 HPLH1, 9q21.3-q22 Chédiak–Higashi syndrome (LYST) (1q42.1 – q42.2) cantly improved in the last Type 2 PRF1, 10q21-22 Griscelli syndrome (15q21) 10 years. Germline mutations Type 3 Munc13-4, 17q25 X-linked lymphoproliferative syndrome in gene coding for proteins im- Type 4 STX11, 6q24.1 Type 1: SH2D1A (SAP) (Xq25) plicated in cytotoxic pathways Type 5 STXBP2, 19p13.3-13.2 Type 2: BIRC4 (XIAP) (Xq25) Wiskott–Aldrich syndrome (WAS, Xp11.4-p11.21) have been described in patients Severe combined immunodeficiency (IL2RG, Xq13.1) with FHLH, hereditary immune Lysinuric protein intolerance (SLC7A7, 14 (14q11.2) deficiency syndromes, vari- Hermansky–Pudlak syndrome (HPS6, 10q24.32) ous viral infections, including Secondary or Reactive Hemophagocytic Syndrome Epstein–Barr virus (EBV), malig- nancies, and immunosuppres- Infection-Associated Hemophagocytic Syndrome sion associated with SHLH.12 Virus-associated hemophagocytic syndrome In spite of these advances, Herpesvirus HIV HLH often poses a clinically diagnostic challenge and treat- Other viruses ment dilemma. Adenovirus Mumps This review summarizes Hepatitis (A, B, C) Enterovirus the most important clinical, Parvovirus B19 Human T-lymphotropic virus Influenza Flavivirus (dengue fever) pathological, and molecular Measles H1N1 features of HLH and provides current treatment strategies for Other infections associated with hemophagocytic syndrome this rare, and sometimes, fatal Bacterial Parasitic Fungal disease. Staphylococcus aureus Salmonella typhi sp Leishmania sp Candida sp Campylobacter sp Rickettsia sp Plasmodium sp Cryptococcus sp Fusobacterium sp Brucella sp (vivax, falciparum) Pneumocystis sp Epidemiology Mycoplasma sp Ehrlichia sp Toxoplasma sp Histoplasma sp The incident rate of HLH is Chlamydia sp Borrelia burgdorferi Strongyloides sp Aspergillus sp variable, occurring in 1 out of Spirochetes sp Legionella sp Mycobacterium tuberculosis Fusarium sp every 3,000 persons in North 13,14 Malignancy-associated hemophagocytic syndrome America, whereas the an- Hematopoietic malignancies Solid tumors nual incidence of adult and T-cell/NK-cell lymphoma/leukemia Hepatocellular carcinoma pediatric cases of HLH in Peripheral T-cell lymphoma (not otherwise specified) Prostatic carcinoma Japan was 1 per 800,000 per- Anaplastic T-cell lymphoma Lung carcinoma sons.15 Approximately 25% of Acute leukemia Classical Hodgkin lymphoma pediatric cases are PHLH, Non-Hodgkin B-cell lymphoma whereas nearly all adult cases are SHLH; the annual Macrophage activation syndrome (association with autoimmune disease) incidence rate of PHLH is Systemic juvenile idiopathic arthritis 1.2 per 1 million children, Still disease Systemic lupus erythematosus whereas the incidence of Kawasaki disease SHLH among adults is un- Rheumatoid arthritis certain.16,17Approximately 80% of patients with FHLH NK = natural killer. are young children (< 1 year Adapted from Rosado FG, Kim AS. Hemophagocytic lymphohistiocytosis: an update on diagnosis and 16 pathogenesis. AJCP 2013:139:713-727. With permission by the American Society for Clinical Pathology. of age). One report showed that, for approximately every

302 Cancer Control October 2014, Vol. 21, No. 4 2,000 inpatient admissions, there was approximately target cell so that granzymes can enter the cytoplasm 1 diagnosis of HLH.17 HLH can occur in all age groups and induce caspase-dependent and caspase-indepen- without predilection for race or sex.10,16 However, a dent apoptosis.20,21 Thus, any defect of the normal higher incidence has been observed in Turkey, which NK cell cytolytic pathway will impair this function, is most likely due to increased consanguinity and a resulting in the disruption of immune surveillance higher prevalence of genetic defects in the cytotoxic and host defense systems. pathway.18 Cytotoxic T lymphocytes (CTLs) play a role simi- lar to NK cells. CTLs express T-cell receptors that can Pathoetiology recognize a specific antigen in the context of class I Natural killer (NK) cells comprise a subset of lym- major histocompatibility complex molecules. When phocytes engaged in immune surveillance and host the immune response is triggered in a healthy indi- defense against cancer and primary or secondary viral vidual, NK cells, CTLs, and histiocytes are activated infections. The steps for killing target cells via NK cells to kill the infected or malignant cells. This process are complex, multistage processes (Fig 1A).19 When is followed by the elimination of the stimulating an- NK cells are activated, they secrete lytic or cytotoxic tigen and termination of the immune response via granules that contain perforin and granzymes at the a feedback loop. All activated cells involved in this immunological synapse to eliminate abnormal cells. process interact with each other via normal receptors As soon as these granules are delivered to a target and secrete proinflammatory cytokines and chemo- cell, perforin permeabilizes the cell membranes of the kines (Fig 1).19,22,23

Triggers CTL or NK Cells sIL2R (CD25) IL-2 CD8 Munc14-3 AS3B1 (HPSII) (FHL3) Perforin (FHL2)

+ IFN-γ Granule CD8 activation T cells NK cells Monocytes, Polarization macrophage Docking /dendritic cells RAB27A (GSII) 2 IL -1 Priming -1 IL γ T 2 - N N Fusion F IF -α LYST ? Fever (CHS) Cytopenia Macrophages STX11 Hyperglyceridemia (FHL4) Munc18-2 Low NK cell activity

(FHL5) Neurological signs Tissue infiltrate and symptoms Hemophagocytosis Hepatic cytolysis Multiorgan failure Lymphocytic infiltrate Target Cells Hyperglyceridemia (infected cells, malignant cells)

IL-6 IL-1b IL-8 Renal failure Lymphocyte infiltrate Fever Fever Cytopenia Hepatic cytolysis Neurological disorder Hypofibrinogenemia Disseminated intravascular coagulation A B

Fig 1A–B. — (A) The normal pathway goes through granule activation, polarization, docking, priming, and fusion. Cytotoxic granules are released into a synaptic gap, entering the target cells to kill them. The defects in FHL and immunodeficiency syndrome (GSII, CHS, and HPSII) impair the normal process of the cytotoxic pathway. Empty granules are seen in perforin deficiency. The question mark indicates that the function of LYST, which may be important for the correct size and function of lytic granules, is not entirely understood. (B) Activated CD8 T lymphocytes cause the activation and proliferation of NK cells with increased proinflammatory cytokines. Hypercytokinemia results in a hyperinflammatory reaction, which then leads to constitutional symptoms and sys- temic illness due to lymphocytic and histocytic infiltrate. TNF-a and IFN-g production contribute to macrophage activation with resulting hemophagocytosis. CHS = Chédiak–Higashi syndrome, CTL = CD8+ cytotoxic T lymphocyte, FHL = familial hemophagocytic lymphohistiocytosis, GSII = type 2 Griscelli syndrome, HPSII = type 2 Hermansky–Pudlak syndrome, IFN = interferon, IL = interleukin, NK = natural killer, TNF = tumor necrosis factor. Panel A is adapted from Fig 1 in Bode SF, Lehmberg K, Maul-Pavicic A, et al. Recent advances in the diagnosis and treatment of hemophagocytic lymphohis- tiocytosis. Arthritis Res Ther. 2012;14(3):213. © 2012 BioMed Central Ltd. Panel B is adapted from Fig 2 in Créput C, Galicier L, Buyse S, et al. Understanding organ dysfunction in hemophagocytic lymphohistiocytosis. Intensive Care Med. 2008;34(7):1177-1187. With kind permission from the originating authors and Springer Science and Business Media.

October 2014, Vol. 21, No. 4 Cancer Control 303 Although the precise pathogenesis of HLH is elu- protein is required for cytolytic granule fusion with sive, a strong link exists between the hyperinflamma- cytoplasmic membrane components to process de- tory response and hemophagocytosis coupled with granulation or exocytosis.37 UNC13D mutation results impaired CTL, NK activity (inherited or acquired), or in defective degranulation. both.21,24-27 The normal function of histiocytes in the Type 4. A total of 10% to 20% of FHLH cases have innate immune reaction includes the presentation of mutated STX11,36 which belongs to a member of the antigen, phagocytosis, and the activation of the adap- soluble N-ethylmaleimide-sensitive factor attachment tive immune system through contact with infected or protein receptor (t-SNARE) family. STX11 binds to targeted cells and cytokine release.21 Antigen-present- SNAP23 in NK cells. Similar to UNC13D, it is involved ing cells (eg, macrophages, histiocytes) are activated in accelerating the fusion in intracellular membrane in HLH. The proinflammatory cytokines (ie, tumor trafficking processes.38 Mutations in STX11 result in necrosis factor [TNF] α], interferon [IFN] γ], interleukin decreased or absent STX11 protein, leading to defects [IL] 1b, IL-6, IL-8, IL-10, IL-12, IL-18, and soluble IL-2 in the endocytotic and exocytotic pathway.34 receptor) are produced by the uncontrolled prolif- Type 5. Mutated STXBP2, also called Munc18-2, eration of histiocytes and T cells. The expansion of has been identified in type 5 FHLH.39 The encoded antigen-specific CTLs that produce a high level of cy- protein plays a critical role in intracellular trafficking, tokines further activates macrophages.21,28,29 The result the control of the SNARE complex assembly, and the of HLH at the tissue and cellular level is tissue necrosis release of cytotoxic granules by NK cells.40 Study find- and hemophagocytosis, leading to multiorgan failure. ings indicate that the STXBP2 mutation could result Hemophagocytosis, which is a hallmark of activated in impaired granule mobilization of granules and loss macrophages, is mediated via the CD163 heme-scav- of the ability to kill bacteria.41 enging receptor.21,28 A brief schematic pathway of the pathophysiology of HLH is illustrated in Fig 1B.22,23 Hereditary Immunodeficiencies Type 2 Griscelli syndrome, Chédiak–Higashi syn- Primary Hemophagocytic Lymphohistiocytosis drome, and type 2 Hermansky–Pudlak syndrome are Familial Hemophagocytic Lymphohistiocytosis: all inherited in an autosomal recessive fashion that FHLH is inherited in an autosomal recessive fash- predispose patients to HLH.2,42 Common clinical and ion and has 5 subtypes. Most patients with FHLH laboratory features for these diseases include oculo- present at younger than 1 year of age.16,30 FHLH has cutaneous albinism, increased susceptibility to infec- also been reported in adolescent and adult patients tions, and defects in CTL and NK cell activity resulting without a familial history.31 In addition to type 1 in immunodeficiencies. FHLH, other subtypes show defects in the perforin/ Type 2 Griscelli syndrome caused by the RAB27A cytotoxic pathway (see Table).9,10,32 The 5 hypomor- mutation is characterized by hypomelanosis with phic FHL mutations might correlate with late-onset immunological abnormalities (defective CTL and NK HLH.33,34 According to Zur Stadt et al,34 types 2 to 4 cell cytotoxic activity) with or without neurological FHLH account for 80% of the HLH cases of Turkish impairment.39,43 The RAB27A-encoded protein inter- origin but only 30% of those of German descent. acts with Munc13-4 during the docking of cytotoxic Type 1. The mutation involved in type 1 FHLH granules to the cell membrane.44 Chédiak–Higashi is unknown. syndrome is associated with granulated cells and en- Type 2. Approximately 20% to 40% of FHLH cas- larged lysosomes because of biallelic mutations in es harbor a PRF1 mutation.33,34 The PRF1 gene was LYST, resulting in the ineffective release of cytotoxic reported in 1999 and encodes a soluble pore-forming granules.39,43,44 The AP3B1 mutation leads to type 2 protein, perforin, synthesized and stored in cytotoxic Hermansky–Pudlak syndrome, which is characterized lymphocytes, along with granzyme serine protease.35 by platelet storage disease, prolonged bleeding, con- Perforin acts as an effector for NK cells and CD8+ genital neutropenia, pulmonary fibrosis, granuloma- CTLs. Mutations in PRF2 impair the function of per- tous colitis, and albinism.45 forin to permeabilize the target cell membrane, allow- ing granzymes to enter the cells (see Fig 1A).19,21 The X-Linked Lymphoproliferative Syndromes mutations are common in families of Middle Eastern Types 1 and 2 X-linked lymphoproliferative (XLP) descent.36 When carrying nonsense perforin muta- syndrome are due to the hemizygous mutation of tions, patients with these mutations were reported SH2D1A and the mutation of XIAP, respectively, and to have higher serum levels of ferritin and soluble both are associated with a high risk of developing IL-2 receptor when compared with other subgroups.30 HLH.12,28,34,46 SH2D1A and XIAP are responsible for Type 3. Approximately 10% to 20% of cases of XLP syndrome due to signaling lymphocytic activation FHLH have a UNC13D gene mutation.34 UNC13D en- molecule–associated protein and deficiencies of the codes a protein unc-13 homolog D or Munc13-4. The X-linked inhibitor of apoptosis protein, respectively.

304 Cancer Control October 2014, Vol. 21, No. 4 XLP is characterized by extreme vulnerability to EBV as dermatomyositis, systemic sclerosis, and mixed infection,28 and the signaling lymphocytic activation connective disorder were also observed in patients molecule–associated protein is a key regulator of nor- with HLH.63,64 mal immune function in T cells, NK cells, and B cells. XIAP encodes a 497-amino-acid antiapoptotic mole- Associated Malignancies cule. Although the pathophysiology of HLH in patients Lymphoma is the most common hematological malig- deficient in the X-linked inhibitor of apoptosis protein nancy associated with HLH.65 Among lymphomas, T-cell is not fully understood, it may be due to defects in lymphoproliferative disorders, such as anaplastic large CTLs or the NK cell cytotoxic pathway (see Fig 1A).19 cell lymphoma, subcutaneous panniculitis–like T-cell SH2D1A and XIAP are proximally located on the same lymphoma, and NK cell lymphoma, were the most chromosome and may interact with each other.28 frequently observed.64,66-70 HLH has also been report- ed in patients with classical Hodgkin lymphoma71,72 Secondary Hemophagocytic Lymphohistiocytosis and other B-cell lymphoproliferative disorders.72-84 Causes of SHLH may include viral, fungal, bacterial, Less frequently, myeloid malignancies such as acute or parasitic infections, as well as hematological malig- myeloid leukemia have been reported in association nancies, autoimmune disorders, or immunosuppres- with HLH.73,74 sion, and particularly post–solid organ transplantation (see Table).9,10 Similar to PHLH (see Fig 1),19,22,23 the Clinical Findings acquired defects in CTL or NK cell cytotoxic path- In general, the early signs and symptoms of HLH are ways have been observed, but the exact molecular nonspecific. No specific laboratory tests are available mechanisms resulting in SHLH are unclear.47 It has for diagnosing HLH.75 The most common clinical symp- been speculated that hypercytokinemia may impair toms and laboratory abnormalities include unexplained the normal functions of CTLs, NK cells, or both, and fevers, cytopenia, and hepatosplenomegaly. Neurolog- individual genetic polymorphisms on leukocyte com- ical symptoms such as altered mental status, seizures, mon antigen might increase susceptibility for HLH in and nerve palsies can be observed.75 Cerebrospinal such patients.48,49 fluid cytology can reveal hemophagocytic cells, but the Infections: EBV is a ubiquitous γ-herpesvirus and absence of these cells does not exclude HLH.21,76,77 In is the most common pathogen associated with HLH.50,51 the late phase of HLH, most patients develop multior- It causes a clonal proliferation and the hyperactivation gan failure (frequently accompanied with coagulopa- of EBV-infected T cells in patients with SHLH.8 Of thy) and acute respiratory distress syndrome.21 interest, most cases of EBV infection with concurrent Typical clinical scenarios in which PHLH should HLH have been reported in children and adolescents, be considered in the differential diagnosis include in- with the highest incidence occurring in East Asia.52 fectious mononucleosis in an infant or young child, According to a study of adult patients with HLH, aseptic meningitis associated with cytopenias, or a vi- in addition to EBV infection, histoplasmosis and ral-like syndrome or illness with fever, cytopenias, and cytomegalovirus (CMV) were the other 2 common organomegaly.78 Of note, in cases of systemic juvenile infectious agents, comprising 19% (4 patients) and arthritis, 30% to 40% of such patients had a subclinical 14% (3 patients) of cases, respectively.17 In a large manifestation of the disease, with 10% to 20% of them study of 96 patients with HLH, 30 were associated presenting with overt clinical symptomatology.79,80 with infection.53 The most common types of infection were viral (41%), mycobacterial (23%), bacterial (23%), Laboratory Findings and fungal (13%).53 In addition to EBV, CMV, and Characteristic laboratory findings include elevated histoplasmosis, other viral agents implicated in HLH serum levels of ferritin, fasting hypertriglyceridemia include HIV, human herpesvirus 8, parvovirus B19, (≥ 265 mg/dL), transaminitis, hyperbilirubinemia, and the hepatitis viruses, enterovirus, flavivirus (dengue elevated levels of lactate dehydrogenase, along with fever), and H1N1, among others.8,54-62 Other infectious decreased levels of fibrinogen (< 1.5 g/L).85 Elevated agents associated with SHLH appear in the Table.9,10 blood levels of proinflammatory cytokines, including Autoimmune Processes: HLH may be associ- IL-6, IL-8, IL-10, IL-12, IL-18, macrophage colony-stim- ated with rheumatology or autoimmune diseases.63 ulating factor, IFN-γ, and TNF-α, as well as elevated A comprehensive literature review of patients with plasma levels of soluble IL-2 receptor (CD25), sCD95 associated HLH and rheumatological diseases identi- ligand, and sCD163, have also been reported.1,81-84 The fied 117 papers describing 421 patients, with the most decreased or loss of NK cell activity is another labora- common rheumatological diseases being systemic ju- tory abnormality that supports the diagnosis of HLH.85 venile arthritis (50.2%), systemic lupus erythematosus A laboratory search for infectious agents is nec- (22.3%), Still disease (8.8%), and Kawasaki disease essary in patients with suspected HLH. Serological (5.9%).63 In addition, connective tissue diseases such assays specific for EBV may be nondiagnostic in some

October 2014, Vol. 21, No. 4 Cancer Control 305 patients; however, the presence of a high EBV DNA load in plasma supports the diagnosis of EBV-associ- ated HLH.50,52 Thus, direct molecular virological assays may allow better detection of this potentially underdi- agnosed disease.50,52

Histological Findings Biopsies of bone marrow and other tissues (eg, lymph nodes) are useful for identifying hemophagocytosis. In general, bone marrow typically shows reactive lymphocytosis, slightly to markedly increased his- A tiocytes, and a marked left-shift myeloid maturation regardless of etiology. In the bone marrow aspirate smear, enlarged histiocytes, engulfing red blood cells, granulocytes, lymphocytes, and occasional plasma cells can be seen; in addition, the spleen with red- pulp expansion and increased hemophagocytosis can be seen on autopsy (see Fig 2). Immunohistochemi- cal studies using histiocyte-specific antibody, such as CD68, CD163, and CD14, are useful for highlighting phagocytic cells as well as engulfed, negative-stained hematopoietic cells.

B Diagnostic Criteria The diagnostic criteria for HLH were established in 19915 and then subsequently revised in 199786 and then updated again in 2004.85 These diagnostic criteria have been widely adopted clinically and represent the current guidelines for HLH. A diagnosis of HLH requires either a documented molecular confirmation or the presence of at least 5 of the following 8 clinical or laboratory parameters85: • Fever • Splenomegaly • Cytopenia affecting ≥ 2 lineages in the C peripheral blood: – Hemoglobin < 90 g/L (< 100 g/L for infants < 4 weeks of age) – Platelets < 100 × 109/L – Neutrophils < 1.0 × 109/L • Hypertriglyceridemia and/or hypofibrinogen- emia, fasting triglycerides ≥ 265 mg/dL, fibrin- ogen ≤ 1.5 g/L • Hemophagocytosis found in the biopsy speci- men of bone marrow, spleen, or lymph nodes • Decreased or absent NK cell activity • Ferritin ≥ 500 mg/L D • sCD25 ≥ 2,400 U/mL Fig 2A–D. — (A) Bone marrow core biopsy showing an increased number Bone marrow hemophagocytosis has a high of histiocytes engulfing erythrocytes, granulocytes, or platelets associated sensitivity rate because rare hemophagocytic his- with focal granulomatous change (H & E, × 200). (B) Spleen with abnormal tiocytes can be detected prior to patients exhibiting proliferation of medium- to large-sized atypical histiocytes associated with increased hemophagocytosis (H & E, × 200). (C) Bone marrow core biopsy overt clinical symptoms of HLH; however, the spec- showing enlarged histiocytes with phagocytosis predominantly in dilated ificity of this test is too low to incorporate it into sinusoidal areas. Normal trilineage hematopoiesis is decreased in number the panel of screening tests for diagnosing HLH.87 (H & E, × 1000). (D) Bone marrow aspirate exhibiting enlarged histiocytes, some containing erythrocytes, or various kinds of hematopoietic elements Therefore, the 2004 HLH diagnostic guidelines set (inset; Wright–Giemsa stain, × 1000). H & E = hematoxylin & eosin. forth by Henter et al85 suggest obtaining materials

306 Cancer Control October 2014, Vol. 21, No. 4 from the other organs if the bone marrow specimen macrophages in the reticuloendothelial system.65,85 In is inconclusive. In addition, the presence of any of PHLH, the ultimate goal of treatment is to replace the the following findings may also provide strong sup- mutated gene or defective immune system.85 portive evidence for the diagnosis: (a) spinal fluid pleocytosis (mononuclear cells), elevated spinal fluid General Management protein, or both, and (b) histological results from The HLH protocol is widely accepted as the standard liver biopsy resembling chronic persistent hepatitis.85 therapeutic approach for HLH (Fig 3).85 The main Other abnormal clinical and laboratory findings can difference distinguishing the 2004 protocol from the include cerebromeningeal symptoms, lymph node 1997 protocol is the administration of cyclosporine A enlargement, jaundice, edema, skin rash, hepatic at the onset of therapy instead of at week 9.85,86 Both enzyme abnormalities, hypoproteinemia, hypona- protocols include dexamethasone, etoposide, and cyc- tremia, increased very-low density lipoprotein, and losporine A for 8 weeks in patients with SHLH who do decreased high density lipoprotein.85,88 not have an identifiable genetic defect.85,86 In cases of A search for novel markers for an HLH diagnosis PHLH, therapy is administered for more than 8 weeks has revealed that serum S-SMase/ceramide activity until hematopoietic stem cell transplantation (HSCT) is elevated in cases of HLH; however, these patients is initiated. Intrathecal therapy with methotrexate and eventually died despite appropriate treatment.89 corticosteroids is recommended for patients with cen- Using flow cytometry to diagnose HLH is not spe- tral nervous system manifestations.85 cific. However, qualitative abnormalities of atypical Supportive care with prophylactic antibiotics, cytotoxic T cells have been reported in the majority blood and platelet transfusions, and treatment with of EBV-associated HLH cases.90 According to a large fluids and electrolytes are all important steps in the cohort study of 494 patients with suspected HLH, the treatment of HLH.99 performance of degranulation assays based on surface up regulation of CD107a on NK cells and CTLs may Familial Hemophagocytic provide a diagnostic value in FHLH.91 A resting NK Lymphohistiocytosis cell degranulation level below 5% was associated with Given the high mortality rate of FHLH, the initial steps sensitivity and specificity rates of 96% and 88%, respec- of treatment are to suppress the hyperinflammatory tively, for diagnosing genetic degranulation disorders.91 process and eliminate abnormal T and NK cells, anti- Molecular studies of gene mutations have involved gen-presenting cells, and phagocytes. A response to PRF129, UNC13D (Munc13-4), STX11, and STXBP2 treatment typically takes up to 8 weeks. In a patient (Munc18-2).37,38,92 RAB27A, LYST, and AP3B12 have with low-risk HLH, corticosteroids and/or intravenous been useful in aiding the diagnosis of inherited im- immunoglobulin or cyclosporine A may be sufficient munodeficiency syndromes.42 to control the dysregulated biological processes.51,85 Moreover, etoposide is recommended to reverse lym- Differential Diagnosis phohistiocytic dysregulation in patients at high risk.8,85 HLH can be a diagnostic challenge when distin- HSCT is recommended for patients with FHLH guishing between HLH and the reactive or malig- and genetic defects and is considered the only known nant histiocytic proliferations (eg, infection-related curative approach.47 A matched related donor is pre- histiocytosis).10,93-95 An autoimmune lymphoprolifera- ferred over an unrelated, partially, or umbilical cord tive syndrome might mimic HLH.96 In neonates, HLH blood–matched donor to achieve maximal hemato- might be difficult to differentiate from neonatal he- poietic stem cell engraftment and reduce the risk of mochromatosis when patients present with acute liver severe graft–host and transplant-related mortality.47 failure97 or storage disease with hyperglycerinemia.16 Only a subset of patients (approximately 20%) have A newly proposed and validated scoring system for matched sibling or parental donors.47 The long-term reactive HLH called HScore may be a practical way experience with HSCT in patients with FHLH is limited to exclude non-HLH cases.98 due to the rarity of the disease.100,101 The current use of reduced intensity conditioning protocols for HSCT Treatment decreases chemotherapy-associated toxicity, includ- HLH has an aggressive clinical course with a high ing veno-occlusive disease.100,101 Patients who do not mortality rate in all age groups. Prognosis depends respond to treatment (based on the 2004 protocol85) on early diagnosis and timely treatment.85 The HLH within 4 to 8 weeks may benefit from second-line 2004 protocol is the most commonly used frontline therapy (eg, antithyroglobulin, alemtuzumab).47 treatment regimen, with the immediate goals of extin- guishing the hyperinflammatory and hypercytokine Secondary Hemophagocytic Lymphohistiocytosis status, controlling underlining disorders (eg, infec- Typically, patients with idiopathic SHLH are treated tion, tumor, autoimmune), and eliminating overactive per the 2004 protocol, which includes a 2-week in-

October 2014, Vol. 21, No. 4 Cancer Control 307 duction phase followed by a 6-week tapering phase.85 according to lymphoma subtype. The use of HSCT in overall survival rates of patients who had HLH and In patients with organ dysfunction or failure, immedi- patients during their first remission may be of benefit T-or B-cell lymphoma were 96 days and 330 days, ate treatment should be started to reduce mortality.85 for those with partial remission or refractory HLH. respectively.117 Rituximab might have partially con- Treatment may be also beneficial for patients who Selected patients with recurrent HLH in complete tributed to longer survival rates in patients with B-cell have relapsed SHLH but are without genetic defects.47 remission should be considered for HSCT.85,99,103 lymphoma–associated HLH; by contrast, allogeneic However, the proportion of adult patients with ac- HSCT should be recommended for patients with T-cell Underlying Disease quired HLH who are eligible for HSCT is low due lymphoma–associated HLH.105 Treatment is largely dependent on clinical status.85 to poor performance status, malnutrition, active in- When HLH is triggered by an acute infection or anoth- fections, and complications from lymphoma therapy. Outcome and Prognosis er condition (eg, rheumatoid disease), treatment of the Similar approaches using disease-specific therapy first Despite advances in therapy and supportive care, the trigger is necessary to eliminate the hyperinflammato- should be employed for other malignancies associated cure rate for HLH, particularly in patients with mul- ry stimulus or hyperimmunological activation. Stable with HLH.104 tiorgan failure, is low.19,23 Clinical outcomes for chil- patients who are less acutely ill may be able to tolerate dren with HLH have been previously determined in initial treatment without HLH-specific therapy.102 Infections 2 important clinical trials. Prior to the 1997 protocol,86 Although they are rare, cases of EBV infection asso- patients with FHLH were not likely to survive beyond Malignancies ciated with HLH can occur in apparently EBV-immu- 1 year.76 Moreover, a study conducted in 2002 sug- The treatment of HLH secondary to lymphoma fre- nocompetent individuals, particularly in adults living gested that overall survival rates increased once the quently includes combined chemotherapy regimens in western countries. The high mortality rate among 1997 protocol was put into practice.99 Patients with patients with EBV-associated HLH is usually due to all types of HLH treated per the 1997 protocol had a a delay in diagnosis or ineffective therapy.50 Howev- 3-year overall survival rate of 55%, and a subgroup er, the 2004 protocol has improved survival rates of of patients who underwent HSCT had a 3-year over- HLH patients with HLH (see Fig 3).85,88 Per Kleynberg and all survival rate of 62%.99,118 In a single, institutional, 7 Schiller, studies have emphasized the. importance of retrospective study of pediatric patients, the 3-year etoposide for the treatment of EBV infection associated overall survival rate was 92% in patients treated with with HLH, describing the drug as the most effective allogeneic HSCT after reduced intensity conditioning Initial therapy Disease for infectious single agent against activating histiocytes. Although and 43% in patients who underwent myeloablative controlled disease intravenous immunoglobulin has been recommended allogeneic HSCT.101 A review of antithymocyte glob- for the treatment of reactivated EBV infection, patients ulin–based therapy in 38 patients with FHLH demon- Nonresponder or 119 familial HLHa with EBV-associated B-lymphoproliferative disorders strated a complete response rate of 73%. Sixteen of Severe, persistent, taking rituximab have also been found to have im- the 19 patients (84%) who underwent consolidation or refractory form proved outcomes.105 The efficacy of a rituximab-con- with HSCT were considered to be cured, and overall 119 Initial 8-week chemotherapy taining regimen was investigated in 42 patients with survival for all study participants was 55%. Japa- HLH who received, on average, 3 rituximab infusions nese patients with EBV-associated HLH were shown to (range, 1–10) at a median dose of 375 mg/m2, along have a survival rate of 86%.120 The results of another with steroids, etoposide, and/or cyclosporine.105 The important HLH study have not yet been published therapy was well tolerated and resulted in clinical (NCT00426101). Familial Nonfamilial Non-HLH HLHa HLHb responderb improvements among 43% of patients. A significantly To date, most studies concentrate on the man- reduced EBV viral load was also observed.105 Because agement of PHLH in children. Limited trials study EBV can also infect T and NK cells, recurrence of EBV adult patients with SHLH,17,67,121 and data demonstrate infection can occur in patients despite rituximab ther- inferior median overall survival rates, ranging from Treatment 121 17 discontinued apy; in such patients, alemtuzumab has been shown 35 days to approximately 2 months. Among trials Continue to be beneficial.106 relating to SHLH, patients with HLH due to malignancy chemotherapy If HLH has had the poorest clinical outcome (median overall sur- until HSCT relapsed Salvage Therapy vival, 1–12 months).122-126 Parikh et al127 reported that The removal of cytokines with plasma or transfusion patients with HLH associated with malignant tumors Resume therapy until HSCT exchange in very young infants has been shown to had a much shorter median overall survival rate of stabilize patients until other therapies have enough 1.4 months compared with 22.8 months among pa- time to work.106-108 Other salvage therapies include tients who had HLH without infection, autoimmune Fig 3. — Schematic algorithm for the treatment of children according to high-dose pulse corticosteroids and alemtuzumab, disease, or idiopathic entity. A report of EBV-associ- the HLH 2004 protocol. Refer to the text and Fig 1 for information on whether to start continuation therapy and perform HSCT. Data from Henter which suppresses CD52-expressing T or B cells and ated HLH outcomes among children revealed a 90% JI, Horne A, Aricó M, et al. HLH-2004: Diagnostic and therapeutic guide- histiocytes.106-108 CMV and adenovirus viremia were overall response rate to multiagent therapy, includ- lines for hemophagocytic lymphohistiocytosis. Pediatr Blood Cancer. common complications of this therapy. Monitoring ing corticosteroids, etoposide, and cyclosporin,128 2007;48(2):124-131. CMV DNA viral load by weekly polymerase chain re- whereas many other patients with infection-associ- a b Familial HLH with or without genetic mutation verified. Nonfamilial HLH 106 61 129 and nongenetic mutations identified. action is standard in patients treated with this agent. ated HLH died within days or months. Dhote et al HLH = hemophagocytic lymphohistiocytosis, HSCT = hematopoietic stem Other reported salvage therapies include an anti-TNF reported an overall mortality rate of 38.5% among cell transplantation. antibody, infliximab,109 and the anti-CD25 antibody patients with autoimmune disease–associated HLH.

308 Cancer Control October 2014, Vol. 21, No. 4 daclizumab.110,111 In some patients with macrophage overall survival rates of patients who had HLH and activation syndrome, inhibiting IL-1 and IL-6 was suc- T-or B-cell lymphoma were 96 days and 330 days, cessful.112 respectively.117 Rituximab might have partially con- In recent clinical trials with blinatumomab, tributed to longer survival rates in patients with B-cell drug-induced HLH was observed.113 Therapy with to- lymphoma–associated HLH; by contrast, allogeneic cilizumab resulted in a rapid clinical improvement;113 HSCT should be recommended for patients with T-cell Tocilizumab is a drug that could be potentially effec- lymphoma–associated HLH.105 tive in other types of HLH and is currently undergoing testing in a clinical trial in children and young adults Outcome and Prognosis (NCT02007239). Failure of salvage regimens is an in- Despite advances in therapy and supportive care, the dicator for considering allogeneic HSCT.72,114 cure rate for HLH, particularly in patients with mul- tiorgan failure, is low.19,23 Clinical outcomes for chil- Allogeneic Hematopoietic Stem Cell dren with HLH have been previously determined in Transplantation 2 important clinical trials. Prior to the 1997 protocol,86 Allogeneic bone marrow transplantation from a relat- patients with FHLH were not likely to survive beyond ed, human leukocyte antigen identical donor is the 1 year.76 Moreover, a study conducted in 2002 sug- treatment of choice for patients with FHLH. However, gested that overall survival rates increased once the few patients have a disease-free sibling who is an 1997 protocol was put into practice.99 Patients with identical human leukocyte antigen match. Presently, all types of HLH treated per the 1997 protocol had a HSCT is the only available treatment to cure FHLH; 3-year overall survival rate of 55%, and a subgroup thus, it represents the definitive therapy of choice for of patients who underwent HSCT had a 3-year over- many patients.101,114 However, it is not uncommon for all survival rate of 62%.99,118 In a single, institutional, . patients to develop recurrence of HLH before a suit- retrospective study of pediatric patients, the 3-year able donor is identified. Thus, preparation for alloge- overall survival rate was 92% in patients treated with neic HSCT should be initiated at the time of diagnosis, allogeneic HSCT after reduced intensity conditioning and it should include human leukocyte antigen typing and 43% in patients who underwent myeloablative and a search for a suitable donor for HSCT.101,114 allogeneic HSCT.101 A review of antithymocyte glob- It is worth noting that, in 1 study, a median dis- ulin–based therapy in 38 patients with FHLH demon- ease-free survival rate was achieved in 9 patients with strated a complete response rate of 73%.119 Sixteen of FHLH during a follow-up period of 33 months (range, the 19 patients (84%) who underwent consolidation 8–69 months).114 In a meta-analysis, 11 studies com- with HSCT were considered to be cured, and overall prising data from 342 patients with EBV-associated survival for all study participants was 55%.119 Japa- HLH were collected and analyzed.115 A total of 54 of nese patients with EBV-associated HLH were shown to the 342 patients underwent HSCT. The transplanta- have a survival rate of 86%.120 The results of another tion-related mortality rate was 20% (11 of 54 patients), important HLH study have not yet been published which was lower than that seen in the control arm (32%; (NCT00426101). 93 of 288 patients); however, no statistically significant To date, most studies concentrate on the man- difference was seen in mortality rates found between agement of PHLH in children. Limited trials study those treated with HSCT and those treated with con- adult patients with SHLH,17,67,121 and data demonstrate ventional immunochemotherapy.115 Therefore, HSCT inferior median overall survival rates, ranging from may not be suitable for patients with EBV-associated 35 days121 to approximately 2 months.17 Among trials SHLH compared with those who have FHLH. relating to SHLH, patients with HLH due to malignancy A nationwide retrospective analysis indicated that had the poorest clinical outcome (median overall sur- reduced intensity conditioning followed by cord blood vival, 1–12 months).122-126 Parikh et al127 reported that transplantation is an alternative and feasible treat- patients with HLH associated with malignant tumors ment for PHLH or FHLH.116 The overall survival rate had a much shorter median overall survival rate of reached in that study was 65.4% ± 6.6% in 13 patients, 1.4 months compared with 22.8 months among pa- a rate comparable with other therapeutic strategies.116 tients who had HLH without infection, autoimmune The treatment dilemma was with patients with en- disease, or idiopathic entity. A report of EBV-associ- graftment failure; however, HLH could be managed ated HLH outcomes among children revealed a 90% in these patients through the use of secondary cord overall response rate to multiagent therapy, includ- blood transplantation.116 ing corticosteroids, etoposide, and cyclosporin,128 Data indicate that HSCT should be used in HLH whereas many other patients with infection-associ- refractory to conventional therapy. A single institu- ated HLH died within days or months.61 Dhote et al129 tional study focusing on therapy for HLH associated reported an overall mortality rate of 38.5% among with T- or B-cell lymphomas reported that the median patients with autoimmune disease–associated HLH.

October 2014, Vol. 21, No. 4 Cancer Control 309 However, in a different study, a subset of patients histiocytosis. More research into the molecular biol- with autoimmune disease–associated HLH treated ogy, immunology, and genetics of hemophagocytic with immunosuppressive agents, such as cyclospo- lymphohistiocytosis is needed to discover effective rine, cyclophosphamide, or tacrolimus, achieved a treatment options for patients with this rare disorder. remission rate of 80%.130 Long-term complications of HLH encompass References therapy-related morbidity — particularly following 1. Usmani GN, Woda BA, Newburger PE. Advances in understanding the pathogenesis of HLH. Br J Haematol. 2013;161(5):609-622. HSCT — and neurological deficits. The latter can man- 2. Lehmberg K, Ehl S. Diagnostic evaluation of patients with suspected ifest months to years following HLH; however, most haemophagocytic lymphohistiocytosis. Br J Haematol. 2013;160(3):275-287. patients return to their normal lives.131 3. Mehta RS, Smith RE. Hemophagocytic lymphohistiocytosis (HLH): a review of literature. Med Oncol. 2013;30(4):740. Validated prognostic factors are lacking among 4. Scott R. Histiocytic medullary reticulosis. Lancet. 1939;(2):194-198. prospective studies in order to guide treatment de- 5. Henter JI, Elinder G, Ost A; FHL Study Group of the Histiocyte Society. Diagnostic guidelines for hemophagocytic lymphohistiocytosis. Semin Oncol. cisions in patients with HLH. Most of the currently 1991;18(1):29-33. available prognostic factors have been derived from 6. Farquhar JW, Claireaux AE. Familial haemophagocytic reticulosis. Arch Dis Child. 1952;27(136):519-525. literature reviews or from single institutional studies. 7. Kleynberg RL, Schiller GJ. Secondary hemophagocytic lymphohistiocy- Earlier studies revealed that liver function ab- tosis in adults: an update on diagnosis and therapy. Clin Adv Hematol Oncol. 2012;10(11):726-732. normalities and cytopenias, along with increasing in 8. Ansuini V, Rigante D, Esposito S. Debate around infection-dependent serum levels of ferritin, soluble CD25, and soluble hemophagocytic syndrome in paediatrics. BMC Infect Dis. 2013;13:15. 9. Verbsky JW, Grossman WJ. Hemophagocytic lymphohistiocytosis: 106 132 CD163, may be indicators of relapse. Kaito et al diagnosis, pathophysiology, treatment, and future perspectives. Ann Med. suggest that age older than 30 years, a fibrinogen deg- 2006;38(1):20-31. 10. Rosado FG, Kim AS. Hemophagocytic lymphohistiocytosis: an update radation product level above 10 mcg/mL, and a ferritin on diagnosis and pathogenesis. Am J Clin Pathol. 2013;139(6):713-727. level above 500 ng/mL are risk factors associated with 11. Alavi Darazam I, Sami R, Ghadir M, et al. Hemophagocytic [correct- ed] lymphohistiocytosis associated with nephrotic syndrome and multi-organ death. Another study revealed that an elevated level failure. Iran J Kidney Dis. 2012;6(6):467-469. of soluble CD25 (> 10,000 U/mL) has a negative im- 12. Arico M, Imashuku S, Clementi R, et al. Hemophagocytic lymphohistio- cytosis due to germline mutations in SH2D1A, the X-linked lymphoproliferative pact on prognosis, with a 5-year survival rate of 36% disease gene. Blood. 2001;97(4):1131-1133. compared with 78% in the control group.133 13. Jordan MB, Allen CE, Weitzman S, et al. How I treat hemophagocytic lymphohistiocytosis. Blood. 2011;118(15):4041-4052. The severity of hyperbilirubinemia, thrombocy- 14. Allen CE, Yu X, Kozinetz CA, McClain KL. Highly elevated ferritin lev- topenia, hyperferritinemia, and cerebrospinal fluid els and the diagnosis of hemophagocytic lymphohistiocytosis. Pediatr Blood Cancer. 2008;50(6):1227-1235. pleocytosis may also be key risk factors for early death 15. Meki A, O’Connor D, Roberts C, et al. Hemophagocytic lymphohistio- among patients with HLH, as are lack of improve- cytosis in chronic lymphocytic leukemia. J Clin Oncol. 2011;29(24):e685-687. 16. Janka GE. Familial and acquired hemophagocytic lymphohistiocytosis. ment in hemoglobin or fibrinogen levels, persisting Annu Rev Med. 2012;63:233-246. thrombocytopenia, and persistent fever following the 17. Henter JI, Elinder G, Söder O, et al. Incidence in Sweden and clinical 134 features of familial hemophagocytic lymphohistiocytosis. Acta Paediatr Scand. initiation of therapy. In EBV-associated HLH, a high 1991;80(4):428-435. viral DNA load is associated with poor outcomes.135 18. Gurgey A, Unal S, Okur H, et al. Neonatal primary hemophagocytic lymphohistiocytosis in Turkish children. J Pediatr Hematol Oncol. 2008;30(12): Active HLH at the time of HSCT and central nervous 871-876. system involvement has been associated with worse 19. Créput C, Galicier L, Buyse S, et al. Understanding organ dysfunction in 103,118 hemophagocytic lymphohistiocytosis. Intensive Care Med. 2008;34(7):1177-1187. outcomes. A single institutional, retrospective 20. Krzewski K, Coligan JE. Human NK cell lytic granules and regulation study of 62 adult patients with HLH showed that a low of their exocytosis. Front Immunol. 2012;3:335. 21. Filipovich AH. Hemophagocytic lymphohistiocytosis (HLH) and related serum albumin level and tumor-associated HLH were disorders. Hematol Am Soc Hematol Educ Prog. 2009:127-131. 2 independent factors.17 In a univariate analysis, old 22. Ménasché G, Feldmann J, Fischer A, et al. Primary hemophagocytic syndromes point to a direct link between lymphocyte cytotoxicity and homeo- age, a high lactate dehydrogenase level, a low serum stasis. Immunol Rev. 2005;203:165-179. albumin level, a high ferritin level, and tumor-associat- 23. Bode SF, Lehmberg K, Maul-Pavicic A, et al. Recent advances in the 17 diagnosis and treatment of hemophagocytic lymphohistiocytosis. Arthritis Res ed HLH were all associated with a worse prognosis. Ther. 2012;14(3):213. In a study focused on infection-associated HLH, age 24. Komp DM, Buckley PJ, McNamara J, et al. Soluble interleukin-2 recep- tor in hemophagocytic histiocytoses: searching for markers of disease activity. older than 50 years, fever not subsiding within 3 days Pediatr Hematol Oncol. 1989;6(3):253-264. of diagnosis of HLH, and the development of dissem- 25. Biondo C, Signorino G, Costa A, et al. Recognition of yeast nucleic acids triggers a host-protective type I interferon response. Eur J Immunol. inated intravascular coagulation were considered to 2011;41(7):1969-1979. be strong indicators of mortality.53 26. Biondo C, Malara A, Costa A, et al. Recognition of fungal RNA by TLR7 has a nonredundant role in host defense against experimental candidiasis. Eur J Immunol. 2012;42(10):2632-2643. Conclusions 27. Costa A, Gupta R, Signorino G, et al. Activation of the NLRP3 inflam- masome by group B streptococci. Immunol J. 2012;188(4):1953-1960. Comprehensive clinical, immunological, and genetic 28. Yang X, Miyawaki T, Kanegane H. SAP and XIAP deficiency in he- workups are required to diagnose hemophagocytic mophagocytic lymphohistiocytosis. Pediatr Int. 2012;54(4):447-454. 29. Jordan MB, Hildeman D, Kappler J, et al. An animal model of he- lymphohistiocytosis. Despite recent advances in the mophagocytic lymphohistiocytosis (HLH): CD8+ T cells and interferon gamma diagnostics and therapy for hemophagocytic lympho- are essential for the disorder. Blood. 2004;104(3):735-743. 30. Ueda I, Ishii E, Morimoto A, et al. Correlation between phenotypic histiocytosis, the disease is incurable for the majority heterogeneity and gene mutational characteristics in familial hemophagocytic of adults with secondary hemophagocytic lympho- lymphohistiocytosis (FHL). Pediatr Blood Cancer. 2006;46(4):482-488.

310 Cancer Control October 2014, Vol. 21, No. 4 31. Sieni E, Cetica V, Piccin A, et al. Familial hemophagocytic lympho- 61. Sharp TM, Gaul L, Meuhlenbachs A, et al; Centers for Disease Control histiocytosis may present during adulthood: clinical and genetic features of a and Prevention. Fatal hemophagocytic lymphohistiocytosis associated with small series. PLoS One. 2012;7:e44649. locally acquired dengue virus infection - New Mexico and Texas, 2012. MMWR 32. Janka G. Hemophagocytic lymphohistiocytosis: when the immune Morb Mortal Wkly Rep. 2014;63(3):49-54. system runs amok. Klin Padiatr. 2009;221(5):278-285. 62. Demircioğlu F, Kazancı E, Genç DB, et al. H1N1 infection-related 33. Zhang K, Jordan MB, Marsh RA, et al. Hypomorphic mutations in PRF1, hemophagocytic lymphohistiocytosis in a child. Turk J Haematol. 2013;30(4): MUNC13-4, and STXBP2 are associated with adult-onset familial HLH. Blood. 426-428. 2011;118(22):5794-5798. 63. Atteritano M, David A, Bagnato G, et al. Haemophagocytic syndrome 34. Zur Stadt U, Beutel K, Kolberg S, et al. Mutation spectrum in children with in rheumatic patients. A systematic review. Eur Rev Med Pharmacol Sci. primary hemophagocytic lymphohistiocytosis: molecular and functional analyses 2012;16(10):1414-1424. of PRF1, UNC13D, STX11, and RAB27A. Hum Mutat. 2006;27(1):62-68. 64. Vella JE, El-Daly H. Hemophagocytic lymphohistiocytosis in a patient 35. Stepp SE, Dufourcq-Lagelouse R, Le Deist F, et al. Perforin gene de- with angioimmunoblastic lymphoma: a case report and review of the literature. fects in familial hemophagocytic lymphohistiocytosis. Science. 1999;286(5446): Int J Surg Pathol. 2012;20(6):606-609. 1957-1959. 65. Weitzman S. Approach to hemophagocytic syndromes. Hematology 36. Horne A, Ramme KG, Rudd E, et al. Characterization of PRF1, STX11 Am Soc Hematol Educ Program. 2011;2011:178-183. and UNC13D genotype-phenotype correlations in familial hemophagocytic 66. Alomari A, Hui P, Xu M. Composite peripheral T-cell lymphoma not lymphohistiocytosis. Br J Haematol. 2008;143(1):75-83. otherwise specified, and B-cell small lymphocytic lymphoma presenting with 37. Feldmann J, Callebaut I, Raposo G, et al. Munc13-4 is essential for hemophagocytic lymphohistiocytosis. Int J Surg Pathol. 2013;21(3):303-308. cytolytic granules fusion and is mutated in a form of familial hemophagocytic 67. Takahashi N, Miura I, Chubachi A, et al. A clinicopathological study of 20 lymphohistiocytosis (FHL3). Cell. 2003;115(4):461-473. patients with T/natural killer (NK)-cell lymphoma-associated hemophagocytic 38. zur Stadt U, Schmidt S, Kasper B, et al. Linkage of familial hemophago- syndrome with special reference to nasal and nasal-type NK/T-cell lymphoma. cytic lymphohistiocytosis (FHL) type-4 to chromosome 6q24 and identification Int J Hematol. 2001;74(3):303-308. of mutations in syntaxin 11. Hum Mol Genet. 2005;14(6):827-834. 68. Krenova Z, Sterba J, Blatny J, et al. A case of anaplastic large cell 39. Cetica V, Pende D, Griffiths GM, et al. Molecular basis of familial he- lymphoma- induced hemophagocytic lymphohistiocytosis in an adolescent mophagocytic lymphohistiocytosis. Haematologica. 2010;95(4):538-541. female. Pediatr Blood Cancer. 2007;49(7):1056. 40. US National Library of Medicine. STXBP2. http://ghr.nlm.nih.gov/gene/ 69. Czuchlewski DR, Oupadia SL, Zhang QY. Diffuse large B-cell lymphoma STXBP2. Published June 23, 2014. Accessed June 25, 2014. with florid hemophagocytosis. Int J Hematol. 2009;89(1):1-2. 41. Zhao XW, Gazendam RP, Drewniak A, et al. Defects in neutrophil 70. Pasqualini C, Jorini M, Carloni I, et al. Cytophagic histiocytic panniculitis, granule mobilization and bactericidal activity in familial hemophagocytic hemophagocytic lymphohistiocytosis and undetermined autoimmune disorder: lymphohistiocytosis type 5 (FHL-5) syndrome caused by STXBP2/Munc18-2 reconciling the puzzle. Ital J Pediatr. 2014;40(1):17. mutations. Blood. 2013;122(1):109-111. 71. Chan K, Behling E, Strayer DS, et al. Prolonged hemophagocytic lym- 42. Johnson TS, Villanueva J, Filipovich AH, et al. Contemporary diagnostic phohistiocytosis syndrome as an initial presentation of Hodgkin lymphoma: a methods for hemophagocytic lymphohistiocytic disorders. J Immunol Methods. case report. J Med Case Rep. 2008;2:367. 2011;364(1-2):1-13. 72. Chaker L, Segeren CM, Bot FJ, et al. Haemophagocytic syndrome and 43. de Saint Basile G, Ménasché G, Fischer A. Molecular mechanisms Hodgkin’s disease variant of Richter’s syndrome after fludarabine for CLL. Eur of biogenesis and exocytosis of cytotoxic granules. Nat Rev Immunol. J Haematol. 2010;85(1):91-92. 2010;10(8):568-579. 73. Alavi S, Ebadi M, Jenabzadeh A, et al. Hemophagocytic lymphohis- 44. Janka GE. Familial and acquired hemophagocytic lymphohistiocytosis. tiocytosis complicating erythroleukemia in a child with monosomy 7: a case Eur J Pediatr. 2007;166(2):95-109. report and review of the literature. Case Rep Hematol. 2013;2013:581073. 45. Wei ML. Hermansky-Pudlak syndrome: a disease of protein trafficking 74. Delavigne K, Bérard E, Bertoli S, et al. Hemophagocytic syndrome and organelle function. Pigment Cell Res. 2006;19(1):19-42. in patients with acute myeloid leukemia undergoing intensive chemotherapy. 46. Pagel J, Beutel K, Lehmberg K, et al. Distinct mutations in STXBP2 Haematologica. 2014;99(3):474-480. are associated with variable clinical presentations in patients with familial 75. Besset S, Schnell D, Azoulay E. Hemophagocytic lymphohistiocytosis hemophagocytic lymphohistiocytosis type 5 (FHL5). Blood. 2012;119(25): mimicking septic shock. Chest. 2012;141(3):835. 6016-6024. 76. Aricò M, Janka G, Fischer A, et al; FHL Study Group of the Histiocyte 47. Sieni E, Cetica V, Hackmann Y, et al. Familial hemophagocytic lympho- Society. Hemophagocytic lymphohistiocytosis. Report of 122 children from the histiocytosis: when rare diseases shed light on Immune system functioning. International Registry. Leukemia. 1996;10(2):197-203. Front Immunol. 2014;5:167. 77. Janka GE. Familial hemophagocytic lymphohistiocytosis. Eur J Pediatr. 48. Muralitharan S, Pathare A, Wali Y, et al. CD45 gene C77G mutation in 1983;140(3):221-230. haemophagocytic lymphohistiocytosis. Acta Haematol. 2007;118(3):160-161. 78. Bhasin A, Tolan RW. Hemophagocytic lymphohistiocytosis--a diagnostic 49. Boxall S, McCormick J, Beverley P, et al. Abnormal cell surface antigen dilemma: two cases and review. Clin Pediatr (Phila). 2013;52(4):297-301. expression in individuals with variant CD45 splicing and histiocytosis. Pediatr 79. Behrens EM, Beukelman T, Paessler M, et al. Occult macrophage Res. 2004;55(3):478-484. activation syndrome in patients with systemic juvenile idiopathic arthritis. J 50. Fox CP, Shannon-Lowe C, Gothard P, et al. Epstein-Barr virus-associated Rheumatol. 2007;34(5):1133-1138. hemophagocytic lymphohistiocytosis in adults characterized by high viral ge- 80. Vastert SJ, van Wijk R, D’Urbano LE, et al. Mutations in the perforin nome load within circulating natural killer cells. Clin Infect Dis. 2010;51(1):66-69. gene can be linked to macrophage activation syndrome in patients with systemic 51. Chen CJ, Huang YC, Jaing TH, et al. Hemophagocytic syndrome: a onset juvenile idiopathic arthritis. Rheumatology (Oxford). 2010;49(3):441-449. review of 18 pediatric cases. J Microbiol Immunol Infect. 2004;37(3):157-163. 81. Behrens EM, Canna SW, Slade K, et al. Repeated TLR9 stimulation 52. Elazary AS, Wolf DG, Amir G, et al. Severe Epstein-Barr virus-associated results in macrophage activation syndrome-like disease in mice. J Clin Invest. hemophagocytic syndrome in six adult patients. J Clin Virol. 2007;40(2):156-159. 2011;121(6):2264-2277. 53. Tseng YT, Sheng WH, Lin BH, et al. Causes, clinical symptoms, and 82. Pachlopnik Schmid J, Ho CH, Chrétien F, et al. Neutralization of IFN outcomes of infectious diseases associated with hemophagocytic lymphohis- gamma defeats haemophagocytosis in LCMV-infected perforin- and Ra- tiocytosis in Taiwanese adults. J Microbiol Immunol Infect. 2011;44(3):191-197. b27a-deficient mice. EMBO Mol Med. 2009;1(2):112-124. 54. Abdelkefi A, Ben Jamil W, Torjman L, et al. Hemophagocytic syndrome 83. Sepulveda FE, Debeurme F, Ménasché G, et al. Distinct severity of after hematopoietic stem cell transplantation: a prospective observational study. HLH in both human and murine mutants with complete loss of cytotoxic effector Int J Hematol. 2009;89(3):368-373. PRF1, RAB27A, and STX11. Blood. 2013;121(4):595-603. 55. Albrecht H, Schäfer H, Stellbrink HJ, et al. Epstein-Barr virus--associ- 84. Tamura M, Gu J, Danen EH, et al. PTEN interactions with focal adhesion ated hemophagocytic syndrome. A cause of fever of unknown origin in human kinase and suppression of the extracellular matrix-dependent phosphatidylinosi- immunodeficiency virus infection. Arch Pathol Lab Med. 1997;121(8):853-858. tol 3-kinase/Akt cell survival pathway. J Biol Chem. 1999;274(29):20693-20703. 56. Fardet L, Blum L, Kerob D, et al. Human herpesvirus 8-associated he- 85. Henter JI, Horne A, Aricó M, et al. HLH-2004: Diagnostic and therapeu- mophagocytic lymphohistiocytosis in human immunodeficiency virus-infected tic guidelines for hemophagocytic lymphohistiocytosis. Pediatr Blood Cancer. patients. Clin Infect Dis. 2003;37(2):285-291. 2007;48(2):124-131. 57. Yilmaz S, Oren H, Demircioğlu F, et al. Parvovirus B19: a cause for 86. Henter JI, Aricò M, Egeler RM, et al. HLH-94: a treatment protocol aplastic crisis and hemophagocytic lymphohistiocytosis. Pediatr Blood Cancer. for hemophagocytic lymphohistiocytosis. HLH study Group of the Histiocyte 2006;47(6):861. Society. Ped Pediatr Oncol. 1997;28(5):342-347. 58. Ardalan MR, Shoja MM, Tubbs RS, et al. Postrenal transplant he- 87. Goel S, Polski JM, Imran H. Sensitivity and specificity of bone marrow mophagocytic lymphohistiocytosis and thrombotic microangiopathy associated hemophagocytosis in hemophagocytic lymphohistiocytosis. Ann Clin Lab Sci. with parvovirus b19 infection. Am J Transplant. 2008;8(6):1340-1344. 2012;42(1):21-25. 59. Henter JI, Chow CB, Leung CW, et al. Cytotoxic therapy for severe 88. David A, Iaria C, Giordano S, et al. Secondary hemophagocytic lym- avian influenza A (H5N1) infection. Lancet. 2006;367(9513):870-873. phohistiocytosis: forget me not! Transpl Infect Dis. 2012;14(5):E121-123. 60. Watanabe M, Shibuya A, Okuno J, et al. Hepatitis A virus infection 89. Jenkins RW, Clarke CJ, Lucas JT, et al. Evaluation of the role of se- associated with hemophagocytic syndrome: report of two cases. Intern Med. cretory sphingomyelinase and bioactive sphingolipids as biomarkers in he- 2002;41(12):1188-1192. mophagocytic lymphohistiocytosis. Am J Hematol. 2013;88(11):E265-72.

October 2014, Vol. 21, No. 4 Cancer Control 311 90. Fadeel B, Orrenius S, Henter JI. Familial hemophagocytic lymphohistio- Japan. Int J Hematol. 2013;98(2):223-230. cytosis: too little cell death can seriously damage your health. Leuk Lymphoma. 117. Yu JT, Wang CY, Yang Y, et al. Lymphoma-associated hemophagocytic 2001;42(1-2):13-20. lymphohistiocytosis: experience in adults from a single institution. Ann Hematol. 91. Bryceson YT, Pende D, Maul-Pavicic A, et al. A prospective evaluation 2013;92(11):1529-1536. of degranulation assays in the rapid diagnosis of familial hemophagocytic 118. Trottestam H, Horne A, Aricò M, et al. Chemoimmunotherapy for he- syndromes. Blood. 2012;119(12):2754-2763. mophagocytic lymphohistiocytosis: long-term results of the HLH-94 treatment 92. Côte M, Ménager MM, Burgess A, et al. Munc18-2 deficiency caus- protocol. Blood. 2011;118(17):4577-4584. es familial hemophagocytic lymphohistiocytosis type 5 and impairs cytotoxic 119. Mahlaoui N, Ouachée-Chardin M, de Saint Basile G, et al. Immu- granule exocytosis in patient NK cells. J Clin Invest. 2009;119(12):3765-3773. notherapy of familial hemophagocytic lymphohistiocytosis with antithymo- 93. Titze U, Janka G, Schneider EM, et al. Hemophagocytic lymphohis- cyte globulins: a single-center retrospective report of 38 patients. Pediatrics. tiocytosis and Kawasaki disease: combined manifestation and differential 2007;120(3):e622-628. diagnosis. Pediatr Blood Cancer. 2009;53(3):493-495. 120. Ohga S, Kudo K, Ishii E, et al. Hematopoietic stem cell transplantation 94. Bode SF, Bogdan C, Beutel K, et al. Hemophagocytic lymphohistio- for familial hemophagocytic lymphohistiocytosis and Epstein-Barr virus-asso- cytosis in imported pediatric visceral leishmaniasis in a nonendemic Area. J ciated hemophagocytic lymphohistiocytosis in Japan. Pediatr Blood Cancer. Pediatr. 2014;165(1):147-153. 2010;54(2):299-306. 95. Aricò M, Allen M, Brusa S, et al. Haemophagocytic lymphohistiocytosis: 121. Shabbir M, Lucas J, Lazarchick J, et al. Secondary hemophagocytic proposal of a diagnostic algorithm based on perforin expression. Br J Haematol. syndrome in adults: a case series of 18 patients in a single institution and a 2002;119(1):180-188. review of literature. Hematol Oncol. 2011;29(2):100-106. 96. Rudman Spergel A, Walkovich K, Price S, et al. Autoimmune lymphop- 122. Machaczka M, Vaktnäs J, Klimkowska M, et al. Malignancy-associ- roliferative syndrome misdiagnosed as hemophagocytic lymphohistiocytosis. ated hemophagocytic lymphohistiocytosis in adults: a retrospective popula- Pediatrics. 2013;132(5):e1440-1444. tion-based analysis from a single center. Leuk Lymphoma. 2011;52(4):613-619. 97. Parizhskaya M, Reyes J, Jaffe R. Hemophagocytic syndrome pre- 123. Allory Y, Challine D, Haioun C, et al. Bone marrow involvement in lympho- senting as acute hepatic failure in two infants: clinical overlap with neonatal mas with hemophagocytic syndrome at presentation: a clinicopathologic study hemochromatosis. Pediatr Dev Pathol. 1999;2(4):360-366. of 11 patients in a Western institution. Am J Surg Pathol. 2001;25(7):865-874. 98. Fardet L, Galicier L, Lambotte O, et al. Development and validation 124. Miyahara M, Sano M, Shibata K, et al. B-cell lymphoma-associated of a score for the diagnosis of reactive hemophagocytic syndrome (HScore). hemophagocytic syndrome: clinicopathological characteristics. Ann Hematol. Arthritis Rheumatol. 2014;66(9);2613-2620. 2000;79(7):378-388. 99. Henter JI, Samuelsson-Horne A, Aricò M, et al. Treatment of he- 125. Majluf-Cruz A, Sosa-Camas R, Pérez-Ramírez O, et al. Hemophago- mophagocytic lymphohistiocytosis with HLH-94 immunochemotherapy and cytic syndrome associated with hematological neoplasias. Leuk Res. bone marrow transplantation. Blood. 2002;100(7):2367-2373. 1998;22(10):893-898. 100. Cooper N, Rao K, Gilmour K, et al. Stem cell transplantation with re- 126. Falini B, Pileri S, De Solas I, et al. Peripheral T-cell lymphoma associ- duced-intensity conditioning for hemophagocytic lymphohistiocytosis. Blood. ated with hemophagocytic syndrome. Blood. 1990;75(2):434-444. 2006;107(3):1233-1236. 127. Parikh SA, Kapoor P, Letendre L, et al. Prognostic factors and out- 101. Marsh RA, Vaughn G, Kim MO, et al. Reduced-intensity conditioning comes of adults with hemophagocytic lymphohistiocytosis. Mayo Clin Proc. significantly improves survival of patients with hemophagocytic lymphohis- 2014;89(4):484-492. tiocytosis undergoing allogeneic hematopoietic cell transplantation. Blood. 128. Kogawa K, Sato H, Asano T, et al. Prognostic factors of Epstein-Barr 2010;116(26):5824-5831. virus-associated hemophagocytic lymphohistiocytosis in children: report of the 102. McClain KL. Treatment and prognosis of hemophagocytic lymphohis- Japan Histiocytosis Study Group. Pediatr Blood Cancer. 2014;61(7):1257-1262. tiocytosis. http://www.uptodate.com/contents/treatment-and-prognosis-of-he- 129. Dhote R, Simon J, Papo T, et al. Reactive hemophagocytic syndrome mophagocytic-lymphohistiocytosis. Accessed July 29, 2014. in adult systemic disease: report of twenty-six cases and literature review. 103. Horne A, Janka G, Maarten Egeler R, et al. Haematopoietic stem Arthritis Rheum. 2003;49(5):633-639. cell transplantation in haemophagocytic lymphohistiocytosis. Br J Haematol. 130. Fukaya S, Yasuda S, Hashimoto T, et al. Clinical features of hae- 2005;129(5):622-630. mophagocytic syndrome in patients with systemic autoimmune diseases: 104. Park HS, Kim DY, Lee JH, et al. Clinical features of adult patients analysis of 30 cases. Rheumatology (Oxford). 2008;47(11):1686-1691. with secondary hemophagocytic lymphohistiocytosis from causes other than 131. Shuper A, Attias D, Kornreich L, et al. Familial hemophagocytic lym- lymphoma: an analysis of treatment outcome and prognostic factors. Ann phohistiocytosis: improved neurodevelopmental outcome after bone marrow Hematol. 2012;91(6):897-904. transplantation. J Pediatr. 1998;133(1):126-128. 105. Chellapandian D, Das R, Zelley K, et al. Treatment of Epstein Barr 132. Kaito K, Kobayashi M, Katayama T, et al. Prognostic factors of he- virus-induced haemophagocytic lymphohistiocytosis with rituximab-containing mophagocytic syndrome in adults: analysis of 34 cases. Eur J Haematol. chemo-immunotherapeutic regimens. Br J Haematol. 2013;162(3):376-382. 1997;59(4):247-253. 106. Marsh RA, Allen CE, McClain KL, et al. Salvage therapy of refractory 133. Imashuku S. Differential diagnosis of hemophagocytic syndrome: un- hemophagocytic lymphohistiocytosis with alemtuzumab. Pediatr Blood Cancer. derlying disorders and selection of the most effective treatment. Int J Hematol. 2013;60(1):101-109. 1997;66(2):135-151. 107. Marsh RA, Jordan MB, Filipovich AH. Reduced-intensity conditioning 134. Trottestam H, Berglöf E, Horne A, et al. Risk factors for early death haematopoietic cell transplantation for haemophagocytic lymphohistiocytosis: in children with haemophagocytic lymphohistiocytosis. Acta Paediatr. an important step forward. Br J Haematol. 2011;154(5):556-563. 2012;101(3):313-318. 108. Strout MP, Seropian S, Berliner N. Alemtuzumab as a bridge to allo- 135. Rouphael NG, Talati NJ, Vaughan C, et al. Infections associated with geneic SCT in atypical hemophagocytic lymphohistiocytosis. Nat Rev Clin haemophagocytic syndrome. Lancet Infect Dis. 2007;7(12):814-822. Oncol. 2010;7(7):415-420. 109. Oda Y, Urushidani Y, Ooi S, et al. Hemophagocytic lymphohistio- cytosis in a rheumatoid arthritis patient treated with infliximab. Intern Med. 2012;51(6):655-657. 110. Lackner H, Urban C, Sovinz P, et al. Hemophagocytic lymphohistio- cytosis as severe adverse event of antineoplastic treatment in children. Hae- matologica. 2008;93(2):291-294. 111. Olin RL, Nichols KE, Naghashpour M, et al. Successful use of the anti-CD25 antibody daclizumab in an adult patient with hemophagocytic lym- phohistiocytosis. Am J Hematol. 2008;83(9):747-749. 112. Bhattacharyya M, Ghosh MK. Hemophagoctic lymphohistiocytosis--re- cent concept. J Assoc Physicians India. 2008;56:453-457. 113. Teachey DT, Rheingold SR, Maude SL, et al. Cytokine release syndrome after blinatumomab treatment related to abnormal macrophage activation and ameliorated with cytokine-directed therapy. Blood. 2013;121(26):5154-5157. 114. Jabado N, de Graeff-Meeder ER, Cavazzana-Calvo M, et al. Treatment of familial hemophagocytic lymphohistiocytosis with bone marrow transplanta- tion from HLA genetically nonidentical donors. Blood. 1997;90(12):4743-4748. 115. Qin Q, Xie Z, Shen Y, et al. Assessment of immunochemotherapy and stem cell transplantation on EBV-associated hemophagocytic lympho- histiocytosis in children: a systematic review and meta analysis. Eur Rev Med Pharmacol Sci. 2012;16(5):672-678. 116. Sawada A, Ohga S, Ishii E, et al. Feasibility of reduced-intensity conditioning followed by unrelated cord blood transplantation for primary hemophagocytic lymphohistiocytosis: a nationwide retrospective analysis in

312 Cancer Control October 2014, Vol. 21, No. 4 Kikuchi–Fujimoto disease is a

rare lymphohistiocytic disorder

that affects young women of

Asian descent more frequently

than persons of other ethnic groups.

Net-Wing Beetle. Photograph courtesy of Sherri Damlo. www.damloedits.com.

Pathogenesis, Diagnosis, and Management of Kikuchi–Fujimoto Disease Darcie Deaver, PhD, Pedro Horna, MD, Hernani Cualing, MD, and Lubomir Sokol, MD, PhD

Background: Kikuchi–Fujimoto disease (KFD) is a rare lymphohistiocytic disorder with an unknown etiopathogenesis. This disease is misdiagnosed as malignant lymphoma in up to one-third of cases and is as- sociated with the development of systemic lupus erythematosus (SLE). Methods: The medical literature between the years 1972 and 2014 was searched for KFD, and the data were collected and analyzed regarding the epidemiology, clinical presentations, diagnosis, management, and suggested diagnostic and treatment algorithms. Results: Although KFD has been reported in other ethnic groups and geographical areas, it is more frequently diagnosed in young women of Asian descent. Patients with the disease typically present with rapidly evolving tender cervical lymphadenopathy, night sweats, fevers, and headache. Diagnosis is based on histopathological examination. Excisional lymph node biopsy is essential for a correct diagnosis. Apoptotic coagulation necrosis with karyorrhectic debris and the proliferation of histiocytes, plasmacytoid dendritic cells, and CD8+ T cells in the absence of neutrophils are characteristic cytomorphology features. Interface dermatitis at the onset of KFD may be a marker for the subsequent evolution of SLE. The natural course of the disease is typically benign. Short courses of steroids, nonsteroidal anti-inflammatory drugs, or hydroxychloroquine can be administered to patients with more severe symptoms. Conclusions: Although KFD was described more than 40 years ago, the etiology of this disease remains un- solved. Infectious or autoimmune processes were proposed but have not been definitively confirmed. Clinical presentation with systemic B symptoms and adenopathy may lead to an erroneous diagnosis of malignant lymphoma. The introduction of modern methods into hematopathology, including immunohistochemistry, flow cytometry, and molecular clonality studies, has decreased the probability of misdiagnosis. Until reliable prognostic markers are available, patients with KFD should have continued long-term follow-up care due to their increased risk of SLE.

From the Departments of Malignant Hematology (DD, LS) and Address correspondence to Darcie Deaver, PhD, Celgene Hematopathology and Laboratory Medicine (PH) at the H. Lee Moffitt Corporation, 1503 Foppiano Loop, Round Rock, TX 78665. Cancer Center & Research Institute, Tampa, Florida, and IHCFLOW E-mail: [email protected] (HC), Lutz, Florida. No significant relationships exist between the authors and the com- Dr Deaver is now affiliated with Celgene Corporation. panies/organizations whose products or services may be referenced Submitted February 18, 2014; accepted July 2, 2014. in this article.

October 2014, Vol. 21, No. 4 Cancer Control 313 Introduction and maculopapular rash. However, no confirmatory Kikuchi–Fujimoto disease (KFD), also known as studies or results from the control samples were avail- Kikuchi disease, is a rare lymphohistiocytic disor- able. Huh et al21 amplified sequences of HHV-8 from der first described in 1972.1,2 KFD generally affects lymph nodes in 6 out of 26 patients with KFD (23%). women of Asian descent between the ages of 20 and They did not detect any viral sequences in the reactive 35 years and has a male:female ratio of 1:2; howev- lymph nodes of the study controls, suggesting that er, new cases of KFD have also been described in HHV-8 may play a role in the pathogenesis of KFD. non-Asian ethnic groups and children in Europe and the United States.3-10 The acute or subacute onset of Parvovirus B19 adenopathy and systemic B symptoms in KFD has his- Zhang et al22 searched for parvovirus B19 in 33 lymph torically led to a misdiagnosis of malignant lymphoma, node samples from patients with KFD and 16 controls although modern hematopathological methods have using several different methods, including PCR, immu- made such misdiagnosis less likely.11-14 Following the nohistochemistry, and in situ hybridization (ISH). A resolution of KFD, concurrent autoimmune disorders significantly higher rate of B19 positivity was seen in have been reported; they may also be more frequently samples from patients with KFD than in controls; B19 diagnosed.15,16 infected cells were mostly composed of lymphocytes and a small number of histiocytes.22 Epidemiology The precise incidence of KFD is unknown; however, Epstein–Barr Virus a large review identified and analyzed 733 patients Hudnall et al23 tested 30 lymph node samples of pa- diagnosed worldwide since 1972.8 Of those cases, 140 tients with KFD and 12 controls for the presence (19%) were pediatric patients, and the male:female of EBV using real-time PCR, EBV-encoded RNA ISH, ratio was 1.4:1.8 (It is worth noting that a higher and EBV latent membrane protein with immunohis- propensity for male sex has only been observed in tochemistry. Cells with apoptotic features positive for children younger than 12 years of age.5) The pre- EBV-encoded RNA were found in the necrotic regions senting symptoms in children are similar to adults, of many KFD cases, suggesting that the disease could although fever and rash are more frequent in pediatric be due to a hyperimmune reaction against EBV infec- patients.8 Children younger than 18 years of age may tion. Hollingsworth et al24 looked for EBV and HHV-6 also demonstrate bilateral cervical lymphadenopathy using PCR and ISH in 20 patients with KFD, but the more frequently than adults.9,10 study results did not support a viral role in the patho- The occurrence of KFD in family members has genesis of KFD. However, Yen et al25 reported EBV rarely been described.17 A search for a link between infection in a child with a cutaneous manifestation of KFD and human leukocyte antigen class 2 alleles KFD, supporting the pathogenic role of EBV infection, in the Japanese population suggested the possibil- and Chiu et al26 detected EBV RNA sequences in all ity of a positive relationship between DPA1*01 and 10 tested samples of KFD but found only a single DPB1*0202 alleles and the disease.18 Because these al- case of EBV-encoded proteins. No evidence of human leles are much more frequent in Japan than in Europe T-lymphotrophic virus or parvovirus B19 was seen in and the United States, this finding may explain the the patient samples of this study.26 higher prevalence of KFD in patients of Asian descent, Overall, the results of studies searching for a viral thus supporting a possible autoimmune pathogenic etiology of KFD have been inconsistent. Laboratory mechanism. methods differed among laboratories, positive results were documented in a small number of samples, and Viral Infections confirmatory studies with control samples were often Epstein–Barr virus (EBV), human herpesvirus (HHV) unavailable. Currently, no definitive evidence suggests types 6, 7, and 8, herpes simplex virus, HIV, human that a known virus plays a key role in the pathogen- T-lymphotrophic virus, and parvovirus B19 are the esis of KFD. most frequently studied viruses in patients with KFD. Autoimmune Mechanism Human Herpesviruses Autoimmune disorders are frequently reported in Cho et al19 studied HHV-6 and HHV-7 in 50 archival patients with KFD, with systemic lupus erythema- samples of KFD and 20 controls using nested poly- tosus (SLE) being the most common disorder linked merase chain reaction (PCR) and found no significant to KFD.27 In many reports, KFD preceded the de- difference in the viral DNA sequences between patients velopment of SLE; however, the diagnosis of KFD and controls. Labrador et al20 identified the DNA of has been reported to simultaneously occur or follow HHV-7 in the affected lymph node of a young patient the diagnosis of SLE.27,28 In one study, patients with with KFD who presented with cervical adenopathy KFD were negative for antinuclear and anti-DNA an-

314 Cancer Control October 2014, Vol. 21, No. 4 tibodies, suggesting that — at least initially — SLE SLE adenopathy is usually mild, generalized, and KFD have distinct pathogenic mechanisms.4 and nontender. The cytomorphology of enlarged A diagnosis of SLE requires at least 4 out of 11 criteria lymph nodes in SLE consists of scattered plasma to be present, and lymphadenitis is not included in cells and immunoblasts, increased vascularity with these criteria.29 Sopeña et al30 found several autoim- Azzopardi phenomenon associated with moderate mune disorders, including SLE, Sjögren syndrome, reactive follicular hyperplasia, or varying degrees of thyroiditis, and leukocytoclastic vasculitis, in 9 (53%) coagulative necrosis with the presence of hematox- of 20 patients with KFD. ylin bodies (Table 1).4,10,27 These features can help Kim et al31 reviewed patients with KFD in the differentiate involvement with SLE compared with context of SLE and noticed an increasing number KFD.27,34 SLE is also associated with higher antinu- of case reports in the medical literature. Among clear antibody titers and organomegaly, which is a 9 cases of KFD and SLE, 7 patients manifested with rare finding in KFD.35 skin disease. Histological evaluation of skin biopsies was consistent with SLE in 3 of the 7 cases. Com- Molecular Biology monly, patients with a simultaneous onset of KFD Molecular pathways implicated in the pathobi- and SLE have flare-ups of lupus; therefore, some re- ology of KFD are not well understood. Ishimura searchers have suggested that concurrent KFD and et al36 reported on a noninvasive method for di- SLE diagnoses are actually lupus lymphadenitis.31 agnosing KFD using gene expression profiling Other researchers suggest that KFD is a forme fruste on peripheral mononuclear cells. The top 5 up- of SLE.32 Lymphadenitis is not included among the regulated genes included FI44L, CXCL10, GBP1, 11 diagnostic criteria of SLE, so it cannot establish EPSTI1, and IFI27. All 5 genes belong to the a diagnosis of SLE as a sole pathological finding; family of interferon-induced genes. Ohshima however, the simultaneous manifestation of histocytic et al37 investigated apoptosis and cell-cycle–associ- necrotizing lymphadenitis with skin rash, cytopenias, ated gene expression in lymph nodes from patients arthralgias, and abnormal results on serological tests with KFD and nonspecific lymphadenitis (NSL). should raise suspicion of SLE and a comprehensive The up regulation of nearly all apoptosis-associated work-up should be completed.29 Paradela et al33 re- genes, including caspase, and the down regulation of ported on a patient with KFD and interface dermatitis apoptosis inhibitory genes, such as BCL2, was seen who subsequently developed SLE. They reviewed the in samples with KFD. Cell-cycle–associated genes medical literature and found an additional 27 cases of were up regulated in all patients with KFD, which KFD with simultaneous nodal and cutaneous involve- is in contrast to patients with NSL.37 Ohshima et al38 ment, 9 of whom subsequently developed SLE. Skin studied cytokine pathways in 10 lymph node samples biopsy was consistent with interface dermatitis in all from patients with KFD and 4 controls with NSL us- of the KFD cases that evolved into SLE. The authors ing immunohistochemistry and reverse transcriptase suggested that interface dermatitis could be a valuable PCR. Results of the study suggested that the cytokine marker of evolution of KFD into SLE.33 However, due and chemokine pathways of interferon γ, interleukin to differing opinions about the possibility of concur- 18, MIG, and interferon γ–induced protein 10 play rent diagnoses of KFD and SLE, further research is an important role in the pathogenesis of apoptosis necessary to reach a definitive conclusion. associated with KFD.38

Table 1. — Histopathological Features of Kikuchi–Fujimoto Disease and Systemic Lupus Erythematosus

Cytomorphology Immunohistochemistry

Kikuchi–Fujimoto Disease Distorted nodal architecture with cortical and paracortical CD68+ nodules with proliferation of histiocytes and immunoblasts, CD123+ coagulative necrosis, abundant apoptotic karyorrhexis, and + crescentic histiocytic nuclei CD4 CD8 T-cell predominance Myeloperoxidase positive Lysozyme positive T-cell immunoblasts

Systemic Lupus Erythematosus Moderate reactive follicular hyperplasia, scattered plasma CD4+ with predominance over CD8+ T cells cells and immunoblasts, with increased vascularity or varying Lymphoid follicles are mixture of small- degrees of coagulative necrosis with Azzopardi phenomenon and medium-sized lymphocytes and presence of hematoxylin bodies Germinal centers of the B cell are BCL2–

October 2014, Vol. 21, No. 4 Cancer Control 315 Clinical Manifestation Diagnosis KFD frequently manifests as an acute or subacute illness Lymph Node Biopsy with systemic B symptoms and painful posterior cer- Although fine-needle aspiration biopsy (FNAB) is a vical lymphadenopathy (Table 2).1,2,4,10,39 Lymph nodes valuable tool for the diagnosis of some lymphopro- are usually smaller, ranging from 0.5 to 4.0 cm.10,27,40 liferative disorders, particularly in relapse settings, Approximately 1% to 22% of patients develop general- excisional biopsy is the preferred diagnostic tool in ized lymphadenopathy.4,39 Kucukardali et al32 analyzed patients presenting with new adenopathy.27 Tong et 244 patients between 1991 and 2006, most of whom al51 analyzed 44 cases of patients with confirmed were from Taiwan (36%); 15 (6%) were from the United KFD or suggested by FNAB. The false-positive and States. Fever was the most common systemic symptom false-negative rates were 37.5% and 50%, respectively. (presenting in 35% of patients). Lymphadenopathy was The overall accuracy of FNAB was about 56%.51 Das et observed in 100% of patients, erythematous rashes in al52 compared FNAB smears of lymph nodes between 10% of patients, and hepatosplenomegaly in 3% of pa- patients with KFD and reactive nodal hyperplasia and tients.32 An association with SLE was seen in 13% of showed overlapping cytological features in both con- patients and viral infections in 10% of patients, although ditions, which suggests the limited diagnostic poten- SLE was more frequent in patients from Asia than Eu- tial of this method. Up to 30% of patients with KFD rope (28% vs 9%).32 The disease was self-limiting in most are initially misdiagnosed, so lymphoma excisional patients (64%), and treatment with corticosteroids was biopsy should be the requested diagnostic method necessary in 16% of patients.32 used for patients with suspected KFD.4,10 Cheng et al41 studied 195 patients who were di- agnosed with KFD between 1989 and 2006 in the Histology and Immunohistochemistry largest retrospective study reported from a single KFD is characterized by a distortion of the normal institution. In this study, 53% of patients presented nodal architecture with cortical and paracortical nod- with tender adenopathy, 38% with fever, and 17% ules with coagulative necrosis and abundant apoptotic with headaches.41 A benign course with a sponta- karyorrhectic debris.1,2,4,10,27 Additional characteristic neous resolution of systemic symptoms and adenop- features include the proliferation of histiocytes and athy was observed in 183 patients (94%); 14 patients immunoblasts with an abundance of CD8+ T cells (15%) developed recurrent disease within 6 months and an absence of neutrophils (Fig 1). Immunohisto- of follow-up; 5 patients (3%) developed autoimmune chemical stains reveal histiocytes expressing CD68, diseases, including SLE (2), Graves disease (2), and myeloperoxidase, and CD4 markers. A predominance mixed connective tissue disease (1); and 1 patient of CD8+ T cells in affected lymph nodes of patients with recurrent KFD died of intracranial hemorrhage with KFD has also been described.53 The expression secondary to thrombocytopenia.41 of the CD123 marker on plasmacytoid dendritic cells also supports a diagnosis of KFD (see Table 1).53 Extranodal Manifestation Kuo et al50 studied 79 cases with KFD and strat- The most commonly affected extranodal organ is the ified KFD into 3 stages according to histopathologi- skin (30%–40%).42,43 Nonspecific variable lesions, in- cluding papules, facial malar erythema, plaques, or Table 2. — Diagnostic Criteria for Kikuchi–Fujimoto Disease nodules, are typically observed.43 Histology of the skin biopsy often resembles that of KFD. Case reports Clinical Localized lymphadenopathy have also indicated an association of KFD with vari- Systemic symptoms ous inflammatory disorders, such as hemophagocytic Fever syndrome, cerebellar ataxia, meningitis, conjunctivitis, Fatigue 39,44-49 arthritis, and myocarditis. Headache Laboratory Tests Pathological Laboratory studies No specific laboratory test is available for diagnosing Leukopenia KFD. A complete blood count is usually within normal Elevated C-reactive protein range.27 Two large reviews observed leukopenia in Erythrocyte sedimentation rate 19% to 43% and anemia in 23% of people with KFD. Biopsy of the lymph node Other laboratory abnormalities include elevated lev- Aggregates of CD68+ histiocytes with occasional els of erythrocyte sedimentation (40%–79%), lactate crescent-shaped nuclei Foci of cell death ranging from isolated apoptotic dehydrogenase (53%), and alanine aminotransferase cells to large areas of geographical necrosis 32,41 (23%). Circulating atypical lymphocytes have also Proliferation of plasmacytoid dendritic cells been reported in the peripheral blood film of approx- No accumulation of eosinophils or neutrophils imately 25% of patients with KFD.50

316 Cancer Control October 2014, Vol. 21, No. 4 cal features. The proliferative stage is characteristic sis, Bartonella henselae, HIV, and EBV, as well as for the expression of various histiocytes, plasma- connective tissue disorders (eg, SLE) and lymphop- cytoid monocytes, and lymphoid cells containing roliferative disorders (Table 3).4,27 The proliferation karyorrhectic fragments and eosinophilic apoptotic stage of KFD may present with features similar to debris.50 The necrotizing stage can be recognized lymphoma and may lead to misdiagnosis.10,54 The pres- based on the presence of a various degree of coag- ence of large atypical cells and immunoblasts of T-cell ulative necrosis; the xanthomatous stage manifests lineage origin cause confusion because these cells with foamy histiocytes. are also characteristic of aggressive lymphoma.1,2,4,50 The minimum criteria for a pathological diagno- Necrosis may or may not be present in lymphoma. sis of KFD include the presence of crescent-shaped Immunohistochemical staining, flow cytometry, and histiocytes and plasmacytoid monocytes with molecular clonality studies can help in the differen- scattered karyorrhexis (see Table 2).10,39 It may be tial diagnosis of these 2 disorders. Melikoglu et al55 histiocytic proliferation, not necrosis alone, that is reported lymphadenopathy in 23% to 34% of patients more characteristic of KFD.27 with SLE. The lymph nodes were small, nontender, and generalized in the majority of patients, which is Differential Diagnosis in contrast to patients with KFD. Compared with KFD, A differential diagnosis of KFD is wide and should other clinical and laboratory findings are necessary include infections such as tuberculosis, toxoplasmo- to diagnose SLE.29

A B

C D Fig 1 A-D. — (A) Low power view of a lymph node with involvement by Kikuchi histiocytic necrotizing nonsuppurative lymphadenitis. The pathognomonic pale foci are clues to the collection of histiocytes located in the center between the benign germinal centers located on the left and right sides of the image. (B) Medium power view showing necrosis and pink debris among histiocytes with round- to sickle-shaped nuclei. Well-formed granulomas are not typically seen. (C) Oil magnification showing sheets of pale histiocytic nuclei with violaceous hue and pink cytoplasm showing early findings of the disease with crescentic histiocytes appearing as tingible bodies. This stage is the most often histological appearance mistaken for large cell lymphoma because of the solid appearance of these large cells. Most of these are plasmacytoid monocytes that derive from plasmacytoid dendritic cells. (D) A more advanced stage of Kikuchi–Fujimoto lymphadenitis recognized by pathologists that shows the typical pink necrotizing nodules composed of histiocytic debris. Note the absence of neutrophils or suppurative abscess, which is a hallmark distinguishing this process from the class of suppurative granulomas.

October 2014, Vol. 21, No. 4 Cancer Control 317 Imaging Studies in size, have a shape that is less round, a reticular Imaging studies may be useful in the assessment of echotexture that is less micronodular, and additional patients with peripheral adenopathy. Computed to- signs of matting and cortical widening than those mography helps to differentiate tuberculous lymph- with lymphoma. adenitis from KFD. Lee at al56 compared computed to- mographic imaging of the lymph nodes of 24 patients Treatment with KFD and 45 lymph nodes from patients with Treatment guidelines have not been established for tuberculous lymphadenitis. Histologically, differences KFD, and recommendations are based on case reports were seen between KFD and tuberculous lymphade- and expert opinion alone. Due to the self-limited, be- nitis regarding the type of necrosis within the lymph nign course of KFD, observation is the most common nodes. By contrast to tuberculous lymphadenitis, approach in management. Patients with symptoms or which manifests with caseation necrosis surround- with involvement of the extranodal tissues, such as ed with granulomatous tissue, KFD is characteristic the central nervous system, skin, and eyes, can benefit for coagulation necrosis with apoptosis of various from treatment with short pulses of corticosteroids, cell types. These differences may be responsible for nonsteroidal anti-inflammatory drugs, and antipyretics changes seen on imaging studies. Indistinct margins (Fig 2). In patients with complicated KFD, glucocorti- of necrotic foci independently predicted the diagnosis coids or hydroxychloroquine might be useful. Chen et of KFD with 80% accuracy in a multivariate analysis.56 al59 reported a rapid response to hydroxychloroquine Calcifications within the lymph nodes were observed in a child with symptomatic KFD. Yoshioka et al60 in tuberculous lymphadenitis alone compared with treated 13 patients with KFD and prolonged fever with KFD and other lymphoproliferative disorders. a short course of methylprednisolone (0.5 g/day for Tsujikawa et al57 compared the size of lymph 3 days). A dramatic resolution of fever was seen in all nodes and the maximum standardized uptake value patients within 24 hours. Four out of 13 patients (40%) in 8 patients with KFD and 14 patients with non-Hod- relapsed.60 Rezai et al61 treated a patient with KFD who gkin lymphoma using 18F-fluorodeoxyglucose pos- had systemic symptoms with a 4-day course of chlo- itron emission tomography/computed tomography roquine and achieved a rapid response. The patient (FDG PET/CT). The sizes of the lymph nodes were was then re-treated with oral hydroxychloroquine smaller in patients with KFD compared with patients 200 mg twice a day for 14 days for recurrent KFD; with indolent or aggressive lymphomas. The maximum the patient’s symptoms resolved within 12 hours.61 standardized uptake value was also higher in cases of Yalcin et al62 administered methylprednisolone 1 m/kg KFD compared with indolent non-Hodgkin lymphoma. for 8 days in a symptomatic patient with KFD who A high maximum standardized uptake value in patients achieved a complete resolution of symptoms. The with KFD has been a contributing factor to misdiagno- researchers tapered treatment with steroids by 8 mg sis with aggressive lymphoma (see Table 3).57 every 3 days, leading to the regression of lymphade- Lo et al58 examined ultrasonographic character- nopathy.62 Rezayat et al63 reported on a patient who istics (size, shape, rims, matting, and echotexture) initially responded to therapy with steroids; when in 137 lymph nodes from 21 patients with KFD and the disease recurred, the patient was treated with 89 lymph nodes from 20 patients with malignant lym- single-agent hydroxychloroquine. However, following phoma. Results of this study suggested that cervical the discontinuation of each agent, the disease relapsed lymphadenopathies in patients with KFD are smaller and the patient required dual therapy.63

Table 3. — Differential Diagnosis of Lymphadenopathy

Variable Kikuchi–Fujimoto Disease Aggressive Lymphoma Systemic Lupus Erythematosus Tuberculosis

Onset Rapid Rapid Slow Slow

Presence of pain Yes No No No

Anatomical distribution Localized Generalized Generalized Localized

Size of lymph nodes 2–4 > 2 2–4 2–5 by CT, cm

FDG/PET avid Yes/High Yes/High Yes/Low, if active disease Yes/Low, if active disease

CT = computed tomography, FDG/PET = 18F-fluorodeoxyglucose positron emission tomography.

318 Cancer Control October 2014, Vol. 21, No. 4 Recurrence Prognosis In a single study, the recurrence rate of KFD was ap- In most patients with KFD, the course of disease is proximately 4%4; however, in a more recent review, benign, with a spontaneous resolution of systemic the recurrence rate was observed to be 15%.41 Bogusz symptoms and adenopathy typically occurring in et al64 identified 65 patients with recurrent KFD in 1 to 4 months.10,27,41 The association of KFD with SLE the published literature until 2013. However, because ranges between 3% and 28% and is higher in Asian approximately 800 cases of KFD have been reported populations.32,41 thus far, the estimated frequency of recurrent KFD In rare instances KFD has a fatal course. The could be less than 10%.32 Recurrences can occur as mortality rate of KFD was reported in 2 large studies long as 8 years after the initial presentation27; there- to be between 0.5% and 2.1%.32,41 The fatal course fore, long-term follow-up is necessary to assess the was due to an infiltration of the myocardium, ce- recurrence rate in KFD. rebral hemorrhage secondary to thrombocytopenia, and an association with SLE and hemophagocytic Pregnancy syndrome.39,41,51,68,69 Few cases have been reported of KFD manifesting during pregnancy. Two reports suggest that treatment Conclusions with antibiotics, steroids, or both have no adverse im- Kikuchi–Fujimoto disease is an idiopathic, rare, benign pacts on the mother, fetus, or throughout the course lymphadenopathy that primarily affects younger peo- of pregnancy.65,66 One miscarriage was described in ple. Since its original description in young Japanese a patient with KFD and evolving SLE.67 females, the disease has been diagnosed in other geo-

Asymptomatic Symptomatic

Nonsteroidal Observation Glucocorticoids Hydroxychloroquine anti-inflammatories

Symptom resolution Persistent symptoms

Observation Workup for simultaneous SLE

Negative Positive

Alternate agent higher doses of Treat SLE glucocorticosteroids and intravenous immunoglobulin

Fig 2. — Therapeutic algorithm. SLE = systemic lupus erythematosus.

October 2014, Vol. 21, No. 4 Cancer Control 319 graphical areas, various ethnic and age groups, and virus or human herpesvirus type 6 as the causative agents. Arch Pathol Lab Med. 1994;118(2):134-140. both sexes. Despite recent advances in pathology, a 25. Yen A, Fearneyhough P, Raimer SS, et al. EBV-associated Kikuchi’s misdiagnosis of malignant lymphoma is still reported; histiocytic necrotizing lymphadenitis with cutaneous manifestations. J Am Acad Dermatol. 1997;36(2 pt 2):342-346. therefore, consultation with a hematopathologist is 26. Chiu CF, Chow KC, Lin TY, et al. Virus infection in patients with his- recommended. Typically, the long-term prognosis of tiocytic necrotizing lymphadenitis in Taiwan. Detection of Epstein-Barr virus, type I human T-cell lymphotropic virus, and parvovirus B19. Am J Clin Pathol. Kikuchi–Fujimoto disease is favorable; however, due 2000;113(6):774-781. to an increased risk of developing systemic lupus 27. Bosch X, Guilabert A, Miquel R, et al. Enigmatic Kikuchi-Fujimoto dis- ease: a comprehensive review. Am J Clin Pathol. 2004;122(1):141-152. erythematosus, close follow-up is recommended. Few 28. Khanna D, Shrivastava A, Malur PR, et al. Necrotizing lymphadenitis patients with severe symptoms or recurrent disease in systemic lupus erythematosus: is it Kikuchi-Fujimoto disease? J Clin Rheu- matol. 2010;16(3):123-124. require treatment with steroids, nonsteroidal anti- 29. American College of Rheumatology. 1997 update of revised systemic inflammatory drugs, or hydroxychloroquine. lupus erythematosus. www.rheumatology.org/Practice/Clinical/Classification/ SLE/1997_Update_of_Revised_Systemic_Lupus_Erythematosus/. Accessed August 6, 2014. References 30. Sopeña B, Rivera A, Vázquez-Triñanes C, et al. Autoimmune manifes- 1. Kikuchi M. Lymphadenitis showing focal reticulum cell hyperplasia tations of Kikuchi disease. Semin Arthritis Rheum. 2012;41(6):900-906. with nuclear debris and phagocytosis. Nippon Ketsueki Gakkai Zasshi. 31. Kim SK, Kang MS, Yoon BY, et al. Histiocytic necrotizing lymphadenitis 1972;35:379-380. in the context of systemic lupus erythematosus (SLE): is histiocytic necrotizing 2. Fujimoto Y, Kojima Y, Yamaguchi K. Cervical subacute necrotizing lymphadenitis in SLE associated with skin lesions? Lupus. 2011;20(8):809-819. lymphadenitis. New Clinicopathol Ent. 1972;20:920-927. 32. Kucukardali Y, Solmazgul E, Kunter E, et al. Kikuchi-Fujimoto disease: 3. Pileri S, Kikuchi M, Helbron D, et al. Histiocytic necrotizing lymph- analysis of 244 cases. Clin Rheumatol. 2007;26(1):50-54. adenitis without granulocytic infiltration. Virchows Arch A Pathol Anat Histol. 33. Paradela S, Lorenzo J, Martínez-Gómez W, et al. Interface dermatitis 1982;395(3):257-271. in skin lesions of Kikuchi-Fujimoto’s disease: a histopathological marker of 4. Dorfman RF. Histiocytic necrotizing lymphadenitis of Kikuchi and Fu- evolution into systemic lupus erythematosus? Lupus. 2008;17(12):1127-1135. jimoto. Arch Pathol Lab Med. 1987;111(11):1026-1029. 34. Dorfman RF, Berry GJ. Kikuchi’s hisiocytic necrotizing lymphadenitis: 5. Lee BC, Patel R. Kikuchi-Fujimoto disease: a 15-year analysis at a an analysis of 108 cases with emphasis on differential diagnosis. Semin Diag children’s hospital in the United States. Clin Pediatr. 2013;52(1):92-95. Pathol. 1988;5(4):329-345. 6. Vassilakopoulos TP, Pangalis GA, Siakantaris MP, et al. Kikuchi’s 35. Smith LW, Gelber AC, Petri M. Diffuse lymphadenopathy as the pre- lymphadenopathy: a relatively rare but important cause of lymphadenopathy senting manifestation of systemic lupus erythematosus. J Clin Rheumatol. in Greece, potentially associated with the antiphospholipid syndrome. Rheu- 2013;19(7);397-399. matol Int. 2010;30(7):925-932. 36. Ishimura M, Yamamoto H, Mizuno Y, et al. A non-invasive diagnosis 7. Onciu M, Medeiros LJ. Kikuchi-Fujimoto lymphadenitis. Adv Anat Pathol. of histiocytic necrotizing lymphadenitis by means of gene expression 2003;10(4):204-211. profile analysis of peripheral blood mononuclear cells. J Clin Immunol. 8. Kim TY, Ha KS, Kim Y, et al. Characteristics of Kikuchi-Fujimoto disease 2013;33(5):1018-1026. in children compared with adults. Eur J Pediatr. 2013;173(1):111-116. 37. Ohshima K, Karube K, Hamasaki M, et al. Apoptosis- and cell cycle-as- 9. Seo JH, Kang JM, Lee H, et al. Histiocytic necrotizing lymphadenitis sociated gene expression profiling of histiocytic necrotising lymphadenitis. Eur in children: a clinical and immunohistochemical comparative study with adult J Haematol. 2004;72(5):322-329. patients. Int J Pediatr Otorhinolaryngol. 2013;77(3):429-433. 38. Ohshima K, Haraoka S, Takahata Y, et al. Interferon-gamma, inter- 10. Deaver D, Naghashpour M, Sokol L. Kikuchi-Fujimoto disease in the leukin-18, monokine induced by interferon-gamma and interferon-gamma-in- United States: three case reports and review of the literature [Erratum appears ducible protein-10 in histiocytic necrotizing lymphadenitis. Leuk Lymphoma. in Mediterr J Hematol Infect Dis. 2014;6(1):E2014023]. Mediterr J Hematol 2002;43(5):1115-20. Infect Dis. 2014;6(1):e2014001. 39. Tsang WY, Chan JK, Ng CS. Kichuchi’s lymphadenitis. A morphologic 11. Ohta K, Endo N, Kaizaki Y. Axillary and intramammary lymphadenop- analysis of 75 cases with special reference to unusual features. Am J Surg athy caused by Kikuchi-Fujimoto disease mimicking malignant lymphoma. Pathol. 1994;18(3):219-231. Breast Cancer. 2013;20(1):97-101. 40. Lin HC, Su CY, Huang CC, et al. Kikuchi’s disease: a review and analysis 12. Cunha BA, Mickail N, Durie N, et al. Fever of unknown origin (FUO) of 61 cases. Otolaryngol Head Neck Surg. 2003;128(5):650-653. caused by Kikuchi’s disease mimicking lymphoma. Heart Lung. 2009;38(5): 41. Cheng CY, Sheng WH, Lo YC, et al. Clinical presentations, laboratory 450-456. results and outcomes of patients with Kikuchi’s disease: emphasis on the 13. Lee DH, Lee JH, Shim EJ, et al. Disseminated Kikuchi-Fujimoto disease association between recurrent Kikuchi’s disease and autoimmune diseases. mimicking malignant lymphoma on positron emission tomography in a child. J J Microbiol Immunol Infect. 2010;43(5):366-371. Pediatr Hematol Oncol. 2009;31(9):687-689. 42. Seno A, Torigoe R, Shimoe K, et al. Kikuchi’s disease (histiocytic 14. Sarantopoulos GP, Palla B, Said J, et al. Mimics of cutaneous lympho- necrotizing lymphadenitis) with cutaneous involvement. J Am Acad Derm. ma: report of the 2011 Society for Hematopathology/European Association for 1994;30(3):504-506. Haematopathology workshop. Am J Clin Pathol. 2013;139(4):536-551. 43. Atwater AR, Longley BJ, Aughenbaugh WD. Kikuchi’s disease: case 15. Patra A, Bhattacharya SK. SLE developing in a follow-up patient of report and systematic review of cutaneous and histopathologic presentations. Kikuchi’s disease: a rare disorder. J Clin Diagn Res. 2013;7(4):752-753. J Am Acad Dermatol. 2008;59(1):130-136. 16. Martínez-Vázquez C, Hughes G, Bordon J, et al. Histiocytic necrotizing 44. Galor A, Georgy M, Leder HA, et al. Papillary conjunctivitis associated lymphadenitis, Kikuchi-Fujimoto’s disease, associated with systemic lupus with Kikuchi disease. Cornea. 2008;27(8):944-946. erythemotosus. QJM. 1997;90(8):531-533. 45. Lim GY, Cho B, Chung NG. Hemophagocytic lymphohistiocytosis pre- 17. Stasiuk A, Teschke S, Williams GJ, et al. Kikuchi-Fujimoto disease: ceded by Kikuchi disease in children. Pediatr Radiol. 2008;38(7):756-761. lymphadenopathy in siblings. CMAJ. 2011;183(1):E58-E60. 46. Sato Y, Kuno H, Oizumi K. Histiocytic necrotizing lymphadenitis (Kiku- 18. Tanaka T, Ohmori M, Yasunaga S, et al. DNA typing of HLA class II chi’s disease) with aseptic meningitis. J Neurol Sci. 1999;163(2):187-191. genes (HLA-DR, -DQ and -DP) in Japanese patients with histiocytic necrotizing 47. Moon JS, Il Kim G, Koo YH, et al. Kinetic tremor and cerebellar ataxia as lymphadenitis (Kikuchi’s disease). Tissue Antigens. 1999;54(3):246-253. initial manifestations of Kikuchi-Fujimoto’s disease. J Neurol Sci. 2009;277(1- 19. Cho MS, Choi HJ, Park HK, et al. Questionable role of human her- 2):181-183. pesviruses in the pathogenesis of Kikuchi disease. Arch Pathol Lab Med. 48. Douglas M, Bradbury R, Kannangara S, et al. Arthritis as an un- 2007;131(4):604-609. usual manifestation of Kikuchi-Fujimoto disease. Rheumatology (Oxford). 20. Labrador J, Aparicio MA, Santos-Briz A, et al. Kikuchi-Fujimoto dis- 2003;42(8):1010-1012. ease: a case supporting a role for human herpesvirus 7 involvement in the 49. Chan JK, Wong KC, Ng CS. A fatal case of multicentric Kikuchi’s his- pathogenesis. Rheumatol Int. 2013;33(12):3065-3068. tiocytic necrotizing lymphadenitis. Cancer. 1989;63(9):1856-1862. 21. Huh J, Kang GH, Gong G, et al. Kaposi’s sarcoma-associated herpes- 50. Kuo TT. Kikuchi’s disease (histiocytic necrotizing lymphadenitis). A virus in Kikuchi’s disease. Hum Pathol. 1998;29(10):1091-1096. clinicopathologic study of 79 cases with an analysis of histologic subtypes, 22. Zhang WP, Wang JH, Wang WQ, et al. An association between par- immunohistology, and DNA ploidy. Am J Surg Pathol. 1995;19(7):798-809. vovirus B19 and Kikuchi-Fujimoto disease. Viral Immunol. 2007;20(3):421-428. 51. Tong T, Chan O, Lee K. Diagnosing Kikuchi disease on fine needle 23. Hudnall SD, Chen T, Amr S, et al. Detection of human herpesvirus DNA aspiration biopsy: a retrospective study of 44 cases diagnosed by cytology in Kikuchi-Fujimoto disease and reactive lymphoid hyperplasia. Int J Clin Exp and 8 by histotopathology. Acta Cytol. 2001;45:953-957. Pathol. 2008;1(4):362-368. 52. Das DK, Mallik MK, Dashti HA, et al. Kikuchi-Fujimoto disease in 24. Hollingsworth HC, Peiper SC, Weiss LM, et al. An investigation of the vi- fine-needle aspiration smears: a clinico-cytologic study of 76 cases of KFD ral pathogenesis of Kikuchi-Fujimoto disease. Lack of evidence for Epstein-Barr and 684 cases of reactive hyperplasia of the lymph node. Diagn Cytopathol.

320 Cancer Control October 2014, Vol. 21, No. 4 2013;41(4):288-295. 53. Gordon JK, Magro C, Lu T, et al. Overlap between systemic lupus erythematosus and Kikuchi Fujimoto disease: a clinical pathology conference held by the Department of Rheumatology at Hospital for Special Surgery. HSS J. 2009;5(2):169-177. 54. Menasce LP, Banerjee SS, Edmondson D, et al. Histiocytic necrotizing lymphadenitis (Kikuchi-Fujimoto disease): continuing diagnostic difficulties. Histopathology. 1998;33(3):248-254. 55. Melikoglu MA, Melikoglu M. The clinical importance of lymphadenopa- thy in systemic lupus erythematosus. Acta Reumatol Port. 2008;33(4):402-406. 56. Lee, S, Yoo JH, Lee SW. Kikuchi disease: differentiation from tubercu- lous lymphadenitis based on patterns of nodal necrosis on CT. AJNR Am J Neuroradiol. 2012;33(1):135-140. 57. Tsujikawa T, Tsuchida T, Imamura Y, et al. Kikuchi-Fujimot disease: PET/CT assessment of a rare cause of cervical lymphadenopathy. Clin Nucl Med. 2011;36(8):661-664. 58. Lo WC, Chang WC, Lin YC, et al. Ultrasonographic differentiation be- tween Kikuchi’s disease and lymphoma in patients with cervical lymphade- nopathy. Eur J Radiol. 2012;81(8):1817-1820. 59. Chen PH, Huang YF, Tang CW, et al. Kikuchi-Fujimoto disease: an amazing response to hydroxychloroquine. Eur J Pediatr. 2010;169(12): 1557-1559. 60. Yoshioka K, Miyashita T, Nakamura T, et al. Treatment of histiocytic necrotizing lymphadenisis (Kikuchi’s disease) with prolonged fever by a single course of methylprednisolone pulse therapy without maintenance therapy: experience with 13 cases. Intern Med. 2010;49(20):2267-2270. 61. Rezai K, Kuchipudi S, Chundi V, et al B. Kikuchi-Fujimoto disease: hydroxychloroquine as a treatment. Clin Infect Dis. 2004;39:e124-e126. 62. Yalcin S, Toprak SK, Erismis B, et al. Management of Kikuchi-Fujimoto disease using glucocorticoid: a case report. Case Rep Med. 2011;2011:230840. 63. Rezayat T, Carroll MB, Ramsey BC, et al. A case of relapsing Kiku- chi-Fujimoto disease. Case Rep Otolaryngol. 2013;2013:364795. 64. Bogusz AM, Bhargava P. Recurrent histiocytic necrotizing lymphadenitis with a long latency in a patient with autoimmunity: a case report and review of literature. Int J Surg Pathol. 2013;21(3):287-296. 65. Altuntas F, Sari I, Canoz O, et al. Kikuchi-Fujimoto disease: a rare but important cause of fever and lymphadenopathy in pregnant women. Am J Hematol. 2006;81(2):118-120. 66. Dubois RE, Bondell S, Krissman PH. Kikuchi–Fujimoto syndrome during pregnancy. South Med J. 1991;84(8):1029-1030. 67. Alijotas RJ, Casellas CM, Ferrer Oliveras R, et al. Recurrent Kiku- chi-Fujimoto disease during pregnancy: report of case evolving into systemic lupus erythematosus and review of published work. J Obstet Gynaecol Res. 2008;34(4 pt 2):595-598. 68. Kampitak T. Fatal Kikuchi-Fujimoto disease associated with SLE and hemophagocytic syndrome: a case report. Clin Rheumatol. 2008;27(8):1073- 1075. 69. Quintás-Cardama A, Fraga M, Cozzi SN, et al. Fatal Kikuchi-Fu- jimoto disease: the lupus connection [Erratum appears in Ann Hematol. 2003;82(6):377]. Ann Hematol. 2003;82(3):186-188.

October 2014, Vol. 21, No. 4 Cancer Control 321 A high degree of clinical suspicion is needed

to diagnose Rosai–Dorman disease.

Eight-Spotted Skimmer. Photograph courtesy of Sherri Damlo. www.damloedits.com.

Rosai–Dorfman Disease: Tumor Biology, Clinical Features, Pathology, and Treatment Samir Dalia, MD, Elizabeth Sagatys, MD, Lubomir Sokol, MD, PhD, and Timothy Kubal, MD

Background: Rosai–Dorfman disease (RDD) is a rare, nonmalignant clinical entity characterized by a group of clinical symptoms and characteristic pathological features. Methods: Articles that reviewed tumor biology, clinical features, pathology, and treatment for RDD were identified in a search of the literature for the years 1990 to 2014. The results from this body of literature were reviewed and summarized. Results: Patients with RDD generally present with massive, painless cervical lymphadenopathy, fevers, and elevated inflammatory markers. Extranodal disease is typical, with the most common sites being the skin and the central nervous system. Rarely, the gastrointestinal tract is involved. Immunohistochemistry remains the mainstay of diagnosis with S100 and CD68 positive cells while CD1a will be negative of involved histiocytes. Histologically, the disease shows the classical characteristic finding of emperipolesis. Many patients do not require treatment; however, surgical resection remains the mainstay of treatment for symptomatic disease. The role of steroids, chemotherapy, and radiation therapy continue to be based on small case series and case reports. Conclusions: RDD has a variable clinical presentation; therefore, a high degree of suspicion and a thorough pathological review are necessary to diagnose this rare clinical entity. Although some patients will experience spontaneous resolution, others may require surgical resection or steroid therapy and radiation or chemother- apy. Given the rarity of the disease and the lack of a clear therapeutic pathway, referring patients to a tertiary center is recommended for confirming the diagnosis and treatment considerations.

Introduction Rosai–Dorman disease (RDD), also known as sinus From the Departments of Medical Oncology (SD), Hematopathology histiocytosis with massive lymphadenopathy, was and Laboratory Medicine (ES), and Malignant Hematology (LS, originally described by Destombes in 1965.1 Subse- TK) at the H. Lee Moffitt Cancer Center & Research Institute and quently, it was characterized as a distinct clinicopatho- the University of South Florida Morsani College of Medicine (SD), 2 Tampa, Florida. logical disorder in 1969 by Rosai and Dorfman. In this Dr Dalia is now affiliated with Mercy Clinic Oncology-Hematology, nonmalignant disorder, patients typically present with Jopin, Missouri. fever, leukocytosis, and nonpainful cervical lymph- Submitted July 5, 2014; accepted August 12, 2014. adenopathy. Although the disease has a predilection Address correspondence to Samir Dalia, MD, Mercy Clinic Oncol- for the lymph nodes in the head and neck, RDD can ogy-Hematology, 3001 McClelland Boulevard, Joplin, MO 64804. also present in any extranodal site, with common sites E-mail: [email protected] including the skin and soft tissue, the central nervous No significant relationships exist between the authors and the com- panies/organizations whose products or services may be referenced system (CNS), and, less commonly, the gastrointestinal in this article. tract.3-9 Histology and immunohistochemistry help

322 Cancer Control October 2014, Vol. 21, No. 4 differentiate RDD from malignant disorders such as often affected than Caucasians and a male predomi- lymphoma and Langerhans cell histiocytosis. Although nance is present.11 Classically, most patients present adenopathy can be significant and disfiguring, RDD is in otherwise good health with symptoms of fever and usually self-limiting and eventually recedes, making massive, nonpainful cervical lymphadenopathy mim- systemic therapy rarely required.10 The aim of this icking lymphoma.2 Patients may have night sweats and review is to provide health care professionals with the weight loss. Painless maculopapular eruptions also scientific framework to gain a better understanding can be reported, and, unlike patients with Langerhans of the tumor biology, clinical features, pathology, and cell histiocytosis, osteolytic bone lesions are rare but treatment for RDD. sclerotic bone lesions sometimes occur.4,11,22,23 The workup of patients with suspected RDD is Tumor Biology similar to that of lymphoma. A detailed history and RDD is a disease of nonmalignant histiocytes that in- physical examination should be performed to exclude filtrate lymph nodes or extranodal tissues. RDD cells other causes of the adenopathy. It is worth noting that exhibit emperipolesis, the nondestructive phagocy- hepatosplenomegaly is rare in RDD, while it is com- tosis of lymphocytes or erythrocytes, which is the monly seen in other histiocytic disorders.11,24 Staging hallmark of the disease and required for diagnosis.2,8 should include contrast computed tomography (CT) The etiology of RDD is unknown and is considered an scans of the neck, chest, abdomen, and pelvis to look idiopathic histiocytosis. The search for an infectious for distant disease. The role of bone marrow biopsy agent linked to RDD has led to conflicting results. is unclear but is usually obtained because primary Some evidence suggests that immune dysfunction and bone marrow disorders are included in the differential viral infections, such as human herpesvirus (HHV), diagnosis of RDD. Laboratory workup should include parvovirus B19, and Epstein–Barr virus (EBV) may screening for EBV, cytomegalovirus, HHV-6, HHV-8, play a role in the pathogenesis.9,11-13 In particular, the and HIV. In addition, the laboratory workup should expression of the HHV-6 antigen has been identified include rheumatoid factor, an antinuclear antibody in the histiocytes present in RDD, while EBV and test, complete blood counts, liver and kidney func- parvovirus have been shown to be present in lympho- tion tests, immunoglobulin levels, and an erythrocyte cytes, which may eventually be phagocytosed by his- sedimentation rate (ESR). A total of 90% of patients tiocytes.13,14 However, in situ hybridization studies for has been reported to have an elevated ESR and poly- EBV-encoded RNA have shown the RDD histiocytes clonal hypergammaglobulinemia with a reversal of to be negative.11,15 In addition, 3 cases of RDD were the albumin:globulin ratio.24 Leukocytosis with neu- demonstrated to be negative for HHV-6.16 Therefore, trophilia, a normochromic normocytic anemia, and the definitive identity of an infectious agent behind a positive rheumatoid factor or antinuclear antibody RDD remains undetermined. value have all been reported.11,13,24 Hemolytic anemia Although RDD has been reported in patients with and eosinophilia are rare.11,24 Ideally, excisional biopsy immunoglobulin (Ig) G4-related disease, no clear ev- should be performed to obtain adequate tissue for idence suggests that these disorders have a common morphological and immunohistochemical analyses etiopathogenesis. In a recent analysis of 29 patients to make a diagnosis. with RDD, low numbers of IgG4-positive plasma cells The differential diagnosis of RDD is broad and and low IgG4/IgG ratios were present when compared is similar to other causes of lymphadenopathy. Non- with IgG4-related disease samples. Forkhead box malignant etiologies include tuberculosis, Wegener P3–positive T-regulatory cells were also lower in granulomatosis, sarcoidosis, IgG4-related disease, ju- number in patients with RDD when compared with venile xanthogranuloma, Erdheim–Chester disease, IgG4-related disease, suggesting that RDD does not fit Gaucher disease, and other histiocytic disorders such into the spectrum of IgG4-related disease.9,17,18 Germ- as Langerhans cell histiocytosis. Malignant etiologies line mutations in SLC29A3, which encodes an intracel- in the differential diagnosis of RDD include Hodgkin lular human equilibrative nucleoside transporter, have lymphoma, non-Hodgkin lymphoma, melanoma, leu- been reported in patients with familial RDD, suggest- kemia, and Langerhans cell sarcoma. ing that RDD may belong to a spectrum of disorders Extranodal involvement by RDD was initially with SLC29A3 mutations, including Faisalabad histio- thought to be uncommon, but some reports suggest cytosis, H syndrome, and pigmented hypertrichosis in that it may be present in up to 40% of cases.4,18 The the setting of insulin-dependent diabetes.19-21 most commonly involved extranodal sites include the skin, CNS, orbit and eyelid, upper respiratory tract, Clinical Features and the gastrointestinal tract.7-9,11-13,17,18,22,25-32 Typically, RDD manifests in childhood and early adult- CNS involvement in the setting of RDD is uncom- hood, with the majority of cases reported in the second mon and has been reported in 210 cases in the English and third decades of life.11 African Americans are more literature.8 The mean age of patients is 39 years and a

October 2014, Vol. 21, No. 4 Cancer Control 323 male prevalence has been reported.8 Commonly, RDD RDD; lymph node structures, including sinusoids, presents with dura-based, extra-axial involvement of are absent (Fig 1).2,11 With fewer histiocytes present the cranium; by contrast, spinal cord and intracerebral showing emperipolesis in extranodal tissue, a careful involvement are rare.3,8 Constitutional symptoms are examination of the biopsies is required and immu- usually absent and neurological symptoms depend on nohistochemical stains may be helpful when RDD is the location of the lesion, with headaches and seizures included in the differential diagnosis. RDD histiocytes commonly reported.3,8 Magnetic resonance imaging of will be positive for immunohistochemical stains CD68 the brain should be performed in suspected cases of (KP-1), CD163, and S100 and are typically negative CNS involvement followed by biopsy, if possible, to rule for CD1a (Fig 2). In most cases, the histiocytes in out other causes of the lesion, including meningioma. RDD are morphologically distinct from Langerhans The cutaneous-only form of RDD (CRDD) is a cell histiocytosis and interdigitating dendritic cells.10 clinically distinct entity from RDD, and some re- Immunohistochemical stains are generally sufficient searchers suggest that it may be a different clinico- to differentiate the rare, morphologically ambiguous pathological entity from nodal RDD.28 In reported cases. Unlike Langerhans cell histiocytosis in which cases of CRDD, patients with CRDD are 45 years old- BRAF V600E mutations can be found, BRAF V600E er compared with patients who have RDD.4 Women mutations in the setting of RDD are negative.33 This with CRDD appear to be more affected than men, and most cases have been seen among Caucasian and Asian populations.4,28 In CRDD, patients typical- ly present with normal laboratory data and no ad- enopathy. Lesions in CRDD can vary, ranging from less than 1 cm to 30 cm or more at their greatest dimensions. Multiple lesions are generally present and are typically red-brown papules or nodules. Rarely, patients can develop extensive confluent in- filtrates. The most common site of skin involvement is the torso followed by the head and neck region.4 Most patients with CRDD follow a benign clinical course, with a frequent and spontaneous resolution of lesions. The workup in patients with suspected CRDD includes a complete skin examination, punch biopsy of the suspected lesion, followed by an expert pathology review, complete blood counts, and ESR. Fig 1. — Section of skin showing histiocytic infiltrate with admixed small The utility of further workup in CRDD, including CT lymphocytes in the dermis. No involvement of the overlying epidermis imaging, is unclear. is present. The histiocytes have abundant eosinophilic cytoplasm and occasional forms show emperipolesis (H & E, × 200). Inset (upper left) shows 2 histiocytes with emperipolesis in the center (H & E, × 400). Pathology H & E = hematoxylin and eosin. In the setting of RDD, grossly involved lymph nodes are enlarged and matted with thickened capsules. On microscopic examination, the normal lymph node ar- chitecture is altered by massive sinusoidal dilation that contains histiocytes, lymphocytes, and plasma cells.10 Emperipolesis within the histiocyte cytoplasm is the classical finding in RDD.2,9,11 The intact lymphocytes, plasma cells, and erythrocytes inside the histiocytes are contained in the intracellular vacuoles, thus al- lowing an escape from degradation by the cytolytic enzymes during their transit through the histiocyte cytoplasm. In addition to the histiocytic proliferation in the dilated sinusoids, reactive lymphoid follicles may be present in the cortex of the lymph node. In the medullary region, increased plasma cells are present, as are small lymphocytes and the occasion- al lipid-laden macrophages.10 In extranodal RDD, Fig 2. — Immunohistochemical stains show the histiocytes expressing S100 (upper left), CD68 (upper right), and CD163 (lower left) while lacking CD1a increased amounts of fibrosis and fewer histiocytes (lower right). In the S100 and CD163 images, histiocytes demonstrate em- are present in the lesions as compared with nodal peripolesis (H & E, × 400). H & E = hematoxylin and eosin.

324 Cancer Control October 2014, Vol. 21, No. 4 finding suggests that a patient’s BRAF V600E muta- In cases with incomplete resection of RDD in- tion status could help differentiate the 2 entities in volving the CNS, a “wait and watch” approach can extremely rare cases in which immunohistochemical be implemented following surgery if neurological stains and morphology findings are equivocal.33 symptoms are reversed.3,8 In the case of persistent CNS symptoms, further treatment with either external Treatment beam radiotherapy or stereotactic radiotherapy has Because RDD is a nonmalignant histiocytic disorder, been successful.8,35 treatment for the disease is advised only in patients In patients with RDD requiring systemic treat- who are symptomatic or have vital organ or system ment, steroids are a first-line therapeutic option that involvement (ie, CNS). In the setting of RDD, 20% of produces responses in both classical RDD and extran- cases show spontaneous regression without therapy.34 odal disease; however, the reliability and durability Relapsing and remitting RDD without treatment may of these responses is unpredictable. In patients with occur in another 70% of patients, complicating the RDD, radiation can be used as a palliative option for timing of when to use therapy.34 For patients requiring symptomatic disease. Although no standard radiation treatment, surgery is an appropriate option for disease guidelines have been established for patients with that can be excised, including single nodal areas, pri- RDD, lymphoma-like approaches with total doses mary CNS involvement, or localized primary CRDD. ranging between 30 and 50 Gy have been employed.36 Remissions with surgery alone have been reported in Radiotherapy can also be effective for preserving vital CNS-only disease.7,31 Surgery is also utilized in those organ and system functions such as in cases of orbital, with involvement of the head and neck to maintain airway, and CNS involvement.3,8,23,26,37 airway patency.32 Although some morbidity exists with For patients with CRDD, therapy is not typically surgical approaches, the majority of patients will re- required; however, surgical excision remains the most main disease free for prolonged periods of time.7,23,31 effective option for treating solitary or small numbers

Pathological Confirmation of Rosai–Dorfman Disease

Limited/localized disease Extensive/systemic disease

Asymptomatic Symptomatic Asymptomatic Symptomatic

Steroids Complete surgical Rituximab resection Interferon Retinoids Residual disease Imatinib Watch and wait vs Vinca alkaloids Asymptomatic Symptomatic surgical resectionb Anthracyclines Alkylating agents Watch and wait vs Methotrexate complete surgical Watch and Radiation Cladribine resectiona wait therapy Clofarabine

Progression with symptoms

Fig 3. — Treatment algorithm for Rosai–Dorfman disease. aIn selected patients with a high risk of future end-organ damage (ie, airway obstruction due to progression). bResection of the selected mass located in an anatomical region with a high risk of end-organ damage due to disease progression.

October 2014, Vol. 21, No. 4 Cancer Control 325 of lesions. Radiotherapy, cryotherapy, topical chemo- tients with this disorder will not require treatment, therapy, and topical isotretinoin have also been used and typically the masses will spontaneously regress. but with varying success.4,5,25,28 For patients who require therapy, surgical resection is In cases of disseminated RDD or those refracto- the mainstay of treatment. Health care professionals ry to surgery or other modalities (eg, radiotherapy, are urged to refer patients to tertiary care centers if steroids), chemotherapy has been used with varying radiation therapy or chemotherapy is required be- degrees of success.23,37-39 Due to the rarity of RDD, cause a standard of care has not been established for clinical trials have not been performed to compare patients with Rosai–Dorfman disease. different chemotherapeutic agents in patients requir- ing therapy. Risk–benefit analyses are based on small References case series and case reports.23,37-40 Agents such as vinca 1. Destombes P. Adenitis with lipid excess, in children or young adults, seen in the Antilles and in Mali. (4 cases) [in French]. Bull Soc Pathol Exot alkaloids, anthracyclines, and alkylating agents have Filiales. 1965;58(6):1169-1175. been used with varying response rates.23,39,40 In a case 2. Rosai J, Dorfman RF. Sinus histiocytosis with massive lymphade- nopathy. A newly recognized benign clinicopathological entity. Arch Pathol. series of 12 patients with RDD and CNS involvement, 1969;87(1):63-70. 2 patients achieved a complete response and both 3. Cooper SL, Jenrette JM. Rosai-Dorfman disease: management of CNS and systemic involvement. Clin Adv Hematol Oncol. 2012;10(3):199-202. were treated with methotrexate and 6-mercaptopu- 4. Frater JL, Maddox JS, Obadiah JM, et al. Cutaneous Rosai-Dorfman rine.23 Thus, a review of RDD with CNS involvement disease: comprehensive review of cases reported in the medical literature since 1990 and presentation of an illustrative case. J Cutan Med Surg. concluded that there may be a benefit in using meth- 2006;10(6):281-290. otrexate and 6-mercaptopurine for these patients.8 5. Kong YY, Kong JC, Shi DR, et al. Cutaneous Rosai-Dorfman disease: a clinical and histopathologic study of 25 cases in China. Am J Surg Pathol. Clofarabine and cladribine have also been shown to 2007;31(3):341-350. have activity in refractory RDD.41-43 Azathioprine and 6. McClellan SF, Ainbinder DJ. Orbital Rosai-Dorfman disease: a literature review. Orbit. 2013;32(5):341-346. interferon α have been shown to have a degree of ef- 7. Purav P, Ganapathy K, Mallikarjuna VS, et al. Rosai-Dorfman disease ficacy in patients with RDD,38,44-46 and, in case reports, of the central nervous system. J Clin Neurosci. 2005;12(6):656-659. 8. Sandoval-Sus JD, Sandoval-Leon AC, Chapman JR, et al. Rosai-Dorf- imatinib and the anti-CD20 antibody rituximab have man disease of the central nervous system: report of 6 cases and review of also been shown to have clinical activity in RDD.47-50 the literature. Medicine (Baltimore). 2014;93(3):165-175. 9. Zhao M, Li C, Zheng J, et al. Extranodal Rosai-Dorfman disease involv- Data on the usage of systemic therapy in RDD are ing appendix and mesenteric nodes with a protracted course: report of a rare limited; therefore, health care professionals should case lacking relationship to IgG4-related disease and review of the literature. Int J Clin Exp Pathol. 2013;6(11):2569-2577. refer patients to tertiary care centers for the treatment 10. Ioachim HL, Medeiros J, eds. Ioachim’s Lymph Node Pathology. 4th of refractory or widespread disease. A treatment al- ed. Philadelphia: Wolters Kluwer/Lippincott Williams & Wilkins; 2009. 11. Foucar E, Rosai J, Dorfman R. Sinus histiocytosis with massive lymph- gorithm for patients with RDD has been proposed adenopathy (Rosai-Dorfman disease): review of the entity. Semin Diagn Pathol. based on the published literature as well as our ex- 1990;7(1):19-73. 12. Noguchi S, Yatera K, Shimajiri S, et al. Intrathoracic Rosai-Dorfman perience (Fig 3). disease with spontaneous remission: a clinical report and a review of the We believe that the surveillance of patients with literature. Tohoku J Exp Med. 2012;227(3):231-325. 13. Mehraein Y, Wagner M, Remberger K, et al. Parvovirus B19 detected in RDD should be similar to that of non-Hodgkin lym- Rosai-Dorfman disease in nodal and extranodal manifestations. J Clin Pathol. phoma. Patients should be closely followed for the 2006;59(12):1320-1326. 14. Luppi M, Barozzi P, Garber R, et al. Expression of human herpesvirus-6 first 2 years after complete remission or diagnosis antigens in benign and malignant lymphoproliferative diseases. Am J Pathol. under a “wait and watch” approach, with clinical ex- 1998;153(3):815-823. 15. Tsang WY, Yip TT, Chan JK. The Rosai-Dorfman disease histiocytes amination and laboratory testing performed every 3 are not infected by Epstein-Barr virus. Histopathology. 1994;25(1):88-90. to 6 months for the first 2 years. Contrast CT scans 16. Ortonne N, Fillet AM, Kosuge H, et al. Cutaneous Destombes-Ro- sai-Dorfman disease: absence of detection of HHV-6 and HHV-8 in skin. J can be obtained as clinically indicated. We recommend Cutan Pathol. 2002;29(2):113-118. that follow-up after 2 years should continue at yearly 17. Liu L, Perry AM, Cao W, et al. Relationship between Rosai-Dorfman disease and IgG4-related disease: study of 32 cases. Am J Clin Pathol. intervals to assess for possible treatment-related tox- 2013;140(3):395-402. icity and future relapses. 18. Wimmer DB, Ro JY, Lewis A, et al. Extranodal Rosai-Dorfman dis- ease associated with increased numbers of immunoglobulin g4 plasma cells involving the colon: case report with literature review. Arch Pathol Lab Med. Conclusions 2013;137(7):999-1004. 19. Bolze A, Abhyankar A, Grant AV, et al. A mild form of SLC29A3 disor- Rosai–Dorfman disease is a nonmalignant histiocytic der: a frameshift deletion leads to the paradoxical translation of an otherwise disorder that classically presents with massive, pain- noncoding mRNA splice variant. PloS One. 2012;7(1):e29708. 20. Melki I, Lambot K, Jonard L, et al. Mutation in the SLC29A3 gene: less cervical lymphadenopathy, fever, and an elevated a new cause of a monogenic, autoinflammatory condition. Pediatrics. erythrocyte sedimentation rate. Common extranodal 2013;131(4):e1308-e1313. 21. Morgan NV, Morris MR, Cangul H, et al. Mutations in SLC29A3, encod- sites include the skin and the central nervous sys- ing an equilibrative nucleoside transporter ENT3, cause a familial histiocytosis syndrome (Faisalabad histiocytosis) and familial Rosai-Dorfman disease. PLoS tem. A high degree of clinical suspicion is needed to Genet. 2010;6(2):e1000833. make the diagnosis because the differential diagnosis 22. Zhu F, Zhang JT, Xing XW, et al. Rosai-Dorfman disease: a retrospective analysis of 13 cases. Am J Med Sci. 2013;345(3):200-210. includes both malignancy and other histiocytic disor- 23. Pulsoni A, Anghel G, Falcucci P, et al. Treatment of sinus histiocytosis ders. Histology shows emperipolesis in the histiocytes, with massive lymphadenopathy (Rosai-Dorfman disease): report of a case and literature review. Am J Hematol. 2002;69(1):67-71. and immunohistochemistry shows histiocytes positive 24. McClain KL, Natkunam Y, Swerdlow SH. Atypical cellular disorders. for S100 and CD68 and negative for CD1a. Most pa- Hematology Am Soc Hematol Educ Program. 2004:283-296.

326 Cancer Control October 2014, Vol. 21, No. 4 25. Wang KH, Chen WY, Liu HN, et al. Cutaneous Rosai-Dorfman disease: clinicopathological profiles, spectrum and evolution of 21 lesions in six patients. Br J Dermatol. 2006;154(2):277-286. 26. Maklad AM, Bayoumi Y, Tunio M, et al. Steroid-resistant extranodal Ro- sai-Dorfman disease of cheek mass and ptosis treated with radiation therapy. Case Rep Hematol. 2013;2013:428297. 27. Foucar E, Rosai J, Dorfman RF. Sinus histiocytosis with massive lymphadenopathy. Current status and future directions. Arch Dermatol. 1988;124(8):1211-1214. 28. Brenn T, Calonje E, Granter SR, et al. Cutaneous Rosai-Dorfman dis- ease is a distinct clinical entity. Am J Dermatopathol. 2002;24(5):385-391. 29. Foucar E, Rosai J, Dorfman RF, et al. The neurologic manifestations of sinus histiocytosis with massive lymphadenopathy. Neurology. 1982;32(4): 365-372. 30. Li HY, Cui HG, Zheng XY, et al. Orbital Rosai-Dorfman Disease in a fifty-eight years old woman. Pak J Med Sci. 2013;29(4):1065-1067. 31. Forest F, N’Guyen AT, Fesselet J, et al. Meningeal Rosai-Dorfman disease mimicking meningioma. Ann Hematol. 2014;93(6):937-940. 32. Foucar E, Rosai J, Dorfman RF. Sinus histiocytosis with massive lymph- adenopathy. Arch Otolaryngol. 1978;104(12):687-693. 33. Bubolz AM, Weissinger SE, Stenzinger A, et al. Potential clinical implications of BRAF mutations in histiocytic proliferations. Oncotarget. 2014;5(12):4060-4070. 34. Lima FB, Barcelos PS, Constâncio AP, et al. Rosai-Dorfman disease with spontaneous resolution: case report of a child. Rev Bras Hematol Hemoter. 2011;33(4):312-314. 35. Symss NP, Cugati G, Vasudevan MC, et al. Intracranial Rosai Dorf- man disease: report of three cases and literature review. Asian J Neurosurg. 2010;5(2):19-30. 36. Toguri D, Louie AV, Rizkalla K, et al. Radiotherapy for steroid-resistant laryngeal Rosai-Dorfman disease. Current Oncol. 2011;18(3):e158-e162. 37. Cooper SL, Chavis PS, Fortney JA, et al. A case of orbital Ro- sai-Dorfman disease responding to radiotherapy. J Pediatr Hematol Oncol. 2008;30(10):744-748. 38. Horneff G, Jürgens H, Hort W, et al. Sinus histiocytosis with massive lymphadenopathy (Rosai-Dorfman disease): response to methotrexate and mercaptopurine. Med Pediatr Oncol. 1996;27(3):187-192. 39. Jabali Y, Smrcka V, Pradna J. Rosai-Dorfman disease: successful long-term results by combination chemotherapy with prednisone, 6-mer- captopurine, methotrexate, and vinblastine: a case report. Int J Surg Pathol. 2005;13(3):285-289. 40. Cohen-Barak E, Rozenman D, Schafer J, et al. An unusual co-occur- rence of Langerhans cell histiocytosis and Rosai-Dorfman disease: report of a case and review of the literature. Int J Dermatol. 2014;53(5):558-563. 41. Simko SJ, Tran HD, Jones J, et al. Clofarabine salvage therapy in re- fractory multifocal histiocytic disorders, including Langerhans cell histiocytosis, juvenile xanthogranuloma and Rosai-Dorfman disease. Pediatr Blood Cancer. 2014;61(3):479-487. 42. Aouba A, Terrier B, Vasiliu V, et al. Dramatic clinical efficacy of cladribine in Rosai-Dorfman disease and evolution of the cytokine profile: towards a new therapeutic approach. Haematologica. 2006;91(12 suppl):ECR52. 43. Tasso M, Esquembre C, Blanco E, et al. Sinus histiocytosis with massive lymphadenopathy (Rosai-Dorfman disease) treated with 2-chlorodeoxyade- nosine. Pediatr Blood Cancer. 2006;47(5):612-615. 44. Le Guenno G, Galicier L, Fieschi C, et al. Dramatic efficiency of pe- gylated interferon in sinus histiocytosis with massive lymphadenopathy. Br J Dermatol. 2011;164(1):213-215. 45. Le Guenno G, Galicier L, Uro-Coste E, et al. Successful treatment with azathioprine of relapsing Rosai-Dorfman disease of the central nervous system. J Neurosurg. 2012;117(3):486-489. 46. Löhr HF, Gödderz W, Wölfe T, et al. Long-term survival in a patient with Rosai-Dorfman disease treated with interferon-alpha. Eur J Cancer. 1995;31A(13-14):2427-2428. 47. Petschner F, Walker UA, Schmitt-Gräff A, et al. “Catastrophic systemic lupus erythematosus” with Rosai-Dorfman sinus histiocytosis. Successful treatment with anti-CD20/rituximab [in German]. Dtsch Med Wochenschr. 2001;126(37):998-1001. 48. Alqanatish JT, Houghton K, Bond M, et al. Rituximab treatment in a child with rosai-dorfman disease and systemic lupus erythematosus. J Rheumatol. 2010;37(8):1783-1784. 49. Pagel JM, Lionberger J, Gopal AK, et al. Therapeutic use of rituximab for sinus histiocytosis with massive lymphadenopathy (Rosai-Dorfman disease). Am J Hematol. 2007;82(12):1121-1122. 50. Utikal J, Ugurel S, Kurzen H, et al. Imatinib as a treatment option for systemic non-Langerhans cell histiocytoses. Arch Dermatol. 2007;143(6): 736-740.

October 2014, Vol. 21, No. 4 Cancer Control 327 LCH is a rare and often underdiagnosed histiocytic disorder with an unknown etiology.

White Butterfly. Photograph courtesy of Sherri Damlo. www.damloedits.com.

Langerhans Cell Histiocytosis Nanette Grana, MD

Background: Langerhans cell histiocytosis (LCH) is a rare histiocytic disorder of unknown etiopathogenesis. Its clinical presentation is variable and ranges from isolated skin or bone disease to a life-threatening multisystem condition. LCH can occur at any age but is more frequent in the pediatric population. A neoplastic origin of this disease has been suggested due to the discovery of the mutually exclusive activating somatic BRAF V600E and MAP2K1 gene mutations that occur in about 75% of patients. Methods: A survey of recent literature focused on the diagnosis, management, and prognosis of Langerhans cell histiocytosis. Data were collected, analyzed, and discussed with an emphasis on contemporary clinical practice. Results: LCH is common in the pediatric population; compared with adults, children usually have a more aggressive clinical course that requires systemic chemotherapy. Patients with low-risk LCH have an excellent prognosis and a long-term survival rate that may be as high as 99%; by contrast, patients with high-risk LCH have a survival rate close to 80%. Typically, adult patients present with limited skin or bone involvement that can be treated with surgical resection or focal radiation therapy, resulting in an overall survival rate of 100%. Smoking cessation can result in the improvement of respiratory symptoms and the spontaneous resolution of pulmonary LCH. Targeted therapy with BRAF inhibitors has been used in select patients with LCH, and the results have been encouraging. Conclusions: Our understanding of LCH has improved in the last 20 years. Available treatment regimens can control the disease in the majority of patients. The discovery of novel driver mutations and the development of targeted therapy promise better outcomes with fewer long-term therapy-related adverse events, particularly for pediatric and adolescent patients.

Introduction Histiocytic disorders are composed of a group of di- verse disorders with a common primary event, ie, the accumulation and infiltration of monocytes, macro- From the Division of Hematology/Oncology, All Children’s Hospital, phages, and dendritic cells in the affected tissues. St Petersburg, Florida. Langerhans cell histiocytosis (LCH), a dendritic disor- Submitted April 1, 2014; accepted August 14, 2014. der, is believed to affect fewer than 1 in 200,000 chil- Address correspondence to Nanette Grana, MD, All Children’s dren; however, any age group can be affected.1 LCH Hospital, 501 6th Avenue South, St Petersburg, FL 33701. E-mail: is the result of the clonal proliferation of immunophe- [email protected] notypical and functionally immature LCH cells, as well No significant relationship exists between the author and the com- panies/organizations whose products or services may be referenced as eosinophils, macrophages, lymphocytes, and, occa- in this article. sionally, multinucleated giant cells.2,3 Other terms for

328 Cancer Control October 2014, Vol. 21, No. 4 LCH include histiocytosis X, eosinophilic granuloma, or both are required for a definitive diagnosis. The Letterer–Siwe disease, and Hand–Schüller–Christian expression of langerin confirms the presence of Bir- disease; however, the preferred term is LCH because beck granules, the cytoplasmic organelles typically the pathological histiocyte common to all of these found in Langerhans cells.4 diagnoses was identified via electron microscopy to have characteristic Birbeck granules identical to those Pathophysiology and Etiology of the Langerhans cell found in the dermal–epidermal The diagnosis of LCH is based on hematological and junction of the skin.4Additional research has shown histological criteria established by the Histiocyte that the pathological histiocyte has the gene expres- Society in 1987.6 Lesions seen in cases of LCH are sion profile of a myeloid-derived precursor dendritic polymorphous that typically vary little from site to cell, not the Langerhans cell in the skin.5 site and from patient to patient; they also feature a Controversy exists regarding whether the clonal monoclonal population of CD1a+ monocytes. proliferation of LCH cells results from a malignant The cause of LCH is unknown. Researchers have transformation or is the result of an immunological debated whether LCH represents a true malignancy stimulus.6 Regardless of the mechanism responsible or a reactive immune condition.10 Studies favoring for the clonal proliferation, the primary treatment, if that LCH is a malignancy have demonstrated that LCH necessary, involves chemotherapeutic agents. Select cells from nonpulmonary lesions are monoclonal,2,8 chemotherapeutic drugs also have immunomodula- whereas other supportive findings include the im- tory activity. mature appearance of lesional LCH, the presence of The nomenclature of histiocytic disorders has cell-cycle dysregulation within lesions, and the pres- changed in the last 50 years. The current nomencla- ence of significant telomere shortening of the LCH ture, which represents combined efforts of the His- cells compared with Langerhans cells from other in- tiocyte Society and the World Health Organization, flammatory lesions.11 By contrast, research supporting separates LCH disorders from non-LCH histiocytic LCH as a reactive process emphasize that clonal cell syndromes and malignancies.7 The nomenclature used populations are commonly present within the immune for LCH indicates the disease extent, which may in- system and that phenotypically immature Langerhans volve a single organ system (unifocal or multifocal) or cells often accumulate in areas of inflammation.12 The multiple organs (involving a limited number or they lesional expression of cytokines, most recently inter- may be disseminated8; Table 19). Treatment decisions leukin 17, which is a key cytokine in several autoim- for patients are based on whether low- or high-risk mune disorders, has been reported.12 organs are involved and whether LCH presents as a Badalian-Very et al13 and Davies et al14 have pro- single- or multisystem disease.8 vided new insight into LCH, demonstrating that about 50% of studied cases exhibit somatic-activating mu- Diagnostic Criteria tations of the proto-oncogene BRAF. The study by The diagnosis of LCH is based on a histological and Badalian-Very et al13 described the first molecular ab- immunophenotypical examination of tissue. The main normality implicated in the pathogenesis of LCH and feature is the morphological identification of the char- is important for several reasons. The identification of acteristic Langerhans cells. In addition, positive stain- activating BRAF gene mutations strongly supports the ing of the lesional cells with CD1a, langerin (CD207), hypothesis that LCH is a neoplastic process, at least in some cases. This observation has clinical implica- Table 1. — Clinical Classification of tions because it suggests that alternative therapeutic Langerhans Cell Histiocytosis approaches aimed at targeting active BRAF should be tested in the setting of LCH. Furthermore, this Single System Unifocal or multifocal organ system involvement mutation may provide a means to assess the status of Unifocal or multifocal bone involvement minimal residual disease in a subset of patients with LCH. Although the study did not discern whether Skin LCH is a neoplasm or an immune dysregulation, its Lymph node results provided critical information to move research in the right direction.13 Brown et al15 recently reported Hypothalamic/pituitary/central nervous system on the novel somatic MAP2K1 mutations in approxi- Other (eg, thyroid) mately 50% of patients with LCH who tested negative for BRAF V600E using a next-generation sequencing Multisystem Involvement of ≥ 2 organs or systems platform. Most of the mutations were in frame dele- From Broadbent V, Gadner H. Current therapy for Langerhans cell tions. Mutations in BRAF and MAP2K1 were mutually histiocytosis. Hematol Oncol Clin North Am. 1998;12(2):327-338.© 1998 exclusive, suggesting that MAP2K1 has an important Reproduced with permission from Elsevier. role in the pathogenesis of LCH. Targeted therapy

October 2014, Vol. 21, No. 4 Cancer Control 329 with BRAF, MEK1, or ERK inhibitors may change the is no longer active but fibrosis and sclerosis are still treatment algorithm of LCH in the near future. present.19 Liver transplantation is the only alternate treatment when hepatic function worsens.19 Clinical Presentation Spleen: Massive splenomegaly may lead to cy- Single System topenias because of hypersplenism and may cause Skin: Seborrheic involvement of the scalp may be respiratory compromise. Typically, splenectomy pro- mistaken for prolonged cradle cap in infants. Infants vides transient relief of the cytopenias because the sometimes present with Hashimoto–Pritzker disease increasing size of the liver and reticuloendothelial (purplish papules on their body), which is also known activation result in peripheral blood sequestration and as congenital self-healing reticulohistiocytosis. This destruction. Splenectomy should only be performed manifestation may be self-limited and oftentimes as a life-saving measure. disappears without therapy. Patients must be closely Lungs: Lungs are less frequently involved in chil- watched for systemic disease, which may present fol- dren than in adults due in part to smoking, which is a lowing the initial appearance of skin lesions. key etiological factor.20 Tachypnea with rib retractions Children and adults may also develop a red pap- is often the first and only clinical sign. The cystic/ ular rash on their groin, abdomen, back, or chest that nodular pattern of the disease reflects the cytokine-in- resembles a rash caused by Candida. They may also duced destruction of lung tissue. Pulmonary involve- develop seborrheic scalp involvement. ment is present in approximately 25% of children with Oral Cavity: Lesions in the oral cavity may pre- multisystem LCH.21 cede evidence of LCH elsewhere and may include Bone Marrow: Most patients with bone marrow hypermobile teeth, gingival hypertrophy, or ulcers of involvement are young children with diffuse disease in the mucosa, tongue, or lips. the liver, spleen, lymph nodes, and skin; these patients Bone: Lytic skull lesions are the most common usually present with significant thrombocytopenia and sites of LCH in children, and the lesion may be asymp- anemia with or without neutropenia.22 Patients with tomatic or painful and is often surrounded by a soft-tis- LCH who are considered at very high risk may present sue mass.16 Other frequently involved skeletal sites are with hemophagocytosis involving the bone marrow.10 the ribs, humerus, and vertebra.17 Spine lesions may Central Nervous System: Neurological problems result in the collapse of the vertebra plana. Orbital involving deficits in cognition, as well as behavior- sites may be affected; proptosis from LCH of the orbit al disturbances and neuromotor dysfunction due to mimics neuroblastoma or rhabdomyosarcoma.18 central nervous system involvement affect at least Pituitary Gland: The posterior part of the pitu- 10% of all patients with LCH and 19% of patients itary can be affected and may lead to central diabetes with multisystem disease.23 Within the last 15 years, insipidus. Involvement of the anterior pituitary may the knowledge and understanding of the findings result in a failure to grow and delayed or precocious on magnetic resonance imaging of the brain in pa- puberty. tients with LCH have grown.24 Classification of central nervous system disease by the Histiocyte Society is Multisystem Disease referenced in Table 2.25 In multisystem LCH, the disease presents in multi- In the hypothalamic pituitary region, the charac- ple organs or body systems, including bone, the ab- teristic features seen on magnetic resonance imaging domen, the gastrointestinal tract (liver and spleen), consist of an enlarged pituitary stalk with the potential lungs, bone marrow, the endocrine and central ner- progression to space-occupying tumors that extend vous systems, skin, and the lymph nodes. to the pituitary and the hypothalamus. In the setting Bone and Other Organ Systems: Patients with of diabetes insipidus, typically a “loss of bright spot” LCH may present with single- or multisystem, multi- can be seen, correlating with the loss of antidiuretic focal bone lesions. hormone-containing granules. The LCH-associated Abdomen and Gastrointestinal Tract: In the pineal gland abnormalities comprise solid masses setting of LCH, the liver and spleen are considered or cystic lesions. Other space-occupying tumorous high-risk organs and any disease involvement of these lesions may occur, although rarely, in the meninges, organs affects a patient’s prognosis. The liver and choroid plexus, and in the brain parenchyma. spleen may become enlarged due to the direct infil- Another frequent presentation of LCH involving tration of LCH cells or as a secondary phenomenon the central nervous system, excluding hypothalamic of excess cytokines, which activate macrophages or pituitary region disease, is a combination of patholog- infiltrate lymphocytes around the bile ducts. A serious ical changes in the cerebellum, basal ganglia, and/or complication of hepatic LCH is sclerosing cholangi- pons, with characteristic patterns seen on magnetic tis.19 A total of 75% of children with sclerosing cholan- resonance imaging. Prosch et al7 termed this pattern gitis will not respond to chemotherapy because LCH “radiological neurodegeneration.”

330 Cancer Control October 2014, Vol. 21, No. 4 Table 2. — Classification of Magnetic Resonance Imaging Treatment progress for LCH has benefited from the for Langerhans Cell Histiocytosis and Intracranial Lesions adoption of standard diagnostic criteria, the standard evaluation of the extent of disease, and stratified treat- Tumorous/Granulomatous Lesions ment.28 International efforts during the last 20 years have shown that combination therapy with vinblas- Granulomatous lesions of skull bones tine/prednisone is an effective therapy for multisystem Hypothalamic pituitary lesions LCH. Trials conducted by the Histiocyte Society con- firmed this regimen as standard therapy for multisys- Hypothalamus tem LCH with and without risk organ involvement.29,30 Anterior pituitary Risk organs and their involvement were defined according to modified Lahey criteria as follows31: Choroid plexus • Hematopoietic: Anemia and/or leukopenia Meninges and/or thrombocytopenia Nontumorous • Liver: Enlargement > 3 cm below the costal Nongranulomatous margin, dysfunction, or both • Spleen: Enlargement > 2 cm below the costal Cerebellar white matter margin Brainstem/pons • Lung: Typical changes via high-resolution com- puted tomography, histopathological diagnosis, Supratentorial white matter or both Atrophy Some cases of LCH have limited involvement and may not require treatment. Treatment of localized skin Cerebellar disease may be unnecessary because, in many cases Midbrain (typically in infants), the lesions will spontaneously regress. Single bone lesions tend to spontaneously Supratentorial resolve during a period of months to years and may Modified from Grois N, Fahrner B, Arceci RJ, et al. Central nervous initiate healing after biopsy. system disease in Langerhans cell histiocytosis. J Pediatr. 2010;156(6): 873-881, 881.e1. © 2010 Reproduced with permission from Elsevier. Preliminary data from a trial conducted by the Histiocyte Society suggest that, for multisystem dis- ease, the treatment duration of 12 months reduces Clinical symptoms depend on the site and the the risk of reactivation compared with 6 months of type of involvement within the central nervous system. total treatment.32 Patients with multisystem LCH at Diabetes insipidus, which represents the hallmark of diagnosis may have a variable clinical course. Those infiltration of the hypothalamic pituitary region, is without risk organ involvement, as well as those with seen in as many as 25% of patients with LCH and as risk organ involvement but who respond to standard many as 50% of patients with multisystem disease.26,27 initial therapy, have an excellent chance of long-term Tumorous lesions of the meninges or choroid survival. Combination prednisone/vinblastine has plexus can lead to headaches, seizures, and other focal been proven to be an effective treatment with minimal symptoms as well as the obstruction of the ventricles toxicity; therefore, it is the standard initial therapy for when intracranial pressure is increased. all patients in whom systemic therapy is indicated.30,33 LCH-associated neurodegenerative lesions are as- Patients with risk organ involvement who do not re- sociated with a highly variable clinical picture.25 Many spond within the first 6 weeks of therapy, particularly patients will be free of neurological symptoms despite those with evident clinical progression, have an un- typical changes of radiological neurodegeneration that favorable prognosis.28,30,34 For such patients, an early have been seen on magnetic resonance imaging for intensification of therapy is justified. years. However, other patients may have clinical neuro- degeneration, with a spectrum of clinical signs ranging Salvage Therapy from mild abnormalities of the reflexes, discrete gait The optimal treatment for relapsed or recurrent LCH disturbances, dysarthria, dysphagia, and motor spas- has not been determined, although several regimens ticity to pronounced ataxia, behavioral disturbances, exist. Patients with recurrent bone disease who have learning difficulties, or severe psychiatric disease. recurrences months after stopping vinblastine/pred- nisone may benefit from treatment with vinblastine/ Therapy prednisone/mercaptopurine.35 Cladribine has also Treatment decisions are based on whether the been shown to be effective for recurrent, low-risk high- or low-risk organs are involved and whether LCH.28 For patients with recurrent or refractory mul- the disease is single system or multisystem (Fig). tisystem or multiorgan involvement, few treatment

October 2014, Vol. 21, No. 4 Cancer Control 331 options exist; however, promising results have been used, duration of follow-up, and method of data collec- reported with combination cladribine/cytarabine36 tion.38 Children at low risk for organ involvement have and stem cell transplantation.37 approximately a 20% likelihood of developing long- term sequelae.38 Patients with multisystem involve- Pediatric Population ment have a 71% likelihood of developing long-term The reported overall incidence of the long-term conse- problems.38-41 The most commonly reported perma- quences of LCH ranges from 20% to 70%. The reason nent consequences are diabetes insipidus, orthopedic for this wide variation is due to sample size, therapy abnormalities, hearing loss, and neurological issues.

Treatment of Low-Risk Disease (single- or multisystem)

Single or multiple bones Multisystem Skin Single bone (lymph nodes, gastrointestinal Central nervous system involvement, diabetes)

Observation Curettage Chemotherapy Chemotherapy (vinblastine) + steroids (vinblastine) + steroids for 6 months for 6–12 months

Topical steroids Radiation therapy

Topical mechlorethamine

Phototherapy

Treatment of High-Risk Disease (multisystem)

Multisystem (bone marrow, liver, spleen, lungs)

Chemotherapy (vinblastine), steroids, 6-mercaptopurine ± methotrexate for 12 months

Fig. — Treatment algorithm for childhood Langerhans cell histiocytosis.

332 Cancer Control October 2014, Vol. 21, No. 4 Patients with reactivations or chronic disease may up to 20% of patients, particularly among those with experience severe permanent consequences that re- multisystem risk organ involvement and age younger duce their quality of life, particularly when the dis- than 2 years. ease affects the central nervous system, the lungs, or leads to hormone deficiencies, neurodegenerative Conclusions syndrome, and lung fibrosis, among other issues.19 Langerhans cell histiocytosis is a rare disease. In the United States, researchers believe that the disease Adult Population goes underdiagnosed. It is most commonly seen in With the exception of pulmonary LCH, the natural young children, but any age group can be affect- history of the disease among adults is unknown. It ed.1 The cause of the disease is unknown, although is estimated that 1 to 2 adult cases of LCH occur per the possibilities of the malignant transformation of 1 million people42; however, the true incidence is un- the myeloid progenitor precursor of Langerhans cell known because this disorder is often underdiagnosed. histiocytosis and immune dysregulation are being Adults with LCH may have symptoms and signs for explored.2-4 Recent discoveries of driver mutations months before receiving a definitive diagnosis. In ad- in BRAF and MAP2K1 genes could change the thera- dition, predominance of lung disease exists in adults peutic armamentarium in Langerhans cell histiocyto- with LCH.43 The lack of clinical trials limits the ability sis from chemotherapy to targeted therapy, resulting of health care professionals to make evidence-based in a better prognosis and a lower rate of long-term recommendations for adult patients with LCH. therapy-related adverse events.

Prognosis References A recent review of the Surveillance, Epidemiology, and 1. Arceci RJ. The histiocytoses: the fall of the Tower of Babel. Eur J Cancer. 1999;35(5):747-769. End Results database revealed that 828 US pediatric 2. Yu RC, Chu C, Buluwela L, et al. Clonal proliferation of Langerhans cases with histiocytoses had been diagnosed between cells in Langerhans cell histiocytosis. Lancet. 1994;343(8900):767-768. 3. Allen CE, Li L, Peters TL, et al. Cell-specific gene expressions in 1973 and 2010 and an improved survival rate was Langerhans cell histiocytosis lesions reveals a distinct profile compared with seen during the last 40 years.44 epidermal Langerhans cells. J lmmunol. 2010;184(8):4557-4567. 4. Lau SK, Chu PG, Weiss LM. Immunohistochemical expression of Lan- In a large national survey study from South Ko- gerin in Langerhans cell histiocytosis and non-Langerhans cell histiocytic rea, 603 patients with LCH were identified between disorders. Am J Surg Pathol. 2008;32(4):615-619. 5. Davies H, Bignell GR, Cox C, et al. Mutations of the BRAF gene in 1986 and 2010. The majority of patients (69.5%) pre- human cancer. Nature. 2002;417(6892):949-954. sented with single-system involvement, 14.1% with 6. Bechan GI, Egeler RM, Arceci RJ. Biology of Langerhans cells and Langerhans cell histiocytosis. Int Rev Cytol. 2006;254:1-43. multisystem disease without risk organ involvement, 7. Writing Group of the Histiocyte Society. Histiocytosis syndromes in and 16.4% with multisystem disease with risk organ children. Lancet. 1987;1(8526):208-209. 8. National Cancer Institute. Langerhans cell histiocytosis treatment involvement. The 5-year overall survival rates in all (PDQ®). http://www.cancer.gov/cancertopics/pdq/treatment/lchistio/Health- 3 prognostic groups were 99.8%, 98.4%, and 77.0%. Professional/. Last modified June 4, 2014. Accessed September 9, 2014. 9. Broadbent V, Gadner H. Current therapy for Langerhans cell histiocy- Long-term adverse events of therapy were identified tosis. Hematol Oncol Clin North Am. 1998;12(2):327-338. in 16.4% patients.45 10. Willman CL, Busque L, Griffith BB, et al. Langerhans’-cell histiocytosis (histiocytosis X)—a clonal proliferative disease. N Engl J Med. 1994;331(3): In a prospective clinical study from Japan, 91 pa- 154-160. tients with LCH were treated with a combined chemo- 11. Egeler RM, Neglia JP, Puccetti DM, et al. Association of Langerhans 46 cell histiocytosis with malignant neoplasms. Cancer. 1993;71(3):865-873. therapy regimen between 1996 and 2001. Five-year 12. Martin-Duverneuil N, ldbaih A, Huong-Xuan K, et al. MRI features of overall survival rates for patients with single-system degenerative Langerhans cell histiocytosis. Eur Radiol. 2006;16(9):2074-2082. 13. Badalian-Very G, Vergilio JA, Degar BA, et al. Recurrent BRAF muta- multifocal and multisystem disease were 100% and tions in Langerhans cell histiocytosis. Blood. 2010;116(11):1919-1923. 94.4%, respectively.46 14. Davies H, Bignell GR, Cox C, et al. Mutations of the BRAF gene in human cancer. Nature. 2002;417(6892):949-954. In a single institutional, retrospective study from 15. Brown NA, Furtado LV, Betz BL, et al. High prevalence of somatic Italy, 121 patients with LCH were treated between MAP2K1 mutations in BRAF V600E negative Langerhans cell histiocytosis. 47 Blood. 2014;124(10):1655-1658. 1968 and 2009. The overall survival rate of the group 16. Slater JM, Swarm OJ. Eosinophilic granuloma of bone. Med Pediatr at 10 years was 93%. Patients 2 years or younger had Oncol. 1980;8(2):151-164. 17. Peng XS, Pan T, Chen LY, et al. Langerhans’ cell histiocytosis of the a worse prognosis; their overall survival rate was 82% spine in children with soft tissue extension and chemotherapy. Int Orthop. compared with 97% for patients older than 2 years. 2009;33(3):731-736. 18. Erly WK1, Carmody RF, Dryden RM. Orbital histiocytosis X. AJNR Am Patients with multisystemic disease with risk organ J Neuroradiol. 1995;16(6):1258-1261. involvement also had worse outcomes compared with 19. Braier J, Ciocca M, Latella A, et al. Cholestasis, sclerosing cholan- 47 gitis, and liver transplantation in Langerhans cell histiocytosis. Med Pediatr. patients without risk organ involvement. 2002;38(3):178-182. Altogether, the above data suggest that the prog- 20. Vassallo R, Ryu JH, Colby TV, et al. Pulmonary Langerhans’-cell his- tiocytosis. N Engl J Med. 2000;342(26):1969-1978. nosis of patients with LCH has improved within the 21. Ronceray L, Pötschger U, Janka G, et al. Pulmonary involvement in last 40 years following the advent of modern chemo- pediatric-onset multisystem Langerhans cell histiocytosis: effect on course and outcome. J Pediatr. 2012;161(1):129-133.e1-3. therapy regimens. Despite excellent outcomes ob- 22. McClain K, Ramsay NK, Robison L, et al. Bone marrow involvement served in the majority of patients, LCH can be fatal in in histiocytosis X. Med Pediatr Oncol. 1983;11(3):167-171.

October 2014, Vol. 21, No. 4 Cancer Control 333 23. Hayward J, Packer R, Finlay J. Central nervous system and Langerhans’ cell histiocytosis. Med Pediatr Oncol. 1990;18(4):325-328. 24. Martin-Duverneuil N, Idbaih A, Hoang-Xuan K, et al. MRI features of neurodegenerative Langerhans cell histiocytosis. Eur Radiol. 2006;16(9): 2074-2082. 25. Grois N, Fahrner B, Arceci RJ, et al. Central nervous system disease in Langerhans cell histiocytosis. J Pediatr. 2010;156(6):873-881, 881.e1. 26. Donadieu J, Rolon MA, Thomas C, et al. Endocrine involvement in pediatric-onset Langerhans’ cell histiocytosis: a population-based study. J Pediatr. 2004;144(3):344-350. 27. Marchand I, Barkaoui MA, Garel C, et al. Central diabetes insipidus as the inaugural manifestation of Langerhans cell histiocytosis: natural history and medical evaluation of 26 children and adolescents. J Clin Endocrinol Metab. 2011;96(9):E1352-E13560. 28. Minkov M, Grois N, Heitger A, et al. Response to initial treatment of multisystem Langerhans cell histiocytosis: an important prognostic indicator. Med Pediatr Oncol. 2002;39(6):581-585. 29. McClain KL. Drug therapy for the treatment of Langerhans cell histio- cytosis. Expert Opin Pharmacother. 2005;6(14):2435-2441. 30. Gadner H, Grois N, Pötschger U, et al. Improved outcome in multisystem Langerhans cell histiocytosis is associated with therapy intensification. Blood. 2008;111(5):2556-2562. 31. Lahey ME. Prognostic factors in histiocytosis X. Am J Pediatr Hematol Oncol. 1981;3(1):57-60. 32. Gadner H, Minkov M, Grois N, et al. Therapy prolongation improves outcome in multisystem Langerhans cell histiocytosis. Blood. 2013;121(25):5006-5014. 33. Minkov M, Steiner M, Pötschger U, et al. Reactivations in multisystem Langerhans cell histocytosis: data of the international LCH registry. J Pediatr. 2008;153(5):700-705, 705.e1-2. 34. Gadner H, Grois N, Arico M, et al. A randomized trial of treatment for multisystem Langerhans’ cell histiocytosis. J Pediatr. 2001;138(5):728-734. 35. Titgemeyer C, Grois N, Minkov M, et al. Pattern and course of sin- gle-system disease in Langerhans cell histiocytosis data from the DAL-HX 83- and 90-study. Med Pediatr Oncol. 2001;37(2):108-114. 36. Bernard F, Thomas C, Bertrand Y, et al. Multi-centre pilot study of 2-chlorodeoxyadenosine and cytosine arabinoside combined chemotherapy in refractory Langerhans cell histiocytosis with hematologic dysfunction. Eur J Cancer. 2005;41(17):2682-2689. 37. Kinugawa N, Imashuku S, Hirota Y, et al. Hematopoietic stem cell trans- plantation (HSCT) for Langerhans cell histiocytosis (LCH) in Japan. Bone Marrow Transplant. 1999;24(8):935-938. 38. Haupt R, Nanduri V, Calevo MG, et al. Permanent consequences in Langerhans cell histiocytosis patients: a pilot study from the Histiocyte Soci- ety-Late Effects Study Group. Pediatr Blood Cancer. 2004;42(5):438-444. 39. Donadieu J, Rolon MA, Pion I, et al. Incidence of growth hormone deficiency in pediatric-onset Langerhans cell histiocytosis: efficacy and safety of growth hormone treatment. J Clin Endocrinol Metab. 2004;89(2):604-609. 40. Komp DM. Long-term sequelae of histiocytosis X. Am J Pediatr Hematol Oncol. 1981;3(2):163-168. 41. Willis B, Ablin A, Weinberg V, et al. Disease course and late sequelae of Langerhans’ cell histiocytosis: 25-year experience at the University of Cal- ifornia, San Francisco. J Clin Oncol. 1996;14(7):2073-2082. 42. Baumgartner I, von Hochstetter A, Baumert B, et al. Langerhans’-cell histiocytosis in adults. Med Pediatr Oncol. 1997;28(1):9-14. 43. Girschikofsky M, Arico M, Castillo D, et al. Management of adult patients with Langerhans cell histiocytosis: recommendations from an expert panel on behalf of Euro-Histio-Net. Orphanet J Rare Dis. 2013;8:72. 44. Golpanian S, Tashiro J, Gerth DJ, et al. Pediatric histiocytoses in the United States: incidence and outcomes. J Surg Res. 2014;190(1):221-229. 45. Kim BE, Koh KN, Suh JK, et al. Clinical features and treatment out- comes of Langerhans cell histiocytosis: a nationwide survey from Korea his- tiocytosis working party. J Pediatr Hematol Oncol. 2014;36(2):125-133. 46. Morimoto A, Ikushima S, Kinugawa N, et al. Improved outcome in the treatment of pediatric multifocal Langerhanscell histiocytosis: results from the Japan Langerhans Cell Histiocytosis Study Group-96 protocol study. Cancer. 2006;107(3):613-619. 47. Maria Postini A, del Prever AB, Pagano M, et al. Langerhans cell histio- cytosis: 40 years’ experience. J Pediatr Hematol Oncol. 2012;34(5):353-358.

334 Cancer Control October 2014, Vol. 21, No. 4 HSCT has an evolving role

in the treatment of some

aggressive lymphoproliferative

and histiocytic disorders.

Mottled Star. Photograph courtesy of Sherri Damlo. www.damloedits.com.

Transplantation in Rare Lymphoproliferative and Histiocytic Disorders Alexis Cruz-Chacon, MD, John Mathews, MD, and Ernesto Ayala, MD

Background: Some uncommon lymphoproliferative and histiocytic disorders may present with an aggressive course and require hematopoietic stem cell transplantation (HSCT) as part of the therapeutic approach. Methods: Published research on the use of HSCT for the treatment of these disorders was reviewed and summarized. Results: Allogeneic HSCT may be indicated in patients with blastic plasmacytoid dendritic cell neoplasia, familial or secondary recurrent hemophagocytic lymphohistiocytosis, and resistant Langerhans cell histiocytosis. Autologous HSCT may be considered in patients with Castleman disease resistant to treatment. No role has been established for the use of HSCT for dendritic cell sarcoma. Conclusions: HSCT has an evolving role in the treatment of select aggressive lymphoproliferative and histiocytic disorders.

Introduction treatment is not dictated by well-designed prospective Atypical lymphoproliferative and histiocytic disorders trials. Some are aggressive — similar to high-grade are composed of several entities that have in com- lymphoma — and transplantation is commonly used mon the presence of lymphoproliferative or histiocytic as initial therapy or following relapse. Nearly all trans- cells with variable degrees of atypia, a poorly defined plantation-related data have been derived from case natural history, and an unclear prognosis. Most of reports and small, uncontrolled series.1-5 these entities are infrequent and, as a consequence, In this review, selected entities, including blastic plasmacytoid dendritic cell neoplasm (BPDCN), he- From the Department of Blood and Marrow Transplantation at the mophagocytic lymphohistiocytosis­ (HLH), Langerhans­ H. Lee Moffitt Cancer Center & Research Institute, Tampa, Florida. cell histiocytosis (LCH), dendritic cell sarcoma,­ and Dr Cruz-Chacon is now in private practice in Puerto Rico and Castleman disease, were included for which data on Dr Mathews is in private practice in Dallas, Texas. transplantation outcomes were available. Whenever Submitted July 15, 2014; accepted August 18, 2014. possible, the role of transplantation in the treatment Address correspondence to Ernesto Ayala, MD, Department of Blood and Marrow Transplantation, Moffitt Cancer Center, 12902 Mag- of each entity was approximated. A summary of the in- nolia Drive, FOB-3 BMT PROG, Tampa, Florida 33612. E-mail: dications for transplantation in these rare lymphopro- [email protected] liferative and histiocytic disorders is found in Table 1. This article may discuss treatment options that have not been ap- proved for use by the US Food and Drug Administration. Blastic Plasmacytoid Dendritic Cell Neoplasm No significant relationships exist between the authors and the com- panies/organizations whose products or services may be referenced BPDCN is a rare, clinically aggressive hematologi- in this article. cal malignancy. This tumor was initially described in

October 2014, Vol. 21, No. 4 Cancer Control 335 Table 1. — Indications for Hematopoietic Stem Cell Transplantation in Select Lymphoproliferative and Histiocytic Disorders Among the Pediatric Population

Disorder Type of Transplantation Indication Conditioning

Blastic plasmacytoid Allogeneic Consider in first remission for all patients Myeloablative or reduced intensity dendritic cell neoplasia Autologous (limited)

Hemophagocytic Allogeneic All patients with the familial form of disease Myeloablative or reduced intensity lymphohistiocytosis Patients with the recurrent or resistant secondary form of the disease Patients with the malignancy-associated form of the disease

Langerhans cell histiocytosis Allogeneic Resistant, recurrent, or high-risk disease Myeloablative or reduced intensity

Dendritic cell sarcoma Allogeneic or autologous No role —

Castleman disease Autologous Multicentric following the failure of High-dose melphalan systemic therapy

1995 as acute agranular CD4+ natural killer (NK) cell for high-risk acute lymphoblastic leukemia without leukemia6; however, the term BPDCN was introduced the need for hematopoietic stem cell transplantation by the World Health Organization7 following the dis- (HSCT); by contrast, BPDCN is more aggressive in covery that the entity arises from the precursors of adults.15 Prospective studies defining the most optimal plasmacytoid dendritic cells (type 2 dendritic cells).8-11 frontline therapy in adults are lacking, whereas retro- The most common presentation in patients with spective studies favor acute lymphoblastic leukemia or BPDCN is brown to violaceous cutaneous lesions, aggressive non-Hodgkin lymphoma therapies for the plaques, or tumors with or without bone marrow initial treatment of adults diagnosed with BPDCN.15,18 involvement and leukemic dissemination.12,13 Some However, most patients responding to initial therapy patients may have a leukemic presentation without will relapse within 2 years irrespective of the type of skin involvement.14 Most patients present with cyto- chemotherapy received.12 penias, lymphadenopathy, and/or splenomegaly.12,15 For additional information on BPDCN, please see Liver, tonsil, paranasal cavity, lung, eye, central ner- the article by Dr Riaz and colleagues on page 279. vous system, and paravertebral involvement have all been reported.12,15 Identifying the specific immuno- Hematopoietic Stem Cell Transplantation phenotype of tumor cells is essential for diagnosis. Due to the reported poor and transient responses to ini- BPDCN malignant cells coexpress CD4 and CD56, tial chemotherapy, adults with BPDCN are frequently and the expression of other plasmacytoid dendrit- offered allogeneic HSCT.18 Most of the available data ic cell–associated markers, including CD123, blood regarding the outcomes following allogeneic HSCT dendritic cell antigen 2, T-cell leukemia 1, and SPIB, come from small retrospective studies.1,15,19 The larg- is useful for the diagnosis of BPDCN.11 Differential est retrospective study included 34 patients from a diagnoses include CD56+ acute myeloid leukemias, European database who received myeloablative con- nasal-type extranodal NK/T-cell lymphoma, subcu- ditioning for allogeneic HSCT.1 The majority of pa- taneous panniculitis-like T-cell lymphoma, and cuta- tients received stem cells from a sibling or matched neous T-cell lymphoma. About two-thirds of patients unrelated donor. The overall survival rate was 41% with BPDCN have genetic abnormalities, but no di- at 3 years, and no relapses were observed 27 months agnostic cytogenetic or molecular changes have been following HSCT.1 Receiving transplantation in the first identified.16 complete remission was associated with a more favor- BPDCN is characterized by an aggressive behavior able outcome than in those transplanted with more with rapid systemic dissemination. Despite an initial advanced disease. When the analysis was restricted to response to systemic chemotherapy, most patients this group of patients, the 3-year disease-free survival relapse and have a poor rate of overall survival (me- and overall survival rates were 45% and 60%, respec- dian, 12–14 months).12,17 The optimal treatment for tively.1 Age, donor, source, and presence of chronic BPDCN is unknown and small retrospective analyses graft-vs-host disease had no impact on survival on alone are available to guide therapy.18 Studies found univariate analysis. that the clinical course and response to therapy differ A smaller, single institution case series demon- among children compared with adults.15 Children have strated the feasibility of allogeneic HSCT in older pa- a good response to similar treatment regimens used tients with the use of reduced intensity conditioning.19

336 Cancer Control October 2014, Vol. 21, No. 4 Four of the 6 adults studied with BPDCN (median broad category that includes autoimmune disorders age, 67 years; range, 55–80 years) underwent reduced and infections associated with HLH (commonly vi- intensity conditioning for allogeneic HSCT. Two pa- ral, although bacterial, fungal, and protozoan infec- tients who received transplantations were in complete tions have been reported28-31) as well as malignancy remission and had sustained remissions at 57 and associated with HLH.32 Malignancy-associated HLH 16 months, respectively.19 The other 2 patients with is typically associated with hematological disorders, active disease relapsed at 6 and 18 months following particularly lymphoma.33-35 The most common types transplantation.19 Therefore, these data suggest that of lymphoma associated with HLH are NK/T-cell and reduced intensity conditioning may be considered for diffuse large B-cell lymphoma.36 older or comorbid patients who are not candidates for No single diagnostic test will confirm HLH; rather, myeloablative conditioning for allogeneic HSCT.18,19 clinical and laboratory data must be used to confirm Several small case series and reports with single the diagnosis. In the first prospective study of HLH cases have been reported of autologous HSCT for the performed internationally, a diagnosis was based on treatment of patients with BPDCN. Patients with chemo- the presence of 5 criteria (fever lasting > 7 days, sple- sensitive disease and early disease presentation alone nomegaly, bicytopenia, hypertriglyceridemia and/or have been found to benefit from autologous HSCT.18 hypofibrinogenemia, and hemophagocytosis).37 In yet Few case reports exist of patients with BPDCN another study, 3 additional criteria were introduced: who have undergone cord blood stem cell transplan- low or absent NK cell activity, hyperferritinemia, and tation. However, one such case was reported by Ra- a high level of soluble interleukin 2 receptor.37 Cur- manathan et al20 who described successful cord blood rently, a diagnosis of HLH can be made either by HSCT in a patient with BPDCN using a preparative molecular diagnosis via the detection of a genetic regimen of thiotepa, fludarabine, and melphalan. mutation characteristic of familial HLH or by fulfilling 5 of the 8 criteria discussed above.22 Hemophagocytic Lymphohistiocytosis HLH is a hyperinflammatory disorder characterized Treatment by the nonmalignant, reactive, uncontrolled prolifer- The therapeutic strategy for HLH involves treatment of ation of histiocytes. The disease results from the un- severe inflammation while also addressing the under- derlying immune dysfunction either from a primary lying trigger. If the patient is acutely ill, then prompt immune deficiency (called familial HLH) or from an care at an intensive care unit and the initiation of acquired failure of immune hemostasis associated HLH-specific treatment are required. Alternatively, if with infection, autoimmunity, or malignancy (called the patient is stable, then a search for the trigger is reactive or secondary HLH).21 initiated and treatment is provided. Typically, deci- HLH is a clinical syndrome biologically charac- sions on how to treat HLH in adult patients are extrap- terized by a highly stimulated but ineffective immune olated from pediatric data.37 Malignancy-associated response. The activation and proliferation of T cells HLH has a worse prognosis than other types of HLH and macrophages are uncontrolled and inflammatory and, generally, successful treatment of the underlying cytokines are overproduced.22 Although the trigger for malignancy is needed prior to the resolution of HLH. hyperinflammation varies, the final pathway is com- In a prospective study performed on an interna- monly the infiltration of multiple organs by activated tional level, Henter et al38 showed that combined che- CD8+ T lymphocytes, macrophages, and hypercyto- motherapy and immunotherapy (etoposide, steroids, kinemia, resulting in end-organ damage. Clinically, and cyclosporine A) improved rates of survival among patients with HLH typically present with high fever, patients with HLH. A total of 113 patients who were hepatosplenomegaly, cytopenias, liver and pulmonary 15 years of age or younger were included. At a median dysfunction, and, frequently, signs of neurological in- follow-up of 3.1 years, the estimated 3-year overall volvement. Multiorgan failure typically occurs during survival rate was 55% (51% in cases of familial HLH).38 the final stage of progressive organ injury. Patients with persistent, recurrent, or familial HLH HLH is commonly divided into 2 types: familial underwent bone marrow transplantation and had a and secondary. Familial HLH is an inherited disorder 3-year survival rate of 62%.38 In another study, patients characterized by various defects on granule-depen- receiving combination cyclophosphamide/vincristine/ dent cytotoxicity. Known genetic mutations include prednisone had a 1-year overall survival rate of 66.7%, the PRF1 and hMunc genes, which account for ap- and the treatment was especially favorable for those proximately 20% to 40% of familial HLH cases.23 Oth- with infection and autoimmune disease–associated ers include X-linked lymphoproliferative disorder, HLH.39 In yet another study, patients receiving treat- Chédiak–Higashi syndrome, Griscelli syndrome, and ment with combination cyclophosphamide/doxorubi- severe combined immunodeficiency.24-26 The trigger cin/vincristine/prednisone had a median overall sur- for HLH is typically infection.27 Secondary HLH is a vival rate of 18 weeks and a 2-year overall survival rate

October 2014, Vol. 21, No. 4 Cancer Control 337 Table 2. — Selected Studies on Allogeneic Transplantation for Hemophagocytic Lymphohistiocytosis

Reference No. of Patients Conditioning Graft Failure (%) Survival Rate

Henter et al38 65 Busulfan/cyclophosphamide/etoposide ± antithymocyte globulin Not reported 62% at 3 y

Baker et al45 91 Busulfan/cyclophosphamide/etoposide ± antithymocyte globulin 9 53% at 5 y

Ouachée-Chardin et al46 48 Busulfan/cyclophosphamide/etoposide ± antithymocyte globulin 22 58% at 5.8 y

Cooper et al47 12 Fludarabine/melphalan/alemtuzumab 0 75% at 2.5 y

Cesaro et al48 61 Busulfan/cyclophosphamide ± etoposide 5 58% at 8 y Busulfan/fludarabine/melphalan or busulfan/fludarabine/thiotepa of 43.9%.40 However, one-half of patients will relapse intensity conditioning for fludarabine and melphalan with standard HLH therapy.37 A review of 22 pediatric with variable doses and a novel, intermediate schedule and adult patients who received alemtuzumab for the of alemtuzumab. The regimen was associated with a treatment of refractory HLH showed that 14 patients low incidence of graft-vs-host disease, the absence (64%) experienced a partial response and 77% of pa- of graft failure, and a low need for subsequent stem tients survived to undergo allogeneic HSCT.4 cell products.49 Compared with children, very few adults with Allogeneic Hematopoietic Stem Cell Transplantation HLH are treated with allogeneic HSCT. In 2 pub- In 1986, Fischer et al42 showed that allogeneic HSCT lished case reports, allogeneic HSCT was used for was curative in patients with familial HLH, a finding the treatment of an underlying hematological malig- confirmed by other reports.43,44 In their international nancy or Epstein–Barr viral infection with associated study, Henter et al32 recommended allogeneic HSCT, HLH.50,51 At the Moffitt Cancer Center, a 22-year-old which was part of the treatment for all study par- woman presented with hepatosplenomegaly, fever, ticipants with persistent, recurrent, or familial types and severe hypotension.52 Bone marrow biopsy and of HLH. Of the 113 patients who entered the study, pathology from splenectomy showed the presence of 65 underwent allogeneic HSCT (15 matched relat- g/Δ hepatosplenic T-cell lymphoma and HLH. Upon ed, 25 matched unrelated, 4 mismatched unrelated, presentation, her ferritin level was 20,700. Initially, 14 haploidentical, 5 cord blood, and 2 unknown). the patient required aggressive treatment for HLH; The most common conditioning regimen included however, once she was clinically stable, the patient myeloablative doses of busulfan, cyclophosphamide, received chemotherapy and achieved a partial and etoposide. The 3-year overall survival rate was response and subsequently underwent allogeneic 62%, which is notable because a small number of HSCT. The conditioning regimen used included fluda- patients had a related donor.38 Accumulated data rabine, cyclophosphamide, thiotepa, and 200 cGy of have established that, for individuals with familial total body irradiation, followed by double umbilical HLH, HSCT is the only long-term curative therapy cord blood transplantation. One year following HSCT, option and should be offered to all patients.38 Table the patient remained on remission from HLH and 2 summarizes the largest published studies in pedi- hepatosplenic lymphoma.52 atric patients.38,45-48 Allogeneic HSCT is a curative treatment option Although the outcomes among patients with HLH that should be offered to all patients with familial, have improved with the use of allogeneic HSCT, sever- recurrent, or persistent types of HLH. In adults with al limitations are apparent. For example, every effort HLH, allogeneic HSCT is frequently used to treat an should be made to achieve HLH remission prior to underlying hematological malignancy.37 HSCT; if not, transplantation-related mortality rates will increase.2 Graft failure is also more frequent Langerhans Cell Histiocytosis (~10%) in HLH than other nonmalignant disorders LCH is characterized by the idiopathic proliferation of and is a cause for concern.2 In addition, transplanta- histiocytes within the reticuloendothelial system and tion-related mortality rates remain high (eg, recurrent can infiltrate virtually any organ system. It can afflict HLH, graft failure, veno-occlusive disease, pneumoni- any age group, although it is predominantly seen in tis); therefore, new approaches for HSCT are needed.2 children. Its clinical presentation and natural history One such development is the introduction of reduced range from benign unifocal to aggressive multifocal intensity conditioning in allogeneic HSCT for HLH. systemic disease. Diagnosis and treatment for adults In 24 patients with HLH, Marsh et al49 used reduced are based on pediatric data.53

338 Cancer Control October 2014, Vol. 21, No. 4 Data from an international registry that includ- patients treated with 2-chlorodeoxyadenosine either ed 269 patients who were 18 years and older re- did not respond or relapsed within 1 year, whereas vealed slightly more affected men than women (143 21% of patients given cytarabine failed to respond to vs 126) with mean ages at diagnosis of 33 years and treatment.56 In a prospective trial, 7 adult patients with 35 years, respectively.54 Single-system LCH was found multisystem LCH (n = 3) or single-system, multifocal in 86 patients (31.4%) and isolated pulmonary LCH LCH (n = 4) were given a short-course, intensive che- was found in 44 cases. A total of 188 patients (68.6%) motherapy regimen that consisted of methotrexate, had multisystem disease and 81 (29.6%) had diabetes doxorubicin, cyclophosphamide, vincristine, pred- insipidus.54 nisone, and bleomycin.57 The overall response rate The diagnosis is made via biopsy of the suspect was 100%, with 5 complete responses and 2 partial lesion. The classic histopathological feature of LCH is responses seen among the participants. After a me- the presence of lesional Langerhans cells with varying dian follow-up of 6.5 years, 4 patients were in first proportions of macrophages, multinucleated giant continuous complete responses and 3 patients had cells, T-lymphocytes, and eosinophils. A definitive di- relapsed after 5, 8, and 62 months.57 agnosis is based of the histopathological finding of at Single-agent chemotherapy represents the treat- least 1 of the following: langerin (CD207) positivity, ment strategy used for multisystem LCH with or with- CD1a positivity, or the presence of Birbeck granules out the involvement of “risk organs,” single-system on electron microscopy.53 Given the minimal symp- LCH with multifocal lesions, and single-system LCH toms upon presentation, a thorough initial workup is with “special site” lesions. Intensive regimens are re- recommended to evaluate the exact extent of involve- served for aggressive presentations. Other treatments ment, including a complete history, physical examina- may include imatinib for cerebral LCH,58 zoledronic tion, laboratory studies, and radiographic evaluation.53 acid for bone disease,59 or lenalidomide.60 Treatment is based on a risk stratification system that was adopted by an expert panel of the Euro- Hematopoietic Stem Cell Transplantation Histio-Net.53 Stratification depends on the extent and Kudo et al3 reported their experience with 15 chil- severity of disease at diagnosis. LCH can be divided dren who had refractory LCH and underwent HSCT into 2 major categories: Single-system LCH is subdi- in Japan. The median age at transplantation was vided further into single-site and multisite disease, and 23 months and all of the participants had previous- multisystem LCH is defined as the involvement of 2 or ly failed conventional chemotherapy. Myeloablative more organs at diagnosis with or without organ dys- conditioning was used in 10 patients and reduced function.53 In the pediatric population, low-risk pa- intensity conditioning was used in 5 patients.3 Umbil- tients account for 20% of all multisystem LCH and ical cord blood was the graft source in 10 patients.3 have an excellent prognosis; they also are charac- Eleven patients became long-term survivors; a 10- terized by the absence of “risk organ” involvement, year overall survival rate of 73% was seen for the including the liver, lungs, and spleen, the hemato- entire group and a 10-year survival rate of 55% was poietic system, and tumorous lesions of the cen- seen among patients with high-risk disease.3 HSCT tral nervous system.53 Patients at high risk make up from parental haploidentical donors was reported 80% of patients with multisystem LCH, have 1 or more in 2 girls (aged 26 months and 5 months) with re- risk organs involved, and have a high mortality rate.55 fractory multisystemic LCH.61 Conditioning included In the setting of single-system LCH, unifocal in- myeloablative doses of busulfan, cyclophosphamide, volvement may be treated with careful observation fludarabine, and etoposide. Prophylaxis to prevent and local therapy, which includes the total excision of graft-vs-host disease included cyclosporine, metho- the lesion with or without radiation therapy. Systemic trexate, mycophenolate, daclizumab, and antithymo- therapy is required for multisystem LCH, single-system cyte globulin. Both patients survived and remained LCH with multifocal lesions, and single-system LCH free of disease for 54 and 44 months, respectively, with “special site” lesions, which are lesions in critical following HSCT.61 anatomical sites (eg, intraspinal, craniofacial bone). Allogeneic HSCT has been reported in an adult Studies focused on the treatment of adult populations patient with LCH, thrombocytopenia, and no radii.62 with LCH are limited. However, several chemotherapy Reduced intensity conditioning for allogeneic HSCT agents have shown to be effective. A retrospective incorporated fludarabine, busulphan, and alemtu- study of 58 adult patients with a mean age of 32 years zumab prior to transplantation. Three years follow- compared 3 commonly used regimens.56 Cytarabine ing transplantation, the patient had stable donor cell was shown to have better efficacy and lower toxicity engraftment, a normalized platelet count, no evidence rates when compared with vinblastine/prednisone of disease progression, and no graft-vs-host disease.62 and 2-chlorodeoxyadenosine. In addition, 84% of pa- These limited data suggest that allogeneic HSCT tients treated with vinblastine/prednisone and 59% of may be effective therapy for patients with LCH who

October 2014, Vol. 21, No. 4 Cancer Control 339 have failed systemic chemotherapy or who have the massive accumulation of polyclonal plasma cells in high-risk disease. the interfollicular region. A mixed form demonstrates For additional information on LCH, please see the areas with both histological patterns.67 article by Dr Grana on page 328. In a major retrospective review of 113 patients, 48% of whom were men with a median age of 43 years Dendritic Cell Sarcoma (range, 4.2–78 years), 53% of patients studied had Dendritic cell sarcoma is a rare, malignant neoplasm multicentric disease.68 Patients with the plasma cell that arises in follicular dendritic cells that form a variant were more likely to have multicentric disease, meshwork in the lymph node follicles and are critical and these patients were more likely to be older, have for antigen presentation. Hyaline Castleman disease B symptoms, palpable disease, peripheral neuropathy, has been implicated as precursor of this entity.63 It extravascular volume overload, coexisting polyneu- typically occurs in young adults and most commonly ropathy, organomegaly, endocrinopathy, monoclonal begins in the lymph nodes of the neck or medias- gammopathy, and skin abnormality (POEMS) syn- tinum; however, it can also be found in extranodal drome, bony sclerosis, anemia, leukocytosis, thrombo- sites as the gastrointestinal tract, the liver, spleen, and cytosis, a high sedimentation rate, hypergammaglobu- bone. Diagnosis depends on a clinical examination, linemia, a low albumin rate, and an elevated creatinine imaging, and pathological assessment.63 level. The 2-, 5-, and 10-year survival rates for the The clinical behavior of the disease is similar to entire group were 92%, 76%, and 59%, respectively.68 low-grade sarcomas with local aggressiveness.63,64 The 5-year overall survival rates among patients with Treatment for dendritic cell sarcoma involves the unicentric and multicentric Castleman disease were complete resection of the primary lesion; however, 91% and 65%, respectively.68 A total of 80% of patients significant risk exists for local relapse and metastatic with unicentric disease was treated with surgery; of disease. In patients with advanced or unresectable these patients, 89% achieved a partial or complete disease, chemotherapy has been used with mixed response.68 Patients with multicentric disease were results. In case reports, selected patients with dis- treated with prednisone alone, alkylator-based che- seminated disease responded to lymphoma-oriented motherapy, interferon, anthracycline-based chemo- chemotherapy regimens.65,66 therapy, or rituximab.68 A single case report of high-dose chemotherapy Patients with multicentric disease may have an and autologous HSCT for the treatment of dendritic associated human herpesvirus 8 infection (up to 50% cell sarcoma was found in the literature. In this case, of the cases) and they frequently present with elevated a 25-year-old man with a primary tumor of the tibia levels of interleukin 6.69 Antibodies against interleukin and surrounding soft tissues was treated with cyclo- 6 or its receptor have become available and have been phosphamide/doxorubicin/vincristine/prednisone tested in clinical trials.68,69 and achieved minimal response.4 Subsequently, the patient underwent chemotherapy mobilization with Hematopoietic Stem Cell Transplantation etoposide/cisplatinum/methylprednisolone sodium The use of HSCT in the setting of Castleman dis- succinate/cytarabine, followed by stem cell collec- ease is limited to a few case reports, particularly tion. The patient then received high-dose carmus- among patients with multicentric disease who have tine/etoposide/cytarabine/melphalan followed by failed other systemic therapies. The first mention of autologous stem cell infusion. He achieved a partial high-dose therapy concurrently with autologous HSCT response but the disease subsequently progressed to was published by Repetto et al.70 They reported on the his regional lymph nodes.4 case of a patient with aggressive Castleman disease At this time, data are insufficient to recommend who received high-dose melphalan and autologous the routine use of HSCT in patients with dendritic HSCT. The patient achieved a complete remission that cell sarcoma. lasted 15 months at the time of publication. Ganti et For a more detailed description of dendritic cell al5 reported on the case of a 39-year-old man who sarcoma and histiocytic neoplasms, please see the presented with peripheral neuropathy, lymphadenop- article by Dr Dalia and colleagues on page 290. athy, pleural effusions, hepatomegaly, and splenomeg- aly. Monoclonal immunoglobulin A was identified Castleman Disease in the serum and a diagnosis of POEMS syndrome Castleman disease is a rare lymphoproliferative dis- was made. The initial treatment included rituximab; order and 2 major histological variants of the dis- following a poor response to treatment, cyclophos- ease have been identified. Abnormal follicles with phamide/mitoxantrone was added. The patient then regressed germinal centers characterize the hyaline underwent mobilization with cyclophosphamide and vascular variant, whereas the plasma cell variant is granulocyte-colony stimulating factor. Subsequently, characterized by hyperplastic germinal centers and he received high-dose chemotherapy with melphalan

340 Cancer Control October 2014, Vol. 21, No. 4 followed by an autologous stem cell infusion. Four- 2. Jordan MB, Filipovich AH. Hematopoietic cell transplantation for he- mophagocytic lymphohistiocytosis: a journey of a thousand miles begins with teen months following transplantation, the monoclonal a single (big) step. Bone Marrow Transplant. 2008;42(7):433-437. spike had nearly disappeared, peripheral neuropathy 3. Kudo K, Ohga S, Morimoto A, et al. Improved outcome of refractory had improved, and the patient was functional and free Langerhans cell histiocytosis in children with hematopoietic stem cell trans- plantation in Japan. Bone Marrow Transplant. 2010;45(5):901-906. of symptoms.5 4. Adam Z, Veselý K, Krejcí M, et al. Interdigitating dendritic cell sarcoma Tal et al71 reported on the case of a 52-year-old of lower extremities resistant to high dose chemotherapy BEAM with peripheral blood stem cell transplantation [in Czech]. Vnitr Lek. 2009;55(2):147-157. man who presented with diarrhea, weight loss, and 5. Ganti AK, Pipinos I, Culcea E, et al. Successful hematopoietic stem- abdominal masses. Lymph node biopsy confirmed the cell transplantation in multicentric Castleman disease complicated by POEMS syndrome. Am J Hematol. 2005;79(3):206-210. plasma cell variant of multicentric Castleman disease. 6. Brody JP, Allen S, Schulman P, et al. Acute agranular CD4-positive The initial treatment was cyclophosphamide, vin- natural killer cell leukemia. Comprehensive clinicopathologic studies includ- ing virologic and in vitro culture with inducing agents. Cancer. 1995;75(10): cristine, prednisone, and rituximab, and the patient 2474-2483. achieved complete remission and a resolution of all his 7. Swerdlow SH, Campo E, Harris NL, et al, eds. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. 4th ed. Lyon, France: symptoms. Eighteen months later, the disease recurred IARC Press; 2008.. and the patient was treated with vinblastine and ritux- 8. Chaperot L, Bendriss N, Manches O, et al. Identification of a leukemic counterpart of the plasmacytoid dendritic cells. Blood. 2001;97(10):3210-3217. 71 imab. Subsequently, he received conditioning with 9. Petrella T, Comeau MR, Maynadié M, et al. ‘Agranular CD4+ CD56+ etoposide, thiotepa, cytarabine, cyclophosphamide, hematodermic neoplasm’ (blastic NK-cell lymphoma) originates from a pop- ulation of CD56+ precursor cells related to plasmacytoid monocytes. Am J and melphalan, followed by autologous peripheral Surg Pathol. 2002;26(7):852-862. blood stem cell transplantation. Fifty months following 10. Hallermann C, Middel P, Griesinger F, et al. CD4+ CD56+ blastic tumor of the skin: cytogenetic observations and further evidence of an origin from 71 transplantation, the patient remained in remission. plasmocytoid dendritic cells. Eur J Dermatol. 2004;14(5):317-322. Although the evidence is limited, data suggest 11. Marafioti T, Paterson JC, Ballabio E, et al. Novel markers of normal and neoplastic human plasmacytoid dendritic cells. Blood. 2008;111(7):3778-3792. a role for autologous HSCT in patients with Castle- 12. Feuillard J, Jacob MC, Valensi F, et al. Clinical and biologic features of man disease. Remissions have been long lasting and CD4(+)CD56(+) malignancies. Blood. 2002;99(5):1556-1563. 13. Julia F, Petrella T, Beylot-Barry M, et al. Blastic plasmacytoid dendritic morbidity rates have been limited despite patients cell neoplasm: clinical features in 90 patients. Br J Dermatol. 2013;169(3): undergoing transplantation with active disease. There- 579-586. 14. Rauh MJ, Rahman F, Good D, et al. Blastic plasmacytoid dendritic cell fore, HSCT should be considered in patients with neoplasm with leukemic presentation, lacking cutaneous involvement: case multicentric Castleman disease who have failed sys- series and literature review. Leuk Res. 2012;36(1):81-86. 15. Pagano L, Valentini CG, Pulsoni A, et al. Blastic plasmacytoid dendritic temic therapies and, in particular, among those with cell neoplasm with leukemic presentation: an Italian multicenter study. Hae- associated POEMS syndrome. matologica. 2013;98(2):239-246. 16. Leroux D, Mugneret F, Callanan M, et al. CD4(+), CD56(+) DC2 acute For a more detailed description of Castleman leukemia is characterized by recurrent clonal chromosomal changes affecting disease, please see the article by Dr Soumerai and 6 major targets: a study of 21 cases by the Groupe Français de Cytogénétique Hématologique. Blood. 2002;99(11):4154-4159. colleagues on page 266. 17. Petrella T, Bagot M, Willemze R, et al. Blastic NK-cell lymphomas (agranular CD4+CD56+ hematodermic neoplasms): a review. Am J Clin Pathol. 2005;123(5):662-675. Conclusions 18. Kharfan-Dabaja MA, Lazarus HM, Nishihori T, et al. Diagnostic and Acknowledging the paucity of the data, allogeneic therapeutic advances in blastic plasmacytoid dendritic cell neoplasm: a fo- cus on hematopoietic cell transplantation. Biol Blood Marrow Transplant. hematopoietic stem cell transplantation has an ac- 2013;19(7):1006-1012. cepted indication in patients with blastic plasmacytoid 19. Dietrich S, Andrulis M, Hegenbart U, et al. Blastic plasmacytoid dendritic cell neoplasia (BPDC) in elderly patients: results of a treatment algorithm dendritic cell neoplasia and in those with familial, employing allogeneic stem cell transplantation with moderately reduced con- recurrent, or persistent hemophagocytic lymphohis- ditioning intensity. Biol Blood Marrow Transplant. 2011;17(8):1250-1254. 20. Ramanathan M, Cerny J, Yu H, et al. A combination treatment approach tiocytosis. It may also be considered in patients with and cord blood stem cell transplant for blastic plasmacytoid dendritic cell recurrent or high-risk Langerhans cell histiocytosis. neoplasm. Haematologica. 2013;98(3):e36. 21. Usmani GN, Woda BA, Newburger PE. Advances in understanding the Autologous hematopoietic stem cell transplantation pathogenesis of HLH. Br J Haematol. 2013;161(5):609-622. may be considered in patients with Castleman disease, 22. Henter J, Elinder G, Ost A; FHL Study Group of the Histiocyte Society. Diagnostic guidelines for hemophagocytic lymphohistiocytosis. Semin Oncol. in particular with associated polyneuropathy, organo- 1991;18(1):29-33. megaly, endocrinopathy, monoclonal gammopathy, 23. Feldmann J, Callebaut I, Raposo G, et al. Munc13-4 is essential for cytolytic granules fusion and is mutated in a form of familial hemophagocytic and skin abnormality syndrome, and also in patients lymphohistiocytosis (FHL3). Cell. 2003;115(4):461-473. with blastic plasmacytoid dendritic cell neoplasia 24. Arico M, Imashuku S, Clementi R, et al. Hemophagocytic lymphohistio- cytosis due to germline mutations in SH2D1A, the X-linked lymphoproliferative who have chemosensitive disease and are not suit- disease gene. Blood. 2001;97(4):1131-1133. able candidates for allogeneic hematopoietic stem cell 25. Janka GE. Familial and acquired hemophagocytic lymphohistiocytosis. Eur J Pediatr. 2007;166(2):95-109. transplantation. Published data do not support the 26. Sanal O, Ersoy F, Tezcan I, et al. Griscelli disease: genotype-phenotype routine use of hematopoietic stem cell transplantation correlation in an array of clinical heterogeneity. J Clin Immunol. 2002;22(4): 237-243. in patients with dendritic cell sarcoma. 27. Henter JI, Ehrnst A, Andersson J, et al. Familial hemophagocytic lym- phohistiocytosis and viral infections. Acta Paediatrica. 1993;82(4):369-372. 28. Risdall RJ, McKenna RW, Nesbit ME, et al. Virus-associated he- References mophagocytic syndrome: a benign histiocytic proliferation distinct from ma- 1. Roos-Weil D, Dietrich S, Boumendil A, et al. Stem cell transplantation lignant histiocytosis. Cancer. 1979;44(3):993-1002. can provide durable disease control in blastic plasmacytoid dendritic cell neo- 29. Jayakrishnan MP, Veny J, Feroze M. Rickettsial infection with he- plasm: a retrospective study from the European Group for Blood and Marrow mophagocytosis. Trop Doct. 2011;41(2):111-112. Transplantation. Blood. 2013;121(3):440-446. 30. Fardet L, Lambotte O, Meynard JL, et al. Reactive haemophagocytic

October 2014, Vol. 21, No. 4 Cancer Control 341 syndrome in 58 HIV-1-infected patients: clinical features, underlying diseases of adult Langerhans cell histiocytosis: experience on seven patients. Ann Oncol. and prognosis. AIDS. 2010;24(9):1299-1306. 2010;21(6):1173-1178. 31. Van Koeveringe M, Brouwer RE. Histoplasma capsulatum reactivation 58. Montella L, Insabato L, Palmieri G. Imatinib mesylate for cerebral Lang- with haemophagocytic syndrome in a patient with chronic lymphocytic leukae- erhans’-cell histiocytosis. N Engl J Med. 2004;351(10):1034-1035. mia. Neth J Med. 2010;68(12):418-421. 59. Montella L, Merola C, Merola G, et al. Zoledronic acid in treat- 32. Janka G, Imashuku S, Elinder G, et al. Infection- and malignancy-as- ment of bone lesions by Langerhans cell histiocytosis. J Bone Min Metab. sociated hemophagocytic syndromes. Secondary hemophagocytic lympho- 2009;27(1):110-113. histiocytosis. Hematol Oncol Clin North Am. 1998;12(2):435-444. 60. Adam Z, Rehák Z, Koukalová R, et al. Lenalidomide induced thera- 33. Koizumi K, Haseyama Y, Machino R, et al. The hemophagocytic syn- peutic response in a patient with aggressive multi-system Langerhans cell drome in prostate cancer revealed by disseminated carcinomatosis of the bone histiocytosis resistant to 2-chloro-deoxyadenosine and early relapsing after marrow. J Urol. 2002;168(3):1101-1102. high-dose BEAM chemotherapy with autologous peripheral blood stem cell 34. García-Suárez J, Bañas H, Krsnik I, et al. Hemophagocytic syndrome transplantation [in Czech]. Vnitr Lek. 2012;58(1):62-71. associated with retinoic acid syndrome in acute promyelocytic leukemia. Am 61. Jun Y, Quan QM, Bin W, et al. Haploidentical parental hematopoietic J Hematol. 2004;76(2):172-175. stem cell transplantation in pediatric refractory Langerhans cell histiocytosis. 35. Machaczka M, Vaktnäs J, Klimkowska M, et al. Acquired hemophago- Pediatr Transplant. 2014;18(4):E124-E129. cytic lymphohistiocytosis associated with multiple myeloma. Med Oncol. 62. Ingram W, Desai S, Gibbs J, et al. Reduced-intensity conditioned 2011;28(2):539-543. allogeneic haematopoietic transplantation in an adult with Langerhans’ cell 36. Han AR, Lee HR, Park BB, et al. Lymphoma-associated hemophago- histiocytosis and thrombocytopenia with absent radii. Bone Marrow Transplant. cytic syndrome: clinical features and treatment outcome. Ann Hematol. 2006;37(7):713-715. 2007;86(7):493-498. 63. Soriano AO, Thompson MA, Admirand JH, et al. Follicular dendritic cell 37. Jordan MB, Allen CE, Weitzman S, et al. How I treat hemophagocytic sarcoma: a report of 14 cases and a review of the literature. Am J Hematol. lymphohistiocytosis. Blood. 2011;118(15):4041-4052. 2007;82(8):725-728. 38. Henter JI, Samuelsson-Horne A, Aricó M, et al. Treatment of he- 64. Chan JK, Fletcher CD, Nayler SJ, et al. Follicular dendritic cell sarcoma. mophagocytic lymphohistiocytosis with HLH-94 immunochemotherapy and Clinicopathologic analysis of 17 cases suggesting a malignant potential higher bone marrow transplantation. Blood. 2002;100(7):2367-2373. than currently recognized. Cancer. 1997;79(2):294-313. 39. Hu Y, Xu J, Wang L, et al. Treatment of haemophagocytic lymphohistio- 65. Shinagare AB, Ramaiya NH, Jagannathan JP, et al. Primary follic- cytosis with cyclophosphamide, vincristine, and prednisone. Swiss Med Wkly. ular dendritic cell sarcoma of liver treated with cyclophosphamide, doxo- 2012;142:w13512. rubicin, vincristine, and prednisone regimen and surgery. J Clin Oncol. 40. Shin HJ, Chung JS, Lee JJ, et al. Treatment outcomes with CHOP 2011;29(35):e849-e851. chemotherapy in adult patients with hemophagocytic lymphohistiocytosis. 66. Lee SY, Lee SR, Chang WJ, et al. Successful treatment of disseminated J Korean Med Sci. 2008;23(3):439-444. interdigitating dendritic cell sarcoma with adriamycin, bleomycin, vinblastine, 41. Marsh RA, Allen CE, McClain KL, et al. Salvage therapy of refractory and dacarbazine chemotherapy. Korean J Hematol. 2012;47(2):150-153. hemophagocytic lymphohistiocytosis with alemtuzumab. Pediatr Blood Cancer. 67. Talat N, Schulte KM. Castleman’s disease: systematic analysis of 416 2013;60(1):101-109. patients from the literature. Oncologist. 2011;16(9):1316-1324. 42. Fischer A, Cerf-Bensussan N, Blanche S, et al. Allogeneic bone 68. Dispenzieri A, Armitage JO, Loe MJ, et al. The clinical spectrum of marrow transplantation for erythrophagocytic lymphohistiocytosis. J Pediatr. Castleman’s disease. Am J Hematol. 2012;87(11):997-1002. 1986;108(2):267-270. 69. Uldrick TS, Polizzotto MN, Yarchoan R. Recent advances in Kaposi 43. Todo S, Fujiwara F, Ikushima S, et al. Allogeneic bone marrow trans- sarcoma herpesvirus-associated multicentric Castleman disease. Curr Opin plantation for familial erythrophagocytic lymphohistiocytosis, with high dose Oncol. 2012;24(5):495-505. VP16-containing conditioning regimen. Leuk Lymphoma. 1990;1(5-6):361-364. 70. Repetto L, Jaiprakash MP, Selby PJ, et al. Aggressive angiofollicular 44. Blanche S, Caniglia M, Girault D, et al. Treatment of hemophagocytic lymph node hyperplasia (Castleman’s disease) treated with high dose lymphohistiocytosis with chemotherapy and bone marrow transplantation: a melphalan and autologous bone marrow transplantation. Hematol Oncol. single-center study of 22 cases. Blood. 1991;78(1):51-54. 1986;4(3):213-217. 45. Baker KS, Filipovich AH, Gross TG, et al. Unrelated donor hematopoietic 71. Tal Y, Haber G, Cohen MJ, et al. Autologous stem cell transplantation in cell transplantation for hemophagocytic lymphohistiocytosis. Bone Marrow a rare multicentric Castleman disease of the plasma cell variant. Int J Hematol. Transplant. 2008;42(3):175-180. 2011;93(5):677-680. 46. Ouachée-Chardin M, Elie C, de Saint Basile G, et al. Hematopoietic stem cell transplantation in hemophagocytic lymphohistiocytosis: a single-cen- ter report of 48 patients. Pediatrics. 2006;117(4):e743-e750. 47. Cooper N, Rao K, Gilmour K, et al. Stem cell transplantation with re- duced-intensity conditioning for hemophagocytic lymphohistiocytosis. Blood. 2006;107(3):1233-1236. 48. Cesaro S, Locatelli F, Lanino E, et al. Hematopoietic stem cell trans- plantation for hemophagocytic lymphohistiocytosis: a retrospective analysis of data from the Italian Association of Pediatric Hematology Oncology (AIEOP). Haematologica. 2008;93(11):1694-1701. 49. Marsh RA, Kim MO, Liu C, et al. An intermediate alemtuzumab sched- ule reduces the incidence of mixed chimerism following reduced-intensity conditioning hematopoietic cell transplantation for hemophagocytic lympho- histiocytosis. Biol Blood Marrow Transplant. 2013;19(11):1625-1631. 50. Kunitomi A, Kimura H, Ito Y, et al. Unrelated bone marrow transplanta- tion induced long-term remission in a patient with life-threatening Epstein-Barr virus-associated hemophagocytic lymphohistiocytosis. J Clin Exp Hematop. 2011;51(1):57-61. 51. Machaczka M, Nahi H, Karbach H, et al. Successful treatment of re- current malignancy-associated hemophagocytic lymphohistiocytosis with a modified HLH-94 immunochemotherapy and allogeneic stem cell transplan- tation. Med Oncol. 2012;29(2):1231-1236. 52. Ayala E, Chalhoub J, Kharfan-Dabaja MA. Umbilical cord blood transplantation induces a durable remission in hepatosplen- ic gamma-delta T cell lymphoma with associated hemophago- cytic lymphohistiocytosis. Am J Hematol. 2014;89(9):934-935. 53. Girschikofsky M, Arico M, Castillo D, et al. Management of adult patients with Langerhans cell histiocytosis: recommendations from an expert panel on behalf of Euro-Histio-Net. Orphanet J Rare Dis. 2013;8:72. 54. Aricó M, Girschikofsky M, Généreau T, et al. Langerhans cell histiocy- tosis in adults. Report from the International Registry of the Histiocyte Society. Eur J Cancer. 2003;39(16):2341-2348. 55. Broadbent V, Gadner H. Current therapy for Langerhans cell histiocy- tosis. Hematol Oncol Clin North Am. 1998;12(2):327-338. 56. Cantu MA, Lupo PJ, Bilgi M, et al. Optimal therapy for adults with Langerhans cell histiocytosis bone lesions. PloS One. 2012;7(8):e43257. 57. Derenzini E, Fina M, Stefoni V, et al. MACOP-B regimen in the treatment

342 Cancer Control October 2014, Vol. 21, No. 4 Special Report

Social Determinants of Racial and Ethnic Disparities in Cutaneous Melanoma Outcomes Valerie M. Harvey, MD, Hitesh Patel, MS, MBA, Sophia Sandhu, MD, Sherrie Flynt Wallington, PhD, and Ginette Hinds, MD

Background: This article sought to elucidate how aspects of poverty and culture may contribute to race- and ethnicity-based disparities in cutaneous melanoma outcomes. Methods: We identified published studies addressing the social determinants of melanoma. Selected review articles included US-based studies comprised of patients representing adults, children, and adolescents. Results: African Americans and Hispanics diagnosed with cutaneous melanoma are more likely to present with more advanced stages of disease at diagnosis and have higher rates of mortality than their nonminority counterparts. These disparities may be a consequence of economic, social, and cultural barriers such as low income, public forms of health insurance, lower levels of education, lower levels of melanoma awareness and knowledge, and lower rates of participation in melanoma screening. No studies in the literature examined the potential impact of social injustice, English proficiency, immigrant status, and health literacy. Conclusions: Substantial gaps exist in our knowledge of the pathways linking social determinants and race- and ethnicity-based disparities in melanoma. More studies are warranted to inform the development of effective interventions aimed at narrowing inequities and improving cutaneous melanoma outcomes among minority populations.

Introduction melanoma are more likely to present with advanced Cutaneous melanoma is a significant public health con- (regional and metastatic) cutaneous melanoma than cern. In 2013, 76,690 incident cases and 9,480 deaths Caucasians.3,4,8-12 Moreover, while the proportions of occurred from cutaneous melanoma in the United local stage or in situ cutaneous melanomas have in- States alone.1 The poor prognosis and limited treatment creased among Caucasians, an opposing trend has options of advanced-stage disease make early detec- been observed among Hispanic men living in Cal- tion and diagnosis critical. Although the incidence of ifornia who present with thicker primary tumors at cutaneous melanoma is greatest in Caucasians,2 most diagnosis.4 Evidence also suggests variability in the studies have shown that racial and ethnic minorities quality of care received by minority patients with cu- diagnosed with cutaneous melanoma are more likely taneous melanoma. A Surveillance, Epidemiology, and to experience worse cutaneous melanoma outcomes.2-7 End Results–based study found that blacks were less Surveillance, Epidemiology, and End Results likely than Caucasians to receive surgical treatment data reveal that Hispanics, African Americans, Amer- for melanoma,13 and those who underwent surgery ican Indians, and Asians diagnosed with cutaneous experienced shorter survival time than other races.13 After accounting for demographical and clini- From the Eastern Virginia Medical School (VMH, HP, SS), Norfolk, cal characteristics, minorities have an approximate Virginia, the Hampton University Skin of Color Research Institute two- to three-fold greater risk of melanoma-specific (VMH), Hampton, Vir­ginia, the Lombardi Comprehensive Cancer 14 Center at Georgetown University Medical Center (SFW), Washing- mortality than their nonminority counterparts. In Af- ton, DC, and the Johns Hopkins University School of Medicine (GH), rican Americans, differences in mortality rates persist Baltimore, Maryland. even after stage at diagnosis is considered.2 Although Submitted May 28, 2014; accepted June 18, 2014. biological factors may account for some of these dif- Address correspondence to Valerie M. Harvey, MD, Department of ferences (cutaneous melanomas in minorities tend Dermatology, Eastern Virginia Medical School, 721 Fairfax Avenue, Suite 200, Andrews Hall, Norfolk, VA 23507. E-mail: to occur at unusual anatomical sites and may be of [email protected] more aggressive histological subtypes), the underly- No significant relationships exist between the authors and the com- ing mechanisms of these disparities remain unclear.2 panies/organizations whose products or services may be referenced in this article. Theoretical Framework This work was supported in part by grants from the US Department of Education (P031B100033) and the National Cancer Institute Freeman’s health disparities cancer model provides (5 K01 CA155417-0​4). a framework for organizing racial and ethnic dis-

October 2014, Vol. 21, No. 4 Cancer Control 343 parities in cancer research (Fig).15,16 The model is of cutaneous melanoma within the United States using based on the premise that social setting contributes such search terms as melanoma, minorities, health to disease outcome and considers 3 major variables, disparities, social determinants, socioeconomic status, ie, poverty, culture, and social justice, and posits an education, income, race, ethnicity, insurance, public important connection between the social determi- insurance, Medicaid, Medicare, African Americans, nants of health and health inequities.16,17 Numerous Hispanics, Asians, Pacific Islanders, sunscreen, sun studies have helped to further elucidate this connec- protection, skin examinations, poverty, cancer dispar- tion to determine how individual health outcomes ities, literacy, US acculturation, melanoma awareness, are shaped by individual motivation and higher-level melanoma knowledge, and immigrants. References social and structural forces (ie, social determinants within selected articles were also reviewed to identify of health).18-25 The model developed by Freeman and additional pertinent publications. Due to the relative Chu16 suggests that many of the factors related to the paucity of studies that included minorities with cuta- successful acquisition of cancer prevention, control, neous melanoma, articles addressing the aspects of and treatment are shaped and influenced by socially social determinants in non-Hispanic whites were also determined elements, including cultural and econom- reviewed to provide context. ic factors, social support networks, the physical and social environment, access to health care services, Barriers Related to Poverty and social and health policies.21-24 Measures of socioeconomic status, such as level of As such, based on this theoretical framework and educational attainment, occupation, income, poverty the literature, this review summarizes how aspects of level, health insurance status, and place of residence, social determinants, including poverty and culture, are key determinants for preventive skin screenings, contribute to race- and ethnicity-based disparities in cutaneous melanoma incidence, stage at diagnosis, the prevention, early detection, diagnosis incidence, and melanoma mortality rates.4,26,27 Regardless of the treatment, and mortality rates of cancer. Given the economic measure employed, the preponderance of paucity of literature linking race-based disparities in studies demonstrates a direct correlation of the inci- cutaneous melanoma to social justice, this article will dence of cutaneous melanoma with measures of high focus on the domains of poverty and culture. socioeconomic status.6,7,26,27,28 Conversely, lower socio- economic status is associated with the development Methods of thicker primary tumors, more advanced stages of The medical literature was searched to identify all disease at the time of diagnosis, and increased mor- published studies that addressed social determinants tality rates.3,5,7,26,27,29,30-32

Social Injustice

Poverty Culture

Diagnosis Post-Treatment Survival Prevention Early Detection and Treatment and and Incidence Quality of Life Mortality

Fig. — Modified model of theoretical framework. From Freeman HP, Chu KC. Determinants of cancer disparities: barriers to cancer screening, diagnosis, and treatment. Surg Oncol Clin N Am. 2005;14(4):655-669. © 2005 Reprinted with permission from Elsevier.

344 Cancer Control October 2014, Vol. 21, No. 4 Income noma who had only achieved a high school education Pollitt et al4 examined the differences in incidence compared with their college graduate counterparts rates of melanoma and tumor thickness between on skin cancer risks and the importance of regular Hispanics and non-Hispanic whites of various socio- self- and physician-performed skin examinations, thus economic groups, which were measured by income, demonstrating the impact of educational status on education, and poverty. Although most cases of cu- patient–physician communication.5 taneous melanoma in non-Hispanic whites occurred within a high socioeconomic strata, only 35% of cuta- Health Insurance neous melanomas in Hispanics occurred within a high Health insurance status also influences cutaneous socioeconomic group.4 Irrespective of race, ethnicity, melanoma outcomes.14,29,38 Kirsner et al39 found that or sex, patients of lower socioeconomic groups had patients covered by Medicare health maintenance thicker tumors (> 2 mm) at diagnosis; however, this organizations (HMOs) were diagnosed in the earli- association was most pronounced among Hispanics, er stages of cutaneous melanoma and experienced a finding that suggests Hispanics may be dispropor- longer survival times than age-matched controls en- tionately burdened by barriers related to poverty.4 rolled in Medicare fee-for-service programs. Similarly, In their examination of cutaneous melanoma sur- Medicare HMO enrollees who were Hispanic were vival rates among beneficiaries of Medicare, Reyes-Or- less likely to be diagnosed with advanced-stage mel- tiz et al32,33 found that patients residing in low-income anoma than patients using fee-for-service programs.40 regions had lower 5-year, melanoma-specific survival Although Hispanics using fee-for-service programs rates than those living in high-income areas. The re- were more likely to have an advanced-stage cutaneous searchers found that the interactions between race, melanoma at diagnosis than non-Hispanic whites us- ethnicity, socioeconomic status, and cutaneous mela- ing fee-for-service programs, no significant difference noma survival rates were greatest among minorities, was seen in stage at diagnosis or median survival rates with non-Caucasians earning less than $30,000 having among non-Hispanic whites and Hispanics enrolled the highest percentages of advanced-stage melanoma in HMOs.40 These disparities may be explained in part and thicker tumors.33 by the “HMO effect.” For example, patients enrolled Treatment for melanoma also varied by socioeco- in HMOs are seen by their primary care physicians nomic status. Medicare enrollees living in poor areas more often than those using a fee-for-service program; were less likely to receive chemotherapy than their therefore, they are more likely to use preventative Medicare counterparts living in wealthier regions.32 services such as skin cancer screenings.39 The duration of Medicaid enrollment inversely Education correlates with cutaneous melanoma stage at the time The association between education and health is of diagnosis.29 One study found that newly enrolled well established.34,35 Education and knowledge may patients were 13 times more likely to be diagnosed help individuals recognize the signs and symptoms with late-stage melanoma, whereas intermittently en- that necessitate prompt medical care and navigate rolled patients were twice as likely to have late-stage through the health care system.36 Geller et al31 found cutaneous melanoma as those not on Medicaid.29 that patients with cutaneous melanoma who were Medicaid beneficiaries continuously enrolled for more less educated presented with more advanced-stage than 1 year were just as likely to be diagnosed with disease and had greater mortality rates. Reductions late-stage disease as those not enrolled in Medicaid.29 in mortality rates for cutaneous melanoma between A second study showed that Medicaid beneficiaries 1993 and 1997 compared with 2003 and 2007 were enrolled at least 3 months prior to diagnosis experi- confined to the most highly educated individuals enced more favorable survival outcomes than those (≥ 13 years of education), while patients with fewer who enrolled upon or after receiving a diagnosis of years of education experienced increases in mortality cancer.41 Together, these findings support the impor- rates during that same time period.31 tance of continuous access to preventive services in Buster et al37 found that people who were less improving mortality rates for melanoma and suggest educated, elderly, or black were more likely to per- that Medicaid services may be sufficient for continu- ceive themselves as being at low risk for developing ously enrolled beneficiaries. skin cancer and were less inclined to receive skin Despite the benefits of continuous enrollment, examinations. In their survey of more than 500 pa- patients on Medicaid experience less favorable out- tients who survived cutaneous melanoma, Pollitt et al5 comes than their non-Medicaid counterparts.41 Pos- found that lower levels of education were associated sible explanations include (1) the receipt of late or with decreased perception and knowledge of risk inadequate treatment, (2) Medicaid beneficiaries for cutaneous melanoma. They also found that phy- commonly consisting of disadvantaged populations sicians were less likely to counsel survivors of mela- with numerous physical comorbidities, psychiatric

October 2014, Vol. 21, No. 4 Cancer Control 345 comorbidities, or both, which may contribute to their risk of cancer is a positive predictor of preventative poor prognosis, and (3) additional barriers, including behaviors.37,56-58 Blacks37,50,59 and Hispanics59-62 perceive lack of transportation and psychosocial support, that themselves to be at very low risk for developing skin may preclude the receipt of adequate treatment or cancer. A study by Pichon et al50 observed no differ- continuous care.5,41 Although minority populations ence in sunscreen use among blacks who reported represent approximately one-third of the US popula- they perceived a high risk of skin cancer versus those tion,42 they account for more than one-half of people who perceived no risk of skin cancer. These findings covered by Medicaid.43 are in contrast to the medical literature on cancer, Health insurance status also affects the diagnostic which shows a positive correlation between perceived staging evaluation of cutaneous melanoma. In one cancer risks and preventative behaviors. study, patients on Medicare and Medicaid were less A study by Buster et al37 found that blacks placed likely than privately insured patients to undergo sen- less emphasis on the importance of regular skin exam- tinel lymph node biopsy for cutaneous melanoma, inations as a method for early detection of skin cancer indicating that publicly insured individuals may be than whites. Both blacks and Hispanics believed that understaged and possibly inadequately treated.44 they could do little to reduce their risk of skin cancer, primarily because too many recommendations exist Barriers Related to Culture about preventing skin cancer to know which ones Because culture can either amplify or reduce the ex- to follow.37 pected negative effects of poverty, an understanding of the cultural contributors to cutaneous melanoma Awareness and Knowledge inequities is essential.45 Risk factors for melanoma, Temoshok et al61 found that both a low level of knowl- such as sun exposure behavior and the aesthetic ben- edge about cutaneous melanoma prior to diagnosis efits of a tanned appearance, can be rooted in cultural and a poor understanding of melanoma treatment were tendencies and preferences. associated with greater tumor thickness. Compared with non-Hispanic whites, both Hispanics60,61,64-66 and Risk Behaviors blacks64,66,67 appear to be less knowledgeable about Compared with Caucasians, minority populations typ- melanoma. Blacks and Hispanics may also be less ically engage in fewer types of behavior that increase likely to seek medical care if they have a suspicious risk for skin cancer.46 Specifically, minority popula- skin lesion.2,67 Even when comparing Hispanics and tions have a lower prevalence of sunburn,47 indoor non-Hispanic whites with similar access to health care, tanning use,47,48 and sunscreen consumption,49 and are Hispanics continued to demonstrate lower levels of more likely to seek shade than Caucasians.49 Female melanoma awareness.61 Among middle school stu- sex, education, income, and age are associated with dents, knowledge emerged as the strongest sun safety sunscreen use in blacks and Hispanics.47,50,51 predictor for Hispanics.68 Knowledge-based interven- tions have been shown to increase monthly self-skin Acculturation examinations in minority populations.59 However, the Acculturation, the process by which immigrants adopt evidence is not sufficient to determine how and if the language, attitudes, behaviors, and norms of their knowledge gaps contribute to race- and ethnic-based host country, has been associated with behavioral disparities in melanoma outcomes. changes in relation to skin cancer risk among Hispan- Individuals are more likely to perform skin self-ex- ics.52-55 US cultural norms favor sunscreen use and sun aminations if they have a high level of knowledge and tanning more than Hispanic cultural norms.52 Accul- awareness about melanoma,66 and patients practicing turation among Hispanics has been linked to higher skin self-examinations can potentially decrease cu- perceived benefits of exposure to ultraviolet radia- taneous melanoma mortality rates by 63%.69 Several tion,55 less worry about skin damage,55 higher rates studies have reported that the rates of skin self-exam- of sunbathing,53 higher rates of indoor tanning,53 and inations9-11,61,70,71 among minority populations and phy- an increased risk of sunburns.54 Of note, a subgroup sician-assisted skin examinations49,71,72 are significant- analysis of Mexicans and Puerto Ricans revealed that ly lower than those of non-Hispanic whites. Among differences in sun protection behaviors varied by Hispanics, factors associated with higher rates of skin country of origin,54 exemplifying the limitations of self-examinations and physician-assisted skin examina- aggregating heterogeneous populations. tions include greater US acculturation, older age, an increased number of melanoma risk factors, physician Perception of Skin Cancer Risk recommendations,62,73,74 fewer skin self-examination In general, the medical literature as it pertains to can- barriers,74 country of origin,73 tanning indoors, a higher cer has shown that a patient’s lack of perceived risk of level of knowledge about skin cancer, a high level of cancer is a barrier to risk reduction and that perceived perceived skin cancer severity, a low worry of skin

346 Cancer Control October 2014, Vol. 21, No. 4 cancer, and added physician-assisted skin examination physician and not knowing to ask or how to ask for benefits.74 The primary reasons Hispanics cited for not a physician-assisted skin examination.62 performing skin self-examinations were lack of aware- ness regarding the necessity of skin self-examinations Language Fluency and lack of knowledge about how to conduct such Low English proficiency has been linked to having an examination.61,62,70 The primary reasons Hispanics less access to care, receiving lower quality care, and provided for not receiving physician-assisted skin ex- having poor health outcomes.75 Although numerous aminations were inadequate amount of time with the studies have found detrimental associations between

Table. — Select US Studies Addressing Social Determinants Across the Cancer Care Continuum for Racial and Ethnic Minorities

Domain Primary Secondary Diagnosis and Treatment Survival and Prevention Prevention Incidence Mortality

Poverty

Race and ethnicity Cormier2 Collins13 Cormier2 Hu3 Collins13 Pollitt4 Rouhani6 Bergfelt8 Black9 Clairwood10 Rouhani11 Wu12

Education Buster37 Singh27 Pollitt4 Wich7 Singh27

Income Buster37 Singh27 Pollitt4 Reyes-Ortiz33 Singh27

Access to health care Coups73 Coups74

Insurance status Halpern38 Wich7 Pollitt29 Halpern38 Rouhani40

Culture

Race and ethnicity Coups46 Buller47 Hall48 Santmyire49

US acculturation Andreeva52 Coups53 Coups54 Heckman55 Hay65 Andreeva68

Melanoma awareness and knowledge Ma60 Kundu59 Piptone61 Temoshok62 Imahiyerobo-Ip71 Arnold70 Imahiyerobo-Ip71

Perceived risk of melanoma Pichon50 Kundo59 Pichon51 Ma60 Piptone61

October 2014, Vol. 21, No. 4 Cancer Control 347 limited English proficiency and health outcomes,76-78 terventions in the future as well as developing cancer we were unable to find any studies that investigated prevention measures and cancer control strategies the role of English proficiency on outcomes among targeting these specific populations. patients with cutaneous melanoma. References Gaps in Knowledge 1. American Cancer Society. Melanoma skin cancer: what is cancer? http://www.cancer.org/acs/groups/cid/documents/webcontent/003120-pdf.pdf. No studies have explored the potential impact of so- Accessed August 13, 2014. cial justice, English proficiency, health beliefs, health 2. Cormier JN, Xing Y, Ding M, et al. Ethnic differences among patients with cutaneous melanoma. Arch Intern Med. 2006;166(17):1907-1914. literacy, disability, immigrant status, or housing sta- 3. Hu S, Parmet Y, Allen G, et al. Disparity in melanoma: a trend analysis tus despite the fact that these variables have been of melanoma incidence and stage at diagnosis among whites, Hispanics, and blacks in Florida. Arch Dermatol. 2009;145(12):1369-1374. shown to contribute to ethnic and racial disparities 4. Pollitt RA, Clarke CA, Swetter SM, et al. The expanding melanoma in many other malignancies.76-81 We were also un- burden in California hispanics: importance of socioeconomic distribution, his- tologic subtype, and anatomic location. Cancer. 2011;117(1):152-161. able to identify studies addressing the post-treat- 5. Pollitt RA, Swetter SM, Johnson TM, et al. Examining the pathways ment quality of life among minority patients with linking lower socioeconomic status and advanced melanoma. Cancer. 2012;118(16):4004-4013. cutaneous melanoma. Much remains unknown about 6. Rouhani P, Hu S, Kirsner RS. Melanoma in Hispanic and black Amer- cutaneous melanoma in other US minority groups, icans. Cancer Control. 2008;15(3):248-253. 7. Wich LG, Ma MW, Price LS, et al. Impact of socioeconomic status and including Asians, Pacific Islanders, American Indians, sociodemographic factors on melanoma presentation among ethnic minorities. and Native Alaskans. The Table illustrates our current J Community Health. 2011;36(3):461-468. 8. Bergfelt L, Newell GR, Sider JG, et al. Incidence and anatomic distri- knowledge on this topic organized along the cancer bution of cutaneous melanoma among United States Hispanics. J Surg Oncol. continuum.2-4,6-13,27,29,33,37,38,40,46-55,59-62,65,68,70,71,73,74 1989;40(4):222-226. 9. Black WC, Goldhahn RT Jr, Wiggins C. Melanoma within a southwest- ern Hispanic population. Arch Dermatol. 1987;123(10):1331-1334. Conclusions 10. Clairwood M, Ricketts J, Grant‐Kels J, et al. Melanoma in skin of color in Connecticut: an analysis of melanoma incidence and stage at diagnosis Hispanics and African Americans diagnosed with in non‐Hispanic blacks, non‐Hispanic whites, and Hispanics. Int J Dermatol. cutaneous melanoma typically present at diagnosis 2014;53(4):425-433. 11. Rouhani P, Pinheiro PS, Sherman R, et al. Increasing rates of mel- during the advanced stages of disease and experi- anoma among nonwhites in Florida compared with the United States. Arch ence high mortality rates. The literature on the social Dermatol. 2010;146(7):741-746. 12. Wu XC, Eide MJ, King J, et al. Racial and ethnic variations in incidence determinants of cutaneous melanoma outcomes in and survival of cutaneous melanoma in the United States, 1999-2006. J Am minorities is limited. In addition, decreased access to Acad Dermatol. 2011;65(5 suppl 1):S26-S37. 13. Collins KK, Fields RC, Baptiste D, et al. Racial differences in survival dermatological care is associated with poor melano- after surgical treatment for melanoma. Ann Surg Oncol. 2011;18(10):2925-2936. ma outcomes; however, how this impacts outcomes 14. Roetzheim RG, Pal N, Tennant C, et al. Effects of health insurance and race on early detection of cancer. J Natl Cancer Inst. 1999;91(16):1409-1415. among minority populations is unclear. Poverty and 15. Freeman HP. Commentary on the meaning of race in science and insurance status are key contributors of socioeconom- society. Cancer Epidemiol Biomarkers Prev. 2003;12(3):232s-236s. 16. Freeman HP, Chu KC. Determinants of cancer disparities: barri- ic status–based disparities in patients with cutaneous ers to cancer screening, diagnosis, and treatment. Surg Oncol Clin N Am. melanoma. Barriers related to poverty also dispro- 2005;14(4):655-669, v. 17. Gerend MA, Pai M. Social determinants of Black-White disparities portionately burden minorities who are more likely in breast cancer mortality: a review. Cancer Epidemiol Biomarkers Prev. to be impoverished and publicly insured. Hispanics 2008;17(11):2913-2923. 18. Braveman P, Egerter S, Williams DR. The social determinants of health: and blacks possess lower self-perceived risk for mel- coming of age. Annu Rev Public Health. 2011;32:381-398. anoma than their counterparts, and they have less 19. Koh HK, Oppenheimer SC, Massin-Short SB, et al. Translating research evidence into practice to reduce health disparities: a social determinants ap- awareness and knowledge about melanoma. They proach. Am J Public Health. 2010;100(suppl 1):S72-S80. are also less likely to participate in melanoma pre- 20. Williams DR, Sternthal M. Understanding racial-ethnic disparities in health: sociological contributions. J Health Soc Behav. 2010;51(suppl):S15-S27. vention and screening. Furthermore, the increasing 2 1. M árquez-Magaña L, Samayoa C, Umanzor C. Debunking ‘race’ and US acculturation among Hispanics is associated with asserting social determinants as primary causes of cancer health dispar- ities: outcomes of a science education activity for teens. J Cancer Educ. increased skin cancer risk behaviors. 2013;28(2):314-318. This review also exposes the paucity of literature 22. Wheeler SB, Reeder-Hayes KE, Carey LA. Disparities in breast cancer treatment and outcomes: biological, social, and health system determinants addressing the social determinants of inequities in and opportunities for research. Oncologist. 2013;18(9):986-993. outcomes among patients with cutaneous melanoma. 23. Krieger N. A glossary for social epidemiology. J Epidemiol Community Health. 2001;55(10):693-700. Although the low incidence and prevalence rates of 24. Berkman LF, Kawachi I, eds. Social Epidemiology. New York: Oxford cutaneous melanoma among Hispanics and blacks University Press; 2000. 25. Wallington SF. Health disparities research and practice: the role of contribute to the sparseness of studies on this topic, language and health communication. In: Wen-Ying C, Hamilton HE, eds. The many of the barriers discussed are potentially mod- Routledge Handbook of Language and Health Communication. New York: Routledge; 2014. ifiable; therefore, they are important to understand. 26. Ortiz CA, Goodwin JS, Freeman JL. The effect of socioeconomic factors Additional studies are needed to unravel the cultural, on incidence, stage at diagnosis and survival of cutaneous melanoma. Med Sci Monit. 2005;11(5):RA163-RA172. economical, and biological complexities that contrib- 27. Singh SD, Ajani UA, Johnson CJ, et al. Association of cutaneous mel- ute to the observed inequities in outcomes among anoma incidence with area-based socioeconomic indicators-United States, 2004-2006. J Am Acad Dermatol. 2011;65(5 suppl 1):S58-S68. patients with cutaneous melanoma. This information 28. Clegg LX, Reichman ME, Miller BA, et al. Impact of socioeconomic may be valuable for the development of effective in- status on cancer incidence and stage at diagnosis: selected findings from the

348 Cancer Control October 2014, Vol. 21, No. 4 surveillance, epidemiology, and end results: National Longitudinal Mortality 57. Katapodi MC, Lee KA, Facione NC, et al. Predictors of perceived breast Study. Cancer Causes Control. 2009;20(4):417-435. cancer risk and the relation between perceived risk and breast cancer screen- 29. Pollitt RA, Clarke CA, Shema SJ, et al. California Medicaid enrollment ing: a meta-analytic review. Prev Med. 2004;38(4):388-402. and melanoma stage at diagnosis: a population-based study. Am J Prev Med. 58. McQueen A, Swank PR, Bastian LA, et al. Predictors of perceived 2008;35(1):7-13. susceptibility of breast cancer and changes over time: a mixed modeling 30. Cokkinides VE, Geller AC, Jemal A. Trends in melanoma mortality approach. Health Psychol. 2008;27(1):68-77. among non-Hispanic whites by educational attainment, 1993-2007. Arch Der- 59. Kundu RV, Kamaria M, Ortiz S, et al. Effectiveness of a knowl- matol. 2012;148(5):587-591. edge-based intervention for melanoma among those with ethnic skin. J Am 31. Geller AC, Miller DR, Lew R, et al. Cutaneous melanoma mortality Acad Dermatol. 2010;62(5):777-784. among the socioeconomically disadvantaged in Massachusetts. Am J Public 60. Ma F, Collado-Mesa F, Hu S, et al. Skin cancer awareness and sun Health. 1996;86(4):538-543. protection behaviors in white Hispanic and white non-Hispanic high school 32. Reyes-Ortiz CA, Goodwin JS, Zhang DD, et al. Socioeconomic students in Miami, Florida. Arch Dermatol. 2007;143(8):983-988. status and chemotherapy use for melanoma in older people. Can J Aging. 61. Pipitone M, Robinson JK, Camara C, et al. Skin cancer awareness 2011;30(1):143-153. in suburban employees: a Hispanic perspective. J Am Acad Dermatol. 33. Reyes-Ortiz CA, Goodwin JS, Freeman JL, et al. Socioeconom- 2002;47(1):118-123. ic status and survival in older patients with melanoma. J Am Geriatr Soc. 62. Roman C, Lugo-Somolinos A, Thomas N. Skin cancer knowledge and 2006;54(11):1758-1764. skin self-examinations in the Hispanic population of North Carolina: the pa- 34. Ross CE, Wu CL. The links between education and health. Am Sociol tient’s perspective. JAMA Dermatol. 2013;149(1):103-104. Rev. 1995;60(5):719-745. 63. Temoshok L, DiClemente RJ, Sweet DM, et al. Factors related to patient 35. Winkleby MA, Jatulis DE, Frank E, et al. Socioeconomic status and delay in seeking medical attention for cutaneous malignant melanoma. Cancer. health: how education, income, and occupation contribute to risk factors for 1984;54(12):3048-3053. cardiovascular disease. Am J Public Health. 1992;82(6):816-820. 64. Cheng CE, Irwin B, Mauriello D, et al. Health disparities among different 36. US Department of Health and Human Services. Healthy People 2020: ethnic and racial middle and high school students in sun exposure beliefs and disparities. http://www.healthypeople.gov/2020/about/disparitiesAbout.aspx. knowledge. J Adolesc Health. 2010;47(1):106-109. Accessed August 13, 2014. 65. Hay J, Coups EJ, Ford J, et al. Exposure to mass media health infor- 37. Buster KJ, You Z, Fouad M, et al. Skin cancer risk perceptions: a com- mation, skin cancer beliefs, and sun protection behaviors in a United States parison across ethnicity, age, education, gender, and income. J Am Acad probability sample. J Am Acad Dermatol. 2009;61(5):783-792. Dermatol. 2012;66(5):771-779. 66. Miller DR, Geller AC, Wyatt SW, et al. Melanoma awareness and self-ex- 38. Halpern MT, Ward EM, Pavluck AL, et al. Association of insurance status amination practices: results of a United States survey. J Am Acad Dermatol. and ethnicity with cancer stage at diagnosis for 12 cancer sites: a retrospective 1996;34(6):962-970. analysis. Lancet Oncol. 2008;9(3):222-231. 67. Friedman LC, Bruce S, Weinberg AD, et al. Early detection of skin 39. Kirsner RS, Wilkinson JD, Ma F, et al. The association of Medicare cancer: racial/ethnic differences in behaviors and attitudes. J Cancer Educ. health care delivery systems with stage at diagnosis and survival for patients 1994;9(2):105-110. with melanoma. Arch Dermatol. 2005;141(6):753-757. 68. Andreeva VA, Reynolds KD, Buller DB, et al. Concurrent psycho- 40. Rouhani P, Arheart KL, Kirsner RS. Differences in melanoma outcomes social predictors of sun safety among middle school youth. J Sch Health. among Hispanic Medicare enrollees. J Am Acad Dermatol. 2010;62(5):768-776. 2008;78(7):374-381. 41. Koroukian SM, Bakaki PM, Raghavan D. Survival disparities by Med- 69. Berwick M, Begg CB, Fine JA, et al. Screening for cutaneous melanoma icaid status. Cancer. 2012;118(17):4271-4279. by skin self-examination. J Natl Cancer Inst. 1996;88(1):17-23. 42. US Department of Commerse. US Census Bureau: 2004 interim na- 70. Arnold MR, DeJong W. Skin self-examination practices in a convenience tional population projects. http://www.census.gov/population/projections/data/ sample of US university students. Prev Med. 2005;40(3):268-273. national/usinterimproj.html. Accessed Augsut 13, 2014. 71. Imahiyerobo-Ip J, Ip I, Jamal S, et al. Skin cancer awareness in com- 43. Artiga S. Health coverage by bace and ethnicity: the potential impact of munities of color. J Am Acad Dermatol. 2011;64(1):198-200. the Affordable Care Act. http://kff.org/disparities-policy/issue-brief/health-cov- 72. Saraiya M, Hall HI, Thompson T, et al. Skin cancer screening among erage-by-race-and-ethnicity-the-potential-impact-of-the-affordable-care-act/. U.S. adults from 1992, 1998, and 2000 National Health Interview Surveys. Accessed August 13, 2014. Prev Med. 2004;39(2):308-314. 44. Bilimoria KY, Balch CM, Wayne JD, et al. Health care system and 73. Coups EJ, Stapleton JL, Hudson SV, et al. Skin cancer screening socioeconomic factors associated with variance in use of sentinel lymph node among Hispanic adults in the United States: results from the 2010 National biopsy for melanoma in the United States. J Clin Oncol. 2009;27(11):1857-1863. Health Interview Survey. Arch Dermatol. 2012;148(7):861-863. 45. Freeman HP. Poverty, culture, and social injustice: determinants of 74. Coups EJ, Stapleton JL, Hudson SV, et al. Skin cancer surveillance cancer disparities. CA Cancer J Clin. 2004;54(2):72-77. behaviors among US Hispanic adults. J Am Acad Dermatol. 2013;68(4): 46. Coups EJ, Manne SL, Heckman CJ. Multiple skin cancer risk behaviors 576-584. in the U.S. population. Am J Prev Med. 2008;34(2):87-93. 75. Shi L, Lebrun LA, Tsai J. The influence of English proficiency on access 47. Buller DB, Cokkinides V, Hall HI, et al. Prevalence of sunburn, sun to care. Ethn Health. 2009;14(6):625-642. protection, and indoor tanning behaviors among Americans: review from 76. Kandula NR, Wen M, Jacobs EA, et al. Low rates of colorectal, cervical, national surveys and case studies of 3 states. J Am Acad Dermatol. 2011;65 and breast cancer screening in Asian Americans compared with non-Hispanic (5 suppl 1):S114-S123. whites: cultural influences or access to care? Cancer. 2006;107(1):184-192. 48. Hall HI, Saraiya M, Thompson T, et al. Correlates of sunburn experienc- 77. Derose KP, Baker DW. Limited English proficiency and Latinos’ use of es among U.S. adults: results of the 2000 National Health Interview Survey. physician services. Med Care Res Rev. 2000;57(1):76-91. Public Health Rep. 2003;118(6):540-549. 78. Jacobs EA, Karavolos K, Rathouz PJ, et al. Limited English proficiency 49. Santmyire BR, Feldman SR, Fleischer AB Jr. Lifestyle high-risk behav- and breast and cervical cancer screening in a multiethnic population. Am J iors and demographics may predict the level of participation in sun-protection Public Health. 2005;95(8):1410-1416. behaviors and skin cancer primary prevention in the United States: results of 79. De Alba I, Hubbell FA, McMullin JM, et al. Impact of U.S. citizenship the 1998 National Health Interview Survey. Cancer. 2001;92(5):1315-1324. status on cancer screening among immigrant women. J Gen Intern Med. 50. Pichon LC, Corral I, Landrine H, et al. Perceived skin cancer risk 2005;20(3):290-296. and sunscreen use among African American adults. J Health Psychol. 80. Gomez SL, Clarke CA, Shema SJ, et al. Disparities in breast cancer 2010;15(8):1181-1189. survival among Asian women by ethnicity and immigrant status: a popula- 51. Pichon LC, Corral I, Landrine H, et al. Sun-protection behaviors among tion-based study. Am J Public Health. 2010;100(5):861-869. African Americans. Am J Prev Med. 2010;38(3):288-295. 81. Havercamp SM, Scandlin D, Roth M. Health disparities among adults 52. Andreeva VA, Unger JB, Yaroch AL, et al. Acculturation and sun-safe with developmental disabilities, adults with other disabilities, and adults not behaviors among US Latinos: findings from the 2005 Health Information Na- reporting disability in North Carolina. Public Health Rep. 2004;119(4):418-426. tional Trends Survey. Am J Public Health. 2009;99(4):734-741. 53. Coups EJ, Stapleton JL, Hudson SV, et al. Linguistic acculturation and skin cancer-related behaviors among hispanics in the southern and Western United States. JAMA Dermatol. 2013;149(6):679-686. 54. Coups EJ, Stapleton JL, Hudson SV, et al. Sun protection and ex- posure behaviors among Hispanic adults in the United States: differences according to acculturation and among Hispanic subgroups. BMC Public Health. 2012;12:985. 55. Heckman CJ, Cohen-Filipic J. Brief report: ultraviolet radiation exposure, considering acculturation among Hispanics (project URECAH). J Cancer Educ. 2012;27(2):342-346. 56. Vernon SW. Risk perception and risk communication for cancer screen- ing behaviors: a review. J Natl Cancer Inst Monogr. 1999;1999(25):101-119.

October 2014, Vol. 21, No. 4 Cancer Control 349 Special Report

Fruit and Vegetable Intake Among Jordanians: Results From a Case-Control Study of Colorectal Cancer Reema F. Tayyem, PhD, Ihab Shehadah, MD, Suhad S. Abu-Mweis, PhD, Hiba A. Bawadi, PhD, Kamal E. Bani-Hani, MD, PhD, Tareq Al-Jaberi, MD, PhD, Majed Al-Nusairr, MD, and Dennis D. Heath, MS

Background: Diets that include fruits and vegetables have been suggested as one way to reduce the risk of developing colorectal cancer (CRC); however, the association between consuming fruits and vegetables and CRC risk is not clear. The objective of the present study is to compare fruit and vegetable intake between 2 groups of Jordanians and further investigate this possible relationship. Methods: A history of fruit and vegetable consumption was obtained from 220 people with CRC and 281 healthy controls, all of whom were from Jordan. Both groups were matched for age, sex, occupation, and marital status. Fruit and vegetable consumption was quantified for the previous 12 months in both groups. Results: Total vegetable intake was associated with the risk of developing CRC. Consuming 5 servings of vegetables a day decreased the risk of developing CRC when compared with no more than 1 serving a day (odds ratio [OR] = 0.23; 95% confidence interval [CI]: 0.55–0.97). A significant direct relationship between CRC risk and consuming cauliflower and cabbage was found; however, no association was found for raw or cooked leafy vegetable and other vegetable types. Consuming several types of fruits also revealed no association with risk of CRC, although an increased intake of dates and figs was associated with a reduced risk of developing CRC. The ORs for the highest intake of servings compared with the lowest intake were 0.48 (95% CI: 0.27–0.87; P = .004) for dates and 0.604 (95% CI: 0.35–1.06; P = .003) for figs. Conclusions: Consuming fruits and vegetables did not significantly correlate with a lowered incidence of CRC. However, a trend of protection was detected for several types of fruits and vegetables.

Introduction with CRC, while a high intake of fruits and vegetables In Jordan, cancer is a major cause of morbidity and may prevent the development of cancer.5,6 Typically, mortality.1,2 Colorectal cancer (CRC) ranks second a diet rich in fruits and vegetables will provide a for newly diagnosed cancer cases among Jordanians; good source of carotenoids, folate, vitamin C, flavo- according to the World Cancer Research Fund, CRC noids, organosulfides, isothiocyanates, and protease ranks first among men and second among women.3 inhibitors.7 These compounds act as antioxidants Generally, many external and internal factors may and may play a role in preventing and reducing the be involved in the development of cancer, and some risk of developing cancer,7 and some data suggest of these factors may act in tandem or separately to that dietary fiber contributes to a reduction in the initiate or promote cancer development.4 risk of developing CRC.3 Furthermore, according to Some research studies have suggested that a low Steinmetz and Potter,8 increasing a person’s intake intake of fruits and vegetables may be associated of fruits and vegetables to more than 3.4 servings per day might reduce the risk of developing cancer. From the Department of Clinical Nutrition and Dietetic (RFT, By contrast, other studies have found no associa- SSA-M) and the Faculty of Medicine (KEB-H) at Hashemite Uni- tion between fruit and vegetable consumption and versity, Zarqa, Jordan, the Gastroenterology Division (IS) at the CRC.9,10 However, Vogtmann et al11 showed that fruit King Hussein Cancer Center, Amman, Jordan, the Departments of Nutrition and Food Technology (HAB) and General and Pediatric intake was inversely associated with the risk of CRC Surgery (TA-J) at the Jordan University of Science and Technology, development, whereas consuming vegetables was Irbid, Jordan, the Gastroenterology Division (MA-N) at the Prince unrelated to risk among middle-aged and older Chi- Hamza Hospital, Amman, Jordan, and the Cancer Prevention and 12 Control Program (DDH) at the Moores Cancer Center, University of nese men. Koushik et al reported that vegetable and California–San Diego, La Jolla, California. fruit intake was inversely related to CRC risk among Address correspondence to Reema F. Tayyem, PhD, Department men but not among women, and the researchers of Clinical Nutrition and Dietetic, Hashemite University, PO Box argued that this association was stronger for colon 150459, Zarqa 13115, Jordan. E-mail: [email protected] than for rectal cancer. Submitted March 24, 2014; accepted June 2, 2014. Many studies that have evaluated the effect of fruit No significant relationships exist between the authors and the com- panies/organizations whose products or services may be referenced and vegetable consumption on developing CRC are in this article. controversial, and knowledge is lacking with regard

350 Cancer Control October 2014, Vol. 21, No. 4 to the association of the CRC process and commonly Food Frequency Questionnaire consumed fruits and vegetables among those in the A validated Food Frequency Questionnaire (FFQ) in Middle East. The change in the Jordanian diet from Arabic was used for to assess the diets of the volun- being high in fruits, vegetables, whole grains, and teers. The FFQ was modified from the Diet History olive oil to a diet low in fruits and vegetables and Questionnaire I of the US National Cancer Institute high in red meat and saturated fat may increase the and was validated for use in the Jordanian setting.14 risk of developing CRC.13 Therefore, the present study Participants were asked about their food intake aimed to investigate the possible association between (specifically fruits and vegetables) before being diag- the number of servings and frequency of fruits and nosed for the CRC group. A 1-year period was chosen vegetables commonly consumed by Jordanians and for the data collected by the FFQ so that seasonal the risk of developing CRC. variations of fruits and vegetables would be available, although most participants indicated a constant di- Materials and Methods etary pattern during the last 5 years. Study Population Food lists in the modified FFQ questions were A total of 504 volunteers participated in the study classified based on 21 types of vegetables and (men = 220; women = 281). Of those, 220 had CRC 21 types of fruits and juices. For each type of food, and 281 were healthy controls. Participants were en- participants were asked whether they separately con- rolled in the study from January 2010 to December sumed each food item (eg, apple, banana, oranges, 2012. Those diagnosed with CRC were recruited from broccoli, sweet pepper). An answer in the affirmative 5 large Jordanian hospitals with oncology services resulted in additional questions related to frequency (King Hussein Cancer Center, King Abdullah Univer- and amount of food consumed in its season (if the sity Hospital, Prince Hamzeh Hospital, Jordan Univer- fruit is seasonal). Additional details were obtained sity Hospital, and Al-Basheer Hospital). for types of food available in different forms (eg, whole, juice, cooked, raw). If the participant’s diet did Inclusion and Exclusion Criteria not include a food type, then related questions were To be included in the study, volunteers had to be skipped and the research assistant moved to another of Jordanian nationality, aged 18 years or older, and question. Participants were asked how frequently on able to verbally communicate. They also had to be average during the last year they consumed 1 stan- free of cancer other than CRC, diabetes mellitus, liver dard serving of a specific food item from 9 different disease, and/or rheumatoid arthritis. Those with CRC categories (< 1 per month, 2–3 per month, 1–2 per must have received a confirmatory diagnosis no later week, 3–4 per week, 5–6 per week, 1 per day, 2–3 per than 1 year from the time of the first interview. Partic- day, 4–5 per day, or 6 per day). Food models and stan- ipants were excluded if they had a critical illness or dard measuring tools were used to help participants were currently hospitalized. To control for confound- estimate the portion size they consumed. Responses ing variables, the control group was recruited from on consumption frequency of a specified serving size hospital personnel, outpatients, visitors, and accom- for each food item were converted into average daily panying persons, and were then matched by age, sex, intake rates. Dietary intake rates were then analyzed occupation, and marital status. Control participants using dietary analysis software (ESHA Food Processor were subjected to the same inclusion and exclusion SQL version 10.1.1; ESHA, Salem, Oregon) with addi- criteria. When control participants were enrolled in tional data on foods commonly consumed in Jordan. the study and were listed as visitors or accompany- ing persons, we ensured that they were unrelated Physical Activity Level to any study volunteers diagnosed with CRC. The The 7-day Physical Activity Recall (PAR) was orig- ratio of volunteers diagnosed with CRC to controls inally developed by Sallis et al15 and was used in was approximately 1:1. The ethical committees of all this study to measure physical activity level. The 5 hospitals approved the study protocol, and written 7-day PAR is an organized questionnaire that charts informed consent was obtained from all participants a participant’s recall of time spent practicing physical prior to starting the study. activity during a 7-day period. It involves various levels of physical activity intensity, such as aerobic Data Collection exercise, work-related activities, walking, gardening, Trained research assistants collected the data via pri- recreation, and leisure activities. The frequency, in- vate interviews in which the participants were in- tensity, duration, and type of the physical activity are formed about the purpose of the research. During the typically taken into consideration when measuring interview, different valid questionnaires were used to the level of physical activity. collect personal and family histories, diet (current and Participants were asked to respond to a PAR past), and physical activity level. question based on the way they used to behave prior

October 2014, Vol. 21, No. 4 Cancer Control 351 to being diagnosed with CRC. The number of hours total energy intake, or physical activity level between spent in different activity levels were obtained and the different levels of fruit and vegetable consumption converted into metabolic equivalents (METs). The among men and women. average METs for walking are 3.3, 4.0 for moder- Statistical analysis (not shown here) revealed that ate activity, and 8.0 for vigorous activity. The score a significant difference was detected in BMI between expressed as MET minute per week was calculated the female cases and controls. A trend in family history as MET level × minutes of activity ÷ day × days per of CRC was seen to decrease as the number of fruits week. The total physical activity MET minutes per and vegetable servings in both men and women in- week was obtained by summing the METs and then creased. For men, regular physical activity was signifi- performing categorical analysis (inactive, minimally cantly different between the categories of vegetable active, or health enhancing physical activity active). consumption (P < .022). Table 2 shows the adjusted ORs of CRC by num- Anthropometric Measurements ber of fruit and vegetable servings in the cases and Weight (measured to the nearest 0.1 kg), height (mea- controls. In general, as the number of total vege- sured to the nearest 1.0 cm), and body mass index table servings increased to 5 servings per day, the (BMI) were calculated per the previously published incidence of CRC significantly decreased (OR 0.23, protocol.16 A family history of CRC was obtained by 95% CI: 0.55–0.97). Moreover, increasing cauliflow- asking participants if any of their first- or second-de- er consumption to more than 2 servings per week gree relatives had CRC or any other type of cancer. increased CRC risk (OR 1.352, 95% CI: 0.21–8.69, P = .001). By contrast, consuming figs and dates re- Statistical Analyses vealed an inverse association with CRC development. All statistical analyses were conducted using IBM SPSS As the number of servings increased up to 1 serving Statistics for Windows version 19.0 (IBM; Armonk, per day, the risk for developing CRC decreased (from New York). Descriptive analyses were conducted to OR 0.60, 95% CI: 0.34–1.06, P = .003, to OR 0.48, 95% examine the frequency of different variables. The CI: 0.27–0.89, P = .006). No relationship was found for consumption of fruit and of vegetables was computed all fruits, raw or cooked leafy vegetables, tomato, sal- in 2 ways, either grouped into 5 categories based on ad, green beans, peas, carrots, sweat peppers, apples, number of servings consumed daily (< 1.0 servings pears, banana, peach, grapes, melon, watermelon, per day [referent category], 2 servings per day, 3 strawberry, oranges, grapefruit, apricots, bommali, servings per day, 4 servings per day, > 5 servings/ aloe vera, and dried fruits. day) or grouped based on frequency (daily, weekly, The adjusted ORs and CIs for the frequency of monthly, monthly, rarely). The referent group was consuming individual fruits, vegetables, and starchy the category with the lowest intake for both types vegetable items are shown in Table 3. After adjusting of computation. potential confounders, the results show that daily con- Multinomial logistic regression was used to calcu- sumption of citrus fruit, apple, peach, melon, water- late odds ratios (ORs) and confidence intervals (CIs), melon, strawberry, and apricot had no effect on CRC and linear regression was used to calculate P values risk. Both fig fruits (OR 0.51, 95% CI: 0.28–0.92), and for trend. Age (continuous), sex, BMI (continuous), dates (OR 0.52, 95% CI: 0.27–0.98) had a significant physical activity level (continuous), total energy in- daily protective effect against CRC risk, while kiwi take (continuous), occupation, education level, marital (OR 0.69, 95% CI: 0.34–1.41) had a weekly protective status, and family history of CRC were evaluated as effect (for all: P value for trend < 0.05). potential confounders. Chi-square was used to detect Consuming different types of vegetables was the differences among categorical variables. The sig- seen to either increase or decrease the risk of de- nificance level was set at P < .05. veloping CRC (Table 4). However, no significant association was detected between any type of Results vegetable and the risk of developing CRC. Leafy Table 1 shows the distribution of standard risk factors vegetables (raw and cooked), tomato, and salad for the study participants by the number of servings showed a protective but insignificant association of fruits and vegetables consumed each day. Cases with CRC risk. In addition, the risk of CRC tended to and controls were matched for several parameters, increase when participants increased their daily con- including age, sex, occupation, and marital status. sumption of cabbage (OR 2.30, 95% CI: 0.28–19.14, Therefore, no significant differences were detected in P trend = .001) and cauliflower (OR 4.46, 95% CI: those parameters when the participants were catego- 0.72–27.68, P trend = .001). For mixed vegetables, rized according to sex and number of fruit or vege- the risk of CRC was reduced even more (OR 0.53, table servings. In addition, no significant differences 95% CI: 0.08–3.56, P trend = .017) when consuming were seen in BMI, tobacco use, family history of CRC, mixed vegetables on a daily basis.

352 Cancer Control October 2014, Vol. 21, No. 4 Table 1. — Characteristics of Study Participants by Frequency of Fruit and Vegetable Intake

Fruit Consumptiona Vegetable Consumptiona P P Value Value ≤ 1 2 3 4 ≥ 5 ≤ 1 2 3 4 ≥ 5

Women

No. of women 148 61 25 12 7 103 73 46 21 10

Age, yb 48.1 49.4 47.9 52.7 50.1 .318 48.0 49.2 49.8 47.6 48.8 .311

Body mass index, kg/m2b 29.3 28.7 29.4 29. 5 27.8 .661 29.7 27.7 29.8 29.6 30.0 .810

Family history of colorectal cancer, % 53.8 25.8 11.8 4.3 4.3 .310 39.8 32.3 16.1 7.5 4.3 .862

Regular physical activity, MET 5033.5 5763.7 6161.3 2712.6 3861.0 .987 5847.3 4540.5 5217.4 3779.1 5329.5 .350

Total caloric intakeb 3528.8 3987.1 3893.3 5050.2 4196.7 .526 3483.9 3815.2 4062.8 4022.1 4208.2 .449

Education (above high school), % 58.6 23.3 10.3 4.7 3 .539 40.5 29.3 19 7.3 3.9 .305

Marital status, %

Married 59 24.8 8.1 4.8 3.3 40 29 18.6 8.1 4.3

Single 50 31.3 18.8 — — .532 62.5 18.8 18.8 — — .765

Divorced 100 — — — 33.3 33.3 33.3 — —

Widower 54.2 16.7 20.8 8.3 — 33.3 33.3 12.5 16.7 4.2

Working, % 45.5 29.5 18.2 4.5 2.3 .202 52 18.2 18.2 6.8 4.5 .401

Tobacco use, % 61.5 15.4 23.1 — — .798 46.2 38.5 7.7 7.7 — .817

Men

No. of men 150 49 34 7 8 92 61 62 18 15

Age, yb 55.4 54.4 55.9 58.9 52.4 .989 54.2 56.0 56.4 54 55.5 .394

Body mass index, kg/m2b 27.8 27.7 27.9 28.6 29.5 .514 27.5 27.6 28.4 27.3 29.2 .293

Family history of colorectal cancer, % 56.5 21.7 15.2 2.2 4.3 .96 37 20.7 28.3 4.3 9.8 .158

Regular physical activity, MET 4579.5 3894.4 3326.9 3630.2 5692.5 .001 5145.0 3854.0 3560.6 4205.1 3859.8 .669

Total caloric intakeb 3827.0 4341.3 4828.2 5617.5 5320.2 .458 3772.7 4153.0 4663.5 4576.4 3677.2 .458

Education (above high school), % 59.8 20.5 14.2 2.5 2.9 .105 37.2 24.7 25.5 7.5 5 .012

Marital status, %

Married 59.9 20.7 13.1 3 3.4 37.1 24.9 24.9 7.2 5.9

Single 100 — — — — .128 66.7 16.7 — — 16.7 .438

Divorced 100 — — — — — — 100 — —

Widower 25 — 75 — — — 25 50 25 —

Working, % 56.8 12.2 16.8 2.4 4.8 .348 43.2 20.8 24.8 5.6 5.6 .282

Tobacco use, % 51.4 28.6 11.4 5.7 2.9 .317 37.1 21.4 25.7 5.7 10 .634

aBy number of servings per day. bMean value. Fruits and vegetables were compiled according to cultural influences. For example, tomatoes and sweet peppers were categorized as vegetables, not fruits; aloe vera is known culturally as a fruit because it is eaten as a dessert rather than as a vegetable closely related to the onion/garlic family. MET = metabolic equivalent.

October 2014, Vol. 21, No. 4 Cancer Control 353 Table 2. — Adjusted ORsa and CIs of Colorectal Cancer by Fruit and Vegetable Servings Among Jordanians

Food Item ≤ 1 Serving 2 Servings 3 Servings 4 Servings 5 Servings P Value per Day per Day per Day per Day per Day for Trend All Fruits AOR (95% CI) 1 (ref) 1.08 (0.62–1.89) 1.00 (0.48–2.07) 0.88 (0.23–3.37) 0.97 (0.22–4.47) .230 Total 132 44 25 10 9 All Vegetables AOR (95% CI) 1 (ref) 1.04 (0.59–1.83) 0.61 (0.33–1.13) 0.90 (0.37–2.23) 0.23 (0.55–0.97) .153 Total 87 63 45 15 10 ≤ 1 Serving 2 Servings 3–4 Servings 5–6 Servings 1 Serving per Week per Week per Week per Week per Day Cooked Leafy Vegetable AOR (95% CI) 1 (ref) 0.67 (0.31–1.45) 0.639 (0.24–1.72) 2.82 (0.21–37.65) 0.77 (0.05–12.95) .453 Total 2 24 8 2 184 Raw Leafy Vegetable AOR (95% CI) 1 (ref) 0.93 (0.49–1.75) 0.64 (0.31–1.28) 0.84 (0.17–4.05) 0.76 (0.41–1.41) .882 Total 50 35 24 4 107 Tomato AOR (95% CI) 1 (ref) 0.74 (0.30–1.79) 0.78 (0.36–1.67) 0.54 (0.18–1.60) 0.53 (0.29–1.02) .269 Total 118 20 34 9 39 Salad AOR (95% CI) 1 (ref) 1.16 (0.32–3.32) 1.04 (0.44–1.53) 0.82 (0.58–2.28) 1.15 (0.61–2.23) .962 Total 58 34 40 8 80 Cabbage AOR (95% CI) 1 (ref) 2.11 (0.37–11.95) — 0.80 (0.06–10.22) — .001 Total 6 11 2 1 200 Carrot AOR (95% CI) 1 (ref) 1.67 (0.73–3.77) 1.18 (0.56–2.50) 1.83 (0.28–11.96) 0.56 (0.23–1.36) .729 Total 18 24 21 5 152 Green Bean AOR (95% CI) 1 (ref) 1.04 (0.31–3.51) — — — .154 Total — 8 — — 212 Pea AOR (95% CI) 1 (ref) 1.78 (0.56–5.64) 1.02 (0.06– 17.66) — — .171 Total 1 11 2 1 205 Corn AOR (95% CI) 1 (ref) 0.44 (0.13–1.51) 0.68(0.15–3.03) — 0.24 (0.06–0.96) .129 Total 5 7 6 — 202 Cauliflower AOR (95% CI) 1 (ref) 1.01 (0.46–2.22) 1.36 (0.42–4.33) — 1.35 (0.21–8.69) .001 Total 6 15 9 2 188 Sweet Pepper AOR (95% CI) 1 (ref) 0.81 (0.41–1.60) 1.72 (0.85–3.49) 0.37 (0.08–1.70) 1.21 (0.64–2.27) .542 Total 50 24 31 4 111 Apple AOR (95% CI) 1 (ref) 0.81 (0.37–1.77) 1.00 (0.532–1.89) 1.05 (0.264–4.17) 0.87 (0.493–1.53) .549 Total 79 25 38 5 73 Pear AOR (95% CI) 1 (ref) 0.69 (0.31–1.53) 0.80 (0.36–1.78) 2.69 (0.434–16.72) 1.25 (0.66–2.37) .108 Total 46 19 18 4 133 Banana AOR (95% CI) 1 (ref) 0.57 (0.27–1.19) 1.02 (0.55–1.89) 1.04 (0.286–3.75) 1.05 (0.57–1.95) .139 Total 70 26 40 5 79

continues on page 355

354 Cancer Control October 2014, Vol. 21, No. 4 Table 2. — Adjusted ORsa and CIs of Colorectal Cancer by Fruit and Vegetable Servings Among Jordanians (continued)

≤ 1 Serving 2 Servings 3–4 Servings 5–6 Servings 1 Serving per Week per Week per Week per Week per Day Pear AOR (95% CI) 1 (ref) 0.69 (0.31–1.53) 0.80 (0.36–1.78) 2.69 (0.434–16.72) 1.25 (0.66–2.37) .108 Total 46 19 18 4 133 Banana AOR (95% CI) 1 (ref) 0.57 (0.27–1.19) 1.02 (0.55–1.89) 1.04 (0.286–3.75) 1.05 (0.57–1.95) .139 Total 70 26 40 5 79 Peach AOR (95% CI) 1 (ref) 0.36 (0.17–0.76) 0.62 (0.30–1.31) 1.52 (0.38–6.13) 0.64 (0.34–1.19) .548 Total 66 23 21 7 103 Grape AOR (95% CI) 1 (ref) 0.67(0.30–1.51) 0.96 (0.50–1.84) 2.34 (0.51–10.69) 1.11 (0.62–1.98) .087 Total 96 22 34 6 62 Melon AOR (95% CI) 1 (ref) 0.51 (0.26–1.00) 1.65 (0.77–3.50) 1.51 (0.19–11.61) 0.90 (0.43–1.87) .119 Total 45 27 29 3 116 Watermelon AOR (95% CI) 1 (ref) 0.51 (0.23–1.14) 0.77 (0.42–1.41) 1.24 (0.27–5.54) 0.72 (0.39–1.32) .939 Total 62 25 36 4 93 Strawberry AOR (95% CI) 1 (ref) 0.85 (0.31–2.30) 1.066 (0.43–2.63) — 1.015 (0.37–2.78) .275 Total 16 14 11 — 179 Orange AOR (95% CI) 1 (ref) 1.07 (0.530–2.18) 1.008 (0.507–2.00) 2.78 (0.65–11.92) 0.85 (0.47–1.54) .91 Total 76 28 29 6 81 Grapefruit AOR (95% CI) 1 (ref) 0.84 (0.22–3.17) 0.95 (0.248–3.68) — 1.00 (0.36–2.82) .193 Total 12 4 6 — 198 Apricot AOR (95% CI) 1 (ref) 0.52 (0.24–1.12) 1.151 (0.47–2.79) 3.423 (0.27–43.71) 0.83 (0.39–1.75) .117 Total 25 14 13 2 166 Fig AOR (95% CI) 1 (ref) 0.69 (0.31–1.57) 0.682 (0.32–1.44) 0.82 (0.12–5.54) 0.60 (0.34–1.06) .003 Total 43 13 18 3 143 Aloe Vera AOR (95% CI) 1 (ref) 0.64 (0.16–2.64) 1.13 (0.36–3.51) — 1.52 (0.60–3.89) .427 Total 17 4 6 — 193 Date AOR (95% CI) 1 (ref) 0.60 (0.235–1.55) 0.68 (0.30–1.53) 0.27 (0.03–2.69) 0.482 (0.27–0.86) .004 Total 34 10 12 1 163 Kiwi AOR (95% CI) 1 (ref) 0.29 (0.05–1.48) 1.02 (0.16–6.59) — 1.20 (0.28–5.21) .033 Total 5 3 3 1 208 Bommali AOR (95% CI) 1 (ref) 2.05 (0.43–9.74) 3.34 (0.93–12.06) — 1.14 (0.23–5.64) .149 Total 4 7 8 — 201 Dried Fruit AOR (95% CI) 1 (ref) 4.13 (0.40–42.91) 1.19 (0.21–6.86) — 0.00 .864 Total 3 5 3 — 209

aEstimated from multinomial logistic regression models and adjusted for age, sex, total energy, MET minutes/week, tobacco use, education level, marital status, work, income, and family history of colorectal cancer. Fruits and vegetables were compiled according to cultural influences. For example, tomatoes and sweet peppers were categorized as fruits, not vegetables; aloe vera is known culturally as a fruit because it is eaten as a dessert rather than as a vegetable closely related to the onion/garlic family. AOR = adjusted odds ratio, CI = confidence interval, MET = metabolic equivalent, OR = odds ratio.

October 2014, Vol. 21, No. 4 Cancer Control 355 Table 3. — AORsa and CIs for Common Fruits Consumed Among Jordanians

Category of Consumption

Item Rarelyb Monthly Weekly Daily P Value for Trend

Apple Cases 14 20 102 84 Controls 17 33 137 94 AOR (95% CI) 1 0.56 (0.18–1.70) 0.84 (0.32–2.16) 0.73 (0.27–1.96) .549

Banana Cases 10 28 107 75 Controls 12 51 140 78 AOR (95% CI) 1 0.89 (0.26–3.05) 0.98 (0.31–3.08) 1.12 (0.34–3.67) .139

Orange Cases 38 20 80 82 Controls 39 36 115 91 AOR (95% CI) 1 0.78 (0.31–1.96) 0.96 (0.49–1.88) 0.90 (0.44–1.82) .91

Pear Cases 58 41 71 50 Controls 78 76 83 44 AOR (95% CI) 1 0.67 (0.34–1.30) 0.83 (0.46–1.51) 1.13 (0.56–2.29) .108

Peach Cases 52 21 74 72 Controls 57 44 109 71 AOR (95% CI) 1 0.52 (0.25–1.12) 0.59 (0.33–1.07) 0.64 (0.32–1.25) .548

Grape Cases 24 10 84 102 Controls 22 38 121 100 AOR (95% CI) 1 0.21 (0.06–0.71) 0.49 (0.22–1.09) 0.62 (0.27–1.40) .087

Melon Cases 62 27 83 48 Controls 77 37 131 36 AOR (95% CI) 1 0.83 (0.40–1.72) 0.61 (0.35–1.07) 0.82 (0.38–1.78) .119

Watermelon Cases 45 25 84 66 Controls 46 39 125 71 AOR (95% CI) 1 0.50 (0.22–1.13) 0.46 (0.25–0.87) 0.54 (0.26–1.11) .94

Strawberry Cases 116 43 45 16 Controls 132 53 79 17 AOR (95% CI) 1 0.54 (0.27–1.06) 0.44 (0.24–0.79) 0.75 (0.26–2.13) .275

Grapefruit Cases 175 12 21 12 Controls 209 22 30 20 AOR (95% CI) 1 0.336 (0.112–1.011) 0.933 (0.453–1.918) 0.763 (0.257–2.26) .193

Apricot Cases 142 14 37 27 Controls 149 31 69 32 AOR (95% CI) 1 0.50 (0.23–1.09) 0.569 (0.32–1.01) 0.82 (0.39–1.71) .117

Fig Cases 121 9 44 46 Controls 111 17 77 76 AOR (95% CI) 1 0.40 (0.13–1.23) 0.58 (0.32–1.05) 0.51 (0.28–0.92) .003

continues on page 357

356 Cancer Control October 2014, Vol. 21, No. 4 Table 3. — AORsa and CIs for Common Fruits Consumed Among Jordanians (continued)

Category of Consumption

Item Rarelyb Monthly Weekly Daily P Value for Trend

Aloe Vera Cases 179 8 16 17 Controls 208 29 31 13 AOR (95% CI) 1 0.24 (0.09–0.63) 0.67 (0.31–1.43) 1.351 (0.52–3.53) .427

Date Cases 120 24 41 35 Controls 122 35 58 66 AOR (95% CI) 1 0.97 (0.48–1.97) 0.93 (0.49–1.73) 0.52 (0.27–0.98) .004

Kiwi Cases 180 15 19 6 Controls 202 36 36 7 AOR (95% CI) 1 0.51 (0.24–1.06) 0.69 (0.34–1.41) 1.14 (0.25–5.06) .033

Bommali Cases 179 15 22 4 Controls 209 31 36 5 AOR (95% CI) 1 0.57 (0.27–1.22) 0.75 (0.37–1.54) 0.85 (0.17–4.28) .149

Dried Fruit Cases 168 31 18 3 Controls 213 47 14 7 AOR (95% CI) 1 0.65 (0.34–1.26) 1.42 (0.55–3.67) 0.00 (0.00–0.00) .864

aAdjusted for age, sex, total energy, physical activity, occupation, education level, marital status, and family history of colorectal cancer. bReference group. Fruits and vegetables were compiled according to cultural influences. For example, tomatoes and sweet peppers were categorized as fruits, not vegetables; aloe vera is known culturally as a fruit because it is eaten as a dessert rather than as a vegetable closely related to the onion/garlic family. AOR = adjusted odds ratio, CI = confidence interval.

Discussion 0.91 for a high consumption level of both fruits and The association between fruit and vegetable consump- vegetables (95% CI: 0.82–1.01). These results suggest tion and CRC risk is inconclusive.17-19 Although the that high intakes of fruits and vegetables have — at association between total number of fruit and veg- most — a modest inverse association with CRC risk,12 etable servings consumed on a daily basis and CRC a fact that is similar to the results of the current study. risk is insignificant, the present study shows that a The potentially protective effects of fruit and veg- significant protective effect was detected when the etable consumption have been attributed to numerous serving number of vegetables increased to 5 servings compounds, including polyphenol, capsaicin, flavo- per day. No association was found between the CRC noids, lycopene, isothiocyanate, selenium, vitamins A, development and consuming leafy vegetables (raw C, and E, folic acid, and beta carotene.24 Fiber can act and cooked), tomato, and salad. Similar results were as anticarcinogenic substance within the colon through seen with the daily consumption of citrus fruit, apple, several mechanisms, one of which is the formation peach, melon, watermelon, strawberry, and apricot. of short-chain fatty acids via fermentation by colonic The results from the current study are in agree- bacteria. Fiber also helps reduce intestinal transit time ment with observations reported elsewhere.20-23 One and increase fecal bulk, decreasing the possibility of large prospective trial that studied dietary fiber and absorbing toxic and carcinogenic substances. In ad- CRC risk found an inverse association between fruit dition, fiber may reduce the production of secondary and vegetable consumption and CRC risk.21 However, bile acid and enhance insulin sensitivity.25 the results of other large prospective studies have The unexpected outcome of the current study was been less clear.20,22,23 A prospective trial conducted by the increase seen in CRC risk as the daily consump- Koushik et al12 enrolled 5,838 volunteers and found tion of cruciferous vegetables (cabbage, cauliflow- that the relative risk for a high level of fruit consump- er) increased; in the case of cauliflower, consuming tion was 0.93 (95% CI: 0.85–1.02), 0.94 for a high level 2 servings or more each week increased this risk. A of vegetable consumption (95% CI: 0.86–1.02), and possible explanation for this result is the storage and

October 2014, Vol. 21, No. 4 Cancer Control 357 Table 4. — AORsa and CIs for Common Vegetables Consumed Among Jordanians

Category of Consumption

Item Rarelyb Monthly Weekly Daily P Value for Trend

Cooked Leafy Vegetables Cases 12 103 101 4 Controls 11 147 121 2 AOR (95% CI) 1 0.31 (0.09–1.007) 0.305 (0.09–1.00) 0.64 (0.07–6.16) .453 Raw Leafy Vegetables Cases 24 40 102 54 Controls 35 47 132 67 AOR (95% CI) 1 1.38 (0.57–3.34) 0.87 (0.40–1.88) 0.75 (0.32–1.77) .882 Tomato Cases 10 14 69 127 Controls 8 12 90 171 AOR (95% CI) 1 1.09 (0.25–4.70) 0.70 (0.23–2.17) 0.49 (0.16–1.45) .269 Salad Cases 17 30 107 66 Controls 18 39 152 72 AOR (95% CI) 1 0.31 (0.09–1.06) 0.38 (0.13–1.09) 0.47 (0.16–1.42) .962 Cabbage Cases 44 132 37 7 Controls 82 176 20 3 AOR (95% CI) 1 1.23 (0.70–2.18) 2.96 (1.25–6.98) 2.30 (0.28–19.14) .001 Carrot Cases 30 77 90 23 Controls 45 111 91 33 AOR (95% CI) 1 1.08 (0.53–2.22) 1.42 (0.69–2.91) 0.71 (0.27–1.87) .729 Broccoli Cases 185 21 10 4 Controls 233 35 8 5 AOR (95% CI) 1 0.72 (0.31–1.66) 1.32 (0.40–4.38) 1.01 (0.13–7.87) .953 Cauliflower Cases 23 99 90 8 Controls 49 142 88 2 AOR (95% CI) 1 1.61 (0.74–3.49) 1.86 (0.84–4.07) 4.46 (0.72–27.68) .001 Sweet Pepper Cases 23 46 97 54 Controls 35 52 129 65 AOR (95% CI) 1 1.42 (0.64–3.16) 1.255 (0.62–2.53) 1.246 (0.55–2.80) .542 Sweet Potato Cases 170 20 27 3 Controls 217 34 27 3 AOR (95% CI) 1 0.32 (0.13–0.79) 0.81 (0.37–1.78) 1.27 (0.10–16.22) .608 Mashed Potato Cases 61 106 52 1 Controls 92 148 39 2 AOR (95% CI) 1 0.83 (0.49–1.30) 1.54 (0.82–2.92) 1.12 (0.06–21.16) .018 Mixed Veggies Cases 117 57 44 2 Controls 114 98 64 5 AOR (95% CI) 1 0.76 (0.43–1.34) 0.66 (0.36–1.21) 0.53 (0.08–3.56) .017

aAdjusted for age, sex, total energy, physical activity, occupation, education level, marital status, and family history of colorectal cancer. bReference group. Fruits and vegetables were compiled according to cultural influences. For example, tomatoes and sweet peppers were categorized as fruits, not vegetables; aloe vera is known culturally as a fruit because it is eaten as a dessert rather than as a vegetable closely related to the onion/garlic family. AOR = adjusted odds ratio, CI = confidence interval.

358 Cancer Control October 2014, Vol. 21, No. 4 culinary processing conditions of cruciferous vegeta- Jordanians eat dates throughout the year and on a bles, which could affect their glucosinolate contents. daily basis; for religious reasons, they may also eat the When vegetables are frozen and thawed, chopped, or whole fig fruit when the fruit is in season. With regard shredded during cooking preparation, the enzyme my- to consuming figs and dates, the present study shows rosinase converts glucosinolates (a chemically stable an inverse association with the development of CRC: compound) to isothiocyanates.26 If these vegetables As the number of servings of figs or dates increased are not cut prior to cooking, then cooking them at by no more than 1 serving a day, the risk for develop- high temperatures will denature their myrosinase con- ing CRC significantly decreased. We are not aware of tent, which results in a lower conversion rate of glu- any research on the association between figs or dates cosinolates to isothiocyanates. Song and Thornalley26 and any type of cancer. However, in vitro studies have demonstrated that vegetables boiled for more than demonstrated an antitumor effect in some substances 30 minutes have no detectable isothiocyanate or found in figs (benzaldehyde)33 and dates (β-D-glucan).34 amine degradation product. Jordanian cuisine large- In a study conducted by Fu et al,35 7 fruits were found ly depends on cooking cabbage and cauliflower as to possess high antioxidant capacities and phenolic whole pieces and for long periods of time using high contents, and these fruits could be an important di- temperatures. In addition, cauliflower may be deep- etary source of natural antioxidants for disease preven- fried and cabbage is usually stuffed, as a whole leaf, tion, particularly diseases caused by oxidative stress with fatty minced meat. Therefore, these vegetables (eg, cancer). Solomon et al36 investigated the correlation might be considered to be fatty dishes; thus, consum- of the skin color of figs with their antioxidant capacity ing them would significantly contribute to a person’s and found that the extracts of darker-colored varieties daily fat intake. This suggests that the cooking practic- had higher contents of phytochemicals compared with es within the culture are working against the protec- the lighter-colored varieties. tive effects of cabbage and cauliflower. Broccoli intake is low in Jordan because it is not considered to be a Study Limitations traditional vegetable. Mixed vegetables were found to Limitations of the current study emerged from the be protective, particularly in men. We propose that a dependence on self-reported data, which were not complementary effect of all the combined vegetables validated with records; therefore, recall bias is expect- gives this potential protective effect against CRC. ed. However, the FFQ has previously been validated Consuming 2 to 4 servings of grapes per week to be adequate for measuring macronutrient and mi- and 2 servings of kiwi per week was found to be cronutrient intake.14 In addition, participants were protective against CRC; however, as the number of conveniently selected, and the impact of cooking on servings increased, the risk of CRC increased (P for the bioavailability of different nutrients was not taken trend < 0.05). Jordanians eat the whole grape, includ- into consideration. ing the seeds, so the protective effect of grapes could be due to compounds found in grape seed, which Conclusions has been documented in other studies of grape seed, Total vegetable consumption was significantly asso- grape seed extract, or both.27,28 Other research has ciated with a reduced risk of developing colorectal also revealed that grape seeds increase cancer cell cancer. Although the consumption of cruciferous vege- apoptosis and inhibit multiple processes, including tables was positively associated with colorectal cancer, the signaling related to epigenetics, growth, prolif- the consumption of figs and dates were inversely asso- eration, oncogenes, metastasis, and inflammation.27,29 ciated with colorectal cancer risk. Therefore, patients Ko et al30 demonstrated that consuming grape and kiwi should be encouraged to consume a variety of fruits or the juices of these fruits may reduce cell damage and vegetables on a daily basis. Further studies are from oxidative stress, suggesting that this effect may recommended to investigate the findings of the cur- be a consequence of the antioxidant activity of fruits rent study, particularly in relation to the consumption in scavenging the reactive oxygen species generated of cruciferous vegetables. during the metabolic processes. A study by Platt et al31 revealed that kiwi exerts a protective effect against the The authors would like to thank the Higher Council genotoxic effects of carcinogenic heterocyclic aromatic of Science and Technology for sponsoring this amines in immortal mammalian cells. Alternatively, an research project. They would also like to thank in vitro study showed that açaí, cashew apple, kiwi, Hana A. Marie for tabulating the results and her help and strawberry had mutagenic effects when assayed at with the manuscript. high concentrations (5%, 10%, and 15%).32 This could partially explain the results of the current study that References 1. US Center for Global Health, Centers for Disease Control and Pre- demonstrated exceeding 2 servings of kiwi per week vention. CDC in Jordan factsheet. http://www.cdc.gov/globalhealth/countries/ may be associated with CRC risk. jordan/pdf/jordan.pdf. Accessed June 12, 2014.

October 2014, Vol. 21, No. 4 Cancer Control 359 2. Ismail SI, Soubani M, Nimri JM, et al. Cancer incidence in Jordan 32. Spada PD, de Souza GG, Bortolini GV, et al. Antioxidant, mutagenic, from 1996 to 2009: a comprehensive study. Asian Pacific J Cancer Prev. and antimutagenic activity of frozen fruits. J Med Food. 2008;11(1):144-151. 2013;14(6):3527-3534. 33. Takeuchi S, Kochi M, Sakaguchi K, et al. Benzaldehyde as a carcinos- 3. World Cancer Research Fund, American Institute for Cancer Research. tatic principle in figs. Agr Biol Chem. 1978;42:1449. Food, Nutrition, Physical Activity, and the Prevention of Cancer: A Global Per- 34. Ishurd O, Zgheela F, Kermagia A, et al. (1→3)-β-D-glucans from Lib- spective. Washington, DC: American Institute for Cancer Research. 2007. yan dates (Phoenix dactylifera L.) and their anti-cancer activities. J Biol Sci. http://www.dietandcancerreport.org/cancer_resource_center/downloads/Sec- 2007;7(3):554-557. ond_Expert_Report_full.pdf. Accessed June 12, 2014. 35. Fu L, Xu BT, Xu XR, et al. Antioxidant capacities and total phenolic 4. American Cancer Society. Cancer Facts & Figures 2014. Atlanta, GA: contents of 62 fruits. Food Chemistry. 2011;129(2):345-350 American Cancer Society; 2014. 36. Solomon A, Golubowicz S, Yablowicz Z, et al. Antioxidant activities 5. Boyle P, Leon ME. Epidemiology of colorectal cancer. Br Med Bull. and anthocyanin content of fresh fruits of common fig fruits (Ficus carica L.). 2002;64:1-25. J Agric Food Chem. 2006;54(20):7717-7723. 6. Terry P, Giovannucci E, Michels KB, et al. Fruit, vegetables, dietary fiber, and risk of colorectal cancer. J Natl Cancer Inst. 2001;93(7):525-533. 7. Chiu BC, Ji BT, Dai Q, et al. Dietary factors and risk of colon cancer in Shanghai, China. Cancer Epidemiol Biomarkers Prev. 2003;12(3):201-208. 8. Steinmetz KA, Potter JD. Vegetables, fruit, and cancer prevention: a review. J Am Diet Assoc. 1996;96(10):1027-1039. 9. Sato Y, Tsubono Y, Nakaya N, et al. Fruit and vegetable consumption and risk of colorectal cancer in Japan: the Miyagi Cohort Study. Public Health Nutr. 2005;8(3):309-314. 10. Voorrips LE, Goldbohm RA, van Poppel G, et al. Vegetable and fruit consumption and risks of colon and rectal cancer in a prospective cohort study: The Netherlands Cohort Study on Diet and Cancer. Am J Epidemiol. 2000;152(11):1081-1092. 11. Vogtmann E, Xiang YB, Li HL, et al. Fruit and vegetable intake and the risk of colorectal cancer: results from the Shanghai Men’s Health Study. Cancer Causes Control. 2013;24(11);1935-1945. 12. Koushik A, Hunter DJ, Spiegelman D, et al. Fruits, vegetables, and colon cancer risk in a pooled analysis of 14 cohort studies. J Natl Cancer Inst. 2007;99(19):1471-1483. 13. Arafa MA, Waly MI, Jriesat S, et al. Dietary and lifestyle characteristics of colorectal cancer in Jordan: a case-control study. Asian Pac J Cancer Prev. 2011;12(8):1931-1936. 14. Tayyem RF, Abu-Mweis SS, Bawadi H, et al. Validation of a Food Frequency Questionnaire to assess macronutrient and micronutrient intake among Jordanians. J Acad Nutr Diet. 2014;114(7):1046-1052. 15. Sallis JF, Haskell WL, Wood PD, et al. Physical activity assessment methodology in the Five-City Project. Am J Epidemiol. 1985;121(1):91-106. 16. Lee RD, Nieman DC. Nutritional Assessment. 6th ed. New York: McGraw Hill; 2012. 17. Baena Ruiz R, Salinas Hernández P. Diet and cancer: risk factors and epidemiological evidence. Maturitas. 2014;77(3):202-208. 18. Nomura AM, Wilkens LR, Murphy SP, et al. Association of vegetable, fruit, and grain intakes with colorectal cancer: the Multiethnic Cohort Study. Am J Clin Nutr. 2008;88(3):730-737. 19. Boffetta P, Couto E, Wichmann J, et al. Fruit and vegetable intake and overall cancer risk in the European Prospective Investigation into Cancer and Nutrition (EPIC). J Natl Cancer Inst. 2010;102(8):529-537. 20. Nomura AM, Hankin JH, Henderson BE, et al. Dietary fiber and col- orectal cancer risk: the multiethnic cohort study. Cancer Causes Control. 2007;18(7): 753-764. 21. Bingham SA, Norat T, Moskal A, et al. Is the association with fiber from foods in colorectal cancer confounded by folate intake? Cancer Epidemiol Biomarkers Prev. 2005;14(6):1552-1556. 22. Park Y, Hunter DJ, Spiegelman D, et al. Dietary fiber intake and risk of colorectal cancer: a pooled analysis of prospective cohort studies. JAMA. 2005;294(22):2849-2857. 23. Schatzkin A, Mouw T, Park Y, et al. Dietary fiber and whole-grain con- sumption in relation to colorectal cancer in the NIH-AARP Diet and Health Study. Am J Clin Nutr. 2007;85(5):1353-1360. 24. Aggarwal BB, Shishodia S. Molecular targets of dietary agents for prevention and therapy cancer. Biochem Pharmacol. 2006;71(10):1397-1421. 25. Young GP, Hu Y, Le Leu RK, et al. Dietary fibre and colorectal cancer: a model for environment-gene interactions. Mol Nutr Food Res. 2005;49(6): 571-584. 26. Song L, Thornalley PJ. Effect of storage, processing and cooking on glucosinolate content of Brassica vegetables. Food Chem Toxicol. 2007;45(2): 216-224. 27. Derry MM, Raina K, Agarwal C, et al. Identifying molecular targets of lifestyle modifications in colon cancer prevention. Front Oncol. 2013;3:119. 28. Kaur M, Agarwal C, Agarwal R. Anticancer and cancer chemopreven- tive potential of grape seed extract and other grape-based products. J Nutr. 2009;139(9):1806S-1812S. 29. Vaid M, Prasad R, Singh T, et al. Grape seed proanthocyanidins reacti- vate silenced tumor suppressor genes in human skin cancer cells by targeting epigenetic regulators. Toxicol Appl Pharmacol. 2012;263(1):122-130. 30. Ko SH, Choi SW, Ye SK, et al. Comparison of the antioxidant activities of nine different fruits in human plasma. J Med Food. 2005;8(1):41-46. 31. Platt KL, Edenharder R, Aderhold S, et al. Fruits and vegetables protect against the genotoxicity of heterocyclic aromatic amines activated by human xenobiotic-metabolizing enzymes expressed in immortal mammalian cells. Mutat Res. 2010;703(2):90-98.

360 Cancer Control October 2014, Vol. 21, No. 4 Ten Best Readings Relating to Rare Lymphoproliferative and Histiocytic Diseases

Gérard L, Bérezné A, Galicier L, et al. Prospective novel diagnostic and therapeutic modalities may im- study of rituximab in chemotherapy-dependent prove outcomes of adult patients with HLH. human immunodeficiency virus associated multi- Rosado FG, Tang YW, Hasserjian RP, et al. Kikuchi- centric Castleman’s disease: ANRS 117 CastlemaB Fujimoto lymphadenitis: role of parvovirus B-19, Trial. J Clin Oncol. 2007;25(22):3350-3356. Epstein-Barr virus, human herpesvirus 6, and human Single-agent chemotherapy is typically effective in herpesvirus 8. Hum Pathol. 2013;44(2):255-259. HIV-associated multicentric Castleman disease; how- Molecular studies using paraffin-embedded archi- ever, chemotherapy cannot be discontinued in most val samples showed no evidence of a positive asso- patients. Rituximab has been shown to be effective ciation between Kikuchi–Fujimoto disease and viral and safe in patients with HIV infection and chemo- infections, including Epstein–Barr virus and human therapy-dependent, multicentric Castleman disease. herpesviruses 6 and 8. Casper C, Munshi N, Ke X, et al. A multicenter, ran- Badalian-Very G, Vergilio JA, Degar BA, et al. Re- domized, double-blind, placebo-controlled study current BRAF mutations in Langerhans cell histio- of the efficacy and safety of siltuximab, an anti- cytosis. Blood. 2010;116(11):1919-1923. interleukin-6 monoclonal antibody, in patients High prevalence, recurrent BRAF mutations in Langer- with multicentric Castleman’s disease. Blood. hans cell histiocytosis indicate that it is a neoplastic disease 2013;122(21):505-505. that may respond to RAF pathway inhibitors. Siltuximab in combination with best supportive care was superior to best supportive care alone for Gadner H, Minkov M, Grois N, et al. Therapy patients with symptomatic multicentric Castleman dis- prolongation improves outcome in multisystem ease and was well tolerated with prolonged exposure. Langerhans cell histiocytosis. Blood. 2013;121(25): 5006-5014. Frankel AE, Woo JH, Ahn C, et al. Activity of SL-401, Reactivations of multisystem Langerhans cell his- a targeted therapy directed to theinterleukin-3 tiocytosis (MS-LCH) are reduced by prolonging initial receptor, in patients with blastic plasmacytoid den- chemotherapy. In addition, the previously high mor- dritic cell neoplasm. Blood. 2014;124(3):385-392. tality rates of children at high risk for MS-LCH have Researchers discovered that treatment with SL-401 been reduced. consisting of the catalytic and translocation domains of diphtheria toxin fused to interleukin 3 resulted in Akkari V, Donadieu J, Piguet C, et al. Hematopoietic a high response rate among patients with blastic plas- stem cell transplantation in patients with severe macytoid dendritic cell neoplasm. Langerhans cell histiocytosis and hematological dysfunction: experience of the French Langer- Perkins SM, Shinohara ET. Interdigitating and fol- hans Cell Study Group. Bone Marrow Transplant. licular dendritic cell sarcomas: a SEER analysis. 2003;31(12):1097-1103. Am J Clin Oncol. 2013;36(4):395-398. The aim of this study was to assess the results of These data demonstrate that most patients with lo- hematopoietic stem cell transplantation (HSCT) in re- calized disease are treated similar to soft-tissue sarcoma fractory Langerhans cell histiocytosis. The researchers with primary surgical resection with or without radiation. concluded that HSCT for refractory Langerhans cell No chemotherapy data were available in the Surveillance, histiocytosis can be highly toxic but can also achieve Epidemiology, and End Results database. The roles of sustained disease control. chemotherapy and radiation therapy remain unclear. Jordan MB, Filipovich AH. Hematopoietic cell Parikh SA, Kapoor P, Letendre L, et al. Prognostic transplantation for hemophagocytic lymphohis- factors and outcomes of adults with hemophago- tiocytosis: a journey of a thousand miles begins cytic lymphohistiocytosis. Mayo Clin Proc. 2014; with a single (big) step. Bone Marrow Transplant. 89(4):484-492. 2008;42(7):433-437. In this large series of adults with secondary he- In this review, the authors discuss recent progress mophagocytic lymphohistiocytosis (HLH) treated at a in the use of hematopoietic stem cell transplantation single tertiary care center, patients with low levels of in patients with hemophagocytic lymphohistiocytosis serum albumin and tumor-associated HLH had poor and potential future strategies, including the use of survival rates. HLH remains elusive and challenging to reduced intensity conditioning regimens. health care professionals who must maintain a high index of suspicion. The recent discovery of several

October 2014, Vol. 21, No. 4 Cancer Control 361 Index for 2014, Volume 21

Vol 21, No 1: Early-Stage Lung Cancer 67 Advanced EGFR Mutation-Positive Non–Small-Cell Lung Cancer: 4 Thoracic Inspirations: Advances in the Case Report, Literature Review, Diagnosis, Staging, and Treatment of and Treatment Recommendations Non–Small-Cell Lung Cancer Andrew Kuykendall, MD, and Alberto Chiappori, MD Eric M. Toloza, MD, PhD 74 Epidermal Growth Factor Receptor 9 Lung Cancer Screening: Advantages, Inhibitors: Coming of Age Controversies, and Applications Amit Mahipal, MD, Nishi Kothari, MD, and Shilpa Gupta, MD Prema Nanavaty, MD, Michael S. Alvarez, DO, and W. Michael Alberts, MD 80 Update on Immune Checkpoint Inhibitors in 15 Minimally Invasive Mediastinal Staging of Lung Cancer Non–Small-Cell Lung Cancer: Benjamin C. Creelan, MD Emphasis on Ultrasonography-Guided Fine-Needle Aspiration 90 Quality of Care of Patients With Cynthia L. Harris, MD, Eric M. Toloza, MD, PhD, Non–Small-Cell Lung Cancer: Jason B. Klapman, MD, et al A Report of a Performance Improvement Initiative 21 Systemic and Targeted Therapies for Fred R. Hirsch, MD, PhD, Robert M. Jotte, MD, PhD, Early-Stage Lung Cancer Carolyn A. Berry, PhD, et al Elizabeth Byron, MD, and Mary Pinder-Schenck, MD

32 Current Clinical Application of Genomic and Proteomic Profiling in Vol 21, No 2: Spinal Oncology: Non–Small-Cell Lung Cancer Diagnosis, Treatment, and Management Tawee Tanvetyanon, MD, Benjamin C. Creelan, MD, and Alberto A. Chiappori, MD 110 Spinal Oncology: An Innovative Field of Its Own? 40 Survivorship Issues for Patients With Frank D. Vrionis, MD, PhD Lung Cancer Christie L. Pratt Pozo, DHSc, Mary Ann A. Morgan, PhD, 114 Primary Spine Tumors: and Jhanelle E. Gray, MD Diagnosis and Treatment 51 Temporal Trends in Demographics and Michelle J. Clarke, MD, Ehud Mendel, MD, and Frank D. Vrionis, MD, PhD Overall Survival of Non–Small-Cell Lung Cancer Patients at Moffitt Cancer Center 124 Spinal Tumor Surgery: Management and the From 1986 to 2008 Avoidance of Complications Matthew B. Schabath, PhD, Zachary J. Thompson, PhD, and Jhanelle E. Gray, MD Michelle J. Clarke, MD, and Frank D. Vrionis, MD, PhD 133 Surgical Management of Primary and 57 Multidisciplinary Therapy of Stage IIIA Non–Small-Cell Lung Cancer: Metastatic Spinal Tumors Long-term Outcome of Chemoradiation Paul E. Kaloostian, MD, Patricia L. Zadnik, BA, With or Without Surgery Arnold B. Etame, MD, PhD, et al Charu Aggarwal, MD, Linna Li, MD, Hossein Borghaei, DO, et al 140 Palliative Strategies for the Management of Primary and Metastatic Spinal Tumors 63 Incidence and Outcomes of Chemotherapy and Radiation in Morbidly Obese Paul E. Kaloostian, MD, Alp Yurter, BS, Patients With Locally Advanced Lung Arnold Etame, MD, PhD, et al and Esophageal Cancers: A Single- Institution Experience Krishna Patel, MD, Elisabeth K. Stephens, PhD, Robert C. Miller, MD, et al

continues on page 363

362 Cancer Control October 2014, Vol. 21, No. 4 Index for 2014, Volume 21

144 Spinal Neoplastic Instability: 215 Studying Cancer Treatment in the Biomechanics and Current Elderly Patient Population Management Options Lodovico Balducci, MD Andreas K. Filis, MD, Kamran V. Aghayev, MD, James J. Doulgeris, MSME, et al 221 BRAF Mutations: Signaling, Epidemiology, and Clinical Experience in Multiple Malignancies 151 Controversial Issues in Kyphoplasty and Richard D. Hall, MD, and Ragini R. Kudchadkar, MD Vertebroplasty in Malignant Vertebral Fractures Ioannis D. Papanastassiou, MD, Andreas K. Filis, MD, 231 PD-1 Pathway Inhibitors: Changing the Maria A. Gerochristou, MD, et al Landscape of Cancer Immunotherapy Dawn E. Dolan, PharmD, and Shilpa Gupta, MD 158 Management of Locally Advanced Pancoast (Superior Sulcus) Tumors With Spine 239 Translational Medicine Simplified: Involvement AKT Goes Cycling Matthias Setzer, MD, Lary A. Robinson, MD, Kiran N. Mahajan, PhD, and Nupam P. Mahajan, PhD and Frank D. Vrionis, MD, PhD 242 Special Report: Novel Pancreatic Cancer 168 Separation Surgery for Spinal Metastases: Vaccines Could Unleash the Army Within Effect of Spinal Radiosurgery on Surgical Treatment Goals Gregory M. Springett, MD, PhD Nelson Moussazadeh, MD, Ilya Laufer, MD, Yoshiya Yamada, MD, et al. 247 Pathology Report: Histopathological and Immunophenotypical Features of Intestinal- 176 Controversy Surrounding Mammography Type Adenocarcinoma of the Gallbladder Screening? Not in Our Opinion and Its Precursors Yan You, MD, Katherine Bui, Jennifer S. Drukteinis, MD, and John V. Kiluk, MD Marilyn M. Bui, MD, PhD, et al

251 Case Report: Follicular Lymphoma With Progression to Diffuse Large B-Cell Lymphoma Vol 21, No 2: Supplement and Concurrent CD5-Negative Mantle Cell Lymphoma-3 Entities in a Lymph Node 5 Expert Perspectives on Evidence-Based Janese A. Trimaldi, MD, Jeremy W. Bowers, MD, Treatment Planning for Patients With Celeste Bello, MD, et al Hepatocellular Carcinoma Jorge Marrero, MD, Mary A. Maluccio, MD, Heather McCurdy, RN, et al Vol 21, No 4: Rare Lymphoproliferative and Histiocytic Diseases Vol 21, No 3: Clinical and 260 Hope for Orphan Lymphoproliferative and Translational Research Histocytic Diseases on the Horizon? Lubomir Sokol, MD, PhD 188 Clinical Trials and Drug Development Amit Mahipal, MD 266 Diagnosis and Management of Castleman Disease 193 Risks and Benefits of Phase 1 Jacob D. Soumerai, MD, Aliyah R. Sohani, MD, Clinical Trial Participation and Jeremy S. Abramson, MD Amit Mahipal, MD, and Danny Nguyen, MD 279 Blastic Plasmacytoid Dendritic Cell Neoplasm: 200 Phase 1 Trial Design: Is 3 + 3 the Best? Update on Molecular Biology, Diagnosis, Aaron R. Hansen, MBBS, Donna M. Graham, MBBCh, and Therapy Gregory R. Pond, PhD, et al Wasif Riaz, MD, Ling Zhang, MD, Pedro Horna, MD, et al

209 Participation of the Elderly Population in Clinical Trials: Barriers and Solutions Aaron C. Denson, MD, and Amit Mahipal, MD continues on page 364

October 2014, Vol. 21, No. 4 Cancer Control 363 Index for 2014, Volume 21

Vol 21, No 4: Rare Lymphoproliferative and Histiocytic Diseases (continued)

290 Dendritic Cell and Histiocytic Neoplasms: Biology, Diagnosis, and Treatment Samir Dalia, MD, Haipeng Shao, MD, PhD, Elizabeth Sagatys, MD, et al

301 Hereditary and Acquired Hemophagocytic Lymphohistiocytosis Ling Zhang, MD, Jun Zhou, MD, and Lubomir Sokol, MD, PhD

313 Pathogenesis, Diagnosis, and Management of Kikuchi–Fujimoto Disease Darcie Deaver, PhD, Pedro Horna, MD, Hernani Cualing, MD, et al

322 Rosai–Dorfman Disease: Tumor Biology, Clinical Features, Pathology, and Treatment Samir Dalia, MD, Elizabeth Sagatys, MD, Lubomir Sokol, MD, PhD, et al

328 Langerhans Cell Histiocytosis Nanette Grana, MD

335 Transplantation in Rare Lymphoproliferative and Histiocytic Disorders Alexis Cruz-Chacon, MD, John Mathews, MD, and Ernesto Ayala, MD

343 Special Report: Social Determinants of Racial and Ethnic Disparities in Cutaneous Melanoma Outcomes Valerie Harvey, MD, Hitesh Patel, MS, MBA, Sophia Sandhu, MD, et al

350 Special Report: Fruit and Vegetable Intake Among Jordanians: Results From a Case-Control Study of Colorectal Cancer Reema F. Tayyem, PhD, Ihab Shehadah, MD, Suhad S. Abu-Mweis, PhD, et al

364 Cancer Control October 2014, Vol. 21, No. 4 Peer Reviewers, 2014

Peer review is the indispensable and critical element in the evaluation of all manuscripts being considered for publication in our journal. The oncology professionals who took part in our peer review process last year are listed below, and we thank them for their invaluable efforts on behalf of Cancer Control. — The Editor

External Reviewers

Aricò, Maurizio, MD Klepin, Heidi D, MD Sloan, Steven, MD, PhD Cambridge Institute for Medical Research, Wake Forest Baptist Medical Center, Boston Children’s Hospital, Cambridge, UK Winston-Salem, NC Boston, MA Baffa, Raffaele, MD Laufer, Ilya, MD Stramer, Susan L, PhD sanofi-aventis, US, Memorial Sloan Kettering Cancer Center, American Red Cross Biomedical Services, Boston, MA New York, NY Gaithersburg, MD Bugalho, Antonio, MD Lichtiger, Benjamin, MD, PhD Tender, Gabriel C, MD Hospital Beatriz Angelo, University of Texas Louisiana State University, Loures, Portugal MD Anderson Cancer Center, Baton Rouge, LA Houston, TX Bydon, Ali, MD Urbanski, Stefan J, MD Johns Hopkins Hospital, Marcus, Hani J, MD University of Calgary, Canada Baltimore, MD Charing Cross Hospital, Ustun, Celalettin, MD London, UK Chang, Shelley, MD University of Minnesota, University of California, Marques, Marisa B, MD Minneapolis, MN Los Angeles, CA University of Alabama, Weiss, Lawrence M, MD Birmingham, AL Cooling, Laura, MD Clarient Pathology Services, University of Michigan, Mattei, Tobias A, MD Aliso Viejo, CA Ann Arbor, MI Ohio State University, Wildes, Tanya M, MD Columbus, OH Falandry, Claire, MD Washington University Centre Hospitalier Lyon-Sud, Mendel, Ehud, MD School of Medicine, Lyon, France Ohio State University, St Louis, MO Columbus, OH Fourney, Daryl R, MD University of Saskatchewan, Moyana, Terence, MD Saskatoon, Canada University of Ottawa, Canada Internal Reviewers Gammon, Richard R, MD (H. Lee Moffitt Cancer Center OneBlood, Orlando, FL O’Malley, Dennis P, MD & Research Institute) University of Central Florida Clarient Pathology Services/ College of Medicine, GE Healthcare, Balducci, Lodovico, MD Orlando, FL Aliso Viejo, CA Baz, Rachid, MD Gerszten, Peter C, MD Pagano, Livio, MD Benson, Kaaron, MD University of Pittsburgh Medical Center, Università Cattolica del Sacro Cuore, Egan, Kathleen M, PhD Pittsburgh, PA Rome, Italy Forsyth, Peter A, MD Ghebeh, Hazem, PhD Placantonakis, Dimitris G, MD, PhD Gilbert, Scott, MD King Faisal Specialist Hospital New York University Langone Gray, Jhanelle E, MD and Research Center, Medical Center and School of Medicine, Green, B Lee, PhD Riyadh, Saudi Arabia New York, NY Horna, Pedro, MD Goldfinger, Dennis, MD Roseff, Susan D, MD Magliocco, Anthony M, MD University of California, Virginia Commonwealth University, Mahipal, Amit, MD Los Angeles, CA Richmond, VA Meade, Cathy, PhD Ivancic, Paul C, PhD Salomon, David S, PhD Pow-Sang, Julio M, MD Yale University School of Medicine, National Cancer Institute, Scott, Jacob G, MD New Haven, CT Frederick, MD Siegel, Erin M, PhD Kelly, James K, MB Saygin, Caner, MD Sokol, Lubomir, MD, PhD Royal Jubilee Hospital, Istanbul University Cerrahpasa Victoria, Canada Medical Faculty, Sondak, Vernon, MD Istanbul, Turkey Toloza, Eric M, MD Khoury, Joseph D, MD Vrionis, Frank D, MD, PhD University of Texas Sciubba, Daniel M, MD MD Anderson Cancer Center, Johns Hopkins Hospital, Houston, TX Baltimore, MD

October 2014, Vol. 21, No. 4 Cancer Control 365 FACULTY POSITION: CUTANEOUS MEDICAL ONCOLOGIST Moffitt Cancer Center, an NCI-designated Comprehensive Cancer Center, is seeking a Medical Oncologist for its Cutaneous Oncology Program. A competitive salary package with excellent benefits, a high level of clinical resources, and outstanding infrastructural research support are available, including protected time for research endeavors. The prospective candidate will be appointed at the Assistant Member level or higher if warranted. Extensive Cancer Center Core facilities for translational research are available, and their use by the candidate for innovative clinical trials will be encouraged. The patient population at Moffitt Cancer Center is a diverse and outstanding resource for the conduct of clinical trials. At Moffitt, significant growth in clinical and translational research, laboratory space resources, and faculty recruitment will be a high priority in the next decade. In 2007, Moffitt established the Comprehensive Melanoma Research Center made possible by a generous philanthropic gift of $20.4 million from Donald A. Adam. This Center conducts research in melanoma and trans- lates it into cutting-edge patient treatment. Moffitt was also recently awarded an NIH Specialized Program in Research Excellence (SPORE) grant for melanoma, and the prospective candidate will be expected to have a substantive role in the clinical and translational research activities of the SPORE and will have access to the career development and other developmental resources provided by the SPORE. Applicants must have a Florida medical license or be eligible for one, an MD, or MD/PhD and be board certified or eligible in internal medicine and board eligible/certified or equivalent in medical oncology. The applicant should be familiar with a multidisciplinary academic clinical practice setting. The successful candidate must have clinical expertise in melanoma and a desire to participate in and design clinical trials, including those involving drug development. Familiarity with other cutaneous malignancies besides melanoma is a plus. Background in clinical and/or translational research is essential, as is an interest in education and teaching. Knowledge of scientific research methods, knowledge of federal guidelines related to conducting clinical trials, knowledge of quality assurance, and excellent spoken and written communication skills are required. An opportunity exists to participate in the clinical activities of other Moffitt clinical programs as well. For inquiries about the position, contact Vernon K. Sondak, MD, Chair, Cutaneous Oncology Department, at [email protected] or 813-745-8788. To apply, visit our Web page at MOFFITT.org/careers.

The H. Lee Moffitt Cancer Center & Research Institute, a rapidly growing NCI-designated Comprehensive Cancer Center, is committed to education through a wide range of residency and fellowship programs. The Cancer Center is composed of a large ambulatory care facility, a 206-bed hospital, with a 36-bed blood and marrow transplant program, 15 state-of-the-art operating suites, a 30-bed intensive care unit, a high- volume screening program, and a basic science research facility. The Moffitt Research Institute is composed of approximately 150 principal investigators, 58 laboratories, and 306,000 square feet of research space. The Moffitt Cancer Center is affiliated with the University of South Florida. Primary and secondary university appointments are available as applicable. Academic rank is commensurate with qualifications and experience.

366 Cancer Control October 2014, Vol. 21, No. 4 FACULTY POSITION: NEUROLOGIST Moffitt Cancer Center’s Neuro-Oncology Department is seeking a neurologist. The Neuro-Oncology Program employs an interdisciplinary approach, offering comprehensive therapy for patients with primary and metastatic tumors of the brain and spinal cord, as well as neurological complications of cancer and its treatments. In ad- dition to focusing on the neurological complications of cancer and its treatment, the neurologist would provide in-house consultation for general neurological problems to the Cancer Center. The successful candidate will develop a strong, clinical, or translational program in general neurology in cancer. The ideal candidate will have significant expertise in general neurology in a cancer setting with an emphasis on neurology. Clinical research and the ability to work closely with an interdisciplinary team of experts, including neurosurgical oncology, neuropathology, neuroradiology, neuropsychology, and laboratory scientists, are required. Moffitt Cancer Center has strong preclinical programs in immunotherapy, drug discovery, genomics, cell-based therapies, and bioinformatics. There is also an extraordinary effort in personalized medicine partnering with the biotechnology/pharmaceutical industry. The Neuro-Oncology Program at Moffitt is a high-volume program, with approximately 500 new patients with brain tumors every year, and is active in the initiation and completion of numerous clinical trials with a well-developed clinical and translational research infrastructure. The Neuro-Oncology Program is an active participant in the National Comprehensive Cancer Network. Successful candidates must have a Florida medical license or be eligible for one, an MD, be board certified/ eligible in neurology, and fellowship trained in neurology. Experience in a clinical, multidisciplinary academic setting is preferred. A commitment to develop clinical research studies is required. The candidate should be experienced in performing and interpreting electroencephalography and electromyography. With a very active Cancer Spine Program and Neurosurgical Division, experience in physical medicine and rehabilitation medicine would be desirable. For inquiries about the position, contact Peter Forsyth, MD, Chair, Department of Neuro-Oncology, at [email protected] or 813-745-3063. To apply, visit our Web page at MOFFITT.org/careers.

FACULTY POSITIONS: PALLIATIVE CARE SPECIALISTS Moffitt Cancer Center is seeking to fill faculty positions in palliative care in its growing Supportive Care Medicine Department. Moffitt recently attained certification in advanced palliative care by The Joint Commission and offers comprehensive interdisciplinary palliative care throughout the course of cancer care. Fellowship training in palliative medicine is preferred, but experience or training may replace this requirement. Clinical and research background in an oncology setting is beneficial but not necessary. The candidate should be board certified or eligible in palliative medicine. Responsibilities include attending on the inpatient pain and palliative care consultation service, sharing in the ambulatory care practice, supervising and instructing palliative care fellows and other trainees, and participating in the clinical, educational, and research activities of the Service. Applicants must be Florida licensed or eligible. We offer a competitive total compensation package and a culture dedicated to the prevention and cure of cancer. For inquiries about the position, contact Diane Portman, MD, Chair, Department of Supportive Care Medicine, at [email protected] or 813-745-1246. To apply, visit our Web page at MOFFITT.org/careers.

Moffitt Cancer Center provides a tobacco-free work environment. It is an equal opportunity, affirmative action employer and a drug-free workplace.

October 2014, Vol. 21, No. 4 Cancer Control 367 Contact and General Information

Cancer Control: Journal of the Moffitt Cancer Center To Cancel a Subscription: is published by H. Lee Moffitt Cancer Center & Re- Please send your cancellation request, search Institute and is included in Index Medicus®/ including your name and address, to the MEDLINE® and EMBASE®/Excerpta Medica, Thom- Editorial Coordinator, as listed to the left. son Reuters Science Citation Index Expanded (Sci- Search®) and Journal Citation Reports/Science Edi- tion. Cancer Control currently has an impact To Order an Individual, Institutional, factor of approximately 3.6. or International Subscription: This peer-reviewed journal contains articles on For information on subscription rates, the spectrum of actions and approaches needed to please contact the Editorial Coordinator. reduce the impact of human malignancy. Cancer Control is sent at no charge to approx- To Request Permission to Reprint imately 15,000* medical professionals, including Copyrighted Materials: oncologists in all subspecialties; selected primary To request permission to reprint tables, figures, care physicians; medical researchers who specialize or materials copyrighted by Cancer Control, in oncology; and others who have a professional please contact the Editorial Coordinator. interest in cancer control. * This includes approximately 1,000 oncologists from over To Inquire About Reprints: 85 countries. For information on obtaining reprints and pricing To Access the Journal Online: information, please contact the Editorial Coordinator. Most issues and supplements of Cancer Control are available at cancercontroljournal.org. To Submit an Article for Publication: The editor welcomes submission of manuscripts To Change Your Mailing Address: pertaining to all phases of oncology care for Please provide your old address and your possible publication in Cancer Control. new address to: Articles are subject to editorial evaluation and Veronica Nemeth, Editorial Coordinator peer review. Author guidelines are available Cancer Control Journal online at cancercontroljournal.org. Moffitt Cancer Center MBC-JRNL 12902 Magnolia Drive Tampa, FL 33612 E-mail: [email protected] Follow us on Twitter Fax: 813-449-8680 @MoffittResearch #MoffittCCJ Phone: 813-745-1348

Celebrating Over 20 Years of Publishing YOUR OPINION COUNTS! Access our readership survey at cancercontroljournal.org

368 Cancer Control October 2014, Vol. 21, No. 4 3 RD ANNUAL SAVE THE DATE STATE-OF-THE-ART March 19-20,2015 Sheraton Sand Key Neuro-Oncology Clearwater Beach, Florida CONFERENCE

CONFERENCE HIGHLIGHTS • Renowned faculty representing the country’s leading institutions • Updates on brain and spine tumors • Preconference dinner presentation on March 19 • Interactive case presentations with discussion • Nurse track session • Call for abstracts

COURSE DIRECTORS Peter Forsyth, MD • Frank Vrionis, MD, MPH, PhD CONFERENCE CONTACT [email protected] • MOFFITT.org/NeuroOncology2015

SPONSORED BY October 2014, Vol. 21, No. 4 Cancer Control 3 Society for Immunotherapy of Cancer Presents Advances in Cancer Immunotherapy™

CME-certified regional program in collaboration with Moffitt Cancer Center

Leading experts examine the latest on the ground-breaking cancer treatment options that use the power of the immune system

Friday, December 5, 2014 8:00 a.m. – 4:00 p.m. Tampa Marriott Waterside Hotel & Marina, Tampa, FL

Improve patient outcomes through a greater understanding of the clinical indications for cancer immunotherapy including the appropriate selection and management of patients as well as its therapeutic effectiveness

PROGRAM ORGANIZERS Keith L. Knutson, PhD – Vaccine & Gene Therapy Institute of Florida James J. Mulé, PhD – Moffitt Cancer Center Vernon K. Sondak, MD – Moffitt Cancer Center

This activity has been approved for AMA PRA Category 1 CreditTM

For more information and to register, please visit: www.sitcancer.org/sitc-meetings/aci2014/fl

4 Cancer Control October 2014, Vol. 21, No. 4