Sarcoma Journal an Exciting Initiative in Peer-Reviewed Professional Education and Advocacy PAGE 4

VOL 1 | NO 1 | FALL 2017 WWW.SARCOMAJOURNAL.COM theSARCOMA Official Journal of The Sarcoma Foundation JOURNAL of America™

FEATURE ARTICLE Sof t Tissue Sarcoma: Diagnosis and treatment PAGE 7

EDITORIAL Introducing The Sarcoma Journal An exciting initiative in peer-reviewed professional education and advocacy PAGE 4

CASE REPORT Bilateral chylothorax in an AIDS patient with newly diagnosed Kaposi sarcoma PAGE 20

CASE REPORT Pulmonary sarcomatoid carcinoma presenting Premier Issue as a necrotizing cavitary lung lesion Diagnostic dilemma PAGE 22 › EDITORIAL‹ VIEWS AND NEWS BY WILLIAM D. TAP, MD | Editor-In-Chief

Introducing The Sarcoma Journal—The Official Journal of the Sarcoma Foundation of America™: An Exciting Initiative in Peer-Reviewed Professional Education and Patient Advocacy

› I WELCOME YOUR he Sarcoma Journal — Official ing affiliations with the Sarcoma Foun- PARTICIPATION IN Journal of the Sarcoma Founda- dation of America and its comprehensive THE SUCCESS OF THE tion of America™ represents a program of sarcoma research, patient sup- SARCOMA JOURNAL Tnew and exciting initiative in pro- port and education and advocacy. As you fessional education. We invite you to share explore the first issue of the journal, you BY SUBMITTING in the excitement surrounding the launch will discover how our editorial content is MANUSCRIPTS, of a medical journal designed to be your an extension of this three-tiered approach. INTERESTING CASE most authoritative and comprehensive The SFA program is characterized by a STUDIES, ORIGINAL source of scientific information on the di- multi-dimensional and uniquely coordi- RESEARCH, AND TOPIC agnosis and treatment of sarcomas and sar- nated outreach program of videos and we- PERSPECTIVES—AS coma sub-types. binars, websites (a new journal website is WELL AS REVIEW On behalf of myself, our editorial launching as well) a sarcoma-specific clin- ARTICLES—AND SHARE board, and editorial staff, I welcome you to ical trials database, newsletters and related YOUR THOUGHTS ON this journal as we explore new treatment materials— all aimed ultimately at finding HOW WE CAN BEST paradigms for this disease, translational a cure for this disease. This profession- SERVE OUR COMMUNITY research that bridges the bench and the al journal complements and extends the AND PATIENTS. clinic, and a broad range of science to en- SFA’s mission. compass the many facets of sarcoma. In Although The Sarcoma Journal has a —WILLIAM D. TAP, my opinion, the startup of this publication position within the SFA umbrella, my fo- MD, CHIEF, MEDICAL could not come at a better time. cus is foremost on ensuring that The Sar- ONCOLOGY SERVICE As cancer specialists and allied health coma Journal contains the most accurate, AT MEMORIAL SLOAN care professionals who attend regular relevant and up to date information avail- KETTERING CANCER meetings of your peers, including ASCO able. I urge you to explore our highly infor- CENTER and CTOS, we have seen a dramatic shift mative and relevant sarcoma-specific con- in management within the last few years. tent—including original reports, review In many ways we are at a threshold of a articles, a Journal Club, expert opinion, new era in sarcoma management, and the meeting reports, and patient advocacy that spectrum of treatment is expanding across encapsulates the latest findings from the subspecialties, promising more effective bench with implications for the bedside. strategies for our patients that are based on Whether it is discussing the latest find- an improved understanding of disease bi- ings in advanced sarcoma sub-types or ology. We need a resource to maintain and implications of genetics as a prognostic clarify our focus on this disease as research factor, you will find the information in opens new avenues for us to consider in this journal, reliably analyzed by our team the management of patients with sarcoma. of experts who are leading sarcoma clini- When I was approached to serve as Edi- cians and investigators. All of the content tor-in-Chief of The Sarcoma Journal by the we provide is presented in a thought-pro- Sarcoma Foundation of America, I began voking, lively and peer-reviewed format; to recruit an esteemed group of colleagues we welcome your comments and sugges- whose knowledge, worldwide reputation tions to keep us on the forefront of patient as thought leaders, and dedicated work as care as we cover a rapidly evolving land- researchers would reflect our commitment scape of new information in the treatment toward finding a cure for sarcoma. Many of sarcomas and frame it within a context of the colleagues who will join me on the directly applicable to enhancing the quali- Editorial Advisory Board have long-stand- ty of patient care.

4 THE SARCOMA JOURNAL | JUNE 2017 | VOL 1, NO 1 the theSARCOMA SARCOMA Of cial Journal Of cial Journal of The Sarcoma of The Sarcoma Foundation JOURNAL of America™ Foundation of America™ JOURNAL Editor-in -Chief WILLIAM D. TAP, MD FALL 2017 Managing Editor FRANK IORIO Managing Director FRANK IORIO Tel: 973-209-8990 Creative Director MARY ELLEN NIATAS Art Director KAREN BLACKWOOD Director, Journal Manufacturing Services MICHAEL WENDT Account Manager, Classified Advertising TIM LAPELLA Tel: (484) 921-5001 Fax: (484) 921-5005

EDITORIAL Chairman STEPHEN STONEBURN President/CEO ALAN J. IMHOFF 4 Introducing The Sarcoma President, Digital & CFO DOUGLAS E. GROSE Chief Digital Officer LEE SCHWEIZER Journal—Official Journal of The Vice President, Digital Publishing AMY PFEIFFER Sarcoma Foundation of President, Custom Solutions JOANN WAHL ™ Vice President, Custom Programs CAROL NATHAN America Vice President, Custom Solutions WENDY RAUPERS William D. Tap, MD SVP, Finance STEVEN J. RESNICK Vice President, Operations JIM CHICCA Vice President, Human Resources & Facility Operations CAROLYN CACCAVELLI Vice President, Marketing & Customer Advocacy FEATURE ARTICLE JIM MCDONOUGH Vice President, Sales MIKE GUIRE 7 Soft tissue sarcoma: Vice President, Society Partners MARK BRANCA Circulation Director JARED SONNERS Diagnosis and treatment Corporate Director, Research & Communications LORI RASKIN Ashley Pariser, MD, Jeffrey Wayne, MD, John P. Hayes, MD, Editorial Director KAREN J. CLEMMENTS and Mark Agulnik, MD COVER: © JOVAN VITANOVSKI In affiliation with Global Academy for Medical Education, LLC. Vice President, Medical Education & Conferences SYLVIA H. REITMAN Vice President, Events DAVID SMALL CASE REPORT Subscription Service Tel: (800) 480-4851

20 Bilateral chylothorax in an AIDS COPYRIGHT © Frontline Medical Communications. No part of this publication patient with newly diagnosed may be reproduced, stored in a retrieval system, or transmitted in any form, or by any means, electronic, mechanical, photocopying, Kaposi sarcoma recording, or otherwise, without written permission of the publisher. Rebecca E. Neril, MD, and Kimberly Lam, MD PERMISSIONS POLICY Authorization to photocopy articles in this publication for internal or personal use, or for the internal or personal use of specific clients, is granted by Frontline Medical Communications to libraries and other users registered with the Copyright Clearance Center (CCC) Transactional Reporting Service, provided that a fee of $3.00 per CASE REPORT article is paid directly to: CCC, 222 Rosewood Dr., Danvers, MA 01923. Telephone: (508) 750-8400, Fax: (508) 750-4744, or at 22 Pulmonary sarcomatoid www.copyright.com. CCC is a not-for-profit organization that provides copyright licensing on behalf of FMC. This consent does not apply to other kinds of copying, such as copying for general distribution, carcinoma presenting as a for advertising or promotional purposes, for creating new collective works, or for resale. necrotizing cavitary lung lesion: Reprint requests: For article reprints, eprints, or licensing in the United States and Canada, please contact Wright’s Media toll free Diagnostic dilemma at 877-652-5295. For all others outside the USA & Canada contact Ray Thibodeau at Gaurang Nandkishor Vaidya, MBBS, Rushikesh Shah, MD, Content Ed Net. Tel: 267-895-1758.

and Amit Dhamoon, MD EDITORIAL AND ADVERTISING POLICY Statements and opinions expressed in articles and communications herein are those of the author(s) and not necessarily those of the editor, publisher, or any organizations endorsing this journal. Neither the editor, publisher, nor organizations endorsing this journal guarantee, warrant, or endorse any product or service advertised in this journal, nor do they guarantee any claim made by the manufacturer of such product or service. Except as noted, authors have reported no competing interests.

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SARCOMAJOURNAL.COM VOL 1, NO 1 | FALL 2017 | THE SARCOMA JOURNAL 5 theSARCOMA Of cial Journal of The Sarcoma › ‹ Foundation AUTHOR GUIDELINES JOURNAL of America™

DESCRIPTION EDITOR-IN-CHIEF The Sarcoma Journal—Official Journal of the Sar- coma Foundation of America™ is the premier practical, peer-reviewed quarterly journal dedicated to William D. Tap, MD Chief, Medical Oncology Service meeting the needs of practicing oncologists. The at Memorial Sloan Kettering journal is specifically focused on sarcomas and Cancer Center sub-types, with a clear and concise style to guide oncologists through detection, diagnosis, treatment, and management of the disease. The Sarcoma Journal — MEDICAL ADVISORY BOARD Official Journal of the Sarcoma Foundation of Ameri- ca™ provides useful information that can be immedi- CO-CHAIR: Crystal Mackall, MD ately applied to the practice of oncology. George Demetri, MD Parker Institute for Cancer Dana-Farber Cancer Immunotherapy, Stanford Manuscripts should be submitted to Frank Iorio at Institute University [email protected]. CO-CHAIR: Robert Maki, MD, PhD INTRODUCTION Raphael Pollock, MD, PhD Northwell Health, Cold The Sarcoma Journal—Official Journal of the Sarco- Wexner Medical Center, Spring Harbor Laboratory ™ The Ohio State University ma Foundation of America publishes peer-reviewed Paul A. Meyers, MD articles and commentaries on all aspects of clinical Mark Agulnik, MD, FRCPC Memorial Sloan-Kettering issues in sarcomas. Robert H. Lurie Compre- Cancer Center hensive Cancer Center, We encourage you to share your expertise with your Northwestern University Alberto Pappo, MD oncology colleagues by submitting articles in the fol- St. Jude Children’s lowing categories: Robert Benjamin, MD, Research Hospital MD Anderson Cancer Case Reports: Interesting, unique or informative cases Center Shreyaskumar Patel, MD that present and unfold in the examining room. MD Anderson Cancer Reviews: Thorough reviews of topics that have broad Charles Forscher, MD Center Cedars-Sinai Comprehen- interest to the practicing oncologist. Emphasis should sive Care Center Peter Pisters, MD be on the practical application of this information in MD Anderson Cancer the clinical arena. John M. Goldberg, MD Center Senior Medical Director Original Research: Clinical studies with sufficient pow- H3 Biomedicine R. Lor Randall, MD, FACS er to be implemented in clinical practice and to be of Huntsman Cancer Center, interest to practicing oncologists. No animal or basic Richard Gorlick, MD University of Utah science studies will be considered, and all research MD Anderson Children’s studies must have been conducted with Institutional Cancer Hospital Richard F. Riedel, MD Duke University Medical Review Board approval. Lee Helman, MD Center Diagnostic Findings: An interesting case or study, or Keck School of Medicine, University of Southern Scott Schuetze, MD an unusual physical finding with a brief synopsis. California University of Michigan PLEASE NOTE THE FOLLOWING: Eugenie S. Kleinerman, MD Samuel Singer, MD • Papers submitted to The Sarcoma Journal—Offi- MD Anderson Cancer Memorial Sloan-Kettering cial Journal of the Sarcoma Foundation of Ameri- Center Cancer Center ca™ should follow the style guidelines of the AMA Manual of Style (10th edition). Andrew S. Kraft, MD Poul HB Sorensen, MD, University of Arizona PhD • Papers that exceed the stipulated word counts will Cancer Center University of British be returned to the author(s) for editing before the Columbia paper is sent out for review. Marc Ladanyi, MD • Papers in which the references do not follow style Memorial Sloan-Kettering Matt van de Rijn, MD will also be returned to the author for revision. Cancer Center Stanford School of Medicine Additional information on author submissions David M. Loeb, MD, PhD should be directed to Frank Iorio at Sidney Kimmel Compre- hensive Cancer Center, [email protected]. Johns Hopkins University

6 THE SARCOMA JOURNAL | FALL 2017 | VOL 1, NO 1 FEATURE ARTICLE Soft Tissue Sarcoma: Diagnosis and Treatment

INTRODUCTION varies based on subtype and ranges from Ashley Pariser, MD, Jeffrey Wayne, MD, John P. Hayes, MD, Soft tissue sarcomas (STSs) are rare adult mature-appearing adipocytes and fibro- Mark Agulnik tumors, with 3.4 new cases per 100,000 blasts to undifferentiated cells with mini- Northwestern University persons or 12,310 expected new cases in mal lipogenic differentiation.4 Feinberg School of Medicine 2016.1 Sarcomas are a heterogeneous col- Leiomyosarcomas are smooth mus- Chicago, IL lection of tumors that affect fat, muscle, cle tumors and are usually located in the DISCLOSURES nerve, nerve sheath, vascular, and connec- retroperitoneum, but have also been as- The authors report no disclosures or conflicts tive tissues. There are more than 50 histo- sociated with peripheral soft tissue and of interest. logical subtypes that comprise this diverse vasculature. Typical histology ranges from category of tumors. Treatment varies by well-defined areas of spindle-shaped cells stage, with limb-sparing surgery represent- to poorly differentiated anaplastic spindle ing the mainstay of curative-intent treat- cells.5,6 Synovial sarcomas are a distinct ment. Radiation and chemotherapy may type of STS that can show epithelial dif- also be considered depending on the size, ferentiation and account for 5% of adult grade, and location of the tumor. Surviv- STSs. The extremities are the most com- al rates have been stagnant until recently, mon presenting location (90%).7 with a disease-specific survival hover- Rhabdomyosarcomas are skeletal mus- ing around 65%.1 Given the complexity cle tumors and are further subdivided into of these cases, all patients ideally should embryonal, alveolar, and pleomorphic sub- be evaluated and treated by a multidisci- types. Embryonal histology ranges from plinary team at an institution with exten- primitive mesenchymal-appearing cells to sive experience treating STS.2 highly differentiated muscle cells. Alveo- lar rhabdomyosarcoma has the worst prog- EPIDEMIOLOGY AND nosis of the subtypes and consists of round CLASSIFICATION cells with high nuclear-to-chromatin ratios The most common STS subtypes are that form “glandular-like” or “alveolar” gastrointestinal stromal tumor (GIST), spaces.8 Pleomorphic rhabdomyosarco- undifferentiate pleomorphic sarcoma mas are composed of rhabdomyoblasts (previously referred to as malignant fi- that can affect many different locations, brous histiocytoma), liposarcoma, leio- but most commonly present on the lower myosarcoma, synovial sarcoma, ma- extremities.9 lignant peripheral nerve sheath tumor, Malignant peripheral nerve sheath tu- rhabdomyosarcoma, and unclassified mor (MPNST) comprises 5% to 10% of all sarcoma.3 Liposarcoma is one of the most STSs. These tumors are associated with common subtypes, comprising 20% neurofibromatosis type 1 (NF-1), with of all STSs; it is subdivided into well- 25% to 50% of tumors occurring in NF-1 differentiated/dedifferentiated liposar- patients. Additionally, most patients have comas, myxoid/round cell liposarcomas, a truncating lesion in the NF1 gene on and pleomorphic liposarcomas. Well-dif- chromosome 17.10 Anghileri et al in their ferentiated liposarcomas tend to occur single institution analysis of 205 patients in the retroperitoneum and limbs, while with MPNSTs found the 2 most common both myxoid and round cell as well as presenting sites were the trunk and ex- pleomorphic liposarcomas more com- tremities. Histologically, these tumors monly originate on the limbs. Histology have dense fascicles of spindle cells.10

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GISTs are the most common STS of CD31, and Ulex europaeus agglutinin 1. the gastrointestinal (GI) tract. Previously, The majority of these tumors occur spo- GISTs were classified as smooth muscle radically; however, radiation exposure, tumors and were not accounted for in the chronic lymphedema, and certain toxins literature as a separate entity distinct from including vinyl chloride and thorium di- leiomyomas, leiomyoblastomas, and leio- oxide are known risk factors.13 myosarcomas.11 GISTs are found through- Undifferentiated sarcomas have no out the GI tract: the most common sites specific features and typically consist of are the stomach (60%) and small intestine primitive mesenchymal cells. (30%). Less common sites include duode- num (4%–5%), esophagus (1%), rectum CLINICAL EVALUATION (1%–2%), and appendix (< 0.2%).12 GISTs › CASE PRESENTATION can be spindle cell, epithelioid, or mesen- Initial Presentation and History chymal tumors. Immunohistochemically, A 55-year-old man presents to his prima- GISTs are KIT (CD117) positive. Other cell ry care physician with a painless mass markers that are also commonly positive in his anterior thigh. The mass has been include CD34 (60%–70%) and smooth present for the past 3 months and he be- muscle actin (SMA) (25%).11 The majori- lieves that it is enlarging. The patient has ty of GISTs (80%) have an activating c-KIT a history of well-controlled hypertension gene mutation. The most common mu- and hyperlipidemia. His medications in- tation site is exon 11, with less common clude atorvastatin and hydrochlorothi- c-KIT gene mutations also occurring at azide. He has no known drug allergies. exon 9 or 13. Not all GISTs have KIT mu- Family history is notable for diabetes and tations. The second most common muta- hypertension. He drinks 4 to 5 alcoholic tion is the PDGFRA mutation (5%–10% of drinks a week and he is a former smok- GISTs).2 A minority of GISTs are negative er. He quit smoking in his 30s and only for both KIT and PDGFRA mutations. smoked intermittently prior to quitting. These tumors were previously called He denies any illicit drug use. He works wild-type, but as the majority have either as a high school principal. Currently, he a succinate dehydrogenase (SDH) loss of feels well. His review of systems is other- function or loss of SDHB protein expres- wise noncontributory. sion, they are now referred to as SDH- deficient GISTs.2 GISTs vary in aggressive- Physical Examination ness from incidental to aggressive. Typi- On physical exam, he is afebrile with a cally, small intestine and rectal GISTs are blood pressure of 132/75 mm Hg, respi- more aggressive than gastric GISTs. Both ratory rate of 10 breaths/min, and oxy- size and mitotic rate help to predict the gen saturation of 99% on room air. He is metastatic potential of the tumor. Tumors a well appearing, overweight male. His less than 2 cm in size and having a mitotic head and neck exam is unremarkable. rate of less than 5 per 50 high-power fields Lung exam reveals clear breath sounds, (hpf) have the lowest risk of metastases, and cardiac exam reveals a regular rate while tumors greater than 5 cm and with and rhythm. His abdomen is obese, soft, more than 5 mitoses per 50 hpf have the and without hepatosplenomegaly. There highest rates of metastases.12 is a large, fixed mass on the anterior lat- Angiosarcomas are rare tumors com- eral aspect of his right thigh. He has no prising 4% of all STSs. Although they appreciable lymphadenopathy. His neu- can occur in any site, the majority are rological exam is unremarkable. cutaneous and occur most frequently in the head and neck regions. These tu- • What are risk factors for sarcoma? mors are either of vascular or lymphatic There are few known risk factors for origin and are comprised of abnormal, sarcoma. Established risks factors in- pleomorphic, malignant endothelial cells. clude prior radiation therapy, chronic The most useful immunohistochemical lymphedema, viruses, and genetic cancer markers include von Willebrand factor, syndromes including Li-Fraumeni syn-

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TABLE 1. Translocations and Cytogenic Events Associated with Forms of Soft Tissue Sarcoma Sarcoma Type Translocations/Cytogenetic Events Genes Involved Gastrointestinal stromal tumor KIT, PDGFRA mutation; loss of SDH expres- KIT, PDGFRA, SDH sion Synovial sarcoma t(X;18)(p11.2;q11.2) SSX1-, SSX2-, or SSX4-SS18 Alveolar soft-part sarcoma t(X;17)(p11;q25) ASPSCR1-TFE3 Myxoid liposarcoma t(12;16)(q13;p11) TLS-CHOP Clear-cell sarcoma t(12;22)(q13;q12) EWSR1-ATF1 Low-grade fibromyxoid sarcoma (Evans’ t(7;16)(q34;p11) FUS-BBF2H7 tumor) Dermatofibrosarcoma protuberans t(17;22)(q22;q13) COL1A1-PDGFB Desmoplastic small round cell tumor t(11;22)(p13;q12) EWSR1-WT1 Ewing sarcoma/round cell sarcomas or Ew- t(11:22)(q24;q12) EWSR1-FLI1, others ing-like (previously called PNET) t(21:22)(q22;q12) EWSR1-ERG Alveolar rhabdomyosarcoma t(2,13)(q35;q14) or t(1;13)(p36;q14) PAX3- or PAX7-FOXO1 Embryonal rhabdomyosarcoma Trisomy 2q, 8 and 20 Loss of heterozygosity at 11p15 Inflammatory myofibroblastic tumor ALK translocations (~50%) Many partner genes drome, hereditary retinoblastoma, and to tumor size, lymph node involvement, NF-1. Other environmental exposures metastases, and grade at time of diagno- include phenoxyacetic acids and chloro- sis (TABLE 2 and TABLE 3). Additionally, tu- phenols.14 The majority of cases are spo- mor depth in relation to deep fascia is radic, with only a minority of patients also taken into account, with superficial having one of these known risk factors.15 tumors being assigned a designation of Up to one third of sarcomas have a specif- “a” and deep tumors a designation of “b.” ic translocation and are driven by fusion Previously, 2 of the most widely used oncogenes (TABLE 1). grading systems were the National Cancer Institute (NCI) and French Federation of • What is the typical presentation for Cancer Centers Sarcoma Group (FNCL- sarcomas? CC) systems, both 3-tier grading systems. A painless mass is the most typical pre- The main components that determine the senting symptom. Size at presentation NCI grade are the tumor’s histologic type varies based on location, with extremity and location and the amount of tumor and head and neck locations typically necrosis. The FNCLCC system evaluation presenting at smaller sizes than retroper- focuses on tumor differentiation, mitot- itoneal tumors.14 Patients may experience ic rate, and amount of tumor necrosis. A pain and numbness as the mass enlarges study that compared the NCI and FNCLCC and impinges on surrounding structures grading systems found that FNCLCC was including nerves and vasculature. The a better predictor of mortality and distant vast majority of patients are without sys- metastasis.16 Previously, the AJCC was a temic symptoms. 4-tier grading system, but the 2010 version was updated to the 3-tier FNCLCC grading • How is sarcoma staged? system. Additionally, the AJCC system has The American Joint Committee on Cancer reclassified single lymph node disease as (AJCC) staging system is the most widely stage III as it confers better survival than used staging system in the United States. metastatic disease.17 It is important that The latest AJCC manual was updated in pathology be evaluated by a sarcoma spe- 2010 to include a 3-tiered grading system cialist as disagreements with regard to his- where the tumor is classified according tologic subtype and grade are common.18,19

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TABLE 2. Staging Soft Tissue Sarcoma: ties that should be considered during the Definitions preliminary work-up and staging of STSs. Conventional imaging includes magnetic Primary tumor (T) resonance imaging (MRI) of the original Tx Primary tumor cannot be assessed tumor site; computed tomography (CT) to T0 No evidence of primary tumor evaluate for pulmonary metastases and, T1 Tumor ≤ 5 cm in greatest dimension depending on location, liver metastases; T1a Superficial tumor and in the case of small, low-grade tumors, chest radiography. MRI is considered the T1b Deep tumor test of choice for soft tissue masses and T2 Tumor > 5 cm in greatest dimension can help delineate benign masses such as T2a Superficial tumor hematomas, lipomas, and hemangiomas T2b Deep tumor from sarcomas.20 It is difficult to compare Note: Superficial tumor is located exclusively above the the accuracy of positron emission tomog- superficial fascia without invasion of the fascia; deep raphy (PET)/CT to CT and MRI because tumor is located either exclusively beneath the superficial most studies have evaluated PET/CT in fascia, superficial to the fascia with invasion of or through parallel with CT and MRI.21 Tateishi et al the fascia, or both superficial yet beneath the fascia. compared the accuracy of conventional Regional lymph nodes (N) imaging, PET/CT, and PET/CT combined NX Regional lymph nodes cannot be assessed with conventional imaging at determining N1 No regional lymph node metastasis the TNM staging for 117 patients. They N2 Regional lymph node metastasis found that conventional imaging correctly classified 77% of patients, PET alone Note: Presence of positive nodes (N1) in M0 tumors is considered stage III correctly classified 70%, PET/CT correctly classified 83%, and PET/CT combined Distant metastasis (M) with conventional imaging correctly M0 No distant metastasis staged 87%.22 M1 Distant metastasis Histologic grade (G) • Which subtypes are most likely to GX Grade cannot be assessed metastasize? G1 Grade 1 Although the vast majority of sarcomas spread hematogenously, 3 have a pro- G2 Grade 2 pensity to spread lymphogenously: ep- G3 Grade 3 ithelioid sarcoma, rhabdomyosarcoma, Adapted with permission from AJCC. Soft tissue sarcoma. In: Edge SB, and clear-cell sarcoma. Additionally, Byrd DR, Compton CC, et al, eds. AJCC cancer staging manual. 7th ed. New York (NY): Springer; 2010:291–8. certain subtypes are more likely to metastasize: leiomyosarcomas, synovial sarcomas, neurogenic sarcomas, rhabdomyosarco- • What are the most important prognostic mas, and epithelioid sarcomas.23 Sarcomas factors? metastasize to the lungs more frequently Prognostic factors include grade, size, than to the liver. The metastatic pattern is and presence of metastases at presenta- defined primarily by sarcoma subtype and tion. Best survival is associated with low- site of primary tumor. Sarcomas rarely me- grade, small tumors with no metastases tastasize to the brain (~1%). at time of diagnosis.14 MANAGEMENT • What imaging should be considered? › CASE CONTINUED Imaging should be undertaken to help The patient undergoes an ultrasound to differentiate between benign and malig- better visualize the mass. Given the het- nant lesions. Ideally, it should be under- erogeneous character of the mass, he is taken before a biopsy is planned as the referred for an MRI to evaluate the mass imaging can be used to plan biopsy as well and a CT scan of the chest, abdomen, and as provide invaluable prognostic informa- pelvis to evaluate for distant metastases. tion. There are several imaging modali- MRI reveals a 5.1 cm × 4.6 cm heteroge-

10 THE SARCOMA JOURNAL | FALL 2017 | VOL 1, NO 1 SOFT TISSUE SARCOMA: DIAGNOSIS AND TREATMENT neous mass invading the superficial fas- TABLE 3. Soft Tissue Sarcoma Stages cia of the rectus femoris muscle. No sus- picious lymph nodes or other masses are Anatomic Stage/Prognostic Group identified on imaging. The patient next Stage IA T1a N0 M0 G1, GX undergoes an image-guided core needle T1b biopsy. Pathology from that procedure is consistent with a stage III, T2bNxMx, Stage IB T2a grade 3, dedifferentiated liposarcoma. T2b Stage IIA T1a G2, G3 • What is the best management approach for this patient? T1b SURGERY Stage IIB T2a G2 Surgery is the mainstay of treatment for T2b STS. Patients with the best prognosis are those who undergo complete resection Stage III T2a, T2b G3 24,25 with negative surgical margins. Goal Any T N1 Any G tumor-free margin is 1 to 3 cm.26 Complete Stage IV Any T Any N M1 Any G resection confers the best long-term survival. Both local and metastatic recurrence Adapted with permission from AJCC. Soft tissue sarcoma. In: Edge SB, Byrd DR, Compton CC, et al, eds. AJCC cancer staging manual. 7th ed. is higher in patients with incomplete resection and positive margins.24,25 In a study that analyzed 2084 localized primary tients with STS of head and neck and deep STSs, patients with negative margins had trunk have higher recurrence rates than a local recurrence rate of 15% versus a rate those with superficial trunk and extremi- of 28% in patients with positive margins. ty STS. A single-institution retrospective This translated into higher 5-year local review demonstrated that patients with recurrence-free survival for patients with completely resectable retroperitoneal sar- negative surgical margins (82%) compared comas have longer median survival (103 to patients with positive margins (65%).27 months) compared to patients with in- Another study similarly found that pa- completely resected abdominal sarcomas tients with negative margins at referral to (18 months).25 their institution who underwent postop- Rosenberg and colleagues compared erative radiation had high local control amputation to limb-sparing surgery and rates of 93% (95% confidence interval [CI] radiation.24 Their prospective analysis of 87% to 97%) at 5, 10, and 15 years.26 Al- 65 patients found no difference in dis- though radiation improves local control, ease-free and overall survival between neither preoperative or postoperative radi- the 2 treatment groups. The limb-sparing ation has been shown to improve progres- treatment group had higher rates of local sion-free or overall survival.28 Other factors recurrence, which was highly correlated that are associated with risk of recurrence with positive surgical margins on pathol- are tumor location, history of previous re- ogy.24 Evidence from this and similar stud- currence, age of patient, histopathology, ies has resulted in radical amputations tumor grade, and tumor size. Approxi- being replaced by conservative limb-spar- mately 40% to 50% of patients with high- ing procedures and radiation therapy. In grade tumors (defined as size > 5 cm, deep those found to have positive margins, location, and high grade) will develop dis- re-resection is an option for some. Patients tant metastases.29 who undergo re-resection have higher Zagars et al found that positive or local control rates than patients with posi- uncertain resection margin had a relative tive margins who do not undergo re-resec- risk of local recurrence of 2.0 (95% CI 1.3 tion. The 5-year control rate for patients to 3.1; P = 0.002), and presentation with who undergo re-resection is 85% (95% locally recurrent disease (vs new tumor) CI 80% to 89%) compared to 78% (95% had a relative risk of local recurrence of CI 71% to 83%) for those who do not un- 2.0 (95% CI 1.2 to 3.4; P = 0.013).26 Pa- dergo re-resection. Similarly, patients who

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undergo re-resection have lower rates of who received preoperative and postop- metastases at 5, 10, and 15 years as well erative EBRT or brachytherapy (primary as higher 5-, 10-, and 15-year disease-free end point was wound complications, and survival rates.26 local control was a secondary end point) showed a trend towards greater local con- › CASE CONTINUED trol with preoperative radiation; howev- The patient is referred for limb-spar- er, the preoperative radiation group had ing surgery after presentation at a significantly more wound complications multidisciplinary tumor board. Pri- compared to the postoperative radiation or to undergoing resection of the tu- group.31 mor, he is also referred to radiation- Yang et al found that postoperative oncology to discuss the risks and benefits EBRT decreases rates of local recurrence of combination radiotherapy and surgery compared to surgery alone in high-grade as opposed to surgical resection alone. extremity sarcomas.32 However, there were no differences in rates of distant metas- • What is the evidence for tases and overall survival between the 2 radiation therapy? treatment groups. Similarly, in patients ›A NEWER RADIATION THERAPY with low-grade sarcoma, there were fewer STRATEGY, Radiation therapy is used in the preopera- local recurrences in those who received tive, intraoperative, and postoperative set- EBRT and surgery as compared to sur- INTENSITY- tings to reduce the risk of local recurrence. gery alone.32 Another study that evaluated MODULATED There are several options for radiation, 164 patients who received either adjuvant RADIATION including external beam radiation thera- brachytherapy or no further therapy after py (EBRT), intraoperative radiation, and complete resection found that brachyther- THERAPY brachytherapy. A newer strategy, intensi- apy reduced local recurrence in high- (IMRT), UTILIZES ty-modulated radiation therapy (IMRT), grade sarcomas. No difference in local re- 3-DIMENSIONAL utilizes 3-dimensional modeling to reduce currence rates was found in patients with radiation dosages. Overall there are no low-grade sarcomas, nor was a significant MODELING TO differences in overall survival or local re- difference found in the rates of distant me- REDUCE RADIATION currence rates between preoperative and tastases and overall survival between the 2 DOSAGES. postoperative radiation in STS.28 treatment groups.33 With regards to IMRT, The rationale behind preoperative ra- a single institution cohort experience with diation is that it reduces seeding of tumor 41 patients who received IMRT following cells, especially at the time of surgery.30 limb-sparing surgery had similar local Additionally, for EBRT, preoperative ra- control rates when compared to historical diation has smaller field sizes and lower controls.34 radiation doses. It can also help to reduce the size of the tumor prior to resection. In- › CASE CONTINUED traoperative radiation is often paired with After discussion of the risks and benefits preoperative radiation as a boost dose of radiation therapy, the patient opts for given only to the area of residual tumor. preoperative radiation prior to resection Suit et al reviewed patients treated of his liposarcoma. He receives 50 Gy of at a single institution with limb-sparing EBRT prior to undergoing resection. Re- surgery and different radiation strategies. section results in R1 margin consistent Local control rates between preoperative with microscopic disease. He receives 16 and postoperative radiation groups were Gy of EBRT as a boost after recovery from not statistically significant. Local recur- his resection.2 rence was linked to grade and size of the tumor in both groups. The authors did • What is the evidence for neoadjuvant and note, however, that the preoperative radi- adjuvant chemotherapy for stage I tumors? ation group tended to have larger tumor CHEMOTHERAPY sizes at baseline compared to the pa- Localized Sarcoma tients who received postoperative radia- For localized sarcoma, limb-sparing re- tion.30 A study that compared 190 patients section with or without radiation forms

12 THE SARCOMA JOURNAL | FALL 2017 | VOL 1, NO 1 SOFT TISSUE SARCOMA: DIAGNOSIS AND TREATMENT the backbone of treatment. Studies have motherapy or no adjuvant chemotherapy evaluated chemotherapy in both the neo- after limb-sparing surgery with or without adjuvant and adjuvant settings, with the radiation therapy. None of the individual vast majority of studies evaluating doxo- trials showed a significant benefit, and all rubicin-based chemotherapy regimens trials had large confidence intervals; how- in the adjuvant settings. Due to the rare ever, the meta-analysis showed significant nature of sarcomas, most studies are not benefit in the chemotherapy treatment sufficiently powered to detect significant groups with regard to local recurrence, dis- benefit from chemotherapy. Several tri- tant recurrence, and progression-free sur- als evaluating chemotherapy regimens vival. No significant difference in overall in the neoadjuvant and adjuvant settings survival was found.37 Pervais et al updated needed to be terminated prematurely the Sarcoma Meta-analysis Collaboration’s due to inadequate enrollment into the 1997 meta-analysis with the inclusion study. 35,36 of 4 new trials that evaluated doxorubi- For stage IA (T1a-Tb, N0, M0, low cin combined with ifosfamide and found grade) tumors, no additional therapy is that both patients who received doxoru- recommended after limb-sparing surgery bicin-based regimens or doxorubicin with with appropriate surgical margins. For ifosfamide had significant decreases in ›FOR STAGE IIB stage IB (T2a-2b, N0, M0, low grade) distant and overall recurrences. Only the AND STAGE III tumors with insufficient margins, re-re- trials that utilized doxorubicin and ifosfa- section and radiation therapy should be mide had an improved overall survival that TUMORS, SURGERY considered, while for stage IIA (T1a-1b, was statistically significant (hazard ratio AND RADIATION N0, M0, G2-3) tumors preoperative or 0.56 [95% CI 0.36 to 0.85]; P = 0.01).29 THERAPY postoperative radiation therapy is recom- Although no significant heterogeneity was mended.2 Studies have not found benefit found among the trials included in either AGAIN FORM of adjuvant chemotherapy in these low- meta-analysis, a variety of sarcomas were THE BACKBONE grade, stage I tumors in terms of progres- included in each clinical trial evaluated. OF THERAPY; sion-free survival and overall survival.37 Given the extremely small number of each sarcoma subtype present in each trial, HOWEVER, • At what stage should chemotherapy subgroup analysis is difficult and prone to NEOADJUVANT be considered? inaccuracies. As a result, it is not known AND ADJUVANT For stage IIb and stage III tumors, surgery if certain histological subtypes are more or and radiation therapy again form the back- less responsive to chemotherapy.37–39 CHEMOTHERAPY bone of therapy; however, neoadjuvant One randomized controlled trial eval- ARE ALSO and adjuvant chemotherapy are also rec- uated neoadjuvant chemotherapy in high- RECOMMENDED AS ommended as considerations. Anthracy- risk sarcomas defined as tumors greater CONSIDERATIONS. cline-based chemotherapy with either sin- than 8 cm or grade II/III tumors. This gle-agent doxorubicin or doxorubicin and study evaluated doxorubicin and ifosfa- ifosfamide in combination are considered mide and found no significant difference first-line chemotherapy agents in locally in disease-free and overall survival in the advanced STS.2,29,37 neoadjuvant therapy group compared to Evidence regarding the efficacy of the control group.35 There remains con- both neoadjuvant and adjuvant chemo- troversy in the literature with regards to therapy regimens in the setting of local- adjuvant chemotherapy. Many oncologists ly advanced high-grade STS has been offer adjuvant chemotherapy to patients mixed. The Sarcoma Meta-analysis with certain stage III subtypes. Examples Collaboration evaluated 14 trials of doxo- of subtypes that may be offered adjuvant rubicin-based adjuvant chemotherapy and therapy include myxoid liposarcomas, found a trend towards overall survival in synovial sarcomas, and leiomyosarco- the treatment groups that received chemo- mas.2 With regards to how many cycles therapy.37 All trials included in the me- of chemotherapy should be considered, ta-analysis compared patients with local- a noninferiority study compared 3 cycles ized resectable soft-tissue sarcomas who of epirubicin and ifosfamide to 5 cycles were randomized to either adjuvant che- of epirubicin and ifosfamide in patients

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with high-risk locally advanced adult the first 4 to 5 years, annual follow-up is STSs. Three cycles of preoperative epi- recommended.2 rubicin and ifosfamide was found to be A study that followed 141 patients noninferior to 5 cycles with regards to with primary extremity STSs for a medi- overall survival.38 an interval of 49 months found that high- grade tumors were most likely to recur • What is this patient’s risk for recurrence? during the first 2 years, with 20% of their The patient is at intermediate risk for re- patients recurring locally and 40% recurrence. Numerous studies have demon- curring distally. Chest x-rays performed strated that tumor size, grade, and location during surveillance follow-up found dis- are the most important factors to determine tant lung metastases in 36 asymptomatic risk of recurrence, with larger size, higher patients and had a positive predictive grades, and deeper locations being associ- value of 92%, a negative predictive value ated with higher risk of recurrence. In an of 97%, and a quality-adjusted life-year analysis of 1041 patients with STS of the of $30,000.40,41 No laboratory testing was extremities, high grade was the most im- found to aid in detection of recurrence. portant risk factor for distant metastases.39 ›IN AN ANALYSIS The highest risk of recurrence is within › CASE CONTINUED OF 1041 PATIENTS the first 2 years. Given that the patient’s The patient does well for 1 year. With WITH STS OF THE initial tumor was located in the extremity, physical therapy, he regains most of the he is more likely to have a distant metas- strength and coordination of the lower EXTREMITIES, HIGH tasis as his site of recurrence; individuals extremity. He is followed every 3 months GRADE WAS THE with retroperitoneal tumors and visceral with chest x-rays and a MRI of the thigh MOST IMPORTANT tumors are more likely to recur locally.40 for the first year. On his fourth follow-up RISK FACTOR For STSs of the extremity, distant metas- clinic visit, he describes increased dysp- FOR DISTANT tases determine overall survival, whereas nea on exertion over the previous few METASTASES. patients with retroperitoneal sarcomas weeks and is found to have multiple lung can die from complications of local me- metastases in both lungs on chest x-ray. tastases.41 Once a patient develops distant He undergoes further evaluation for me- metastases, the most important prognostic tastases and is not found to have any oth- factor is the size of the tumor, with tumors er metastatic lesions. Bronchoscopy and larger than 10 cm having a relative risk of biopsy of 1 of the lung nodules confirms 1.5 (95% CI 1.0 to 2.0).39 recurrent dedifferentiated liposarcoma.

• What are the recommendations for • Should this patient undergo surveillance? metastectomy? Surveillance recommendations are based An analysis of 3149 patients with STS on the stage of the sarcoma. Stage I tu- treated at Memorial Sloan-Kettering mors are the least likely to recur either who developed lung metastases found locally or distally. As a result, it is rec- that patients with pulmonary metastases ommended that stage I tumors be fol- have survival rates of 25%. The most im- lowed with history and physical exam portant prognostic factor for survival was every 3 to 6 months for the first 2 to 3 complete resection of all metastases.42 For years, and then annually after the first 2 stage IV disease, surgery is used only in to 3 years. Chest x-rays should be con- certain instances. In instances where tu- sidered every 6 to 12 months.2 For stage mor is more localized or limited, removal II–IV tumors, history and physical exam of metastases or metastectomy can play a is recommended every 3 to 6 months for role in management.2 the first 2 to 3 years. Chest and distant metastases imaging should also be per- › CASE CONTINUED formed every 3 to 6 months during this Because the patient’s metastases are lim- time frame. For the next 2 years, histo- ited to the lungs, he is referred for metas- ry and physical exam and imaging are tectomy. He undergoes wedge resection recommended every 6 months. After for definitive diagnosis but it is not possi-

14 THE SARCOMA JOURNAL | FALL 2017 | VOL 1, NO 1 SOFT TISSUE SARCOMA: DIAGNOSIS AND TREATMENT ble to completely resect all of the metas- 4.1 months (95% CI 2.8 to 5.4) for doxo- tases. He is thus referred to a medical on- rubicin alone. The objective response rate cologist to discuss his treatment options. was 18.2% (95% CI 9.8 to 29.6) for olaratumab/doxorubicin compared to 7.5% • What are treatment options for (95% CI 2.5 to 6.6) for doxorubicin alone. unresectable or metastatic disease? Furthermore, the median overall survival METASTATIC DISEASE for olaratumab plus doxorubicin was 26.5 Unlike local and locally advanced dis- months (95% CI 20.9 to 31.7) compared to ease, chemotherapy forms the backbone 14.7 months for doxorubicin alone (95% of treatment in stage IV disease. Doxoru- CI 5.5 to 26.0). Impressively, this im- bicin and olaratumab or doxorubicin and proved response was notable across histo- ifosfamide in combination are consid- logical types. Furthermore, patients who ered first line in metastatic disease. Re- had previously been treated with more sponse rates for single-agent doxorubicin than 1 regimen and those who were treat- range from 16% to 27%, while phase 2 ment naïve had similar response rates.46 and phase 3 studies of doxorubicin and ifosfamide have found response rates • What are second-line treatment options? ranging from 18% to 36%.43 In addition, Doxorubicin has been used in combina- ›COMBINATION the effectiveness of doxorubicin and if- tion with several other agents including THERAPY osfamide phase 2 and 3 trials varied. Ed- dacarbazine (DTIC) as well as DTIC and DEMONSTRATED monson et al found a tumor regression ifosfamide (MAID). Borden et al evalu- rate of 34% for doxorubicin and ifosfa- ated patients with metastatic STS and BETTER TUMOR mide as compared to 20% for doxorubi- randomly assigned the patients to either RESPONSE THAN cin alone.44 In comparison, Santoro et al doxorubicin or doxorubicin and DTIC. DOXORUBICIN found a response rate of 21.3% for doxo- Combination therapy demonstrated better ALONE: 30% rubicin alone and 25.2% for doxorubicin tumor response than doxorubicin alone: COMPLETE OR 45 and ifosfamide. Neither study found 30% complete or partial response for com- PARTIAL RESPONSE increased survival benefit for doxoru- bination therapy and 18% for doxorubicin bicin and ifosfamide when compared alone.47 However, Omura et al found sim- FOR COMBINATION to doxorubicin alone. In a Cochrane re- ilar rates of efficacy between doxorubicin THERAPY AND 18% view evaluating randomized trials that and combination doxorubicin and DTIC FOR DOXORUBICIN compared doxorubicin and combination in women with recurrent or nonresect- ALONE. chemotherapy regimens, response rates able uterine sarcomas.48 MAID has never varied from 14% for doxorubicin in com- been directly compared in a randomized bination with streptomycin to 34% for trial to doxorubicin alone. In a study that doxorubicin and ifosfamide. Most trials compared MAID to doxorubicin and DTIC did not show a significant benefit for (AD) in patients with unresectable or met- combination therapies when compared astatic sarcomas, MAID had superior re- to doxorubicin alone.43 Mean survival sponse rates (32% versus 17%), but there with doxorubicin or doxorubicin and if- was no difference with regards to overall osfamide is 12 months. High rates of re- survival (mean survival of 12.5 months).49 currence highlight the need for addition- Several additional regimens have un- al chemotherapy regimens. dergone evaluation in metastatic and re- The newest approved agent is olara- current STSs. Gemcitabine has been used tumab, a monoclonal antibody that binds both as a single agent and as part of com- platelet-derived growth factor receptor bination therapy in many studies. Studies alpha and prevents receptor activation. with gemcitabine in combination with A phase 1-b and phase 2 trial evaluated either docetaxel or DTIC have been the patients with locally advanced and met- most efficacious. In a phase 2 trial, pa- astatic STS and randomly assigned them tients with metastatic STS were randomly to either olaratumab and doxorubicin or assigned to either gemcitabine alone or doxorubicin alone.46 Progression-free sur- gemcitabine and docetaxel. Combination vival for olaratumab/doxorubicin was 6.6 therapy had a higher response rate (16% months (95% CI 4.1 to 8.3) compared to versus 8%) and longer overall survival

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(17.9 months versus 11.5 months) than • What are the newest approved and gemcitabine alone.50 Furthermore, a phase investigational agents? 2 trial of gemcitabine and docetaxel in A recently approved agent is trabectedin, a patients with unresectable leiomyosar- tris tetrahydroisoquinoline alkaloid isolat- coma showed an overall response rate ed from ascidians that binds to the minor of 56%, with 3 complete and 15 partial groove of DNA and causes disruptions in responses among the 34 patients enrolled the cell cycle. Samuels et al reported data in the study.51 from a single-arm, open-label expanded A phase 2 trial randomly assigned access trial that evaluated patients with ad- patients with unresectable or metastatic vanced metastatic sarcomas.56 In this study, STS to either DTIC or combination gem- patients with liposarcomas and leiomyo- citabine and DTIC.52 Gemcitabine-DTIC sarcomas had an objective response rate of had a superior progression-free survival 6.9% (95% CI 4.8 to 9.6) as compared to at 3 months (56% [95% CI 43% to 69%]) a rate of 5.9% (95% CI 4.4 to 7.8) for all as compared to DTIC alone (37% [95% assessable patients. Median survival was CI 23.5% to 50%]). Furthermore, mean 11.9 months for all patients, with improved progression-free survival and overall median survivals for liposarcoma and leio- ›GIVEN THE RARITY survival were improved in the gemcit- myosarcomas of 16.2 months (95% CI 14.1 OF SARCOMAS AS abine-DTIC group (4.2 months and 16.8 to 19.5) compared to 8.4 months (95% CI A WHOLE, MANY months) as compared to the DTIC group 7.1 to 10.7 months) for other subtypes.56 (2.0 months and 8.2 months).52 DTIC has Schöffski et al evaluated eribulin, a TRIALS HAVE a single-agent response rate of 16%, but chemotherapeutic agent that affects micro- HAD DIFFICULTY has been shown to be particularly effec- tubule dynamics, in a phase 2 trial of pa- RECRUITING tive in the setting of leiomyosarcomas.49 tients with progressive or high-grade STS ADEQUATE NUMBERS with progression on previous chemothera- OF PATIENTS TO HAVE • Does response to treatment regimens py. They found a median progression-free SUFFICIENT POWER differ by histologic subtype? survival of 2.6 months (95% CI 1.7 to 6.2) The majority of STS trials include many for adipocytic sarcoma, 2.9 months (95% TO DEFINITELY different histologic subtypes. Given the CI 2.4 to 4.6) for leiomyosarcoma, 2.6 DETERMINE IF THE rarity of sarcomas as a whole, many trials months (95% CI 2.3 to 4.3) for synovial TREATMENT UNDER have had difficulty recruiting adequate sarcoma, and 2.1 months (95% CI 1.4 to INVESTIGATION HAS numbers of patients to have sufficient 2.9) for other sarcomas.57 CLINICAL BENEFIT. power to definitely determine if the treat- Van der Graaf and colleagues randomly ment under investigation has clinical assigned patients with metastatic nonad- benefit. Furthermore, the patients recruit- ipocytic STS to pazopanib or placebo in ed have been heterogeneous with regard a phase 3 trial. Pazopanib is a small-mol- to subtype. Many older studies hypoth- ecule endothelial growth factor inhibitor esized that the efficacy of chemothera- with activity against vascular endothe- peutic agents vary based on histologic lial growth factors 1, 2, and 3 as well as subtype; however, for most subtypes the platelet-derived growth factors. Median number of individuals included in those progression-free survival was 4.6 months trials was too low to evaluate efficacy (95% CI 3.7 to 4.8) with pazopanib com- based on subtype. pared to 1.6 months (95% CI 0.9 to 1.8) Some exceptions exist, however. For with placebo.58 Adipocytic sarcomas (li- example, both gemcitabine-DTIC and posarcomas) were excluded from the trial gemcitabine-docetaxel have been found to because phase 2 trials had found a lower be particularly effective in the treatment rate of progression-free survival (26%) for of leiomyosarcomas.50,52 Additionally, a them compared to other subtypes. retrospective study found a 51% overall response rate for patients with myxoid • What are the most common toxicities liposarcomas treated with trabectedin.53 associated with the approved and Studies of patients with angiosarcoma investigational chemotherapeutic agents? treated with paclitaxel have demonstrated Toxicities were seen with each of the reg- response rates of 43% and 53%.54,55 imens studied and were common in the

16 THE SARCOMA JOURNAL | FALL 2017 | VOL 1, NO 1 SOFT TISSUE SARCOMA: DIAGNOSIS AND TREATMENT randomized trials, with higher rates of long-term survival. Due to the rarity of toxicities in the combination chemother- STSs, trials often have limited enrollment, apy regimens. The most common toxic- and little progress has been made with re- ities are myelosuppression, nausea, and gards to treatment and survival rates for vomiting. In the doxorubicin trials, the metastatic and unresectable disease. All most common toxicities were myelosup- patients should be evaluated and treated pression, nausea, and vomiting.44 at specialized sarcoma centers. This case Ifosfamide both as an individual agent highlights the need for continued research and in combination with doxorubicin has and clinical trials to improve overall higher rates and higher grades of toxicity survival of patients with sarcoma. TSJ than doxorubicin alone. Myelosuppres- sion is the most common toxicity associ- CORRESPONDENCE ated with ifosfamide, and the most com- Ashley Pariser, MD, Resident, Department of Medicine, 44 Northwestern University Feinberg School of Medicine monly affected cell line is leukocytes. Chicago, IL. Accepted for publication Jan/Feb 2017; Combination doxorubicin and ifosfamide Hosp Phys; Vol. 12, Part1 also had high rates of nausea and vomiting (95%) and alopecia (100%).35 REFERENCES Neutropenia is the most common tox- 1. American Cancer Society. Cancer facts ›ALL PATIENTS icity associated with gemcitabine and and figures 2016. American Cancer Soci- SHOULD BE dacarbazine, while their most common ety Web site. www.cancer.org/acs/groups/ EVALUATED nonhematologic toxicities are fatigue and content/@research/documents/document/ acspc-047079.pdf. Accessed December 20, nausea.52,59 Trabectedin’s most common AND TREATED 2016. AT SPECIALIZED toxicities are nausea (29%), neutropenia 2. National Comprehensive Cancer Network. (24%), and fatigue (23%). It has also been NCCN clinical guidelines in oncology: soft SARCOMA shown to cause increased alkaline phos- tissue sarcoma. 2016 CENTERS. THIS phatase (20%) and alanine aminotransfer- 3. Coindre J, Terrier P, Guillou L, et al. Predictive value of grade for metastasis development in CASE HIGHLIGHTS ase (19%) levels.56 In a phase 2 study of the main histologic types of adult soft tissue THE NEED FOR eribulin, 50% of patients had neutropenia, sarcomas: a study of 1240 patients from the and other toxicities included fatigue, al- French Federation of Cancer Centers Sarcoma CONTINUED opecia, nausea, sensory neuropathy, and Group. Cancer 2001;91:1914–26. RESEARCH AND thrombocytopenia.57 Pazopanib is gener- 4. Dei Tos A. Liposarcoma: new entities and CLINICAL TRIALS evolving concepts. Ann Diagn Pathol 2000;4: ally well tolerated; the most common tox- 252–66. TO IMPROVE icities are fatigue (65%), diarrhea (58%), 5. Wile AG, Evans HL, Romsdahl MM. Leio- OVERALL SURVIVAL nausea (54%), and hypertension (41%).58 myosarcoma of soft tissue: a clinicopatholog- OF PATIENTS WITH Higher rates of neutropenia, mucositis, ic study. Cancer 1981;48:1022–32. nausea, vomiting, diarrhea, and transfu- 6. Hashimoto H, Daimaru Y, Tsuneyoshi M, En- SARCOMA. joji M. Leiomyosarcoma of the external soft sion reactions were seen with olaratumab tissues. A clinicopathologic, immunohisto- and doxorubicin compared to doxorubicin chemical, and electron microscopic study. alone in phase 1b and 2 studies.46 Cancer 1986;57:2077–88 7. Fisher C. Synovial sarcoma. Ann Diagn › CASE CONTINUED Pathol 1998;2:401–21. Given his poor prognosis with unresect- 8. Newton WA Jr, Gehan EA, Webber BL, et al. able metastatic undifferentiated liposar- Classification of rhabdomyosarcomas and related sarcomas. Pathologic aspects and coma, the patient considers a clinical proposal for a new classification--an Inter- trial prior to undergoing combined thera- group Rhabdomyosarcoma Study. Cancer py with doxorubicin and ifosfamide. He 1995;76:1073–85. tolerates therapy well with stable disease 9. Furlong MA. Pleomorphic rhabdomyosarcoma in adults: a clinicopathologic study of 38 at 6 months. cases with emphasis on morphologic variants and recent skeletal muscle-specific markers. CONCLUSION Mod Pathol. 2001;14:595–603. STSs are a heterogeneous collection of 10. Anghileri M, Miceli R, Fiore M. Malignant rare tumors. Low-grade, localized tumors peripheral nerve sheath tumors: prognostic factors and survival in a series of pa- have the best prognosis, and patients who tients treated at a single institution. Cancer undergo complete resection have the best 2006;107:1065–74.

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11. Miettinen M, Lasota J. Gastrointestinal stro- 25. Lewis J, Leung D, Woodruff J, et al. Retroper- mal tumors–definition, clinical, histological, itoneal soft-tissue sarcoma: analysis of 500 immunohistochemical, and molecular ge- patients treated and followed at a single insti- netic features and differential diagnosis. Vir- tution. Ann Surg 1998;288:355–65. chows Archive 2001;438:1–12. 26. Zagars GK, Ballo MT, Pisters PW, et al. Sur- 12. Miettinen M, Lasota J. Gastrointestinal stromal gical margins and reresection in the man- tumors: pathology and prognosis at different agement of patients with soft tissue sarcoma sites. Semin Diagn Pathol 2006;23:70–83. using conservative surgery and radiation ther- 13. Young RJ, Brown NJ, Reed MW, et al. Angio- apy. Cancer 2003;97:2544–53. sarcoma. Lancet Oncol 2010;11:983–91. 27. Stojadinovic A, Leung DH, Hoos A. Analysis 14. Cormier JN, Pollock RE. Soft tissue sarcomas. of the prognostic significance of microscopic CA Cancer J Clin 2004;54:94–109. margins in 2,084 localized primary adult soft tisusse sarcomas. Ann Surg 2002;235:424–34. 15. Penel N, Grosjean J, Robin YM, et al. Fre- 28. O’Sullivan B, Davis AM, Turcotte R, et al. Pre- quency of certain established risk factors operative versus postoperative radiotherapy in soft tissue sarcomas in adults: a prospec- in soft-tissue sarcoma of the limbs: a random- tive descriptive study of 658 cases. Sarcoma ized trial. Lancet 2002;359:2235–41. 2008;2008:459386. 16. Guillou L, Coindre JM, Bonichon F, et al. 29. Pervaiz N, Colterjohn N, Farrokhyar F, et al. A Comparative study of the National Cancer systematic meta-analysis of randomized con- Institute and French Federation of Cancer trolled trials of adjuvant chemotherapy for lo- Centers Sarcoma Group grading systems in calized resectable soft-tissue sarcoma. Cancer a population of 410 adult patients with soft 2008;113:573–81. tissue sarcoma. J Clin Oncol 1997;15:350–62. 30. Suit HD, Mankin HJ, Wood WC, Proppe KH. 17. Maki RG, Moraco N, Antonescu CR, et al. To- Preoperative, intraoperative, and postopera- ward better soft tissue sarcoma staging: build- tive radiation in the treatment of primary soft ing on American joint committee on cancer tissue sarcoma. Cancer 1985;55:2659–67 staging systems versions 6 and 7. Ann Surg 31. O’Sullivan B, Davis AM, Turcotte R, et al. Pre- Oncol 2013;20:3377–83. operative versus postoperative radiotherapy 18. Shiraki M, Enterline HT, Brooks JJ, et al. in soft-tissue sarcoma of the limbs: a random- Pathologic analysis of advanced adult soft ized trial. Lancet 2002;359:2235–41. tissue sarcomas, bone sarcomas, and me- 32. Yang J, Chang A, Baker A, et al. Randomized sotheliomas. The Eastern Cooperative On- prospective study of the benefit of adjuvant cology Group (ECOG) experience. Cancer radiation therapy in the treatment of soft tis- 1989;64:484–90. sue sarcomas of the extremity. J Clin Oncol 19. Presant CA, Russell WO, Alexander RW, Fu 1998;16:197–203. YS. Soft-tissue and bone sarcoma histopa- 33. Pisters PW, Harrison LB, Leung DH, et al. thology peer review: The frequency of dis- Long-term results of a prospective random- agreement in diagnosis and the need for sec- ized trial of adjuvant brachytherapy in soft ond pathology opinions. The Southeastern tissue sarcoma. J Clin Oncol 1996;14:859–68. Cancer Study Group experience. J Clin Oncol 34. Alektiar KM, Brennan MF, Healey JH, Singer 1986; 4:1658–61. S. Impact of intensity-modulated radiation 20. Sundaram M, McLeod RA. MR imaging of tu- therapy on local control in primary soft-tis- mor and tumorlike lesions of bone and soft sue sarcoma of the extremity. J Clin Oncol tissue. AJR Am J Roentgenol 1990;155:817– 2008;26:3440–5. 24. 35. Gortzak E, Azzarelli A, Buesa J, et al. A ran- 21. Ioannidis JP, Lau J. 18F-FDG PET for the di- domized phase II study on neo-adjuvant che- agnosis and grading of soft-tissue sarcoma: a motherapy for ‘high-risk’ adult soft-tissue sar- meta-analysis. J Nucl Med 2003;44:717–24. coma. Eur J Cancer 2001;37:1096–1103. 22. Tateishi U, Yamaguchi U, Seki K, et al. Bone 36. Fakhari N, Ebm C, Kostler WJ, et al. Inten- and soft-tissue sarcoma: preoperative staging sified adjuvant IFADIC chemotherapy in with fluorine 18 fluorodeoxyglucose PET/ combination with radiotherapy versus ra- CT and conventional imaging. Radiology diotherapy alone for soft tissue sarcoma: 2007;245:839–47. long-term follow-up of a prospective random- 23. Zagars GK, Ballo MT, Pisters PW, et al. Prog- ized feasibility trial. Wein Klin Wochenschr nostic factors for patients with localized 2010;122:614–9. soft-tissue sarcoma treated with conservation 37. Adjuvant chemotherapy for localised resect- surgery and radiation therapy: an analysis of able soft-tissue sarcoma of adults: meta-anal- 1225 patients. Cancer 2003;97:2530–43 ysis of individual data. Lancet 1997;350: 24. Rosenberg S, Tepper J, Glatstein E, et al. The 1647–54. treatment of soft-tissue sarcomas of the ex- 38. Gronchi A, Frustaci S, Mercuri M, et al. Short, tremities: prospective randomized evalua- full-dose adjuvant chemotherapy in high-risk tions of (1) limb-sparing surgery plus radia- adult soft tissue sarcomas: a randomized tion therapy compared with amputation and clinical trial from the Italian Sarcoma Group (2) the role of adjuvant chemotherapy. Ann and the Spanish Sarcoma Group. J Clin On- Surg 1982;196:305–14. col 2012;30:850–56.

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39. Pisters PW, Leung DH, Woodruff J. Analysis soft tissue and bone sarcomas. J Clin Oncol of prognostic factors in 1,041 patients with lo- 1993;11:1276–85. calized soft tissue sarcomas of the extremities. 50. Maki R, Wathen K, Patel SR, et al. Ran- J Clin Oncol 1996;14:1679–89. domized phase II study of gemcitabine and 40. Whooley B, Gibbs J, Mooney M. Primary Ex- docetaxel compared with gemcitabine alone tremity Sarcoma: What is the Appropriate in patients with metastatic soft tissue sarco- Follow-up? Annals of Surg Oncol 2000; 7: mas: results of sarcoma alliance for research 9-14. through collaboration study 002 [corrected]. J 41. Whooley BP, Mooney MN, Gibbs JF, Gray- Clin Oncol 2007; 25: 2755–63. bill WG. Effective follow-up strategies in soft 51. Hensley ML, Maki R, Venkatraman E, et al. tissue sarcoma. Sem Surg Oncol 1999;17: Gemcitabine and docetaxel in patients with 83–87. unresectable leiomyosarcoma: results of a 42. Billingsley KG, Burt ME, Jara E, et al. Pul- phase II trial. J Clin Oncol 2002;12:2824–31. monary metastases from soft tissue sarcoma: 52. Garcia-del-Muro X, Lopez-Pousa A, Maurel J, analysis of patterns of diseases and postme- et al. Randomized phase II study comparing tastasis survival. Ann Surg 1999;229:602–10. gemcitabine plus dacarbazine versus dacarba- 43. Bramwell VH, Anderson D, Charette ML; Sar- zine alone in patients with previously treat- coma Disease Site Group. Doxorubicin-based ed soft tissue sarcoma: a Spanish Group for chemotherapy for the palliative treatment of Research on Sarcomas study. J Clin Oncol adult patients with locally advanced or meta- 2011;29:2528–33. static soft tissue sarcoma. Cochrane Database 53. Grosso F, Jones RL, Demetri GD, et al. Efficacy Syst Rev 2003;(3):CD003293. of trabectedin (ecteinascidin-743) in advanced 44. Edmonson J, Ryan L, Blum R. Randomized pretreated myxoid liposarcomas: a retrospec- comparison of doxorubicin alone versus ifos- tive study. Lancet Oncol 2007;7:595–602. famide plus doxorubicin or mitomycin, doxo- 54. Italiano A, Cioffi A, Penel N, et al. Compar- rubicin, and cisplatin against advanced soft ison of doxorubicin and weekly paclitaxel tissue sarcomas. J Clin Oncol 1993;11:1269– efficacy in metastatic angiosarcomas. Cancer 75. 2012;118:3330–6. 45. Santoro A, Tursz T, Mouridsen H. Doxorubi- 55. Penel N, Italiano A, Ray-Coquard I, et al. Met- cin versus CYVADIC versus doxorubicin plus astatic angiosarcomas: doxorubicin-based reg- ifosfamide in first-line treatment of advanced imens, weekly paclitaxel and metastasectomy soft tissue sarcomas: a randomized study of significantly improve outcome. Ann Oncol the European Organization for Research and 2012;23:517–23. Treatment of Cancer Soft Tissue and Bone 56. Samuels BL, Chawla S, Patel S, et al. Clinical Sarcoma Group. J Clin Oncol 1995;13:1537– outcomes and safety with trabectedin therapy 45. in patients with advanced soft tissue sarco- 46. Tap WD, Jones RL, Van Tine B, et al. Olara- mas following failure of prior chemotherapy: tumab and doxorubicin versus doxorubicin results of a worldwide expanded access pro- alone for treatment of soft-tissue sarcoma: an gram study. Ann Oncol 2013;24:1703–9. open-label phase 1b and randomised phase 2 57. Schöffski P, Ray-Coquard IL, Cioffi A, et al. trial. Lancet 2016;388:488–97. Activity of eribulin mesylate in patients 47. Borden EC, Amato DA, Rosenbaum C, et al. with soft-tissue sarcoma: a phase 2 study in Randomized comparison of three adriamycin four independent histolical subtypes. Lancet regimens for metastatic soft tissue sarcomas. J 2011;11:1045–52. Clin Oncol 1987;5:840–50. 58. Van der Graaf W, Blay JY, Chawla S, et al. 48. Omura GA, Major FJ, Blessing JA, et al. A Pazopanib for metastatic soft-tissue sarcoma randomized study of adriamycin with and (PALETTE): a randomized, double-blind, without dimethyl triazenoimidazole carbox- placebo-controlled phase 3 trial. Lancet amide in advanced uterine sarcomas. Cancer 2012;379:1879–86. 1983;52:626–32. 59. Dileo P, Morgan JA, Zahrieh D, et al. Gemcit- 49. Antman K, Crowley J, Balcerzak SP, et al. abine and vinorelbine combination chemo- An intergroup phase III randomized study therapy for patients with advanced soft tissue of doxorubicin and dacarbazine with or sarcomas: results of a phase II trial. Cancer without ifosfamide and mesna in advanced 2007;109:1863–9.

SARCOMAJOURNAL.COM VOL 1, NO 1 | FALL 2017 | THE SARCOMA JOURNAL 19 › CASE REPORT ‹ CLINICAL CASES AND PRESENTATIONS REBECCA E NERIL, MD, AND KIMBERLY LAM, MD

Bilateral chylothorax in an AIDS patient with newly diagnosed Kaposi sarcoma

Rebecca E Neril, MD, and aposi sarcoma is an angiopro- ular plaques on the back and lower ex- Kimberly Lam, MD; Depart- liferative tumor that is associat- tremities. As described by dermatology, ment of Internal Medicine, ed with human herpes virus-B there was a violaceous indurated plaque SBH Health System, Bronx, New York K(HIV-B). Mucocutaneous disease on the left axillae, violaceous indurated is the most common site for manifesta- plaques with superficial scale grouped DISCLOSURES The authors report no tion of AIDS-related Kaposi sarcoma, on the left midlateral back, and hyperpig- disclosures or conflicts of commonly affecting the lower extreme- mented lichenified plaques and papules interest. ties, oral mucosa, face, and genitalia. on bilateral shins, with some with plate- Pleural effusions can occur in 36%-60% like scale. Two punch biopsies were tak- of patients with Kaposi sarcoma, and it en of the skin lesions, which confirmed has been documented that chylothorax Kaposi sarcoma, plaque stage from the is a rare, but plausible presentation in lesion biopsied on the back, and patch patients with Kaposi sarcoma.1 We pres- stage from the lesion biopsied in the left ent here a case of bilateral chylothorax axilla. Cytology of the pleural fluid was in a patient with AIDS-related Kaposi negative for malignant cells. On review sarcoma. by the radiologist of the CT scan of the chest, there was no indication of gross CASE PRESENTATION AND SUMMARY distention of the thoracic duct. Treatment A 52-year-old MSM male with AIDS options were offered to the patient, and

(CD4, <20 mm3 ; viral load, 58 copies/ml) the patient was considering options for presented to the emergency department chemotherapy and home hospice given with complaints of shortness of breath, his advanced disease state at the time of productive cough, and diarrhea for 2 discharge. days prior to presentation. His medical history also included chronic obstruc- DISCUSSION tive pulmonary disease, coronary artery Chylothorax occurs with a thoracic duct disease, and hyperlipidemia.The patient obstruction, which results in leakage of was not on HAART because of his his- lymphatic fluid into the pleural cavity. tory of noncompliance. The results of a The two leading causes of chylothorax chest X-ray and computed-tomography are trauma and malignancy, with lym- (CT) scan showed that the patient had phoma being the most common cause of bilateral pleural effusion and a spiculat- chylothorax among those with malignan- ed 14-mm nodule in the left upper lobe. cy.2 Chylothorax, however, is a rare but The patient underwent ultrasound-guid- documented complication of Kaposi sar- ed placement of a 12-French left-sided coma. Marais and colleagues reported the chest catheter, and a milky white fluid case of a 3-year-old HIV-positive patient was aspirated from the left pleural space. with newly diagnosed Kaposi sarcoma Laboratory analysis of the pleural fluid who was found to have tumor infiltra- confirmed an exudate with an elevated tion in the thoracic duct leading to bi-

triglyceride level of 120 mg/dL (chylous, lateral chylothorax.3 Maradona and col- >110 mg/dL) indicating chylothorax. leagues described a 40-year-old man with On close physical examination, the AIDS-related Kaposi sarcoma who was patient was found to have multiple irreg- found to have pleural and pericardial Ka-

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FIGURE 1. Chest X-ray showing bilateral pleu- FIGURE 2. A helical computed-tomography ral effusion blunting the costophrenic angles. scan of the chest showed bilateral pleural effusion. posi sarcoma with chylothorax.4 Priest tive chylothorax in a patient with AIDS- and colleagues wrote about a 32-year-old related Kaposi sarcoma. TSJ patient with AIDS with biopsy-proven Kaposi sarcoma who required multiple CORRESPONDENCE therapeutic thoracenteses for rapidly re- Rebecca E Neril, MD; Department of Inter- 5 nal Medicine, SBH Health System, Bronx, New current left chylothorax effusions. York. Accepted for publication April 11, 2016. There are two leading discussions as JCSO 2017;15(3):e174-e175. doi: https://doi. › CHYLOTHORAX, to the pathophysiology of chylothorax org/10.12788/jcso.0261 HOWEVER, IS A RARE that is related to Kaposi sarcoma: chy- BUT DOCUMENTED lothorax developing secondary to meta- REFERENCES COMPLICATION OF static disease or the development of chy- 1. Sridar S, Garza EG, Cox J, Rumbak MJ. Se- lothorax secondary to primary Kaposi rosanguineous pleural effusions in a patient KAPOSI SARCOMA. sarcoma arising from the pleural region.6 with HIV and Kaposi sarcoma: pleuroscop- One case report examined pleural and ic findings.J Bronchology Interv Pulmonol. 2011;18(4):337-339. lung biopsies in a 34-year-old patient 2. Light RW. Chylothorax and pseudochylotho- with AIDS-related Kaposi sarcoma that rax. In: Light RW, ed. Pleural diseases. 6th ed. showed immunohistochemical staining Philadelphia: Lippincott Williams & Wilkins, that was suggestive of early-stage Ka- 2013:412-426. posi sarcoma of lymphatic endothelial 3. Marais BJ, Pienaar J, Gie RP. Kaposi sarcoma with upper airway obstruction and bi- origin. The authors were attempting to lateral chylothoraces. Pediatr Infect Dis J. illustrate that Kaposi sarcoma may have 2003;22:926-928. a stem-cell origin which can differenti- 4. Maradona JA, Carton JA, Asensi V, Rodri- ate into lymph cells. Kontantinopoulos guez-Guardado A. AIDSrelated Kaposi sarco- and colleagues postulated that in situ ma with chylothorax and pericardial involvement satisfactorily treated with liposomal Kaposi sarcoma can arise from the lym- doxorubicin. AIDS. 2002;16(5):806. phatic system with a resultant clinical 5. Priest ER, Weiss R. Chylothorax with Kaposi presentation of chylothorax.7 The more sarcoma. South Med J. 1991;84:806-807. mainstream thought however, is that 6. Pantanowitz L, Dezube BJ. Kaposi sarcoma in chylothorax has been found to develop unusual locations. BMC Cancer. 2008;8:190. secondary to metastatic disease. The 7. Konstantinopoulos PA, Dezube BJ, Pantanow- itz L. Morphologic and immunophenotypic present case, therefore, illustrates an evidence of in situ Kaposi sarcoma. BMC Clin unusual presentation of cytology nega- Pathol. 2006;30:6:7.

SARCOMAJOURNAL.COM VOL 1, NO 1 | FALL 2017 | THE SARCOMA JOURNAL 21 › CASE REPORT ‹ CLINICAL CASES AND PRESENTATIONS GAURANG NANDKISHOR VAIDYA, MBBS, RUSHIKESH SHAH, MD, AMIT DHAMOON, MD

Pulmonary sarcomatoid carcinoma presenting as a necrotizing cavitary lung lesion: diagnostic dilemma

Gaurang Nandkishor Vaidya, ulmonary sarcomatoid carcinoma of his neck. He denied any fever, chest MBBS; Rushikesh Shah, MD; (PSC) is a rare histological sub- pain, sick contacts, or joint pain. He had and Amit Dhamoon, MD Department of Internal Ptype that has an aggressive course a history of about 40 pack-years of smok- 1 Medicine, SUNY Upstate with average survival of 11-13 months. ing, and his brother had recently been di- Medical University, Syra- In clinical practice, the possible presen- agnosed with lung cancer. A tender fluc- cuse, New York tations of this rare cancer are not wide- tuant mass was detected in the nape of DISCLOSURES ly known, resulting in a misdiagnosis. his neck on examination (FIGURE 1). The authors report no That is what happened with our patient, The patient had presented 9 months disclosures or conflicts of interest. who presented with necrotizing cavitary earlier with persistent cough and he- lung lesion and soft tissue necrotizing moptysis, and at that visit was found lymphadenitis. The clinical picture was to have a cavitary lesion in the right reminiscent of tuberculosis or granulo- lung measuring 2 cm (0.8 in). He had matosis with polyangiitis and was fur- undergone a computed-tomograpghy ther confounded by negative comput- (CT)-guided biopsy of the lesion, which ed-tomography (CT)-guided biopsy and had shown acute and chronic inflamma- bronchoscopy findings, which added to tion with fibrosis, and he had negative the delay in diagnosis. With the current- bronchoscopy findings. The patient test- ly available knowledge, the diagnosis of ed negative for tuberculosis during the PSC depends largely on evaluation of first visit but he left the hospital against the surgically resected specimen, which the medical advice of the physicians in most cases is avoided until there is and he was lost to follow-up until his a high suspicion of PSC. Biopsy is not re-presentation. useful due to extensive necrosis, as will On physical examination at his re-pre- be seen in our case. Consequently, most sentation, the patient seemed cachec- of the data in the literature is based on tic, with a blood pressure of 94/62 mm case series of autopsy specimen, and the of Hg. The mass in the nape of his neck clinical characteristics of PSC remain was about 3 cm (1.2 in) long, with ery- unclear. The rarity of PSC has prevent- thema of the surrounding skin (FIGURE 1). ed its characterization in literature. We Bronchial breath sounds were heard in report here a rare presentation of PSC the right upper lobe of the lung, like- with necrotizing lung lesion, to add to ly due to the underlying cavitary lesion the paucity of the current data. (FIGURE 2B). Relevant lab findings included a negative HIV test and repeat AFB CASE PRESENTATION (acid-fast bacilli) sputum cultures. A AND SUMMARY CT-guided biopsy with contrast of the A 58-year-old homeless man presented thorax showed an interval increase in the to the Upstate University Hospital, Syra- size of the cavitary lesion in the patient’s cuse, New York, with a 25-pound weight right upper lobe, now measuring about loss during the previous month and asso- 10 cm (4 in). Also seen were multiple ciated productive cough and hemoptysis nodules elsewhere in both lungs, with for a week and a painful mass in the nape the largest measuring 8 mm (0.3 in). A

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CT scan of the neck showed 3 cm cystic mass within the posterior subcutaneous soft tissue of the C3 level, confirming the examination finding of the neck mass ( FIGURE 2A) with peripheral enhancement and surrounding infiltrative changes, likely abscess or malignant lymph node versus necrotic infection. He underwent bronchoscopy, which again failed to re- veal any endobronchial lesions. Broncho- alveolar lavage was sent for microbiologi- cal analysis, including AFB and fungus, but came back negative. Transbronchial FIGURE 1. Fluctuant mass, about 3 cm long, in the nape of the neck, after drainage, biopsy cytology revealed fragments of showing erythema of the surrounding skin. tumor composed of large pleomorphic cells without glandular or squamous A B differentiation, within large areas of necrosis (Figure 3). Immunohistochemical studies showed strong reactivity with cytokeratin CAM5.2 (FIGURE 4), weak and focal reactivity with cytokeratin AE1/AE3 (FIGURE 5), and lack of reactivity with CD20, CD3, CD30, S-100, MART-1, TTF- 1 and p63, all findings consistent with sarcomatoid carcinoma. The patient underwent fine-needle aspiration and drainage of the neck lesion and the culture grew mixed or- FIGURE 2. A, A computed-tomography scan of the neck, showing a cystic ganisms The results of a bone scan, lesion in the posterior soft tissue (green arrow). B, A large necrotic cavitary which was done within a week, showed region in the right upper lobe of the lung (yellow arrow). multiple foci of uptake in the ribs and cervical spine. Given the patient’s advanced disease, he was started on palli- why both elements co-exist in the tumor, ative radiotherapy with radiosensitizing but Franks and colleagues some theories chemotherapy with carboplatin (target have been postulated in the literature, AUC 6) and paclitaxel (135 mg/m2 over including possible origin from a single, 24 hours). His symptoms of hemopty- aberrant stem cell with progenies differ- sis improved transiently after the first entiating in two separate pathways.3 cycle, but he became hypotensive and Sarcomatoid carcinoma consists of drowsy during the second cycle of ther- spectrum of tumors including pleomor- apy, and the family decided to make the phic carcinoma, spindle cell carcinoma, patient comfort care and withdraw all giant cell carcinoma, carcinosarcoma, further treatment. He was discharged to and blastoma.3,4 It usually shows male hospice. preponderance, and association with smoking.3 The diagnosis commonly oc- DISCUSSION curs in the sixth decade of life, except PSC is a rare variant of non-small-cell for pulmonary blastoma, which is more carcinoma lung cancer, accounting for common in the fourth decade andnwith up to 0.4% of lung malignancy.1 It was equal gender distribution.4 recently subtyped by the World Health The presenting symptoms can be vari- Organization as a non-small cell lung car- able and nonspecific, but predominantly cinoma with certain amount of differen- include chest pain, cough, hemoptysis, tiation resembling sarcoma or containing and/or weight loss.5 Radiologically, pul- elements of sarcoma.2-4 It is not known monary sarcomatoid cancer presenting

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the distinction between cancer and other mimicking conditions. This is especially true for rare tumors such as PSC, which often results in misdiagnosis and a delay in administering the proper treatment. Transbronchial biopsy in cases such as the present case, carries FIGURE 3. Images from the bronchoscopic biopsy, showing alveoli replaced by pleo- little benefit because the diagnosis morphic and spindle cells. Hematoxylin and eosin stain, x50 (left) and x200 (right). depends on the site from which Arrows are artifacts from the microscope. the biopsy is taken and whether the biopsied tissue is representative of the entire mass. The diagnosis can be suspected based on the clinical and radiological findings but confirmation requires a surgical resection to delineate the accurate cytology and architec- ture.5,6,8 Huang and colleagues showed a misdiagnosis rate of PSC of >70% preoperatively.4 Re- FIGURE 4. Biopsy tissue showing positivity to CAM 5.2. Hematoxylin and eosin stain, sective surgery is feasible only in x200. patients with high index of suspicion for a malignancy, which in most cases requires previous confirmation with a biopsy. The rarity of this cancer, its unusual presentations, and the lack of specific testing preclude early diagnosis and timely treatment of this fatal condition. Initial treatment options for localized or with limited spread disease is resec- tive surgery. The role of chemo- or radiation therapy is not known, but they have not previously shown promising results,6,8 except in some cases when they are used as postoperative adjuvant FIGURE 5. Biopsy sample showing focal reactivity to AE1/AE3. chemotherapy4 or in bulky, locally inva- Hematoxylin and eosin stain, x200 sive tumors.1 The recurrence rate after surgery is very high, resulting in a poor as a necrotizing cavitary lesion in the 5-year survival rate.1,8 Experimental lung is a rare finding, seldom reported therapies, such as antibodies that target in the past.6,7 The presentation in our epidermal growth factor receptor mu- case, with necrotizing lymphadenitis, tations, have not shown much success was reminiscent of an infectious or au- either.8 In conclusion, the outlook for toimmune etiology such as tuberculosis patients with PSC with the current avail- or granulomatosis with polyangiitis. The able knowledge and treatment protocols, presence of extensive necrosis in the le- is dismal. sion and the characteristic heterogeneity Most of the current knowledge and of the tumor had resulted in inconclu- data in the literature is based on cas- sive biopsy findings during the previous es from autopsy or early-stage surgical presentation. In clinical practice, there is resections rather than on patients with over-reliance on biopsy findings to make advanced cancer.5 Moreover, the role of

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surgical resection in PSC is questionable, CORRESPONDENCE given the high recurrence rate. Subse- Gaurang Nandkishor Vaidya, MD; Accepted for publica- quently, the clinical and pathological tion January 12, 2016. JCSO 2017;15(2):103-105. doi: https://doi.org/10.12788/jcso.0259. manifestations have yet to be well characterized.4 There has been advance with REFERENCES the publication of more studies recent- 1. Martin LW, Correa AM, Ordonez NG, et al. ly. Cytokeratin markers such as CAM Sarcomatoid carcinoma of the lung: a predictor of poor prognosis. Ann Thorac Surg. 5.2 and AE1/AE3 are commonly useful 2007;84(3):973-980. to support the diagnosis when suspect- 2. Brambilla E, Travis WD, Colby TV, Corrin B, ed.3 Other markers, including the carci- Shimosato Y. The new World Health Orga- noembryonic antigen, CD15, and thyroid nization classification of lung tumours. Eur transcription factor-1 may be variably Respir J. 2001;18(6):1059-1068. positive, based on the differentiation of 3. Franks TJ, Galvin JR. Sarcomatoid carcinoma of the lung: histologic criteria and the cancer. Other exciting prospects in common lesions in the differential diag- the study of PSC include the suggestion nosis. Arch Pathol Lab Med. 2010;134(1): of a modified vimentin histologic score 49-54. for better characterization of the cancer 4. Huang SY, Shen SJ, Li XY. Pulmonary sarcomatoid carcinoma: a clinicopathologic and the discovery of high plateletderived study and prognostic analysis of 51 cas- growth factor receptor beta immunohis- es. http://wjso. biomedcentral.com/arti- tochemistry expression in PSC as a po- cles/10.1186/1477-7819-11-252. Published tential target for future therapy. 2013. Accessed March 12, 2017. 5. Travis WD. Sarcomatoid neoplasms of the lung and pleura. Arch Pathol Lab Med. CONCLUSION 2010;134(11):1645-1658. Pulmonary sarcomatoid lung cancer can 6. Pelosi G, Sonzogni A, De Pas T, et al. Review present with a predominant necrotizing article: pulmonary sarcomatoid carcino- picture that mimics diseases such as tu- mas: a practical overview. Int J Surg Pathol. berculosis. In such case, transbronchial 2010;18(2):103-120. 7. Chang YL, Lee YC, Shih JY, Wu CT. Pulmo- biopsy carries little benefit because the nary pleomorphic (spindle) cell carcinoma: diagnosis depends on whether the biop- peculiar clinicopathologic manifestations sied tissue is representative of the entire different from ordinary non-small cell carci- mass, often confounded by the extensive noma. Lung Cancer. 2001;34(1):91-97. necrosis. More data is needed to deter- 8. Park JS, Lee Y, Han J, et al. Clinicopatholog- ic outcomes of curative resection for sarco- mine prognostic factors and appropriate matoid carcinoma of the lung. Oncology. therapeutic strategies. TSJ 2011;81(3-4):206-213.

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