Histiocytic and Dendritic Cell Lesions

L. Jeffrey Medeiros, MD MD Anderson Cancer Center Outline

2016 classification of Histiocyte Society Langerhans cell histiocytosis / sarcoma Erdheim-Chester disease Juvenile xanthogranuloma Malignant histiocytosis Histiocytic sarcoma Interdigitating dendritic cell sarcoma Follicular dendritic cell sarcoma Rosai-Dorfman disease Hemophagocytic lymphohistiocytosis Writing Group of the Histiocyte Society Major Groups of Histiocytic Lesions Group Name

L Langerhans-related

C Cutaneous and mucocutaneous

M Malignant histiocytosis

R Rosai-Dorfman disease

H Hemophagocytic lymphohistiocytosis

Blood 127: 2672, 2016 L Group

Langerhans cell histiocytosis Indeterminate cell tumor Erdheim-Chester disease

S100

Normal Langerhans cells Langerhans Cell Histiocytosis “Old” Terminology Eosinophilic granuloma Single lesion of bone, LN, or skin

Hand-Schuller-Christian disease Lytic lesions of skull, exopthalmos, and diabetes insipidus

Sidney Farber Letterer-Siwe disease 1903-1973 Widespread visceral disease involving liver, spleen, bone marrow, and other sites

Histiocytosis X Umbrella term proposed by Sidney Farber and then Lichtenstein in 1953 Louis Lichtenstein 1906-1977 Langerhans Cell Histiocytosis Incidence and Disease Distribution

Incidence

Children: 5-9 x 106 Adults: 1 x 106

Sites of Disease Poor Prognosis Bones 80% Skin 30% Liver Pituitary gland 25% Spleen Liver 15% Bone marrow Spleen 15% Bone Marrow 15% High-risk organs Lymph nodes 10% CNS <5% Blood 127: 2672, 2016 N Engl J Med 379: 856, 2018 Langerhans Cell Histiocytosis Solitary lesion of bone

Eosinophilic Granuloma

CD1a Langerhans Cell Histiocytosis Lungs

Associated with smoking

BRAF V600E CD207 Langerhans Cell Histiocytosis Lymph Nodes CD1a

LNs can be localized or a part of disseminated disease

This patient had generalized LNs and BRAF V600E mutation Langerhans Cell Histiocytosis Morphologic Features

Frequency Feature 100% Langerhans cells (<5-75%) 92% Eosinophils 84% Multinucleated giant cells 75% Small lymphocytes 61% Necrosis 49% Neutrophils 29% Foamy histiocytes

Mild atypia (reactive type) in ~50% of cases Mitotic rate: 0-23/10 high power fields

Arch Pathol Lab Med 107: 59, 1983 Langerhans Cell Histiocytosis Immunophenotype and EM

Immunophenotype

S100+, CD1a+, CD207/langerin+

+/- BRAF V600E (mutation specific antibody)

+/- CD4, CD11c, CD45/LCA, CD68, lysozyme+

Note: S100, CD1a, and CD207/langerin are not restricted to Langerhans cells

Electron Microscopy

Birbeck granules (aka Langerhans bodies) CD207

Am J Surg Pathol 41: 1390, 2017 Cyclin D1 Langerhans Cell Histiocytosis Birbeck Granules

Also known as X bodies or Langerhans bodies

Birbeck granules are characteristic (but not unique to) Langerhans cells Presence is a reflection of membrane activity; function debated Contain langerin = a type II transmembrane lectin receptor

Francoise Basset, PhD

J Invest Dermatol 37: 51, 1961 Michael S. C. Birbeck, PhD CR Acad Sci (Paris) 261:5719, 1965 1925-2005 Langerhans Cell Histiocytosis Mutations in BRAF/MAP2K1 Are Common

Blood 116: 1919, 2010

BRAF V600E 18/40 (45%) MAP2K1 11/40 (27.5%)

Blood 124: 1655, 2014 Nucleus Extracellular Cytoplasm • • ERK: Extracellular signal‐regulated kinase MAPK: Mitogen‐activated protein kinase MAP2K1 gene Encoded by ARAF

EGFR p90Rsk MEK1/2 ERK 1/2 Proteins PDGFR BRAF RAS Transcription factors VEGFR

Regulation of proliferation, apoptosis, RTK metabolism and immune response HRAS, KRAS and NRAS GTP‐binding proteins: CRAF MAPK/ ERK PATHWAY P P 85% of LCH cases have genetic abnormalities of the MAPK pathway

They likely all do

Blood 128: 2533, 2016 Langerhans Cell Histiocytosis Misguided Myeloid Dendritic Cell Model

Model to explain the widely disparate presentations of LCH

Distribution of disease depends on the cell in which mutation/ERK activation occurs

Hematology Am Soc Hematol Educ Program 2015;2015:559-564 Immunity 44: 439, 2016 “Histiocytosis X (HX) has the advantage of widespread use, although it has been applied to other types of histiocytosis. The generally recognized Langerhans cell derivation of HX makes Langerhans cell histiocytosis an attractive alternative.”

Arch Pathol Lab Med 107: 59, 1983 Langerhans Cell Histiocytosis (LCH) Rarely Associated with Lymphomas

Mantle cell lymphoma LCH

No BRAF V600E or MAP2K1 mutations

Lymphomas 5 Classical Hodgkin lymphoma 1 Mantle cell lymphoma 1 Angioimmunoblastic T-cell CD1a LCH was <10%; incidental Sergio Pina Oviedo, MD Mod Pathol 30: 734, 2017 Langerhans Cell Histiocytosis Differential Diagnosis

Dermatopathic lymphadenopathy Indeterminate dendritic cell tumor Langerhans cell sarcoma Dermatopathic Lymphadenopathy

S100

Benign reaction pattern associated with skin disease CD1a Indeterminate Dendritic cell Tumor

Thought to be derived from normal precursors of Langerhans cells (so-called indeterminate cells)

Patients present with > nodules, papules or plaques on skin

Dermis-based disease that can extend into subcutaneous fat

Histologically looks like Langerhans cells histiocytosis But often no eosinophils

Immunophenotype: CD1a+, S100+, CD207-

Electron microscopy: No Birbeck granules

Genetics: ETV3-NCOA2/t(1;8)(q23.1;8q13.3) reported in 3 cases

Highly variable clinical course: Spontaneous regression or progression Indeterminate Dendritic Cell Tumor

CD1a

A negative langerin/CD207 is required to make this diagnosis CD207 Langerhans Cell Sarcoma

Definition A high-grade neoplasm with overt malignant cytologic features and Langerhans cell phenotype History Rarely preceded by typical LCH (in my experience)

Age and Sites of Disease Median 41 yrs (10-72yrs) Extranodal ~ 80% (most often skin); nodal ~ 20%

Ancillary Support for Diagnosis Immunohistochemistry: S-100+, CD1a+, CD207/langerin+ Electron microscopy: Birbeck granules

Genetics Rare cases with monoclonal IGH rearrangements

Prognosis ~50% mortality as a result of progressive disease Langerhans Cell Sarcoma

CD207 Erdheim-Chester Disease Definition

“A clonal, systemic proliferation of histiocytes, commonly having a foamy (xanthomatous) component and containing Touton giants cells.”

2017 WHO book p. 481

Described by W. Chester in single author paper in German in 1930.

J. Erdheim was mentor

Renamed Erdheim-Chester disease in 1972

Jacob Erdheim, MD William Chester, MD Erdheim-Chester Disease Clinicopathologic Features Age and Sex Ratio Median 53 years (range, 20-74) Sex ratio: 3 to 1 male predominance Symptoms Can be asymptomatic or aggressive; related to sites Dull and deep bone pain common (especially knees) Histologic features Bland histiocytes infiltrate tissues Foamy or eosinophilic cytoplasm; Touton giant cells Fibrosis is common; +/- lymphocytes, plasma cells, eos No mitoses, necrosis, granulomas, emperipolesis Looks/phenotypes like juvenile xanthogranuloma Imaging Bilateral, symmetric cortical osteosclerosis of long bones Surrounds aorta (“coated”) or kidney (“hairy kidney”) Genetics BRAF V600E mutations in ~50%, ~4% NRAS, ~10% PI3KA Blood Advances 1:357, 2017 Erdheim-Chester Disease

Positive CD14 CD68 CD163 Fascin Factor XIII

Negative CD1a CD207

S100+ ~20%

CD68 CD1a Erdheim-Chester Disease Radiologic Images

Case courtesy of Dr Andrew Lawson Radiopaedia.org, rID: 29803

Case courtesy of Dr Andrew Dixon, Radiopaedia.org, rID: 9351 CGroup

Many different lesions – most on skin

Can subdivide into two broad groups Xanthogranuloma Non-xanthogranuloma Juvenile Xanthogranuloma

Affects children >> adults Rare: < 1% of all pediatric tumors Single, few, or multiple lesions on skin: yellow papules 0.5-1 cm Often regress spontaneously Long bones are not involved Rarely patients have visceral involvement or disseminated disease Can cause symptoms or death due to local invasion Genetics Localized CGH: chromosomal abnormalities uncommon (~5%) Disseminated CGH: nonspecific chromosomal abnormalities described

1 case with MAPK1 mutation (Oncotarget 8: 46065, 2017)

Mod Pathol 30:1234, 2017 Juvenile Xanthogranuloma

Immunophenotype CD14+ CD68+ CD163+ Factor XIIIa +/- S-100+ ~20% Fascin+ ~20% CD1a- CD207/langerin - MAPK Pathway Mutations in Histiocytic Lesions A Unifying Feature in Pathogenesis

LCH = Langerhans cell histiocytosis JXG = Juvenile xanthogranuloma ECD = Erdheim-Chester disease

Hematology Am Soc Hematol Educ Program 2015; 2015:559-564 M Group

Histiocytic sarcoma Interdigitating dendritic cell sarcoma Langerhans cell sarcoma

“…we recommend reusing the old-term malignant histiocytosis, and refer to the phenotype as a subtype.”

Blood 127: 2672, 2016 Histiocytic Sarcoma Definition and Clinicopathologic Features Definition A malignant proliferation of cells with morphologic and immunophenotypic features of mature tissue histiocytes Epidemiology Median age = 52 y; males = females Subset associated with B-cell lymphoma (transdifferentiation) Rare pts with mediastinal germ cell tumor and isochromosome 12p Presentation Often extranodal (GI tract, skin, soft tissues) Can be nodal or disseminated (“malignant histiocytosis”) Genetics Subset of cases with monoclonal Ig rearrangements Limited data on mutations (until recently) Outcome Clinically aggressive; poor response to therapy 60-80% of patients die of disease 2017 WHO book p. 468-470 Histiocytic Sarcoma CD11c

CD163 Histiocytic Sarcoma Immunophenotype

Positive Vimentin S100 (weak or focal), Ki-67 10-20% ZBTZ46 (Mod Pathol 31:1479, 2018)

Variably Positive Fascin

Weakly and variably positive CD45/LCA, CD68, lysozyme

Negative CD1a, CD207/langerin CD21, CD23, CD35, clusterin CD34, myeloperoxidase EMA, keratins, melanoma-associated antigens B-cell and T-cell antigens 2017 WHO book p. 475 Methods 28 cases of histiocytic sarcoma NGS, hybrid capture, 447 gene panel Copy number analysis Results 16 (57%) with mutations in RAS-MAPK pathway MAP2K1 most common 6 (21%) with mutations of PI3K-AKT-MTOR pathway 13 (48%) loss of CDKN2A / p16 7 (25%) with aberrant somatic mutation signature

Suggests possible B-cell origin Mod Pathol 2019 (Epub) Interdigitating Dendritic Cell Sarcoma

CD163

S100 Interdigitating Dendritic Cell Sarcoma Definition and Clinicopathologic Features

Definition A neoplastic proliferation of spindle to ovoid cells with phenotypic features similar to those of interdigitating dendritic cells Epidemiology Rare Usually adults; males > females Presentation Solitary lymph node involvement most common Can be extranodal or widely disseminated Genetics Subset of cases with monoclonal IGH rearrangements Rare cases reported with BRAF V600E mutation Outcome Clinically aggressive 50% of patients die of disease 2017 WHO book p. 476 Interdigitating Dendritic Cell Sarcoma Immunophenotype

Positive S100 (diffuse and intense), vimentin Ki-67 10-20%

Variably Positive Fascin

Weakly and variably positive CD45/LCA, CD68, lysozyme

Negative CD1a, CD207/langerin CD21, CD23, CD35, clusterin CD34, myeloperoxidase EMA, keratins, melanoma-associated antigens B-cell and T-cell antigens

2017 WHO book p. 476 Cell of Origin/Lineage of Histiocytes FDCs Are Different – Arise from MSC

MSC = mesenchymal stem cell Sem Cell Dev Biol 2018 (in press) Follicular Dendritic Cell Sarcoma Definition and Clinicopathologic Features Definition A neoplasm with morphologic and immunophenotypic features of follicular dendritic cells Epidemiology Usually adults; males = females Small subset arises in hyaline-vascular Castleman disease Presentation Extranodal 58%, Nodal 31%, both 11% Genetics Subset of cases with monoclonal IGH rearrangements Complex karyotype Mutations in genes that regulate NF-kB pathway 0-20% of cases reported with BRAF V600E mutation Outcome Need to resect completely; +/- XRT or chemotherapy ~1/3 of pts recur locally; ~1/3 distant metastases 2017 WHO book p. 476-479 Follicular Dendritic Cell Sarcoma Immunophenotype and Electron Microscopy

Positive (often variable/focal) Vimentin CD21, CD23, CD35 CXCL13, clusterin, D2-40, EGFR, fascin Ki-67: 5-25% Weakly and variably positive CD68, EMA, S100 (focal), HLA-DR Negative CD1a, CD207/langerin CD34, myeloperoxidase Keratins, melanoma-associated antigens B-cell and T-cell antigens

Electron microscopy Long cytoplasmic processes; desmosomes 2017 WHO book p. 475-476 Follicular Dendritic Cell Sarcoma Spindled CD35 Follicular Dendritic Cell Sarcoma Epithelioid

CD21 Inflammatory Pseudotumor-like FDC Sarcoma A Different Disease

Epidemiology Young or middle-aged adults; women >> men

Presentation Spleen or liver; rarely the GI tract

Presentation Asymptomatic or abdominal pain

Immunophenotype and Genetics CD21+ CD23+ Smooth muscle actin +/- Epstein-Barr virus + and monoclonal

Outcome Clinically indolent; often cured by resection but can recur

2017 WHO book, p 478-479 Inflammatory Pseudotumor-like FDC Sarcoma Spleen

Clusterin

EBER R Group

Rosai-Dorfman disease Rosai-Dorfman Disease History First described in detail by Rosai and Dorfman in 1969 Designated as sinus histiocytosis with massive lymphadenopathy Arch Pathol Lab Med 87: 63, 1969 Also described by two other groups Destombes et al. in ~ 1965 (Bull Soc Pathol Exot 65: 481, 1972) Azoury and Reed in 1966 (N Engl J Med 274: 928, 1966)

Pierre-Paul Destombes, MD Elliott Foucar, MD

Juan Rosai, MD Ronald F. Dorfman, MD Rosai-Dorfman Disease Clinicopathologic Features Most cases are sporadic

Rare familial forms H (Faisalabad) syndrome SLC29A3 mutation Autoimmune lymphoproliferative syndrome TNFRSF6 mutation

Presentation ~60% Lymphadenopathy Bilateral large, painless cervical LNs Other lymph node groups can be involved +/- fever, night sweats, weight loss, fatigue

~40% Extranodal sites of disease Sem Diagn Pathol 33:244, 2016 Rosai-Dorfman Disease Bilateral Cervical Lymphadenopathy is Common Rosai-Dorfman Disease Lymph Node

Emperipolesis (greek) Em = inside Peri =around Polesis = going about Extranodal Sites Involved by RDD

Anatomic Site Frequency Nasal cavity and paranasal sinuses 11.3%

Soft tissue 8.9%

Orbit/eyelid 8.5%

Bones 7.8%

Skin 6.8%

Genitourinary system 6.4%

Major salivary glands 5.2%

Central nervous system 4.7%

Oral cavity 2.6%

Lungs, larynx, liver, tonsil, breast, Each < 2% GI tract, thyroid, heart

E. Foucar et al. Semin Diagn Pathol 7:19, 1990 Rosai-Dorfman Disease Soft Tissue

Emperipolesis is less in RDD at extranodal sites S-100 Rosai-Dorfman Disease Immunophenotype

Positive S100 protein CD68 CD163 Fascin HLA-DR

S100 Negative Beware CD1a IgG4 plasma cells can be CD207/langerin numerous in RDD CD3, CD20 7/21 (33%) cases with KRAS or MAP2K1 mutation Sofia Garces, MD

All point mutations KRAS exon 2 (n=2) or exon 4 (n=2) MAP3K1 exon 1 (n=1) or exon 3 (n=2)

VAF ~ 5%

Mutations correlated with Head and neck site Younger age Multifocal disease

No correlation with outcome

MAP2K1 c.157 T>G p.F53V Mod Pathol 30: 1367, 2017 Before After

N Engl J Med 377: 2398, 2017 Rosai-Dorfman Disease Associated with Lymphoma

NLPHL

RDD Age: Median 46 years (23-77) Sex: 7 women; 5 men Site: 11 lymph nodes; 1 skin Size: 3-20 mm Associated lymphomas: 10 Hodgkin lymphoma (6 NLPHL, 4 CHL) 1 CLL/SLL 1 MALT lymphoma Ipox: S100+, cyclin D1+, pERK 6/7+ Genes: No mutations (n=4) Follow up: No impact on therapy Mod Pathol 32: 16, 2019 No RDD elsewhere H Group

Hemophagocytic lymphohistiocytosis Hemophagocytic lymphohistiocytosis (HLH) Definition and Classification Definition A syndrome of severe immune activation and dysregulation characterized by hyperactive macrophages and lymphocytes, proinflammatory cytokine hypersecretion, tissue infiltration, hemophagocytosis, and organ damage. Types of HLH Primary (familial) Genetic defects that impair cytotoxic immune function Secondary Malignant neoplasms Non-malignant Infection Autoimmune disease Following organ transplantation Iatrogenic immune suppression Cancer 123:3229, 2017 Hemophagocytic lymphohistiocytosis Primary

Epidemiology Most patients are young children Incidence is 1 in 50,000-100,000 live births Genetics Biallelic mutations in genes that encode for molecules involved in cytotoxic granule activation, fusion, function, etc. Examples: PRF1 (perforin), STX11 (syntaxin 11), SH2D1A (XLP) Mendelian inheritance for many of these genes Survival Median = 2 months without treatment Therapy Etoposide, dexamethasone, and intrathecal methotrexate Allogeneic stem cell transplantation Hemophagocytic lymphohistiocytosis Secondary Epidemiology Most patients are adults Malignant neoplasms are usually hematologic Lymphomas, acute leukemias, MDS, T/NK-cell neoplasms Infection EBV, CMV, bacteria, fungi, protozoa Autoimmune (AKA macrophage activation syndrome) Systemic lupus erythematosus, juvenile RA, polymyositis Organ Transplantation Stem cell or solid organ Mortality Rate 80% Therapy Treat the neoplasm Suppress immune activation Hemophagocytic lymphohistiocytosis Criteria for Diagnosis

1. Fever 2. Splenomegaly 3. Cytopenias affecting >2 cell lineages 4. Elevated triglycerides and/or hypofibrinogenemia 5. Hemophagocytosis in bone marrow, spleen, or lymph nodes 6. Low or absent NK-cell activity 7. Elevated serum ferritin 8. High levels of soluble IL-2 receptor alpha

5 of 8 criteria are required to establish diagnosis of HLH Genetic testing, if positive, trumps

One can establish a diagnosis of HLH without morphologic evidence

Pediatr Blood Cancer 48:124, 2007 Hemophagocytic lymphohistiocytosis Secondary to EBV Infection

LN Patient with mantle cell lymphoma who died of HLH

Spleen

EBER Secondary Hemophagocytic lymphohistiocytosis Bone Marrow

Often easier to find HLH in smear than in biopsy