1/18/2019

Histiocytic and Dendritic Lesions

L. Jeffrey Medeiros, MD MD Anderson Cancer Center

Outline

2016 classification of Society / Erdheim-Chester disease Interdigitating sarcoma Follicular dendritic cell sarcoma Rosai-Dorfman disease Hemophagocytic lymphohistiocytosis

Writing Group of the Histiocyte Society

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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 Single lesion of bone, LN, or skin

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

Sidney Farber Letterer-Siwe disease 1903-1973 Widespread visceral disease involving , , , and other sites

Histiocytosis X Umbrella term proposed by Sidney Farber and then Lichtenstein in 1953 Louis Lichtenstein 1906-1977

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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

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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 61% Necrosis 49% 29% Foamy

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)

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CD207

Am J Surg Pathol 41: 1390, 2017 Cyclin D1

Langerhans Cell Histiocytosis

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

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Extracellular MAPK/ ERK PATHWAY

RTK

VEGFR

PDGFR EGFR Cytoplasm

RAS GTP-binding proteins: Proteins HRAS, KRAS and NRAS

ARAF BRAF CRAF

P Encoded by MAP2K1 gene MEK1/2

P ERK 1/2

Nucleus Transcription Regulation of proliferation, apoptosis, • MAPK: Mitogen-activated protein kinase p90Rsk factors metabolism and immune response • ERK: Extracellular signal-regulated kinase

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

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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 and attractive alternative.”

Arch Pathol Lab Med 107: 59, 1983

Langerhans Cell Histiocytosis (LCH) Rarely Associated with

Mantle cell 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

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Langerhans Cell Histiocytosis Differential Diagnosis

Dermatopathic Indeterminate dendritic cell tumor

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

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

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Indeterminate Dendritic Cell Tumor

CD1a

A negative langerin/CD207 is required to make this diagnosis CD207

Langerhans Cell Sarcoma

Definition A high-grade 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

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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) 3 men to 1 woman 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, , 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

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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

C Group

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

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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

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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 40-50% of cases with BRAF V600E mutation 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 B-cell and T-cell antigens 2017 WHO book p. 475

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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 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

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18 spindle cell melanoma (SCM) and 9 interdigitating dendritic cell sarcoma (IDCS) assessed with a panel of antibodies MUM-1, B-catenin, SOX10, MiTF, p75

Equivalent immunostaining profiles; all SOX10+

“the morphologic and immunophenotypic features of SCM and IDCS appear to be virtually indistinguishable from one another, raising the question as to whether these 2 entities represent a pathobiologically similar or even identical process.”

Am J Surg Pathol 40: 1270, 2016

Cell of Origin/Lineage of Histiocytes FDCs Are Different – Arise from MSC

MSC = mesenchymal 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 ~1/3 of pts recur locally; ~1/3 distant metastases 2017 WHO book p. 476-479

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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

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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

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Rosai-Dorfman Disease History Described 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 Juan Rosai, MD Ronald F. Dorfman, MD

Rosai-Dorfman Disease A Case Report

Richard J. Reed, MD

Azoury FJ, Reed RJ. N Eng J Med 274:928-930, 1966

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

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Rosai-Dorfman Disease Bilateral 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

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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

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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

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H Group

Hemophagocytic lymphohistiocytosis

Hemophagocytic lymphohistiocytosis (HLH) Definition and Classification Definition A syndrome of severe immune activation and dysregulation characterized by hyperactive and lymphocytes, proinflammatory cytokine hypersecretion, tissue infiltration, , and organ damage. Types of HLH Primary (familial) Genetic defects that impair cytotoxic immune function Secondary Malignant Non-malignant 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 , dexamethasone, and intrathecal methotrexate Allogeneic stem cell transplantation

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Hemophagocytic lymphohistiocytosis Secondary Epidemiology Most patients are adults Malignant neoplasms are usually hematologic Lymphomas, acute , MDS, T/NK-cell neoplasms Infection EBV, CMV, bacteria, fungi, protozoa Autoimmune (AKA activation syndrome) Systemic 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. 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

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Secondary Hemophagocytic lymphohistiocytosis Bone Marrow

Often easier to find HLH in smear than in

Paul Langerhans 1847-1888

Paul Langerhans Circa 1867

Paul and Margarethe Langerhans Grave site on Madeira Island 1885

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