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

Group Name

L Langerhans-related

C Cutaneous and mucocutaneous

M Malignant histiocytosis

R Rosai-Dorfman disease

H Hemophagocytic lymphohistiocytosis

Major Groups of Histiocytic Lesions

Blood 127: 2672, 2016

L GroupLangerhans cell histiocytosisIndeterminate cell tumorErdheim-Chester disease

S100

Normal Langerhans cells

Langerhans Cell Histiocytosis“Old” Terminology

Eosinophilic granulomaSingle lesion of bone, LN, or skin

Hand-Schuller-Christian diseaseLytic lesions of skull, exopthalmos, and

diabetes insipidus

Letterer-Siwe diseaseWidespread visceral disease involving liver,

spleen, bone marrow, and other sites

Histiocytosis XTerm suggested by S. Farber and proposed by

L. Lichtenstein in 1953 Louis Lichtenstein1906-1977

Sidney Farber1903-1973

Langerhans Cell HistiocytosisIncidence and Disease Distribution

Incidence

Children: 5-9 x 106

Adults: 1 x 106

Sites of Disease

Bones 80%Skin 30%Pituitary gland 25%Liver 15%Spleen 15%Bone Marrow 15%Lymph nodes 10%CNS <5%

Poor Prognosis

LiverSpleen

Bone marrow

High-risk organs

Blood 127: 2672, 2016N Engl J Med 379: 856, 2018

Langerhans Cell HistiocytosisSolitary lesion of bone

CD1a

Eosinophilic Granuloma

Langerhans Cell HistiocytosisLymph Nodes

CD1a

LNs can be localized or a part of disseminated disease

This patient had generalized LNsand BRAF V600E mutation

Arch Pathol Lab Med 107: 59, 1983

Langerhans Cell HistiocytosisMorphologic 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

Langerhans Cell HistiocytosisImmunophenotype

Immunophenotype

S100+, CD1a+, CD207/langerin+

Cyclin D1 is usually +

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

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

Langerhans Cell HistiocytosisBirbeck Granules

Michael S. C. Birbeck, PhD1925-2005

Also known as 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

J Invest Dermatol 37: 51, 1961CR Acad Sci (Paris) 261:5719, 1965

Francoise Basset, PhD

Blood 124: 1655, 2014

Blood 116: 1919, 2010

Langerhans Cell HistiocytosisMutations in BRAF/MAP2K1 Are Common

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

Blood 128: 2533, 2016

85% of LCH cases have genetic abnormalities of the MAPK pathway

They likely all do

PD

GFR

VEG

FR

RTK

EGFR

Cytoplasm

Extracellular

RAS Proteins

GTP-binding proteins:HRAS, KRAS and NRAS

ARAF BRAF CRAF

MEK1/2

ERK 1/2

Nucleus Regulation of proliferation, apoptosis, metabolism and immune response

Encoded by MAP2K1 gene

p90RskTranscription

factors

P

P

Mitogen activated protein kinase (MAPK) / Extracellular signal regulated kinase (ERK) pathway

Langerhans Cell HistiocytosisMisguided 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

Arch Pathol Lab Med 107: 59, 1983

“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.”

Br J Hematol 169: 3-13,2015

Langerhans Cell HistiocytosisLungs

CD207BRAF V600E

Associated with smoking

Langerhans Cell HistiocytosisDifferential Diagnosis

Indeterminate dendritic cell tumor

Langerhans cell sarcoma

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

CD207A negative langerin/CD207 is required to make this diagnosis

Langerhans Cell Sarcoma

History Rarely preceded by typical LCH (in my experience)

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

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

GeneticsRare cases with monoclonal IGH rearrangements

Prognosis ~50% mortality as a result of progressive disease

DefinitionA high-grade neoplasm with overt malignant cytologic features and Langerhans cell phenotype

Langerhans Cell Sarcoma

CD207

Erdheim-Chester DiseaseDefinition

Jacob Erdheim, MD William Chester, MD

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

J. Erdheim was mentor

Renamed Erdheim-Chester disease in 1972

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

2017 WHO book p. 481

Erdheim-Chester DiseaseClinicopathologic Features

Age and Sex RatioMedian 53 years (range, 20-74)Sex ratio: 3 to 1 male predominance

SymptomsCan be asymptomatic or aggressive; related to sitesDull and deep bone pain common (especially knees)

Histologic featuresBland histiocytes infiltrate tissues

Foamy or eosinophilic cytoplasm; Touton giant cellsFibrosis is common; +/- lymphocytes, plasma cells, eosNo mitoses, necrosis, granulomas, emperipolesis

ImagingBilateral, symmetric cortical osteosclerosis of long bonesSurrounds aorta (“coated”) or kidney (“hairy kidney”)

GeneticsBRAF V600E mutations in ~50%, ~4% NRAS, ~10% PI3KA

Blood Advances 1:357, 2017

Erdheim-Chester Disease

CD68 CD1a

PositiveCD14CD68CD163FascinFactor XIIIa

NegativeCD1aCD207

Erdheim-Chester DiseaseRadiologic Images

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

Case courtesy of Dr Andrew LawsonRadiopaedia.org, rID: 29803

Blood 124:1119, 2014

23 patients with both LCH and ECD

BRAF V600E in 11/16 (69%) LCH and 9/11 (82%) ECD

LCH ECD

C Group

Many different lesions

Can subdivide into 2 broad groupsXanthogranulomaNon-xanthogranuloma

Juvenile Xanthogranuloma

Affects children >> adults

Rare: < 1% of all pediatric tumors

Single, few, or multiple lesions on skin: yellow papules 0.5-1 cmOften regress spontaneously

Long bones are not involved

Rarely patients have visceral involvement or disseminated diseaseCan cause symptoms or death due to local invasion

GeneticsLocalized

CGH: chromosomal abnormalities uncommon (~5%)

Disseminated CGH: nonspecific chromosomal abnormalities described

BRAF V600E and MAPK1 mutations reported (few cases) (Oncotarget 8: 46065, 2017; Hum Pathol 69: 118, 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

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

LCH = Langerhans cell histiocytosisJXG = Juvenile xanthogranulomaECD = Erdheim-Chester disease

M GroupHistiocytic 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 SarcomaDefinition and Clinicopathologic Features

DefinitionA malignant proliferation of cells with morphologic and immunophenotypic features of mature tissue histiocytes

EpidemiologyMedian age = 52 y; males = femalesSubset associated with B-cell lymphoma (transdifferentiation) Rare pts with mediastinal germ cell tumor and isochromosome 12p

PresentationOften extranodal (GI tract, skin, soft tissues) Can be nodal or disseminated (“malignant histiocytosis”)

GeneticsSubset of cases with monoclonal Ig rearrangements

OutcomeClinically aggressive; poor response to therapy60-80% of patients die of disease

2017 WHO book p. 468-470

Transdifferentiation

Stoecker and Wang. Arch Pathol Lab Med 137: 865, 2013

Histiocytic SarcomaCD11c

CD163

Histiocytic SarcomaImmunophenotype

Positive VimentinS100 (weak or focal), Ki-67 10-20%ZBTZ46 (Mod Pathol 31:1479, 2018)

Variably PositiveFascin

Weakly and variably positiveCD45/LCA, CD68, lysozyme

NegativeCD1a, CD207/langerin

CD21, CD23, CD35, clusterin

CD34, myeloperoxidase

EMA, keratins, melanoma-associated antigens

B-cell and T-cell antigens 2017 WHO book p. 475

Mod Pathol 2019 (Epub)

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

Interdigitating Dendritic Cell Sarcoma

S100

CD163

Interdigitating Dendritic Cell SarcomaDefinition and Clinicopathologic Features

DefinitionA neoplastic proliferation of spindle to ovoid cells with phenotypic features similar to those of interdigitating dendritic cells

EpidemiologyRare Usually adults; males > females

PresentationSolitary lymph node involvement most commonCan be extranodal or widely disseminated

GeneticsSubset of cases with monoclonal IGH rearrangementsRare cases reported with BRAF V600E mutation

OutcomeClinically aggressive50% of patients die of disease

2017 WHO book p. 476

Interdigitating Dendritic Cell SarcomaImmunophenotype

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

Variably PositiveFascin

Weakly and variably positiveCD45/LCA, CD68, lysozyme

NegativeCD1a, CD207/langerin

CD21, CD23, CD35, clusterin

CD34, myeloperoxidase

EMA, keratins, melanoma-associated antigens

B-cell and T-cell antigens

2017 WHO book p. 476

BH Durham, Sem Cell Dev Biol 86: 62, 2019

Cell of Origin/Lineage of HistiocytesFDCs Are Different – Arise from MSC

MSC = mesenchymal stem cell

Follicular Dendritic Cell SarcomaDefinition and Clinicopathologic Features

DefinitionA neoplasm with morphologic and immunophenotypic features of follicular dendritic cells

EpidemiologyUsually adults; males = femalesSmall subset arises in hyaline-vascular Castleman disease

PresentationExtranodal 58%, Nodal 31%, both 11%

GeneticsSubset of cases with monoclonal IGH rearrangementsComplex karyotypeMutations in genes that regulate NF-kB pathway0-20% of cases reported with BRAF V600E mutation

OutcomeNeed 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 SarcomaImmunophenotype and Electron Microscopy

Positive (often variable/focal)VimentinCD21, CD23, CD35 CXCL13, clusterin, D2-40, EGFR, fascinKi-67: 5-25%

Weakly and variably positiveCD68, EMA, S100 (focal), HLA-DR

NegativeCD1a, 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 SarcomaSpindled

CD35

Follicular Dendritic Cell SarcomaEpithelioid

CD21

R Group

Rosai-Dorfman disease

Rosai-Dorfman DiseaseHistory

Juan Rosai, MD Ronald F. Dorfman, MD

Described in detail by Rosai and Dorfman in 1969

Designated as sinus histiocytosis with massive lymphadenopathyArch Pathol Lab Med 87: 63, 1969

First described in French in 1965 by Destombes

Reported as adenitis with lipid excessBull Soc Pathol Exot Filiales 58: 1169, 1965

Pierre-Paul Destombes, MD

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

Rosai-Dorfman Disease A Case Report

Richard J. Reed, MD

Rosai-Dorfman DiseaseClinicopathologic 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 DiseaseBilateral Cervical Lymphadenopathy is Common

Rosai-Dorfman DiseaseLymph Node

Emperipolesis (greek)Em = insidePeri =aroundPolesis = going about

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,

GI tract, thyroid, heart

Each < 2%

Extranodal Sites Involved by RDD

E. Foucar et al. Semin Diagn Pathol 7:19, 1990

Rosai-Dorfman DiseaseSoft Tissue

S-100

Emperipolesis is less in RDD at extranodal sites

Rosai-Dorfman DiseaseImmunophenotype

S100

Positive

S100 protein

CD68

CD163

Fascin

HLA-DR

Negative

CD1a

CD207/langerin

CD3, CD20

Beware

IgG4 plasma cells can be numerous in RDD

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

7/21 (33%) cases with KRASor MAP2K1 mutation

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 ageMultifocal disease

No correlation with outcome

Sofia Garces, MD

N Engl J Med 377: 2398, 2017

Before After

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-malignantInfectionAutoimmune diseaseFollowing organ transplantationIatrogenic immune suppression Cancer 123:3229, 2017

Hemophagocytic lymphohistiocytosisPrimary

Epidemiology

Most patients are young childrenIncidence 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

Mendelian inheritance for many of these genes

Survival

Median = 2 months without treatment

Therapy

Etoposide, dexamethasone, and intrathecal methotrexateAllogeneic stem cell transplantation

Hemophagocytic lymphohistiocytosisSecondary

Epidemiology

Most patients are adultsMalignant neoplasms are usually hematologic

Lymphomas, acute leukemias, MDS, T/NK-cell neoplasms

InfectionEBV, CMV, bacteria, fungi, protozoa

Autoimmune (AKA macrophage activation syndrome)Systemic lupus erythematosus, juvenile RA, polymyositis

Organ TransplantationStem cell or solid organ

Mortality Rate

80%

Therapy

Treat the neoplasmSuppress immune activation

Hemophagocytic lymphohistiocytosisCriteria for Diagnosis

1. Fever2. Splenomegaly3. Cytopenias affecting >2 cell lineages 4. Elevated triglycerides and/or hypofibrinogenemia5. Hemophagocytosis in bone marrow, spleen, or lymph nodes6. Low or absent NK-cell activity7. Elevated serum ferritin8. High levels of soluble IL-2 receptor alpha

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

Pediatr Blood Cancer 48:124, 2007

One can establish a diagnosis of HLH without morphologic evidence

Hemophagocytic lymphohistiocytosisSecondary to EBV Infection

Patient with mantle cell lymphoma who died of HLH

EBER

LN

BM smear

Paul LangerhansCirca 1867

Paul Langerhans1847-1888

Paul and Margarethe Langerhans1885

Grave site on Madeira Island