Chapter 10: Histiocytic and Dendritic Cell Neoplasms

· Definition

o Neoplasms derived from phagocytes and dendritic cells

o Neoplasms in WHO classification

§ Histiocytic sarcoma

§ Langerhans cell histiocytosis

§ Langerhans cell sarcoma

§ Interdigitating dendritic cell sarcoma/tumor

§ Follicular dendritic cell sarcoma/tumor

§ Dendritic cell sarcoma, not otherwise specified

· Incidence

o < 1% of tumors presenting in lymph nodes

o True histiocytic malignancy is a “vanishing diagnosis”

· Epidemiology

o Detailed data difficult to obtain because of disease rarity

o No significant geographical or racial differences in incidence

· Pathophysiology

o Normal cellular counterparts

§ Phagocytic cells (antigen-processing)

§ Dendritic cells (antigen-presenting)

§ Common cellular origin (BM stem cell), except perhaps follicular dendritic cells

§ Independent lines of differentiation

· Histiocytes/Macrophages

o Primary role: removal of particulate antigen

o Derived from the circulating blood monocyte pool

o Can demonstrate phagocytosis

§ Usually not a feature of histiocytic malignancies

§ More common in benign proliferations of histiocytes (hemophagocytic syndrome)

o Markers

§ CD68

§ Acid phosphatase

§ Nonspecific esterases

§ Most prominent in epithelioid histiocytes

· Lysozyme (decreases with increase in phagocytosis)

· Alpha-1-antitrypsin

o Less specific markers

§ Antibodies to cell surface receptors for the Fc portion of IgG:

· CD16, CD32, CD64

§ Complement receptors:

· CD21, CD35

§ Cellular activation and adhesion molecules:

· CD11a, CD11b, CD11c, CD14, CD18

· Langerhans Cells/Interdigitating Dendritic Cells

o Primary role: presenting antigens to T lymphocytes

o Langerhans cells (LC)

§ Birbeck granules

§ Found primarily in skin

§ Can migrate to PB (veiled cells)

§ Enter LNs via afferent lymphatics; reside in paracortex as interdigitating dendritic cells

o Langerhans cell immunophenotype

§ MHC Class II

§ S-100

§ CD1a

§ CD4

o Interdigitating dendritic cells

§ MHC Class II

§ S-100

· Follicular Dendritic Cells (FDC)

o Primary role: present antigens to B lymphocytes

o Most likely not of hematopoietic origin

o Found in follicles where they form a meshwork to trap antigens

o Contain iccosomes: antigen-antibody complexes in organelles

o Needed for B-cell activation

o Immunophenotype: CD21+, CD23+, CD35+

· Survival

o Histiocytic sarcoma and IDC sarcoma

§ Aggressive

§ Potential for systemic spread

o FDC tumors

§ Localized

§ Potential for local invasion and recurrence

§ Distant metastases are infrequent

o LC histiocytosis

§ Wide spectrum of clinical behavior; correlates with extent of organ system involvement and age of the patient

Hemophagocytic Syndrome (HPS)

· Recognized as a clinical syndrome by Scott and Robb-Smith (1939)

· Non-neoplastic, proliferative disorder of macrophages

· Important in DDX of histiocytic neoplasms

· More common than histiocytic neoplasms

· Immunodeficiency or other hematopoietic malignancies

· Fulminant clinical course (often fatal)

· Pathogenesis of HPS

o Infection with EBV (or another virus) is a frequent precipitating event

o Excessive production of cytokines and chemokines (“cytokine storm”)

o Profound and uncontrolled macrophage activation with marked phagocytosis

o Pancytopenia

Histiocytic Sarcoma

· Definition

o Malignant proliferation of cells showing morphologic and immunophenotypic features similar to those of mature tissue histiocytes

o Expression of one or more histiocytic markers (without dendritic cell markers)

o Exclusion of extramyeloid manifestations of acute monocytic leukemia

· Historical annotation: virtually all “diffuse histiocytic lymphoma” cases are now DLBCL. Most cases of “histiocytic medullary reticulosis” and “malignant histiocytosis” are now considered systemic ALCL or hemophagocytic syndrome

· Epidemiology

o Rare (only few series of bone fide neoplasms)

o Wide age range (median 46 years)

o Male predilection (in some studies)

o Subset of cases associated with prior mediastinal germ cell tumors

o Other cases associated with malignant lymphoma (preceding or subsequent), or with myelodysplasia

· Sites of Involvement

o 1/3: Lymph nodes

o 1/3: Skin, solitary or multiple lesions

o 1/3: Other extranodal sites (mostly GI)

o Some patients present with “malignant histiocytosis” (systemic, multiple sites of involvement)

· Clinical Features

o Systemic symptoms (fever and weight loss), even in patients with solitary mass

o Skin manifestations vary widely

§ Benign-appearing rash

§ Solitary lesions

§ Innumerable tumors on trunk and extremities

o GI lesions

§ Possible intestinal obstruction

o Hepatosplenomegaly (relatively common)

o Bone

§ Lytic lesions

o Bone marrow

§ Pancytopenia

· Etiology: unknown

· Morphology

o Effacement of architecture by a diffuse, non-cohesive proliferation of neoplastic cells

· Cells

o Usually polymorphic

o Large

o Round to oval (spindling focally)

o Cytoplasm

§ Abundant

§ Eosinophilic

§ May be foamy

o Nuclei

§ Large

§ Round to oval

§ Eccentric

o Large multinucleated cells (common)

o Vesicular chromatin

o Variable atypia

o Variable number of reactive cells

§ Small lymphocytes

§ Plasma cells

§ Benign histiocytes

§ Eosinophils

o May be indistinguishable from DLBCL or ALCL

o Markers necessary

· Immunophenotype

o By definition

§ Presence of histiocytic markers

· CD68

· Lysozyme (Golgi pattern)

· CD11c

· CD14

§ Absence of specific myeloid markers

· MPO

· CD33

· CD34

o Usually positive

§ CD45

§ CD45RO

§ HLA-DR

§ CD4

o S-100 may be positive (weak or focal)

o Ki67: variable (10-90%; mean 20%)

o Negative

§ B and T-cell markers

§ LC and IDC markers (CD1a, CD21, CD35)

§ CD30

§ HMB-45

§ EMA

§ CK

· Genetics

o By definition, no clonal immunoglobulin or TCR genes

· Postulated Cell of Origin

o Mature tissue histiocyte

· Prognosis

o Aggressive neoplasm

o Poor response to therapy

o High clinical stage (III/IV) at presentation (70%)

o 60% die of progressive disease

Langerhans Cell Histiocytosis (LCH)

· Definition

o Neoplastic proliferation of Langerhans cells

o CD1a+

o S-100+

o Birbeck granules on EM

· Synonyms

o Histiocytosis X (Lichtenstein, 1953)

o Langerhans cell granulomatosis

o Eosinophilic granuloma

o Hand-Schüller-Christian disease

o Letterer-Siwe disease

· Epidemiology

o ~5 per million

o Childhood

o Male:female ratio 3.7:1

o Common in Whites of Northern Europe descent

· Sites of Involvement

o Unifocal disease (solitary eosinophilic granuloma)

o Usually in bones (skull, femur, pelvis, ribs) and less often lymph nodes, skin, and lung

o Multifocal, unisystem disease (Hand-Schüller-Christian disease)

§ Several sites of involvement in one organ system, usually bone

o Multifocal, multisystem disease (Letterer-Siwe disease)

§ Multiple organ systems: bone, skin, liver, spleen, and LNs

· Clinical Features of Unifocal Disease

o Older children, adults

o Lytic bone lesions (diaphysis) with erosion into soft tissues

· Clinical Features of Multifocal, Unisystem Disease

o Young children

o Multiple destructive bone lesions, adjacent soft tissue masses

o Skull often involved with exophthalmos, diabetes insipidus, and tooth loss

· Clinical Features of Multifocal, Multisystem Disease

o Infants

o Fever, skin manifestations, hepatosplenomegaly, lymphadenopathy, bone lesions, pancytopenia

o LCH of the lung in adults generally presents as innumerable bilateral nodules, usually less than 2.0 cm in diameter