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

·        Etiology

o       Unknown

o       No convincing evidence for viruses

·        Morphology

o       Langerhans cells in appropriate milieu

o       Longitudinal nuclear grooves (twisted, whelk-shaped), inconspicuous nucleoli

o       Inflammatory background of histiocytes, eosinophils, neutrophils, and lymphocytes

o       Necrotic foci (eosinophilic abscesses), occasionally

o       Preferential involvement of the sinuses in lymph nodes, followed by paracortex

o       Red pulp in spleen

·        Grading

o       Degree of atypia does not correlate with outcome

·        Ultrastructure

o       Cytoplasmic birbeck granule

·        Tennis racket-shaped

·        200-400 nm in length; 33 nm in width

·        Can be absent in 25% of Langerhans cells

o       Lysosomes present

o       Cell junctions absent

·        Immunophenotype

o       CD1a+ and S-100+

o       Vimentin+ and CD4+

o       Placental alkaline phosphatase+ (only neoplastic LCs; normal LCs are negative)

o       Variable stain for CD45, CD68, and lysozyme

o       (CD34, CD30, MPO, and EMA negative)

o       Surface adhesion molecules different in neoplastic and non-neoplastic LCs

o       Ki-67 usually stains between 2% to 25% of the LCs with a mean of approximately 10%

·        Enzyme Cytochemistry

o       Positive for adenosine triphosphase, α-D-mannosidase, α-naphthyl acetate esterase, α-naphthyl butyrate esterase, and acid phosphatase

o       Negative for TRAP, peroxidase, 5'-nucleotidase, and β-glucuronidase, and chloroacetate esterase

·        Genetics

o       Monoclonal

o       IgH gene, and beta, gamma, and delta chain genes of the TCR are germline

·        Prognosis

o       Related to organs involved

o       Absence of bone lesions with multiorgan involvement is poor prognostic sign

o       Progression of unifocal to multisystem disease ~10%

o       Unifocal disease >95% survival

o       75% survival when 2 organs involved

o       Prompt response to therapy better prognosis

o       LCH of lung can regress after cessation of smoking


Langerhans Cell Sarcoma

·        Definition

o       Neoplastic proliferation of Langerhans cells

o       Overtly malignant cytologic features

o       Can present de novo or progress from antecedent LCH

·        Epidemiology

o       Rare

o       Adults and children (median age 41 years)

o       Female predominance (in contrast to LCH)

·        Sites of Involvement

o       Multiorgan involvement

o       Lymph nodes, liver, spleen, lung and bone

·        Morphology

o       Large malignant cells

o       Nuclei with occasional grooves, prominent nucleoli

o       Mitoses high (>50/10 HPF)

o       Rare eosinophils (prominent inflammatory infiltrate absent)

o       Sinusoidal pattern in lymph nodes

·        Ultrastructure

o       Birbeck granules can be identified

·        Immunophenotype

o       CD1a+ and S100+

o       CD1a may be focal

o       Some expression of CD68, CD45 and lysozyme

o       Ki-67 ranges from 10% to 60% with a median of 22%

·        Prognosis

o       Aggressive

o       Overall survival ~50%


Interdigitating Dendritic Cell Sarcoma/Tumor

·        Definition

o       Neoplastic proliferation of spindle to ovoid cells with phenotypic features of IDCs

o       Term tumor/sarcoma is used because of the variable cytological grade and clinical behavior encountered in these neoplasms

·        Synonyms

o       Reticulum cell sarcoma/tumor.

o       Interdigitating cell sarcoma/tumor.

·        Epidemiology

o       Extremely rare neoplasm

o       Most studies represent single cases or very small series

o       Largest series consisted of 4 cases

o       Mostly elderly adults with no sex predilection

·        Sites of Involvement

o       Wide presentation

o       Solitary LN (most common)

o       Skin, intestinal, soft tissue, and hepatosplenomegaly been reported

·        Clinical features

o       Usually asymptomatic mass

o       Systemic symptoms: fatigue, fever, night sweats

o       Complete remission after localized treatment

·        Etiology

o       Unknown

·        Morphology

o       Paracortical distribution with residual follicles

o       Usually forms fascicles, a storiform pattern, and whorls of spindled to ovoid cells

o       Usually abundant slightly eosinophilic cytoplasm, often indistinct border

o       Vesicular chromatin, small to large distinct

·        Immunophenotype

o       S-100 +

o       Negative for vimentin and CD1a

o       Variably, weakly + for CD68, lysozyme, and CD45

o       Negative for FDCs (CD21 and CD35), MPO, CD34, specific B and T-cell antigens, CD30, CK, EMA

·        Prognosis and predictive factors

o       Range from benign localized disease to widespread lethal disease



Follicular Dendritic Cell Sarcoma/Tumor

·        Definition

o       Neoplastic proliferation of spindle to ovoid cells showing morphologic and phenotypic features of follicular dendritic cells

o       Term sarcoma/tumor is used because of the variable cytologic grade and indeterminate clinical behavior in many cases

·        Synonyms

o       Reticulum cell sarcoma/tumor

o       Dendritic reticulum cell sarcoma/tumor.

·        Epidemiology

o       Rare neoplasm

o       Most studies are single case reports or small series

o       The largest series consisted of 13 and 17 cases

o       Wide age range, with an adult predominance

o       Equal sex distribution

o       Association with Castleman disease in 10-20% of the cases, usually hyaline vascular type

o       Castleman disease may precede the tumor occur simultaneously

o       May be an increased incidence in patients with treatment for longstanding schizophrenia

·        Sites of involvement

o       In LNs (between one-half to two-thirds of cases)

o       Cervical LNs most often affected

o       Also common LNs: maxillary, mediastinal, mesenteric and retroperitoneum

o       Extranodal sites: tonsil, spleen, oral cavity, GI tract, liver, soft tissue, skin, and breast

o       Common sties of metastasis: LNs, lung, and liver

·        Etiology

o       Unknown

·        Morphology

o       Spindle to ovoid cell proliferation

o       Forms fascicles, storiform patterns, and whorls

o       Uncommon, fluid-filled cystic spaces, some in perivascular location resembling thymoma, or amyloidal changes

o       Cells with plump slightly eosinophilic cytoplasm and indistinct cell borders

o       Nuclei elongated, with vesicular or granular finely dispersed chromatin, small but distinct nucleoli

o       Occasional multinucleated cells, occasionally resembling Warthin-Finkeldy giant cells

o       Pseudonuclear  inclusions may be seen

·        Immunophenotype

o       Generally demonstrate the phenotype of non-neoplastic FDCs

o       Positive for one or more of the FD markers, including CD21, CD35, and CD23

o       Usually positive for desmoplakin, vimentin, fascin, HLA-DR, and often positive for EMA

o       Variably positive for S-100 and CD63

o       CD45 and CD20 occasionally expressed

o       Negative for CD1a, lysozyme, MPO, CD34, CD3, CD79a, CD30, HMB-45, and CKs

o       Ki-67 range from 1% to 25 % with a mean value of 13%

·        Prognosis and predictive factors

o       Behavior typically indolent

o       Treatment with complete surgical excision, with or without adjuvant radiotherapy or chemotherapy

o       Local recurrences in about 40% to 50 % and metastasis in about 20% of pts often after local recurrence

o       Poorer prognosis: intra-abdominal presentation, significant cytologic atypia, extensive coagulative necrosis, high proliferation index, large tumor >6cm

o       10% to 20% pts die of disease, often after a long time



Dendritic Cell Sarcoma, Not Otherwise Specified

·        Definition

o       Occasional dendritic cell neoplasms do not fall into well-defined categories, as defined in the previous sections

o       Have been called indeterminate cell sarcoma/tumor

o       Extremely rare cases reported

o       Dx of exclusion, not well characterized morphologically and immunophenotypically

o       Tumors positive for CD1a and S-100 protein but without Birbeck granules have been called indeterminate neoplasms said to derive from a cell in transition between a Langerhans cell and an interdigitating dendritic cell

o       In a recent large series with multiple markers and EM no cases of this category were found