Histiocytic Sarcoma
Roberto N. Miranda, MD
Key Facts
Terminology
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Malignant neoplasm composed of mature histiocytes
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Diagnosis based mainly on morphology and immunophenotype
Etiology/Pathogenesis
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Transdifferentiation in subset of cases
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B-cell lymphoma and HS are clonally related
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Suggests that B cells can switch phenotype to histiocytic lineage
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Clinical Issues
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HS often presents as painless solitary mass
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Clinical course can be indolent or aggressive
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Bone marrow involvement is unusual
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Must exclude acute monocytic leukemia/monocytic sarcoma
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Microscopic Pathology
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Diffuse pattern
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Large cells with abundant eosinophilic cytoplasm
Ancillary Tests
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Immunophenotype
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CD163(+), CD68 (KP1 and PGM1)(+), and lysozyme(+)
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CD45(+), CD45RO(+), and HLA-DR(+)
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CD4(+/-), CD15(+/-)
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Ki-67(+): 5-50% (median: 15%)
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Top Differential Diagnoses
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Monocytic/myeloid sarcoma
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Langerhans cell histiocytosis/sarcoma
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Malignant histiocytic tumor, unclassified
TERMINOLOGY
Abbreviations
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Histiocytic sarcoma (HS)
Synonyms
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True histiocytic lymphoma
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Extramedullary monocytic tumor
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Malignant histiocytosis is historical term
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Not a true synonym as this term encompassed a number of entities
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Definitions
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Malignant neoplasm composed of mature histiocytes
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Diagnosis mainly based on morphology and immunophenotype
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Tumor cells are positive for histiocyte-associated markers, such as CD68, CD163, and lysozyme
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Tumor cells are negative or show minor reactivity for dendritic or follicular dendritic cell markers
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Monocytic/histiocytic neoplasms associated with acute myeloid leukemia, myeloproliferative neoplasms, or myelodysplastic syndromes are excluded
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Better considered as monocytic sarcoma
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ETIOLOGY/PATHOGENESIS
Postulated Normal Cell Counterpart
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Phagocytic histiocyte or macrophage derived from bone marrow monocytes
Etiology
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Unknown
Pathogenesis
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Histiocytic and monocytic tumors are closely related
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Some cases arise as 2nd malignancy after chemotherapy
Concept of “Transdifferentiation”
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Patient has both lymphoid and histiocytic tumors that are clonally related
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In most patients, histiocytic tumors follow or are synchronous with lymphoid neoplasms
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Rare histiocytic tumors precede lymphoid neoplasms
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This occurrence suggests that mature lymphoid cells can switch phenotypes to histiocytic lineage
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Process may require initial de-differentiation &/or subsequent re-differentiation
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Examples in literature include
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HS and follicular lymphoma
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HS and splenic marginal zone lymphoma
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HS and B-lymphoblastic leukemia/lymphoma
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Interdigitating dendritic cell sarcoma (IDCS) and follicular lymphoma
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IDCS and chronic lymphocytic leukemia/small lymphocytic lymphoma
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Histiocytic neoplasms associated with follicular lymphoma share
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t(14;18)(q32;q21)/IgH-BCL2 and IgH rearrangements
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Suggests common clonal origin of follicular lymphoma and histiocytic neoplasms
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Supports that lymphoid neoplasms can transform into histiocytic neoplasms
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An example of lineage plasticity
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This concept also may encompass subset of sporadic histiocytic or dendritic cell sarcomas that
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Bear monotypic IgH gene rearrangements
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Show IgH/BCL2 translocation also identified in histiocytes
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Express B-cell transcription factor Oct-2 but are negative for CD20, CD79a, and PAX-5
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Possible mechanisms explaining monoclonal IgH gene rearrangements in HS
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Lineage infidelity of primitive cells, supported by association with germ cell tumors
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Dual genotype of histiocytes, which rearrange B- or T-cell antigen receptor genes
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Artifactual detection of pseudoclones by polymerase chain reaction (PCR)
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False-positive clonal rearrangements detected when there are too few lymphocytes for analysis
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Duplicate testing tends to eliminate this artifact
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True small clonal response by nonneoplastic lymphocytes to presence of tumor
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Analysis of microdissected histiocytes may help define origin of clonal gene rearrangements
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There is experimental evidence that immature or committed B cells can give rise to
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Macrophages, natural killer cells, and T cells
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CLINICAL ISSUES
Epidemiology
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Incidence
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HS is rare, with only a few cases reported
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Most cases of “malignant histiocytosis” were described before immunohistochemical or molecular studies
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Most of these cases are now recognized as other neoplasms
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Most are diffuse large B-cell lymphoma and anaplastic large cell lymphoma
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Cases diagnosed as “histiocytic lymphoma” in Rappaport classification are, in fact, large cell lymphoma
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Age
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Wide age range: 1-89 years
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Median age: 51 years
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Most cases occur in adults
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Gender
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Male to female ratio is 1.2 to 1
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Site
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Most cases arise in extranodal sites
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Most common: Gastrointestinal tract, soft tissue, skin, spleen, and liver
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Lymphadenopathy is less common
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Presentation
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Usually presents as painless solitary mass
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Lesions usually present for < 1 year
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Most patients have stage I disease
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Systemic symptoms, such as fever and weight loss, in subset of cases
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Soft tissue masses may reach up to 12 cm in diameter
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Skin manifestations are variable
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Rash is common
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Solitary or numerous lesions
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Intestinal involvement may lead to abdominal pain, obstruction, or hematochezia
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Bone marrow (BM) involvement is rare
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Association with diffuse BM involvement is better considered as acute monocytic leukemia
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Subset of cases with patchy BM involvement are considered as HS
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Laboratory Tests
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There are no diagnostic studies available
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Pancytopenia or 1 or more cytopenias in some patients
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Natural History
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Clinical course can be indolent or aggressive
Treatment
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Patients reported have not been uniformly treated
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Surgical excision with wide margins was attempted when feasible
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Combined chemotherapy and radiation therapy in subset of patients
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Chemotherapy regimens used have been variable
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CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone)
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Regimens designed to treat acute leukemia
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Prognosis
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HS is often aggressive with poor response to therapy
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60-80% of patients may die of progressive disease
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Worst prognosis in patients with high-stage disease
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Patients with clinically localized disease and small primary tumors have more favorable long-term outcome
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Recurrences in subset of these patients (˜ 20%)
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MACROSCOPIC FEATURES
General Features
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Solitary mass is most common
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Infiltrative margins
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Median size: 7 cm (range: 1.8-12 cm)
MICROSCOPIC PATHOLOGY
Histologic Features
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Focal or diffuse effacement of nodal or extranodal architecture
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Focal nodal involvement is often paracortical
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Sinusoidal distribution can occur but is uncommon
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Soft tissue involvement displays infiltrative borders
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Necrosis is frequent, and its extent is variable
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Neoplastic cells are large, noncohesive, and round to oval
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Cells are usually > 20 µm in largest dimension
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Abundant cytoplasm, usually eosinophilic
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Spindle cells can be present focally
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Hemophagocytosis by neoplastic cells can be present
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Cytoplasmic vacuoles or xanthomatous appearance can be noted in some cases
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Emperipolesis can be present focally
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Mitotic figures are conspicuous but variable in number
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Nuclei are large; central or eccentric location
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Round to oval, or frequently with irregular folds and pleomorphic
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Chromatin is fine, and nucleoli may be prominent
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Few giant multinucleated cells are common
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Usually prominent inflammatory background
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Small lymphocytes, plasma cells, neutrophils, eosinophils, and benign histiocytes
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When neutrophils are abundant, tumor can mimic inflammatory lesion
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HS of central nervous system is notorious for heavy neutrophilic infiltrate
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ANCILLARY TESTS
Immunohistochemistry
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1 or more histiocytic or histiocyte-associated markers are positive
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CD163(+), CD68 (KP1 and PGM1)(+), and lysozyme
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CD68 and lysozyme: Cytoplasmic &/or Golgi/paranuclear pattern of staining
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CD163: Membranous and cytoplasmic
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Usually (> 90%) CD45(+), CD45RO(+), and HLA-DR(+)
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CD4(+/-), CD15(+/- and dim)
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S100(+/-): When positive, S100 is expressed in < 25% of neoplastic cells
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Ki-67(+): 5-50% (median: 15%)
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α-1-antitrypsin(+/-), α-1-antichymotrypsin(+/-)
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Less sensitive and less specific; not widely used
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CD1a(-), langerin/CD207(-)
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Follicular dendritic cell markers(-)
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CD21, CD23, CD35, and CNA.42
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CD13(-), CD33(-), myeloperoxidase(-)
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Pan-T-cell antigens(-)
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B-cell markers(-)
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Melanoma and carcinoma markers(-)
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Flow Cytometry
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Commonly positive
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CD4, CD11c, CD45, CD45RO, CD68, CD163, and HLA-DR
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Subset of cases positive
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CD11b, CD13, CD15, CDw32, CD36, CD43, Mac387, and factor XIIIa
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Cytogenetics
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No characteristic findings
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Isochromosome 12p in cases associated with germ cell tumors
Molecular Genetics
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Usually negative for monoclonal T- and B-cell antigen receptor gene rearrangements
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Variable proportion of cases show monoclonal IgH gene rearrangements by PCR
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Histologic and immunophenotypic features are those of usual HS
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Similar gene rearrangements or translocations can occur in HS and preceding B-cell lymphoma
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Postulated to represent examples of “transdifferentiation”
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Electron Microscopy
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Cells show ample cytoplasm containing variable amounts of lysosomes and phagosomes
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Negative for Birbeck granules, desmosomes, or cellular junctions
Enzyme Cytochemistry
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Histiocytes are strongly positive for butyrate (nonspecific) esterase
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Acid phosphatase(+/-)
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Chloroacetate esterase(-)
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Myeloperoxidase is usually negative, but it can be weakly positive in subset of cases
DIFFERENTIAL DIAGNOSIS
Monocytic/Myeloid Sarcoma
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Neoplasm composed of monocytes
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Usually associated with acute myeloid leukemia, myeloproliferative neoplasm, or myelodysplastic syndrome
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Monocytic or myelomonocytic cell predominant represents approximately 40% of myeloid sarcomas
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Small subset of these tumors is composed of large histiocytic rather than monocytic cells
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Commonly affected sites include lymph nodes, gastrointestinal tract, skin, and soft tissues
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Histology and immunophenotype similar to HS
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Less pleomorphic than HS
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Ki-67 usually > 50%
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Myeloperoxidase positive in subset of cases
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Myelomonocytic marker MNDA(+) favors monocytic rather than histiocytic phenotype
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Variably CD56(+)
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Langerhans Cell Histiocytosis/Sarcoma
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Cytologically bland cells with grooved or twisted nuclei
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Pleomorphic cells in rare cases of Langerhans cell sarcoma
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Eosinophils are commonly present
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Immunophenotype
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S100 protein(+), CD1a(+), and langerin/CD207(+)
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Birbeck granules present by electron microscopy
Malignant Histiocytic Tumor, Unclassified
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Malignant neoplasms with morphologic and ultrastructural features of HS
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