Histiocytic Sarcoma

Histiocytic Sarcoma
Roberto N. Miranda, MD
CT of neck shows a 10 cm histiocytic sarcoma of soft tissue image, displaying extensive necrosis image. Calcified thyroid cartilage image is noted as a reference. (Courtesy P. Bhosale, MD.)
Histiocytic sarcoma. Low magnification shows diffuse effacement of the nodal architecture.
TERMINOLOGY
Abbreviations
  • Histiocytic sarcoma (HS)
Synonyms
  • True histiocytic lymphoma
  • Extramedullary monocytic tumor
  • Malignant histiocytosis is historical term
    • Not a true synonym as this term encompassed a number of entities
Definitions
  • Malignant neoplasm composed of mature histiocytes
    • Diagnosis mainly based on morphology and immunophenotype
      • Tumor cells are positive for histiocyte-associated markers, such as CD68, CD163, and lysozyme
      • Tumor cells are negative or show minor reactivity for dendritic or follicular dendritic cell markers
  • Monocytic/histiocytic neoplasms associated with acute myeloid leukemia, myeloproliferative neoplasms, or myelodysplastic syndromes are excluded
    • Better considered as monocytic sarcoma
ETIOLOGY/PATHOGENESIS
Postulated Normal Cell Counterpart
  • Phagocytic histiocyte or macrophage derived from bone marrow monocytes
Etiology
  • Unknown
Pathogenesis
  • Histiocytic and monocytic tumors are closely related
  • Some cases arise as 2nd malignancy after chemotherapy
Concept of “Transdifferentiation”
  • Patient has both lymphoid and histiocytic tumors that are clonally related
    • In most patients, histiocytic tumors follow or are synchronous with lymphoid neoplasms
      • Rare histiocytic tumors precede lymphoid neoplasms
    • This occurrence suggests that mature lymphoid cells can switch phenotypes to histiocytic lineage
      • Process may require initial de-differentiation &/or subsequent re-differentiation
  • Examples in literature include
    • HS and follicular lymphoma
    • HS and splenic marginal zone lymphoma
    • HS and B-lymphoblastic leukemia/lymphoma
    • Interdigitating dendritic cell sarcoma (IDCS) and follicular lymphoma
    • IDCS and chronic lymphocytic leukemia/small lymphocytic lymphoma
  • Histiocytic neoplasms associated with follicular lymphoma share
    • t(14;18)(q32;q21)/IgH-BCL2 and IgH rearrangements
    • Suggests common clonal origin of follicular lymphoma and histiocytic neoplasms
    • Supports that lymphoid neoplasms can transform into histiocytic neoplasms
      • An example of lineage plasticity
    • This concept also may encompass subset of sporadic histiocytic or dendritic cell sarcomas that
      • Bear monotypic IgH gene rearrangements
      • Show IgH/BCL2 translocation also identified in histiocytes
      • Express B-cell transcription factor Oct-2 but are negative for CD20, CD79a, and PAX-5
  • Possible mechanisms explaining monoclonal IgH gene rearrangements in HS
    • Lineage infidelity of primitive cells, supported by association with germ cell tumors
    • Dual genotype of histiocytes, which rearrange B- or T-cell antigen receptor genes
    • Artifactual detection of pseudoclones by polymerase chain reaction (PCR)
      • False-positive clonal rearrangements detected when there are too few lymphocytes for analysis
      • Duplicate testing tends to eliminate this artifact
    • True small clonal response by nonneoplastic lymphocytes to presence of tumor
    • Analysis of microdissected histiocytes may help define origin of clonal gene rearrangements
    • There is experimental evidence that immature or committed B cells can give rise to
      • Macrophages, natural killer cells, and T cells
CLINICAL ISSUES
Epidemiology
  • Incidence
    • HS is rare, with only a few cases reported
    • Most cases of “malignant histiocytosis” were described before immunohistochemical or molecular studies
      • Most of these cases are now recognized as other neoplasms
      • Most are diffuse large B-cell lymphoma and anaplastic large cell lymphoma
    • Cases diagnosed as “histiocytic lymphoma” in Rappaport classification are, in fact, large cell lymphoma
  • Age
    • Wide age range: 1-89 years
      • Median age: 51 years
      • Most cases occur in adults
  • Gender
    • Male to female ratio is 1.2 to 1
Site
  • Most cases arise in extranodal sites
    • Most common: Gastrointestinal tract, soft tissue, skin, spleen, and liver
    • Lymphadenopathy is less common
Presentation
  • Usually presents as painless solitary mass
    • Lesions usually present for < 1 year
    • Most patients have stage I disease
  • Systemic symptoms, such as fever and weight loss, in subset of cases
  • Soft tissue masses may reach up to 12 cm in diameter
  • Skin manifestations are variable
    • Rash is common
    • Solitary or numerous lesions
  • Intestinal involvement may lead to abdominal pain, obstruction, or hematochezia
  • Bone marrow (BM) involvement is rare
    • Association with diffuse BM involvement is better considered as acute monocytic leukemia
      • Subset of cases with patchy BM involvement are considered as HS
Laboratory Tests
  • There are no diagnostic studies available
    • Pancytopenia or 1 or more cytopenias in some patients
Natural History
  • Clinical course can be indolent or aggressive
Treatment
  • Patients reported have not been uniformly treated
  • Surgical excision with wide margins was attempted when feasible
  • Combined chemotherapy and radiation therapy in subset of patients
    • Chemotherapy regimens used have been variable
      • CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone)
      • Regimens designed to treat acute leukemia
Prognosis
  • HS is often aggressive with poor response to therapy
  • 60-80% of patients may die of progressive disease
    • Worst prognosis in patients with high-stage disease
  • Patients with clinically localized disease and small primary tumors have more favorable long-term outcome
    • Recurrences in subset of these patients (˜ 20%)
MACROSCOPIC FEATURES
General Features
  • Solitary mass is most common
  • Infiltrative margins
  • Median size: 7 cm (range: 1.8-12 cm)
MICROSCOPIC PATHOLOGY
Histologic Features
  • Focal or diffuse effacement of nodal or extranodal architecture
    • Focal nodal involvement is often paracortical
    • Sinusoidal distribution can occur but is uncommon
  • Soft tissue involvement displays infiltrative borders
    • Necrosis is frequent, and its extent is variable
  • Neoplastic cells are large, noncohesive, and round to oval
    • Cells are usually > 20 µm in largest dimension
      • Abundant cytoplasm, usually eosinophilic
    • Spindle cells can be present focally
    • Hemophagocytosis by neoplastic cells can be present
    • Cytoplasmic vacuoles or xanthomatous appearance can be noted in some cases
    • Emperipolesis can be present focally
  • Mitotic figures are conspicuous but variable in number
  • Nuclei are large; central or eccentric location
    • Round to oval, or frequently with irregular folds and pleomorphic
    • Chromatin is fine, and nucleoli may be prominent
    • Few giant multinucleated cells are common
  • Usually prominent inflammatory background
    • Small lymphocytes, plasma cells, neutrophils, eosinophils, and benign histiocytes
      • When neutrophils are abundant, tumor can mimic inflammatory lesion
      • HS of central nervous system is notorious for heavy neutrophilic infiltrate
ANCILLARY TESTS
Immunohistochemistry
  • 1 or more histiocytic or histiocyte-associated markers are positive
    • CD163(+), CD68 (KP1 and PGM1)(+), and lysozyme
      • CD68 and lysozyme: Cytoplasmic &/or Golgi/paranuclear pattern of staining
      • CD163: Membranous and cytoplasmic
    • Usually (> 90%) CD45(+), CD45RO(+), and HLA-DR(+)
    • CD4(+/-), CD15(+/- and dim)
    • S100(+/-): When positive, S100 is expressed in < 25% of neoplastic cells
    • Ki-67(+): 5-50% (median: 15%)
    • α-1-antitrypsin(+/-), α-1-antichymotrypsin(+/-)
      • Less sensitive and less specific; not widely used
    • CD1a(-), langerin/CD207(-)
    • Follicular dendritic cell markers(-)
      • CD21, CD23, CD35, and CNA.42
    • CD13(-), CD33(-), myeloperoxidase(-)
    • Pan-T-cell antigens(-)
    • B-cell markers(-)
    • Melanoma and carcinoma markers(-)
Flow Cytometry
  • Commonly positive
    • CD4, CD11c, CD45, CD45RO, CD68, CD163, and HLA-DR
  • Subset of cases positive
    • CD11b, CD13, CD15, CDw32, CD36, CD43, Mac387, and factor XIIIa
Cytogenetics
  • No characteristic findings
  • Isochromosome 12p in cases associated with germ cell tumors
Molecular Genetics
  • Usually negative for monoclonal T- and B-cell antigen receptor gene rearrangements
  • Variable proportion of cases show monoclonal IgH gene rearrangements by PCR
    • Histologic and immunophenotypic features are those of usual HS
    • Similar gene rearrangements or translocations can occur in HS and preceding B-cell lymphoma
    • Postulated to represent examples of “transdifferentiation”
Electron Microscopy
  • Cells show ample cytoplasm containing variable amounts of lysosomes and phagosomes
  • Negative for Birbeck granules, desmosomes, or cellular junctions
Enzyme Cytochemistry
  • Histiocytes are strongly positive for butyrate (nonspecific) esterase
  • Acid phosphatase(+/-)
  • Chloroacetate esterase(-)
  • Myeloperoxidase is usually negative, but it can be weakly positive in subset of cases
DIFFERENTIAL DIAGNOSIS
Monocytic/Myeloid Sarcoma
  • Neoplasm composed of monocytes
    • Usually associated with acute myeloid leukemia, myeloproliferative neoplasm, or myelodysplastic syndrome
    • Monocytic or myelomonocytic cell predominant represents approximately 40% of myeloid sarcomas
  • Small subset of these tumors is composed of large histiocytic rather than monocytic cells
    • Some authorities acknowledge 2 subsets of cases with histiocytic cytology
      • HS: Neoplastic cells replace BM in patchy fashion and represent < 25% of cellularity
      • Acute monocytic leukemia: Neoplastic cells diffusely replace BM and represent ≥ 25% of cellularity
  • Commonly affected sites include lymph nodes, gastrointestinal tract, skin, and soft tissues
  • Histology and immunophenotype similar to HS
    • Less pleomorphic than HS
    • Ki-67 usually > 50%
    • Myeloperoxidase positive in subset of cases
    • Myelomonocytic marker MNDA(+) favors monocytic rather than histiocytic phenotype
    • Variably CD56(+)
Langerhans Cell Histiocytosis/Sarcoma
  • Cytologically bland cells with grooved or twisted nuclei
    • Pleomorphic cells in rare cases of Langerhans cell sarcoma
  • Eosinophils are commonly present
  • Immunophenotype
    • S100 protein(+), CD1a(+), and langerin/CD207(+)
  • Birbeck granules present by electron microscopy
Jul 8, 2016 | Posted by in PATHOLOGY & LABORATORY MEDICINE | Comments Off on Histiocytic Sarcoma

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