Histiocytic Sarcoma



Histiocytic Sarcoma


Roberto N. Miranda, MD





Key Facts


Terminology



  • Malignant neoplasm composed of mature histiocytes


  • Diagnosis based mainly on morphology and immunophenotype


Etiology/Pathogenesis



  • Transdifferentiation in subset of cases



    • B-cell lymphoma and HS are clonally related


    • Suggests that B cells can switch phenotype to histiocytic lineage


Clinical Issues



  • HS often presents as painless solitary mass


  • Clinical course can be indolent or aggressive


  • Bone marrow involvement is unusual



    • Must exclude acute monocytic leukemia/monocytic sarcoma


Microscopic Pathology



  • Diffuse pattern


  • Large cells with abundant eosinophilic cytoplasm


Ancillary Tests



  • Immunophenotype



    • CD163(+), CD68 (KP1 and PGM1)(+), and lysozyme(+)


    • CD45(+), CD45RO(+), and HLA-DR(+)


    • CD4(+/-), CD15(+/-)


    • Ki-67(+): 5-50% (median: 15%)


Top Differential Diagnoses



  • Monocytic/myeloid sarcoma


  • Langerhans cell histiocytosis/sarcoma


  • Malignant histiocytic tumor, unclassified







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

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Jul 8, 2016 | Posted by in PATHOLOGY & LABORATORY MEDICINE | Comments Off on Histiocytic Sarcoma

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