Aggressive sporadic histiocytic sarcoma with immunoglobulin heavy chain gene rearrangement and t(14;18)
Histiocytic sarcoma (HS) is a rare but aggressive malignant neoplasm of histiocytic lineage with a poor prognosis. Immunohistochemically, the neoplastic cells are positive for CD163, CD68, and lysozyme, and negative for B and T cell markers. However, molecular studies on the origin of the neoplastic cells remain inconclusive. A 54-year-old woman was admitted to our hospital because of painful swelling of the left knee. Examination revealed generalized lymphadenopathy and splenomegaly. HS was diagnosed according to morphologic and immunohistochemical features observed on biopsy of the left inguinal lymph node. The tumor demonstrated a clonal immunoglobulin heavy chain gene rearrangement and a clonal cytogenetic abnormality including t(14;18) which was confirmed by fluorescence in situ hybridization analysis showing the IgH/BCL2 fusion gene. The neoplastic cells were negative for PAX5, a B cell associated transcription factor, and positive for CEBPβ, a transcription factor mediating macrophage and myeloid differentiation. Positron emission tomography showed disseminated areas of increased 18F-fluorodeoxyglucose uptake in multiple lymph nodes, the liver, spleen, both lungs, both kidneys, and many bony sites. The patient received localized irradiation therapy followed by chemotherapy, she failed to respond and died of the disease progression. The case findings suggest lineage promiscuity or plasticity related to the pathogenesis of HS.
KeywordsHistiocytic sarcoma t(14;18) Immunoglobulin heavy chain gene rearrangement PAX5 CEBPβ
Histiocytic sarcoma (HS) is a rare neoplasm characterized by malignant proliferation of cells showing morphologic and immunophenotypic features of mature tissue histiocytes . It can affect infants to the elderly, but mainly occurs in adult men. HS has been documented to present in lymph nodes and extranodal sites such as the skin, gastrointestinal tract, soft tissue, and bone. Systemic symptoms such as fever and weight loss are relatively common. Patients often already have clinically advanced disease at presentation and usually experience an aggressive clinical course with poor response to therapy [1, 2]. The diagnosis of HS relies on morphology and the presence of immunophenotypic features of histiocytic lineage. Although clonal immunoglobulin heavy chain (IgH) gene rearrangements are not usually present in HS, they have recently been reported in some cases, with or without previous or concurrent B cell lymphoma [3, 4, 5]. Molecular studies remain inconclusive regarding the cellular origin. We report a case of aggressive sporadic HS with IgH rearrangement and t(14;18), suggesting lineage promiscuity or plasticity related to the pathogenesis.
2 Case report
Before confirmation of the HS diagnosis, palliative radiation therapy of 30 Gy was administered for 17 days to the left knee region because of severe pain. Aggravation of hepatosplenomegaly and lymphadenopathy with high fever occurred during the radiation therapy. We administered combination chemotherapy consisting of cyclophosphamide, adriamycin, vincristine, etoposide, and prednisolone but this failed to induce a response other than a temporary reduction of hepatosplenomegaly and lymphadenopathy. She developed pneumonia, liver dysfunction, and disseminated intravascular coagulation with rapid exacerbation of hepatosplenomegaly and lymphadenopathy, and she died from respiratory and liver failure shortly after completion of chemotherapy.
HS is a rare neoplasm with an etiology that remains unknown. Its diagnosis relies on morphology and the presence of immunophenotypic features of histiocytic lineage. Immunohistochemically, the neoplastic cells are positive for one or more histiocytic markers such as CD163, CD68, and lysozyme, and negative for markers of B and T cells as well as those of myeloid cells and epithelioid cells. In particular, CD163 is considered to be a specific histiocytic marker and significant in the diagnosis of HS [5, 6, 7]. The tumor usually lacks clonal IgH or T cell receptor (TCR) gene rearrangements . However, HS has been recently reported in patients with previous or concurrent B cell lymphoma/leukemias showing clonal IgH rearrangement [3, 4, 5, 8, 9, 10, 11, 12, 13]. Feldman et al. provided convincing evidence that patients with follicular lymphoma (FL) and subsequent or synchronous histiocytic/dendritic cell (H/DC) sarcoma shared genotypic identities, suggesting a possible mechanism of transdifferentiation from a mature lymphoid phenotype to an H/DC phenotype. Chen et al.  reported that nine of 23 patients with sporadic H/DC sarcoma showed clonal IgH rearrangements. Vos et al.  also reported that three of five patients with sporadic HS had clonal IgH rearrangements. On the basis of these reports, the diagnosis of HS no longer requires the absence of IgH rearrangement, irrespective of previous or concurrent B cell lymphoma.
A genetic hallmark of FL is t(14;18) involving an IgH/BCL2 fusion gene confirmed by FISH or polymerase chain reaction (PCR) analysis. This genetic event was usually detected in HS cases associated with FL. To our knowledge, it was detected in only two sporadic HS cases including the present case . Xie et al.  reported that enforced expression of CEBPα and β in differentiated B cells caused them to transdifferentiate to macrophages in vitro by inhibiting the B cell commitment transcription factor PAX5. Feldman et al. showed that all H/DC sarcomas lacked PAX5 and exhibited up-regulation of CEBPβ and PU.1. They postulated that changes in these transcription factors might have led to transdifferentiation from a mature lymphoid phenotype to an H/DC phenotype . Bassarova et al.  showed that transdifferentiation of B cell lymphoma to histiocytic sarcoma was associated with loss of expression of PAX5. Chen et al. noted that all sporadic H/DC sarcomas with clonal IgH rearrangements were negative for PAX5 and BOB.1, another B cell associated transcription factor . In the present case, the neoplastic cells were negative for PAX5 and positive for CEBPβ. Taken together with the previous findings, this suggests that the absence of PAX5 may be crucial in the pathogenesis of not only HS cases associated with B cell lymphoma but also sporadic cases with clonal IgH rearrangements. It was thought that the absence of PAX5 expression led to the absence of B cell markers such as CD20 and CD79a in all HS with IgH gene rearrangements. Transdifferentiation of FL to HS through changes in transcription factors such as loss of PAX5 expression may have occurred in the asymptomatic early stage of the disease in the present case, although we cannot completely eliminate the possibility of concurrent FL in other lesions. The diversity in the pathogenesis of HS also suggests lineage promiscuity or plasticity in the hematopoietic system [14, 15, 16, 17].
PET is a functional imaging modality widely used for evaluation of malignant neoplasms including malignant lymphoma. Although there are few reports of PET or PET-CT in HS [18, 19, 20], these techniques are very useful for evaluation of disease dissemination in HS because the tumor has FDG avidity and the majority of cases present with extranodal involvement.
Some cases of HS presenting with skin or clinically localized disease respond well to chemotherapy regimens similar to those used for treatment of malignant lymphoma and demonstrate a favorable long-term outcome [2, 21, 22]. However, most cases of HS have an aggressive clinical course, mainly because of widespread disease and poor response to therapy. Such cases require prompt diagnosis and initiation of treatment that combines more effective chemotherapy regimens including new anticancer drugs such as thalidomide , radiation therapy, and hematopoietic stem cell transplantation.
We would like to thank Dr. Shigeo Nakamura, Professor of Department of Pathology and Clinical Laboratories, Nagoya University School of Medicine, for the pathological diagnosis.
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