International Journal of Hematology

, Volume 92, Issue 4, pp 659–663 | Cite as

Aggressive sporadic histiocytic sarcoma with immunoglobulin heavy chain gene rearrangement and t(14;18)

  • Eiko Hayase
  • Mitsutoshi Kurosawa
  • Masakatsu Yonezumi
  • Sachiko Suzuki
  • Hiroaki Suzuki
Case Report


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.


Histiocytic sarcoma t(14;18) Immunoglobulin heavy chain gene rearrangement PAX5 CEBPβ 

1 Introduction

Histiocytic sarcoma (HS) is a rare neoplasm characterized by malignant proliferation of cells showing morphologic and immunophenotypic features of mature tissue histiocytes [1]. 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

A 54-year-old woman was admitted to our hospital because of gait disturbance caused by painful swelling of the left knee, associated with fever. Physical examination revealed left cervical and left inguinal lymphadenopathy and splenomegaly. Contrast-enhanced computed tomography (CT) demonstrated mild splenomegaly with low-density splenic masses; cervical, para-aortic, intrapelvic, and inguinal lymphadenopathy; small nodules in both lungs, and masses in the left renal hilus and sinus. Whole body positron emission tomography (PET)-CT showed increased 18F-fluorodeoxyglucose (FDG) uptake in multiple lymph nodes, the liver, spleen, both lungs, both kidneys, and many bony sites including the distal end of the left femur (Fig. 1). Serum levels of lactate dehydrogenase and soluble interleukin-2 receptor were slightly elevated. Biopsy of the left inguinal lymph node showed a diffuse noncohesive proliferation of large neoplastic cells with abundant eosinophilic cytoplasm, round to oval or irregularly folded nuclei, and often prominent nucleoli. Immunohistochemical studies showed neoplastic cells were positive for lysozyme, CD68, CD163, CD45RO, vimentin, and S-100, and negative for keratin, CD1a, CD3, CD5, CD8, CD20, CD21, CD30, CD34, CD35, CD43, CD79a, CD138, BCL2, ALK, and myeloperoxidase. Small infiltrating lymphocytes were positive for CD3 or CD20 (Fig. 2). These findings confirmed the diagnosis of HS. Cytological analysis of a bone marrow aspirate revealed an infiltration of neoplastic histiocytes with hemophagocytosis (Fig. 3). Cytogenetic analysis of the lymph node biopsy showed a clonal abnormality of 47,XX, del(2)(q21q31), +8, t(14;18)(q32;q21) in all 24 metaphase cells analyzed. The t(14;18) translocation was confirmed by fluorescence in situ hybridization (FISH) analysis showing an IgH/BCL2 fusion gene (Fig. 4). The tumor also showed rearrangements of the immunoglobulin heavy chain (IgH) gene and BCL2 gene by Southern blot hybridization. In addition, 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, despite genotypic features of B cell origin (Fig. 5).
Fig. 1

PET-CT shows dissemination of increased 18F-FDG uptake

Fig. 2

a Lymphnode biopsy shows a diffuse noncohesive proliferation of large neoplastic cells with abundant eosinophilic cytoplasm, round to oval or irregularly folded nuclei and often prominent nucleoli (H&E stain, ×400). Immunohistochemical staining shows that neoplastic cells are positive for b lysozyme, c CD68 and d CD163, and negative for e CD3 and f CD20 (×400)

Fig. 3

Bone marrow smear shows erythrophagocytosis by a neoplastic cell with an irregular nucleus (May–Giemsa stain, ×1,000)

Fig. 4

The neoplastic cells shows fusion of the BCL2 and IgH signals, which is consistent with the presence of t(14;18) by FISH (×1,250). Arrowheads indicate dual fusion signal of IgH/BCL2 probe, thin arrow indicates signal of IgH(14q32) probe, and thick arrow indicates signal of BCL2(18q21) probe

Fig. 5

Immunohistochemical staining shows that neoplastic cells are negative for a PAX5 and positive for b CEBP β (×400)

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.

3 Discussion

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 [1]. 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. [4] reported that nine of 23 patients with sporadic H/DC sarcoma showed clonal IgH rearrangements. Vos et al. [5] 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 [4]. Xie et al. [14] 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 [3]. Bassarova et al. [11] 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 [4]. 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 [23], 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.


  1. 1.
    Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, Thile J eds. World Health Organization classification of tumours of haematopoietic and lymphoid tissues. 4th ed. Lyon: International Agency for Research on Cancer (IARC); 2008.Google Scholar
  2. 2.
    Hornick JL, Jaffe ES, Fletcher CDM. Extranodal histiocytic sarcoma: clinicopathologic analysis of 14 cases of a rare epithelioid malignancy. Am J Surg Pathol. 2004;28:1133–44.CrossRefPubMedGoogle Scholar
  3. 3.
    Feldman AL, Arber DA, Pittaluga S, Martines A, Burke JS, Raffeld Camos M, Warnke R, Jaffe ES. Clonally related follicular lymphomas and histiocytic/dendritic cell sarcomas: evidence for transdifferentiation of the follicular lymphoma clone. Blood. 2008;111:5433–9.CrossRefPubMedGoogle Scholar
  4. 4.
    Chen W, Lau SK, Fong D, Wang J, Wang E, Arber DA, Weiss LM, Huang Q. High frequency of clonal immunoglobulin receptor gene rearrangements in sporadic histiocytic/dendritic cell sarcomas. Am J Surg Pathol. 2009;33:863–73.CrossRefPubMedGoogle Scholar
  5. 5.
    Vos JA, Abbondanzo SL, Barekman CL, Andriko JW, Miettinen M, Aguilera NS. Histiocytic sarcoma: a study of five cases including the histiocyte marker CD163. Mod Pathol. 2005;18:693–704.CrossRefPubMedGoogle Scholar
  6. 6.
    Nguyen TT, Schwartz EJ, West RB, Warnke RA, Arber DA, Natkunam Y. Expression of CD163 (hemoglobin scavenger receptor) in normal tissues, lymphomas, carcinomas, and sarcomas is largely restricted to the monocyte/macrophage lineage. Am J Surg Pathol. 2005;29:617–24.CrossRefPubMedGoogle Scholar
  7. 7.
    Mikami M, Sadahira Y, Suetsugu Y, Wada H, Sugihara T. Monocyte/macrophage-specific marker CD163+ histiocytic sarcoma: case report with clinical, morphologic, immunohistochemical, and molecular genetic studies. Int J Hematol. 2004;80:365–9.CrossRefPubMedGoogle Scholar
  8. 8.
    Wetzler M, Kurzrock R, Goodacre AM, McLaughlin P, Ku S, Talpatz M. Transformation of chronic lymphocytic leukemia to lymphoma of true histiocytic type. Cancer. 1995;76:609–17.CrossRefPubMedGoogle Scholar
  9. 9.
    Alvaro T, Bosch R, Salvado MT, Piris MA. True histiocytic lymphoma of the stomach associated with low-grade B-cell mucosa-associated lymphoid tissue (MALT)-type lymphoma. Am J Surg Pathol. 1996;20:1406–11.CrossRefPubMedGoogle Scholar
  10. 10.
    Feldman AL, Minniti C, Santi M, Downing JR, Raffeld M, Jaffe ES. Histiocytic sarcoma after acute lymphoblastic leukaemia: a common clonal origin. Lancet Oncol. 2004;5:248–50.CrossRefPubMedGoogle Scholar
  11. 11.
    Bassarova A, Trøen G, Fosså A, Ikonomou IM, Beiske K, Nesland JM, Delabie J. Transformation of B cell lymphoma to histiocytic sarcoma: somatic mutations of PAX-5 gene with loss of expression cannot explain transdifferentiation. J Hematop. 2009;2:135–41.CrossRefPubMedGoogle Scholar
  12. 12.
    Zhang D, McGuirk J, Ganguly S, Persons DL. Histiocytic/dendritic cell sarcoma arising from follicular lymphoma involving the bone: a case report and review of literature. Int J Hematol. 2009;89:529–32.CrossRefPubMedGoogle Scholar
  13. 13.
    Wang E, Hutchinson CB, Huang Q, Sebastian S, Rehder C, Kanaly A, Moore J, Dato M. Histiocytic sarcoma arising in indolent small B-cell lymphoma: report of two cases with molecular/genetic evidence suggestive of a ‘transdifferentiation’ during the clonal evolution. Leuk Lymphoma. 2010;51:802–12.CrossRefPubMedGoogle Scholar
  14. 14.
    Xie H, Ye M, Feng R, Graf T. Stepwise reprogramming of B cells into macrophages. Cell. 2004;117:663–76.CrossRefPubMedGoogle Scholar
  15. 15.
    Cobaleda C, Schebesta A, Delogu A, Busslinger M. Pax5: the guardian of B cell identity and function. Nat Immunol. 2007;8:463–70.CrossRefPubMedGoogle Scholar
  16. 16.
    Yu D, Allman D, Goldschmidt MH, Atchison ML, Monroe JG, Thomas-Tikhonenko A. Oscillation between B-lymphoid and myeloid lineages in Myc-induced hematopoietic tumors following spontaneous silencing/reactivation of the EBF/Pax5 pathway. Blood. 2003;101:1950–5.CrossRefPubMedGoogle Scholar
  17. 17.
    Cobaleda C, Jochum W, Busslinger M. Conversion of mature B cells into T cells by dedifferentiation to uncommitted progenitors. Nature. 2007;449:473–7.CrossRefPubMedGoogle Scholar
  18. 18.
    Yaman E, Ozturk B, Erdem O, Gokcora N, Coskun U, Uluoglu O, Benekli M. Histiocytic sarcoma: PET-CT evaluation of a rare entity. Ann Nucl Med. 2008;22:715–7.CrossRefPubMedGoogle Scholar
  19. 19.
    Buonocore S, Valente AL, Nightingale D, Bogart J, Souid AK. Histiocytic sarcoma in a 3-year-old male: a case report. Pediatrics. 2005;116:e322–5.CrossRefPubMedGoogle Scholar
  20. 20.
    Alexiev BA, Sailey CJ, McClure SA, Ord RA, Zhao XF, Papadimitriou JC. Primary histiocytic sarcoma arising in the head and neck with predominant spindle cell component. Diagn Pathol. 2007;2:1–7.CrossRefGoogle Scholar
  21. 21.
    Pileri SA, Grogan TM, Harris NL, Banks P, Campo E, Chan JK, Favera RD, Delsol G, De Wolf-Peeters C, Falini B, Gascoyne RD, Gaulard P, Gatter KC, Isaacson PG, Jaffe ES, Kluin P, Knowles DM, Mason DY, Mori S, Müller-Hermelink HK, Piris MA, Ralfkiaer E, Stein H, Su IJ, Warnke RA, Weiss LM. Tumours of histiocytes and accessory dendritic cells: an immunohistochemical approach to classification from the International Lymphoma Study Group based on 61 cases. Histopathology. 2002;41:1–29.CrossRefPubMedGoogle Scholar
  22. 22.
    Yoshida C, Takeuchi M. Histiocytic sarcoma: identification of its histiocytic origin using immunohistochemistry. Intern Med. 2008;47:165–9.CrossRefPubMedGoogle Scholar
  23. 23.
    Abidi MH, Tove I, Ibrahim RB, Maria D, Peres E. Thalidomide for the treatment of histiocytic sarcoma after hematopoietic stem cell transplant. Am J Hematol. 2007;82:932–3.CrossRefPubMedGoogle Scholar

Copyright information

© The Japanese Society of Hematology 2010

Authors and Affiliations

  • Eiko Hayase
    • 1
  • Mitsutoshi Kurosawa
    • 1
  • Masakatsu Yonezumi
    • 1
  • Sachiko Suzuki
    • 1
  • Hiroaki Suzuki
    • 2
  1. 1.Department of HematologyNational Hospital Organization Hokkaido Cancer CenterSapporoJapan
  2. 2.Department of Diagnostic PathologyNational Hospital Organization Hokkaido Cancer CenterSapporoJapan

Personalised recommendations