Indian Journal of Pathology and Microbiology

: 2015  |  Volume : 58  |  Issue : 4  |  Page : 537--539

Concomitant follicular lymphoma and histiocytic sarcoma: A rare progression, trans-differentiation or co-occurrence?

Anuj Verma, Tanuja Shet 
 Department of Pathology, Tata Memorial Hospital, Mumbai, Maharashtra, India

Correspondence Address:
Dr. Tanuja Shet
Department of Pathology, Tata Memorial Hospital, Parel, Mumbai - 400 012, Maharashtra


Trans-differentiation of follicular lymphoma (FL) into a histiocytic sarcoma (HS) is a rare event and usually occurs as a sequential event. We report a case where in the same node with two distinct areas one of low-grade FL and another with HS was observed. This patient was a 58 years old with generalized lymphadenopathy and Ann Arbor Stage III disease. The cervical node biopsy on histological examination revealed two distinct areas, firstly a FL with nodular architecture and the other a smaller focus of sheets of pleomorphic histiocytic cells diffusely arranged at the edge of the section contiguous with FL with few cells in transiting phase. On immunohistochemistry the FL was positive for CD20, CD10, PU.1, PAX5 and Bcl2, while the large histiocytic cells were positive for CD163, CD68, LCA, and PU.1, weakly for PAX5 and negative for CD20, CD10, CD30, CD3, CD1a, Bcl2, S100, and Alk-1. The therapeutic implications of this diagnosis and postulated theories on trans-differentiation are discussed.

How to cite this article:
Verma A, Shet T. Concomitant follicular lymphoma and histiocytic sarcoma: A rare progression, trans-differentiation or co-occurrence?.Indian J Pathol Microbiol 2015;58:537-539

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Verma A, Shet T. Concomitant follicular lymphoma and histiocytic sarcoma: A rare progression, trans-differentiation or co-occurrence?. Indian J Pathol Microbiol [serial online] 2015 [cited 2021 Jul 25 ];58:537-539
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The WHO classification of low-grade B-cell lymphomas is based on fact that most low-grade B-cell lymphomas recapitulate markers depending on their cell of origin.[1] Lineage specific committed cells under normal circumstances do not transform into another committed lineage. However, transformation of a neoplastic clone of one committed lineage to other lineage has been described and in last few years transformation of low-grade B-cell lymphoma to histiocytic and dendritic cell neoplasm (H/DCN) is increasingly being recognized. These tumors more commonly occur metachronously and rarely synchronously.[2],[3] Most commonly accepted theory is the model of trans-differentiation in which tumor of a committed lineage, by-passes the progenitor stage, retains primary tumor's immunophenotype or expression signature in the transformed neoplasm.[2],[3],[4] They occur at distant sites from primary tumor like spleen, bone marrow, and skin but very rarely seen in the same specimen.[2],[3],[4] Only few case reports and a case series of maximum eight cases of FL transforming into H/DCN have been reported until date.[2],[4],[5],[6] In this report, we describe a rare case of FL with synchronous histiocytic sarcoma (HS) in same lymph node which to the best of our knowledge is not reported in literature. The importance of this occurrence and implications are discussed.

 Case Report

A 58-year-old male patient presented with complaint of generalized lymphadenopathy since 2 months which was progressively increasing but patient had no B symptoms. The largest node palpable was cervical and measured 2.5 cm × 2.0 cm × 1.0 cm. A positron emission tomography-computed tomography scan revealed an Ann Arbor Stage III disease with multiple cervical, abdominal, and thoracic nodes with SUV ranging from 7 to 15 while the cervical node had SUV of 17. This cervical node was biopsied. This biopsy was reported as follicular lymphoma (FL) low-grade at one institute and HS at another institute. The dual nature of disease was missed by both centers and case was referred to us for a second opinion. Staging marrow of the patient was done and was not involved. The patient after diagnosis was prescribed RCHOP (Rituximab with Cyclophosphamide Hydroxydaunorubicin Oncovin, Prednisolone) and received one cycle with partial response but was lost to follow-up subsequently.

 Histopathological Findings

Histological examination of the submitted paraffin block at low power revealed two distinct areas, firstly a predominant lesion (Area I) a lymphoma with nodular architecture forming 85% of the lesion and the other a smaller focus (Area II) of sheets of pleomorphic large cells diffusely arranged at the edge of the section contiguous with Area I with few cells in transiting phase forming 15% of the lesion. On higher power nodular lesion was composed predominantly of centrocytes with occasional centroblasts. Centrocytes were also seen in inter-nodular areas and no diffuse areas were noted. The smaller area/Area II was composed of large, round, polymorphic, noncohesive cells with abundant foamy cytoplasm. Nucleus was large, eccentrically placed with prominent nucleoli, vesicular chromatin, irregular nuclear membrane and moderate atypia. Many multinucleate forms were noted. Phagocytosed neutrophils were seen in the cells hinting at their histiocytic nature. Reactive neutrophils and eosinophils were seen distributed irregularly in this area [Figure 1]. On immunohistochemistry, the cells of nodular lesion (FL) were positive for LCA, CD20, CD10, PU.1, PAX5, and Bcl2, while the large histiocytic cells were positive for CD163, CD68, LCA, and PU.1, weakly for PAX5 and negative for CD20, CD10, CD30, CD3, CD1a, Bcl2, S100 and Alk-1 [Figure 2]. Thus a diagnosis of HS arising from trans-differentiation in low-grade FL was made.{Figure 1}{Figure 2}


H/DCN form <1% of hematolymphoid neoplasm and represent a group of tumors originating from histiocytes and dendritic cells derived from monocytes giving rise to HS, Langerhans cell histiocytosis and interdigitating cell sarcoma (IDCS). HS is positive for CD163, CD68, lysozyme and LCA and is negative for CD1a, langerin, CD3, and CD20. S100 expression is weak and focal. FL, on the other hand, is a low-grade neoplasm of mature B-cell representing 20% of all lymphomas and undergoes a high-grade transformation in 25–35% of cases, usually to diffuse large B-cell lymphoma (DLBCL).[1]

Transformation of low-grade B-cell lymphoma to H/DCN has been more commonly reported than other hematolymphoid neoplasms like acute leukemia and DLBCL.[4],[7] Among low-grade B-Cell neoplasms transformation is described commonly in chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) and FL.[4] There are very few case reports describing trans-differentiation in splenic marginal zone lymphoma and extranodal marginal zone lymphoma (mucosa-associated lymphoid tissue-lymphoma).[5],[8] Among these FL is more commonly associated with transformation into HS while SLL/CLL is more prone to transform into IDCS.[4],[7]

Feldman et al.first established clonal relationship between primary tumor and trans-differentiated component and subsequently other authors have also reported that these seemingly different components are clonally linked.[2],[3],[5],[7] Three pathways have been described by the studies for this transformation. First is the dedifferentiation model in which a committed clone of cell regresses to common pluripotent progenitor stage and then differentiates along another lineage. In common progenitor model both component arise from pluripotent progenitor cell. Only one such case has been described while other investigators failed to confirm presence of immature progenitor cells and thus rejecting this model. While the third and most widely accepted model is of trans-differentiation in which mature cell of one lineage by an incompletely understood mechanism of genetic and epigenetic changes differentiates into a mature cell of different lineage.[2],[3],[4],[5],[6]

Data from recent studies have highlighted fact that there is more plasticity between lymphoid and myeloid series than was previously known. Xie et al. in their study confirmed that mature B-cell can be reprogrammed and trans-differentiated into macrophage by enforced expression of C/EBP α and β transcription factors along with restriction of B-cell specific transcription factor PAX5. PU.1 expression coupled with down-regulation of CD19 also plays a role in trans-differentiation to macrophage. It has also been proved that expression of PAX5 prevents trans-differentiation of B-cells into cells of myeloid series and deletion of PAX5 causes regression of mature lymphoid cells to precursor forms.[9],[10] PAX5 is an important B-cell transcription factor and its expression helps B-lymphocyte to maintain its identity. Cobaleda et al. described development of non-B-cell neoplasm in cells with continued Bcl2 expression and absent PAX5 expression.[9] Though Bcl2 expression is an important hallmark of FL, the transformed component can be negative for it a finding similar to that of our case. This negative Bcl2 immunohistochemistry was seen despite confirmed IgH/Bcl2 mutation.[2],[4] We have not obtained clonality evaluation in our study but the weak PAX5 and strong PU1 in our case testifies to the above theory and confirm B-cell lineage of the HS. The detection of immunoglobulin rearrangement within some sporadic H/DCN further points toward the possibility that some of these may be trans-differentiated B-cell lymphomas and should probably be treated in similar fashion.[1]

FL and HS both are seen in elderly patients. In a review of 22 cases of B-cell neoplasm with H/DCN transformation by Stoecker and Wang, median age was 61.5 years with 77% males a finding similar to our case. Only 4 had follow-up with survival ranging 3–19.5 months with median of 6.5 months.[4] At present, HS are treated with aggressive chemotherapy but the response noted have been variable. No standard protocol has been yet established while there is no role of rituximab.[1],[4] The implications for accurate diagnosis of both components are related to therapeutic impact wherein recognition of higher grade component connotes poor prognosis in an indolent lymphoma like FL while recognition of FL component in HS indicated need for therapy like a B-cell lymphoma with rituximab inclusion.

To summarize, low-grade B-cell lymphoma rarely undergo transformation to H/DCN, and such cases are expected to have a poorer survival. Expression and suppression of various transcription factors like PU.1 and PAX5 with other unknown genetic changes play a role in trans-differentiation, and further studies must be conducted to decipher them.

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