Composite lymphoma: the interface between Hodgkin's and non-Hodgkin's lymphoma

Hodgkin's lymphoma is a rare neoplasm mainly affecting young people. Within the last decade, nodular lymphocyte-predominant Hodgkin's lymphoma (NLPHL) has been separated from all other cases of the so-called classical type. Moreover, the derivation of Hodgkin's lymphoma from germinal centre B-cells has been established, giving rise to a possible clonal relationship between Hodgkin's lymphoma and the non-Hodgkin's lymphomas (NHLs). The interface between them therefore has both diagnostic and biological aspects. Diagnostic difficulties arise, due to overlapping definitions, between biologically unrelated entities, e.g. classical Hodgkin's lymphoma and NLPHL or anaplastic large cell lymphoma, respectively. On the other hand, there is a biological grey zone regarding composite lymphomas consisting of Hodgkin's lymphoma and any NHL. This simultaneous or subsequent occurrence of Hodgkin's lymphoma and non-Hodgkin's lymphomas may, or may not, be clonally related. For management purposes lymphomas, e.g. NLPHL and T cell-rich B-cell lymphoma, must be distinguished along a continuous spectrum of progression.     

Composite diffuse large B-cell lymphoma and CD20-positive peripheral T-cell lymphoma

Composite lymphoma is defined as two or more distinct types of lymphoma in a single anatomical site. Among various combinations, composite B-cell and T-cell non-Hodgkin's lymphomas (CBTL) are very infrequent. Herein we describe a 66-year-old female with CBTL presenting with lymphadenopathy, multiple bone lesions and an epidural tumor. Light microscopic examination of a biopsied cervical node revealed a dual population of lymphoid cells: sheets of large cells admixed with medium-sized cells. The large cells expressed B-cell markers and showed immunoglobulin light chain restriction, consistent with diffuse large B-cell lymphoma (DLBCL). The medium-sized cells were positive for CD20 as well as T-cell markers. Because polymerase chain reaction amplification showed monoclonal rearrangement of the T-cell receptor β chain gene, this population was compatible with peripheral T-cell lymphoma not otherwise specified (PTCL-NOS). We therefore made a diagnosis of composite DLBCL and CD20-positive PTCL-NOS. Complete remission was achieved after six cycles of R-CHOP regimen (rituximab, doxorubicin, vincristine, cyclophosphamide and prednisolone). This is the first report of CD20-positive PTCL-NOS associated with composite lymphoma. Moreover, a literature review of composite DLBCL and PTCL-NOS indicates that this rare clinical entity may be featured by efficacy of systemic chemotherapy in spite of prevalent extranodal lesions.     

Composite lymphoma: association of a follicular lymphoma and a chronic lymphocytic leukemia

We report the case of a 71-year-old woman presenting with composite lymphoma (CL) composed of a follicular lymphoma and a B-cell chronic lymphocytic leukemia. CL is a rare lymphoproliferative disorder, characterized by two distinct morphological and immunophenotypical patterns in the same anatomical site, most frequently of biclonal origin. This entity must be distinguished from transformation of low-grade lymphoma into high-grade lymphoma and from lymphoma with differentiation such as follicular lymphoma with marginal differentiation. In this context, molecular analysis including immunoglobulin rearrangement, sequencing and FISH analyses is determinant and can be improved by tissue microdissection. Routinely, CL must not be misdiagnosed because of its prognosis and treatment implication.     

Composite T lymphoblastic leukemia/lymphoma and diffuse large B-cell lymphoma: case report

This report concerns a unique case of a composite lymphoma composed of T-lymphoblastic leukemia/lymphoma (T-LBL) and diffuse large B-cell lymphoma (DLBCL) in a 72-year-old woman with generalized lymphadenopathy, splenomegaly and ascites. Laboratory findings showed increased lactate dehydrogenase and soluble interleukin-2 receptor. The biopsy specimen showed replacement of the normal architecture of the lymph nodes by a tumor containing a dual cell population composed of large lymphocytes and medium-sized lymphocytes. Sheets of large lymphocytes often were punctuated by clusters of medium-sized lymphocytes. Flow cytometry and immunohistochemical analysis showed a composite lymphoma with both T-LBL and DLBCL. The T-LBL expressed CD1a, CD3, CD4, CD8, and terminal deoxynucleotidyl transferase. The DLBCL expressed CD19 and CD20, CD23, bcl-2, bcl-6, MUM1 and immunoglobulin κ light chain. Polymerase chain reaction detected a monoclonal pattern of T-cell receptor γ and immunoglobulin heavy chain rearrangements in the same specimen. She received eight cycles of R-CHOP (rituximab+cyclophosphamide, doxorubicin, vincristine, prednisone) therapy and achieved complete remission. She has shown no signs of recurrence 20 months after the diagnosis. We describe here a very unusual and, to the best of our knowledge, an as yet never reported case of a primary composite lymphoma of T-LBL and DLBCL.     

Composite B-cell and T-cell non-Hodgkin lymphoma of the tibia

We report a unique case of de novo composite lymphoma in the tibia of a 35-year-old man who presented with increasingly frequent and intense pain in the right upper leg. He was otherwise healthy without significant medical history. A plain radiograph of the right leg showed a permeative lesion with alternating areas of radiolucency and radiodensity in the upper third of the tibia. Magnetic resonance imaging showed a large, heterogeneous enhancing lesion involving the medullary and cortical bone of the proximal tibia with cortical disruption and extension into the adjacent soft tissue. A biopsy showed sheets and clusters of large cells, punctuated by clusters of small, irregular lymphocytes. Flow cytometry and immunohistochemical analysis showed composite lymphoma: diffuse large B-cell lymphoma (DLBCL) and peripheral T-cell non-Hodgkin lymphoma with predominantly small cell morphologic features. The DLBCL expressed CD19, CD20, CD79a, CD5, CD10, CD23, CD38, CD117, bcl-2, and bcl-6, with monotypic expression of immunoglobulin kappa light chain. The T cells expressed CD2, CD3, CD5, CD7, and CD8, with partial loss of CD4. Clonal rearrangement of T-cell receptor gamma chain gene was found. Neither the large B cells nor the small T cells expressed Epstein-Barr virus-encoded RNA. Physical examination and radiologic studies showed no evidence of lymphadenopathy, organomegaly, or other mass lesions in the body. No peripheral lymphocytosis or bone marrow involvement was present.     

Composite splenic marginal zone lymphoma and mantle cell lymphoma arising from 2 independent B-cell clones

We report the first case of composite lymphoma involving both mantle cell lymphoma (MCL) and splenic marginal zone lymphoma (SMZL) with circulating villous lymphocytes. Morphological, immunohistochemical, immunophenotyping, as well as detailed genetic studies (fluorescence in situ hybridization, IGVH gene sequencing), were performed and confirmed the existence of 2 independent, unrelated tumor clones. The MCL component expressed IgMD lambda, was CD5+, harbored a t(11;14)(q13;q32) involving CCND1, and showed an unmutated VH1-18 gene rearrangement. The SMZL component expressed IgMD kappa, was CD5-, showed a t(10;14)(q24;q32) and an unmutated VH3-7 gene rearrangement. Interestingly, this t(10;14) targeted the NFKB2 gene. Only a single other case of SMZL with t(10;14)/NFKB2 has been reported. Taken together, these data indicate that the MCL and SMZL arose as a consequence of independent malignant transformation events within an antigen-naive B-cell population. This case highlights the importance of a multidisciplinary approach and tissue diagnosis in these complex situations.     

Composite recurrent hodgkin lymphoma and diffuse large B-cell lymphoma: one clone, two faces

We describe a composite lymphoma with recurrent Hodgkin lymphoma and diffuse large B-cell lymphoma components manifesting as a single, perforated small intestinal tumor in a 56-year-old man with a history of classical Hodgkin lymphoma and recent relapse in the bone marrow. The resected mass had 2 morphologically and immunophenotypically distinct components; 1 showed a pleomorphic cellular infiltrate with fibrosis and contained numerous, large Hodgkin/Reed-Sternberg-like cells and variants. The tumor cells were CD30+ and focally positive for CD15 but CD20-, CD79a-, and PAX-5-. In situ hybridization for Epstein-Barr virus (EBV) was strongly positive in the large pleomorphic tumor cells. The adjacent component displayed sheets of relatively uniform, large lymphoid cells with typical morphologic features of diffuse large cell lymphoma. The tumor cells showed uniform expression of tested B-cell antigens, absence of CD30 or CD15, and complete absence of EBV-encoded RNA. Separate molecular studies with immunoglobulin heavy and k light chain gene rearrangements clearly demonstrated an identical rearrangement pattern, indicating derivation from the same clone, which was confirmed by direct DNA sequencing analysis. Such distinctly different morphology, immunophenotype, and EBV status in different components within a clonally related single tumor mass is striking.     

Composite ALK-negative anaplastic large cell lymphoma and small lymphocytic lymphoma involving the right inguinal lymph node

Anaplastic large cell lymphoma and small lymphocytic lymphoma are two lymphoid malignancies with completely distinct morphologies and natural histories. We present a rare case of composite anaplastic large cell lymphoma and small lymphocytic lymphoma in an inguinal lymph node of an otherwise healthy 47-year-old male patient. Immunohistochemical and molecular studies identified the two populations clearly. Their separation is imperative as anaplastic large cell lymphoma can be an aggressive neoplasm and easily overlooked in cases of small lymphocytic lymphoma with a small population of anaplastic large cell lymphoma cells.     

Composite marginal zone B-cell lymphoma and classical Hodgkin's lymphoma: a clinicopathological study of 12 cases

AIMS: Classical Hodgkin's lymphoma (cHL) rarely coexists as composite lymphoma with B-cell non-Hodgkin's lymphoma (B-NHL). We characterized 12 cases of composite marginal zone B-cell lymphoma (MZBL) and cHL by immunohistochemistry and molecular biology. METHODS AND RESULTS: Eight patients had gastric MZBL of mucosa-associated lymphoid tissue (MALT)-type, in five cases with a diffuse large B-cell lymphoma component. Concurrent cHL was observed either in the stomach wall, regional, or distant lymph nodes. One patient each had composite pulmonary/thyroid MZBL of MALT-type and cHL. In two cases, nodal composite MZBL and cHL was observed. cHL displayed features of mixed cellularity type in 10 cases, while in two cases only scattered Hodgkin- and Reed-Sternberg (H/RS) cells were noted. H/RS cells expressed CD30, multiple myeloma oncogene 1 protein (MUM1P), p53 (100%), CD15 (58%), CD20 (58%) and Epstein-Barr virus-associated LMP1 (50%). No t(11;18)(q21;q21) was detected in composite MZBL of MALT-type and cHL. CONCLUSIONS: MZBL and cHL may occur as composite lymphoma, possibly reflecting clonal lymphoma progression. Derivation from extranodal MZBL of MALT-type should be excluded in cases in which a diagnosis of primary extranodal cHL is considered.     

Composite lymphoma. A clinicopathologic analysis of nine patients with Hodgkin's disease and B-cell non-Hodgkin's lymphoma

Nine patients had composite lymphoma in which Hodgkin's disease (HD) and non-Hodgkin's lymphoma (NHL) involved the same anatomic site. Two of these patients had relapses of their tumors. In one, the initial biopsy specimen contained follicular and diffuse large cell NHL with unclassifiable HD, but the relapse showed diffuse large cell NHL with nodular sclerosis HD. In the other patient, both biopsy specimens showed follicular mixed NHL; the HD component in the initial biopsy specimen was nodular sclerosis, whereas, at relapse, it had the appearance of interfollicular HD. In the remaining seven patients, the HD component was subclassified as nodular sclerosis (three specimens) or mixed cellularity (three specimens), or it was unclassifiable (one specimen). The NHL component was categorized as diffuse large cell (two specimens), diffuse large cell immunoblastic (two specimens), follicular and diffuse large cell (one specimen), diffuse mixed small and large cell (one specimen), and lymphocytic lymphoma of intermediate differentiation (modified Rappaport classification) (one specimen). Paraffin section immunoperoxidase studies were done on the NHL component in eight patients (nine specimens) and on the HD component in six patients (seven specimens). In each of these, the NHL component was leukocyte common antigen (LCA) positive and Leu-M1 negative. In addition, the neoplastic cells were L26 positive and UCHL-1 negative, indicating a B-cell phenotype. In five of seven immunophenotyped cases, Reed-Sternberg (RS) and Hodgkin's (H) cells from the HD areas were Leu-M1 positive and LCA negative, reflecting an immunophenotype that is typical of non-lymphocyte-predominant HD. In two specimens, the malignant cells were negative for Leu-M1 and LCA (with positive internal controls). Composite lymphomas composed of HD and NHL are unusual, and cases of coexistent HD of the non-lymphocyte-predominant subtype and NHL are even less common. The results of the current study and a review of the literature indicate that this phenomenon usually involves a B-cell NHL that coexists with HD, perhaps further suggesting a close relationship between the malignant cells of HD (RS and H cells) and B lymphocytes.     

Composite mantle cell and follicular lymphoma. A case report

We describe the association of 2 types of small B-cell lymphomas with different morphologic and immunophenotype patterns inside the same lymph node. Morphologically distinct zones were detected and studied with immunohistochemistry analyses. Most of the areas examined were characteristic of classic mantle cell lymphoma (CD20+, CD5+, cyclin D1+) with nodular and mantle zone areas. However, other areas had the morphologic and immunohistochemistry pattern of follicular lymphoma (CD20+, CD10+, Bcl2+). The diagnosis of both lymphomas was confirmed by polymerase chain reaction detection of both Bcl-1 MTC and Bcl-2 MBR rearrangements. DNA degradation in fixed tissue prevented a complete polymerase chain reaction analysis of immunoglobulin heavy chain rearrangements, but a single immunoglobulin H rearrangement was detected at the FR3 locus. These findings confirm the presence of a monoclonal cell population but do not demonstrate the same clonal origin for both lymphoma populations.     

Composite angioimmunoblastic T-cell lymphoma and diffuse large B-cell lymphoma: a case report and review of the literature

We report a rare case of composite angioimmunoblastic T-cell lymphoma (AILT) and diffuse large B-cell lymphoma occurring in a 48-year-old woman with generalized lymphadenopathy and hepatosplenomegaly. The patient initially sought care at a local hospital with a single enlarged left cervical lymph node. Histologic examination of the node was interpreted as an atypical immunoblastic proliferation. She developed generalized lymphadenopathy 10 months later and was referred to our institution for further evaluation. The recent biopsy of the cervical node showed typical features of AILT Flow cytometric immunophenotyping identified an aberrant CD4+ T-cell population that lacked surface CD3. Polymerase chain reaction analysis of the T-cell receptor gamma gene revealed a clonal rearrangement. In addition to the AILT, the lymph node showed partial involvement by a diffuse large B-cell lymphoma. The B lymphoma cells and admixed immnunoblasts and Reed-Sternberg-like B cells in the AILT were positive for Epstein-Barr virus (EBV) by in situ hybridization. Ourfindings raise the possibility that the EBV-associated large B-cell lymphoma is a secondary event in AILT via EBV infection or reactivation followed by clonal expansion of an immortalized EBV-infected B cell clone.     

Composite chronic lymphocytic leukemia/small lymphocytic lymphoma and follicular lymphoma are biclonal lymphomas: a report of two cases

Composite lymphomas (CLs) consisting of 2 indolent B-cell lymphomas are rare. We present 2 CL cases composed of chronic lymphocytic leukemia (CLL) and follicular lymphoma (FL), each with unique clinicopathologic features. In the first case, the FL was negative for IGH-BCL2 and harbored a novel IGH-associated translocation; in the second case, the CL manifested in the skin. The individual components in both CLs were derived from different B-cell clones. This is the first complete characterization, including molecular analysis, of CLs composed of leukemic CLL and FL and the first report of a cutaneous CL derived from 2 low-grade B cell lymphomas. Our results provide additional supporting evidence that CLs of indolent B-cell lymphomas are biclonal and suggest that they are pathogenetically different from CLs composed of a low-grade B-cell lymphoma and an aggressive B-cell lymphoma or Hodgkin lymphoma, which are usually clonally related.     

Composite mantle cell and diffuse large B-cell lymphoma: report of two cases

Composite lymphomas are rare and involve the concurrent evolution of 2 distinct lymphoma types within a single organ or tissue. This study describes 2 cases of composite mantle cell lymphoma (MCL) and diffuse large B-cell lymphoma (DLBCL), which has not previously been reported. Each case demonstrated distinct populations of CD20 positive small and large atypical B cells. In both cases, only the small lymphocytes were positive for CD5 and cyclin D1, and fluorescence in situ hybridization (FISH) showed a t(11;14) translocation in the small lymphocytes but not in the large cells. Molecular studies for B-cell clonality showed a possible clonal relationship between the 2 components in one case but not the other. This study describes in detail the morphology, immunophenotype, FISH, and molecular analysis of both components in each case. To the authors' knowledge, this represents the first report of juxtaposition of MCL with DLBCL that does not represent transformation of the mantle cell component.     

Composite small lymphocytic lymphoma and extra-medullary myeloid tumor: a potential diagnostic pitfall

Reported herein is a case of composite small lymphocytic lymphoma (SLL) and extramedullary myeloid tumor (EMT) occurring in the same lymph node. Routine morphologic examination revealed a diffuse proliferation of small mature lymphocytes with numerous irregularly dispersed nodules, closely resembling SLL with prominent proliferation centers or Richter's transformation. Flow cytometric immunophenotyping and immunohistochemical stains demonstrated the presence of SLL cells as well as myeloblasts, confirming the diagnosis of a composite SLL and EMT. Conventional cytogenetics and fluorescence in situ hybridization studies revealed inversion 16 chromosome involving the core binding factor beta and myosin heavy chain 11 genes, characteristic of acute myeloid leukemia with abnormal bone marrow eosinophils and inv(16) or t(16;16) [CBFbeta/MYH11]. In conclusion, the occurrence of SLL and EMT in the same lymph node is rare and multiparameter approach is essential for a definitive diagnosis.