VI.	Malignant Lymphomas that Mimic Other Lymphomas of a Different Type with Very Different Clinical Implications (continued) Marsha Kinney, James Cook and Steven Swerdlow

Case 11 Diagnosis: T-cell rich large B-cell lymphoma Clinical History: The patient is a 43 year-old man who presented with right cervical adenopathy. A biopsy was performed at an outside institution, where a diagnosis of classical Hodgkin lymphoma was rendered. The patient was treated, and responded well. However, after 5 years, the patient relapsed, and a second biopsy was performed. At the time of relapse, the new and original biopsies were reviewed in consultation, both of which showed identical findings. The slide provided demonstrates the features in the original specimen. Morphology: The histologic sections demonstrated an essentially diffuse, heterogeneous infiltrate composed of small lymphocytes, histiocytes, occasional large transformed cells, and scattered large atypical cells with prominent nucleoli. Some of the large atypical cells were binucleate or multinucleate. Immunophenotype: Immunohistochemical stains showed the small lymphocytes to consist predominantly of CD3 positive T-cells. The large atypical cells were strongly positive for CD20 and CD45 (LCA), and coexpressed OCT2 and BOB1. The atypical cells were negative for CD30, but were strongly positive for CD15. An EBER stain for Epstein-Barr virus was negative. T-cell/Histiocyte-Rich Large B-cell Lymphoma (TCRLBCL): Histologically, TCRLBCL is defined as a diffuse proliferation of large neoplastic B-cells that represent <10% of the total cellularity. [1, 2, 3, 4] Small B-cells are rare to absent. The majority of the infiltrate consists of benign, small T-cells, usually with a prominent admixed histiocytic proliferation. The neoplastic B-cells may display a variety of cytologic features. In some cases, the B-cells may be predominantly of centroblastic or immunoblastic morphology. In some cases, Reed-Sternberg-like cells are present. In still other cases, large multilobate cells are present that resemble that L&H cells ("popcorn cells") of nodular lymphocyte predominant Hodgkin lymphoma (nLPHL). Phenotypic studies of TCRLBCL are best accomplished via immunohistochemistry, as the relatively rare neoplastic B-cells may be difficult to characterize by flow cytometry. [4] Using immunostains, most cases of TCRLBCL will be strongly positive for CD45 (LCA) and CD20, [1, 5] and will show expression of the B-cell transcription factors OCT2 and BOB1. [6] CD10 and BCL6 have been described in a subset of cases. Although usually negative for CD30 and CD15, up to one third may be positive for CD30 and rare CD15 positive cases have also been described, as seen in the case above. [1, 4, 5] In some cases, immunohistochemical stains for kappa and lambda light chains may show monotypic staining. Clinically, these patients typically present with advanced disease, with involvement of multiple lymph node groups, spleen, and often bone marrow. [7, 8, 9] Due to the usual presentation at advanced stage, patients with TCRLBCL often show an aggressive clinical course. However, at least some studies have suggested that when adjusted for stage, T-cell rich large B-cell morphology is not an independent prognostic indicator. [7, 8] The revised 2008 WHO classification recognizes TCRLBCL as a distinct subtype of DLBCL. [10] These cases display characteristic morphologic and phenotypic findings that create diagnostic difficulties for the lymph node pathologist. In particular, cases of TCRLBCL may be confused with several others forms of lymphoma, including classical Hodgkin lymphoma, nLPHL and peripheral T-cell lymphoma, unspecified (PTCLU). TCRLBCL versus classical Hodgkin lymphoma: In a subset of TCRLBCL, the large atypical B-cells include a population of binucleate cells with large nucleoli ("Reed-Sternberg-like" cells). In conjunction with the non-neoplastic background that usually consists of small T-cells and numerous admixed epithelioid histiocytes, these findings raise a differential diagnosis with classical Hodgkin lymphoma. In particular, these findings may be suggestive of lymphocyte rich classical Hodgkin lymphoma or, if eosinophils and plasma cells are prominent, mixed cellularity Hodgkin lymphoma. This differential diagnosis is best addressed using a panel of immunohistochemical stains. Evaluation of CD20 and CD45 (LCA) stains are particularly important. While CD20 and LCA may be seen on the neoplastic cells of classical Hodgkin lymphoma in a minority of cases (approximately 25% in most studies), these antigens will typically be found on only a minority of the neoplastic cells within the case, and the intensity of staining is usually variable but weak overall. [11, 12] In contrast, the neoplastic cells of TCRLBCL are generally expected to show uniform and strong staining in the vast majority of the neoplastic B-cells. CD30 and CD15 are typically absent in TCRLBCL, although as mentioned above, occasional exceptions will occur. [1, 5] Especially useful in this differential are the B-cell transcription factors OCT2 and BOB1. Abnormalities in these transcription factors are frequent in classical Hodgkin lymphoma, and are thought to contribute to the lack of functional immunoglobulin heavy chain rearrangements in Reed-Sternberg cells. Nearly all cases of classical Hodgkin lymphoma will be negative for either OCT2 or BOB1 or, in at least two thirds of cases, both of these markers; the expression of both OCT2 and BOB1 is very rare in classical Hodgkin lymphoma. [13, 14] In contrast, most cases of TCRLBCL will show expression of both of these markers. [6] TCRLBCL versus nodular lymphocyte predominant Hodgkin lymphoma: Some cases of TCRLBCL contain large atypical multilobate cells that strongly resemble the L&H cells (so-called "popcorn cells") associated with nLPHL. In fact, there may be an etiological relationship between TCRLBCL and nLPHL, [15] as discussed below. The distinction between these two entities is very important, as the two diagnoses suggest very different clinical outcomes. nLPHL is usually localized, and is an especially indolent lymphoproliferative disorder, such that localized therapy alone might be considered in some patients. [16] TCRLBCL, in contrast, is usually disseminated, and is associated with an adverse clinical course that will typically be managed with multiagent chemotherapy, similar to other diffuse large B-cell lymphomas. Distinguishing between these entities is therefore critical for proper therapy. By definition, all cases of nLPHL will display, at least focally, a nodular growth pattern. The nodules are composed of large, expanded follicular dendritic cell meshworks that contain a predominance of small B-cells, some with a germinal center cell phenotype, admixed with numerous CD57 positive T-cells. [16] Large, multinucleate "popcorn cells" are present within the nodules, frequently surrounded by rosettes of CD3 positive T-cells that usually coexpress CD57. Some cases will display inter-nodular areas with scattered "popcorn cells." The inter-nodular areas in these cases strongly resemble TCRLBCL. [17] Recognition of the nodular areas within nLPHL is essential for correct diagnosis. Although the nodules are often apparent on routine H&E sections, immunohistochemical stains for CD21 and CD57 may be very valuable in difficult cases. Expanded nodules of CD21 positive FDC networks are expected in all cases of nLPHL, while such nodules should be rare if not completely absent in TCRLBCL. CD57 positive T-cells are typically increased in nLPHL, and most cases will show rosettes of CD57 positive T-cells around the "popcorn cells." CD57 positive cells are infrequent in most cases of TCRLBCL, and only rarely form rosettes around large B-cells. [18] It should be noted at this point that there clearly are cases of nLPHL that show, in subsequent biopsies, evolution to a morphology consistent with TCRLBCL. In some cases, nLPHL and TCRLBCL may even be identified within the same specimen. [15, 19] A precise cutoff point at which to diagnose nLPHL with a coexisting TCRLBCL, vs. nLPHL with expanded interfollicular areas, has not yet been defined. However, it appears reasonable to reserve a diagnosis of concurrent TCRLBCL for cases with at least large expanses of lymph node occupied by a proliferation with T-cell rich large B-cell morphology, without admixed FDC nodules. These findings have led to a question of whether TCRLBCL represents a "diffuse form" of nLPHL. In fact, comparative genomic hybridization studies performed on the micro-dissected CD20 positive cells from nLPHL and TCRLBCL, do display some common cytogenetic findings, supporting a pathogenetic relationship in at least some cases. [20] However, in the great majority of cases, TCRLBCL presents as a clinical de novo lymphoma, without a prior diagnosis of nLPHL. TCRLCL versus peripheral T-cell lymphoma: Because the vast majority of the infiltrate in cases of TCRLBCL is composed of T-cells, some cases are easily misdiagnosed as a peripheral T-cell lymphoma, unspecified (PTCLU). The key to the correct diagnosis, usually accomplished by an initial round of immunohistochemical stains, is recognition that the scattered large, atypical cells are CD20 positive B-cells while the more numerous CD3 positive cells are cytologically unremarkable. In difficult cases, such as those with a degree of atypia in the background T-cells, a panel of T-cell immunostains should be employed in order to rule out an aberrant T-cell phenotype. PCR studies for a T-cell receptor gamma chain rearrangement, may also be useful to ensure the T-cells represent a polyclonal population. In approximately one half to two thirds of cases of TCRLBCL, a monoclonal immunoglobulin heavy chain rearrangement may be detected. [5, 21] The absence of a monoclonal immunoglobulin rearrangement, however, never excludes the diagnosis of TCRLBCL as the primers employed for immunoglobulin heavy chain analysis in most labs have a high false negative rate. Lastly, it should also be remembered that some T-cell lymphomas will have coexisting large B-cell proliferations. [22, 23, 24, 25] In such cases, the large B-cells are frequently EBV-positive. EBER stains may therefore also be of assistance, as most TCRLBCL would appear to be negative for EBV. [1] References: Lim MS, Beaty M, Sorbara L, et al. T-cell/histiocyte-rich large B-cell lymphoma: a heterogeneous entity with derivation from germinal center B cells. Am J Surg Pathol 26: 1458-1466, 2002. Delabie J, Vandenberghe E, Kennes C, et al. Histiocyte-rich B-cell lymphoma. A distinct clinicopathologic entity possibly related to lymphocyte predominant Hodgkin's disease, paragranuloma subtype. Am J Surg Pathol 16: 37-48, 1992. Gatter KC, Warnke R, Diffuse Large B-cell Lymphoma. in Tumours of Haematopoietic and Lymphoid Tissues. Jaffe ES, Harris NL, Stein H, et al., [Eds.] IARC Press: Lyons. 2001, 171-174. Macon WR, Williams ME, Greer JP, et al. T-cell-rich B-cell lymphomas. 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