LIM domain only 2 (LMO2) expression distinguishes T-lymphoblastic leukemia/lymphoma from indolent T-lymphoblastic proliferations.

AIMS: An indolent T-lymphoblastic proliferation (iT-LBP) is a benign, reactive expansion of immature terminal deoxynucleotidyl transferase (TdT)-positive T cells found in extrathymic tissues. iT-LBP can be challenging to distinguish from malignant processes, specifically T-lymphoblastic lymphoma (T-LBL), given the overlapping clinical and histological features. Recently, it has been shown that LIM domain only 2 (LMO2) is overexpressed in T-LBL but not in reactive immature TdT+ T cells in the thymus. On the basis of these findings, the aim of this study was to investigate the expression of LMO2 by using immunohistochemistry and its role in differentiating iT-LBPs from T-LBLs. METHODS AND RESULTS: We retrospectively identified cases of iT-LBP and T-LBL from the pathology archives of four institutions. Seven iT-LBP cases (including five new cases that have not been reported in the literature) and 13 T-LBL cases were analysed. Clinical, morphological, immunophenotypic and molecular data were analysed. Immunohistochemical staining with LMO2 was performed on all iT-LBP and T-LBL cases. A review of five new iT-LBP cases showed similar morphological, immunophenotypic and molecular features to those of previously reported cases. All iT-LBP cases were negative for LMO2 (0/7), whereas 92% of T-LBL cases (12/13) expressed LMO2; the sensitivity was 92% (confidence interval 64-100%) and the specificity was 100% (confidence interval 59-100%). CONCLUSION: We confirm previously published findings that iT-LBP cases show highly overlapping morphological and immunophenotypic features with T-LBL. Importantly, LMO2 expression is a sensitive and specific marker with which to rule out iT-LBP.

Indolent T-cell lymphoproliferative disease of the gastrointestinal tract.

Primary gastrointestinal (GI) T-cell lymphoma is an infrequent and aggressive disease. However, rare indolent clonal T-cell proliferations in the GI tract have been described. We report 10 cases of GI involvement by an indolent T-cell lymphoproliferative disease, including 6 men and 4 women with a median age of 48 years (range, 15-77 years). Presenting symptoms included abdominal pain, diarrhea, vomiting, food intolerance, and dyspepsia. The lesions involved oral cavity, esophagus, stomach, small intestine, and colon. The infiltrates were dense, but nondestructive, and composed of small, mature-appearing lymphoid cells. Eight cases were CD4(-)/CD8(+), 1 was CD4(+)/CD8(-), and another was CD4(-)/CD8(-). T-cell receptor-γ chain gene rearrangement identified a clonal population in all 10 cases. There was no evidence of STAT3 SH2 domain mutation or activation. Six patients received chemotherapy because of an initial diagnosis of peripheral T-cell lymphoma, with little or no response, whereas the other 4 were followed without therapy. After a median follow-up of 38 months (range, 9-175 months), 9 patients were alive with persistent disease and 1 was free of disease. We propose the name "indolent T-LPD of the GI tract" for these lesions that can easily be mistaken for intestinal peripheral T-cell lymphoma, and lead to aggressive therapy.

Improvements in observed and relative survival in follicular grade 1-2 lymphoma during 4 decades: the Stanford University experience.

Recent studies report an improvement in overall survival (OS) of patients with follicular lymphoma (FL). Previously untreated patients with grade 1 to 2 FL treated at Stanford University from 1960-2003 were identified. Four eras were considered: era 1, pre-anthracycline (1960-1975, n = 180); era 2, anthracycline (1976-1986, n = 426); era 3, aggressive chemotherapy/purine analogs (1987-1996, n = 471); and era 4, rituximab (1997-2003, n = 257). Clinical characteristics, patterns of care, and survival were assessed. Observed OS was compared with the expected OS calculated from Berkeley Mortality Database life tables derived from population matched by gender and age at the time of diagnosis. The median OS was 13.6 years. Age, gender, and stage did not differ across the eras. Although primary treatment varied, event-free survival after the first treatment did not differ between eras (P = .17). Median OS improved from 11 years in eras 1 and 2 to 18.4 years in era 3 and has not yet been reached for era 4 (P < .001), with no suggestion of a plateau in any era. These improvements in OS exceeded improvements in survival in the general population during the same period. Several factors, including better supportive care and effective therapies for relapsed disease, are likely responsible for this improvement.

Uterine Rosai-Dorfman disease (sinus histiocytosis with massive lymphadenopathy).

We report a unique case of Rosai-Dorfman disease (sinus histiocytosis with massive lymphadenopathy) involving the uterus. A 63-yr-old female with a history of parathyroid adenoma and cavernous sinus meningioma underwent total abdominal hysterectomy for a possible uterine malignancy. The histologic findings consisted of a nodular, mass-like infiltration of the myometrium by clusters, cords, and sheets of CD163-positve, S100-positive histiocytes with lymphocytophagocytosis (emperipolesis). The cells were negative for CD1a and langerin. Occasional plasma cells and erythrocytes were also present. Most of the histiocytes had pale, vacuolated, or foamy cytoplasm. In all cases, the nuclei were small and eccentric. No mitotic figures were identified. Two prior cases of Rosai-Dorfman disease have been reported in the female genital tract: 1 in the cervix and 1 in the bilateral ovaries. Rosai-Dorfman disease should be added to the differential diagnosis of histiocyte-rich lesions in the female genital tract. The diagnosis should be strongly considered in the presence of the characteristic histology with lymphocytophagocytosis (emperipolesis). A limited immunohistochemical panel consisting of CD163, S100, and CD1a and/or langerin will confirm the diagnosis in most cases.

CD137 is expressed in follicular dendritic cell tumors and in classical Hodgkin and T-cell lymphomas: diagnostic and therapeutic implications.

CD137 (also known as 4-1BB and TNFRSF9) is a member of the tumor necrosis factor receptor superfamily. Originally identified as a costimulatory molecule expressed by activated T cells and NK cells, CD137 is also expressed by follicular dendritic cells, monocytes, mast cells, granulocytes, and endothelial cells. Anti-CD137 immunotherapy has recently shown promise as a treatment for solid tumors and lymphoid malignancies in preclinical models. We defined the expression of CD137 protein in both normal and neoplastic hematolymphoid tissue. CD137 protein is expressed by follicular dendritic cells in the germinal center and scattered paracortical T cells, but not by normal germinal-center B cells, bone marrow progenitor cells, or maturing thymocytes. CD137 protein is expressed by a select group of hematolymphoid tumors, including classical Hodgkin lymphoma, T-cell and NK/T-cell lymphomas, and follicular dendritic cells neoplasms. CD137 is a novel diagnostic marker of these tumors and suggests a possible target for tumor-directed antibody therapy.

Indolent T-lymphoblastic proliferation (iT-LBP): a review of clinical and pathologic features and distinction from malignant T-lymphoblastic lymphoma.

In recent years, a new pathologic entity has emerged: indolent T-lymphoblastic proliferation (iT-LBP). iT-LBPs share immunophenotypic similarities with T-lymphoblastic lymphoma; however, T-lymphoblastic proliferations are clinically indolent, and unlike the malignant counterpart, these expansions of nonclonal terminal deoxynucleotidyl transferase (TdT)+ T cells do not require treatment. Here we review the clinical and pathologic features, which are required for an accurate diagnosis of an iT-LBP. We demonstrate specific criteria can be used to accurately diagnose iT-LBP, notably: (1) confluent groups of TdT+ T cells in a biopsy specimen, (2) relative preservation of surrounding normal lymphoid architecture, (3) TdT+ T cells without morphologic atypia, (4) absence of thymic epithelium, (5) nonclonal TdT+ T cells, (6) immunophenotype of developmentally normal immature thymic T cells, and (7) clinical evidence of indolence (follow-up >6 mo without progression).

In situ mantle cell lymphoma: clinical implications of an incidental finding with indolent clinical behavior.

BACKGROUND: Cyclin D1-positive B cells are occasionally found in the mantle zones of reactive lymphoid follicles, a condition that has been called "in situ mantle cell lymphoma". The clinical significance of this lesion remains uncertain. DESIGN AND METHODS: The clinical and pathological characteristics, including SOX11 expression, of 23 cases initially diagnosed as in situ mantle cell lymphoma were studied. RESULTS: Seventeen of the 23 cases fulfilled the criteria for in situ mantle cell lymphoma. In most cases, the lesions were incidental findings in reactive lymph nodes. The t(11;14) was detected in all eight cases examined. SOX11 was positive in seven of 16 cases (44%). Five cases were associated with other small B-cell lymphomas. In two cases, both SOX11-positive, the in situ mantle cell lymphoma lesions were discovered after the diagnosis of overt lymphoma; one 4 years earlier, and one 3 years later. Twelve of the remaining 15 patients had a follow-up of at least 1 year (median 2 years; range, 1-19.5), of whom 11 showed no evidence of progression, including seven who were not treated. Only one of 12 patients with an in situ mantle cell lymphoma lesion and no diagnosis of mantle cell lymphoma at the time developed an overt lymphoma, 4 years later; this case was also SOX11-positive. The six remaining cases were diagnosed as mantle cell lymphoma with a mantle zone pattern. Five were SOX11-positive and four of them were associated with lymphoma without a mantle zone pattern. CONCLUSIONS: In situ mantle cell lymphoma lesions are usually an incidental finding with a very indolent behavior. These cases must be distinguished from mantle cell lymphoma with a mantle zone pattern and overt mantle cell lymphoma because they may not require therapeutic intervention.

Human Germinal Center-associated Lymphoma (HGAL) Is a Reliable Marker of Normal and Neoplastic Follicular Helper T Cells Including Angioimmunoblastic T-Cell Lymphoma.

The diagnosis of angioimmunoblastic T-cell lymphoma (AITL) is complex and requires the demonstration of a T-follicular helper (TFH) phenotype. Immunophenotypic markers that detect the TFH phenotype are highly variable, thereby necessitating the use of 3 to 5 TFH markers to substantiate a TFH phenotype. We tested the utility of germinal center markers human germinal center-associated lymphoma (HGAL) and LIM-domain only 2 (LMO2) in detecting a TFH phenotype. We compared their staining to that of 6 TFH markers in current use, PD-1, ICOS, CXCL13, SAP, CD10, and BCL6, in a cohort of 23 AITL. Our results show that although both markers can detect a TFH phenotype, HGAL was superior to LMO2 in the percent of cells stained and the intensity of staining, 2 variables used to generate H-scores. Using H-scores as the metric, HGAL was most comparable to BCL6 among the currently used TFH markers and was more sensitive than CXCL13, SAP, CD10, and LMO2. PD-1 and ICOS emerged as the most robust of the 8 markers tested in this study in detecting a TFH phenotype. We conclude that HGAL is a reliable marker of TFH cells and can aid in the diagnosis of lymphomas of TFH derivation, particularly in the recognition of early patterns of AITL.

CD20-Negative Nodular Lymphocyte-Predominant Hodgkin Lymphoma: A 20-Year Consecutive Case Series From a Tertiary Cancer Center.

CONTEXT.­: Nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) is a rare, indolent Hodgkin lymphoma subtype with distinct clinicopathologic features and treatment paradigms. The neoplastic lymphocyte-predominant cells typically express bright CD20 and other B-cell antigens, which distinguishes them from Hodgkin/Reed-Sternberg cells of lymphocyte-rich classic Hodgkin lymphoma. OBJECTIVE.­: To characterize the clinicopathologic features of CD20-negative NLPHL at a single institution. DESIGN.­: A retrospective search for CD20-negative NLPHL in our pathology archives and medical records was conducted. RESULTS.­: Of 486 NLPHL patients identified with CD20 available for review, 14 (2.8%) had LP cells with absent CD20 expression. Patients with prior rituximab administration (n = 7) and insufficient clinical history (n = 1) were excluded, leaving 6 patients with rituximab-naïve, CD20-negative NLPHL. A broad immunohistochemical panel showed the LP cells in all cases expressed B-cell antigens, particularly Oct-2, although PAX5 and CD79a were frequently also dim. CD30, CD15, and Epstein-Barr virus-encoded small RNAs were negative in all evaluated cases. Two patients had high-risk variant immunoarchitectural pattern D. One patient had extranodal disease, involving the spleen and bone, and was suspected to have large cell transformation. Standard NLPHL therapy was given, including local radiation and/or chemotherapy. Of 5 patients with available follow-up, 4 are alive in complete remission after therapy, and 1 is alive with relapsed disease. CONCLUSIONS.­: NLPHL can lack CD20 de novo without prior rituximab therapy. In such cases, extensive immunophenotyping helps distinguish NLPHL from lymphocyte-rich classic Hodgkin lymphoma, which differ in clinical behavior and therapy. In our series, CD20-negative NLPHL showed both classic and variant histologic patterns and the expected range of clinical behavior seen in NLPHL, including 1 case with suspected large cell transformation.

Follicular lymphomas with plasmacytic differentiation include two subtypes.

Follicular lymphomas with plasmacytic differentiation were described more than two decades ago. However, the possibility that some of these reported cases are marginal zone lymphomas or composite lymphomas must be considered. In addition, it is also uncertain whether follicular lymphomas with plasmacytic differentiation have any unique cytogenetic or other features. Therefore, fluorescence immunophenotypic and interphase cytogenetic analysis of 14 well-characterized follicular lymphomas with plasmacytic differentiation was performed using a CD138 antibody to identify the plasma cells and with BCL2, BCL6, IGH@ and MALT1 break-apart probes and a chromosome 12 centromeric probe. CD10 was expressed in 12/14 cases, BCL6 in 12/12 cases and BCL2 in 12/14 cases. At least one cytogenetic abnormality was identified in 12/14 cases. The same abnormality was present in both the plasmacytic (CD138+) and non-plasmacytic (CD138-) component in all 10 evaluable cases. BCL2 rearrangements were present in seven cases (5 IGH@ rearranged, 1 IGH@-not rearranged, 1 IGH@-not evaluable), BCL6 rearrangement in two (1 also with BCL2/IGH@ rearrangement), +12 in 1, +MALT1 without +18 in 1, IGH@ rearrangement without other abnormalities in 1 and IGH@ rearranged or partially deleted in 1 case. No cases showed +BCL6 (3q27) or a MALT1 rearrangement. All six cases with an isolated BCL2 rearrangement had predominantly interfollicular plasmacytic cells whereas, 6/7 cases without the translocation had concentrations of intrafollicular or perifollicular plasmacytic cells (P<0.005), as did the case with BCL2 and BCL6 translocations. These results support the existence of bona fide follicular lymphomas with plasmacytic differentiation and support the clonal relationship of the neoplastic lymphoid and plasma cells in at least most of these cases. The differential distribution of the plasma cells, specifically in relation to the presence or absence of an isolated BCL2 rearrangement suggests that the latter cases may be distinctive, sharing some features with marginal zone lymphomas.

Castleman disease: an update on classification and the spectrum of associated lesions.

Since its initial description, researchers have expanded the spectrum of Castleman disease to include not only the classic and well-recognized hyaline-vascular type, but also the plasma cell type and multicentric types of broader histologic range, including human herpes virus-8-associated Castleman disease. These less common subtypes of Castleman disease are less familiar, and may be under-recognized. Also of practical importance, current authors are restructuring the classification of multicentric Castleman disease to accommodate the emerging pathogenic role of human herpes virus-8 and its association with the recently described plasmablastic variant. In addition to an increased risk of lymphoma, patients with Castleman disease also are at increased risk for other related neoplasms, including Kaposi sarcoma and follicular dendritic cell tumors, which are of prognostic and therapeutic relevance. This review focuses on the histologic diagnosis of Castleman disease, current and emerging concepts in its pathogenesis and classification, and associated histopathologic entities.

Indolent In Situ B-Cell Neoplasms With MYC Rearrangements Show Somatic Mutations in MYC and TNFRSF14 by Next-generation Sequencing.

Systemic high-grade B-cell lymphomas (HGBCLs) with MYC gene rearrangements are clinically aggressive. In situ lesions with indolent behavior have not been described to date. We have identified 2 cases of in situ B-cell neoplasms with MYC rearrangements (IS-BCN, MYC) occurring, and focally confined to ≤4 lymphoid follicles in otherwise healthy individuals and without clinical progression despite minimal intervention (surgical only). Morphologically similar to systemic HGBCLs, the low power view of these lesions showed a starry sky pattern with numerous mitotic figures. High power imaging demonstrated these cells to be medium-large in size with irregular nuclear contours, immature chromatin, and prominent nucleoli. Immunophenotypically these cells were light chain restricted, positive for CD20, CD10, c-Myc, and dim or negative for BCL2 with a Ki67 proliferative index of >95%. By fluorescence in situ hybridization studies, we detected MYC translocations in these cells but no rearrangements in BCL2 or BCL6. Microdissection of neoplastic cells in these patients followed by targeted next-generation sequencing identified a mutation in MYC, D2N, and an indel in TNFRSF14. Mutations in ID3 or TCF3 were not identified. Although rare, these lesions should be separated from HGBCLs involving follicles but with systemic spread which has been previously described. Unlike systemic lymphomas with MYC gene rearrangements, these in situ B-cell neoplasms with MYC rearrangements did not require systemic therapy and no progression has been seen in either patient beyond 1 year (29 and 16 mo). Our work offers pathologic and biologic insight into the early process of B-cell neoplasia.

The frequency of immunoglobulin heavy chain gene and T-cell receptor gamma-chain gene rearrangements and Epstein-Barr virus in ALK+ and ALK- anaplastic large cell lymphoma and other peripheral T-cell lymphomas.

We previously identified a relatively high frequency of B-cell proliferations along with simultaneous T-cell receptor gamma-chain gene (TRG) and immunoglobulin heavy chain gene (IGH) rearrangements in a series of angioimmunoblastic T-cell lymphoma and peripheral T-cell lymphoma, unspecified. Here, we report on a series of 74 peripheral T-cell lymphoma (PTCL) cases composed entirely of specific PTCL subtypes, including 28 cases of ALK+ anaplastic large-cell lymphoma (ALCL), 35 cases of ALK- ALCL, and 11 cases that represent other specific PTCL subtypes. We performed IGH and TRG gene rearrangement studies and in situ hybridization for Epstein-Barr virus (EBV) to determine the frequency of IGH clonality and to investigate the relationship between EBV, clonality, and associated B-cell proliferations. Using BIOMED-2 PCR assays, we detected TRG clones in 64 of 74 (86%) cases and IGH clones in 6 of 74 (8%) cases, with all IGH-positive cases exhibiting a concurrent TRG clone. Despite the detection of occasional IGH clones, there was no correlation between IGH clonality and EBV, and B-cell proliferations were not identified in any of the cases. These findings suggest that other factors contribute to IGH clonality and demonstrate that, in the absence of an associated B-cell proliferation, IGH clonality occurs infrequently (8%) in specific PTCL subtypes.

Immunohistochemical characterization of nasal-type extranodal NK/T-cell lymphoma using a tissue microarray: an analysis of 84 cases.

Nasal-type extranodal natural killer (NK)/T-cell lymphoma is an uncommon malignancy. By using a tissue microarray, we characterized 84 cases of extranodal NK/T-cell lymphoma with regard to expression of 18 immunohistochemical markers and the presence of Epstein-Barr virus (EBV) RNA. In our series, CD2 was positive in 69 (93%) of 74 cases, CD3 in 68 (84%) of 81, CD5 in 22 (27%) of 81, CD20 in 0 (0%) of 82, CD29 in 75 (91%) of 82, CD30 in 29 (35%) of 84, CD43 in 81 (96%) of 84, CD54 in 58 (72%) of 81, CD56 in 46 (58%) of 79, CD62L in 23 (28%) of 83, CD183 in 66 (80%) of 83, BCL2 in 33 (39%) of 84, cutaneous lymphocyte antigen in 21 (25%) of 84, granzyme B in 70 (83%) of 84, Ki-67 in 59 (71%) of 83, linker for activation of T cells in 60 (71%) of 84, perforin in 66 (86%) of 77, TIA1 in 76 (90%) of 84, and EBV in 73 (87%) of 84. Hierarchical cluster analysis separated primary cutaneous cases from cases manifesting in other sites based on lower expression of the cell adhesion molecule CD54.

Nodular lymphocyte-predominant Hodgkin lymphoma presenting as fulminant hepatic failure in a pediatric patient: a case report with pathologic, immunophenotypic, and molecular findings.

A 7-year-old boy presented with fulminant hepatic failure requiring liver transplant. Serologic testing ruled out infectious and autoimmune causes. During transplant surgery he was found to have enlarged periportal lymph nodes that were biopsied. Nodular lymphocyte-predominant Hodgkin lymphoma was diagnosed based on histologic examination of the lymph node and liver. The L&H cells within the lymph node were positive for CD20 whereas those within the liver were not, although they were positive for other B-cell markers. After extensive work-up, the cause of liver failure could only be attributed to the involvement by lymphoma. In addition, B-cell clonality was established among the neoplastic cells with the same clone detected in all sampled tissues. Hodgkin lymphoma as a cause of hepatic failure is rare and has not been previously reported in a pediatric patient.

Next-generation sequencing of idiopathic multicentric and unicentric Castleman disease and follicular dendritic cell sarcomas.

Castleman disease (CD) is a rare lymphoproliferative disorder subclassified as unicentric CD (UCD) or multicentric CD (MCD) based on clinical features and the distribution of enlarged lymph nodes with characteristic histopathology. MCD can be further subtyped based on human herpes virus 8 (HHV8) infection into HHV8-associated MCD, HHV8-/idiopathic MCD (iMCD), and polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin change (POEMS)-associated MCD. In a subset of cases of UCD, an associated follicular dendritic cell sarcoma (FDCS) may be seen. Although numerous reports of the clinical and histologic features of UCD, MCD, and FDCS exist, an understanding of the genetic and epigenetic landscape of these rare diseases is lacking. Given this paucity of knowledge, we analyzed 15 cases of UCD and 3 cases of iMCD by targeted next-generation sequencing (NGS; 405 genes) and 3 cases of FDCS associated with UCD hyaline vascular variant (UCD-HVV) by whole-exome sequencing. Common amplifications of ETS1, PTPN6, and TGFBR2 were seen in 1 iMCD and 1 UCD case; the iMCD case also had a somatic DNMT3A L295Q mutation. This iMCD patient also showed clinicopathologic features consistent with a specific subtype known as Castleman-Kojima disease (thrombocytopenia, anasarca, fever, reticulin fibrosis, and organomegaly [TAFRO] clinical subtype). Additionally, 1 case of UCD-HVV showed amplification of the cluster of histone genes on chromosome 6p. FDCS associated with UCD-HVV showed mutations and copy number changes in known oncogenes, tumor suppressors, and chromatin structural-remodeling proteins.

Epstein-Barr virus negative clonal plasma cell proliferations and lymphomas in peripheral T-cell lymphomas: a phenomenon with distinctive clinicopathologic features.

Clonal B-cell populations have been described in peripheral T-cell lymphomas (PTCL) as secondary Epstein-Barr virus (EBV) driven B-cell expansions that may evolve to an overt B-cell lymphoma. EBV-negative B-cell proliferations associated with T-cell lymphomas are uncommon and not well characterized. We studied 15 patients who developed an EBV-negative B-cell proliferation or malignant lymphoma associated with PTCL. The T-cell tumors were 8 PTCL, not otherwise specified, 4 angioimmunoblastic T-cell lymphomas, and 3 cutaneous PTCL. The B-cell component was intermingled with the PTCL in all patients and it was classified as clonal/monotypic plasma cell proliferation in 8 lesions, clonal/monotypic large B-cell proliferation in 4 patients, and B-cell lymphoma with plasmacytic/plasmablastic differentiation in 3 patients. Two patients had 2 clonally unrelated plasma cell proliferations associated with the same PTCL. All cases showed cytoplasmic Ig light chain restriction. Clonal IgH and T-cell receptor rearrangements were detected in 11/12 and 11/13 cases examined, respectively. EBV, cytomegalovirus, and HHV-8 were not observed in any of the examined cases. Sequential samples in 7 patients showed persistence of the PTCL and the B-cell component in 4, the PTCL without the B-cell lymphoma in 2, and progression of the B-cell neoplasm in 1. Patients followed an aggressive clinical course similar to conventional PTCL. In conclusion, EBV-negative clonal or mononotypic B-cell proliferations in patients with PTCL present with a spectrum of lesions ranging from plasma cell proliferations to overt lymphomas with plasmacytic/plasmablastic features. The distinctive features of these patients suggest that these lesions represent a specific phenomenon in PTCL.

Morphologic and immunophenotypic variants of nodal T-cell lymphomas and T-cell lymphoma mimics.

Given their relative rarity, one of the primary diagnostic difficulties in nodal T-cell lymphomas is recognizing their range of histologic patterns. This is complicated by the fact that most mature T-cell lymphomas retain some functional characteristics of nonneoplastic T cells, ie, the capacity to secrete cytokines and costimulate immune cell growth, and, thus, are associated with obscuring nonneoplastic immune cells. Sessions 2 and 3 of the Society for Hematopathology/European Association for Haematopathology Workshop focused on these issues and conditions that may simulate T-cell lymphomas. We summarize salient features of presented cases, including the varied patterns seen in angioimmunoblastic T-cell lymphoma (AITL) and other more poorly characterized morphologic and functional nodal T-cell lymphoma subsets. Many cases illustrated the difficulties distinguishing AITL from peripheral T-cell lymphoma, unspecified, when the neoplasms manifest only some AITL features. The usefulness of separately classifying T-cell lymphomas that demonstrate follicular, perifollicular, or T-zone patterns of infiltration; significance of immunophenotypically distinct subsets that express cytotoxic markers or have features of central memory T cells; diagnostic difficulties posed by B-cell proliferations that accompany T-cell lymphomas; and T-cell lymphoma mimics related to genetic disorders, immune dysregulation, and drug reactions are also discussed.

The frequency of B- and T-cell gene rearrangements and epstein-barr virus in T-cell lymphomas: a comparison between angioimmunoblastic T-cell lymphoma and peripheral T-cell lymphoma, unspecified with and without associated B-cell proliferations.

We report on a series of 58 cases of angioimmunoblastic T-cell lymphoma (AILT) and 59 cases of peripheral T-cell lymphoma, unspecified (PTCL-NOS). Subsets of cases from both diagnostic groups were complicated by associated B-cell proliferations, and we performed B- and T-cell clonality studies and in situ hybridization for Epstein-Barr virus (EBV) to investigate the relationship between B-cell proliferation, B-cell clonality, and EBV. Using multiplex polymerase chain reaction assays based on the BIOMED-2 collaborative study, we detected TCRgamma T-cell clones in 78 and 81% of AILT and PTCL-NOS cases, respectively, and IGH B-cell clones in 34 and 35% of AILT and PTCL-NOS cases, respectively. The majority of cases contained EBV-positive cells, including 50% of AILT and 57% of PTCL-NOS cases, and cases with B-cell proliferations were more often EBV-positive. Although a relatively high rate of B-cell clonality has been shown for AILT, our findings for PTCL-NOS differ from previous reports in that B-cell clonality was relatively frequent. Overall, a positive B-cell clone correlated, in part, with the presence of a B-cell proliferation but not with EBV. Our findings demonstrate that B-cell clonality is a common finding in AILT and PTCL-NOS, and its presence should not negate the diagnosis established by morphologic, immunophenotypic, and clinical findings.

Isolated Follicles Enriched for Centroblasts and Lacking t(14;18)/BCL2 in Lymphoid Tissue: Diagnostic and Clinical Implications.

We sought to address the significance of isolated follicles that exhibit atypical morphologic features that may be mistaken for lymphoma in a background of reactive lymphoid tissue. Seven cases that demonstrated centroblast-predominant isolated follicles and absent BCL2 staining in otherwise-normal lymph nodes were studied. Four of seven cases showed clonal B-cell proliferations amid a polyclonal B cell background; all cases lacked the IGH-BCL2 translocation and BCL2 protein expression. Although three patients had invasive breast carcinoma at other sites, none were associated with systemic lymphoma up to 44 months after diagnosis. The immunoarchitectural features of these highly unusual cases raise the question of whether a predominance of centroblasts and/or absence of BCL2 expression could represent a precursor lesion or atypical reactive phenomenon. Differentiating such cases from follicular lymphoma or another mimic is critical, lest patients with indolent proliferations be exposed to unnecessarily aggressive treatment.