Cutaneous CD4 small/medium-sized pleomorphic T-cell lymphoma (CSTCL) is a cutaneous T-cell lymphoma defined by a predominance of small-to-medium-sized CD4 pleomorphic T cells, with a favorable clinical course. Cases are also characterized by the presence of a rich infiltrate of reactive B cells. Recently, it has been reported that follicular helper T cells (TFH cells) display a distinct gene expression profile, positive for PD-1, CXCL13, and BCL-6. We report for the first time the expression of PD-1 and other TFH cell markers in CSTCLs and discuss its biologic significance. Sixteen CSTCLs were included in this study, and also 20 reactive inflammatory conditions, 10 primary cutaneous marginal zone, 10 follicular center lymphomas, and 5 primary CD30 cutaneous lymphomas. They were immunohistochemically analyzed for a large panel of markers. Double immunoperoxidase labeling of paraffin sections was performed for PD-1, OCT-2, and BCL-6. Clonal Ig and T-cell receptor rearrangements and Epstein-Barr virus-encoded RNA expression were also evaluated. Morphologic and clinical data were reviewed. Histologic examination showed a dense polymorphic lymphoid infiltrate throughout the dermis. Atypical large CD4 cells were positive for PD-1, CXCL13, and BCL-6 in all cases, and were attached in small clusters, or formed rosettes around CD30/OCT-2+ B blast cells. Epstein-Barr virus was not apparent in any of the cases. A dominant T-cell clone was identified in 14 cases, whereas polymerase chain reaction IgH gene rearrangement studies showed that all cases were polyclonal. None of the patients had lymphadenopathy or showed any evidence of systemic disease, nor did they have any previous history of mycosis fungoides or drug reactions. FTH cell markers are not exclusive to angioimmunoblastic lymphadenopathy but may also be seen in neoplastic cells of CSTCLs. Moreover, these findings suggest that B-cell stimulation by FTH could also take place in some cutaneous T-cell lymphomas.
The role of caveolin 1 (CAV1), a structural component of caveolae in breast cancer is controversial, although most studies suggest that it functions as a tumor-suppressor gene. In addition, some studies have identified CAV1 as a marker of myoepithelial cells. Since myoepithelial markers are frequently expressed in breast carcinomas with a basal-like phenotype, which are frequently occurring tumors in women with BRCA1 germline mutations, we evaluated whether CAV1 was associated with a basal-like phenotype in 509 sporadic and 47 hereditary BRCA1-/BRCA2-associated carcinomas. Immunohistochemistry was performed on tissue microarrays and cases were classified as having a basal-like-phenotype if they were estrogen-receptor- and HER2-negative but cytokeratin 5/6- and/or epidermal growth factor receptor-positive. In sporadic carcinomas, CAV1 expression was found in 21 out of 496 valuable cases (4.2%). A basal-like-phenotype was found in 53 out of 498 (10.6%) cases. A strong association was found between CAV1 expression and a basal-like-phenotype, since 52% of tumors that expressed CAV1 had this phenotype, compared with only 9% of CAV1-negative carcinomas (p<0.001). CAV1 was expressed in six (12.8%) familial cases, five of which had a basal-like-phenotype (p = 0.009). Moreover, these six CAV1-positive cases were BRCA1 tumors. The difference in the frequency of CAV1 expression between BRCA1- and BRCA2-associated tumors was statistically significant (p = 0.024). In conclusion, this study reports for the first time CAV1 expression in BRCA1 and BRCA2 hereditary breast cancer and identifies CAV1 as a marker associated with a basal-like-phenotype in both hereditary and sporadic breast cancer.
Key Points• SPIB is an Ets transcription factor involved in plasmacytoid dendritic cell differentiation.• SPIB protein expression can be used as a marker for human blastic plasmacytoid dendritic cell neoplasms.SPIB is an Ets transcription factor that is expressed exclusively in mature B cells, T-cell progenitors, and plasmacytoid dendritic cells. In the present study, we developed a novel mAb against the SPIB protein and characterized its expression in major hematolymphoid neoplasms, including a series of 45 cases of blastic plasmacytoid dendritic cell (BPDC) neoplasms and their potential cutaneous mimics. We found that SPIB is expressed heterogeneously among B-and T-cell lymphoma types. Interestingly, SPIB is expressed in a large proportion of nongerminal center type DLBCLs. In cutaneous neoplasms, SPIB is overexpressed in all BPDC neoplasms, but none of its cutaneous mimics. SPIB remains overexpressed in all cases that lack 1 or 2 of the markers used for BPDC neoplasms (ie, CD4, CD56, TCL1, and CD123). We conclude that SPIB expression can be used as a tool for diagnosing BPDC neoplasms, but it needs to be tested in conjunction with the growing arsenal of markers for human plasmacytoid dendritic cells. (Blood. 2013;121(4):643-647) IntroductionSPIB is an Ets family transcription factor that is expressed exclusively in mature B cells, T-cell progenitors, and plasmacytoid dendritic cells. 1-3 SPIB is required for full BCR signaling and T cell-dependent Ab responses. 4 SPIB is central to the germinal center (GC) reaction because those in SPIB-deficient mice are smaller, persist for less time after immunization, and contain more apoptotic cells than those of wild-type animals. 4 During B-cell maturation, it is first induced in the pre-B-to immature B-cell transition, 5 overexpressed during the GC reaction, 3 and repressed by PRDM1/Blimp1 once plasmacytic differentiation has been initiated. 6 Interestingly, SPIB has also been shown to target Blimp1 directly, providing a regulatory loop essential for the maintenance of GC and memory B cells, thereby preventing the initiation of the plasma cell program of differentiation. 7 Under neoplastic conditions, the SPIB locus has been found to be affected by chromosomal imbalances comprising gains/ amplifications and translocations in activated B-cell (ABC)-type diffuse large B-cell lymphoma (DLBCL) cell lines and clinical samples. 8,9 In fact, SPIB is one of the components of the Wright algorithm that classifies DLBCLs into the GC and ABC types according to their expression profile. 10 In addition, knock-down of SPIB by RNAi is toxic to ABC DLBCL cell lines, but not to other DLBCL subtypes or myeloma, suggesting a role for this putative oncogene in the pathogenesis of ABC-type DLCBL. 8,11 Together with its role during B-cell differentiation, SPIB has been shown to be a key regulator of human plasmacytoid dendritic cell development 1,12 and a component of the signature of blastic plasmacytoid dendritic cell (BPDC) neoplasms, 13 which were formerly known as blastic natural kille...
Peripheral T-cell lymphoma (PTCL) is a clinically aggressive disease, with a poor response to therapy and a low overall survival rate of around 30% after 5 years. We have analyzed a series of 105 cases with a diagnosis of PTCL using a customized NanoString platform that includes 208 genes associated with T-cell differentiation, oncogenes and tumor suppressor genes, deregulated pathways and stromal cell subpopulations. A comparative analysis of the various histological types of PTCL (angioimmunoblastic T-cell lymphoma, AITL; PTCL-with T follicular helper phenotype, PTCL-TFH; PTCL-not otherwise signified, PTCL-NOS) showed that specific sets of genes were associated with each of the diagnoses. These included TFH markers, cytotoxic markers and genes whose expression was a surrogate for specific cellular subpopulations, including follicular dendritic cells, mast cells and genes belonging to precise survival (NF-κB) and other pathways. Furthermore, the mutational profile was analyzed using a custom panel that targeted 62 genes in 76 cases distributed in AITL, PTCL-TFH and PTCL-NOS. The main differences between the three nodal PTCL classes involved the RHOAG17V mutations (p<0.0001), which were approximately twice as frequent in AITL (34.09%) as in PTCL-TFH (16.66%) cases, but were not detected in PTCL-NOS. A multivariate analysis identified gene sets that allowed the series of cases to be stratified into different risk groups. This study supports and validates the current division of PTCL into these three categories, identifies sets of markers that can be used for a more precise diagnosis, and recognizes the expression of B-cell genes as an IPI-independent prognostic factor for AITL.
The Epstein–Barr virus (EBV), Kaposi sarcoma herpesvirus (KSHV) and human T-lymphotropic virus (HTLV-1) are lymphomagenic viruses with region-specific induced morbidity. The RIAL-CYTED aims to increase the knowledge of lymphoma in Latin America (LA), and, as such, we systematically analyzed the literature to better understand our risk for virus-induced lymphoma. We observed that high endemicity regions for certain lymphomas, e.g., Mexico and Peru, have a high incidence of EBV-positive lymphomas of T/NK cell origin. Peru also carries the highest frequency of EBV-positive classical Hodgkin lymphoma (HL) and EBV-positive diffuse large B cell lymphoma, not otherwise specified (NOS), than any other LA country. Adult T cell lymphoma is endemic to the North of Brazil and Chile. While only few cases of KSHV-positive lymphomas were found, in spite of the close correlation of Kaposi sarcoma and the prevalence of pathogenic types of KSHV. Both EBV-associated HL and Burkitt lymphoma mainly affect young children, unlike in developed countries, in which adolescents and young adults are the most affected, correlating with an early EBV seroconversion for LA population despite of lack of infectious mononucleosis symptoms. High endemicity of KSHV and HTLV infection was observed among Amerindian populations, with differences between Amazonian and Andean populations.
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