Key Points HVLL is a chronic EBV+ lymphoproliferative disorder of childhood with risk to develop systemic lymphoma. The disease shows favorable response to conservative therapy despite the presence of a T- or NK-cell monoclonal proliferation.

Epstein-Barr virus (EBV)-positive diffuse large B-cell lymphoma of the elderly was included as a provisional entity in the 2008 WHO lymphoma classification. Most reports of this disease come from Asia and little is known about it in other regions of the world, including Latin America. Therefore, in this study, 305 diffuse large B-cell lymphomas in patients above 50 years were analyzed, 136 from Mexico and 169 from Germany. EBV was detected by Epstein-Barr early RNA (EBER) in situ hybridization. Only cases with EBER þ in the majority of tumor cells were regarded as EBV þ diffuse large B-cell lymphoma. The prevalence of EBV þ diffuse large B-cell lymphoma in Mexican patients was found to be 7% (9 of 136), whereas only 2% (4 of 169) of the German cases were positive. The median age at diagnosis was 66 years in the Mexican cohort, as opposed to 77 years in the German group. The site of presentation was in both groups predominantly nodal in nine cases (70%) and extranodal in four cases (30%). Of the 13 EBV þ cases, 10 (77%) were classified as polymorphic and 3 (23%) as monomorphic type. The polymorphic cases showed a non-germinal center B-cell immunophenotype (CD10À MUM1 þ ). Twelve cases (92%) were LMP1 positive and two (15%) expressed EBNA2. An interesting finding was the high frequency of EBV type B with the LMP1 30 bp deletion found in the Mexican cases (50%). Eight of the 11 evaluable cases were B-cell monoclonal by polymerase chain reaction. In summary, we found a similar prevalence of EBV þ diffuse large B-cell lymphoma of the elderly in a Mexican population compared with what has been reported in Asian countries, and in contrast to the low frequency in Western populations (1-3%). However, compared with the Asian series, the Mexican patients were younger at diagnosis, presented predominantly with nodal disease and rarely expressed EBNA2 protein.Modern Pathology (2011Pathology ( ) 24, 1046Pathology ( -1054 doi:10.1038/modpathol.2011 published online 15 April 2011 Keywords: EBV; elderly; large cell lymphoma; Mexico Epstein-Barr virus (EBV) is a ubiquitous herpesvirus that infects 490% of the human population establishing persistent latent infection in the host. 1Although EBV infection is benign in most individuals, it has been linked to the etiology of a rather broad spectrum of B-cell lymphoproliferations both

Key Points• PTFL is a monoclonal B-cell neoplasia with low genomic complexity and recurrent TNFRSF14 mutations/ deletions.• The genetic profiles of conventional t(14;18) 2 and t(14;18) 1 FL are similar but distinct from PTFL.Pediatric-type follicular lymphoma (PTFL) is a variant of follicular lymphoma (FL) with distinctive clinicopathological features. Patients are predominantly young males presenting with localized lymphadenopathy; the tumor shows high-grade cytology and lacks both BCL2 expression and t(14;18) translocation. The genetic alterations involved in the pathogenesis of PTFL are unknown. Therefore, 42 PTFL (40 males and 2 females; mean age, 16 years; range, 5-31) were genetically characterized. For comparison, 11 cases of conventional t(14:18) 2 FL in adults were investigated. Morphologically, PTFL cases had follicular growth pattern without diffuse areas and characteristic immunophenotype. All cases showed monoclonal immunoglobulin (IG) rearrangement. PTFL displays low genomic complexity when compared with t(14;18) 2 FL (mean, 0.77 vs 9 copy number alterations per case; P < .001). Both groups presented 1p36 alterations including TNFRSF14, but copy-number neutral loss of heterozygosity (CNN-LOH) of this locus was more frequently observed in PTFL (40% vs 9%; P 5 .075). TNFRSF14 was the most frequently affected gene in PTFL (21 mutations and 2 deletions), identified in 54% of cases, followed by KMT2D mutations in 16%. Other histone-modifying genes were rarely affected. In contrast, t(14;18) 2 FL displayed a mutational profile similar to t(14;18) 1 FL.In 8 PTFL cases (19%), no genetic alterations were identified beyond IG monoclonal rearrangement. The genetic landscape of PTFL suggests that TNFRSF14 mutations accompanied by CNN-LOH of the 1p36 locus in over 70% of mutated cases, as additional selection mechanism, might play a key role in the pathogenesis of this disease. The genetic profiles of PTFL and t(14;18) 2 FL in adults indicate that these are two different disorders. (Blood. 2016;128(8):1101-1111

Interleukin (IL)-27 is a novel heterodimeric cytokine of the IL-12 family that is composed of two subunits, Epstein-Barr virus (EBV)-induced gene 3 (EBI3) and p28. EBI3 is expressed at high levels in EBV-transformed B-cell lines and is induced in vitro by the EBV oncogene LMP1 in a nuclear factor (NF)-kappaB-dependent manner. We show here that EBI3 expression is up-regulated in human T-cell leukemia virus type 1 (HTLV-1)-infected cell lines and IL-2-dependent leukemic cells from adult T-cell leukemia/lymphoma (ATL) patients, compared to normal activated T cells. EBI3 expression was decreased in HTLV-1-transformed cells after treatment with the NF-kappaB inhibitor BAY11-7082 and was induced in Jurkat cells by expression of HTLV-1 wild-type Tax oncoprotein, but not by the Tax mutant M22, which is defective for NF-kappaB activation. In situ analysis of EBI3 and p28 expression in Hodgkin's lymphomas (HLs), in various EBV-associated lymphoproliferative disorders (LPDs) (including post-transplant LPDs and nasal-type NK/T-cell lymphomas), and in ATL showed that EBI3 was expressed by neoplastic cells in all cases of HL and of LMP1-positive EBV-associated LPD, at variable levels in ATL cases, but rarely in control T-cell lymphomas. In contrast, in all lymphomas tested, no or few tumoral cells expressed p28. Consistent with these data, no significant p28 or IL-27 expression was detected in HL-derived cell lines, or in EBV- or HTLV-1-transformed cell lines. This selective overexpression of EBI3 by transformed cells suggests that EBI3 may play a role, independently from its association to p28, in regulating anti-viral or anti-tumoral immune responses.

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Fifty-five cases of t(14;18)− follicular lymphoma (FL) were genetically characterized by targeted sequencing and copy number (CN) arrays. t(14;18)− FL predominated in women (M/F 1:2); patients often presented during early clinical stages (71%), and had excellent prognoses. Overall, t(14;18)− FL displayed CN alterations (CNAs) and gene mutations carried by conventional t(14;18)+ FL (cFL), but with different frequencies. The most frequently mutated gene was STAT6 (57%) followed by CREBBP (49%), TNFRSF14 (39%), and KMT2D (27%). t(14;18)− FL showed significantly more STAT6 mutations and lacked MYD88, NOTCH2, MEF2B, and MAP2K1 mutations compared with cFL, nodal marginal zone lymphoma (NMZL), and pediatric-type FL (PTFL). We identified 2 molecular clusters. Cluster A was characterized by TNFRSF14 mutations/1p36 alterations (96%) and frequent mutations in epigenetic regulators, with recurrent loss of 6q21-24 sharing many features with cFL. Cluster B showed few genetic alterations; however, a subgroup with STAT6 mutations concurrent with CREBBP mutations/16p alterations without TNFRSF14 and EZH2 mutations was noted (65%). These 2 molecular clusters did not distinguish cases by inguinal localization, growth pattern, or presence of STAT6 mutations. BCL6 rearrangements were demonstrated in 10 of 45 (22%) cases and did not cluster together. Cases with predominantly inguinal presentation (20 of 50; 40%) had a higher frequency of diffuse growth pattern, STAT6 mutations, CD23 expression, and a lower number of CNAs, in comparison with noninguinal cases (5.1 vs 9.1 alterations per case; P &lt; .05). STAT6 mutations showed a positive correlation with CD23 expression (P &lt; .001). In summary, t(14;18)− FL is genetically a heterogeneous disorder with features that differ from cFL, NMZL, and PTFL.

We studied eight patients with characteristic features of angioimmunoblastic T cell lymphoma (AILD-TL) associated with more than 25% of large B cells. Polymerase chain reaction (PCR) analysis showed a clonal rearrangement of the T cell receptor (TCR)-gamma chain gene in all cases. One additional case showed a clonal rearrangement of the TCR-beta chain gene by Southern blot hybridization. PCR analysis showed a clonal immunoglobulin rearrangement in three cases presenting with more than 50% of large B cells whereas the other cases had a germline configuration. In 6/8 cases, doublelabeling immunohistochemistry and in situ hybridization demonstrated that Epstein-Barr virus (EBV) was mostly present in the large B cells but also detected in some T cells. We further evaluated the frequency of AILD-TL with more than 25% of large B cells in the 106 cases collected by the French GELA group and found an incidence of 18%. The outcome of these patients did not differ significantly from those with less than 25% of B cells. With this approach we confirm the heterogeneity of AILD-TL features and the possible association with a substantial numbers of CD20 + , EBV + large B cells. We propose to denominate these cases as 'AILD-TL rich in large B cells' and to consider them as a different entity which can be misdiagnosed as a reactive process or as T cell rich B cell lymphoma.

Carcinoid tumors are common neoplasms developing in gastrointestinal and respiratory tract. They are rarely found in the kidney. To date, approximately 40 cases of primary renal carcinoid tumors have been reported, with less of a third of them occurring within a horseshoe kidney. These cases appear to have a better prognosis, even in the presence of distant metastases, compared to those arising in normal kidneys.