BackgroundCyclin D1-negative mantle cell lymphoma is difficult to distinguish from other small B-cell lymphomas. The clinical and pathological characteristics of patients with this form of lymphoma have not been well defined. Overexpression of the transcription factor SOX11 has been observed in conventional mantle cell lymphoma. The aim of this study was to determine whether this gene is expressed in cyclin D1-negative mantle cell lymphoma and whether its detection may be useful to identify these tumors.

IntroductionMantle cell lymphoma (MCL) represents ϳ 5%-10% of all nonHodgkin lymphomas. It is characterized by the expansion of mature B-clonal lymphocytes harboring the t(11;14)(q13;q32) translocation, which induces overexpression of cyclin D1, and consequent cell cycle deregulation. In addition, MCL tumor cells carry a high number of secondary chromosomal and molecular alterations affecting proteins involved in cell cycle progression, senescence, and cellular response to DNA damage. 1 The prognosis for this disease is in most cases extremely poor, with a median survival of 5-7 years. 2 Conventional chemotherapeutic regimens have been the standard treatment of MCL. However, all these strategies are rapidly confronted with the onset of resistance, and allogenic bone marrow transplantation represents the only potential curative approach in young patients. 3 Recently, new therapeutic approaches have been entered into the clinic, and the proteasome inhibitor bortezomib was approved for the treatment of relapsed/refractory MCL. 4 Bortezomib induces a p53-independent cytotoxicity, mediated by the proapoptotic BH3-only protein NOXA, and the generation of reactive oxygen species in MCL cells. 5 Further studies have shown a synergism between bortezomib and the BH3-mimetics, obatoclax and ABT-737, highlighting the relevance of NOXA induction to counteract the protective effect of MCL-1 accumulation in proteasomecompromised cells. 6,7 Hypotheses to explain how MCL cells can acquire resistance to bortezomib include the overexpression and/or accumulation of antiapoptotic BCL-2 proteins, the rise of a bortezomib-resistant nuclear factor-B activity, and an increased proteasomal activity. [8][9][10] Despite these studies, the precise mechanism by which bortezomib-resistant MCL cases could lose the capacity to undergo NOXA-mediated mitochondrial apoptosis remains unclear.A key defect might reside within the endoplasmic reticulum (ER) stress pathway, because its activation in MCL cells exposed to bortezomib has been recently shown to elicit NOXA transcription. 11 ER homeostasis is controlled by the immunoglobulin heavy chain binding protein (BiP), also referred as 78-kDa glucose-regulated protein (Grp78). BiP/Grp78 forms a large multiprotein complex with a set of other ER molecular chaperones, including the heat shock protein of 90 kDa (Hsp90) ER homolog, Grp94, protein disulfide isomerase, calcium binding protein, and cyclophilin B. 12 Under nonstressed conditions, BiP/Grp78 binds to and maintains in an inactive monomeric state the ER transmembrane PKR-like ER kinase, inositol requiring protein 1 (IRE1), and the bZIP activating transcription factor 6. 13,14 After proteasome inhibition, the accumulation of polyubiquitinated and misfolded proteins within the ER lumen leads to BiP/Grp78 dissociation from the luminal domains of these sensor proteins, leading to the initiation of the unfolded protein response (UPR): the cytosolic domain of activating transcription factor 6 is cleaved, enabling the protein to translocate and to activ...

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

Primary adrenal lymphoma is extremely rare, accounting for o1% of non-Hodgkin lymphomas, and lymphomaassociated chromosomal translocations have yet to be reported in this entity. We performed a retrospective study of 10 cases in immunocompetent patients including 4 males and 6 females with a median age of 68 years. The most common presenting symptoms were abdominal pain and fever; unexpectedly, clinically evident adrenal insufficiency was detected only in one patient. The mean tumor size at diagnosis was 8.5 cm. Half of the patients had bilateral involvement. All cases presented with stage IE disease without regional nodal involvement. Histologically, eight cases were diffuse large B-cell lymphoma, all of which carried a nongerminal center B-cell phenotype. Fluorescence in situ hybridization revealed BCL6 gene rearrangement in 5 (83%) of 6 diffuse large B-cell lymphomas investigated. The remaining cases were one case each of plasmablastic lymphoma and extranodal NK/T-cell lymphoma, nasal type, the first and third case of primary adrenal lymphoma of these particular lymphoma subtypes in the English literature, respectively. At a median follow-up of 4.5 months, 7 patients died of lymphoma, 1 died of an unrelated disease, 1 was alive with disease, and 1 was alive without disease. The prognosis of these patients was poor as compared with those with nodal diffuse large B-cell lymphoma. We speculate that the poor outcome of primary adrenal lymphoma might be related to the bulky tumor size at presentation, non-germinal center B-cell phenotype, and frequent BCL-6 gene rearrangement. Keywords: adrenal insufficiency; diffuse large B-cell lymphoma; NK/T-cell lymphoma; plasmablastic lymphoma; primary adrenal lymphoma; Taiwan Although secondary involvement of the adrenal glands by non-Hodgkin's lymphoma is not uncommon, primary adrenal lymphoma is extremely rare and accounts for o1% of all non-Hodgkin's lymphoma cases. 1 In the English literature, most of the papers on primary adrenal lymphomas are singlecase reports and literature reviews based on a small number of cases except two large series. [1][2][3][4][5] Up to half of the small number of reported patients with primary adrenal lymphoma were associated with adrenal insufficiency and there is a high rate of