As a follow up to our description of NK-cell enteropathy(1), we identified another novel and indolent gastrointestinal (GI) T-cell lymphoproliferative disorder that can be mistaken for an aggressive T-cell lymphoma.(2) We reported 10 cases with a median age of 48 years (range, 15-77 years). 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 double-negative for CD4 and CD8. T-cell receptor-gamma chain gene rearrangement identified a clonal population in all 10 cases. There was no evidence of STAT3 SH2 domain mutation or activation, an abnormality that has been linked to T-cell large granular lymphocyte leukemia. 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. None of the patients showed evidence of progression beyond the GI tract, with the exception of the one case that was double negative for CD4/CD8, possibly an indication for an alternate diagnosis. 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. As noted above, mutations in STAT3 and also STAT5 have been linked to some forms of T-cell lymphoma and leukemia, Given the central role of STAT3 and STAT5B in the control of T-cell proliferative responses and in gamma delta T-cell development, and accumulating evidence for their involvement in T-cell tumorigenesis, we and our collaborators reasoned that these genes could potentially play a role in hepatosplenic gamma delta T-cell lymphomas as well. To carry out this study, twenty one cases of HSTCL with available formalin-fixed paraffin-embedded tissue were retrieved from the consultation files of the Hematopathology Section of the National Cancer Institute.(3) Seven cases (33.3%) were found to have a STAT5B somatic mutation. All shared the same hot spot mutation, c.1924AC (N642H). Two additional cases (9.5 %) had a STAT3 somatic missense mutation (c.1981GT; p.D661Y and c.1919AT; p.Y640F). All remaining cases showed wild type STAT3 at the targeted sites. STAT3 and STAT5B missense mutations were mutually exclusive. The high frequency of STAT5B and STAT3 mutations in gamma delta HSTCL strongly suggests that deregulation of the STAT pathway is an important oncogenic event in the pathogenesis of this lymphoma. This study was done in collaboration with Dr. Mark Raffeld, of the Specialized Diagnostics Unit, LP, CCR, NCI. In collaboration with Dr. Andrew Feldman's group at Mayo Clinic, we explored the genetic and clinical diversity of ALK-negative anaplastic large cell lymphoma.(4) ALK-negative anaplastic large cell lymphoma (ALCL) is a CD30-positive T-cell non-Hodgkin lymphoma that morphologically resembles ALK-positive ALCL but lacks chromosomal rearrangements of the ALK gene. 73 ALK-negative ALCLs and 32 ALK-positive ALCLs were studied. Chromosomal rearrangements of DUSP22 and TP63 were identified in 30% and 8% of ALK-negative ALCLs, respectively. These rearrangements were mutually exclusive and were absent in ALK-positive ALCLs. Five-year overall survival rates were 85% for ALK-positive ALCLs, 90% for DUSP22-rearranged ALCLs, 17% for TP63-rearranged ALCLs, and 42% for cases lacking all three genetic markers (p0.0001). Thus, ALK-negative ALCL is a genetically heterogeneous disease with widely disparate outcomes following standard therapy. DUSP22 and TP63 rearrangements may serve as predictive biomarkers to help guide patient management. The clinical and pathological spectrum of T-cell and NK-cell malignancies was further explored through participation in a workshop organized jointly by the European Association for Haematopathology and the Society for Hematopathology. These tumors pose a challenge to the diagnostic pathologist. The panel reviewed over 200 submitted cases, which were grouped into five categories: (i) angioimmunoblastic T-cell lymphoma and T-follicular-helper-cell-associated lymphomas; (ii) CD30-positive T-cell lymphomas/lymphoproliferative diseases; (iii) extranodal T-cell and NK-cell neoplasms; (iv) EBV-associated T-cell/NK-cell lymphomas/lymphoproliferative diseases; and (v) peripheral T-cell lymphoma, not otherwise specified, post-transplant lymphoproliferative disorders, and mimics. The report summarized the discussions and conclusions of the workshop, and highlighted areas in which diagnostic categories should be revised in preparation of the revised WHO classification. (5) We have continued our studies of in situ follicular lymphoma (FL). In a longstanding collaboration with the group of Dr. Bertrand Nadel, using high resolution array CGH we explored the genetic aberrations in FL in situ (FLIS), partial involvement by FL, duodenal FL, and nodal FL, Grades 1-2 and Grade 3, with reactive hyperplasia as an additional control(6, 7) The pathogenesis of FL is a multi-hit process progressing over many years through the accumulation of numerous genetic alterations. Besides the hallmark t(14;18), it is still unclear which other oncogenic hits contribute to the early steps of transformation and in which precursor stages these occur. Surprisingly, alterations involving several relevant (onco)genes were found in all entities, but at significantly lower proportions than in overt FL . While the number of alterations clearly assigns all these entities as precursors, the pattern of partial involvement by FL alterations was quantitatively and qualitatively closer to that of FL , indicating significant selective pressure in line with its faster rate of progression. Among the most notable alterations, we observed and validated deletions of 1p36 and gains of the 7p and 12q chromosomes and related oncogenes, which include some of the most recurrent oncogenic alterations in overt FL (TNFRSF14, EZH2, MLL2). By further delineating distinctive and hierarchical molecular and genetic features of early FL entities, our analysis underlines the importance of applying appropriate criteria for the differential diagnosis. It also provides a first set of candidates likely to be involved in the cascade of hits that pave the path of the various progression phases to FL development. 1. Mansoor A, Pittaluga S, Beck PL, et al. NK-cell enteropathy: a benign NK-cell lymphoproliferative disease mimicking intestinal lymphoma: clinicopathologic features and follow-up in a unique case series. Blood. 2011;117:1447-1452. 2. Perry AM, Warnke RA, Hu Q, et al. Indolent T-cell lymphoproliferative disease of the gastrointestinal tract. Blood. 2013;122:3599-3606. 3. Nicolae A, Xi L, Pittaluga S, et al. Frequent STAT5B Mutations in gammadelta Hepatosplenic T-cell Lymphomas. Leukemia. 2014. 4. Parilla Castellar ER, Jaffe ES, Said JW, et al. ALK-negative anaplastic large cell lymphoma is a genetically heterogeneous disease with widely disparate clinical outcomes. Blood. 2014. 5. Attygalle AD, Cabecadas J, Gaulard P, et al. Peripheral T-cell and NK-cell lymphomas and their mimics; taking a step forward - report on the lymphoma workshop of the XVIth meeting of the European Association for Haematopathology and the Society for Hematopathology. Histopathology. 2014;64:171-199. 6. Mamessier E, Song JY, Eberle FC, et al. Early lesions of follicular lymphoma: a genetic perspective. Haematologica. 2014;99:481-488. 7. Mamessier E, Broussais-Guillaumot F, Chetaille B, et al. Nature and importance of follicular lymphoma precursors. Haematologica. 2014;99:802-810.