• Diagnostic signatures for PTCL subtypes and 2 novel subgroups with distinct oncogenic pathway and prognostic importance in PTCL-NOS were identified. • Demonstrated that ALK(-) ALCL is a distinct molecular entity and the tumor microenvironment has prognostic significance in AITL patients.Peripheral T-cell lymphoma (PTCL) encompasses a heterogeneous group of neoplasms with generally poor clinical outcome. Currently 50% of PTCL cases are not classifiable: PTCL-not otherwise specified (NOS). Gene-expression profiles on 372 PTCL cases were analyzed and robust molecular classifiers and oncogenic pathways that reflect the pathobiology of tumor cells and their microenvironment were identified for major PTCL-entities, including 114 angioimmunoblastic T-cell lymphoma (AITL), 31 anaplastic lymphoma kinase (ALK)-positive and 48 ALK-negative anaplastic large cell lymphoma, 14 adult T-cell leukemia/lymphoma and 44 extranodal NK/T-cell lymphoma that were further separated into NK-cell and gdT-cell lymphomas. Thirty-seven percent of morphologically diagnosed PTCL-NOS cases were reclassified into other specific subtypes by molecular signatures. Reexamination, immunohistochemistry, and IDH2 mutation analysis in reclassified cases supported the validity of the reclassification. Two major molecular subgroups can be identified in the remaining PTCL-NOS cases characterized by high expression of either GATA3 (33%; 40/121) or TBX21 (49%; 59/121). The GATA3 subgroup was significantly associated with poor overall survival (P 5 .01). High expression of cytotoxic genesignature within the TBX21 subgroup also showed poor clinical outcome (P 5 .05). In AITL, high expression of several signatures associated with the tumor microenvironment was significantly associated with outcome. A combined prognostic score was predictive of survival in an independent cohort (P 5

The tumor microenvironment plays an important role in the biologic behavior of follicular lymphoma (FL), but the specific cell subsets involved in this regulation are unknown. To determine the impact of FOXP3-positive regulatory T cells (Tregs) in the progression and outcome of FL patients, we examined samples from 97 patients at diagnosis and 37 at first relapse with an anti-FOXP3 monoclonal antibody. Tregs were quantified using computerized image analysis. The median overall survival (OS) of the series was 9.9 years, and the FL International Prognostic Index (FLIPI) was prognostically significant. The median Treg percentage at diagnosis was 10.5%. Overall, 49 patients had more than 10% Tregs, 30 between 5% to 10%, and 19 less than 5%, with a 5-year OS of 80%, 74%, and 50%, respectively (P ‫؍‬ .001). Patients with very low numbers of Tregs (< 5%) presented more frequently with refractory disease (P ‫؍‬ .007). The prognostic significance of Treg numbers was independent of the FLIPI. Seven transformed diffuse large B-cell lymphomas (DLBCLs) had lower Treg percentages (mean: 3.3%) than FL grades 1,2 (mean: 12.1%) or 3 (mean: 9%) (P < .02).

Rare cases of histiocytic and dendritic cell (H/DC) neoplasms have been reported in patients with follicular lymphoma (FL), but the biologic relationship between the 2 neoplasms is unknown. We studied 8 patients with both FL and H/DC neoplasms using immunohistochemistry, fluorescence in situ hybridization (FISH) for t(14;18), and polymerase chain reaction (

A high content of PD-1-positive cells predicted favorable outcome of FL patients, whereas a marked reduction is observed in transformation.

Purpose: The therascreen PIK3CA mutation assay and the alpha-specific PI3K inhibitor alpelisib are FDA-approved for identifying and treating patients with advanced PIK3CA-mutated (PIK3CAmut) breast cancer (BC). However, it is currently unknown to what extend this assay detects most PIK3CA mutations in BC. This information is critical as patients and clinicians are using this and other genomic assays to indicate alpelisib. Methods: Data from 6338 patients with BC was explored across 10 publicly available studies. The primary objective was to evaluate the proportion and distribution of PIK3CA mutations in BC. Secondary objectives were (1) to evaluate in silico the spectrum of PIK3CA mutations in BC that would be captured by the therascreen panel; (2) to evaluate the proportion and distribution of PIK3CA mutations in hormone receptor-positive/HER2-negative (HR+/ HER2−), HER2+, and triple-negative BC (TNBC); and (3) to explore the identification of PIK3CA mutations in a cohort of 48 HR+/HER2− advanced BC patients by the Guardant B360 circulating tumor DNA (ctDNA) assay. Results: Patients with PIK3CAmut tumors represented 35.7% (2261/6338). Five PIK3CA mutations comprised 73% of all PIK3CA mutations: H1047R (35%), E545K (17%), E542K (11%), N345K (6%), and H1047L (4%). Therascreen gene list would capture 72% of all PIK3CA mutations and 80% of patients with a known PIK3CAmut BC. Among patients with double PIK3CAmut tumors (12% of all PIK3CAmut), the therascreen panel would capture 78% as harboring 1 single PIK3CA mutation, 17% as PIK3CAmut undetected, and 5% as PIK3CA double-mut. PIK3CA mutation rates were lower in TNBC (16%) compared to HR+/HER2 (42%) and HER2+ (31%) BC; however, the distribution of the 4 main PIK3CA mutations across subtypes was similar. Finally, 28% of PIK3CA mutations identified in ctDNA in 48 patients with advanced HR+/HER2− BC were not part of the therascreen panel.

IntroductionMature microRNAs (miRNAs) are naturally occurring small noncoding RNAs that act as negative regulators of gene expression through messenger RNA interference. These molecules were described for the first time in 1993 by Ambros and colleagues in Caenorhabditis elegans (Lee et al 1 ), and to date, hundreds of miRNAs have been identified in other species, including viruses. 2,3 miRNAs are encoded by intronic or intergenic DNA regions, primarily as large molecules that can exceed 1 Kb, and are cleaved by an RNase complex into fragments with characteristic stem-loop structures. In the cytoplasm, a RNase called Dicer further cleaves miRNA to generate a duplex molecule of 21 to 25 nucleotides in length. 4 One of the 2 chains is the mature miRNA that binds a protein complex called the RNA-induced silencing complex (RISC). When a miRNA and a messenger RNA exhibit total complementarities, RISC is capable of degrading target messenger RNA, 4 whereas if an incomplete base pairing complementarity takes place, translational silencing of the target occurs. Through these mechanisms, miRNAs decrease translation of human genes. 5,6 miRNAs play an important role in cellular proliferation and differentiation and embryonic development, and they also act as oncogenes or tumor suppressor genes. 7-10 Notably, the majority of miRNAs are found in cancer-associated genomic regions or in chromosome-fragile sites, 11 suggesting an important role for miRNAs in human tumorigenesis. There is also evidence that the influence of miRNAs in oncogenesis might be indirectly driven. For example, the presence of some viruses in a cell may change the host miRNA pattern. 12 Viruses may participate in the origin of some tumors, such as the Epstein-Barr virus (EBV) in Hodgkin lymphoma (HL).HL is a neoplasm characterized by the presence of relatively few tumoral cells (Hodgkin and Reed-Sternberg cells) in a nonneoplastic microenvironment. 13 Hodgkin and Reed-Sternberg cells arise from germinal center B cells. 14 Classic HL (cHL) is subclassified according to the morphology of Reed-Sternberg cells and the composition of the cellular background into nodular sclerosis, mixed cellularity, lymphocyte-rich, and lymphocyte depletion. 15 The 2 former subtypes are the most frequent forms of cHL and contain a variable proportion of neoplastic cells.EBV is present in the malignant cells of 40% to 60% of cHL patients. However, the precise role of the EBV in the pathogenesis of cHL is unknown. It has been reported that viruses have their own miRNA set, 16 and that there is an interaction between the host miRNAs and virus miRNAs. 17,18 The interaction between the virus and the malignant cells in cHL might be mediated in part by miRNAs.To investigate whether a specific expression signature of miRNAs is associated with cHL, we assessed the expression of 156 miRNAs, the majority of which are related to hematopoiesis or tumorigenesis, 7,8,11 in lymph nodes from patients with nodular sclerosis and mixed cellularity cHL and compared the expression patterns with tho...

PCSM-TCL is a heterogeneous group of tumors with differentiated clinical and pathological characteristics with impact in the outcome of the patients.

γδ T-cells represent a minor T-cell subset mainly distributed in mucosal surfaces. Two distinct lymphomas derived from these cells have been recognized: hepatosplenic γδ T-cell lymphoma (HSTL) and primary cutaneous γδ T-cell lymphoma (PCGD-TCL). However, whether other anatomic sites may also be involved and whether they represent a spectrum of the same disease is not well studied. The lack of TCRβ expression has been used to infer a γδ origin when other methods are not available. We studied 35 T-cell tumors suspected to be γδ TCL using monoclonal antibodies reactive with TCR δ or γ in paraffin sections. We were able to confirm γδ chain expression in 22 of 35 cases. We identified 8 PCGD-TCL, 6 HSTL, and 8 γδ TCL without hepatosplenic or cutaneous involvement involving mainly extranodal sites. Two such cases were classified as enteropathy associated T-cell lymphoma, type II. The other γδ TCL presented in the intestine, lung, tongue, orbit and lymph node. In addition we observed 13 cases with mainly extranodal involvement that lacked any TCR expression (“TCR silent”). In all cases an NK origin was excluded. In conclusion, the lack of TCRβ expression does not always predict a γδ T-cell derivation since TCR silent cases may be found. The recognition of γδ TCL presenting in extranodal sites other than skin and liver/spleen expands the clinical spectrum of these tumors. However, non- HSTL γδ TCL do not appear to represent a single entity. The relationship of these tumors to either HSTL or PCGD-TCL requires further study.