Lymphoma Disease Discovery and Definition

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Mediastinal gray zone lymphoma (MGZL) has immuno-pathological features intermediate between mediastinal classical Hodgkin lymphoma (classic Hodgkin lymphoma) and primary mediastinal thymic B-cell lymphoma (PMBL), and was first reported from our laboratory in 2005. The intermediate pathology of MGZL has led to uncertainty regarding its biological relationship to classic Hodgkin lymphoma and PMBL and optimum therapeutic strategy. Immunohistochemistry analysis show most MGZL expressed CD20, like PMBL, and CD15, like classic Hodgkin lymphoma. We performed gene expression profiling on paraffin embedded tumor tissue from patients with MGZL (20), classic Hodgkin lymphoma (18) and PMBL (17) and show that MGZL cluster between classic Hodgkin lymphoma and PMBL. Analysis of specific expression signatures reveals germinal B-cell and interferon regulatory factor 4 signatures were relatively low in MGZL and classic Hodgkin lymphoma compared to PMBL and indicated down regulation of the B-cell program in MGZL, which is a hallmark of classic Hodgkin lymphoma. T-cell and macrophage signatures were higher in MGZL and classic Hodgkin lymphoma compared to PMBL, consistent with infiltrating immune cells, which are found in classic Hodgkin lymphoma. The NFkappaB survival pathway signature was higher in MGZL than PMBL and may explain the greater treatment resistance. Furthermore, we showed that like classic Hodgkin lymphoma, MGZL and PMBL express NFKappaB inducing kinase (NIK), indicating activation of the non-canonical pathway. While this work confirms that MGZL is pathobiologically intermediate between classic Hodgkin lymphoma and PMBL, they case MGZL have a biology associated with increased immune infiltrating cells and NFkappaB survival pathways, while downregulating the B-cell program similar and yet distinct from classical Hodgkin lymphoma. Histiocytic sarcoma is a rare malignant neoplasm that may occur de novo or in the context of a previous hematologic malignancy or mediastinal germ cell tumor. Here, we performed whole exome sequencing and RNA-Seq on twenty-one archival cases of primary histiocytic sarcoma. We identified a high number of genetic alterations within the RAS-RAF-MAPK pathway in 21/21 cases, with alterations in NF1 (6/21), MAP2K1 (5/21), PTPN11 (4/21), BRAF (4/21), KRAS (4/21), NRAS (1/21) and LZTR1 (1/21), including single cases with homozygous deletion of NF1, high-level amplification of PTPN11 and a novel TTYH3-BRAF fusion. Concurrent NF1 and PTPN11 mutations were present in 3/21 cases, and 5/7 cases with alterations in NF1 and/or PTPN11 had disease involving the gastrointestinal tract. Following unsupervised clustering of gene expression data, cases with NF1 and/or PTPN11 abnormalities formed a distinct tumor subgroup. A subset of NF1/PTPN11 wild-type cases had frequent mutations in B-cell lymphoma associated genes and/or clonal IG gene rearrangements. Our findings expand the current understanding of the molecular pathogenesis of this rare tumor and suggest the existence of a distinct subtype of primary histiocytic sarcoma characterized by NF1/PTPN11 alterations with predilection for the gastrointestinal tract. The diagnosis of nodal marginal zone lymphoma can be challenging, with the differential diagnosis including other low-grade B-cell lymphomas, reactive hyperplasia, and even some cases of peripheral T-cell lymphoma (PTCL). PTCL may have a perifollicular growth pattern mimicking nodal marginal zone lymphoma. We and others have noted an atypical distribution of T-follicular helper (TFH) cells in some cases of nodal marginal zone lymphoma. this study was prompted by the diagnosis of nodal marginal zone lymphoma in several cases in which a marked increase of TFH cells, as determined by staining for programmed death-1 (PD1), had prompted suspicion for a diagnosis of PTCL. We analyzed PD1 staining in 48 cases of nodal marginal zone lymphoma to characterize the extent and pattern of the PD1-positive infiltrate. Three main patterns of PD1 staining were identified: follicular pattern (peripheral, n=16; central, n=9; mixed, n=3), diffuse pattern (n=4), and a reduced or normal staining pattern in residual follicles (n=16). A comprehensive analysis of other TFH markers was undertaken in 14 cases with a high content of PD1-positive cells that were confirmed as B-cell lymphoma by clonality analysis. This study illuminated the diverse immunohistochemical patterns encountered in nodal marginal zone lymphoma and highlights a diagnostic pitfall important for diagnostic accuracy. Monomorphic posttransplant lymphoproliferative disorders (PTLD) have been defined as lymphoid or plasmacytic proliferations that fulfil criteria for one of the B-cell or T/NK-cell neoplasms recognized in immunocompetent hosts in the current WHO Classification. Low grade B-cell neoplasms have historically been excluded from this category, although rare reports of marginal zone lymphoma (MZL) have been described. We reported nine cases of posttransplant EBV-negative MZL, all arising in solid organ transplant recipients. Seven were extranodal MZL (EMZL) of MALT type, all of which had gastrointestinal (GI) involvement. Notably, the preferential involvement of intestine distinguishes posttransplant EMZL from sporadic cases. Immunoglobulin light chain restriction was seen in all cases, with PCR showing a monoclonal pattern in seven of eight cases with successful amplification of PCR products. A clonally unrelated recurrence was seen in one case. Next generation sequencing (NGS) identified recurrent mutations previously reported in MZL in 3/5 cases. MZL was diagnosed at least one year after transplant. Mean follow-up was 33.4 months, with an indolent clinical course observed. A subset responded to reduction in immunosuppression and anti-CD20 therapy alone. These data support designation of EBV-negative MZL as an uncommon form of monomorphic PTLD. NK-cell enteropathy, also referred to as lymphomatoid gastropathy, is a recently described, rare indolent NK-cell lymphoproliferative disorder that involves single or multiple sites along the gastrointestinal tract. Patients often present with vague gastrointestinal symptoms, including abdominal pain, constipation, diverticulosis, and reflux, but they have no prior history of celiac disease, inflammatory bowel disease, or malabsorption. The lesions exhibit a chronic, relapsing clinical course, and usually do not show prolonged response to chemotherapy. A distinction from aggressive NK or T-cell lymphoma is of paramount importance to avoid unnecessary aggressive therapies. The pathogenesis of NK-cell enteropathy has been unknown and it was unresolved whether it represents a true neoplastic process, partly due to the challenges of demonstrating clonality in NK cells. We characterized the clinicopathologic features and investigated the mutational profiles and related aberrant signal pathways in this rare entity. We reported the mutational profile of NK-cell enteropathy. We demonstrated recurrent JAK3 K563_C565del mutations in 30% (3/10) of cases, confirming its nature as a neoplasm.