Lymphoma Disease Discovery and Definition

纵隔灰色区淋巴瘤（MGZL）具有介于纵隔经典霍奇金淋巴瘤（classic Hodgkin lymphoma，经典霍奇金淋巴瘤）和原发性纵隔胸腺b细胞淋巴瘤（primary纵隔胸腺b细胞淋巴瘤，PMBL）之间的免疫病理特征，本实验室于2005年首次报道。MGZL的中间病理导致其与经典霍奇金淋巴瘤和PMBL的生物学关系和最佳治疗策略的不确定性。免疫组织化学分析显示，大多数MGZL表达CD20，如PMBL， CD15，如经典霍奇金淋巴瘤。我们对MGZL（20）、经典霍奇金淋巴瘤（18）和PMBL（17）患者的石蜡包埋肿瘤组织进行了基因表达谱分析，发现MGZL聚集在经典霍奇金淋巴瘤和PMBL之间。特异性表达特征分析显示，与PMBL相比，MGZL和经典霍奇金淋巴瘤的生发b细胞和干扰素调节因子4特征相对较低，表明MGZL中b细胞程序下调，这是经典霍奇金淋巴瘤的标志。与PMBL相比，MGZL和经典霍奇金淋巴瘤的t细胞和巨噬细胞特征更高，与经典霍奇金淋巴瘤中发现的浸润性免疫细胞一致。MGZL患者的NFkappaB生存通路信号高于PMBL患者，这可能解释了MGZL患者更强的治疗耐药性。此外，我们发现与经典霍奇金淋巴瘤一样，MGZL和PMBL表达NFKappaB诱导激酶（NIK），表明非典型途径的激活。虽然这项工作证实了MGZL在病理生物学上介于经典霍奇金淋巴瘤和PMBL之间，但他们发现MGZL在生物学上与免疫浸润细胞和NFkappaB存活途径的增加有关，同时下调b细胞程序，这与经典霍奇金淋巴瘤相似，但又不同。组织细胞肉瘤是一种罕见的恶性肿瘤，可能发生在新生或在背景下，以前的血液系统恶性肿瘤或纵隔生殖细胞肿瘤。在这里，我们对21例原发性组织细胞肉瘤进行了全外显子组测序和RNA-Seq。我们在21/21例病例中发现了RAS-RAF-MAPK通路中的大量遗传改变，其中NF1（6/21）、MAP2K1（5/21）、PTPN11（4/21）、BRAF（4/21）、KRAS（4/21）、NRAS（1/21）和LZTR1（1/21）发生了改变，包括NF1纯合缺失、PTPN11高水平扩增和新型TTYH3-BRAF融合的单个病例。3/21的病例同时存在NF1和PTPN11突变，5/7的NF1和/或PTPN11突变的病例有累及胃肠道的疾病。在对基因表达数据进行无监督聚类后，NF1和/或PTPN11异常的病例形成了一个独特的肿瘤亚组。NF1/PTPN11野生型病例的一个子集在b细胞淋巴瘤相关基因和/或克隆IG基因重排中经常发生突变。我们的发现扩大了目前对这种罕见肿瘤的分子发病机制的理解，并提示存在一种独特的原发性组织细胞肉瘤亚型，其特征是NF1/PTPN11的改变，并倾向于胃肠道。淋巴结边缘区淋巴瘤的诊断具有挑战性，其鉴别诊断包括其他低级别b细胞淋巴瘤、反应性增生，甚至一些外周t细胞淋巴瘤（PTCL）。PTCL可能具有类似淋巴结边缘区淋巴瘤的滤泡周围生长模式。我们和其他人注意到t -滤泡辅助细胞（TFH）在一些淋巴结边缘区淋巴瘤病例中的非典型分布。本研究是由几个诊断为淋巴结边缘区淋巴瘤的病例引起的，其中TFH细胞显著增加，通过程序性死亡-1 （PD1）染色确定，这引起了对PTCL诊断的怀疑。我们分析了48例淋巴结边缘区淋巴瘤的PD1染色，以表征PD1阳性浸润的程度和模式。发现三种主要的PD1染色模式：滤泡模式（外周，n=16；中心，n=9；混合，n=3），弥漫性模式（n=4），残余滤泡减少或正常染色模式（n=16）。对14例经克隆分析证实为b细胞淋巴瘤的高含量pd1阳性细胞进行了其他TFH标志物的综合分析。本研究阐明了淋巴结边缘区淋巴瘤的不同免疫组织化学模式，并强调了诊断准确性的重要诊断缺陷。单纯性移植后淋巴细胞增生性疾病（PTLD）被定义为淋巴细胞或浆细胞增生，符合当前WHO分类中免疫功能正常的宿主所识别的b细胞或T/ nk细胞肿瘤之一的标准。低级别b细胞肿瘤历来被排除在这一类别之外，尽管有罕见的边缘区淋巴瘤（MZL）的报道。我们报告了9例移植后ebv阴性MZL，均发生在实体器官移植受者中。7例为MALT型结外MZL (EMZL)，均累及胃肠道。值得注意的是，肠道优先受累将移植后EMZL与零星病例区分开来。所有病例均可见免疫球蛋白轻链限制性反应，PCR扩增成功的8例病例中有7例显示单克隆模式。一例无性系无关复发。下一代测序（NGS）在3/5的MZL病例中发现了先前报道的复发性突变。MZL在移植后至少一年被诊断出来。平均随访33.4个月，临床病程为无痛。一个亚群对减少免疫抑制和单独抗cd20治疗有反应。这些数据支持ebv阴性MZL作为一种罕见的单态PTLD的指定。nk细胞肠病，也称为类淋巴瘤胃病，是一种最近发现的罕见的惰性nk细胞淋巴增生性疾病，累及胃肠道的单个或多个部位。患者通常表现为模糊的胃肠道症状，包括腹痛、便秘、憩室病和反流，但既往无乳糜泻、炎症性肠病或吸收不良史。病变表现为慢性复发的临床过程，通常对化疗没有长期的反应。区分侵袭性NK细胞淋巴瘤或t细胞淋巴瘤对于避免不必要的侵袭性治疗至关重要。NK细胞肠病的发病机制尚不清楚，也不清楚它是否代表一个真正的肿瘤过程，部分原因是在NK细胞中证明克隆性的挑战。我们描述了这种罕见的实体的临床病理特征，并研究了突变谱和相关的异常信号通路。我们报道了nk细胞肠病的突变谱。我们在30%（3/10）的病例中发现复发性JAK3 K563_C565del突变，证实了其作为肿瘤的性质。

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.