Lymphoma Disease Discovery and Defintion

我们继续探索ebv驱动的t细胞和b细胞淋巴细胞增生性疾病的性质。在过去的一年里，我们描述了一系列与EBV相关的粘膜和皮肤淋巴增生性病变，这些病变具有独特的病理和临床特征。（Dojcinov et al., Am J surgical Pathol, 2010）这种新描述的实体具有独特的临床特征，对临床管理和治疗有影响，并且可以在老年人和经常免疫功能低下的患者群体中进行保守管理。研究组包括9名男性和15名女性患者，中位年龄77岁（42-101岁）。8例免疫抑制剂包括硫唑嘌呤（AZA）、甲氨蝶呤（MTX）或环孢素a （CyA）。16例患者仅有年龄相关性免疫衰老。患者表现为孤立的明显边界溃疡，累及粘膜或皮肤部位。组织学上病变包含多形性浸润和非典型大b细胞母细胞，具有霍奇金/里德-斯特恩伯格（RS）细胞样形态。无论IS的解剖部位或病因如何，其病理特征都是相同的。PCR结果显示，31%（5/16）克隆型IgH重排，克隆型和限制性t细胞型重排分别为43%（6/14）和29%（4/14）。26%的患者（5/19）接受了标准化疗和/或放疗。47%的病变（9/19）在未经治疗的情况下自发消退，16%（3/19）的病变以复发和缓解为特征。所有可用随访的医源性病变（5/5）对IS减少有反应。在20.5个月（3-72个月）的中位随访期间，所有患者均获得完全缓解，无疾病相关死亡。我们提出EBV阳性粘膜皮肤溃疡（EBVMCU）作为一种新认识的临床病理实体，具有霍奇金样特征和自限性，无痛病程，通常对保守治疗反应良好。与各种形式的IS相关意味着一个共同的发病机制，通常涉及限制性和克隆t细胞反应。这种疾病的局域性可能是由于对EBV免疫监测的最小和局域性缺失。浆母细胞淋巴瘤（PBL）被认为是弥漫性大b细胞淋巴瘤的一种亚型，与浆细胞骨髓瘤的浆母细胞转化具有许多相似的形态学和免疫表型特征。在人类免疫缺陷病毒（HIV）感染的情况下，两种类型的肿瘤都可能与eb病毒（EBV）相关，因此使它们的区分具有挑战性。此外，这些实体之间的生物学关系尚不清楚。我们报道了4例发生在HIV感染背景下的浆母细胞淋巴瘤，其临床和遗传特征与浆细胞骨髓瘤有重叠（Taddesse-Heath等）。Mod Pathol, 2009)。我们回顾了临床、形态学和细胞遗传学的发现，并使用MYC分离重排探针进行了免疫组织化学、EBV原位杂交、染色体分析和荧光原位杂交（FISH）。除了具有浆母细胞淋巴瘤的结外病变、浆母细胞形态和表型特征外，4例中有3例的临床表现也与浆细胞骨髓瘤重叠，即单克隆血清免疫球蛋白和溶解性骨病变。此外，这些病例表现出在浆细胞骨髓瘤中更常见的复杂的细胞遗传学变化。一个独特的特征是存在MYC （8q24.1）重排，这在所有4例中都被FISH证实。MYC易位与多发性骨髓瘤的肿瘤进展有关，但在浆母细胞淋巴瘤中很少有报道。这些病例显示浆母细胞淋巴瘤与浆细胞骨髓瘤浆母细胞变体之间的临床和生物学关系。我们认为MYC的失调可能是一种共同的遗传机制，赋予b细胞肿瘤在分化后期的浆母细胞形态和侵袭性临床过程。在随访中（Valera et al. In press）， 41例PBL中有20例（49%）发现MYC重排，免疫球蛋白（IG）基因在大多数肿瘤中是伴发基因。MYC重排在ebv阳性肿瘤（19例中有14例，74%）中比ebv阴性肿瘤（21例中有9例，43%）中更常见（p < 0.05）。在所有PBL中未检测到BCL2、BCL6、MALT1或PAX5的重排，但在31-41%的检查病例中观察到这些位点的增加。40个PBL中有12个可以研究3个或更多的基因座，在3个或更多的基因座中有多个同时获得。根据MYC观察，患者的生存期没有差异，但最长生存期（大于50个月）的4例患者没有或很少的获益（少于3次）。在另一项关于浆细胞分化肿瘤的研究中，我们描述了表达免疫球蛋白A （IgA）的骨外浆细胞瘤。在最近发表的一项研究中（Shao et al., Am J Surg Pathol），通过形态学、免疫组织化学和PCR检测免疫球蛋白重链和kappa轻链基因，分析了9例出现在淋巴结的iga阳性浆细胞瘤和3例出现在结外的浆细胞瘤。实验室特征与临床表现相关。中位年龄32岁，6例患者年龄小于30岁。67%（6/9）的淋巴结病患者存在免疫系统功能障碍。6/11例检测到IgA m -尖峰，且m蛋白几乎都小于30 g/L。所有患者均无进展为浆细胞骨髓瘤。我们的研究结果表明，IgA浆细胞瘤可能代表了髓外浆细胞瘤的一种独特形式，其特征是年龄小，与自身免疫性疾病相关，淋巴结频繁受累，进展为浆细胞骨髓瘤的风险低。本小组先前描述了儿童和青年年龄组的边缘区淋巴瘤。到目前为止，染色体畸变还没有在儿科和年轻成人人群中进行分析。我们进行了一项研究，利用荧光原位杂交（FISH）和RT-PCR分析儿童和年轻人淋巴结和结外边缘区淋巴瘤的遗传改变（Rizzo等）。Mod Pathol 2010)。结果与临床表现和免疫表型相关。符合这些标准的病例有41例。年龄范围为1.5 ~ 29岁，18岁以下占49%。85%的边缘带淋巴瘤病例显示免疫球蛋白重链基因重排的证据。59%的病例为淋巴结边缘区淋巴瘤，发病时中位年龄为16岁，M/F比为7:1。21%的淋巴结边缘区淋巴瘤病例包含遗传畸变。17%的人携带18三体，其中一例携带3三体。在一个病例中，免疫球蛋白重链基因易位到一个未知的伴侣基因。41%的病例为结外边缘区淋巴瘤，中位年龄为24岁，M/F比为1.4:1。18%的结外边缘区淋巴瘤病例包含遗传畸变。1例存在涉及IGH和MALT1基因的t(14;18)， 1例存在四倍体，1例包含3三体。总的来说，在儿童和青年人群中，边缘区淋巴瘤遗传畸变的发生率很低，但畸变与成人人群相似。遗传畸变的低发生率可能与保守治疗的总体良好临床结果有关。

We have continued our work exploring the nature of EBV-driven T-cell and B-cell lymphoproliferative disorders. In the past year, we described a series of EBV associated mucosal and cutaneous lymphoproliferative lesions characterized by distinctive pathological and clinical features. (Dojcinov et al., Am J Surg Pathol, 2010) This newly described entity has distinctive clinical features that impact on clinical management and treatment, and can be managed conservatively in this elderly and often immunocompromised patient population. The study group comprised 9 male and 15 female patients, median age 77 years (range 42-101). Immunosuppression in 8 cases included azathioprine (AZA), methotrexate (MTX) or cyclosporin-A (CyA). 16 patients had only age related immunosenescence. The patients presented with isolated sharply circumscribed ulcers involving mucosal or cutaneous sites. Histologically the lesions contained a polymorphous infiltrate and atypical large B-cell blasts with Hodgkin/ Reed-Sternberg (RS) cell-like morphology. The pathological features were identical regardless of the anatomical site or cause of IS. PCR revealed 31% (5/16) clonal IgH rearrangements with 43% (6/14) and 29% (4/14) clonal and restricted T-cell patterns respectively. 26% of patients (5/19) received standard chemotherapy and/or radiotherapy. 47% of lesions (9/19) regressed spontaneously with no treatment and 16% (3/19) were characterized by a relapsing and remitting course. All of the iatrogenic lesions (5/5) with available follow up responded to reduction of IS. All patients achieved complete remission with no disease associated deaths over a median follow up period of 20.5 months (range 3-72). We proposed the term EBV positive Mucocutaneous Ulcer (EBVMCU) as a newly recognized clinico-pathological entity with Hodgkin-like features and a self limited, indolent course, generally responding well to conservative management. Association with various forms of IS implies a common pathogenetic mechanism, frequently involving restricted and clonal T-cell responses. The localized nature of the disease may be due to a minimal and localized lapse in immunosurveillance over EBV. Plasmablastic lymphoma (PBL), which is considered a subtype of diffuse large B-cell lymphoma, shares many similar morphological and immunophenotypic features with plasmablastic transformation of plasma cell myeloma. In the setting of human immunodeficiency virus (HIV) infection, both types of neoplasms can be associated with Epstein-Barr virus (EBV), thus making their distinction challenging. Moreover, the biological relationship between these entities remains unclear. We reported four unique cases of plasmablastic lymphoma occurring in the setting of HIV infection that had overlapping clinical and genetic features with plasma cell myeloma (Taddesse-Heath, et al. Mod Pathol, 2009). We reviewed the clinical, morphological, and cytogenetic findings and performed immunohistochemistry, in situ hybridization for EBV, chromosome analysis, and fluorescent in situ hybridization (FISH) using the MYC break-apart rearrangement probe. In addition to extra-nodal disease, plasmablastic morphology, and phenotype typical of plasmablastic lymphoma, three of the four cases also showed clinical findings overlapping with plasma cell myeloma, that is, monoclonal serum immunoglobulin and lytic bone lesions. Furthermore, these cases showed complex cytogenetic changes that are more commonly observed in plasma cell myeloma. A unique feature was the presence of MYC (8q24.1) rearrangement confirmed by FISH in all four cases. MYC translocation has been associated with tumor progression in multiple myeloma but has only rarely been previously reported in plasmablastic lymphoma. These cases show a clinical and biological relationship between plasmablastic lymphoma and the plasmablastic variant of plasma cell myeloma. We suggested that dysregulation of MYC may be a common genetic mechanism that imparts plasmablastic morphology and aggressive clinical course to B-cell neoplasms at a later stage of differentiation. In a follow up (Valera et al. in press), MYC rearrangements were identified in 20 of 41 (49%) PBL and the immunoglobulin (IG) genes were the partners in most tumours. MYC rearrangements were more common in EBV-positive (14 of 19, 74%) than EBV-negative (9 of 21, 43%) tumours (p less than 0.05). No rearrangements of BCL2, BCL6, MALT1 or PAX5 were detected in any PBL but gains of these loci were observed in 31-41% of the cases examined. Twelve of the 40 PBL in which 3 or more loci could be investigated had multiple simultaneous gains in 3 or more loci. No differences in the survival of the patients according to MYC were observed but the four patients with the longest survival ( greater than 50 months) had no or low number of gains ( less than 3). In another study of neoplasms with plasmacytic differentiation, we characterized extraosseous plasmacytomas expressing immunoglobulin A (IgA) These tumors are rare and not well understood. In a recent study in press (Shao et al., Am J Surg Pathol), nine cases of IgA-positive plasmacytomas presenting in lymph node and three in extranodal sites were analyzed by morphology, immunohistochemistry, and PCR examination of immunoglobulin heavy and kappa light chain genes. Laboratory features were correlated with clinical findings. The median age was 32 , with 6 patients younger than 30. 67% (6/9) of the patients with nodal disease had evidence of immune system dysfunction. An IgA M-spike was detected in 6/11 cases, and the M-protein was nearly always less than 30 g/L. All patients had an indolent clinical course without progression to plasma cell myeloma. Our results suggest that IgA plasmacytomas may represent a distinct form of extramedullary plasmacytoma characterized by young age, association with autoimmune disease, frequent lymph node involvement and low risk of progression to plasma cell myeloma. Our group previously described marginal zone lymphomas in the pediatric and young adult age group. To date, chromosomal aberrations had not been analyzed in the pediatric and young adult population. We undertook a study to analyze genetic alterations in nodal and extranodal marginal zone lymphomas in children and young adults using fluorescence in situ hybridization (FISH) and RT-PCR (Rizzo et al. Mod Pathol 2010). The findings were correlated with clinical features at presentation and immunophenotype. Forty-one cases were identified meeting these criteria. The age range was 1.5-29 years old with 49% of the cases less than 18 years of age. 85% of the marginal zone lymphoma cases tested showed evidence of immunoglobulin heavy chain gene rearrangement. Fifty-nine percent of the cases were nodal marginal zone lymphomas with a median age at presentation of 16 years and an M/F ratio of 7:1. Twenty-one percent of the nodal marginal zone lymphoma cases contained genetic aberrations. Seventeen percent contained trisomy 18 with one case containing an additional trisomy 3. A translocation of the immunoglobulin heavy chain gene to an unknown partner gene was present in one case. Forty-one percent of the cases were extranodal marginal zone lymphomas with a median age of 24 years and a M/F ratio of 1.4:1. Eighteen percent of the extranodal marginal zone lymphoma cases contained genetic aberrations. The t(14;18) involving the IGH and MALT1 genes was present in one case, tetraploidy was present in one case, and another case contained trisomy 3. Overall the incidence of genetic aberrations in marginal zone lymphomas in the pediatric and young adult population is low, but the aberrations seen are similar to those seen in the adult population. The low incidence of genetic aberrations may correlate with the generally excellent clinical outcome with conservative therapy.