Lymphoma Disease Discovery and Defintion

我对经典霍奇金淋巴瘤和其他b细胞淋巴瘤之间的相互关系有着长期的兴趣。这些观察结果为Reed-Sternberg细胞起源于b细胞提供了早期证据。2005年，我们描述了纵隔灰色区淋巴瘤，我们认为这是结节硬化亚型的经典霍奇金淋巴瘤和原发性纵隔大b细胞淋巴瘤之间缺失的一环。我们最近的研究旨在更好地了解纵隔灰色区淋巴瘤，与经典霍奇金淋巴瘤和原发性纵隔大b细胞淋巴瘤进行比较。我们之前通过比较速冻组织和石蜡包埋组织的滤泡淋巴瘤DNA，验证了Illumina金门甲基化法对来自800多个基因的1505个CPG位点的评估。我们使用这个平台来比较纵隔灰色区淋巴瘤、经典霍奇金淋巴瘤和原发性纵隔大b细胞淋巴瘤通过显微解剖分离的肿瘤DNA。主成分分析表明，纵隔灰色区淋巴瘤具有明显的表观遗传谱，介于经典霍奇金淋巴瘤和原发性纵隔大b细胞淋巴瘤之间，但与弥散性大b细胞淋巴瘤明显不同。对常见的低甲基化和高甲基化CPG靶标的分析证实了主成分分析的结果。根据表观遗传谱，我们建立了分类预测模型，可以区分纵隔灰色区淋巴瘤、经典霍奇金淋巴瘤和原发性纵隔大b细胞淋巴瘤，最终联合预测率为100%。我们的研究结果证实了纵隔灰色区淋巴瘤与经典霍奇金淋巴瘤和原发性纵隔大b细胞淋巴瘤的密切关系。然而，也观察到重要的差异，从而允许与两个母实体进行明确区分。因此，纵隔灰色区淋巴瘤不能被归为经典霍奇金淋巴瘤或原发性纵隔大b细胞淋巴瘤，验证了在who分类中创建一个中间类别的决定。在另外的研究中，我们用荧光原位杂交检查了纵膈灰色区淋巴瘤的遗传畸变。通过形态学、免疫表型和荧光原位杂交对灰色区淋巴瘤（27例）、纵隔复合淋巴瘤（3例）和纵隔同步/异时性淋巴瘤（3例）进行分析。24/33例（73%）患者的纵隔受累是确定的。患者队列以男性为主（M: F比20:13），中位年龄32岁（范围16-91岁）。有纵隔疾病的患者明显比无明显纵隔疾病的患者年轻（中位年龄：29.5岁）（中位年龄：55岁）。在33%的患者中观察到2p16.1 （REL/BCL11A位点）的扩增，而在55%的患者中观察到影响9p24.1中JAK2/PDL2位点的改变。进一步的研究显示，8/30例（27%）和7/26例（27%）的CIITA基因座16p13.13重排显示8q24 （MYC）增加。涉及2p16.1、9p24.1和8q24的遗传畸变在明显纵隔受累的病例中发病率更高。然而，与没有已知纵隔受累的病例相比，这在统计学上并不显著。27例灰带淋巴瘤中有12例在形态学上更接近经典霍奇金淋巴瘤，而其他灰带淋巴瘤的形态学特征更接近大b细胞淋巴瘤。灰色带淋巴瘤的两个形态学组Cyclin E（75%和93%）和p63（分别为50%和53%）的表达相似。这些发现进一步支持灰色区淋巴瘤、经典霍奇金淋巴瘤和纵隔大b细胞淋巴瘤之间的密切关系，并提示一些无纵隔疾病的灰色区淋巴瘤可能具有相似的遗传改变。在合作研究中，一项NCI临床试验正在研究纵隔灰色区淋巴瘤的治疗结果。我们的实验室一直对滤泡性淋巴瘤有长期的兴趣，源于我们在1974年的关键观察，显示肿瘤细胞和淋巴滤泡之间的关系。在2002年，我们描述了滤泡性原位淋巴瘤。我们已经描述了区分滤泡性原位淋巴瘤与滤泡性淋巴瘤部分累及的标准，并且最近的研究表明，滤泡性原位淋巴瘤患者随后发生临床相关滤泡性淋巴瘤的风险非常低。滤泡性原位淋巴瘤似乎是外周血中携带BCL2/IGH易位的循环细胞的组织对应物，在50岁以上的50%以上的健康成年人中可以检测到。我们正在研究滤泡性淋巴瘤原位遗传畸变的程度，将其与完全或部分累及淋巴结的滤泡性淋巴瘤进行比较，方法是对全谱病变的激光捕获显微解剖分离的b细胞分离的DNA进行阵列CGH。在2008年发表于《Blood》的一篇全体文章中，我们报道了在FL患者中出现的组织细胞/树突状细胞（H/DC）肉瘤。我们提供的证据表明，H/DC肉瘤与潜在的FL具有克隆相关性，两者都携带相同的IGH基因重排和t（14:18）。我们提供的证据表明，这些肿瘤是通过转分化过程产生的，通过抑制PAX5和上调PU.1和CEBP β介导。这项研究首次证明了成熟的人b细胞在体内或体外的转分化。再加上我们之前对组织细胞树突状细胞肿瘤与急性淋巴细胞白血病（t细胞或b细胞谱系）相关的描述，我们的研究为造血系统细胞之间非凡的谱系可塑性提供了证据。我们的工作导致了许多其他新颖的观察，并有代表性的例子，如所述。我们提供了新的见解，发生率和临床行为的树突状细胞瘤在儿童年龄组。我们描述了一种独特的EBV相关病变，粘膜皮肤溃疡，尽管其组织学特征令人担忧，但临床过程缓慢，我们已经描述了西方世界最大的一系列与年龄相关的EBV驱动的淋巴细胞增生。我们扩大了对儿童和年轻人边缘区淋巴瘤的先前研究，并将其与成人进行了比较，并对病变进行了遗传表征。我们发现了C-MYC易位在浆母细胞淋巴瘤中的高发，并为浆母细胞淋巴瘤和具有浆母细胞特征的浆细胞骨髓瘤之间的密切关系提供了证据。我们描述了淋巴结产生iga的浆细胞肿瘤，并描述了其不寻常的临床特征，通常发生在年轻患者中，通常与自身免疫性疾病相关，但进展为浆细胞骨髓瘤的风险较低。最后，我们确定了一种新的疾病实体，nk细胞肠病，它模仿nk细胞或t细胞淋巴瘤，但具有惰性的临床过程。这项研究发表在《Blood》杂志上，并附有一篇社论，强调了这项研究的重要性。

I have had a long-standing interest in the interrelationship between classical Hodgkin lymphoma and other B-cell lymphomas. These observations helped provide early evidence for a B-cell origin of the Reed-Sternberg cell. In 2005 we described mediastinal gray zone lymphomas, which we proposed to be a missing link between classical Hodgkins lymphoma of the nodular sclerosis subtype and primary mediastinal large B-cell lymphoma. Our recent studies have been directed towards a better understanding mediastinal gray zone lymphoma, in comparison with classical Hodgkins lymphomas and primary mediastinal large B-cell lymphoma. We had previously validated the Illumina golden gate methylation assay for the assessment of 1505 CPG sites from over 800 genes by comparing follicular lymphoma DNA from snap frozen and paraffin-embedded tissue. We used this platform to compare tumor DNA isolated by microdissection from mediastinal gray zone lymphoma, classical Hodgkins lymphoma, and primary mediastinal large B-cell lymphoma. Principal component analysis demonstrated that mediastinal gray zone lymphoma has a distinct epigenetic profile intermediate between classical Hodgkins lymphomas and primary mediastinal large B-cell lymphoma but remarkably different from that of diffuse large B-cell lymphoma. Analysis of common hypo- and hypermethylated CPG targets confirmed the findings of the principal component analysis. Based on the epigenetic profiles we were able to establish class prediction models that could distinguish between mediastinal gray zone lymphoma, classical Hodgkins lymphomas and primary mediastinal large B-cell lymphoma with a final combined prediction of 100%. Our findings confirm the close relationship between mediastinal gray zone lymphoma and both classical Hodgkins lymphomas and primary mediastinal large B-cell lymphoma. However, important differences were observed as well, allowing a clear distinction from both parent entities. Thus, mediastinal gray zone lymphoma cannot be assigned to either classical Hodgkins lymphomas or primary mediastinal large B-cell lymphoma, validating the decision to create an intermediate category in the who classification. In additional studies we have examined the genetic aberrations of mediastinal gray zone lymphoma by fluorescent in situ hybridization. . We analyzed cases of gray zone lymphoma (n=27), mediastinal composite lymphoma (n=3) and mediastinal synchronous/metachronous lymphoma (n=3) by morphology, immunophenotyping and fluorescence in situ hybridization. Mediastinal involvement was assured in 24/33 patients (73%). The patient cohort showed a male predominance (M: F ratio; 20:13) and a median age of 32 years (range, 16-91 years). Patients with mediastinal disease were significantly younger (median age: 29.5 years) than patients presenting without evident mediastinal disease (median age: 55 years). Gains including amplifications in 2p16.1 (REL/BCL11A locus) were observed in 33% of all patients, whereas alterations affecting the JAK2/PDL2 locus in 9p24.1 were present in 55%. Further studies revealed rearrangement of the CIITA locus at 16p13.13 in 8/30 cases (27%) and 7/26 cases (27%) demonstrated gains of 8q24 (MYC). Genetic aberrations involving 2p16.1, 9p24.1 and 8q24 showed a higher incidence in cases with evident mediastinal involvement. However, this was not statistically significant when compared to cases without known mediastinal involvement. Twelve of the 27 cases of gray zone lymphoma were morphologically more reminiscent of classical Hodgkins lymphoma, whereas the other gray zone lymphomas presented with morphological features more closely resembling large B-cell lymphoma. Both morphological groups of gray zone lymphoma were similarly positive for Cyclin E (75% and 93%) and p63 (50% and 53%, respectively) expression. These findings further support a close relationship between gray zone lymphoma, classical Hodgkins lymphoma and mediastinal large B-cell lymphoma, and suggest that some cases of gray zone lymphoma without mediastinal disease may share similar genetic alterations. In collaborative studies, the treatment outcome of mediastinal gray zone lymphoma is being studied in an NCI clinical trial. Our laboratory has had a long standing interest in follicular lymphoma, stemming from our pivotal observations in 1974, showing a relationship between the neoplastic cells and the lymphoid follicle. In 2002 we described follicular lymphoma in situ. We have delineated criteria for the distinction of follicular lymphoma in situ from partial involvement by follicular lymphoma, and in recent studies have shown that patients with follicular lymphoma in situ are at very low risk for subsequent clinically relevant follicular lymphoma. Follicular lymphoma in situ appears to be the tissue counterpart of circulating cells in the peripheral blood carrying the BCL2/IGH translocation, which can be detected in more than 50% of healthy adults over the age of 50. We are studying the extent of genetic aberrations in follicular lymphoma in situ, as compared to follicular lymphoma fully involving or partially involving lymph nodes by performing array CGH of DNA isolated from B-cells isolated by laser capture microdissection of the full spectrum of lesions. In a Plenary article appearing in Blood in 2008, we reported histiocytic/dendritic cell (H/DC) sarcomas arising in patients with FL. We provided evidence that the H/DC sarcomas were clonally related to the underlying FL, both carrying the same IGH gene rearrangement, and the t(14:18). We provided evidence that these tumors arose through a process of transdiffentiation, mediated through repression of PAX5 and upregulation of PU.1 and CEBP beta. This study was the first demonstration of transdifferentiation in a mature human B-cell in an in vivo or in vitro setting. Coupled with our earlier descriptions of histiocytic dendritic cells neoplasms in association with acute lymphocytic leukemia of either T-cell or B-cell lineage, our studies provided evidence for extraordinary lineage plasticity among cells of the hematopoietic system. Our work has led to a number of other novel observations, with representative examples as noted. We provided new insights into the incidence and clinical behavior of blastic plasmacytoid dendritic cell neoplasms in the pediatric age group. We described a unique EBV-related lesion, mucocutaneous ulcer, which despite alarming histological features has an indolent clinical course, and we have characterized the largest series of age-related EBV driven lymphoproliferations in the Western world. We expanded our prior studies of marginal zone lymphoma in the pediatric and young adult population, and characterized the lesions genetically, comparing them with their adult counterparts. We identified a high incidence of C-MYC translocation in plasmablastic lymphoma , and provided evidence for a close relationship between plasmablastic lymphoma and plasma cell myeloma with plasmablastic features. We described IgA-producing plasma cell neoplasms of lymph nodes, and characterized their unusual clinical features, typically occurring in young patients, often associated with autoimmune disease, but with a low risk of progression to plasma cell myeloma. Finally, we identified a new disease entity, NK-cell enteropathy, which mimics NK-cell or T-cell lymphoma, but has an indolent clinical course. This study was published as a Plenary article in Blood, along with an accompanying Editorial, highlighting the significance of the study.