Lymphoma Disease Discovery and Definition

儿童结节性边缘带淋巴瘤(PNMZL)是一种少见的B细胞肿瘤，主要影响男性儿童和年轻人。这种惰性淋巴瘤具有不同于传统结节边缘带淋巴瘤(NMZL)的明显特征。临床上，它与儿科类型滤泡性淋巴瘤(PTFL)有重叠的特征。为了探讨PNMZL与成人NMZL的区别及其与PTFL的关系，采用综合方法对45例PNMZL进行了形态和遗传学特征分析，包括部分病例的完整外显子组测序、靶向下一代测序、拷贝数(CN)和DNA甲基化阵列。14例(31%)被诊断为PNMZL，31例(69%)PNMZL与PTFL有重叠的组织学特征，包括少量残留的类似于PTFL的锯齿状生发中心，以及PNMZL特有的以滤泡间B细胞为主的成分。所有病例均表现出较低的基因组复杂性(1.2个改变/例)，复发的1p36/TNFRSF14拷贝数中性杂合性改变丢失和CN丢失(11%)。与PTFL相似，PNMZL中突变频率最高的基因是MAP2K1(42%)、TNFRSF14(36%)和IRF8(34%)。DNA甲基化分析显示PTFL与PNMZL之间无显著差异。在传统的NMZL中常见的基因改变在PNMZL中没有。综上所述，我们展示了重叠的临床、形态和分子表现，包括低遗传复杂性、MAP2K1、TNFRSF14和IRF8的反复改变，以及相似的甲基化特征。我们的结果表明，PNMZL和PTFL可能是同一种疾病的一部分，在组织学谱上存在差异。作为单一实体，可命名为儿童型滤泡性淋巴瘤，伴或不伴边缘带分化。结外形式的滤泡性淋巴瘤不同于结节性滤泡性淋巴瘤，这是因为经常没有bcl2重排(bcl2-R)，而且倾向于局限于皮肤而不扩散。其他结外滤泡性淋巴瘤的性质，包括女性生殖道下部的滤泡性淋巴瘤，还没有明确的定义。对15例累及宫颈和阴道的女性下生殖道滤泡性淋巴瘤的临床病理和分子特征进行了研究。所有患者都有局限性疾病，没有骨髓受累的证据。大多数病例呈弥漫性分布，以大的中心细胞为显著特征。这导致了大多数推荐病理学家对弥漫性大B细胞淋巴瘤的担忧。所有病例均有卵泡中心起源。FISH检测bcl2基因重排阴性者占91%。NGS显示，这些病例特别缺乏染色质修饰基因(CREBBP和KMT2D)突变，这些基因是结节性FL的标志。突变最多的基因是TNFRSF14(60%)。所有患者均无进展性疾病，无论接受何种治疗，均获得持久的完全缓解。中位随访期为7.8年(0.2~20.5年，平均8.9年)，总存活率为100%。这些发现共同表明，该肿瘤不同于结节性FL，在临床病理和分子水平上类似于原发皮肤滤泡中心淋巴瘤。尽管有大细胞的成分，但它的特点是分期有限，行为总是良性的。认识和认识这一实体是非常重要的区别于较高级别的淋巴瘤和防止不必要的治疗，因为它仍然是局部的，进展和复发的风险很低。这项工作在2022年的病理学会议上进行了口头介绍，目前正在为最终出版做准备。自1994年修订的欧美成熟淋巴肿瘤分类发表以来，通过反复的国际努力，血液病理学家、遗传学家、分子科学家和临床医生达成了广泛的共识，随后对成熟淋巴肿瘤的分类进行了更新。近年来，随着基因组研究提供了许多新的见解，免疫系统恶性肿瘤的表征取得了重大进展，改变了一些实体的定义，并导致了对其他实体的认识。与我的合作者一起，我领导了一项重大的国际努力，以更新淋巴肿瘤的分类。我们遵循了成功用于世界卫生组织血液肿瘤分类第三版和第四版的相同程序。许多实体的定义、推荐的研究和诊断标准都得到了广泛的改进。一些被认为是临时性的类别现在被升级为确定实体。一些疾病的术语已被修改，以使命名法适应当前对其生物学的了解，但这些修改仅限于有充分理由的情况。最近基因组研究的主要发现影响了许多疾病的概念框架和诊断标准。这些变化将对最佳临床管理产生影响。我们在2022年发表的报告中总结了这项工作的结论，提出了成熟淋巴、组织细胞和树突状细胞肿瘤的国际共识分类(ICC)。

Pediatric nodal marginal zone lymphoma (PNMZL) is an uncommon B-cell neoplasm affecting mainly male children and young adults. This indolent lymphoma has distinct characteristics that differ from conventional nodal marginal zone lymphoma (NMZL). Clinically, it shows overlapping features with pediatric-type follicular lymphoma (PTFL). To explore the differences between PNMZL and adult NMZL and its relationship to PTFL, a series of 45 PNMZL cases was characterized morphologically and genetically using an integrated approach including whole exome sequencing in a subset of cases, targeted next generation sequencing, and copy number (CN) and DNA methylation arrays. Fourteen cases (31%) were diagnosed as PNMZL, whereas 31 cases (69%) showed overlapping histological features between PNMZL and PTFL including a minor component of residual serpiginous germinal centers reminiscent of PTFL and a dominant interfollicular B-cell component characteristic of PNMZL. All cases displayed low genomic complexity (1.2 alterations/case) with recurrent 1p36/TNFRSF14 copy number-neutral loss of heterozygosity alterations and CN loss (11%). Similar to PTFL, the most frequently mutated genes in PNMZL were MAP2K1 (42%), TNFRSF14 (36%), and IRF8 (34%) DNA-methylation analysis showed no major differences between PTFL and PNMZL. Genetic alterations typically seen in conventional NMZL, were absent in PNMZL. In summary, we demonstrated overlapping clinical, morphological and molecular findings including low genetic complexity, recurrent alterations in MAP2K1, TNFRSF14 and IRF8, and similar methylation profiles. Our results indicate that PNMZL and PTFL are likely part of a single disease with variation in the histological spectrum. As a single entity, it could designated as pediatric-type follicular lymphoma, with or without marginal zone differentiation. Extranodal forms of follicular lymphoma differ from nodal follicular lymphoma based on the frequent absence of BCL2-rearrangement (BCL2-R) and the tendency to remain confined to the skin without dissemination. The nature of other extranodal follicular lymphoma, including those of the lower female genital tract, is not well defined. We studied 15 cases of follicular lymphoma of the lower female genital tract involving cervix and vagina to determine their clinicopathological and molecular characteristics. All patients had localized disease, with no evidence of bone marrow involvement. The majority of cases had a diffuse pattern and large centrocytes were a prominent feature. This led to the concern for diffuse large B-cell lymphoma by most referring pathologists. All the cases had a follicle center derivation. The majority (91%) were negative for BCL2 gene rearrangement by FISH. NGS showed these cases specifically lacked mutations in chromatin modifying genes (CREBBP and KMT2D) which are hallmark of nodal FL. The most mutated gene was TNFRSF14(60% cases). None of the patients had progressive disease with all achieving durable complete remission regardless of the treatment received. Median follow-up period was 7.8 years (range: 0.2-20.5 years and mean: 8.9 years) with 100% overall survival. Together these findings show that this tumor distinct from nodal FL and is clinicopathologically and molecularly like primary cutaneous follicle center lymphoma. Despite component of large cells, it is characterized by limited stage presentation and invariably benign behavior. Awareness and recognition of this entity is very important to distinguish it from higher grade lymphomas and to prevent unnecessary treatment as it remains localized with low risk of progression and relapse. This work was presented orally at the pathology meetings in 2022, and is being prepared for final publication. Since the publication of the Revised European-American Classification of mature lymphoid neoplasms in 1994, subsequent updates of the classification of mature lymphoid neoplasms have been generated through iterative international efforts to achieve broad consensus among hematopathologists, geneticists, molecular scientists, and clinicians. Significant progress in the characterization of malignancies of the immune system in the last years, with many new insights provided by genomic studies, have changed the definition of some entities, and have led to the recognition of other entities. With my collaborators, I have led a major international effort to update the classification of lymphoid neoplasms. We have followed the same process that was successfully used for the 3rd and 4th editions of the WHO classification of hematological neoplasms. The definition, recommended studies, and criteria for the diagnosis of many entities have been extensively refined. Some categories considered provisional are now upgraded to definite entities. Terminology of some diseases has been revised to adapt nomenclature to the current knowledge of their biology, but these modifications have been restricted to well-justified situations. Major findings from recent genomic studies have impacted the conceptual framework and diagnostic criteria for many disease entities. These changes will have an impact on optimal clinical management. The conclusions of this work are summarized in our published report in 2022 as the proposed International Consensus Classification (ICC) of mature lymphoid, histiocytic, and dendritic cell tumors.