Lymphoma Disease Discovery and Definition

淋巴瘤疾病的发现和定义

• 批准号: 10702983
• 负责人: Elaine Jaffe
• 金额: $ 92.04万
• 依托单位: DIVISION OF CLINICAL SCIENCES - NCI
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10702983
• 关键词: 1p36; Adult; Affect; American; Awareness; B-Cell Neoplasm; B-Lymphocytes; BCL2 gene; Behavior; Benign; Biology; Bone Marrow Involvement; CREBBP gene; Categories; Cell Proliferation; Cells; Cellular Structures; Centrocyte; Cervix Uteri; Characteristics; Child; Childhood; Chromatin; Classification; Clinical; Clinical Management; Consensus; Cutaneous; DNA Methylation; Derivation procedure; Diagnosis; Diffuse Pattern; Disease; Disease remission; European; Extranodal; Female genitalia; Follicular Lymphoma; Functional disorder; Gene Rearrangement; General Population; Genes; Genetic; Genomic approach; Genomics; Goals; Heel; Hematologic Neoplasms; Histiocytic and Dendritic Cell Neoplasms; Histologic; Immune system; Indolent; International; Knowledge; Limited Stage; Localized Disease; Loss of Heterozygosity; Lymphoid; Lymphoma; MAP2K1 gene; Malignant Neoplasms; Methylation; Minor; Modification; Molecular; Morphology; Mutate; Mutation; Nature; Nodal; Nomenclature; Oral; Pathogenesis; Pathologic; Pathologist; Pathology; Patients; Process; Prognosis; Progressive Disease; Publications; Publishing; Recurrence; Relapse; Reporting; Residual state; Risk; Scientist; Series; Signal Pathway; Skin; Structure of germinal center of lymph node; Terminology; Translating; Update; Vagina; Variant; Work; base; clinical practice; diagnostic criteria; diagnostic tool; disease classification; exome sequencing; follow-up; genetic approach; herpesvirus entry mediator; improved; insight; large cell Diffuse non-Hodgkin' s lymphoma; lymphoid neoplasm; male; meetings; next generation sequencing; novel diagnostics; pediatric follicular lymphoma; prevent; reproductive tract; treatment response; tumor; unnecessary treatment; young adult

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.

小儿淋巴结边缘区淋巴瘤（PNMZL）是一种罕见的B细胞肿瘤， 主要是男孩和年轻人。这种惰性淋巴瘤有明显的特点 与传统的结边缘区淋巴瘤（NMZL）不同。从临床上看， 与小儿型滤泡性淋巴瘤（PTFL）重叠的功能。探讨 PNMZL与成人NMZL之间的差异及其与PTFL的关系，一系列45个PNMZL 采用综合方法，对20例患者进行了形态学和遗传学特征分析，包括 在病例子集中的全外显子组测序、靶向下一代测序和拷贝 数字（CN）和DNA甲基化阵列。14例（31%）被诊断为PNMZL，而 31例（69%）显示PNMZL和PTFL之间的组织学特征重叠，包括 残留的匍匐性生发中心的次要成分使人联想到PTFL， 滤泡间B细胞成分特征PNMZL。所有病例均显示低基因组 复杂性（1.2个变异/例），伴有复发性1 p36/TNFRSF 14拷贝数中性丢失， 杂合性改变和CN丢失（11%）。与PTFL相似，最常发生突变的 PNMZL中的基因是MAP 2K 1（42%）、TNFRSF 14（36%）和IRF 8（34%）。 PTFL和PNMZL之间无显著差异。遗传变异通常见于 传统的NMZL，在PNMZL中不存在。总之，我们证明了重叠的临床， 形态学和分子学发现，包括低遗传复杂性、复发性改变 在MAP 2K 1、TNFRSF 14和IRF 8中，以及类似的甲基化谱。我们的结果表明 PNMZL和PTFL可能是单一疾病的一部分，组织学变化 江西篇章作为一个单一的实体，它可以指定为小儿型滤泡性淋巴瘤， 或无边缘区分异。滤泡性淋巴瘤的结外形式不同， 淋巴结滤泡性淋巴瘤的基础上经常缺乏BCL 2重排（BCL 2-R）和 倾向于保持局限于皮肤而不扩散。其他节点的性质 滤泡性淋巴瘤，包括女性下生殖道的滤泡性淋巴瘤，并没有很好的定义。 我们研究了15例女性下生殖道滤泡性淋巴瘤， 和阴道，以确定其临床病理和分子特征。所有患者 有局限性疾病，没有证据表明骨髓受累。大多数情况下， 弥漫型和大的中心细胞是一个突出的特征。这引起了人们对 弥漫性大B细胞淋巴瘤。所有病例均有卵泡 中心求导大多数（91%）阴性BCL 2基因重排的FISH。NGS 显示这些病例特别缺乏染色质修饰基因（CREBBP和 KMT 2D），其中TNFRSF 14基因突变最多（60%）。没有一 患者的病情进展，所有患者均达到持久的完全缓解， 所接受的治疗。中位随访期为7.8年（范围：0.2-20.5年， 平均：8.9年），总生存率为100%。这些发现表明， 与淋巴结FL不同，在临床病理学和分子学上与原发性皮肤 滤泡中心淋巴瘤尽管是大细胞的组成部分，但其特征在于有限的 舞台表演和总是良性的行为。认识和承认这一实体是 非常重要的是要区分它从更高级别的淋巴瘤，并防止不必要的 治疗，因为它仍然是局部的，进展和复发的风险低。这项工作是 在2022年的病理学会议上口头提出，并正在准备最后的 出版物自修订的欧美成熟分类出版以来， 1994年，成熟淋巴样肿瘤分类的后续更新 通过反复的国际努力， 这是血液病理学家、遗传学家、分子科学家和临床医生的共识。 近年来免疫系统恶性肿瘤特征的重大进展 多年来，基因组研究提供了许多新的见解，改变了一些人的定义。 这是一个实体，并导致了其他实体的认可。我和我的合作者们 这是国际上更新淋巴肿瘤分类的一项重大努力。我们有 遵循了成功用于世界卫生组织第三版和第四版的相同过程， 血液肿瘤的分类。定义、推荐研究和标准 许多实体的诊断已经得到了广泛的改进。审议的一些类别 临时实体现在升级为确定实体。一些疾病的术语 修订以适应其生物学的当前知识的命名，但这些 修改仅限于有充分理由的情况。最近的主要发现 基因组研究影响了许多人的概念框架和诊断标准， 疾病实体。这些变化将对最佳临床管理产生影响。的 我们在2022年发表的报告中总结了这项工作的结论， 成熟淋巴细胞、组织细胞和树突状细胞的国际共识分类（ICC） 细胞肿瘤