ALK阳性大B细胞淋巴瘤：七例的临床病理与分子特征分析

ALK-positive large B-cell lymphoma: a clinicopathological and molecular characteristics analysis of seven cases

PATHOLOGY

影响因子:3

分区:医学3区 / 病理学3区

发表日期:2024 Dec

作者: Xuan Wang, Hongmei Yi, Qingxiao Liu, Tuanjie Guo, Anqi Li, Binshen Ouyang, Yimin Li, Yuxiu Zhang, Haimin Xu, Lei Dong, Xu Wang, Chaofu Wang

DOI: 10.1016/j.pathol.2024.05.014

摘要

间变性淋巴瘤激酶（ALK）阳性大B细胞淋巴瘤（ALK+ LBCL）是一种罕见且高度侵袭性的淋巴瘤，具有特征性的ALK重排。虽然涉及ALK的融合基因多种多样，但ALK融合伙伴对ALK蛋白表达的影响及其遗传特征尚未充分阐明。本研究对七例ALK+ LBCL进行了详尽的临床、组织病理/免疫表型及分子分析，旨在探讨ALK融合基因与ALK蛋白表达的相关性，并丰富该肿瘤的遗传特征。我们结合临床、组织病理/免疫表型和分子研究（包括三例进行的下一代测序和六例的RNA检测），发现五种不同类型的ALK融合基因，分别为CLTC、NPM1、PABPC1、SEC31A和TFG。值得注意的是，只有NPM1::ALK融合显示核及细胞质ALK染色，其他四种融合基因均表现为细胞质染色。分析显示，CLTC::ALK融合导致独特的细胞质高尔基区域局灶性颗粒状异质染色模式。此外，检测到六个潜在临床意义的基因突变，包括TET2、CHD2、DTX1、KMT2D、LRP1B和XPO1。所有病例中均观察到5-羟甲基胞嘧啶（5hmC）的丧失。我们报道了七例ALK+ LBCL，探讨融合基因与ALK蛋白表达的关系，增强了对该肿瘤遗传特征的理解。本研究还发现几乎所有病例中都存在5hmC的缺失，与TET2突变无关。

Abstract

Anaplastic lymphoma kinase-positive large B-cell lymphoma (ALK+ LBCL) is a rare and highly aggressive lymphoma with characteristic ALK rearrangements. Various fusion genes involving ALK have been demonstrated, but the influence of the ALK fusion partners on ALK protein expression and the genetic characteristics of ALK+ LBCL remain relatively unknown. In this study, we conducted an extensive clinicopathological and molecular analysis on seven cases of ALK+ LBCL to explore the correlation between ALK fusion genes and ALK protein expression, thereby enriching the genetic characteristics of this tumour. We integrated the findings from clinical, histopathological/immunophenotypic, and molecular studies, including three samples subjected to next-generation sequencing, and six cases underwent RNA-based ALK fusion gene detection. We identified five distinct types of ALK fusion genes, including CLTC, NPM1, PABPC1, SEC31A, and TFG. Notably, only the NPM1::ALK fusion showed nuclear and cytoplasmic ALK staining, and the remaining four fusion genes resulted in cytoplasmic ALK staining. Our analysis revealed that the CLTC::ALK fusion resulted in a unique cytoplasmic perinuclear Golgi zone focal granular heterogeneous staining pattern of ALK. Additionally, we identified six potentially clinically significant gene mutations, including TET2, CHD2, DTX1, KMT2D, LRP1B, and XPO1. Furthermore, in all cases, the absence of 5-hydroxymethylcytosine (5hmC) was observed. We present seven cases of ALK+ LBCL, discussing the correlation between fusion genes and ALK protein expression, and enhancing our understanding of the genetic attributes of this tumour. This study also shows the loss of 5hmC in nearly all seven ALK+ LBCL cases, independently of TET2 mutations.