Department of Pathology, Radboud University Medical Center, Nijmegen, The Netherlands.
Department of Hematology, Radboud University Medical Center, Nijmegen, The Netherlands.
Blood Adv. 2023 Oct 10;7(19):5911-5924. doi: 10.1182/bloodadvances.2023010412.
Despite high cure rates in classic Hodgkin lymphoma (cHL), relapses are observed. Whether relapsed cHL represents second primary lymphoma or an underlying T-cell lymphoma (TCL) mimicking cHL is underinvestigated. To analyze the nature of cHL recurrences, in-depth clonality testing of immunoglobulin (Ig) and T-cell receptor (TCR) rearrangements was performed in paired cHL diagnoses and recurrences among 60 patients, supported by targeted mutation analysis of lymphoma-associated genes. Clonal Ig rearrangements were detected by next-generation sequencing (NGS) in 69 of 120 (58%) diagnoses and recurrence samples. The clonal relationship could be established in 34 cases, identifying clonally related relapsed cHL in 24 of 34 patients (71%). Clonally unrelated cHL was observed in 10 of 34 patients (29%) as determined by IG-NGS clonality assessment and confirmed by the identification of predominantly mutually exclusive gene mutations in the paired cHL samples. In recurrences of >2 years, ∼60% of patients with cHL for whom the clonal relationship could be established showed a second primary cHL. Clonal TCR gene rearrangements were identified in 14 of 125 samples (11%), and TCL-associated gene mutations were detected in 7 of 14 samples. Retrospective pathology review with integration of the molecular findings were consistent with an underlying TCL in 5 patients aged >50 years. This study shows that cHL recurrences, especially after 2 years, sometimes represent a new primary cHL or TCL mimicking cHL, as uncovered by NGS-based Ig/TCR clonality testing and gene mutation analysis. Given the significant therapeutic consequences, molecular testing of a presumed relapse in cHL is crucial for subsequent appropriate treatment strategies adapted to the specific lymphoma presentation.
尽管经典霍奇金淋巴瘤（cHL）的治愈率很高，但仍会出现复发。复发的 cHL 是否代表第二原发淋巴瘤或模拟 cHL 的潜在 T 细胞淋巴瘤（TCL）尚未得到充分研究。为了分析 cHL 复发的性质，对 60 例患者的配对 cHL 诊断和复发样本进行了深入的免疫球蛋白（Ig）和 T 细胞受体（TCR）重排克隆性检测，同时对淋巴瘤相关基因进行了靶向突变分析。通过下一代测序（NGS）在 120 个（58%）诊断和复发样本中的 69 个中检测到克隆性 Ig 重排。在 34 例病例中可以建立克隆关系，在 24 例患者（71%）中确定了克隆相关的复发 cHL。通过 IG-NGS 克隆性评估确定 10 例患者（34 例患者中的 29%）为克隆无关的 cHL，在配对的 cHL 样本中鉴定出主要相互排斥的基因突变，从而得到证实。在复发超过 2 年的患者中，能够建立克隆关系的 cHL 患者中约有 60%显示为第二原发 cHL。在 125 个样本中的 14 个（11%）中鉴定出克隆性 TCR 基因重排，在 14 个样本中的 7 个中检测到 TCL 相关基因突变。回顾性病理复习并结合分子发现，在 5 名年龄>50 岁的患者中一致认为存在潜在的 TCL。这项研究表明，cHL 复发，尤其是在 2 年之后，有时代表新的原发性 cHL 或模拟 cHL 的 TCL，这可以通过基于 NGS 的 Ig/TCR 克隆性检测和基因突变分析发现。鉴于其具有重要的治疗意义，对 cHL 假定的复发进行分子检测对于随后采用适合特定淋巴瘤表现的适当治疗策略至关重要。
