Roschewski Mark, Phelan James D, Jaffe Elaine S
Lymphoid Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD.
Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD.
Blood. 2024 Dec 19;144(25):2593-2603. doi: 10.1182/blood.2023020911.
Diffuse large B-cell lymphoma (DLBCL) encompasses a diverse spectrum of aggressive B-cell lymphomas with remarkable genetic heterogeneity and myriad clinical presentations. Multiplatform genomic analyses of DLBCL have identified oncogenic drivers within genetic subtypes that allow for pathologic subclassification of tumors into discrete entities with shared immunophenotypic, genetic, and clinical features. Robust classification of lymphoid tumors establishes a foundation for precision medicine and enables the identification of novel therapeutic vulnerabilities within biologically homogeneous entities. Most cases of DLBCL involving the central nervous system (CNS), vitreous, and testis exhibit immunophenotypic features suggesting an activated B-cell (ABC) origin. Shared molecular features include frequent comutations of MYD88 (L265P) and CD79B and frequent genetic alterations promoting immune evasion, which are hallmarks of the MCD/C5/MYD88 genetic subtype of DLBCL. Clinically, these lymphomas primarily arise within anatomic sanctuary sites and have a predilection for remaining confined to extranodal sites and strong CNS tropism. Given the shared clinical and molecular features, the umbrella term primary large B-cell lymphoma of immune-privileged sites (IP-LBCL) was proposed. Other extranodal DLBCL involving the breast, adrenal glands, and skin are often ABC DLBCL but are more heterogeneous in their genomic profile and involve anatomic sites that are not considered immune privileged. In this review, we describe the overlapping clinical, pathologic, and molecular features of IP-LBCL and highlight important considerations for diagnosis, staging, and treatment. We also discuss potential therapeutic vulnerabilities of IP-LBCL including sensitivity to inhibitors of Bruton tyrosine kinase, immunomodulatory agents, and immunotherapy.
弥漫性大B细胞淋巴瘤（DLBCL）涵盖了一系列侵袭性B细胞淋巴瘤，具有显著的基因异质性和众多临床表现。DLBCL的多平台基因组分析已在基因亚型中确定了致癌驱动因素，这使得肿瘤能够根据病理分为具有共同免疫表型、基因和临床特征的离散实体。对淋巴肿瘤进行可靠的分类为精准医学奠定了基础，并能够在生物学上同质的实体中识别新的治疗靶点。大多数累及中枢神经系统（CNS）、玻璃体和睾丸的DLBCL病例表现出提示活化B细胞（ABC）起源的免疫表型特征。共同的分子特征包括MYD88（L265P）和CD79B的频繁共突变以及促进免疫逃逸的频繁基因改变，这些是DLBCL的MCD/C5/MYD88基因亚型的标志。临床上，这些淋巴瘤主要发生在解剖学上的免疫豁免部位，并且倾向于局限于结外部位，具有很强的CNS嗜性。鉴于其共同的临床和分子特征，提出了“免疫豁免部位原发性大B细胞淋巴瘤（IP-LBCL）”这一统称。其他累及乳腺、肾上腺和皮肤的结外DLBCL通常是ABC DLBCL，但其基因组图谱更具异质性，且累及的解剖部位不被认为是免疫豁免部位。在本综述中，我们描述了IP-LBCL重叠的临床、病理和分子特征，并强调了诊断、分期和治疗的重要注意事项。我们还讨论了IP-LBCL潜在的治疗靶点，包括对布鲁顿酪氨酸激酶抑制剂、免疫调节剂和免疫治疗的敏感性。
