Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.
Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.
Mod Pathol. 2023 May;36(5):100104. doi: 10.1016/j.modpat.2023.100104. Epub 2023 Jan 23.
PDGFRB-activating mutations have been reported in pediatric myofibroma and myofibromatosis. However, recurrent gain-of-function PDGFRB mutations have not been documented in sarcomas with myogenic differentiation. Driven by occasional sarcomas harboring PDGFRB mutations, we investigated their prevalence and clinicopathologic and genomic features in a large cohort of sarcomas. An institutional targeted DNA next-generation sequencing database was searched for sarcomas with myogenic differentiation harboring hotspot PDGFRB gene alterations. Among 3300 patients with sarcomas, 21 (0.6%) patients were identified (17 women, 4 men) with an age range of 35 to 88 years. The site distribution included 13 gynecologic tract (12 uteri, 1 vagina), 4 bone and soft tissue, and 4 viscera. All except 1 were high grade. Most patients were diagnosed as sarcomas with myogenic differentiation based on partial staining for 1 or more muscle markers, whereas 6 were labeled as leiomyosarcoma (LMS). Most tumors showed monomorphic spindle morphology, with either heterogeneous features of myofibroblastic and smooth muscle differentiation or an undifferentiated phenotype. Hormone receptors were negative in all uterine cases. PDGFRB immunostaining in all cases tested was strong and diffuse, whereas PDGFRA was negative/focal. The most frequent PDGFRB mutations were exon 12 (43%), exon 14 (N666K/S/T) (38%), and exon 18 (D850Y/H/V or insertion/deletion) (19%). The most frequent co-existing genetic alterations (26% to 37%) occurred in CDKN2A/B, TP53, TERT, and MED12. Moreover, PDGFRB-mutant sarcomas had an overall distinct genomic landscape compared with both uterine and soft tissue LMS control groups. These tumors were associated with a highly aggressive clinical course, with frequent distant metastases (81%) and death (76%), regardless of anatomic location, and worse overall survival compared with the 2 LMS control groups. This is the first study documenting recurrent hotspot PDGFRB alterations in high-grade sarcomas, which show a predilection for uterine location and myogenic differentiation that fall short of the diagnostic criteria for LMS. Further studies are needed to investigate the therapeutic potential of kinase inhibitors in this group of tumors.
PDGFRB 激活突变已在儿科肌纤维瘤和肌纤维瘤病中报道。然而，具有肌源性分化的肉瘤中并未记录到复发性功能获得性 PDGFRB 突变。受偶尔携带 PDGFRB 突变的肉瘤驱动，我们在一个大型肉瘤队列中研究了它们的患病率以及临床病理和基因组特征。对具有肌源性分化且携带热点 PDGFRB 基因突变的肉瘤进行了机构靶向 DNA 下一代测序数据库搜索。在 3300 名肉瘤患者中，发现 21 名（0.6%）患者（17 名女性，4 名男性），年龄范围为 35 至 88 岁。部位分布包括 13 个妇科管（12 个子宫，1 个阴道）、4 个骨和软组织以及 4 个内脏。除 1 例外，其余均为高级别。大多数患者被诊断为具有肌源性分化的肉瘤，其依据是 1 种或多种肌肉标志物的部分染色，而 6 例被标记为平滑肌肉瘤（LMS）。大多数肿瘤表现为单形性梭形形态，具有成纤维细胞和平滑肌分化的异质性特征或未分化表型。所有子宫病例的激素受体均为阴性。所有病例的 PDGFRB 免疫染色均为强且弥漫性，而 PDGFRA 为阴性/局灶性。最常见的 PDGFRB 突变是外显子 12（43%）、外显子 14（N666K/S/T）（38%）和外显子 18（D850Y/H/V 或插入/缺失）（19%）。最常见的共存遗传改变（26%至 37%）发生在 CDKN2A/B、TP53、TERT 和 MED12 中。此外，与子宫和软组织 LMS 对照组相比，PDGFRB 突变肉瘤具有总体独特的基因组景观。这些肿瘤与高度侵袭性的临床病程相关，无论解剖位置如何，远处转移（81%）和死亡（76%）均很常见，与 2 个 LMS 对照组的总生存率相比更差。这是首次在高级别肉瘤中记录到复发性热点 PDGFRB 改变的研究，这些肉瘤表现出对子宫位置和肌源性分化的偏好，但不符合 LMS 的诊断标准。需要进一步研究以探讨这组肿瘤中激酶抑制剂的治疗潜力。
