Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA.
Department of Pathology, Stanford University School of Medicine, Stanford, CA.
Am J Surg Pathol. 2022 Jan 1;46(1):3-10. doi: 10.1097/PAS.0000000000001720.
Platelet-derived growth factor receptor A (PDGFRA) is a receptor tyrosine kinase that is activated by mutations in 10% of gastrointestinal stromal tumors (GISTs) and 55% to 70% of inflammatory fibroid polyps. PDGFRA-mutant GISTs are usually epithelioid and occur predominantly in the stomach. Succinate dehydrogenase-deficient GISTs also arise in the stomach and are usually epithelioid, as are some KIT-mutant GISTs. Recently, avapritinib was approved to treat PDGFRA D842V-mutant GISTs, which do not respond to conventional targeted therapy. Here, we evaluate the utility of PDGFRA immunohistochemistry (IHC) to predict PDGFRA mutations to direct targeted therapy. PDGFRA IHC was performed at 1:3000 and 1:10,000 dilutions on a tissue microarray containing 153 GISTs (126 KIT-mutant, 17 PDGFRA-mutant, and 10 succinate dehydrogenase-deficient). The "positive" staining threshold was defined as 50% of neoplastic cells staining at moderate intensity. PDGFRA IHC was 75.0% and 80.9% specific for PDGFRA mutations at 1:3000 and 1:10,000 dilutions, respectively, and it was 100% sensitive at both. On the basis of its higher specificity, a 1:10,000 dilution was used to stain whole-tissue sections of GISTs and other gastric tumor types. Combining tissue microarray and whole-tissue data, PDGFRA IHC was 94.4% sensitive and 81.0% specific for PDGFRA-mutant GIST among all 210 GISTs, and it was 84.1% specific among 149 GISTs with an epithelioid component. PDGFRA was positive in a subset of inflammatory fibroid polyps (15/30; 50%), monophasic synovial sarcomas (5/10; 50%), inflammatory myofibroblastic tumors (5/10; 50%), and plexiform fibromyxomas (2/8; 25%). It was negative in poorly differentiated adenocarcinoma (0/20), diffuse large B-cell lymphoma (0/10), glomus tumor (0/10), gastrointestinal neuroectodermal tumor (0/10), leiomyoma (0/10), gastric schwannoma (0/8), and gastroblastoma (0/3). Among GISTs, PDGFRA IHC is highly sensitive and moderately specific for PDGFRA-mutant tumors; it also can be positive in inflammatory fibroid polyp and some other mesenchymal tumor types. PDGFRA positivity could be used to triage epithelioid GISTs for PDGFRA sequencing to determine optimal therapy.
血小板衍生生长因子受体 A (PDGFRA) 是一种受体酪氨酸激酶，在 10%的胃肠道间质瘤 (GIST) 和 55%至 70%的炎症性纤维息肉中发生突变而被激活。PDGFRA 突变的 GIST 通常为上皮样，主要发生在胃中。琥珀酸脱氢酶缺陷型 GIST 也发生在胃中，通常也是上皮样的，一些 KIT 突变的 GIST 也是如此。最近，阿伐普利尼被批准用于治疗 PDGFRA D842V 突变的 GIST，这些肿瘤对常规靶向治疗没有反应。在这里，我们评估 PDGFRA 免疫组织化学 (IHC) 预测 PDGFRA 突变以指导靶向治疗的效用。在包含 153 个 GIST（126 个 KIT 突变、17 个 PDGFRA 突变和 10 个琥珀酸脱氢酶缺陷）的组织微阵列上，以 1:3000 和 1:10,000 的稀释度进行 PDGFRA IHC。“阳性”染色阈值定义为中等强度染色的肿瘤细胞比例为 50%。PDGFRA IHC 在 1:3000 和 1:10,000 稀释度下对 PDGFRA 突变的特异性分别为 75.0%和 80.9%，在两种稀释度下的敏感性均为 100%。基于其更高的特异性，使用 1:10,000 的稀释度对 GIST 和其他胃肿瘤类型的全组织切片进行染色。基于组织微阵列和全组织数据，在所有 210 个 GIST 中，PDGFRA IHC 对 PDGFRA 突变的 GIST 的敏感性为 94.4%，特异性为 81.0%，在具有上皮样成分的 149 个 GIST 中特异性为 84.1%。PDGFRA 在一部分炎症性纤维息肉 (30 个中的 15 个; 50%)、单相滑膜肉瘤 (10 个中的 5 个; 50%)、炎症性肌纤维母细胞瘤 (10 个中的 5 个; 50%)和丛状纤维粘液瘤 (8 个中的 2 个; 25%)中呈阳性。在低分化腺癌 (20 个中 0 个)、弥漫性大 B 细胞淋巴瘤 (10 个中 0 个)、血管球瘤 (10 个中 0 个)、胃肠道神经外胚层肿瘤 (10 个中 0 个)、平滑肌瘤 (10 个中 0 个)、胃 schwannoma (8 个中 0 个)和胃母细胞瘤 (3 个中 0 个)中均为阴性。在 GIST 中，PDGFRA IHC 对 PDGFRA 突变肿瘤具有高度敏感性和中等特异性；它也可以在炎症性纤维息肉和一些其他间充质肿瘤类型中呈阳性。PDGFRA 阳性可用于上皮样 GIST 的 PDGFRA 测序，以确定最佳治疗方案。
