Department of Pathology, University Health Network.
Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada.
Am J Surg Pathol. 2021 Sep 1;45(9):1264-1273. doi: 10.1097/PAS.0000000000001715.
Alpha-inhibin expression has been reported in pheochromocytomas and paragangliomas (PPGLs). We analyzed alpha-inhibin immunohistochemistry in 77 PPGLs (37 pheochromocytomas [PCCs] and 40 paragangliomas) and correlated the results with catecholamine profile, tumor size, Ki-67 labeling index, succinate dehydrogenase B subunit and carbonic anhydrase IX (CAIX) staining, and genetic pathogenesis. PPGLs were classified as pseudohypoxic cluster 1 disease with documented VHL mutation or SDHx mutation or biochemical phenotype, whereas NF1-driven and RET-driven PPGLs and those with a mature secretory (adrenergic or mixed adrenergic and noradrenergic) phenotype were classified as cluster 2 disease. The Cancer Genome Atlas data on INHA expression in PPGLs was examined. Alpha-inhibin was positive in 43 PPGLs (56%). Ki-67 labeling indices were 8.07% and 4.43% in inhibin-positive and inhibin-negative PPGLs, respectively (P<0.05). Alpha-inhibin expression did not correlate with tumor size. Alpha-inhibin was expressed in 92% of SDHx-related and 86% of VHL-related PPGLs. CAIX membranous staining was found in 8 of 51 (16%) tumors, including 1 SDHx-related PCC and all 5 VHL-related PCCs. NF1-driven and RET-driven PPGLs were negative for alpha-inhibin and CAIX. Alpha-inhibin was expressed in 77% of PPGLs with a pseudohypoxia signature, and 20% of PPGLs without a pseudohypoxia signature (P<0.05). PPGLs with a mature secretory phenotype were negative for CAIX. The Cancer Genome Atlas data confirmed higher expression of INHA in cluster 1 than in cluster 2 PPGLs. This study identifies alpha-inhibin as a highly sensitive (90.3%) marker for SDHx/VHL-driven pseudohypoxic PPGLs. Although CAIX has low sensitivity, it is the most specific biomarker of VHL-related pathogenesis. While alpha-inhibin cannot replace succinate dehydrogenase B subunit immunohistochemistry for detection of SDHx-related disease, it adds value in prediction of cluster 1 disease. Importantly, these data emphasize that alpha-inhibin is not a specific marker of adrenal cortical differentiation, as it is also expressed in PCCs.
抑黑素在嗜铬细胞瘤和副神经节瘤（PPGLs）中已有报道。我们分析了 77 例 PPGLs（37 例嗜铬细胞瘤[PCC]和 40 例副神经节瘤）的抑黑素免疫组化，并将结果与儿茶酚胺谱、肿瘤大小、Ki-67 标记指数、琥珀酸脱氢酶 B 亚单位和碳酸酐酶 IX（CAIX）染色以及遗传发病机制相关联。PPGL 被归类为具有明确 VHL 突变或 SDHx 突变或生化表型的假缺氧簇 1 疾病，而 NF1 驱动和 RET 驱动的 PPGL 以及具有成熟分泌（肾上腺素能或混合肾上腺素能和去甲肾上腺素能）表型的 PPGL 被归类为簇 2 疾病。我们还检查了癌症基因组图谱中 PPGLs 中 INHA 表达的数据。43 例 PPGL 中（56%）抑黑素阳性。抑黑素阳性和抑黑素阴性 PPGL 的 Ki-67 标记指数分别为 8.07%和 4.43%（P<0.05）。抑黑素的表达与肿瘤大小无关。SDHx 相关的 92%和 VHL 相关的 86%的 PPGL 表达抑黑素。51 例肿瘤中有 8 例（16%）发现 CAIX 膜染色，包括 1 例 SDHx 相关的 PCC 和所有 5 例 VHL 相关的 PCC。NF1 驱动和 RET 驱动的 PPGL 对抑黑素和 CAIX 均为阴性。77%具有假缺氧特征的 PPGL 表达抑黑素，而 20%无假缺氧特征的 PPGL 不表达抑黑素（P<0.05）。具有成熟分泌表型的 PPGL 对 CAIX 为阴性。癌症基因组图谱的数据证实，簇 1 的 INHA 表达高于簇 2 的 PPGL。本研究确定抑黑素是 SDHx/VHL 驱动的假缺氧 PPGL 的高度敏感（90.3%）标志物。尽管 CAIX 的敏感性较低，但它是 VHL 相关发病机制最特异的生物标志物。虽然抑黑素不能代替琥珀酸脱氢酶 B 亚单位免疫组化来检测 SDHx 相关疾病，但它增加了对簇 1 疾病的预测价值。重要的是，这些数据强调，抑黑素不是肾上腺皮质分化的特异性标志物，因为它也在 PCC 中表达。
