Weill Cornell Medicine, New York Presbyterian Hospital, 525 East 68th Street, F766, New York, NY, 10065, USA.
Department of Pathology, Robert J. Tomsich Pathology and Laboratory Medicine Institute, Cleveland Clinic, 9500 Euclid Avenue, L25, Cleveland, OH, 44195, USA.
Mod Pathol. 2018 Jul;31(7):1131-1140. doi: 10.1038/s41379-018-0021-y. Epub 2018 Feb 13.
The two main precursors of vulvar squamous cell carcinoma, usual and differentiated vulvar intraepithelial neoplasia (VIN), have distinctive etiology, pathogenesis, and natural history. Usual type VIN is often associated with high-risk HPV and differentiated VIN has de novo p53 genetic alterations that are unrelated to HPV infection. GATA-binding protein 3 (GATA3) is a tumor suppressor that shows increased expression in several types of human malignancies including breast and bladder carcinomas. Little is known regarding the expression of GATA3 in vulvar squamous neoplasms. We have systematically examined the expression of GATA3 in 119 vulvar lesions and neoplasms including 20 cases of lichen sclerosus, 12 cases of lichen simplex chronicus, 30 cases of usual type VIN, 34 cases of differentiated VIN, and 23 cases of squamous cell carcinoma. Similar to adjacent non-neoplastic epidermis, moderate to strong GATA3 expression was retained in all cases of lichen sclerosus, lichen simplex chronicus, and usual type VIN. However, in comparison, the GATA3 immunostaining pattern in differentiated VIN was distinct. Partial/complete loss of GATA3 expression in the basal layer with or without loss in the parabasal layer was observed in 30/34 (88%) of differentiated VIN cases. Significant loss of GATA3 expression was also observed in all (7/7) squamous cell carcinomas associated with usual type VIN and in 13/16 (81%) of those associated with differentiated VIN. There was no significant correlation between loss of GATA3 expression and overexpression of p53 in differentiated VIN. Our study shows that loss of GATA3 expression is seen in the vast majority (87%) of vulvar squamous cell carcinomas. Downregulation of GATA3 may be an early event during tumorigenesis in differentiated VIN but not in HPV-related usual type VIN. Our data suggests that application of GATA3 immunohistochemistry along with p53 may be a useful tool in facilitating the accurate diagnosis of VIN.
外阴鳞状细胞癌的两个主要前体，普通型和分化型外阴上皮内瘤变（VIN），具有不同的病因、发病机制和自然史。普通型 VIN 常与高危型 HPV 相关，而分化型 VIN 则具有与 HPV 感染无关的新出现的 p53 基因改变。GATA 结合蛋白 3（GATA3）是一种肿瘤抑制因子，在包括乳腺癌和膀胱癌在内的多种人类恶性肿瘤中表达增加。关于 GATA3 在外阴鳞状肿瘤中的表达知之甚少。我们系统地检测了 119 例外阴病变和肿瘤中的 GATA3 表达，包括 20 例硬化性苔藓、12 例慢性单纯性苔藓、30 例普通型 VIN、34 例分化型 VIN 和 23 例鳞状细胞癌。与相邻的非肿瘤性表皮相似，所有硬化性苔藓、慢性单纯性苔藓和普通型 VIN 病例均保留了中度至强的 GATA3 表达。然而，相比之下，分化型 VIN 的 GATA3 免疫染色模式是不同的。在 34 例分化型 VIN 中有 30 例（88%）观察到基底细胞层部分/完全丧失 GATA3 表达，伴或不伴副基底层丧失。在与普通型 VIN 相关的所有 7/7 例鳞状细胞癌和与分化型 VIN 相关的 13/16 例（81%）中也观察到 GATA3 表达的显著丧失。在分化型 VIN 中，GATA3 表达缺失与 p53 过表达之间无显著相关性。我们的研究表明，绝大多数（87%）外阴鳞状细胞癌存在 GATA3 表达缺失。GATA3 的下调可能是分化型 VIN 肿瘤发生过程中的早期事件，但不是 HPV 相关的普通型 VIN。我们的数据表明，应用 GATA3 免疫组化染色结合 p53 可能是准确诊断 VIN 的有用工具。
