Departments of Urology.
Oncolocy.
Appl Immunohistochem Mol Morphol. 2021 Sep 1;29(8):619-625. doi: 10.1097/PAI.0000000000000938.
The antibody-drug conjugate enfortumab-vedotin acts by targeting nectin-4, a protein that is nearly ubiquitously expressed in conventional urothelial cancer. However, expression of nectin-4 in morphologic variants of urothelial carcinoma and nonurothelial histotypes was unknown. Immunohistochemistry for nectin-4 using was performed on 169 patients including 83 with nonmuscle invasive bladder cancer and 86 patients with muscle invasive bladder cancer. Staining was scored for intensity (0 to 3) and extent (% positive cells) using the histological score system, where >15 was considered positive. Overall, 72/83 (87%) samples of nonmuscle invasive urothelial carcinoma were positive, including 29/30 (97%) noninvasive papillary urothelial carcinomas, 7/8 (87.5%) carcinomas in situ, 36/45 (80%) papillary urothelial carcinomas invading the lamina propria. Overall, 50/86 muscle invasive tumors were positive, including 15/22 (68.2%) urothelial carcinomas, 7/10 (70%) squamous cell carcinomas, 3/11 (28%) micropapillary tumors, 4/6 (66%) adenocarcinomas, 2/4 (50%) nested carcinomas, 5/8 (63%) plasmacytoid, 1/10 (10%) sarcomatoid carcinomas, and 0/15 (0%) small cell carcinomas. Whole transcriptome RNA sequencing revealed that compared with conventional urothelial carcinomas, most sarcomatoid carcinomas and all but 2 small cell carcinomas expressed very low levels of nectin-4 mRNA but expressed significant levels of either trop2 or ERBB2, which are the molecular targets of 2 other antibody-drug conjugates-sacituzumab gavitecan (trop2) or trastuzumab deruxtecan (ERBB2/HER2). In summary, our study demonstrates that there is heterogeneity of expression of nectin-4 in morphologic variants of urothelial cancer and nonurothelial histotypes, and suggests that testing expression of nectin-4 should be considered in morphologic variants or nonurothelial histotypes found to have lower expression.
抗体药物偶联物 enfortumab-vedotin 通过靶向 nectin-4 起作用，nectin-4 是一种在传统尿路上皮癌中几乎普遍表达的蛋白质。然而，nectin-4 在尿路上皮癌的形态变异型和非尿路上皮组织类型中的表达尚不清楚。对 169 名患者（包括 83 名非肌肉浸润性膀胱癌患者和 86 名肌肉浸润性膀胱癌患者）进行了 nectin-4 的免疫组织化学染色。使用组织学评分系统对染色强度（0 至 3）和阳性细胞百分比（%）进行评分，其中 >15 被认为是阳性。总体而言，83 例非肌肉浸润性尿路上皮癌样本中有 72 例（87%）为阳性，包括 30 例非浸润性乳头状尿路上皮癌中的 29 例（97%）、8 例原位癌中的 7 例（87.5%）、45 例固有层浸润性乳头状尿路上皮癌中的 36 例（80%）。总体而言，86 例肌肉浸润性肿瘤中有 50 例（68.2%）为阳性，包括 22 例尿路上皮癌中的 15 例（68.2%）、10 例鳞状细胞癌中的 7 例（70%）、11 例微乳头状肿瘤中的 3 例（28%）、6 例腺癌中的 4 例（66%）、4 例巢状癌中的 2 例（50%）、8 例浆细胞样癌中的 5 例（63%）、10 例肉瘤样癌中的 1 例（10%）和 15 例小细胞癌中的 0 例（0%）。全转录组 RNA 测序显示，与传统尿路上皮癌相比，大多数肉瘤样癌和除 2 例小细胞癌外的所有癌均表达极低水平的 nectin-4 mRNA，但表达高水平的 trop2 或 ERBB2，这是另外 2 种抗体药物偶联物——sacituzumab gavitecan（trop2）或 trastuzumab deruxtecan（ERBB2/HER2）的分子靶点。总之，我们的研究表明，nectin-4 在尿路上皮癌的形态变异型和非尿路上皮组织类型中存在表达异质性，并提示在发现表达较低的形态变异型或非尿路上皮组织类型时，应考虑检测 nectin-4 的表达。
