Over the past decade, several distinct novel renal epithelial neoplasms driven by underlying tuberous sclerosis comples (TSC)/mammalian target of rapamycin (MTOR) pathway mutations have been described. We report herein two distinctive TSC2-mutated renal cell carcinomas which do not fit any previously described entity. The two renal carcinomas occurred in young patients (ages 10 and 31 y), and were characterized by highly permeative growth within the kidney with metastases to perirenal lymph nodes. The neoplastic cells were predominantly large, multinucleated giant cells having variably eosinophilic to xanthomatous cytoplasm with basophilic stippling and frequent vacuolization. While the discohesive nature of the neoplastic cells, xanthomatous cytoplasm, immunoreactivity for histiocytic markers and minimal immunoreactivity for conventional epithelial markers raised the possibility of a histiocytic neoplasm, multifocal immunoreactivity for cytokeratin 20 helped establish their epithelial nature. Despite the aggressive growth pattern of these neoplasms and lymph node metastases, mitotic figures were rare and Ki-67 indices were low (<1%). One patient with follow-up shows no evidence of disease seven years after nephrectomy with no adjuvant therapy. Next-generation sequencing demonstrated TSC2 mutations in each case. By immunohistochemistry, downstream markers of mTOR pathway activation S6K1, 4EBP1, and glycoprotein nonmetastatic melanoma protein B were all highly expressed in these neoplasms, suggesting mTOR pathway activation as the neoplastic driver. While the cytokeratin 20 immunoreactivity and focal basophilic cytoplasmic stippling suggest a relationship to eosinophilic solid and cystic renal cell carcinoma, and cytoplasmic vacuolization suggests a relationship to eosinophilic vacuolated tumor, these neoplasms appear to be distinctive given their permeative growth patterns and predominant xanthomatous giant cell morphology. Addition of cytokeratin 20 to a panel of epithelial markers helps avoid misdiagnosis in such cases.

在过去的十年中，已经描述了由潜在的结节性硬化症 ( TSC)/哺乳动物雷帕霉素靶标(MTOR)通路突变驱动的几种不同的新型肾上皮肿瘤。我们在此报告了两种不同的TSC2突变肾细胞癌，它们不符合任何先前描述的实体。这两种肾癌发生在年轻患者（10 岁和 31 岁）中，其特征是肾脏内高度渗透性生长并转移至肾周淋巴结。肿瘤细胞主要是大的多核巨细胞，具有可变的嗜酸性至黄色细胞质，伴有嗜碱性点彩和频繁的空泡化。虽然肿瘤细胞的粘附性，黄色瘤细胞质、组织细胞标志物的免疫反应性和常规上皮标志物的最小免疫反应性增加了组织细胞肿瘤的可能性，细胞角蛋白 20 的多灶性免疫反应性有助于确定其上皮性质。尽管这些肿瘤和淋巴结转移具有侵袭性生长模式，但有丝分裂象很少见且 Ki-67 指数很低 (<1%)。一名接受随访的患者在没有辅助治疗的肾切除术后七年没有发现任何疾病迹象。下一代测序展示了TSC2每种情况下的突变。通过免疫组织化学，mTOR 通路激活的下游标志物 S6K1、4EBP1 和糖蛋白非转移性黑色素瘤蛋白 B 均在这些肿瘤中高表达，表明 mTOR 通路激活是肿瘤驱动因素。虽然细胞角蛋白 20 免疫反应性和局灶性嗜碱性细胞质点彩表明与嗜酸性实性和囊性肾细胞癌有关，细胞质空泡化表明与嗜酸性空泡化肿瘤有关，但考虑到它们的渗透性生长模式和主要的黄色瘤样巨细胞形态，这些肿瘤似乎是独特的. 将细胞角蛋白 20 添加到一组上皮标记物中有助于避免此类病例的误诊。