Objective: To understand the clinicopathological and molecular genetic characteristics of aggressive renal mucinous tubular and spindle cell carcinoma (MTSCC). Methods: The clinical features, histology, immunophenotype, molecular characteristics and prognosis of 4 cases of metastatic/recurrent renal MTSCC that were submitted to the Peking University Third Hospital (2 cases), Institute of Urology, Peking University (one case) and Zhejiang Provincial People's Hospital (one case) from 2015 to 2020 were retrospectively reviewed and analyzed. Results: Among the four patients, two were male and two were female. The average age was 58 years, ranging from 28 to 77 years. Three patients underwent radical nephrectomy, while one underwent partial nephrectomy. The tumor size was 2-8 cm (mean, 5.6 cm). There were two cases classified as pT3a, one case as pT1b and one case as pT1a. Histologically, the tumors were mainly composed of tubules and spindle cell cords. For nuclear grade, three cases were G3 and one case was G2. Extracellular mucus was present in all four cases. Sarcomatoid features and tumor necrosis were observed in one and three cases, respectively. Immunohistochemistry showed that PAX8 (4/4), AMACR (4/4), CK7 (4/4), CKpan (3/3), vimentin (3/3) and CK8/18 (2/2) were positive in the tumor cells, but CAⅨ (1/4) or CD10 (2/3) were focally positive or negative. Fluorescence in situ hybridization showed that no trisomy of chromosomes 7 and l7 (2/2). Targeted next generation sequencing were performed in all four cases and showed that 3 cases had mutations in Hippo pathway involving MET (2/4), NF2 (1/4) and NTRK1 (1/4) genes. The other potentially pathogenic mutations involved KDM6A, SETD2 and PALB2. The follow-up period was 13 to 99 months. The time between diagnosis and metastasis/recurrence ranged from 6 to 58 months. Two patients died after lung metastasis occurred, one had multi-organ and multi-site lymph node metastases, and one achieved disease-free survival after resection of metastatic/recurrent foci. Conclusions: Renal MTSCC is a rare and distinct entity. The presence of high nuclear grade and pathological stage, high-grade morphology, lymphovascular invasion, and tumor necrosis suggests potential aggressive behaviors. It is thus recommended to report these histological features and conduct active follow-up and surveillance after surgery. The frequent mutations in MET, NF2 and NTRK1 suggest that dysregulation of Hippo pathway may be related to the development and progression of renal MTSCC.
目的： 探讨转移/复发的肾脏黏液小管状和梭形细胞癌（mucinous tubular and spindle cell carcinoma，MTSCC）的临床病理及分子遗传学特点。 方法： 回顾性观察和分析2015—2020年北京大学第三医院（2例）、北京大学泌尿外科研究所（1例）和浙江省人医院（1例）存档的共4例转移/复发的MTSCC的临床特征、组织学、免疫表型和分子遗传学特点以及预后。 结果： 本组病例包含女性2例，男性2例；原发瘤确诊年龄28~77岁（平均年龄58岁）；3例行根治性肾脏切除，1例行部分切除；原发瘤最大径2~8 cm（平均直径5.6 cm）。2例病理分期为pT3a，其余分别为pT1a和pT1b。组织学上，肿瘤主要由管状和梭形细胞条索构成；核级别3例呈3级，1例呈2级；4例均有细胞外黏液；1例可见梭形细胞肉瘤样变；3例出现肿瘤性坏死。免疫组织化学方面，肿瘤细胞表达PAX8（4/4）、α-甲酰基辅酶A消旋酶（AMACR，4/4）、细胞角蛋白（CK）7（4/4）、广谱细胞角蛋白（CKpan，3/3）、波形蛋白（3/3）和CK8/18（2/2），不表达或局灶表达碳酸酐酶Ⅸ（CAⅨ，1/4）和CD10（2/3）。荧光原位杂交显示未见第7号和17号染色体获得（2/2）。4例均进行靶向下一代测序检测，结果显示3例出现Hippo通路的分子发生突变，涉及的基因有：MET（2/4）、NF2（1/4）、NTRK1（1/4）；其他可能致病的突变基因有KDM6A、SETD2和PALB2等。术后随访13~99个月，发现转移/复发的时间为6~58个月，2例出现肺转移后死亡，1例出现多脏器和多部位淋巴结转移，1例行转移/复发灶切除后无病生存。 结论： 肾脏MTSCC是一种罕见的独立实体，出现较高的WHO/国际泌尿病理协会（ISUP）分级和病理分期、高级别形态、脉管浸润以及肿瘤性坏死提示其可能具有侵袭性，建议在病理报告中给予提示并进行术后积极随访和监测。MET、NF2和NTRK1突变提示Hippo通路失调可能与MTSCC的发生发展有关。.