琥珀酸脱氢酶缺陷型肾细胞癌的临床病理学、超微结构及分子特征

Succinate dehydrogenase-deficient renal cell carcinoma:a clinicopathological,ultrastructural and molecular analysis

目的探讨琥珀酸脱氢酶缺陷型肾细胞癌(succinate dehydrogenase-deficient renal cell carcinoma,SDH RCC)的临床病理特征、免疫表型、超微结构、分子特征及鉴别诊断。方法对解放军东部战区总医院2010至2019年间11例SDH RCC进行光镜观察、免疫组织化学染色、超微结构研究及随访,并对其中7例进行高通量DNA靶向测序,分析其分子病理特征。结果11例患者中女性4例,男性7例。患者年龄24~62岁,平均年龄41.4岁,中位年龄41岁。低倍镜下,该类型肾癌以实性片状、小管状结构为主,局部有微囊改变,其中4例呈巢团状、梁索状结构分布于疏松水肿的间质或瘢痕周围,类似于嗜酸细胞腺瘤。高倍镜下,肿瘤细胞胞质呈絮状嗜酸性,可见特征性的半透明空泡。琥珀酸脱氢酶B在8例中呈明确阴性表达,有阳性内对照;其余3例肿瘤细胞呈片状或灶性微弱表达,而肿瘤内正常肾小管及血管内皮细胞呈强阳性表达。高通量DNA靶向测序显示,7例送检病例(包括3例琥珀酸脱氢酶B表达不明确的病例)中均检测出琥珀酸脱氢酶B基因致病性突变,未见琥珀酸脱氢酶其他相关基因突变。其中4例为琥珀酸脱氢酶B错义突变,1例移码突变,1例剪接突变,还有1例为获得终止密码子突变。结论SDH RCC是一种特殊类型且具有遗传倾向或伴随其他癌症综合征的肾细胞癌,在诊断该类型肾癌时应建议患者行高通量测序检测相关突变情况明确诊断,并密切随访观察。

Objective To investigate the clinicopathological features,immunophenotype,ultrastructure,genetic alterations and prognosis of succinate dehydrogenase-deficient renal cell carcinoma(SDH RCC).Methods A total of 11 SDH RCCs,diagnosed from 2010 to 2019,were selected from the Department of Pathology of Nanjing Jingling Hospital,Nanjing University School of Medicine for clinicopathologic,immunohistochemical(IHC),ultrastructural investigation and follow-up.The molecular features of seven cases were analyzed by the panel-targeted DNA next generation sequencing(NGS).Results There were seven males and four females,with ages ranging from 24 to 62 years(mean 41.4 years,median 41 years).Microscopically,SDH RCC was mainly composed of solid and tubular structures with local cystic change.Four cases showed nested or trabecular structure distributed in a loose hypocellular connective tissue or around scar,similar to oncocytoma.The neoplastic cells demonstrated flocculent eosinophilic cytoplasm with typical intracytoplasmic vacuoles.Immunohistochemically,eight cases were negative for SDHB;three cases showed focal and weak expression,whereas normal renal tubular and vascular endothelial cells demonstrated strong cytoplasmic staining.NGS of DNA targeted-panel detected pathogenic mutations of SDHB gene in seven cases(including three cases with equivocal IHC expression of SDHB),without any mutations in other SDH related genes.There were four cases of SDHB missense mutation,one case of frameshift mutation,one case of splicing mutation,and one case of acquired stop codon mutation.Conclusions SDH RCC is a distinct variant of RCCs with genetic tendency or with hereditary cancer syndrome.NGS is recommended to detect the related gene mutations for a definitive diagnosis.The patients should be closely followed up.