Zhang W, Chu J, Zou Y W, Jiang Y X, Wei Z M, Zhong D C, Liu Y, Li Y J, Yu W J
Department of Pathology, 971 Hospital of PLA Navy, Qingdao 266071, China.
Department of Pathology, Zaozhuang Municipal Hospital, Zaozhuang, 277000, China.
Zhonghua Bing Li Xue Za Zhi. 2019 Feb 8;48(2):120-126. doi: 10.3760/cma.j.issn.0529-5807.2019.02.009.
To investigate the clinicopathologic characteristics, molecular and genetic features, differential diagnoses and prognosis of fumarate hydratase-deficient renal cell carcinoma (FH-RCC). The immunohistochemical (IHC) expression of FH in 391 renal neoplasms in tissue chips collected from the Affiliated Hospital of Qingdao University and 971 Hospital of PLA Navy from January 2011 to December 2017 was evaluated. The clinicopathologic data of eight FH negative cases were collected.Polymerase chain reaction (PCR) and sequencing were used to detect the changes in FH gene in three cases. Interphase FISH with a dual color and break-apart probe was applied to detect the TFE3 gene alteration in the cases showing TFE3 protein expression. Among the eight patients, seven were male and one was female, and age ranged from 28 to 50 years (mean 39 years). Tumor size ranged from 3.5 cm to 12.0 cm (mean 7.9 cm). Renal pelvis invasion was identified in six cases, and the tumor emboli in renal vein and inferior vena cava were found in four patients. The cut surface of most tumors was solid, colorful, grayish white or yellow with no clear border showing invasive growth pattern. Microscopically, the tumors showed different proportions of papillary, tubular cystic, cribriform and solid structures. The tumor cells were rounded or polygonal with eosinophilic or amphotropic cytoplasm, round or oval nuclei, and focal large and prominent nucleoli (WHO/ISUP grade 3-4). Two cases had sarcomatoid or rhabdoid components. Intravascular tumor emboli were found in five cases. IHC staining showed most tumors expressed PAX8(7/8), CK19(7/8), vimentin (6/8) and P504s(8/8). However, other immunomarkers including CK7, CD10, CD117, RCC, 34βE12, HMB45 and Melan A were all negative. Sequencing showed all three cases had FH gene mutations in exon 1. FISH revealed no TFE3 gene translocation or amplification in the two cases with TFE3 IHC expression. Follow-up data were available in seven patients with the follow-up period from 11 to 66 months. Among them, five patients died between 11 to 31 months after the surgery because of extensive distant metastases of the tumor to the lung, liver and lymph nodes. The other two patients were alive at the 36th and 66th month after the surgery. Morphologically, FH-RCC overlaps with papillary RCC, collecting duct carcinoma and tubular-cystic RCC, showing a mixture of papillary, tubular cystic, cribriform or tubular papillary structures with at least focal large and prominent nucleoli. The negative expression of FH and the detection of FH gene mutation could facilitate the diagnosis of the tumor. FH-RCC is a high aggressive tumor, prone to metastasize, and is associated with poor prognosis. The timely diagnosis of FH-RCC could benefit the patients and their relatives as well.
探讨延胡索酸水合酶缺陷型肾细胞癌（FH-RCC）的临床病理特征、分子和遗传特征、鉴别诊断及预后。评估2011年1月至2017年12月期间从青岛大学附属医院和解放军海军第九七一医院收集的组织芯片中391例肾肿瘤中FH的免疫组化（IHC）表达。收集8例FH阴性病例的临床病理资料。采用聚合酶链反应（PCR）和测序检测3例FH基因的变化。应用双色和断裂分离探针的间期荧光原位杂交（FISH）检测显示TFE3蛋白表达的病例中的TFE3基因改变。8例患者中，男性7例，女性1例，年龄28至50岁（平均39岁）。肿瘤大小为3.5 cm至12.0 cm（平均7.9 cm）。6例发现肾盂侵犯，4例发现肾静脉和下腔静脉肿瘤栓子。大多数肿瘤切面实性、多彩、灰白色或黄色，边界不清，呈浸润性生长模式。镜下，肿瘤呈现不同比例的乳头状、管状囊性、筛状和实性结构。肿瘤细胞圆形或多边形，胞质嗜酸性或两性，核圆形或椭圆形，局灶性大且明显的核仁（WHO/ISUP 3-4级）。2例有肉瘤样或横纹肌样成分。5例发现血管内肿瘤栓子。IHC染色显示大多数肿瘤表达PAX8（7/8）、CK19（7/8）、波形蛋白（6/8）和P504s（8/8）。然而，其他免疫标志物包括CK7、CD10、CD117、RCC、34βE12、HMB45和Melan A均为阴性。测序显示所有3例在外显子1均有FH基因突变。FISH显示2例TFE3 IHC表达的病例中无TFE3基因易位或扩增。7例患者有随访数据，随访时间为11至66个月。其中，5例患者在术后11至31个月因肿瘤广泛远处转移至肺、肝和淋巴结而死亡。另外2例患者在术后第36个月和66个月存活。形态学上，FH-RCC与乳头状RCC、集合管癌和管状囊性RCC重叠，表现为乳头状、管状囊性、筛状或管状乳头状结构的混合，至少局灶性大且明显的核仁。FH的阴性表达和FH基因突变的检测有助于肿瘤的诊断。FH-RCC是一种高侵袭性肿瘤，易于转移，预后不良。FH-RCC的及时诊断对患者及其亲属也有益处。
