延胡索酸水合酶缺陷型肾细胞癌的临床病理学特征

Clinicopathological characteristics of fumarate hydratase-deficient renal cell carcinoma

目的探讨延胡索酸水合酶缺陷型肾细胞癌(fumarate hydratase-deficient renal cell carcinoma,FH-RCC)的临床病理特征、鉴别诊断及预后。方法应用组织芯片及免疫组织化学技术检测青岛大学附属医院和解放军海军第九七一医院2011年1月至2017年12月391例不同组织类型肾肿瘤延胡索酸水合酶(FH)的表达,筛选出8例FH完全阴性表达的病例,应用聚合酶链反应(PCR)及测序技术对其中3例进行FH基因突变检测,对其中2例TFE3蛋白表达阳性病例应用TFE3双色分离探针进行荧光原位杂交(FISH)检测TFE3基因。结果8例FH阴性表达的患者中,男性7例,女性1例;发病年龄28~50岁(平均年龄39岁);肿瘤直径3.5~12.0 cm(平均7.9 cm),其中6例手术时可见肾盂侵犯,4例见肾静脉及下腔静脉内瘤栓形成。切面大多为实性,灰白、灰黄色或多彩状,境界不清,侵袭性生长明显,显微镜下瘤组织多呈结节状浸润性生长(5/8),排列方式多样,常表现为乳头状、管囊状、筛网状、实性片状等不同结构的混合,癌细胞胞质丰富,嗜酸或双嗜性,核圆形或不规则,均可见至少灶状分布大而明显的嗜酸性核仁(WHO/国际泌尿病理协会Ⅲ~Ⅳ级),2例分别伴有肉瘤样或横纹肌样分化,5例间质脉管内查见癌栓。免疫组织化学:癌组织大多弥漫强阳性表达PAX8(7/8)、细胞角蛋白(CK19,7/8)、波形蛋白(6/8)、P504s(8/8),CK7、CD10、CD117、肾细胞癌标志物(RCC)、34βE12、HMB45、Melan A均阴性。3例测序结果均显示FH基因第1号外显子存在突变。2例免疫组织化学TFE3蛋白阳性表达的病例,FISH检测结果表明TFE3基因均未发生易位或扩增。7例获得随访,随访时间11~66个月,其中5例于术后11~31个月(平均20个月)因广泛远处转移而死亡,2例术后36和66个月存活。结论FH-RCC形态学上与Ⅱ型乳头状肾癌、集合管癌或管状囊性癌有重叠,乳头状、管囊状、筛网状、管状乳头状等多种排列方式的混合存在以及癌细胞至少灶状出现大而明显的核仁是该类型肾细胞癌的重要组织学特征,免疫组织化学FH染色和FH基因突变检测有助于明确诊断。该类型肾癌具有很强的侵袭性,生物学行为凶险,预后很差。及时准确的病理诊断对FH-RCC患者预后的评估及亲属相关病变的早期发现、及时治疗具有重要的临床意义。

Objective To investigate the clinicopathologic characteristics, molecular and genetic features, differential diagnoses and prognosis of fumarate hydratase-deficient renal cell carcinoma (FH-RCC).Methods 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.Results 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.Conclusions 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.