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琥珀酸脱氢酶缺陷型肾细胞癌11例临床病理分析

Succinate Dehydrogenase-Deficient Renal Cell Carcinoma: Clinicopathological Analysis of 11 Cases

  • 摘要:
    目的 探讨琥珀酸脱氢酶(succinate dehydrogenase, SDH)缺陷型肾细胞癌的临床病理特征、免疫表型、分子遗传学改变及预后。
    方法 收集四川大学华西医院2016–2023年诊断的11例SDH缺陷型肾细胞癌,总结其形态学、免疫组织化学和DNA测序结果。
    结果 11例患者包括男性5例,女性6例。患者年龄22~71岁,平均39.7岁。其中5例位于右肾,5例位于左肾,1例为双肾肿瘤。镜下肿瘤细胞结构多样,呈片状、巢团状和腺管样分布,少数病例可见乳头状结构。肿瘤胞浆丰富,嗜酸性,呈絮状,部分可见胞浆内空泡。其中7例(63.6%)为低级别〔国际泌尿病理协会(ISUP)/WHO 2016分级1~2级〕,4例(4/11,36.4%)为高级别(ISUP/WHO 2016分级3级)。低级别患者平均年龄32.1岁,高级别患者平均年龄58.0岁。免疫组织化学染色显示11例肿瘤细胞均SDHB表达缺失,其中1例同时伴SDHA表达缺失,配对盒蛋白8(paired box 8, PAX-8)、延胡索酸水合酶(fumarate hydratase, FH)和上皮细胞膜抗原(epithelial membrane antigen, EMA)阳性,角蛋白7(cytokeratin 7, CK7)阴性,Ki-67阳性指数1%~30%。7例行SDHB全部外显子Sanger测序,检出1例移码突变c.236Tdel(p.K80Rfs*),1例错义突变c.725G>A(p.Arg242His)。还有1例通过下一代测序检出SDHB大片段缺失(Exon 4-8 del)。10例获得随访资料,随访时间4~138个月,平均随访时间32.8个月,所有患者均存活。其中5例出现肿瘤复发或转移,包括3例高级别患者和2例低级别患者。
    结论 SDH缺陷型肾细胞癌少见,总体发病年龄相对较年轻,可出现双侧肿瘤。低级别患者多数较年轻,Ki-67指数通常<5%,个别病例经长期随访可出现复发转移。高级别患者通常年龄较大,Ki-67指数较高,易复发和转移。SDHB免疫组化表达缺失可帮助诊断该肿瘤,但SDHB蛋白表达缺失不一定能检出SDHB基因突变。

     

    Abstract:
    Objective To investigate the clinicopathological features, immunophenotypes, molecular genetic alterations, and prognosis of succinate dehydrogenase-deficient renal cell carcinoma (SDH-RCC).
    Methods A total of 11 cases of SDH-RCC diagnosed at West China Hospital, Sichuan University between 2016 and 2023 were selected for clinicopathological, immunohistochemical, and DNA sequencing analyses.
    Results Among the 11 cases of SDH-RCC, there were 5 male patients and 6 female patients. The patients' ages ranged from 12 to 71 years, with an average age of 39.7 years. Among them, 5 patients had tumors located in the right kidney, 5 had tumors located in the left kidney, and 1 patient had bilateral tumors. Microscopic observation showed that the tumor cells of the SDH-RCC patients displayed a wide spectrum of structures, forming sheet-like, nested, and glandular structures. In addition, tumor cells in papillary structures were observed in some cases. The tumor cells had abundant cytoplasm, was eosinophilic, and contained flocculent materials. Intracytoplasmic vacuolations were observed in some of the cells. Among all the patients, 7 (7/11, 63.6%) showed typical low-grade features (grade 1-2 according to the International Society of Urological Pathology ISUP/WHO 2016 classification), and 4 (4/11, 36.4%) showed high-grade features (grade 3 according to the ISUP/WHO 2016 classification). The average ages of patients with low-grade and high-grade features were 32.1 years and 58.0 years, respectively. Immunohistochemical staining of all 11 cases demonstrated negative results for SDHB and cytokeratin 7 (CK7), and positive staining results for paired box 8 (PAX-8), fumarate hydratase (FH), and epithelial membrane antigen (EMA). Their Ki-67 index was 1%-30%. In one case, the loss of SDHB expression was also accompanied by a loss of SDHA expression. Sanger sequencing was performed to examine all the exons of SDHB in 7 cases. One case showed a frameshift mutation, c.236Tdel (p.K80Rfs*), and another case harbored a missense mutation, c.725G>A (p.Arg242His). In another case, next generation sequencing revealed that large fragments of SDHB (Exon 4-8 del) were missing. Follow-up data were available for 10 patients. The follow-up time ranged from 4 to 138 months, with the average being 32.8 months, and all patients survived. Metastasis and recurrence were reported in 5 cases, with 3 of them showing high-grade features and 2 showing low-grade features.
    Conclusion SDH-RCC is rare and the patients demonstrate a relatively young age of onsets. Patients may present with bilateral tumors. Tumors with low-grade features usually occur in young patients, with their Ki-67 index usually being lower than 5%. Individual cases may experience tumor recurrence and metastasis over a long period of follow-up. Tumors with high-grade features tend to occur in older patients who have a higher Ki-67 index, and who are prone to recurrence and metastasis. Negative immunohistochemical staining results for SDHB can assist in tumor diagnosis, but the loss of SDHB protein expression does not necessarily lead to the detection of SDHB gene mutation.

     

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