遗传性平滑肌瘤病和肾细胞癌综合征相关性肾癌的临床特征分析:一项全国多中心回顾性研究

Clinical features of hereditary leiomyomatosis and renal cell carcinoma syndrome-associated renal cell carcinoma:a multi-center real-world retrospective study

目的探讨我国遗传性平滑肌瘤病和肾细胞癌综合征相关性肾癌(HLRCC-RCC)患者的临床特征以及系统治疗的有效性。方法去回顾性分析2008年1月至2021年12月在国内15家医疗中心基因诊断明确有FH胚系突变的119例HLRCC-RCC患者的临床资料。男73例,女46例;中位年龄38(13,74)岁;中位肿瘤直径6.5(1.0,20.5)cm。I~Ⅱ期38例(31.9%),Ⅲ~V期81例(68.1%)。本组119例中11例同时表现为皮肤平滑肌瘤,46例女性HLRCC-RCC患者中44例有子宫肌瘤病史。总结患者的病理特点、治疗方法,以及患者预后生存情况。结果本研究119例中,共86例患者接受手术治疗,其中根治性肾切除术70例,肾部分切除术5例,减瘤性肾切除术11例;其余33例初诊转移患者行肾穿刺活检术。基因检测结果显示119例均存在FH基因胚系突变,其中94例FH基因点突变,18例FH基因插人/缺失突变,4例FH基因剪接突变,2例FH基因大片段缺失,1例FH基因拷贝数变异。免疫组化染色结果显示113例患者2-SC强阳性,FH阴性。本组共102例患者接受系统治疗,包括44例初诊转移患者和58例术后转移患者。其中酪氨酸激酶抑制剂(TKI)联合免疫检查点抑制剂(ICI)治疗组33例,贝伐单抗联合厄洛替尼治疗组8例,TKI单药治疗组61例。所有患者均获得随访,中位随访时间17(3,82)个月。生存分析结果显示TKI联合ICI治疗组中位PFS为18(5,38)个月,中位OS未达到;贝伐单抗联合厄洛替尼治疗组中位PFS为12(5,14)个月,中位OS为30(10,32)个月;TKI单药治疗组中位PFS为10(364)个月,中位OS为44(10,74)个月。TKI联合ICI治疗组的PFS(P=0.009)和OS(P=0.006)均优于贝伐单抗联合厄洛替尼治疗组;TKI联合ICI治疗组的PFS(P=0.003)和OS(P=0.028)均优于TKI单药治疗组。结论HLRCC-RCC罕见,具有家系遗传特性,恶性程度高,预后不佳,易出现转移。免疫组化染色2-SC强阳性及FH阴性可为临床诊断提供重要依据,基因检测显示FH基因胚系突变可明确诊断。初步研究结果证实TKI联合ICI治疗转移性HLRCC-RCC的临床效果较好,但有待大样本多中心随机对照临床研究进一步验证。

Objective To investigate the clinical features and therapeutic efficacy of patients with hereditary leiomyomatosis and renal cell carcinoma(RCC)syndrome-associated RCC(HLRCC-RCC)in China.Methods The clinical data of 119 HLRCC-RCC patients with fumarate hydratase(FH)germline mutation confirmed by genetic diagnosis from 15 medical centers nationwide from January 2008 to December 2021 were retrospectively analyzed.Among them,73 were male and 46 were female.The median age was 38(13,74)years.The median tumor diameter was 6.5(1.0,20.5)cm.There were 38 cases(31.9%)in stage I-II and 81 cases(68.1%)in stage II-IV.In this group,only 11 of 119 HLRCC-RCC patients presented with skin smooth muscle tumors,and 44 of 46 female HLRCC-RCC patients had a history of uterine fibroids.The pathological characteristics,treatment methods,prognosis and survival of the patients were summarized.Results A total of 86 patients underwent surgical treatment,including 70 cases of radical nephrectomy,5 cases of partial nephrectomy,and 11 cases of reductive nephrectomy.The other 33 patients with newly diagnosed metastasis underwent renal puncture biopsy.The results of genetic testing showed that 94 patients had FH gene point mutation,18 had FH gene insertion/deletion mutation,4 had FH gene splicing mutation,2 had FH gene large fragment deletion and 1 had FH gene copy number mutation.Immunohistochemical staining showed strong 2-succinocysteine(2-SC)positive and FH negative in 113 patients.A total of 102 patients received systematic treatment,including 44 newly diagnosed patients with metastasis and 58 patients with postoperative metastasis.Among them,33 patients were treated with tyrosine kinase inhibitor(TKI)combined with immune checkpoint inhibitor(ICI),8 patients were treated with bevacizumab combined with erlotinib,and 61 patients were treated with TKI monotherapy.Survival analysis showed that the median progression-free survival(PFS)of TKI combined with ICI was 18(5,38)months,and the median overall survival(OS)was not reached.The median PFS and OS were 12(5,14)months and 30(10,32)months in the bevacizumab combined with erlotinib treatment group,respectively.The median PFS and OS were 10(3,64)months and 44(10,74)months in the TKI monotherapy group,respectively.PFS(P=0.009)and 0S(P=0.006)in TKI combined with ICI group were better than those in bevacizumab combined with erlotinib group.The median PFS(P=0.003)and median OS(P=O.028)in TKI combined with ICI group were better than those in TKI monotherapy group.Conclusions HLRCC-RCC is rare but has a high degree of malignancy,poor prognosis and familial genetic characteristics.Immunohistochemical staining with strong positive 2-SC and negative FH can provide an important basis for clinical diagnosis.Genetic detection of FH gene germ line mutation can confirm the diagnosis.The preliminary study results confirmed that TKI combined with ICI had a good clinical effect,but it needs to be confirmed by the results of a large sample multi-center randomized controlled clinical study.