Yu Yanfei, Shen Qi, Xia Mancheng, Huang Cong, Li Xuesong, He Shiming, Wang Aixiang, Wang Suxia
Department of Urology, Peking University First Hospital, No. 8 Xishiku St., Xicheng District, Beijing, China.
Institute of Urology, Peking University, Beijing Key Laboratory of Urogenital Diseases (Male) Molecular Diagnosis and Treatment Center, National Urological Cancer Center, No. 8 Xishiku St., Xicheng District, Beijing, 100034, China.
World J Urol. 2025 Sep 22;43(1):567. doi: 10.1007/s00345-025-05941-6.
Fumarate hydratase (FH)-deficient renal cell carcinoma (RCC) represents a rare and aggressive subtype of RCC, closely associated with hereditary leiomyomatosis and renal cell cancer syndrome (HLRCC). The limited understanding of this disease presents significant clinical challenges in its management. To date, robust evidence supporting the efficacy of systemic therapies for FH-deficient RCC remains scarce.
The objective of this study is to assemble a relatively large single-center cohort of FH-deficient RCC, focusing on clinical, pathological, and immune cell infiltration characteristics, particularly CD4-positive (CD4⁺) and CD8-positive (CD8⁺) T-cell infiltrates. This aims to enhance our understanding of FH-deficient RCC and provide evidence-based support for optimizing its systemic treatment strategies.
We have retrospectively reviewed clinicopathologic and genetic prognostic data of patients operated on for renal tumor between January 2013 and June 2023 at Peking University First Hospital. Additionally, we employed multiplex immunofluorescence to evaluate the expression profiles of T cells within the tumor-infiltrating microenvironment of these patients.
This study analyzed 27 patients (median age: 39.3 years; range 16-70; M: F = 14:13) with 31 renal tumors, including two multifocal cases. Histopathological evaluation revealed 25 high-grade tumors (WHO/ISUP G3-4) and two low-grade tumors (one with focal high-grade features and one entirely low-grade). Immunohistochemistry demonstrated universal strong 2SC positivity in all cases, while GATA3 expression (7 cases) was largely focal. Genomic profiling of 23 patients identified 18 germline and 3 somatic FH mutations, with two cases lacking FH alterations; MSI-L was detected in two tumors (others MSS). Multiplex immunofluorescence of 19 FH-deficient renal cell carcinomas revealed elevated PD-L1 expression (63.16% tumor cells) and distinct immune infiltration patterns: CD4 T cell density exceeded CD8 cells overall (1,125 vs. 336/mm², P = 0.005), with higher T cell accumulation at tumor margins (CD4: 1,431/mm²; CD8: 332/mm²) versus centers (CD4: 911/mm²; CD8: 164/mm²; P=0.005, P=0.017). CD4 dominance persisted across all regions, suggesting a unique immunophenotypic signature in FH-deficient tumors. In FH-deficient RCC, only PD-L1 expression significantly predicted survival: PD-L1-positive patients had prolonged OS (median NR vs. 29.73 months in PD-L1-negative; P = 0.03).
This analysis highlights the spatial heterogeneity of T-cell infiltration in FH-deficient RCCs and suggests a potential role for PD-L1-targeted therapies in this subset of tumors. These findings suggest a distinct spatial distribution of immune cell subsets within FH-deficient RCCs, with a pronounced enrichment of CD4-positive cells relative to CD8-positive cells, particularly at the tumor margin. This pattern may have important implications for understanding the tumor immune microenvironment and developing targeted immunotherapies for this subtype of RCC.
富马酸水合酶（FH）缺陷型肾细胞癌（RCC）是RCC中一种罕见且侵袭性强的亚型，与遗传性平滑肌瘤病和肾细胞癌综合征（HLRCC）密切相关。对这种疾病的了解有限，给其治疗带来了重大临床挑战。迄今为止，支持FH缺陷型RCC全身治疗疗效的有力证据仍然很少。
本研究的目的是收集一个相对较大的单中心FH缺陷型RCC队列，重点关注临床、病理和免疫细胞浸润特征，特别是CD4阳性（CD4⁺）和CD8阳性（CD8⁺）T细胞浸润。这旨在增进我们对FH缺陷型RCC的了解，并为优化其全身治疗策略提供循证支持。
我们回顾性分析了2013年1月至2023年6月在北京大学第一医院接受肾肿瘤手术患者的临床病理和基因预后数据。此外，我们采用多重免疫荧光法评估这些患者肿瘤浸润微环境中T细胞的表达谱。
本研究分析了27例患者（中位年龄：39.3岁；范围16 - 70岁；男：女 = 14:13）的31个肾肿瘤，包括2例多灶性病例。组织病理学评估显示25个高级别肿瘤（WHO/ISUP G3 - 4）和2个低级别肿瘤（1个有局灶性高级别特征，1个完全为低级别）。免疫组织化学显示所有病例均普遍强2SC阳性，而GATA3表达（7例）大多为局灶性。对23例患者的基因分析发现18个胚系和3个体细胞FH突变，2例无FH改变；2个肿瘤检测到微卫星低度不稳定（MSI - L）（其他为稳定微卫星状态（MSS））。对19例FH缺陷型肾细胞癌的多重免疫荧光显示程序性死亡受体配体1（PD - L1）表达升高（63.16%肿瘤细胞），且免疫浸润模式不同：总体上CD4 T细胞密度超过CD8细胞（1125对336/mm²，P = 0.005），肿瘤边缘T细胞聚集高于中心（CD4：1431/mm²；CD8：332/mm²）（中心CD4：911/mm²；CD8：164/mm²；P = 0.005，P = 0.017）。所有区域均以CD4为主，提示FH缺陷型肿瘤具有独特的免疫表型特征。在FH缺陷型RCC中，只有PD - L1表达显著预测生存：PD - L1阳性患者总生存期延长（中位未达到 vs. PD - L1阴性患者的29.73个月；P = 0.03）。
该分析突出了FH缺陷型RCC中T细胞浸润的空间异质性，并提示PD - L1靶向治疗在这一肿瘤亚组中的潜在作用。这些发现表明FH缺陷型RCC中免疫细胞亚群存在独特的空间分布，相对于CD8阳性细胞，CD4阳性细胞明显富集，尤其是在肿瘤边缘。这种模式可能对理解肿瘤免疫微环境以及为这种亚型的RCC开发靶向免疫治疗具有重要意义。
