富马酸水合酶(FH)缺乏的肾细胞癌是罕见的肿瘤,其特征是FH基因具有广泛的形态学异质性和致病性突变。它们经常表现出攻击行为,快速扩散到远处的器官,所以新的治疗方案已经被探索,包括EGFR抑制剂和PD-L1表达用于靶向免疫治疗。在这里,我们调查了11例原发性FH缺乏的肾细胞癌和7例远处转移瘤,以评估肿瘤异质性,甚至在转移部位,并估计向不同器官的特定扩散率.此外,对肿瘤进行了免疫组织化学PD-L1表达和EGFR突变检测.大多数转移病例涉及腹部淋巴结(4/7,57%),其次是腹膜(3/7,42%),肝脏(2/7,29%),和肺(1/7,14%)。在组织学上记录了六个转移灶,揭示形态异质性结构通常与相应的原发性肾肿瘤不同。腹膜受累在形态上类似于良性反应性间皮瘤或原发性腹膜间皮瘤,因此主张进行准确的免疫组织化学小组,包括PAX8和FH,达到正确的诊断。还记录了纯的低级别SDH型原发性FH缺乏的肾细胞癌。至于治疗,在60%的原发性肾脏肿瘤中发现了显着的PD-L1标记,而他们都没有携带致病性EGFR突变。我们的数据表明,FH缺乏的肾细胞癌在转移中也可能在形态上异质,涉及淋巴结,肝脏,和腹膜比其他肾肿瘤更常见。由于后者的频率很高(42%),病理学家应该总是关心排除间皮组织衍生的模数,以及罕见的初级低品位类型的出现。最后,与EGFR突变相反,PD-L1表达可能是治疗这些肿瘤的可能的预测生物标志物。
Fumarate hydratase (FH)-deficient renal cell carcinomas are rare neoplasms characterized by wide morphologic heterogeneity and pathogenetic mutations in the FH gene. They often show aggressive behavior with rapid diffusion to distant organs, so novel therapeutic scenarios have been explored, including EGFR inhibitors and PD-L1 expression for targeted immunotherapy. Herein, we investigated a series of 11 primary FH-deficient renal cell carcinomas and 7 distant metastases to evaluate tumor heterogeneity even in metastatic sites and estimate the specific spread rates to various organs. Furthermore, the tumors were tested for immunohistochemical PD-L1 expression and EGFR mutations. Most metastatic cases involved the abdominal lymph nodes (4/7; 57%), followed by the peritoneum (3/7; 42%), the liver (2/7; 29%), and the lungs (1/7; 14%). Six metastatic localizations were histologically documented, revealing a morphologic heterogeneous architecture often differing from that of the corresponding primary renal tumor. Peritoneal involvement morphologically resembled a benign reactive mesothelial process or primary peritoneal mesothelioma, thus advocating to perform an accurate immunohistochemical panel, including PAX8 and FH, to reach a proper diagnosis. A pure low-grade succinate dehydrogenase-looking primary FH-deficient renal cell carcinoma was also recorded. As for therapy, significant PD-L1 labeling was found in 60% of primary renal tumors, whereas none of them carried pathogenetic EGFR mutations. Our data show that FH-deficient renal cell carcinoma may be morphologically heterogeneous in metastases as well, which involve the lymph nodes, the liver, and the peritoneum more frequently than other renal tumors. Due to the high frequency of this latter (42%), pathologists should always be concerned about ruling out mesothelial-derived mimickers, and the occurrence of rarer, primary, low-grade-looking types. Finally, contrary to EGFR mutations, PD-L1 expression could be a possible predictive biomarker for the therapy of these tumors.