Comparison of Primary and Metastatic Fumarate Hydratase-Deficient Renal Cell Carcinomas Documents Morphologic Divergence and Potential Diagnostic Pitfall With Peritoneal Mesothelioma

IF 7.1 1区 医学 Q1 PATHOLOGY
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Abstract

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.

比较原发性和转移性FH缺陷肾细胞癌,发现其与腹膜间皮瘤在形态学上存在差异和潜在的诊断隐患。
富马酸氢化酶(FH)缺乏性肾细胞癌是一种罕见的肿瘤,其特点是形态异质性大,FH基因存在致病突变。它们通常表现出侵袭性,并迅速扩散到远处器官,因此人们一直在探索新的治疗方案,包括表皮生长因子受体(EGFR)抑制剂和表达 PD-L1 的靶向免疫疗法。在此,我们对11例原发性FH缺陷肾细胞癌和7例远处转移瘤进行了一系列研究,以评估肿瘤在转移部位的异质性,并估算向各器官的特定扩散率。此外,我们还对肿瘤进行了免疫组化PD-L1表达和表皮生长因子受体突变检测。大多数转移病例涉及腹腔淋巴结(4/7,57%),其次是腹膜(3/7,42%)、肝脏(2/7,29%)和肺部(1/7,14%)。组织学记录显示有六个转移部位,其形态结构往往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,因此主张进行精确的免疫组化检查,包括 PAX 8 和 FH,以得出正确的诊断。此外,还发现了一种纯低度SDH外观的原发性FH缺陷肾细胞癌。在治疗方面,60%的原发性肾肿瘤中发现了明显的PD-L1标记,而这些肿瘤均未携带致病性表皮生长因子受体(EGFR)突变。我们的数据显示,FH缺陷型肾细胞癌的转移瘤在形态上也可能存在异质性,与其他肾肿瘤相比,转移瘤更常累及淋巴结、肝脏和腹膜。由于后者的发生率较高(42%),病理学家应始终注意排除间皮细胞来源的模仿者,以及发生较罕见的原发性低分级类型。最后,与表皮生长因子受体突变相反,PD-L1的表达可能是治疗这些肿瘤的预测性生物标志物。
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来源期刊
Modern Pathology
Modern Pathology 医学-病理学
CiteScore
14.30
自引率
2.70%
发文量
174
审稿时长
18 days
期刊介绍: Modern Pathology, an international journal under the ownership of The United States & Canadian Academy of Pathology (USCAP), serves as an authoritative platform for publishing top-tier clinical and translational research studies in pathology. Original manuscripts are the primary focus of Modern Pathology, complemented by impactful editorials, reviews, and practice guidelines covering all facets of precision diagnostics in human pathology. The journal's scope includes advancements in molecular diagnostics and genomic classifications of diseases, breakthroughs in immune-oncology, computational science, applied bioinformatics, and digital pathology.
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