A Clinicopathological and Molecular Analysis of Fumarate Hydratase (FH)-deficient Renal Cell Carcinomas with Heterogeneous Loss of FH Expression. (September 2022)

• Record Type: Journal Article
• Authors: Anderson, William J.; Tsai, Harrison K.; Sholl, Lynette M.; Hirsch, Michelle S.
• Is Part Of: International journal of surgical pathology. Volume 30:Number 6(2022)
• Page Start: 606
• Page End: 615
• Publication Date: 2022-09
• Subjects: fumarate -- hydratase -- renal cell carcinoma -- kidney -- HLRCC -- FH -- 2SC -- immunohistochemistry -- next generation sequencing; Pathology, Surgical -- Periodicals; 617.07
• DOI: 10.1177/10668969221074600
• Languages: English
• ISSNs: 1066-8969

Abstract

Aims . Fumarate hydratase (FH)-deficient renal cell carcinoma (RCC) is a rare aggressive renal malignancy associated with hereditary leiomyomatosis and RCC syndrome (HLRCC). Tumors exhibiting heterogeneous (ie, patchy) FH loss by immunohistochemistry have rarely been described, may be diagnostically challenging, and have never been the focus of a study. We aimed to investigate the FH mutational status of FH-deficient RCC with heterogeneous versus complete FH loss, to characterize additional genetic drivers, and to evaluate 2SC immunohistochemistry in this setting. Methods and Results . We studied FH-deficient RCC with heterogeneous ( n = 3) and complete ( n = 4) FH loss. Targeted next-generation sequencing (NGS) was performed on all tumors. No patients had a known history of HLRCC. All tumors had histological features within the morphologic spectrum described for FH-deficient RCC. All 7 tumors were immunoreactive for 2SC. Molecularly, all 7 tumors revealed multiple hits involving the FH locus resulting in complete loss of wild-type alleles. All tumors with heterogeneous FH loss harbored FH missense variants within domain 2 of the protein, and each had concomitant copy neutral loss of heterozygosity (CN-LOH). In complete FH loss tumors, FH alterations included splice variants with concomitant loss of heterozygosity ( n = 2) and homozygous gene deletions ( n = 2). Other non-recurrent alterations included biallelic alterations of TP53, NF2, SMAD4 and activation of PIK3CA . Conclusions . Our series highlights how heterogeneous FH loss (patchy positive staining) is an important staining pattern to recognize since it is compatible with a diagnosis of FH-deficient RCC and should prompt additional ancillary studies (confirmatory 2SC immunohistochemistry and/or molecular testing) and genetic evaluation.