Hereditary leiomyomatosis and renal cell carcinoma (HLRCC) syndrome is an autosomal dominant syndrome that results from mutations in the fumarate hydratase (FH) gene. Patients with HLRCC are at risk for smooth muscle tumors of the uterus and skin as well as renal tumors. The renal cell carcinomas associated with HLRCC are usually high stage at presentation, aggressive, and have poor clinical outcomes. Therefore these patients and family members would benefit from early identification and appropriate surveillance. In small studies, HLRCC-associated uterine leiomyomas have been noted to display characteristic morphologic features including eosinophilic cytoplasmic inclusions, prominent eosinophilic nucleoli, and perinucleolar halos. Limited data suggest that positive staining for 2-succinocysteine (2SC) and loss of staining for FH by immunohistochemistry (IHC) can help with identification of HLRCC. The aim of this study was to evaluate the ability of morphology and IHC for FH and 2SC to help identify HLRCC in young patients with uterine smooth muscle tumors. We identified 194 evaluable uterine leiomyomas from women less than 40 years of age. We found FH gene aberrations by mutation analysis in 5 cases, a 2.6% incidence. Of these 5 cases, 4 displayed the characteristic morphologic features outlined above, whereas 1 did not. All 5 tumors with FH gene abnormalities showed positive staining for 2SC, whereas no FH gene aberrations were found in the 2SC-negative cases. Loss of FH staining was seen in 2 of the 5 cases, 1 with frameshift mutation and the other with homozygous deletion, whereas the remaining 3 cases with missense FH gene mutations were FH positive. Our study shows that morphologic features can be helpful for detection of HLRCC in uterine leiomyomas, although they may not be present in every case. IHC for 2SC and FH can be helpful: presence of positive staining for 2SC is sensitive and specific for detection of FH gene aberrations, whereas loss of staining for FH is specific but not sufficiently sensitive, as cases with missense mutations in the FH gene can show retained staining.
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*Department of Pathology, University of California San Francisco, San Francisco, CA
†University of South Carolina School of Medicine, Columbia, SC
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Conflicts of Interest and Source of Funding: The authors have disclosed that they have no significant relationships with, or financial interest in, any commercial companies pertaining to this article.
Correspondence: Karuna Garg, MD, Department of Pathology, University of California San Francisco, 505 Parnassus Avenue, San Francisco, CA 94127 (e-mail: firstname.lastname@example.org).