Morphologic and molecular characteristics of uterine leiomyomas in hereditary leiomyomatosis and renal cancer (HLRCC) syndrome

Hereditary leiomyomatosis and renal cell cancer (HLRCC) is a hereditary cancer syndrome where affected individuals are predisposed to the development of multiple leiomyomas of the skin and uterus and aggressive forms of kidney cancer. Affected individuals harbor a germline heterozygous loss-of-function mutation of fumarate hydratase (FH) gene. Uterine leiomyomas are present in up to 77 percent of women with this syndrome. Previous studies have shown that inactivation of the FH gene is unusual for non-syndromic leiomyomas. Therefore, it might be possible to distinguish two genetic groups of smooth muscle tumors: the most common group of sporadic uterine leiomyomas without FH gene inactivation and the more unusual group of HLRCC leiomyomas in patients that harbor a germline mutation of FH, although the exact prevalence of hereditary HLRCC is unknown. We reviewed the clinical, morphological and genotypical features of uterine leiomyomas in 19 HLRCC patients with FH germline mutations. Patients with HLRCC syndrome were younger in age compared with regular leiomyomata. DNA was extracted by microdissection and analysis of LOH at 1q43 was performed. Uterine leiomyomas in HLRCC have young age onset and are multiple with size ranging from 1 to 8 cm. Histopathologically, HLRCC leiomyomas frequently had increased cellularity, multinucleated cells and atypia. All cases showed tumor nuclei with large orangiophillic, nucleoi surrounded by a perinucleolar halo similar to the changes found in HLRCC renal cell cancer. Occasional mitoses were found in three cases; however the tumors did not fulfill the criteria for malignancy. Our study also showed that LOH at 1q43 was frequent in HLRCC leiomyomas (8/10 cases), similarly to what it has been previously found in renal cell carcinomas from HLRCC patients. LOH is considered to be the second hit that inactivates the FH gene. We conclude that uterine leiomyomas associated with HLRCC syndrome have characteristic morphologic features. Both, uterine leiomyomas and renal cell carcinoma share some morphological nuclear changes and genotypical features in HLRCC patients. The specific morphological features of the uterine leiomyomas that we describe, may help to identify patients that may be part of the hereditary syndrome.