Detailed Morphologic and Immunohistochemical Characterization of Myomectomy and Hysterectomy Specimens From Women With Hereditary Leiomyomatosis and Renal Cell Carcinoma Syndrome (HLRCC)

Abstract

Hereditary leiomyomatosis and renal cell carcinoma syndrome (HLRCC), caused by a germline mutation in the fumarate hydratase (FH) gene, predisposes patients to uterine and cutaneous smooth muscle tumors and an aggressive type of renal cell carcinoma. Almost all women with HLRCC develop symptomatic uterine leiomyomas resulting in surgery at young ages, presenting an ideal opportunity for early detection of these patients and the implementation of surveillance measures for renal cell carcinoma. FH-deficient uterine leiomyomas can show characteristic morphologic features (FH-d morphology) that have been previously described. Immunohistochemistry (IHC) for FH can also be helpful in detecting FH deficiency in leiomyomas, which manifests as complete loss of staining for FH. However, the distribution and topography of FH-d morphology and FH loss by IHC in the context of multiple leiomyomas in patients with HLRCC has not been evaluated. The aim of this study is to describe in detail the clinical and pathologic characteristics of uterine leiomyomas from women with HLRCC. Six patients with proven FH germline mutations were included. All available slides were reviewed and FH IHC staining was performed on multiple blocks when possible. Clinical data were extracted from online medical records. All 6 patients presented with symptomatic uterine fibroids and underwent myomectomy (age 24 to 36 y), followed by hysterectomy in 2 patients (age 31 and 40 y). Specimens showed conventional leiomyomas, cellular leiomyomas and leiomyomas with bizarre nuclei. FH-d morphology was present in leiomyomas from all patients and was typically observed as a diffuse finding in the majority of slides across different leiomyoma types. FH-d morphology was absent in some leiomyoma sections from one patient and the morphologic features were focal and subtle in leiomyomas from 2 patients. Both hysterectomy specimens were also notable for showing scattered irregular tongues and nodules of smooth muscle proliferation (leiomyomatosis-like) in the background myometrium. Immunohistochemical staining of multiple slides per patient for FH showed either retained staining in all sections (2/6 cases), loss of staining in all sections (1 case) or variable staining across different leiomyomas (3 cases). In conclusion, patients with HLRCC undergo surgery at young ages for highly symptomatic uterine leiomyomas. FH-d morphology is usually a diffuse and well developed finding across different leiomyomas but may be absent or focal and subtle. FH IHC can show variable results and presence of retained FH staining should not be used to exclude the possibility of HLRCC. Referral for genetic counselling and testing should be considered in a young patient with uterine leiomyomas showing FH-d morphology even if immunohistochemical staining for FH is retained.