Fumarase-deficient Uterine Leiomyomas

Abstract

Loss-of-function germline mutations in the fumarase (FH)-gene of the Krebs cycle characterize hereditary leiomyomatosis and renal cell cancer (HLRCC)-syndrome. Fumarase (FH)-deficiency can be diagnosed by the loss of immunohistochemical expression. In this study, we investigated the occurrence and clinicopathologic features of FH-deficient uterine smooth muscle tumors (SMTs). A total of 1583 uterine and 157 non-uterine SMTs were examined using a polyclonal FH antibody and automated immunohistochemistry, and 86 uterine leiomyomas with an FH loss were identified. The frequencies of FH-deficiency for subcohorts of uterine SMTs were 1.6% for unselected non-atypical leiomyomas, 1.8% for cellular leiomyomas, 37.3% for atypical leiomyomas, and 0% for leiomyosarcomas. One extrauterine, retroperitoneal ER-positive leiomyoma, was also FH-deficient. The patient age of FH-deficient uterine leiomyomas was 20-52 years (median, 38 years). Grossly these tumors were often soft and amorphous resembling a fibrothecoma. Histologically the FH-deficient non-atypical leiomyomas lacked cellular packeting and distinct collagenous zones and showed chain-like or palisading nuclear arrangements, prominent staghorn-shaped blood vessels, oval nuclei with no or at most, mild atypia, small eosinophilic nucleoli, and a low mitotic rate (0-1/10 HPFs). The FH-deficient atypical leiomyomas had nuclear atypia often manifesting as multinucleation, prominent eosinophilic nucleoli, and mitotic activity up to 7/10 HPFs, with atypical mitoses seen in 32% of cases. However, similar histologic changes were seen in some non FH-deficient atypical leiomyomas. Loss-of-function FH-gene mutations including 5 whole gene deletions and 3 frameshift mutations were identified in 8 of 16 FH-deficient non-atypical leiomyomas using multiplex ligation-dependent probe amplification and Sanger sequencing, respectively. Follow-up data on patients with FH-deficient atypical uterine leiomyomas revealed 19 patients alive (median follow-up 27 years) and 5 patients dead. Deaths were 9-30 years after surgery at median age of 72 years; causes of death could not be determined. These results indicate that FH-deficient uterine leiomyomas occur with a high frequency among atypical leiomyomas and infrequently in non-atypical leiomyomas and are often histologically distinctive. They seem to have a low biologic potential and lack any significant association with leiomyosarcoma.

Leiomyoma with bizarre nuclei: a morphological, immunohistochemical and molecular analysis of 31 cases

“…Although somatic FH mutations were identified in six of the FH-deficient leiomyomas, germline testing revealed normal FH status in five (unsuccessful in the sixth). Similarly Miettinen et al 38 reported that 5% of the uterine smooth muscle tumors analyzed (n=1583) were FH-deficient by immunohistochemistry with most (79%) being leiomyomas with bizarre nuclei. They noted that while similar histologic features were often seen in both FH-deficient and FH-proficient leiomyomas with bizarre nuclei those that were FH-deficient were more likely to have staghorn vessels, prominent eosinophilic nucleoli, and perinucleolar halos.…”

“…Although molecular studies on leiomyomas with an aberrant immunoprofile are limited, especially those implementing germline testing, data thus far favors these tumors to harbor somatic mutations. 36 , 38 , 40 In a series of 194 leiomyomas from patients less than 40 years, Joseph et al 40 identified five tumors that were 2SC-positive (two of them completely FH-negative), and four of these were classified as “highly suspicious for hereditary leiomyomatosis and renal cell carcinoma syndrome” based upon morphology. Molecular analysis identified somatic mutations in four leiomyomas and homozygous deletion of the FH gene in the other, but germline testing was not performed.…”

“…They noted that while similar histologic features were often seen in both FH-deficient and FH-proficient leiomyomas with bizarre nuclei those that were FH-deficient were more likely to have staghorn vessels, prominent eosinophilic nucleoli, and perinucleolar halos. Miettinen et al 38 also performed molecular analysis on 16 FH-deficient tumors (not specified as to whether leiomyomas with bizarre nuclei) and identified FH deletions in five and frameshift mutations in three leiomyomas.…”

Mesenchymale und gemischte Uterustumoren

“…Einige der zahlreichen Leiomyomvarianten verdienen eine genauere Betrachtung [10] [12]. Diese Knoten, die sich meist bei jungen Frauen finden, weisen oft eine deutliche Kernpolymorphie und einen erhöhten Zellreichtum auf, wobei differenzialdiagnostisch Leiomyome mit bizarren Zellkernen im Raum stehen (.…”

“…FH-defiziente Leiomyome finden sich in etwa 0,4-1,6 % aller nichtselektierten Leiomyome ohne Atypien sowie in 1,8 % aller zellreichen Leiomyome und etwa einem Drittel aller Leiomyome mit bizarren Zellkernen [13]. Eine FH-Defizienz konnte bis dato hingegen noch nicht in Leiomyosarkomen nachgewiesen werden [12].…”