Uterine smooth muscle tumors with features suggesting fumarate hydratase aberration: detailed morphologic analysis and correlation with S-(2-succino)-cysteine immunohistochemistry

Rare, sporadic uterine leiomyomas arise in the setting of severe metabolic aberration due to somatic fumarate hydratase mutation. Germline mutations account for the Hereditary Leiomyomatosis and Renal Cell Carcinoma syndrome, which predisposes for cutaneous and uterine leiomyomas and aggressive renal cell carcinomas. Altered fumarate hydratase leads to fumarate accumulates in affected cells with formation of S-(2-succino)-cysteine, which can be detected with polyclonal antibody. High levels of these modified cysteine residues are found characteristically in fumarate hydratase-deficient cells, but not in normal tissues or tumors unassociated with Hereditary Leiomyomatosis and Renal Cell Carcinoma syndrome. We hypothesized that S-(2-succino)-cysteine-positive leiomyomas, indicating fumarate hydratase aberration, have morphologic features that differ from those without S-(2-succino)-cysteine positivity. Hematoxylin and eosin-stained slides of uterine smooth muscle tumors were prospectively analyzed for features suggesting Hereditary Leiomyomatosis and Renal Cell Carcinoma Syndrome, such as prominent eosinophilic macronucleoli with perinucleolar halos, yielding 9 cases. Germline genetic testing for fumarate hydratase mutations was performed in 3 cases. A detailed morphological analysis was undertaken, and S-(2-succino)-cysteine immunohistochemistry was performed with controls from a tissue microarray [leiomyomas (19), leiomyosarcomas (29), and endometrial stromal tumors (15)]. Of the 9 study cases, 4 had multiple uterine smooth muscle tumors. All cases had increased cellularity, staghorn vasculature, and fibrillary cytoplasm with pink globules. All cases had inclusion-like nucleoli with perinuclear halos (7 diffuse, 1 focal). All showed diffuse granular cytoplasmic labeling with the S-(2-succino)-cysteine antibody. Two of 3 tested patients had germline fumarate hydratase mutations. Only 1 leiomyoma from the tissue microarray controls was immunohistochemically positive, and it showed features similar to other immunohistochemically positive cases. Smooth muscle tumors with fumarate hydratase aberration demonstrate morphological reproducibility across cases and S-(2-succino)-cysteine immuno-positivity. Although the features described are not specific for germline fumarate hydratase mutation or the Hereditary Leiomyomatosis and Renal Cell Carcinoma syndrome, their presence should suggest fumarate hydratase aberration. Identifying these cases is an important step in the diagnostic workup of patients with possible Hereditary Leiomyomatosis and Renal Cell Carcinoma.