Rare, sporadic uterine
leiomyomas arise in the setting of severe metabolic aberration due to a 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 accumulation in affected cells with formation of S-(2-succino)-cysteine, which can be detected with the 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 nine cases. Germline genetic testing for
fumarate hydratase mutations was performed in three cases. A detailed morphological analysis was undertaken, and S-(2-succino)-cysteine immunohistochemical analysis was performed with controls from a tissue microarray (
leiomyomas (19),
leiomyosarcomas (29), and
endometrial stromal tumors (15)). Of the nine study cases, four 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 three tested patients had germline
fumarate hydratase mutations. Only one
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 the 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.