Do urinary bladder smooth muscle neoplasms show morphologic and immunophenotypic features of their uterine fumarate hydratase-deficient counterparts?

While the morphologic and immunophenotypic features of smooth muscle neoplasms of the uterus and skin have been well-described in relationship to fumarate hydratase (FH) deficiency (FHD), a potential association of urinary bladder smooth muscle tumors with FH tumor predisposition syndrome (FHTPS) has not been previously investigated. Given an index urinary bladder leiomyoma which showed some of the purported morphologic features seen in uterine FHD leiomyomas, we performed a multi-institutional search for bladder smooth muscle tumors to further evaluate a putative FHTPS association. Cases were re-reviewed for the presence of the following well-described FHD-associated cytomorphologic features: macronucleoli ("cherry red") surrounded by halo, isolated nuclear pleomorphism ("symplastic" nuclei), cytoplasmic eosinophilic globules, staghorn vasculature, alveolar-pattern edema, and chain-like distribution of smooth muscle fibers. Tumors with available material underwent whole-slide staining for FH and 2SC immunohistochemistry. A total of 40 bladder smooth muscle tumors (35 leiomyomas, 5 leiomyosarcomas) were collected from patients (33 females, 17 males) of ages 30-86 years (mean=56.3 years). Among leiomyomas, cytoplasmic eosinophilic globules were seen most frequently (31%), followed by CMV-like macronucleoli (17%), staghorn-type vasculature (11%), "symplastic" nuclei (9%), and alveolar-pattern edema (6%). Among the leiomyosarcomas, cytoplasmic eosinophilic globules or CMV-like macronucleoli were infrequently seen (20%), while staghorn-type vasculature was seen in 60% and "symplastic" nuclei were seen in all (100%) tumors. No cases exhibited chain-like muscle fibers. Of the stained tumors, all (100%) showed retained FH expression and negative 2SC immunoreactivity. Three female patients with bladder leiomyomas had a prior history of uterine leiomyomas all lacking FHD histology. Although a subset of bladder smooth muscle tumors show overlapping morphologic features with uterine FHD leiomyomas, they do not appear to harbor FHD or an association with FHTPS, although the findings warrant confirmation in future studies, perhaps inclusion of FH and/or 2SC immunohistochemistry.