Letters

FGFR3 alterations in urothelial carcinoma

November 2019—We read with interest the case described by Vormittag-Nocito, et al., of metastatic bladder adenocarcinoma with associated molecular pathology findings (September 2019). However, we would like to point out what we believe to be an important update related to the significance of FGFR3 alterations in urothelial carcinoma.¹ When referring to TP53 and FGFR3 alterations in urothelial carcinoma, the authors write that “no targeted therapy or prognostic implications can be made about these mutations at this time.” On the contrary, we want to bring to readers’ attention that FGFR3 alterations (present in approximately 20 percent of urothelial carcinomas) are currently actionable and targetable in advanced-stage urothelial carcinoma, as erdafitinib, an FGFR inhibitor, was recently approved by the FDA for use in this disease.²

We offer an illustrative case to demonstrate this point because we anticipate that cases like these will become increasingly common. Physicians should be aware that FGFR blockade may be a therapeutic option for patients with advanced urothelial carcinoma and is currently approved for patients with specific FGFR3 alterations.

An 85-year-old female was referred to gynecologic oncology for vaginal bleeding. The clinical history was notable for a history of high-grade urothelial carcinoma treated with chemotherapy and cystectomy. Physical exam was notable for a vaginal mass.

Biopsy revealed a poorly differentiated carcinoma. On morphologic grounds, the possibility of a primary vaginal or cervical squamous carcinoma was considered, and the immunohistochemical overlap between squamous carcinoma and urothelial carcinoma was noted, as both may label for P63 and GATA3 and overexpress P16. Positivity for CK20 or uroplakin would favor urothelial carcinoma, whereas demonstration of high-risk HPV by in situ hybridization would support a cervical or vaginal primary. Immunohistochemical studies showed the tumor cells were strongly positive for P63, GATA3, CK7, and CK20, most consistent with metastatic urothelial carcinoma.

Immunohistochemistry for PD-L1 was negative, and expression of mismatch repair proteins was retained, both reducing the probability of clinical benefit from immune checkpoint blockade. Platinum-based chemotherapy was recommended, and targeted massively parallel sequencing panels were ordered on the vaginal biopsy. An FGFR3-TACC3 fusion transcript was detected, a recurrent abnormality seen in urothelial carcinoma. This further supported the diagnosis of metastatic urothelial carcinoma, as well as introduced the option of the newly approved targeted FGFR inhibitor, erdafitinib.