PAX8 positivity in nested variant of urothelial carcinoma: a potential diagnostic pitfall

Nested variant of urothelial carcinoma is a rare variant of urothelial carcinoma morphologically characterized by infiltrative nests of cytologically bland urothelial cells. It is widely recognized that nested variant of urothelial carcinoma can closely mimic von Brunn nests. However, nested variant of urothelial carcinoma with tubule formation can also resemble nephrogenic adenoma, where immunohistochemical positivity for PAX8 has been used to establish the diagnosis of nephrogenic adenoma. Following anecdotal examples of PAX8 positive nested variant of urothelial carcinoma, we formally evaluated 23 cases of nested variant of urothelial carcinoma from 2011 to 2018. Cases were collected from our institution and evaluated for their architectural pattern and PAX8 expression. Except for 1 case from the renal pelvis, cases were located in the bladder. The majority (14/23 [61%]) showed solid nests with at least focal tubular differentiation. PAX8 immunoreactivity was strong (3+) in 7 (30%), moderate (2+) in 6 (26%), and negative in 10 (44%) cases. Four (57%) of the cases with strong expression and 3 (50%) of those with moderate staining showed diffuse immunoreactivity. Moderate-strong immunoreactivity was seen in 4/6 (66.7%) cases with solid nests, 8/14 (57.1%) with solid nests and tubules, and 1/3 (33.3%) with large nests. In conclusion, PAX8 can be positive in a significant proportion of nested variant of urothelial carcinoma cases, and recognition of this finding is important to avoid misdiagnosis of nested variant of urothelial carcinoma as nephrogenic adenoma based on PAX8 expression, particularly in cases with tubular differentiation and limited sampling.