Noninvasive low-grade papillary urothelial carcinoma with degenerative nuclear atypia: a grading pitfall

Abstract

Noninvasive low-grade papillary urothelial carcinoma is a papillary neoplasm with orderly appearance and mild nuclear pleomorphism. Some cases show significant nuclear pleomorphism with degenerative atypia leading to grading difficulties. A retrospective review of the pathology files identified 16 cases diagnosed as noninvasive low-grade papillary urothelial carcinoma with degenerative atypia. Fifteen cases were consults. The average age was 46 years (range 19-78). The average size was 1.7cm (range: 0.3-3.5). The submitting diagnoses in consults were noninvasive high-grade papillary urothelial carcinoma (n=6), condyloma (n=1), atypical papillary lesion (n=1), prominent umbrella cells (n=1), and not given (n=6). Ki-67 proliferation rate was <5% in 10 of 10cases (100%), and the cells with large atypical nuclei were negative. Microscopically, there were scattered cells with nuclei larger than 5 times the size of stromal lymphocytes but displayed smudgy chromatin and occasional multinucleation and intranuclear vacuoles. Next-generation sequencing identified the following mutations: HRAS (n=4), FGFR3 (n=3), KRAS (n=3), BRAF (n=1), PDGFRA (n=1), and PIK3CA (n=1). Other deleterious mutations were identified, but none in genes characteristic of high-grade tumors. Follow-up was available in 6 patients (median 32 months). One patient recurred with a noninvasive low-grade papillary urothelial carcinoma 20 months after the index case. All the remaining patients had no evidence of disease at the last follow-up. No patient died or had disease progression. The combination of preservation of polarity, low mitotic activity, Ki-67<5% with the larger atypical nuclei negative for Ki-67, along with nuclear atypia that is degenerative are features used to classify these tumors as low grade.