Histological and molecular characterization of lateral extension in papillary urothelial carcinoma: implications for classification and management

INTRODUCTION: Lateral extension (LE) in urinary bladder papillary urothelial carcinoma (PUC) refers to the phenomenon where atypical urothelium is seen extending laterally in a flat configuration from the base of the papillary tumour. LE is recognized but poorly defined, resulting in inconsistent diagnoses and interpretations amongst pathologists, ranging from atypia to carcinoma in situ (CIS). Herein, we aim to better characterize LE in high-grade PUC, utilizing en bloc transurethral resection specimens. METHODS: We reviewed 37 en bloc specimens from 25 patients and performed comprehensive morphological, molecular and immunohistochemical characterization of PUC and LE components. RESULTS: Three morphological patterns were seen: no LE (n = 24), LE with lower-grade cytomorphology compared to adjacent PUC (lower-grade LE, n = 10), and LE with cytomorphology similar to adjacent PUC (higher-grade LE, n = 3). Mean LE length was 4.7 mm (range 1.5-10.8 mm). LE extended to mucosal margins in 12/13 (92%). Differential next-generation sequencing was performed on paired PUC and adjacent LE components in 11/13 tumours with LE. In 9/11 (82%), LE and PUC showed at least a subset of shared pathogenic/likely pathogenic alterations, supporting clonality between the two components; in five tumours, there were additional alterations specific to PUC, with and without LE-specific alterations. Immunohistochemical staining for CK20 and p53 showed LE with abnormal CK20 in all 11/11 tumours and aberrant p53 in 3/11 (27%). PUC and LE showed concordant p53 staining patterns in 10/11 (91%) and CK20 in only 6/11 (55%) specimens. CONCLUSION: We find that LE can extend at least 1 cm from the base of PUC, suggesting consideration for wider resection margins if complete surgical resection is desired. Additionally, LE is clonally related to PUC in most cases, albeit with heterogeneous relationships, as evidenced by both molecular and immunohistochemical findings. Notably, LE can show immunohistochemical findings similar to those commonly reported for CIS. Recognition of LE may improve diagnostic consistency and reduce overdiagnosis of CIS in the setting of prior papillary tumours.