Small Cluster Invasion Is an Efficient Pathological Predictor for Extraurothelial Recurrence-Free and Overall Survival in Patients With Upper Urinary Tract Urothelial Carcinoma

Purpose: Histological parameters of tumor invasiveness such as tumor budding (BD) are effective prognostic indicators in various cancer types. However, histological evaluation of BD is sometimes challenging, particularly in the setting of predominantly single tumor cells and/or a mixture of dense inflammatory cells. This study aimed to define small cluster invasions (SCIs) as larger cell clusters than BD, which are observed in the invasive frontal region, and investigate their prognostic effects on upper urinary tract urothelial carcinoma (UUTUC). Materials and Methods: This retrospective study included 157 patients with invasive UUTUCs (86 and 71 with renal pelvic and ureteral cancers) who underwent total nephroureterectomy or partial ureteral resection at our institution. The cutoff point for the number of cancer cells composing a single SCI was set at ≥ 5 and < 15; high SCI was defined as ≥ 10 SCIs under ×20 objective magnification. The correlation between SCI status and clinicopathological parameters and the effects of SCI status on recurrence and prognosis were examined. Results: The median observation period was 58.8 months. High SCI was observed in 53 (34%) tumors and significantly associated with ureteral location, postoperative chemotherapy, higher pathological T category, lymphovascular invasion, pathological lymph node metastasis, nonpapillary gross finding, positive surgical margin, concomitant subtype histology, and high BD. Using multivariate analysis, only high SCI was independently associated with shorter extraurothelial recurrence-free survival ( P < .0001, hazard ratio [HR] = 11.0) and overall survival ( P < .0001, HR = 10.7). Conclusions: SCI might be a novel prognostic factor in patients with invasive UUTUC.