Our group aimed to better define the long-term risk of recurrence, progression to muscle-invasive disease, and CSM in 521 patients with primary TaLG (n=491) or papillary urothelial neoplasm of low malignant potential (PUNLMP, n=30) at the University Health Network (Toronto, Canada). Using over 30 years of patient records, we analyzed recurrence rates, progression, and survival outcomes. We were particularly surprised by a few metastatic biopsies that were consistent with LG disease, prompting us to explore their genetic landscape. RNA sequencing was conducted on four metastatic cases to identify potential molecular signatures that may distinguish these rare, aggressive tumors from more indolent cases. Additionally, recognizing that interobserver variability in pathological grading remains a real issue, we assessed this variability using the two grading systems with three renowned uro-pathology experts from North America and Europe.
With a median follow-up of nearly 10 years, 350 patients experienced recurrence, with most occurring within five years, however, about 10% of patients who never recurred during the first 4 years, presented with a tumour recurrence after 5 years. In addition, 57 progressed in stage, 20 developed metastases and 15 ultimately died from BC (median of 9.6 years after diagnosis). These findings were an eye-opener and sobering.
However, cancer-specific survival probabilities were reassuring at 0.99, 0.98, and 0.96 at 5-, 10- and 15- years, respectively, reinforcing that serious outcomes remain, fortunately, rare. Interestingly, metastatic TaLG had transcriptomic profiles which were more adverse than indolent tumours, in keeping with higher-grade tumors despite phenotypically appearing similar to indolent tumors. Our study also demonstrated that even among renowned uro-pathology experts, variability in grading remains a major issue. Grading concordance for the 2004/2022 system discriminating between LG and high grade was 0.78 (95%CI: 0.65-0.90) only. For distinguishing between grades 1, 2, and 3 in the WHO 1973 classification, the kappa coefficient was a disappointing 0.41 (95%CI: 0.32-0.50). However, this grading variability did not affect the findings related to progression outcomes in LG disease.
This study with long-term data, one of the longest ever reported, challenges the assumption that primary TaLG NMIBC never progresses to lethal disease if followed long enough. However, the risk of BC-related mortality is extremely low in patients who are recurrence-free for the first 5 years. In light of the important variability in pathological grading even among experts, minimizing pathological grading variability remains critical.
Written by: Alexandre Zlotta, MD, PhD & Amy Chan, MSc
- Division of Urology, Department of Surgery, Mount Sinai Hospital, Sinai Health System, Toronto, Ontario, Canada
- Divisions of Urology and Surgical Oncology, Department of Surgery, University Health Network, Toronto, Ontario, Canada