Urothelial carcinoma arises from epithelial cells lining the urinary system. Most urothelial carcinomas occur in the urinary bladder, whereas upper tract urothelial carcinoma (UTUC), involving the renal calyx, pelvis, and ureter, accounts for 5%–10% of urothelial carcinomas (1, 2). The prognosis of UTUC depends on the T stage, which shows a 5-year survival rate from 90.2% to 18.5% through stages T1 to T4 (3). Risk classification stratifies UTUC as low- or high-risk, with low-risk cases allowing kidney-sparing surgeries, such as segmental ureterectomy and endoscopic ablation (4). In contrast, definitive treatment with nephroureterectomy is required for high-risk patients with adverse features. In addition, perioperative chemotherapy provides benefits in overall survival (OS) and cancer-specific survival with much concrete evidence in an adjuvant setting (5). The clinical staging of UTUC is restricted because of the pitfalls of computed tomography (CT) urography in discriminating between the T stages of carcinoma in situ and T2 (6). Thus, appropriate tools are required to evaluate the disease burden and to stratify risk classification.

Carbohydrate antigen 19-9 (CA 19-9) is a sialylated Lewis antigen. It is a tumor marker that predicts tumor stage, disease burden, and recurrence in pancreatic and gastrointestinal cancers (7–9). Although CA 19-9 is not a diagnostic marker in urothelial carcinoma, it is reportedly associated with the disease burden and aggressive features of bladder cancer, implying poor prognosis (10–12). In the present study, serum CA 19-9 levels in patients with UTUC were evaluated to reveal its clinical relevance implicating tumor burdens and clinical outcomes.

In bladder cancer, CA 19-9 is associated with adverse pathologic stages, characterized by muscular layer invasion and metastasis, thereby leading to poorer survival rates in bladder cancer patients with high CA 19-9 levels (12, 15). Furthermore, accumulating data suggest that urothelial cancers might produce CA19-9 to reflect tumor aggressiveness and tumor burdens (10, 12, 16).

However, there have been no reports evaluating the prognostic value of CA 19-9 for UTUC. In the present study, CA 19-9 was associated with a high tumor burden represented by higher T and N stages, and led to worse outcomes in metastasis-free survival and OS. CA 19-9 is highly expressed in the serum of patients with pancreatic or colon cancer (17). In pancreatic cancer, CA 19-9 is a useful diagnostic and prognostic marker for evaluating the tumor stage, treatment response, and OS. Similar to the study on UTUC, preoperative CA 19-9 levels are associated with tumor resectability and pancreatic cancer stage. A decrease in CA 19-9 levels after surgery reflects favorable survival outcomes, and elevated CA 19-9 levels imply worse survival outcomes (18). In addition, the CA 19-9 level is useful for evaluating disease progression or remission in response to treatment (19, 20). This study investigated only preoperative CA 19-9 levels, but serial measurements following treatment would be valuable in predicting prognostic outcomes. The diagnostic value of CA 19-9 is disappointing because of high false-positive rates in normal conditions and other diseases, such as liver cirrhosis, pancreatitis, and benign gastrointestinal diseases (21). However, in discriminating between benign and malignant pancreatic nodules, it is valuable, with a specificity of 90%.

In this study, PSM analysis was conducted to mitigate adverse features, such as T and N stages, reflecting tumor burden, which is associated with poor outcomes. PSM corrected the imbalance between low- and high-CA 19-9 level groups regarding T and N stages, reflecting tumor burden. Interestingly, after PSM analysis, high CA 19-9 levels indicated worse prognosis, thereby affirming CA 19-9 as an independent prognostic marker, not only based on tumor burden but also its aggressiveness. Similar findings have been reported in pancreatic cancer, providing worse prognosis in multivariate analysis of CA 19-9 level, tumor grade, and tumor size (22). Furthermore, in colorectal cancer, high CA 19-9 levels are related to poor oncologic outcomes, including OS and disease-free survival on PSM analysis (23).

This study is limited by the fact that it had a relatively small sample size and a retrospective study design. However, this report is valuable, considering the low incidence of UTUC with concomitant measurement of CA 19-9 and data queries from a prospective patient enrollment system. Moreover, monitoring CA 19-9 levels may provide preoperative risk classification and facilitate strategic follow-up and adjuvant treatment. Thus, further studies are required to include a larger number of patients and serial follow-up of CA 19-9 in the treatment course.

The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.

The studies involving human participants were reviewed and approved by Institutional review board of Seoul National University Hospital. Written informed consent for participation was not required for this study in accordance with the national legislation and the institutional requirements.

Conceptualization: S-HJ. Data collection: S-HJ, JH, HY, CJ, HK, JK, CK. Data analysis: S-HJ, HY, JK. Data visualization: S-HJ. Data interpretation: S-HJ, JH, HY, CJ, HK, CK, JK. Manuscript writing: S-HJ. Supervision: S-HJ, HY, JK. All authors contributed to the article and approved the submitted version.

This research was supported by a Basic Science Research Program through National Research Foundation of Korea (NRF), funded by the Ministry of Education (NRF-2018R1D1A1B07041191) and by Seoul National University Hospital (0320202190).

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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