Detection of a group of classic serum tumor markers (CSTMs) aids in the differential diagnosis and disease assessment of upper tract urothelial carcinoma (UTUC)

Introduction

Urinary epithelial transitional cell carcinoma (TCC) includes renal pelvic cancer, ureteral cancer, bladder cancer, and urinary tract cancer. To date, most studies have focused on identifying a diagnostic and prognostic index for bladder carcinoma. Some indicators, such as CxBladder monitor, UroVysion, nuclear matrix protein 22 (NMP-22), and bladder tumor antigen, have been used in the diagnosis and monitoring of TCC; however, few biomarkers have achieved both high sensitivity and specificity (1). Other biomarkers, such as fibroblast growth factor receptor 3 (FGFR3), p53, pRb, p21, Ki67, and vascular endothelial growth factor (VEGF), have been used as prognostic factors for bladder cancer in previous studies (2-6). Some genomic biomarkers have been proposed in recent research; however, only a few established prognostic factors have been found to effectively assess the tumor progression of upper tract urothelial carcinoma (UTUC) (7-14). Some classic serum tumor markers (CSTMs), such as carbohydrate associated cancer antigen (CA) 199, CA125, carcinoembryonic antigen (CEA), and alpha-fetoprotein (AFP), which are widely used in the diagnosis of different types of gastrointestinal cancer (15), appear to have additional evaluative functions. This study analyzed seven CSTMs—CA242, CA199, CA125, CEA, AFP, squamous cell carcinoma antigen (SCC), and CA724—which are commonly used in clinical detection and were partially abnormal in the majority of cases, to evaluate their role in the differential diagnosis and disease assessment of UTUC. It aimed to explore the potential relationship between changes in CSTMs and changes in UTUC. We present this article in accordance with the REMARK reporting checklist (available at https://tau.amegroups.com/article/view/10.21037/tau-2026-0387/rc).

Methods

Ethics statement

This study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The protocol was approved by the Ruijin Hospital Ethics Committee (No. 34, Year 2021), and all the patients provided written informed consent.

Study subjects

A total of 140 unilateral affected patients, of whom 60 had UTUC, 44 had clear cell renal cell carcinoma (ccRCC), and 36 had non-tumoral hydronephrosis (NTHN) (with ipsilateral renal dysfunction), were included in this retrospective, descriptive analysis. Of the UTUC patients, 56 underwent surgical therapy between 2014 and 2020 at the Department of Urology, Ruijin Hospital (53 underwent radical nephroureterectomy, and the remaining three underwent radical nephrectomy due to misdiagnosis as kidney carcinoma). Data from ccRCC and NTHN patients at Ruijin Hospital between 2018 and 2019 were collected as controls.

All the UTUC diagnoses, as well as recurrence, implantation, and metastasis diagnoses, were confirmed by pathological analysis (biopsy or surgical specimens). Preoperative examinations identified one case of multiple distant metastasis, and two cases of both lymphatic metastasis and multiple distant metastasis, for whom surgical therapy was not suitable. Additionally, one patient without detectable metastasis refused surgery. None of the patients in the UTUC group had concurrent bladder or urethral TCC, and none had received radiotherapy, chemotherapy, or immuno-therapy prior to initial CSTM testing. Among the ccRCC patients, one had preoperative metastasis (iliac joint metastasis), and one had a tumor thrombus in the main renal vein.

Parameters

Both the serum values and abnormal rates (ARs) of the CSTMs (CA242, CA199, CA125, CEA, AFP, SCC, and CA724) were recorded. Comparisons of CSTMs were performed among the UTUC, ccRCC, NTHN, and ccRCC + NTHN groups, as well as within UTUC cases between preoperative and short-term postoperative (≤3 months), short-term postoperative and long-term postoperative (>6 months, ≤1 year)/during progressive disease (PD), and short-term postoperative and postoperative PD periods. If a CSTM showed statistical significance in any of the comparisons in this study, it was included in the proposed test strategy. The strategy derived from these comparisons was re-evaluated across all comparisons and compared with single CSTMs to assess its application value.

Pathological analysis was also performed in 56 UTUC patients, who were non-metastatic and had undergone surgical treatment. The tumor load, grade, and infiltration were analyzed in relation to both the values and number of abnormal values (NAV) of the preoperative CSTMs. Pathological sections were also specifically stained to detect the expression of CA724, CA125, CEA, AFP, and CA199; antibodies (Abs) for the immunohistochemical staining of CA242 and SCC were not available. The tumor tissues and paired paracancerous tissues were compared.

Biochemical detection of CSTMs

Serum CSTM testing is a routine preoperative examination for all patients in our department and has become a standard follow-up procedure for UTUC patients in recent years. The serum levels of CA242, CA199, CA125, CEA, AFP, SCC, and CA724 were detected by chemiluminescence (Beckman Coulter Diagnostics, Brea, California, American) at the Department of Clinical Laboratory, Ruijin Hospital, affiliated with Shanghai Jiao Tong University School of Medicine, Shanghai, China. The normal reference values were as follows: CA199 <35 U/mL, CA242 <20 U/mL, CA724 <8.2 U/mL, CA125 <35 U/mL, CEA <5 ng/mL, AFP <9 ng/mL, and SCC <1.5 ng/mL.

In this study, 39 UTUC patients underwent CSTM testing in the short-term postoperative period, and 23 of these patients underwent CSTM testing in the long-term postoperative period—either without recurrence and metastasis or during PD with recurrence or metastasis.

Tumor load assessment

The tumor load was assessed by calculating the tumor volume using the maximum tumor dimensions in three orthogonal planes (length, width, and height) measured from kidney computed tomography (CT) images or surgical specimens. Tumor volume was calculated using the following formula: π/6× length × width × height (16).

Statistical analysis

The levels of each CSTM were expressed as the mean ± standard deviation (SD). Measurement data between groups were compared using the group t-test, paired t-test, chi-square test of a four-fold table, Fisher’s exact test, Wilcoxon two-sample test, and linear correlation analysis. Statistical analyses were performed using SPSS version 23. All tests were two-tailed, and a P value <0.05 was considered statistically significant. For analyses with n≥45, P<0.05 corresponded to a power >0.8 and effect size >1 (17).

Results

General parameters

Comparisons of gender, age, affected side, body mass index (BMI), renal function, and metastasis rate among the three groups are presented in Table 1.

Values of the CSTMs in the UTUC, ccRCC, and NTHN patients

The values of CA242 (8.42±8.82 vs. 5.07±4.68 U/mL, P=0.01), CA199 (24.73±36.60 vs. 11.16±10.96 U/mL, P=0.008), and CEA (4.38±6.41 vs. 2.25±1.05 ng/mL, P=0.02) were significantly higher in the UTUC group than in the ccRCC group. The value of CEA (4.38±6.41 vs. 2.39±1.32 ng/mL, P=0.01) was significantly higher in the UTUC group than in the NTHN group. The values of CA199 (24.73±36.60 vs. 13.49±16.37 U/mL, P=0.03) and CEA (4.38±6.41 vs. 2.33±1.20 ng/mL, P=0.02) were significantly higher in the UTUC group than in the ccRCC + NTHN group (Table 2).

ARs of the CSTMs in the UTUC, ccRCC, and NTHN patients

The ARs of CA199 (18.33% vs. 4.55%, P=0.03), CEA (16.67% vs. 4.55%, P=0.04), SCC (21.67% vs. 6.82%, P=0.03), and CA724 (13.33% vs. 0.00%, P=0.01) were significantly higher in the UTUC patients than in the ccRCC patients. The ARs of CEA (16.67% vs. 4.55%, P=0.007) and CA724 (13.33% vs. 0.00%, P=0.02) were significantly higher in the UTUC patients than in the NTHN patients. The ARs of CA199 (18.33 vs. 5.00%, P=0.01), CEA (16.67% vs. 2.50%, P=0.003), SCC (21.67% vs. 10.00%, P=0.03), and CA724 (13.33% vs. 0.00%, P=0.001) were significantly higher in the UTUC patients than in the ccRCC + NTHN patients (Table 2).

Preoperative and postoperative values of the CSTMs

In the UTUC patients, the preoperative values of CA242 (8.44±8.66 vs. 4.41±3.05 U/mL, P=0.004) and CA199 (21.23±26.08 vs. 10.16±8.08 U/mL, P=0.009) were significantly higher than the short-term postoperative values. In the UTUC patients, the long-term postoperative/PD values of CA242 (6.87±4.77 vs. 4.66±3.16 U/mL, P=0.007) and AFP (3.71±1.74 vs. 3.08±1.42 ng/mL, P=0.03) were significantly higher than the short-term postoperative values. In the postoperative PD patients, the values of CA242 (7.11±5.93 vs. 5.13±4.11 U/mL, P=0.03), CA199 (27.40±25.12 vs. 11.59±6.58 U/mL, P=0.03), and AFP (4.23±2.12 vs. 2.87±1.37 ng/mL, P=0.02) during PD were significantly higher than the short-term postoperative values (Table 3).

Preoperative and postoperative ARs of the CSTMs

The preoperative ARs of CA199 (20.51% vs. 2.56%, P=0.01) and CEA (15.38% vs. 0.00%, P=0.01) were significantly higher than the short-term postoperative values in the UTUC patients (Table 3).

CSTM testing strategy in UTUC

Based on the above results, six CSTMs (CA242, CA199, CEA, AFP, SCC, and CA724) were selected for testing in the UTUC patients. We re-evaluated the CA242 + CA199 + CEA + AFP + SCC + CA724 test strategy across all comparisons, and found that, using this strategy, the NAV in the CSTMs was significantly higher in the UTUC group than in the ccRCC (P=0.003), NTHN (P=0.01), and ccRCC + NTHN groups (P=0.001). In the UTUC group, the preoperative NAV in the CSTMs was significantly higher than the short-term postoperative NAV (P=0.0003). In the UTUC group, the long-term postoperative/PD NAV in the CSTMs was significantly higher than the short-term postoperative NAV (P=0.001). In the UTUC group, the postoperative PD NAV in the CSTMs was significantly higher than the short-term postoperative NAV in the same patients (P=0.005, Tables 2,3).

Pathological manifestations and CSTMs in UTUC

In 56 patients with surgical specimens, the NAV in the CSTMs according to the proposed test strategy was significantly associated with tumor load, which averaged 31,935.96±72,663.83 mm³ (P<0.001). No single CSTM showed a significant linear correlation with tumor load (P>0.05 for all markers). All other pathological parameters, including grade, submucosa invasion, muscle invasion, adventitia invasion, renal parenchyma invasion, and perirenal fat invasion, had no significant influence on the values, ARs, or NAV in the CSTMs according to the proposed test strategy, except for three statistically significant differences: (I) the CA125 value was significantly higher in cases with muscle invasion than in cases without muscle invasion (13.41±10.44 vs. 8.56±3.19 U/mL, P=0.02); (II) the AFP value was significantly higher in cases without submucosa invasion than in cases with submucosa invasion (3.77±1.75 vs. 2.66±1.20 ng/mL, P=0.02); and (III) the SCC AR was significantly higher in cases without adventitia invasion than cases with adventitia invasion (25.00% vs. 0.00%, P=0.02, Table 4).

Immunohistochemical staining of five CSTMs in UTUC and paracancerous tissues

In the tissues of 4 randomly selected UTUC patients, strong Ab labelling was observed for CA199 and CEA, moderate Ab labelling for AFP and CA724, and weak Ab labelling for CA125, while no labelling was observed in the paracancerous tissues (Figure 1). There was no statistical difference between the H-scores of Ab labelling for each CSTM in tumoral tissues and these in paracancerous tissues, but the total H-score from all 4 cases of Ab labelling for 5 CSTMS in tumoral tissues was significantly higher than that in paracancerous tissues (42.31±79.58 vs. 0.00±0.00, P=0.048). After excluding CA125, the H-score in tumoral tissues was still higher (34.35±72.58 vs. 0.00±0.00, P=0.050).

Figure 1 Immunohistochemical staining of CTSMs in UTUC and paired paracancerous tissue. (A) Strong CA199-Ab labelling in UTUC tissue (×200); (B) no CA199-Ab labelling in UTUC tissue (×100); (C) weak CA125-Ab labelling in UTUC tissue (very small amount) (×100); (D) no CA125-Ab labelling in UTUC tissue (×100); (E) strong CEA-Ab labelling in UTUC tissue (×200); (F) no CEA-Ab labelling in UTUC tissue (×100); (G) weak AFP-Ab labelling in UTUC tissue (×100); (H) no AFP-Ab labelling in UTUC tissue (×100); (I) strong CA724-Ab labelling in UTUC tissue (×100); (J) no CA724-Ab labelling in UTUC tissue (×200). Ab, antibody; AFP, alpha-fetoprotein; CA, cancer antigen; CEA, carcinoembryonic antigen; CSTM, classic serum tumor marker; UTUC, upper tract urothelial carcinoma.

Discussion

UTUC is usually easy to diagnose; however, it can sometimes be misdiagnosed as renal carcinoma, or NTHN. In this study, 3 (5%) patients were initially diagnosed with renal carcinoma and underwent radical nephrectomy instead of the classic surgery for UTUC, radical nephrectourectomy, resulting in clearly different prognoses. In UTUC, disease progression, such as recurrence and metastasis, is not easily detected or definitely diagnosed, even with imaging examinations. Thus, simple indicators are needed to differentiate UTUC from other upper urinary tract diseases and to monitor disease progression and treatment efficacy.

Some indicators, such as CxBladder monitor, UroVysion, NMP22, and bladder tumor antigen, have been used in the diagnosis and monitoring of TCC; however, few biomarkers have achieved both high sensitivity and specificity (1). Only a few established prognostic factors have been found to effectively assess tumor progression in UTUC (7-9). Recent research has shown that plasma circulating tumor DNA (ctDNA) is highly predictive of muscle-invasive and non-organ-confined UTUC, and is strongly prognostic for progression-free survival and cancer-specific survival (10,11,18). However, one study found no association between circulating tumor cell enumeration or ctDNA status and any of the clinical outcomes evaluated (11).

Rose et al. reported that urine tumor DNA (utDNA) also appears promising for the diagnosis, staging, and prognosis of urothelial carcinoma, as well as for monitoring therapy response, detecting minimal residual disease, and conducting surveillance (12). A multidimensional bioinformatic model based on utDNA for preoperative samples accurately identified non-metastatic UTUC with high specificity (96.25%) and sensitivity (96.77%), regardless of stage or grade (13). However, further research on utDNA in UTUC is required. Tests, such as DNA methylation-based classification (19), TIM-3 expression (20), and urine DNA methylation (21) tests, have also been developed but their clinical value has yet to be determined. The expensive and time-consuming nature of these new methods also limits their development and adoption. Consequently, there is a lack of clinically recognized bio-indicators for the diagnosis, differential diagnosis, and disease status assessment of UTUC.

CSTMs, including CA242, CA199, CA125, CEA, AFP, SCC, and CA724, are the most commonly used indicators for predicting and monitoring the residual and recurrent status of tumors. SCC antigen has been used to predict SCC (22,23). All the other CSTMs are primarily associated with digestive system cancer or reproductive cancer (14,24-28). However, some CSTMs have been reported to play unconventional roles: CEA and SCC have been used for lung cancer diagnosis and prognosis (29,30); CA125 and CA199 have been shown to be significant markers of endometrium pathology (31); and SCC has shown moderate diagnostic value for hepatocellular carcinoma (32). Thus, these CSTMs may have additional unique value for the diagnosis and prognosis of cancers. However, among these seven CSTMs, only CEA has been reported as an early marker of malignancy in upper urinary tract urotheliomas and is closely associated with recurrence and survival (33,34).

This study found that the ARs of most of the single CSTMs and the NAVs in the group of CSTMs were significantly higher in the UTUC group than in the ccRCC, NTHN, and ccRCC + NTHN groups, suggesting their potential value in differentiating UTUC from other common upper urinary tract diseases, whether malignant or benign. These findings also suggest a potential concordant relationship between CSTMs and UTUC. The postoperative CSTM parameters were significantly lower than the preoperative CSTM parameters, but increased again in patients with postoperative PD, indicating that changes in the group of CSTMs reflect the course of disease. For differential diagnosis, CEA and CA724 demonstrated the strongest performance, while for disease assessment, CA242 performed best. Thus, no single CSTM appears to be able to serve both functions.

According to the results of all the comparisons, six CSTMs (CA242, CA199, CEA, AFP, SCC, and CA724) were associated with UTUC. A test strategy based on these six CSTMs was established for clinical detection. The relationship between this strategy and the differential diagnosis and assessment of UTUC was validated across all comparisons. The P values were consistently low and the positive results covered all the comparisons. Thus, the recommended strategy was considered practical, with ARs appearing to be more informative than absolute values.

At the pathological level, tumor load, grade, and depth of invasion showed no significant relationship with most of the single CSTMs. Similarly, grade and depth of invasion were not significantly associated with the group of CSTMs. However, the NAV in the CSTMs based on the proposed strategy was linearly correlated with tumor load. These findings suggest that CSTMs reflect tumor cell quantity, are likely produced by tumor cells, perhaps from the beginning, and that NAV in CSTMs may serve as a useful indicator for assessing disease progression.

The immunohistochemical labelling results confirmed that the UTUC tissues, but not the paracancerous tissues, contained significant levels of CSTMs, at least including CA199, CA125, CEA, AFP, and CA724. Among these, CA199 and CEA were strongly expressed, while CA125 was expressed at low levels (but still significantly higher than in paracancerous tissues). These findings were highly consistent with previous biochemical results and the recommended strategy based on these results. Overall, the results suggest that CSTMs are specifically secreted by UTUC cells, supporting the practicality of the recommended test strategy and explaining the concordance between changes in CSTMs and UTUC disease progression.

The group testing of CSTMs is simple, feasible, and inexpensive, making it an effective method. However, due to extensive data processing and the limited sample size, the results presented in this article are preliminary, and further in-depth studies are needed, particularly to investigate the relationship between CSTMs and clinical events and prognosis.

Conclusions

CSTMs may aid in the differential diagnosis and disease assessment of UTUC. Group CSTM testing was shown to be more valuable than single CSTM testing. The recommended test strategy includes CA242, CA199, CEA, AFP, SCC, and CA724.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the REMARK reporting checklist. Available at https://tau.amegroups.com/article/view/10.21037/tau-2026-0387/rc

Data Sharing Statement: Available at https://tau.amegroups.com/article/view/10.21037/tau-2026-0387/dss

Peer Review File: Available at https://tau.amegroups.com/article/view/10.21037/tau-2026-0387/prf

Funding: This research was funded by a grant from the Science and Technology Commission of Shanghai Municipality Project (No. 21S31903700) and a grant from the Guangci Clinical Technology and Innovation Program (GCTIP) of Ruijin Hospital (No. GCQH-2024-15).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tau.amegroups.com/article/view/10.21037/tau-2026-0387/coif). All authors report grant support from the Science and Technology Commission of Shanghai Municipality Project (No. 21S31903700) and the Guangci Clinical Technology and Innovation Program (GCTIP) of Ruijin Hospital (No. GCQH-2024-15). The authors have no other conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. This study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The protocol was approved by the Ruijin Hospital Ethics Committee (No. 34, Year 2021), and all the patients provided written informed consent.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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(English Language Editor: L. Huleatt)