Abstract
Background
Clear cell papillary renal cell tumor (ccpRCT) is a novel tumor entity which shares morphologic features with clear cell renal cell carcinoma (ccRCC) and papillary RCC (pRCC). The aim of this study was to comprehensively explore the clinicopathological features and prognostic factors of ccpRCT in the real-world setting with the largest cohort to date.
Methods
A total of 59,076 eligible RCC patients diagnosed between 2016 and 2021 in the Surveillance, Epidemiology, and End Results database were included in this retrospective analysis. The demographic and clinicopathological variables of ccpRCT patients were compared to those of ccRCC or pRCC patients. The survival curves were generated via the Kaplan-Meier method. The Cox proportional hazards model was used to compare the differences in overall survival (OS) and disease-specific survival (DSS).
Results
Compared with ccRCC and pRCC patients, those with ccpRCT were more frequently diagnosed with lower grade (G1/2) and lower stage (I/II), and exhibited prolonged OS and DSS. Univariate Cox regression analysis revealed that age at diagnosis; histological grade; tumor (T), node (N), metastasis (M) and overall stage; treatment type; and history of cancer were significantly associated with both OS and DSS. In addition, age at diagnosis and treatment type were crucial prognostic factors in terms of both OS and DSS according to multivariate Cox regression analysis.
Conclusions
Our study demonstrated the highly favorable outcomes in ccpRCT patients with low potential of lymph node invasion, metastasis, or disease specific death, and surgery is associated with improved outcomes.
Keywords: Renal cell carcinoma (RCC), clear cell papillary renal cell tumor (ccpRCT), clinicopathological features, prognostic factors
Highlight box.
Key findings
• The patients with clear cell papillary renal cell tumor (ccpRCT) have low rather than no malignant potential, and surgery is associated with improved outcomes.
What is known, and what is new?
• Previous reports have shown that ccpRCT is an indolent histologic subtype with highly favorable outcomes in comparison to other renal cell carcinoma (RCC) subtypes, contradicting to some studies showing that ccpRCT may experience recurrence and metastasis.
• In this study, we aimed to comprehensively explore the clinicopathological features and prognostic factors of ccpRCT in the real-world setting with the largest cohort to date. We identified that ccpRCT harbored highly favorable outcomes, while lymph node invasion, metastasis, and disease specific death were very rare. Besides, surgery can be recommended as the cornerstone of treatment, as it can significantly improve the OS and DSS of patients with ccpRCT.
What is the implication, and what should change now?
• Our study validated the highly favorable outcomes of ccpRCT patients with low potential of lymph node invasion, metastasis, and causing disease specific death, and surgery can serve as the benchmark for the treatment.
Introduction
Renal cell carcinoma (RCC), accounting for approximately 90% of all renal malignancies and 3% of all cancers, is the most common solid lesion within the kidney (1). In 2022, there were an estimated 434,840 new cases of RCC and 155,953 deaths globally (2). Histologically, RCC comprises a broad spectrum of different entities, among which clear cell RCC (ccRCC), papillary RCC (pRCC), and chromophobe RCC are the three main subtypes (3). The fourth edition of the World Health Organization (WHO) classification of kidney tumors has introduced a novel subtype: clear cell papillary RCC (ccpRCC), which shares morphologic features with ccRCC and pRCC (4).
In 2006, Tickoo et al. firstly reported a neoplasm occurring in patients with end-stage renal disease, which was recognized as ccpRCC in 2016 by the WHO classification (5). Although ccpRCC is a relatively rare tumor in the clinic, accounting for only 2–4% of all RCC cases, it is the fourth most common subtype of RCC (6) . In 2018, Massari and colleagues systemically reviewed 24 publications and included a total of 362 ccpRCC patients with detailed follow-up information and concluded that ccpRCC exhibits an indolent clinical behavior (7). Weng et al. reported the largest cohort of 89 ccpRCC patients, which demonstrated a highly favorable prognosis without recurrence or metastasis (8). Recently, the fifth version of the WHO classification has challenged the definition of ccpRCC, and reclassified it as clear cell papillary renal cell tumor (ccpRCT) (9). However, owing to the relatively small sample size or lack of appropriate comparisons with other RCC subtypes within the available studies, there is a need to better define the clinical behavior of ccpRCT in the real-world setting.
In this study, we aimed to comprehensively explore the clinicopathologic features and prognosis factors of ccpRCT, with a large population-based cohort of well-characterized RCC patients. We present this article in accordance with the STROBE reporting checklist (10) (available at https://tau.amegroups.com/article/view/10.21037/tau-2025-468/rc).
Methods
Study design
In this population-based retrospective cohort study, the patient data were retrieved from the Surveillance, Epidemiology, and End Results (SEER) database (17 registries, November 2023 submission, year of diagnosis: 2000–2021), which covers approximately 26.5% of the U.S. population. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. We collected and analyzed the data in accordance with the SEER Research Data Use Agreement.
Patient selection
The patients diagnosed with kidney cancer (site recode: kidney parenchyma, and the third edition of International Classification of Diseases for Oncology code: C64.9) between 2016 and 2021 were initially identified with the aid of SEER Stat software (version 8.4.3). As presented in Figure 1, the inclusion criteria were as follows: (I) age ranging from 18 to 89 years old; (II) the specified subtypes including ccRCC (histology code 8310), pRCC (8260), and ccpRCT (8323), and (III) classification as a primary lesion. Exclusion criteria were: (I) absence of American Joint Committee on Cancer (AJCC) tumor-node-metastasis (TNM) staging information; (II) missing follow-up data; or (III) bilateral disease or unknown tumor laterality.
Figure 1.
Study flowchart of patient screening. Out of 94,635 kidney cancer patients, a summary of 59,076 eligible renal cell carcinoma cases were included in the final analysis. ccpRCT, clear cell papillary renal cell tumor; ccRCC, clear cell renal cell carcinoma; pRCC, papillary renal cell carcinoma; TNM, tumor-node-metastasis.
Variables and outcomes
As previous reported (11), we retrieved demographic and clinicopathological information from the SEER database, including the database-assigned patient identifier, age at diagnosis, sex, race/ethnicity, year of diagnosis, histologic subtype, tumor grade, laterality, AJCC TNM staging and overall stage, treatment details, prior cancer history, survival status, and follow-up duration. The primary outcome was overall survival (OS), defined as the time interval between initial diagnosis and all-cause death. The second endpoint was disease-specific survival (DSS), which was introduced as the time between initial diagnosis and death attributed to kidney cancer.
Statistical analysis
The distribution of continuous variables was assessed via the Anderson-Darling test with the R package nortest (version 1.0-4). Continuous variables that deviated from a normal distribution were summarized as medians with interquartile ranges (IQRs) and evaluated with the Kruskal-Wallis rank-sum test. Categorical data were reported as counts and percentages and compared using either Pearson’s Chi-squared test or Fisher’s exact test implemented in the tableone R package (version 0.13.2). Survival outcomes were visualized through Kaplan-Meier plots, with between-group differences assessed via log-rank testing using the survminer (version 0.4.9) and survival (version 3.7-0) R packages. The missing data were imputed multiply using chained equations within the R package mice (version 3.16.0) (12). The Cox proportional hazards model was utilized to evaluate both primary and secondary endpoints with the R package survival (version 3.7-0). The results are presented as hazard ratio (HR) with the corresponding 95% confidence interval (CI) and P value. Statistical significance was defined as a two-sided P value less than 0.05. All statistical analyses were conducted with R software (version 4.3.1; R Foundation for Statistical Computing, Vienna, Austria).
Results
Patient characteristics at baseline
Initially, a total of 94,635 kidney cancer patients diagnosed between 2016 and 2021 were identified. After implementation of the screening pipeline (Figure 1), a summary of 59,076 eligible participants were included in the final analysis, with 797 ccpRCT, 48,605 ccRCC, and 9,674 pRCC cases, respectively. Table 1 summarized the demographic and clinicopathological characteristics of RCC patients. The ccpRCT group was characterized by a younger median age [63 (IQR, 54–70) years], lower male predominance (54.1%), and more favorable tumor features including higher rates of low-grade tumors (G1‒G2) and lower incidence of advanced stage disease (stage III/IV), compared to both ccRCC and pRCC (all P<0.001). The surgical treatment was more frequently performed in ccpRCT patients (96.4%) than those with ccRCC (90.8%) or pRCC (92.5%). The detailed TNM staging comparisons are listed in Table 1.
Table 1. Characteristics of 59,076 RCC patients according to histologic type.
| Variables | ccpRCT (n=797) | ccRCC (n=48,605) | pRCC (n=9,674) | P value |
|---|---|---|---|---|
| Age (years) | 63.00 [54.00, 70.00] | 63.00 [54.00, 71.00] | 65.00 [57.00, 72.00] | <0.001 |
| Gender | <0.001 | |||
| Female | 366 (45.9) | 17,707 (36.4) | 2,313 (23.9) | |
| Male | 431 (54.1) | 30,898 (63.6) | 7,361 (76.1) | |
| Year of diagnosis | <0.001 | |||
| 2016 | 7 (0.9) | 7,713 (15.9) | 1,659 (17.1) | |
| 2017 | 8 (1.0) | 8,214 (16.9) | 1,591 (16.4) | |
| 2018 | 155 (19.4) | 7,908 (16.3) | 1,650 (17.1) | |
| 2019 | 202 (25.3) | 8,545 (17.6) | 1,744 (18.0) | |
| 2020 | 204 (25.6) | 7,732 (15.9) | 1,406 (14.5) | |
| 2021 | 221 (27.7) | 8,493 (17.5) | 1,624 (16.8) | |
| Race | <0.001 | |||
| Black | 286 (35.9) | 2,970 (6.1) | 2,750 (28.4) | |
| Other | 30 (3.8) | 4,607 (9.5) | 511 (5.3) | |
| White | 481 (60.4) | 41,028 (84.4) | 6,413 (66.3) | |
| Grade | <0.001 | |||
| G1 | 218 (27.4) | 5,263 (10.8) | 1,029 (10.6) | |
| G2 | 375 (47.1) | 21,961 (45.2) | 4,032 (41.7) | |
| G3 | 74 (9.3) | 10,597 (21.8) | 2,530 (26.2) | |
| G4 | 18 (2.3) | 3,602 (7.4) | 235 (2.4) | |
| Unknown | 112 (14.1) | 7,182 (14.8) | 1,848 (19.1) | |
| T stage | <0.001 | |||
| T1 | 719 (90.2) | 32,269 (66.4) | 7,494 (77.5) | |
| T2 | 24 (3.0) | 4,078 (8.4) | 1,085 (11.2) | |
| T3 | 51 (6.4) | 10,961 (22.6) | 954 (9.9) | |
| T4 | 2 (0.3) | 751 (1.5) | 68 (0.7) | |
| TX | 1 (0.1) | 546 (1.1) | 73 (0.8) | |
| N stage | 0.001 | |||
| N0 | 750 (94.1) | 44,044 (90.6) | 8,785 (90.8) | |
| N1 | 8 (1.0) | 1,830 (3.8) | 373 (3.9) | |
| NX | 39 (4.9) | 2,731 (5.6) | 516 (5.3) | |
| M stage | <0.001 | |||
| M0 | 786 (98.6) | 43,622 (89.7) | 9,272 (95.8) | |
| M1 | 11 (1.4) | 4,925 (10.1) | 388 (4.0) | |
| MX | 0 | 58 (0.1) | 14 (0.1) | |
| AJCC stage | <0.001 | |||
| I | 718 (90.1) | 31,392 (64.6) | 7,380 (76.3) | |
| II | 23 (2.9) | 3,064 (6.3) | 980 (10.1) | |
| III | 44 (5.5) | 9,000 (18.5) | 889 (9.2) | |
| IV | 12 (1.5) | 5,149 (10.6) | 425 (4.4) | |
| Surgery | <0.001 | |||
| No | 29 (3.6) | 4,452 (9.2) | 729 (7.5) | |
| Yes | 768 (96.4) | 44,153 (90.8) | 8,945 (92.5) | |
| History of cancer | <0.001 | |||
| No | 149 (18.7) | 7,580 (15.6) | 2,038 (21.1) | |
| Yes | 648 (81.3) | 41,025 (84.4) | 7,636 (78.9) | |
| Laterality | 0.03 | |||
| Left | 408 (51.2) | 23,705 (48.8) | 4,843 (50.1) | |
| Right | 389 (48.8) | 24,900 (51.2) | 4,831 (49.9) |
Data are presented as n (%) or median [interquartile range]. AJCC, American Joint Committee on Cancer; ccpRCT, clear cell papillary renal cell tumor; ccRCC, clear cell renal cell carcinoma; M, metastasis; N, node; pRCC, papillary renal cell carcinoma; RCC, renal cell carcinoma; T, tumor.
Comparison of the survival outcomes of different RCC subtypes
The Kaplan-Meier curves of OS and DSS were illustrated in Figure 2. During a median follow-up of 28 months (IQR, 11–48 months), ccpRCT patients exhibited prolonged OS than did ccRCC (HR =0.62, 95% CI: 0.47‒0.81, P<0.001) and pRCC (HR =0.72, 95% CI: 0.54‒0.95, P=0.02) patients. In terms of DSS, similar difference were observed between ccpRCT and ccRCC patients (HR =0.41, 95% CI: 0.27‒0.63, P<0.001) or pRCC patients (HR =0.58, 95% CI: 0.38‒0.91, P=0.02).
Figure 2.
Kaplan-Meier plot of survival outcomes for renal cell carcinoma patients according to histological subtype. (A) Overall survival; (B) disease-specific survival. ccpRCT, clear cell papillary renal cell tumor; ccRCC, clear cell renal cell carcinoma; CI, confidence interval; HR, hazard ratio; pRCC, papillary renal cell carcinoma.
Prognostic factors for ccpRCT
To explore the prognostic significance of the clinicopathological variables in ccpRCT patients, both univariate and multivariate Cox regression analyses were conducted. As shown in Figure 3, age at diagnosis; histological grade; AJCC T, N, M and overall stage; treatment type; and history of cancer were significantly associated with both OS and DSS, while gender was significantly related to OS rather than DSS. Furthermore, the multivariate Cox analysis demonstrated that age at diagnosis and treatment type were crucial prognostic factors in terms of both OS and DSS (Figure 4).
Figure 3.
Forest plot for univariate Cox regression analyses of factors associated with ccpRCT patients’ prognosis. AJCC, American Joint Committee on Cancer; ccpRCT, clear cell papillary renal cell tumor; CI, confidence interval; HR, hazard ratio; M, metastasis; N, node; T, tumor.
Figure 4.
Forest plot for multivariate Cox regression analyses of selected factors associated with ccpRCT patients’ prognosis. AJCC, American Joint Committee on Cancer; ccpRCT, clear cell papillary renal cell tumor; CI, confidence interval; HR, hazard ratio; M, metastasis; N, node; T, tumor.
Discussion
To the best of our knowledge, this is the largest cohort of 797 ccpRCT patients in which the clinical behavior was compared with that of 48,605 ccRCC patients and 9,674 pRCC cases. The major findings were as follows: (I) ccpRCT harbors highly favorable outcomes, while lymph node invasion, metastasis, and disease specific death are very rare; (II) surgery could be recommended as the cornerstone of treatment, as it can significantly improve the OS and DSS of patients with ccpRCT.
Despite overlapping features, ccpRCT exhibits distinct clinical behavior and histopathological characteristics (13,14). On immunohistochemistry, ccpRCT is characterized by diffuse cytokeratin 7 positivity, cup-shaped carbonic anhydrase IX staining, and negative results of α-methylacyl-CoA racemase, transcription factor E3, and CD10 (6,15). Comparing with other RCC subtypes including those with prominent fibromyomatous stroma, ccpRCT is well documented without von Hippel-Lindau gene mutation, loss of chromosome 3p or gain of chromosomes 7 and 17 (15,16). Unlike the 1.5–2.0:1 predominance in men over women among all RCC cases (17), a higher proportion of females (45.9%) was found in the current ccpRCT cohort, which is in line with previous findings (8,18,19). Furthermore, RCC histological subtypes are known to vary by race, and patients of African descent constituted 35.9% of all ccpRCT cases. The percentage of African American patients varied greatly between studies and ranged between 19.1% and 80.9%, which can be attributed to the limited sample size and potential population bias (8,19,20).
Previous reports have shown that ccpRCT has an indolent histologic subtype in comparison to other RCC subtypes (7,21-23). Our findings validated the favorable pathological features of ccpRCT, as 86.6% of the grade-defined cases were G1‒2 and 93.2% were T1‒2. However, in contrast to the prior reports with no lymph node invasion or metastasis, the lymph node invasion and distant metastasis do exist, even with a small percentage (N1: 1.0%, and M1: 1.4%). Furthermore, during the follow-up period, 21 (2.6%) patients suffered from disease specific deaths, which was against the previous reports without any cancer specific deaths. In 2015, Diolombi et al. reported a cohort of 58 ccpRCT patients, among which two metastases occurred during the follow‒up period of only 21 months (24). Recently, two cases of metastatic ccpRCT have been reported, on the basis of the morphological, immunophenotypic features and targeted molecular profiling (25,26). Furthermore, one local recurrence occurred in a cohort of 90 ccpRCT patients, which overall indicated the need of caution to conclude that ccpRCT does not metastasize or cause disease specific death (20). The discrepancies in prognosis may stem from several factors. First, earlier studies likely underreported ccpRCT, as in this study only 15 (1.8%) patients were diagnosed within the first two years, while recent advances in immunohistochemical and molecular profiling have refined diagnostic accuracy. Additionally, previous studies had insufficient sample sizes, which reduced their statistical robustness to detect low-probability events, whereas the large-scale population-based samples can effectively address this limitation.
Owing to the increasing evidence supporting the indolent nature of ccpRCT and reclassification of this tumor in the latest edition of WHO classification, the current treatment recommendations were challenged and the most reasonable treatment option for ccpRCT would be active surveillance (1,27,28). However, in this study, it shows that surgery can subsequently improve the prognosis of ccpRCT patients in terms of both OS and DSS. Owing to the overlapping morphologic and immunohistochemical features with other RCC subtypes, it is difficult to conclude a reliable diagnosis within a small biopsy sample (29,30). The inconclusion of prior molecular profiling studies has made it impossible to achieve accurate diagnoses with next‒generation sequencing techniques in the clinical setting (8,19,31). Furthermore, the paucity of radiomic investigations on ccpRCT fundamentally constrains its accurate preoperative characterization (32,33). Overall, it would be hasty to alter treatment suggestions or follow-up strategies now.
We must acknowledge some limitations before interpreting the results. First, the retrospective nature of our study would likely decrease the reliability of the final conclusions. Second, the histologic diagnoses were made independently according to standardized diagnostic criteria without central review, which may result in some misclassification of histologic type, as some ccpRCT tumors display morphologic features overlapping with ccRCC and pRCC. Furthermore, ccpRCT was characterized with low grade (G1/G2). In this study, 11.6% of all ccpRCT patients were diagnosed with high grade (G3/G4), which were in line with previous reports (8,21,33). Third, the survival advantage of surgery could be attributed to the selection bias and indication bias, as patients with good perform status and favorable clinical staging are more likely to be recommended for surgical treatment. Even though this study is the largest cohort, most ccpRCT cases (98.1%) were diagnosed through 2018, two years later after the introduction of ccpRCT as a novel tumor entity within the fourth edition of the WHO classification, resulting in an insufficient sample size and a relatively short follow-up period. Further well-designed risk-stratified prospective randomized trials are needed to address this limitation. Fourth, ccpRCTs are more frequently presented with bilaterality (8). However, the discordance in diagnosis timing (synchronous versus metachronous), treatment approaches (surgery versus no surgery), and pathological subtypes introduces additional complexity to the study, the patients with bilateral tumors were excluded in this study, and more evidence are needed to optimize the clinical management of those with bilateral kidney tumors (34). Finally, due to the design of SEER database, some detailed information about the clinical, pathological, radiological, and molecular presentations is unavailable.
Conclusions
In summary, by analyzing the clinicopathological features and prognostic factors of ccpRCT in the largest cohort to date, our study validated the highly favorable outcomes of ccpRCT patients with low potential of lymph node invasion, metastasis, and causing disease specific death, and surgery is associated with improved outcomes. Additionally, further well-designed and unbiased studies with larger sample size and longer follow‒up time should be conducted to bolster our findings and deepen our understanding of the biological behavior of ccpRCT with different treatment strategies.
Supplementary
The article’s supplementary files as
Acknowledgments
We would like to thank the SEER database for generating, curating and providing high-quality clinical data about kidney cancer.
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. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. This study only adopted publicly accessible and patient deidentified data. As such, it was exempt from the ethical approval and informed consent.
Footnotes
Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://tau.amegroups.com/article/view/10.21037/tau-2025-468/rc
Funding: This work was supported by grants from the Young Elite Scientists Sponsorship Program by Jiangsu Association for Science and Technology (No. JSTJ‒2024‒387), Jiangsu Province’s High-Level Talent Training Program (No. 2024‒3‒2367), Youth Medical Talent Program of Jiangsu Province (No. QNRC2016073), Nanjing Medical Science and Technology Development Foundation for Distinguished Young Scholars (No. JQX18003), Research Project of Xinjiang Uygur Autonomous Region Health Commission (No. 2025001QNKYXM654021877), and Science and Technology Planning Project of Ili Kazakh Autonomous Prefecture (No. YJC2025A14).
Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tau.amegroups.com/article/view/10.21037/tau-2025-468/coif). The authors have no conflicts of interest to declare.
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