Introduction
Renal cell carcinoma (RCC) represents a heterogeneous group of renal cancers that originate from the epithelial cells of the renal tubules1. These cancers exhibit a wide spectrum of genetic and epigenetic abnormalities and rank among the 10 most prevalent cancer types worldwide. In 2020, RCC accounted for more than 400,000 new cases globally, with a clear male predominance2–4. The most common subtypes are clear cell RCC (ccRCC), comprising approximately 75% of cases, followed by papillary RCC (pRCC, ~15%) and chromophobe RCC (chRCC, ~5%)3–6.
The classification of RCC has undergone substantial evolution over the past two decades, driven by advances in histologic and molecular pathology. The 2004 World Health Organization (WHO) classification introduced several histologic subtypes with distinct genetic, biologic, and clinical behaviors. Subsequent updates, including the WHO 2022 (5th edition) classification6, reflect further refinements based on improved understanding of tumor morphology, immunohistochemistry (IHC), genomics, and epidemiology7.
New renal tumor entities, such as fumarate hydratase (FH)-deficient RCC, succinate dehydrogenase (SDH)-deficient RCC, and tubulocystic RCC, are now classified separately due to their unique morphologies, molecular profiles, and clinical relevance7,8. Emerging provisional entities, such as eosinophilic solid and cystic RCC, have also been described, although additional evidence is required for formal recognition. These novel subtypes display prognostic diversity, ranging from indolent to aggressive tumors, underscoring the importance of precise classification to guide therapeutic strategies and genetic counseling8.
In parallel, the International Society of Urological Pathology (ISUP) introduced a new grading system, later adopted in the WHO 2022 classification7–9. This system, based on nucleolar prominence and specific histologic features such as sarcomatoid and rhabdoid differentiation, has demonstrated better reproducibility compared with the traditional Fuhrman grading system10,11.
Similarly, the tumor-node-metastasis (TNM) staging system, currently in its 8th edition, remains a cornerstone in the prognostication and management of RCC (2024 College of American Pathologists)11,12. Additional factors such as tumor necrosis (TN) and lymphovascular invasion (LVI) have emerged as independent prognostic markers, further enriching the understanding of RCC progression and treatment outcomes11–14.
In this context, the present study aimed to re-evaluate renal tumor cases from the Department of Surgical Pathology at Centro Médico ABC, diagnosed between 2013 and 2022, using the WHO 2022 classification criteria. Furthermore, this study sought to determine the applicability of the updated ISUP grading and TNM staging systems and to identify any newly recognized or emerging RCC subtypes within this cohort. This work represents one of the first systematic efforts to apply the latest classification frameworks to a comprehensive dataset within a Mexican population.
Material and methods
Study population: a total of 93 cases of RCC diagnosed between January 2013 and January 2022 were included from the Department of Surgical Pathology, Centro Médico ABC, after an electronic search in the systems, applications and products in data processing (SAP), implemented by the company TIMSA (Tecnologías de Información y Manufactura S.A. de C.V.)-unint system, which compiles pathology reports from both the Santa Fe and Observatorio campuses. Initially, a total of 216 cases were identified, but 123 were excluded due to a lack of available slides or damaged samples, leaving 93 eligible cases for analysis. Clinicopathologic data, including age, sex, laterality, tumor size, histologic grade, LVI, TN, and TNM stage, were obtained from pathology reports.
Material collection: formalin-fixed, paraffin-embedded tumor tissues were retrieved from the pathology archives after ethical approval by institutional review boards. The samples included partial, total, and radical nephrectomies performed during the study period. Slides were stained with hematoxylin and eosin and reviewed by two expert uropathologists and one pathology resident using an Olympus BX41 double-head microscope.
Original pathology review: initial diagnoses followed the WHO 2004 classification and the Fuhrman grading system. Tumor size, laterality, and TNM staging were recorded from the original reports, whereas tumor subtypes were determined based on predominant histologic features. Cases with < 10% malignant cells or those reclassified as urothelial carcinomas were excluded.
Second pathology review using updated classifications: for this study, available slides were re-evaluated using WHO 2022 (5th edition) criteria, the ISUP grading system, and the 8th edition of the AJCC TNM staging system. The review included assessment of tumor subtypes, nuclear grade, TN, LVI, and the presence of sarcomatoid and rhabdoid differentiation. When the original slides were insufficient, new sections were prepared from paraffin blocks. Evaluations were performed independently by two pathologists blinded to previous results.
IHC: IHC staining was performed for cases requiring confirmation of tumor subtype. Markers included carbonic anhydrase IX (CAIX) for ccRCC (Fig. 1), CK7 and CD117 for chRCC, and FH to rule out FH-deficient RCC. Staining was conducted using the automated BenchMark ULTRA system, following standardized protocols for deparaffinization, antigen retrieval, and 3,3′-diaminobenzidine chromogen in immunohistochemistry visualization.
Figure 1. A: representative image of a typical clear cell renal carcinoma case. B: immunohistochemical staining for carbonic anhydrase IX (CAIX) shows a “box-like” pattern, consistent with clear cell renal carcinoma. C: the papillary clear cell tumor shows papillae lined by cuboidal cells with clear cytoplasm. D: immunohistochemistry for CAIX shows a “cup-shaped” pattern, confirming the diagnosis.
Staging and analysis: samples were reclassified according to TNM (8th edition), assigning pathological stages based on tumor size and histologic characteristics. Tumor grade was re-evaluated using the ISUP system. Quantitative variables were analyzed using normality tests (Kolmogorov-Smirnov), whereas qualitative variables were expressed as frequencies and proportions. Statistical analyses were performed using the Statistical Package for the Social Sciences version 28.
Results
A total of 93 patients were included. There was a predominance of male patients (78.49%). Age at diagnosis ranged from 26 to 89 years, with a mean of 63.98 ± 13.64 years. The mean tumor size was 5.95 ± 4.78 cm (Table 1).
Table 1. Clinical characteristics of patients included in the present study
| Clinical characteristics | Number (%) | ||||
|---|---|---|---|---|---|
| Recorded cases 2013-2022 | 216 | ||||
| Unavailable cases | 123 | ||||
| Mean age at diagnosis ± SD (years) | 63.98 | ||||
| 13.64 | |||||
| Sex, n (%) | |||||
| Men | 78.49 (73) | ||||
| Women | 20 (19) | ||||
| Mean tumor size in centimeters ± SD (cm) | 5.95 ± 4.78 | ||||
| Laterality, n (%) | |||||
| Right | 55.91 (52) | ||||
| Left | 41.93 (39) | ||||
| Not specified | 2.15 (2) | ||||
| Initial diagnosis, n (%) | |||||
| Clear cell | 70.96 (66) | ||||
| Chromophobe | 12.90 (12) | ||||
| Papillary type 1 | 5.37 (5) | ||||
| Oncocytoma | 2.15 (2) | ||||
| Papillary and clear cell | 1.07 (1) | ||||
| Clear cell renal carcinoma associated with translocation | 1.07 (1) | ||||
| Clear cell papillary carcinoma | 1.07 (1) | ||||
| Papillary type 1 and clear cell | 1.07 (1) | ||||
| Others | 4.3 (4) | ||||
| Fuhrman grade, WHO/ISUP, n (%) | 87.91 (80) | ||||
| I | 10.7 (10) | ||||
| II | 48.3 (45) | ||||
| III | 17.2 (16) | ||||
| IV | 10.7 (10) | ||||
| Not applicable | 12.9 (12) | ||||
| Sarcomatoid change | 4.3 (4) | ||||
| Rhabdoid change | 3.2 (3) | ||||
|
A total of 92 cases included information on tumor size. Fuhrman grade was assigned in 80 cases, including all clear cell renal carcinoma cases. WHO: World Health Organization; ISUP: International Society of Urological Pathology. |
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Representative slides from all 93 cases were independently reviewed by two experienced pathologists using the WHO 2022 morphologic criteria, ISUP recommendations, and updates from the genitourinary pathology society (GUPS). Results showed 86% concordance with the original diagnoses (Table 2). Among the reviewed cases, 69.89% corresponded to ccRCC, 11.82% to chRCC, 5.37% to pRCC, and the remainder to less frequent subtypes such as oncocytoma, mucinous tubular and spindle cell carcinoma, and urothelial carcinoma (Table 2). None of the tumors exhibited features consistent with FH-deficient RCC, SDH-deficient RCC, or eosinophilic solid and cystic RCC, nor with other recently described entities.
Table 2. Results of histologic re-evaluation according to the 2022 ISUP system and the 2022 WHO classification
| Histologic reclassification | Number (%) | ||||
|---|---|---|---|---|---|
| Clear cell | 65 (69.8) | ||||
| Chromophobe | 11 (11.8) | ||||
| Papillary | 5 (5.3) | ||||
| Oncocytoma | 3 (3.2) | ||||
| Mucinous tubular and spindle cell renal carcinoma | 2 (2.1) | ||||
| Clear cell papillary tumor | 1 (1) | ||||
| Papillary adenoma | 1 (1) | ||||
| Epithelial and stromal tumor | 1 (1) | ||||
| Clear cell renal carcinoma associated with translocation | 1 (1) | ||||
| Others | 3 (3.2) | ||||
| WHO/ISUP grade change, n (%) | 77 (82.7) | ||||
| I | 9 (11.6) | ||||
| II | 39 (50) | ||||
| III | 10 (12.9) | ||||
| IV | 6 (7.7) | ||||
| Not applicable | 15 (16.1) | ||||
| Downgraded to grade I | 4 (5.1) | ||||
| Upgraded to grade II | 1 (1.2) | ||||
| Upgraded to grade III | 1 (1.2) | ||||
| Upgraded to grade IV | 7 (9) | ||||
| Sarcomatoid change not previously identified | 3 (3.7) | ||||
| Rhabdoid change not previously identified | 4 (5) | ||||
| Lymphovascular invasion, n (%) | 7 (7.5) | ||||
| Tumor necrosis, n (%) | 20 (21.5) | ||||
| Tumor necrosis by morphologic type | |||||
| Clear cell renal carcinoma | 18 (19.3) | ||||
| Chromophobe | 1 (1) | ||||
| Mucinous tubular and spindle cell RCC | 1 (1) | ||||
|
The WHO/ISUP grade was assigned only to cases of clear cell and papillary renal carcinoma. RCC: renal cell carcinoma; WHO: World Health Organization; ISUP: International Society of Urological Pathology. |
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Initially, cases were graded using the Fuhrman system: 12.5% grade 1, 56.25% grade 2, 20% grade 3, and 11.25% grade 4. Subsequently, application of the ISUP system yielded a distribution of 11.68% grade 1, 50.64% grade 2, 12.98% grade 3, and 7.79% grade 4. Compared with the original grading, changes were observed in 16% of cases. In addition, sarcomatoid differentiation was identified in 4.3% of cases and rhabdoid differentiation in 3.22%, both previously unreported (Table 2).
TN and LVI were assessed. TN was present in 21.50% of cases, classified as ≤ 5% in 35%, 6-49% in 60%, and ≥ 50% in 5%. LVI was identified in 7.52% of cases, predominantly in ccRCC (71.42%). Both features were frequently associated with ISUP grade 4 and advanced TNM stages.
A total of 90 cases were restaged using the 8th edition TNM system: pT1a in 35% of cases, pT1b in 22%, pT2a in 6%, pT2b in 5%, pT3a in 12%, and pT3b in 2%. No pT4 cases were identified. Comparison with the original staging revealed reclassification in 59% of cases, with a higher proportion assigned to lower TNM stages after update (Table 2).
These findings highlight the relevance of new classifications and diagnostic tools in identifying previously unreported features and refining the prognostic categorization of RCC.
Discussion
The present study aimed to review RCC cases diagnosed between 2013 and 2022 at Centro Médico ABC, according to the most recent WHO 2022 classification, ISUP and GUPS updates on renal tumors, and to assess the presence of newly recognized or emerging/provisional entities. Cases were also evaluated according to the new ISUP grading, and adverse prognostic factors such as TN, LVI, and sarcomatoid/rhabdoid differentiation were analyzed using the latest TNM edition. None of the reviewed cases showed features of the newly described entities, and all corresponded to well-established RCC subtypes.
Comparison between ISUP and Fuhrman grading systems in clear cell and pRCC revealed discrepancies in 16% of cases, underscoring the limitations of Fuhrman grading, including suboptimal reproducibility, as noted in prior studies. In contrast, the ISUP system – based solely on nucleolar prominence for grades 1-3 and sarcomatoid or rhabdoid differentiation for grade 4 – has demonstrated greater objectivity and superior prognostic value.
Assessment of adverse prognostic factors revealed TN in 21.5% of cases, most commonly in ccRCC. TN is known to have prognostic significance in this subtype, though it carries less impact in papillary tumors. LVI was identified in 7.52% of cases, more frequent in ISUP grades 3 and 4, and associated with a higher risk of metastasis and poorer survival, independent of tumor size.
Comparison between the 8th and previous TNM editions showed significant reclassification, with an increase in lower-stage cases. For instance, pT1a cases rose to 35%, whereas pT2 cases decreased notably. This reflects fundamental differences between the third and eighth TNM definitions, particularly regarding tumor size thresholds.
No newly described or emerging entities were identified, which may be explained by the Cohort’s mean age of 63.98 years, whereas some recently defined subtypes, such as SDH-deficient RCC, are more frequently reported in younger adults (≤ 45 years). This is consistent with previous studies, such as Kwon et al.15, who reported reclassification of a subset of adults with unclassified RCC (mean age 58 years), and Clemmensen et al.16, who reclassified a subset of early-onset RCC (< 46 years). Thus, the likelihood of identifying newly described entities in an older cohort remains low.
Conclusion
This study represents, to our knowledge, the first re-evaluation of renal neoplasms in a Mexican patient cohort. The findings emphasize that newly described entities constitute a small proportion of cases in populations with a higher mean age. Moreover, the evaluation of additional prognostic factors in this existing cohort – such as ISUP grading, TNM 8th edition staging, and rhabdoid/sarcomatoid features – enables the updating of previously published prognostic models and comparison with current systems such as the University of California, Los Angeles Integrated Staging System and the stage, size, grade, and necrosis score.
Funding
The authors declare that they have not received funding.
Conflicts of interest
The authors declare no conflicts of interest.
Ethical considerations
Protection of humans and animals: The authors declare that the procedures followed complied with the ethical standards of the responsible human experimentation committee and adhered to the World Medical Association and the Declaration of Helsinki. The procedures were approved by the institutional Ethics Committee.
Confidentiality, informed consent, and ethical approval: The authors have followed their institution’s confidentiality protocols, obtained informed consent from patients, and received approval from the Ethics Committee. The SAGER guidelines were followed according to the nature of the study.
Declaration on the use of artificial intelligence. The authors declare that no generative artificial intelligence was used in the writing of this manuscript.
