Clinical profile and risk factors identified in patients with renal cancer in Mexican population

Abstract

Introduction

Renal cell carcinoma, ranked 14th in global incidence, is more common in men. Its incidence rates increase with age, peaking in individuals older than 75 years. The classic triad is present in only 17% of cases. Surgical management involves total or partial nephrectomy, both associated with potential complications.

Objective

To identify the clinical profile and risk factors in patients with renal cell carcinoma.

Methodology

An observational, cross-sectional, and analytical study was conducted on patients with renal cell carcinoma treated surgically in the Urology Department from January 2020 to June 2023. Demographic and clinical characteristics were analyzed in relation to TNM staging, histologic subtype, and morbidity and mortality.

Results

Among 83 patients, 48 (57%) were men, with a mean age of 59.2 years (SD 10.5). Hypertension (HTN) and obesity were the most frequent comorbidities, each affecting 37 patients (44.6%). Flank pain (37 patients, 44.6%) and hematuria (23 patients, 27.7%) were the most common manifestations. Age >50 years was associated with advanced stages (p = 0.003, OR 5.744, 95% CI 1.698–19.424), while obesity was associated with a lower risk of advanced stages (p = 0.0042, OR 0.220, 95% CI 0.075–0.648). Complications of open nephrectomy included bleeding in 26 patients (38.8%) and organ injury in 2 patients (2.9%). Mortality was reported in 1 patient.

Conclusion

Age >50 years is a risk factor for advanced stages, while obesity is associated with a lower risk. Hematuria and flank pain were common, whereas abdominal mass was rarely reported.

Resumen

Introducción

El cáncer renal, en el 14° lugar de incidencia mundial, es más común en hombres. Las tasas de incidencia aumentan con la edad, alcanzando su mayor incidencia en mayores de 75 años. La tríada clásica se presenta en el 17% de los casos. El manejo quirúrgico incluye nefrectomía total o parcial, con posibles complicaciones.

Objetivo

Identificar el perfil clínico y factores de riesgo en pacientes con cáncer renal.

Material y métodos

Estudio observacional, transversal y analítico en pacientes con cáncer renal que recibieron cirugía en Urología entre enero de 2020 y junio de 2023. Se analizaron características demográficas y clínicas en relación con estadio TNM, subtipo histológico y morbimortalidad.

Resultados

De 83 pacientes, 48 (57%) fueron hombres, con una edad media de 59.2 (DE 10.5) años. HTA y obesidad fueron las comorbilidades más frecuentes 37 (44.6%) cada uno. El dolor en fosa renal 37 (44.6%) y la hematuria 23 (27.7%) fueron las manifestaciones más comunes. La edad >50 años se asoció con estadios avanzados (p = 0.003, OR 5.744, IC 95% 1.698−19.424), la obesidad se asoció con menor riesgo de estadios avanzados (p = 0.0042, OR 0.220, IC 95% 0.075−0.648). Complicaciones reportadas fueron sangrado en 26 (38.8%) y lesión a órganos en 2 (2.9%) de las nefrectomías abiertas. La mortalidad fue de 1 paciente.

Conclusión

La edad >50 años es un factor de riesgo para estadios avanzados, mientras que la obesidad se asocia con menor riesgo. La hematuria y el dolor en fosa renal fueron frecuentes, la masa abdominal fue escasa.

Introduction

According to the World Health Organization (WHO) International Agency for Research on Cancer (IARC) database, renal cancer (RC) ranks 14th in global incidence and 16th in mortality.¹

Incidence rates increase with age in both sexes, reaching their highest incidence in individuals older than 75 years. According to the age standardized rate (ASR), the risk of developing RC increases gradually from the age of 40–44 years, and from 65 to 70 years this increase is significantly higher.² In Mexico, the incidence of RC is almost twice as high in men than in women, being 4305 in men and 2122 in women. The same proportion applies to mortality, with 2248 male deaths per year versus 1131 in the female population.¹

The most common acquired risk factors include arterial hypertension (AHT), diabetes mellitus, obesity and smoking. Other factors described are prolonged use of analgesics and long-term dialysis. There is an increase in the incidence of CR in patients with hypertension. Lipid peroxidation, oxidative modifications in low-density lipoproteins (LDL), and the renin-angiotensin-aldosterone system have been proposed as possible mechanisms by which hypertension is a risk factor.^3–7

Conversely, it is estimated that approximately 20% of RC worldwide is attributable to excess body weight, with central adiposity demonstrating the strongest association.⁸ Despite the established relationship between renal cell carcinoma (RCC) and obesity as a risk factor for its development, the literature describes an "obesity paradox" where patients with RCC and obesity demonstrate a more favorable prognosis compared to those with a normal body mass index (BMI).^9,10

Likewise, smoking has been classified as a moderate carcinogenic risk.¹¹ Those who have smoked for more than 20 years have a greater than 50% greater chance of developing RC than those who have never smoked.^11–13

More than 50% of RC are incidental findings from routine imaging procedures, and most are still asymptomatic at diagnosis. On the other hand, the classic triad of hematuria, flank pain and abdominal mass only occur in 4 to 17% of cases.¹⁴

Clear cell RC is the most common histological subtype in adults. It is characterized by a cytoplasm rich in glycogen and related to the deletion of chromosome 3p, where genes such as VHL, PBRM1, SETD2 and BAP1¹⁵ are included. Papillary RC accounts for 10 to 15%, while chromophobe RC accounts for 5%. The remaining subtypes (oncocytoma, tubular carcinoma, tubulocystic renal cell carcinomas, among many others) are rare and comprise an incidence of less than 1%.²

Treatment of RC depends on the stage and intrinsic characteristics of the tumor; for stages I to III partial or radical nephrectomy is recommended, the latter being preferred in tumors larger than 7 cm and those with regional lymphadenopathy or vascular involvement. Radical nephrectomy is the surgical treatment of choice for stage IV patients.¹¹

The risk factors for RC are well defined, and despite the silent clinical manifestations, a clinical profile can be established to develop screening protocols and achieve timely detection. The present article aims to show the clinical profile and risk factors identified in patients with RC in a tertiary hospital.

Material and methods

Analytical cross-sectional study including patients of both sexes aged over 18 years who underwent kidney surgery for the treatment of RC during the period from January 2020 to June 2023. Patients were previously evaluated by the Department of Surgical Oncology of the hospital at the Centro Médico Nacional de Occidente of the IMSS. Patients undergoing adjuvant therapies or who were not candidates for surgical intervention were excluded.

Sample size

Consecutive cases were included during the period from January 2020 to June 2023, a total of 80 patients were included.¹⁶

The information was collected by reviewing the database of patients in the Department of Urology of our institution, considering the variables related to age, sex, hypertension, obesity, smoking, renal replacement therapy, family history of RC, symptoms at presentation, laterality, TNM stage, histological subtype, type of surgery, transoperative and postoperative complications and mortality.

The American Joint Committee on Cancer (AJCC) TNM system in its eighth edition was used for clinical stage classification. Considering stage I as T1N0M0, stage II as T2N0M0, stage III as T3N0-1M0 or T1-2N1M0 and stage IV as T4 with any N and M0 or Any T and N with M1; according to the TNM classification of the RC, T was considered as tumor size and extension, N as invasion to lymph nodes and M as distant metastasis.

Statistical analysis

The results are expressed as mean and standard deviation or number and percentage. IBM SPSS Statistics (version 21; IBM Corp., Armonk, NY, USA) was used for statistical analysis. Descriptive statistics were performed using percentage and raw number for categorical variables, and continuous variables as mean ± standard deviation. Data were analyzed using the Chi-square test for qualitative data. Results were reported as odds ratios (OR) and a multivariate logistic regression model was performed to adjust for confounding factors, with 95% confidence intervals with p value throughout. Differences were considered significant at p < 0.05 with 95% confidence intervals.

Ethical considerations

The study complied with the Declaration of Helsinki and its amendments, the General Health Law and the regulations of the host institution regarding human research. The protocol was approved by the Local Health Research and Ethics Committee under registry number R-2023-1301-197. Informed consent was requested since it was a retrospective review of the patient database and was a risk-free research study in accordance with current legislation. This study adhered to the ethical guidelines of the Belmont Report, always guaranteeing an adequate use of the data obtained from the patients.

Results

Of the 83 patients with a diagnosis of RC, 48 (57.8%) were men and 35 (42.2%) were women. The mean age was 59.2 (SD 10.5) years for both sexes, with no significant difference between the mean calculated between the two groups. The most reported comorbidities were hypertension and obesity with 37 patients (44.6%) each, followed by smoking with 34 (41%) and dialysis with 4 (4.8%). None reported a history of RC in the family.

At the time of diagnosis, 18 (21.7%) patients had stage I, 3 (3.6%) had stage II, 34 (41%) had stage III and 28 (33.7%) had stage IV disease, of which 23 (27.7% of the total) presented metastases. Of the 23 patients with metastases, only 18 (78%) showed the presence of a characteristic symptom from classic triad of RC (hematuria, flank pain or abdominal mass). The most common histologic subtype was clear cell RCC in 71 (85.5%) patients, followed by papillary in 6 (7.2%), chromophobe cell in 4 (4.8%) and oncocytoma in 1 (1.2%). In one patient (1.2%), the disease was secondary to metastasis from another cancer.

Age older than 50 years implied a higher risk of advanced stages of RC (III and IV) (p = 0.003, OR 5.744, 95% CI 1.698−19.424). Obesity was associated with a lower presentation of advanced stages (p = 0.0042, OR 0.220, 95% CI 0.075−0.648). On the other hand, male sex, diagnosis of hypertension, smoking or history of renal replacement therapy were not associated with an increased risk of advanced stages (Tables 1 and 2). The presence of 3 or more risk factors did not associate with an increased risk of advanced stages of RC (III and IV) (p = 0.478, OR 1.171, 95% CI 0.422–3.249).

Table 1.

Analysis of presentation in advanced clinical stages according to the clinical characteristics of the study population.

	P value	Odds ratio	95% confidence interval
Age over 50 years	0.003	5.744	1.698−19.424
Male sex	0.662	0.798	0.289−2.199
Hypertension	0.657	1.252	0.465−3.372
Obesity (BMI > 30 kg/m^2)	0.0042	0.220	0.075−0.648
Smoking	0.757	1.174	0.425−3.238
Renal replacement therapy	0.244	0.317	0.042−2.403

Table 2.

Multivariate logistic regression analysis for risk of advanced stages.

Variable	Regression coefficient (β)	P value	aOR (95% CI)
Sex	1.449	0.055	4.260 (0.970−18.705
Arterial hypertension	0.661	0.380	1.936 (0.443−8.456)
Obesity	2.072	0.003	7.944 (2.054−30.721)
Age over 50 years	−3.113	0.010	0.044 (0.004−0.477)
Smoking	−0.608	0.365	0.545 (0.146−2.026)
Renal replacement therapy	0.354	0.790	1.425 (0.105−19.277)

Regarding clinical manifestations, flank pain was present in 37 (44.6%) patients, hematuria in 23 (27.7%) and abdominal mass in 3 (3.6%). On the other hand, 14 (16.9%) patients reported other symptoms such as anorexia, anemia, hypertension, nocturia and weight loss. Six patients (7.2%) were asymptomatic, of these, 3 were stage I, 3 were stage III and 1 had metastases.

The surgical approaches employed were open radical resection in 58 (69.9%), radical laparoscopy in 9 (10.8%), renal biopsy in 10 (12.1%) and partial nephrectomy in 6 (7.2%). Of the total population, 50 (60.2%) did not present immediate or early surgical complications. Among the complications, bleeding was reported in 29 patients (34.9%) and organ damage in 4 (4.8%). Open radical nephrectomy did not represent a greater association of complications (p = 0.60, OR 2.573, CI 0.897–7.380).

The minimum hospital stay was 1 day, the maximum was 20 with a mean of 3.4 days (SD 2.1).

Overall mortality was 1 patient (0.8%), and metastasis and organ damage were reported during open radical resection.

Discussion

Renal cell carcinoma is a disease that presents significant variations in its incidence and clinical characteristics, defying the generalizations established by previous research.

In contrast to the findings reported by the International Agency for Research on Cancer and by Znaor,^1,17 this study did not reveal a significant difference in incidence between sexes. However, Bukavina et al., as well as several studies, detail an approximate mean age of 75 years for the diagnosis of RC, while the mean age for the subjects in our study was 59.2 years (SD 10.54).¹⁸

Macleod and his research group demonstrated that the incidence of RCC increases with age, particularly in individuals aged over 60 years, who had a higher incidence compared to the 50–54 years age group (p < 0.000). In their study including 77,260 patients, the authors reported that 71% of RCC cases occurred in subjects older than 60 years. The same study reports a significant association between age and RCC.¹⁹

Among the risk factors, 44.6% of the patients in our study reported a diagnosis of hypertension, in line with numerous investigations, hypertension is an exhaustively described risk factor; in the meta-analysis by Al-Bayati et al. a higher incidence of RC is demonstrated in patients with hypertension. The same article in its review of longitudinal cohort studies in 3 different countries found an increased risk of RC due to smoking with an approximate relative risk of 1.3 to 2.3. It is worth mentioning that almost half of our population (44.6%) reported positive smoking.⁴

In addition to the above, Kim and his research group found a risk of RC attributable to hypertension of 11.7 (95%, CI 11.1–12.3) cases per 100,000 person-years, with 56% (95% CI, 53.1–58.8) of cases with hypertension among patients with CR.³

Our study found that being over 50 years old is a risk factor for presenting with more advanced stages of this type of cancer. Karakiewicz et al. analyzed the impact of age on the prognosis of clear cell carcinoma, concluding that older age is a poor prognostic factor and recommending that treatment be adjusted according to age.²⁰ Since age is associated with higher expression of genes related to altered renal cell (RC) metabolism, as well as greater immune response instability and extracellular matrix architecture, this may provide a pathophysiological explanation for the observed phenomenon.²¹

Several authors agree with a relative risk of RC of 1.57 in men with obesity and 1.72 in women with obesity. In addition to the above, in the same population-based study, an association was found between an increase in BMI of 5 kg/m² with a 25% higher risk of developing CR.^17–19,22 In our study, obesity was reported in 37% of patients. Bhaskaran reported 9639 cases per year in the United Kingdom, of which 1567 (16%) are attributable to overweight and obesity. This is explained by the association between obesity as a risk factor for RC and methylation of obesity-related genes, such as leptin receptor for example.^23,24

In agreement with Choi⁹ and colleagues, who reported lower stages, as well as smaller size tumors and less likelihood of symptoms or metastasis, patients with obesity presented a less advanced stage than those without obesity. Regarding overall survival, Choi documented HRs of 0.37 and 0.35 for cancer-specific survival and recurrence-free survival, respectively, in patients with obesity. As mentioned above, in their systematic review, Kim¹⁰ and colleagues report a higher overall survival rate in patients with obesity compared to patients with a normal BMI (HR 0.75), as well as a better progression-free survival rate (HR 0.71). Although the study by Choi et al. suggests that survival can be explained by a greater nutritional reserve in patients and a more exhaustive screening for any pathology in patients with obesity, when an analysis was made with the specific tumor stage stratifying by TNM, no explanation was found. This coincides with the findings of our work. However, other studies^25,26 suggest that this paradox may be due to methodological inconsistencies, or the definition of obesity based only on body mass index. This indicates the need to investigate this phenomenon in more depth and with a more homogeneous methodology.

Even though our research indicated a history of dialysis in only 4.8% of patients, Lee and colleagues documented the appearance of RC after an average of 124 (SD 60) months of dialysis in 22 patients. Meanwhile, Kojima reports RC after an average of 11.2 (SD 7.2) days of dialysis, 81.8% of which were associated with acquired renal disease.^27,28 In comparison with the clinical manifestations observed in our population, the study by Adem reported flank pain in 65%, hematuria in 37%, abdominal mass in 6%, and 13.1% asymptomatic patients. The same study reported only 1% of patients with the classic triad. While Rodriguez et al. reported on flank pain in 48% of patients, hematuria in 38% and abdominal mass in 9.5% in their study, they did not report any patients with the classic triad.^29,30 While the percentage of patients presenting the classic triad is consistently low in most studies, a homogeneity in the frequency of clinical manifestations can be observed, which can be an advantage for early detection and timely treatment. Regarding other symptoms, Ikuerowo’s work describes 61 patients with anemia and other manifestations in a sample of 101 patients with CR.³¹

In contrast to our study, in Adem’s investigation with a total of 107 patients, 16.8% were stage I, 57% were stage II, 17.8% were stage III and only 8.4 were stage IV.

While our research did not demonstrate a significant association between open radical nephrectomy and complications, numerous studies have reported a higher incidence of complications in total nephrectomy (TN) compared to partial nephrectomy (PN). Pierorazio’s research indicates that the glomerular filtration rate (GFR) of patients treated by stage 1 RC decreases from 1 to 40 ml/min/1.73 m² in the immediate postoperative period, with an improvement within 6 months thereafter, and remains stable after that time.³²

Regarding PN, patients with a baseline GFR greater than 90 ml/min/1.73 m² experience a smaller reduction in their postoperative GFR than those who received TN.^32,33

Conversely, Perazella’s study mentions a relative risk for Chronic Kidney Disease (CKD) of 3.7 for TN compared to PN and a HR of 1.5 for Acute Kidney Injury (AKI) in TN compared to PN.³⁴

Conclusion

A significant proportion of the global population exhibits risk factors associated with RC. However, clinical manifestations are non-specific and not always present. The consideration of risk factors and clinical manifestations could reduce treatment costs and patient morbidity and mortality.

The present investigation details the frequency of the risk factors previously described, within which the male sex did not present a majority in our study. Age over 50 years showed a higher risk of presenting stages III and IV, while obesity demonstrated a lower risk. Conversely, among the classic triad, only hematuria and flank pain were evident in a significant proportion of our population.

Funding

This research did not receive external funding.