Keywords
clinicopathological - Malaysia - prognosis - renal cell carcinoma - survival
Introduction
In Malaysia, renal malignancies account for the 12th highest cause of cancer death, with 532 cases (1.8% of all cancer deaths) recorded in 2020.[1] There has been a significant increase in the global incidence of renal cell carcinoma (RCC) due to better screening program and improvements in imaging technologies, which have led to increased incidental findings of asymptomatic, localized renal tumors.[2] Data on RCC prognostics and mortality are limited in Malaysia. We present a report from a tertiary center in northern Malaysia on prognostic and survival data among renal cancer patients. Identifying clinicopathological risk factors may offer prognostic insight to aid patient discussions and improve treatment outcomes.
Materials and Methods
Data Sources
A retrospective review of the Cancer Registry database of Hospital Sultanah Bahiyah Alor Setar (HSBAS), covering the period from January 2015 to December 2020, was performed. Clinical and histopathological data on patients with RCC managed surgically at HSBAS were collected. Follow-up duration and mortality status were retrieved via the electronic medical record or phone call. The 8th edition of TNM staging proposed by the American Joint Committee on Cancer was used for pathological tumor staging. Tumor grading was assigned according to the World Health Organization/International Society of Urological Pathology (ISUP) grading system. The survival status of patients was obtained from the patient's record and Malaysian National Registration Department. Ethical approval was formally obtained from the National Medical Research Registry (NMRR) Ethical Committee (Ref no: NMRR ID-23–02310-U7Y).
Study Sample
The study cohort comprised adult patients aged 18 to 90 years with histopathologically confirmed RCC (International Classification of Diseases, Tenth Revision, Clinical Modification code: C64) who were selected from the cancer registry database. Patients who underwent surgery or received initial treatment at other health care centers were excluded. Patients with insufficient clinical data or who defaulted on follow-up appointments were also excluded from this cohort.
Statistical Analysis
Statistical analyses were performed using IBM SPSS Statistics version 22 (IBM, United States). Overall survival based on the clinicopathological prognostic factors was determined using the Cox proportional hazards regression method, with hazard ratio (HR) as the measure. Factors that were shown to have statistical significance in univariate analysis were then further subjected to multivariate analysis. Survival curves and survival rates were derived from Kaplan–Meier and life table analyses. A p-value of less than 0.05 was considered to have statistical significance.
Results
A total of 104 patients with RCC who underwent nephrectomy in HSBAS were included. We observed that higher body mass index, smoking habit, and symptomatic presentations are significantly associated with an unfavorable prognosis. The baseline demographics are shown in [Table 1].
Table 1
Baseline clinical characteristics
|
Characteristics
|
Number of cases, n (%)
|
p-Value
|
|
Mean age (range), y
|
58.5 (28–88)
|
0.599
|
|
Young age (≤ 40 years) (%)
|
10 (9.6)
|
0.896
|
|
Men/Women (%)
|
70.2/29.8
|
0.851
|
|
Ethnicity (%)
|
|
0.640
|
|
Malay
Chinese
Indian
|
68 (65.4)
29 (27.9)
7 (6.7)
|
|
Mean BMI
|
24.6 ± 5.5
|
0.001*
|
|
Smoking habit (%)
|
40 (38.5)
|
0.002*
|
|
Diabetes mellitus (%)
|
25 (24.0)
|
0.252
|
|
Symptoms (%)
|
|
0.043*
|
|
Incidental
Hematuria
Loin pain
Hematuria and loin pain
Anemia
Others
|
32 (30.8)
40 (38.5)
18 (17.3)
5 (4.8)
34 (31.5)
6 (5.8)
|
Abbreviation: BMI, body mass index.
* denotes p-value is significant (<0.05).
When histopathological data were reviewed, we found that larger tumor size, higher pathological T staging, nodal involvement, metastatic spread, higher ISUP grading, variant histologies, and sarcomatoid changes on histology are predictive of worse prognosis. The perioperative and histological characteristics are presented in [Table 2].
Table 2
Perioperative and histological characteristics
|
Characteristics
|
Number of cases, n (%)
|
p-Value
|
|
Mean tumor size (range) (cm)
|
7.5 ± 4.1
|
< 0.001*
|
|
Pathological stage (%)
|
|
0.002*
|
|
pT1
pT2
PT3
pT4
|
34 (32.7)
21 (20.2)
42 (40.4)
7 (6.7)
|
|
Tumor spread (%)
|
|
< 0.001*
|
|
Organ confined (T1–2N0M0)
Locally advanced (T3–4N0M0)
Metastatic (TanyN1M0 or TanyN0M1)
|
39 (37.5)
29 (27.9)
36 (34.6)
|
|
Venous invasion (%)
|
11 (10.6)
|
0.212
|
|
Perinephric or sinus fat invasion (%)
|
31 (29.8)
|
0.130
|
|
Adrenal involvement (%)
|
2 (1.9)
|
0.656
|
|
Nodal involvement (%)
|
16 (15.4)
|
< 0.001*
|
|
Histology (%)
|
|
< 0.001*
|
|
Clear cell
Papillary
Chromophobe
Acquired cystic disease
Collecting duct
Mucinous tubular and spindle cell
Tubulocystic
Squamous cell
Unclassified
|
74 (71.2)
10 (9.6)
6 (5.8)
5 (4.8)
2 (1.9)
2 (1.9)
2 (1.9)
1 (1.0)
2 (1.9)
|
|
Sarcomatoid changes
|
5 (4.8%)
|
< 0.001*
|
|
WHO/ISUP grade (%)
|
|
<0.001*
|
|
Grade I
Grade II
Grade III
Grade IV
|
14 (13.5)
42 (40.4)
29 (27.9)
68 (7.7)
|
Abbreviation: WHO/ISUP, World Health Organization/International Society of Urological Pathology.
Over a median follow-up period of 14 months (interquartile range 5–38), the 5-year cancer-specific survival rate was 71.2% ([Table 3]). Symptomatic patients showed worse survival (p = 0.043, HR 2.7, 95% confidence interval [CI] 1.03–7.07). RCC TNM staging significantly affected survival (p < 0.001), with stage 4 patients demonstrating the worst prognosis ([Fig. 1]).
Table 3
5-year cancer-specific survival of RCC patients
|
Stage (%)
|
|
|
I
II
III
IV
Overall
|
95.3
88.2
77.8
31.4
71.2
|
Abbreviation: RCC, renal cell carcinoma.
Fig. 1 Pathological staging affects cancer-specific survival probability.
When adjusted for TNM stage in a multivariate analysis, smoking habit (p = 0.003, HR 3.2, 95% CI 1.50–6.82), larger tumor size (p = 0.042, HR 1.08, 95% CI 1.00–1.16), nodal metastasis (p = 0.005, HR 3.06, 95% CI 1.41–6.64), ISUP grading (p = 0.008, HR 2.08, 95% CI 1.21–3.58), and sarcomatoid features (p = 0.001, HR 5.94, 95% CI 2.01–17.59) were found to be significant independent prognostic parameters for RCC cancer-specific survival ([Table 4]).
Table 4
Univariate and multivariate analysis of clinicopathological factors with renal cell carcinoma cancer-specific survival
|
Univariate analysis
|
Multivariate analysis
|
|
HR
|
95% CI
|
p-Value
|
HR
|
95% CI
|
p-Value
|
|
BMI
|
0.875
|
0.809–0.946
|
0.001*
|
0.926
|
0.851–1.007
|
0.071
|
|
Smoking
|
3.329
|
1.583–7.002
|
0.002*
|
3.256
|
1.526–6.948
|
0.002*
|
|
Symptomatic
|
2.702
|
1.033–7.070
|
0.043*
|
1.830
|
0.698–4.800
|
0.219
|
|
Loin pain
|
2.942
|
1.411–6.136
|
0.004*
|
1.364
|
0.646–2.878
|
0.416
|
|
Anemia
|
3.551
|
1.717–7.343
|
0.001*
|
1.529
|
0.723–3.234
|
0.267
|
|
Tumor size
|
1.154
|
1.074–1.241
|
< 0.001*
|
1.075
|
1.001–1.154
|
0.048*
|
|
Nodal spread
|
7.595
|
3.631–15.887
|
< 0.001*
|
2.777
|
1.291–5.973
|
0.009*
|
|
ISUP
|
2.695
|
1.654–4.391
|
< 0.001*
|
2.047
|
1.184–3.539
|
0.010*
|
|
Sarcomatoid
|
16.571
|
5.638–48.706
|
< 0.001*
|
5.784
|
1.958–17.086
|
0.001*
|
|
Variant histology
|
9.193
|
2.046–41.303
|
0.004*
|
3.300
|
0.731–14.907
|
0.121
|
Abbreviations: BMI, body mass index; CI, confidence interval; HR, hazard ratio; ISUP, International Society of Urological Pathology.
Discussion
The incidence of RCC in Malaysia is growing and accounts for approximately 2% of cancer deaths locally. The 5-year survival for RCC patients in our study is 71%, which is marginally higher than the 69% survival reported by the University Malaya Medical Center in 2013.[3] At HSBAS, the 5-year cancer-specific survival for stage I is 95%, 83% for stage II/III, and 31% for stage IV, which is comparable to data obtained regionally.[3]
[4]
In our study population, the distribution of RCC among the various ethnic groups was found to be similar to that reported by the Malaysian cancer registry.[5] We did not find that younger patients below 40 years of age had significantly more advanced tumors or poorer survival. We also observed no significance between gender and renal cancer disease survival in our analysis. Up to 30% of the patients in this study had RCC found incidentally on imaging studies. Asymptomatic incidental tumors are significantly associated with better prognostic outcomes. Obesity was found to be associated with an increased risk of RCC, which was postulated to be due to elevated levels of fasting serum and free insulin-like growth factor (IGF-1) that contribute to the growth and proliferation of renal cell cancer.[6] Patients with a cigarette smoking habit were identified to be at an increased risk of death compared with nonsmokers (HR = 3.3, 95% CI = 1.5–6.9).
We have also demonstrated that tumor size, as a continuous variable in a proportional hazards regression model, exhibited a strong association with survival (HR = 1.2, 95% CI = 1.1–1.2). This relationship is evident even after adjusting for TNM staging on multivariate testing (HR = 1.1, 95% CI = 1.0–1.2). The prevalence of node-positive renal cell cancer ranges from 2 to 10%.[7] Our results indicated that nodal involvement independently predicts RCC cancer-specific survival both univariably and multivariably (HR = 2.8, 95% CI = 1.3–6.0).
There has been a consensus that the primary morphotypes of RCC are of prognostication significance, and our findings paralleled that reflection. The higher the ISUP grade, the poorer the survival outcome of our cohort (HR = 2.0, 95% CI = 1.2–3.5). It is also established that sarcomatoid changes are indicators of poor prognosis with implications for treatment effectiveness.[8]
[9]
[10] Sarcomatoid histology among our patients was associated with significantly worse cancer-specific survival (HR = 5.8, 95% CI = 2.0–17.1). Among the five most common histological subtypes, it is shown that patients with collecting duct and unclassified RCC variants have the poorest outcomes.[11] Our study also demonstrates a worse prognosis for patients with variant histology, especially in collecting duct RCC, but this difference disappears after adjusting for disease stage.[12]
In the present study, we characterized the clinical and pathological data and prognosticated survival outcomes among RCC patients during a 5-year period at a tertiary hospital in Malaysia. Early diagnostic detection and treatment of RCC before the onset of clinical symptoms or metastatic status confer better survival. Tobacco smoking history negatively affects survival. The presence of nodal involvement, venous infiltration, or sarcomatoid morphology on operative histology was significantly associated with a worse prognosis.
The limitations encountered include this being a single-center experience and retrospective in nature. The sample size volume was also a limitation in our study, as it was derived from a single-center database. Despite these limitations, the findings reported in our study provide invaluable information for improving RCC patient long-term management and disease outcome. We hope that our data can serve as a reference for further research on renal cancers in a Malaysian-based population with its diverse ethnic background. The establishment of a multi-institutional database among RCC patients in Malaysia would provide more accurate prognostication of survival and mortality.
