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ORIGINAL ARTICLE
Year : 2022 | Volume
: 33
| Issue : 3 | Page : 124-129
The risk of subsequent malignancies in patients with renal cell carcinoma: A nationwide, population-based study
Yu-Cheng Lu1, Yu-Chieh Tsai2, Po-Ming Chow1, Wen-Ching Weng3, Wei-Yi Huang4, Shih-Chieh Jeff Chueh1, Kao-Lang Liu5, Kuo-How Huang1
1 Department of Urology, National Taiwan University Hospital, College of Medicine, National Taiwan University, Taipei, Taiwan
2 Department of Oncology, National Taiwan University Hospital, College of Medicine, National Taiwan University, Taipei, Taiwan
3 Department of Surgery, Kinmen Hospital; Department of Health, Executive Yuan; Institute of Health and Welfare Policy, National Yang-Ming University, Taipei, Taiwan
4 Institute of Health and Welfare Policy, National Yang-Ming University; Department of Health, NHI Medical Expenditure Negotiation Committee, Executive Yuan, Taipei, Taiwan
5 Department of Medical Imagine, National Taiwan University Hospital, College of Medicine, National Taiwan University, Taipei, Taiwan
Correspondence Address:
Kao-Lang Liu
Medical Imagine, National Taiwan University Hospital, 7 Chung-Shan South Road, Zhongzheng District, Taipei 100
Taiwan
Kuo-How Huang
Department of Urology, National Taiwan University Hospital, 7 Chung-Shan South Road, Zhongzheng District, Taipei 100
Taiwan
Source of Support: None, Conflict of Interest: None
DOI: 10.4103/UROS.UROS_135_21
Purpose: The purpose was to investigate the risk of subsequent malignancies in patients with renal cell carcinoma (RCC) using hospital-based cancer registry database and a nationwide health insurance database. Materials and Methods: We used the following three databases: Cancer Registry Database of National Taiwan University Hospital (NTUH), National Health Insurance Research Database (NHIRD), and registry for catastrophic illness patients, a subset from NHIRD. We identified patients with RCC and analyzed the risk of subsequent malignancies in these patients. Results: Of the 1188 patients with RCC treated at NTUH, 141 (11.9%) had subsequent malignancies. Cancers in the colon, liver, prostate, lung and stomach were the five most common other primary malignancies. The nationwide analysis showed that 4.68% of the RCC patients had subsequent malignancies. The percentage was significantly higher than that in the general population in Taiwan. The five most common subsequent malignancies in patients with RCC were bladder, liver, colon, lung, and prostate cancer. The risk of developing these subsequent cancers in RCC patients was also significantly higher than that in the general population. Conclusion: Subsequent malignancies were noted in a high proportion of patients with RCC in Taiwan. It is a multifactorial process and the mechanism is still uncertain. This important issue warrants further studies to elucidate the mechanism.
Keywords: Colon cancer, liver cancer, lung cancer, prostate cancer, renal cell carcinoma, subsequent malignancies
A high proportion of patients with renal cell carcinoma (RCC) are more likely to develop subsequent malignancies. Several studies have suggested that subsequent malignancies may be caused by the same factors, such as exposure to carcinogens, genetic mutations, or the impact of chemotherapy or radiotherapy.[1] This is an essential clinical issue that could shed light on the disease's etiology. It is also important to study the related malignancies because this may help in identifying people at high risk of acquiring second primary malignancies for screening.[1] However, the etiology of subsequent malignancy is complicated and mostly unknown.
According to estimates, 2.8%–3.6% of patients with cancer develop subsequent malignancies, and 13.5%–13.9% of patients with subsequent malignancies have at least one urologic malignancy.[2] This indicates that patients with urologic cancers have a higher risk of developing subsequent malignancies.[2],[3] Several studies have found an elevated risk of secondary malignancies in patients with RCC.[4],[5],[6],[7] However, the majority of these studies relied on hospital- or regional-based databases as their data source. There is only one nationwide cohort study that was conducted on this topic in the Norwegian population, and it found that patients with RCC tend to have a considerable chance of acquiring additional subsequent malignancies in future.[4] In Taiwan, RCC accounts for 1% of all new cancer cases recorded each year, with an incidence rate of 3.5/100,000 people in 2007, which was significantly lower than that of the West. In Asian communities, the true incidence rate of subsequent malignancies in patients with RCC is unknown. Therefore, we conducted this nationwide, population-based study to investigate whether patients with RCC are at risk of acquiring subsequent malignancies in future.
Materials and MethodsData sources
In this study, three databases were used. The first was the Cancer Registry database of National Taiwan University Hospital (NTUH), which covered the period from March 1977 to September 2008. Clinical and histopathological data on all patients with RCC treated at NTUH were collected and verified by full-time registrars. For the detection of any errors or inconsistencies, duplicate checks, and quality control processes were carried out on a regular basis. Antecedent, synchronous, or subsequent primary malignancies were identified. Malignancies detected concurrently or within 90 days of RCC diagnosis are defined as “synchronous” malignancies, whereas “subsequent” malignancies are defined as those diagnosed after 90 days following RCC diagnosis. The Robson staging system was used to determine the pathological stage of cancers.[8] The Institutional Review Board of NTUH, Taipei, Taiwan, approved this study with approval code no. 201306091W, and consents were waived.
The National Health Insurance Research Database (NHIRD) was the second database used in this study. Since the launch of Taiwan's single-payer national health insurance program in 1995, the Taiwan National Health Insurance Bureau has collected records of all inpatient and outpatient medical benefit claims for nearly the entire Taiwan population. As of 2005, over 99% of the population was covered by the program. All of the data collected by this initiative are referred to as the NHIRD.
The study relied on a third database called the registry for catastrophic illness patients, which was a subset of the NHIRD. It comprised patients with catastrophic illnesses such as cancer who had their original claims data retrieved from the NHIRD database between 1995 and 2008. The dataset was constructed using data that correspond to any of the cancer-related International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) codes, or other cancer-related codes. The cancer treatment codes and the disease-category codes of “ACODE_ICD9_1 ~ 3” with the first three digits from 140 to 239; the diagnosis codes “ACODE_ICD9_1 ~ 3” with the first three digits from A08 to A17; and the cancer-surgery-related codes “ICD_OP_CODE” with the first three digits from V57 to V58 were included.
Study sample
The study cohort comprised patients with RCC (ICD-9-CM code: 189.0) who were selected from the database of the registry for catastrophic illness patients. All study subjects had their incidence of subsequent malignancies calculated. Subsequent malignancies were defined as those diagnosed after 90 days following the RCC diagnosis.
Statistical analysis
Unless otherwise specified, continuous variables were expressed as mean ± standard deviation and compared using the Student's t-test, whereas categorical variables were presented as percentages and compared using the Chi-square test. In addition, the Cox proportional hazards model was used to determine the variables related to RCC patient survival. Statistical significance was defined as two-tailed P ≤ 0.05. All data were analyzed using the Statistical Package for the Social Sciences software version 13 (SPSS Inc., Chicago, IL, USA).
ResultsFrom 1977 to 2008, 1188 patients with RCC were treated at NTUH, according to the Cancer Registry database of NTUH. [Table 1] summarizes the demographic and clinicopathological characteristics of these patients. Their mean age was 58.1 years, with a median follow-up period of 6.4 years, and 141 (11.9%) of them had at least one other primary malignancy. The most prevalent histological type of RCC was clear cell carcinoma, and the other primary malignancies were colon, liver, prostate, lung, and stomach cancers, regardless of gender. As indicated in [Table 1], there were apparent differences between male and female patients with RCC in terms of other primary malignancies, with uterine and nasopharyngeal cancers being the most common subsequent malignancies in females.
Table 1: Demographic and clinicopathological data and the five most common subsequent malignancies of the 1188 patients treated for renal cell carcinoma based on the Cancer Registry database of National Taiwan University HospitalBased on the nationwide database of registry for catastrophic illness patients from the NHIRD, 3122 patients with RCC were retrieved, with 1889 of them being males and 1233 being females and a mean age of 61.9 years. The median follow-up period was 4.7 years. [Table 2] shows the incidence rate and relative risk (RR) of subsequent cancers in patients with RCC and the general population. Patients with RCC had an incidence rate of subsequent malignancies of 4.68% and a significantly higher risk of subsequent cancers compared to the general population, regardless of gender (RR: 1.96, P < 0.001). About 37% of patients with RCC who acquired subsequent cancers went on to develop other primary malignancies. [Table 3] shows the incidence rate and RR of the most prevalent five subsequent malignancies in patients with RCC and the general population. The most prevalent five subsequent malignancies in patients with RCC, regardless of gender, were bladder, liver, colon, lung, and prostate cancers. The RR of subsequent malignancies was significantly higher in patients with RCC than that in the general population. Moreover, the incidence rate and RR of subsequent bladder cancer were significantly higher in the patients with RCC than that in the general population (993 vs. 83/100,000 people, RR: 12.0, P < 0.001). On the other hand, the incidence and RR of subsequent bladder, lung, and liver cancers in both genders were also significantly higher in patients with RCC than that in the general population. However, the male and female patients with RCC exhibited some variance. Male patients with RCC had a significantly higher incidence and RR of subsequent prostate cancer than the general male population (741 vs. 203/100,000 people, RR: 3.65, P < 0.001), whereas female patients with CRC had a lower incidence and RR of subsequent breast cancer than the general female population, with no statistically significant difference (487 vs. 629/100,000 people, RR: 0.77, P = 0.53).
Table 2: The comparative risk of multiple cancer between those with renal cell carcinoma and the total population based on the registry for catastrophic illness patients from the National Health Insurance Research Database
Table 3: The comparative likelihoods of the five most common subsequent primary malignancies between those with renal cell carcinoma and the total population based on the registry for catastrophic illness patients from the National Health Insurance Research Database Discussion Subsequent malignancies have been reported to occur at a rate of 4.5%–26.9% in previous studies,[2],[4],[6],[9],[10],[11],[12],[13] and as high as 30%–41.3% in studies based on autopsies.[14] In a recent nationwide cohort study conducted on the Norwegian population, Beisland et al. detected a 16.1% incidence rate of subsequent malignancies in patients with RCC over a 7-year period.[4] The current study estimated the rate of subsequent malignancies at 11.9% using the NTUH's Cancer Registry database and 4.68% using the registry for catastrophic illness patients. In the two studies, the percentage was much greater than that of the general population, which is consistent with previously published figures. Using population-based databases to conduct nationwide studies results in a larger sample size without patient selection, thereby eliminating bias from geographic, environmental, and referral patterns. In contrast, hospital-based series offer the advantages of more precise tumor staging, pathology reports, and fewer database errors. As a result, we analyzed data from two different databases to get the most accurate estimate of the incidence of subsequent malignancies in patients with RCC. The median follow-up period in our analysis was 6.4 years for the NHIRD-based cohort with a subsequent malignancy rate of 4.68%, whereas it was 4.7 years for the hospital-based Cancer Registry cohort with a subsequent malignancy rate of 11.9%. Our study consistently showed a similar incidence rate of subsequent malignancies to earlier studies. In compliance with institutional guidelines for individual disease stages, all patients with RCC treated at a hospital-based database received regular follow-up via imaging studies, including chest X-ray, computed tomography, or magnetic resonance imaging. The higher risk of subsequent malignancies in the hospital-based Cancer Registry cohort than in the NHIRD-based cohort may be explained in part by the increased incidental detection of these cancers at an early stage through regular routine imaging.
According to the American Cancer Society, one in every five Americans will develop cancer throughout their lifetime, and a third of them will acquire subsequent malignancies, as well.[3] Among renal parenchymal tumors, RCC is the most common and is often associated with other primary malignancies.[3],[15],[16],[17],[18] Matzkin et al. reported that patients with RCC are more likely to develop other malignancies than those with other genitourinary cancers.[2] Additionally, Nakata et al. indicated that RCC (20.8%) was more frequently associated with subsequent malignancies in the Japanese population than bladder (15.5%) and prostate cancers (12.5%).[19] Previous studies have found that RCC is frequently associated with a variety of cancers, including prostate, breast, colorectal, bladder, and lung cancers, as well as non-Hodgkin's lymphoma.[4],[5],[6],[7],[13],[20]
Beisland et al. reported that prostate, bladder, lung, breast, and colon cancers are the five most prevalent subsequent malignancies following RCC diagnosis in a nationwide, population-based cohort study.[4] Colon cancer was shown to be the most prevalent cancer, followed by liver, prostate, lung, and urinary bladder cancers in this study, based on the NTUH Cancer Registry database. This supports Sato et al.'s notion that population-level cancer incidence influences the development of other primary malignancies.[7]
Other studies have also established a link between RCC and bladder cancer.[5],[9],[10],[21] Begg et al. found that patients with RCC are more likely to develop bladder cancer.[21] A higher standardized incidence ratio for bladder cancer was also identified by Jesen et al. after RCC was diagnosed.[9] The increased risk of subsequent bladder or prostate cancer in NHIRD-based cohort can be attributed to surveillance bias caused by frequent visits to urologic clinics during RCC follow-up. Common genetic or environmental factors may also have a role; smoking, for example, is a well-known common carcinogen associated with RCC and bladder cancer.
Several risk factors are known to be associated with RCC, including genetics, ethnicity, smoking, obesity, hypertension, chronic kidney disease, and phenacetin or contraceptive use, which explain the increased risk of subsequent malignancies that share the same risk factors. For instance, it has been observed that hormonal exposure increases the risk of RCC. Several prior findings have shown estrogen or progesterone receptors in RCC tissue.[22] Additionally, Banerjee et al. showed that estradiol caused renal tissue to acquire micronuclei and aneuploidy.[23] It is still unclear whether estrogen contributes to kidney tumorigenesis.[23],[24] In this study, we also observed that patients with RCC were more likely to acquire hormone-related malignancies, such as prostate and breast cancers.
The NTUH Cancer Registry Center provided the first database we used for this study. It benefits from a quality control audit that comprises chart cross-checking and a standard coding system conducted by full-time registrars. As a result, we can expect all the clinical and pathological data in the database to be accurately coded. Most notably, our institute implements standardized diagnostic and therapeutic protocols for a variety of cancers, thereby eliminating any possibility of bias. To get a more accurate picture of the general population, we also studied the registry for catastrophic illness patients' database from the NHIRD, which is a nationwide, population-based database that comprises medical claims for almost 99% of the Taiwanese population. Using this database, researchers can eliminate the possibility of bias due to environmental factors and referral patterns by retrieving a large and unselected sample. As an added benefit, because it was not created for academic purposes, this database contains only actual claims records for the studied population, reducing the possibility of selection bias.
This study has a number of limitations. Firstly, this study is retrospective. Secondly, the database is missing important clinical data, including medical comorbidities and clinical presentations. Additionally, extended observation with changes in treatment and diagnostic approaches for various malignancies may lead to bias. Thirdly, while errors in disease coding in the insurance database are unavoidable, all claim records from the National Health Insurance System are subjected to a rigorous quality control process, including spot checks of medical charts by competent record review teams.
ConclusionsIn Taiwan, a large proportion of patients with RCC develop subsequent malignancies. It is a complicated process with an unknown mechanism. Patients with RCC have a greater lifetime risk of acquiring other malignancies. Further investigations are warranted, as well as a greater emphasis on the diagnosis of other malignancies during follow-up care.
Financial support and sponsorship
Nil.
Conflicts of interest
Prof. Shih-Chieh Jeff Chueh, an editorial board member at Urological Science, had no role in the peer review process of or decision to publish this article. The other authors declared no conflicts of interest in writing this paper.
References
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