Case report
In July 2021, a 65-year-old man was admitted to the Huanghe Sanmenxia Hospital Affiliated to Henan University of Science and Technology (Sanmenxia, China) with complaints of intermittent hematuria for 8 months, accompanied by frequent urination, urgency, dysuria, and incomplete and interrupted urination. The patient had no other abnormalities such as hypertension or heart disease. In 2004, the patient underwent a cholecystectomy for cholecystitis. The patient had type 2 diabetes for 6 years, and their blood sugar level was under satisfactory control using metformin [500 mg once a day (qd)] + glimepiride tablets (2.5 mg qd). The patient had smoked 10 cigarettes per day for 40 years. Color ultrasonography of the urinary system revealed thickening of the bladder wall (Fig. 1A) and hyperechoic right kidney (Fig. 1B). Blood flow signals were observed in a strongly echogenic area of the right kidney (Fig. 1C). The patient underwent further urinary system computed tomography urography (CTU) examination to assist in the assessment of their condition. A total of 1 h before the examination, the patient drank 500–1,000 ml of water and held their urine. During the examination, the patient was in a supine position with both arms raised. After routine scanning using a dual-source 64-row spiral CT machine (spiral mode; scanning layer thickness, 5 mm; rotation time, 0.8 sec; pitch, 1.375:1; tube voltage, 120 kV; Siemens Healthineers), iohexol (300 mg/ml; GE Healthcare) was injected at a flow rate of 3.0–3.5 ml/sec (injection volume of ~90 ml), and then arterial phase, venous phase and excretion phase scanning were performed (tube current 250–300 mA in the arterial phase and venous phase, and 80–150 mA in the excretion phase). Urinary system CTU showed an oval mass measuring ~20 mm in the upper pole of the right kidney (Fig. 1D and E). The renal mass was significantly enhanced in the arterial phase, showing a ‘fast-in and fast-out’ pattern (‘fast-in’ refers to the contrast agent entering the renal tumor, causing it to appear earlier than the renal cortex; ‘fast-out’ means that the contrast agent leaves the renal tumor earlier than it leaves the renal cortex) (Fig. 1D and E). Bladder CTU examination revealed no obvious abnormal tumors (Fig. 1F).
After 9 days, the patient underwent cystoscopy, which revealed multiple carpet-like tumor protrusions in the trigone area, posterior wall, and the left and right walls of the bladder. The largest mass was ~5×5 mm, located at the ureteral orifice on the left side of the bladder (data not shown). Pathological examination after transurethral resection of bladder tumor (TURBT) revealed high-grade invasive bUC. Firstly, the resected specimens were stained with hematoxylin and eosin (H&E). The resected specimens were fixed with 10% formalin, embedded in paraffin, and cut into 4-µm tissue sections. After the paraffin sections were dewaxed in xylene I and II for 5 min, they were incubated in 100, 100, 95 and 85% ethanol solutions for 1 min, 1 min, 30 and 20 sec, respectively, and then rinsed with distilled water for 30 sec. After staining with hematoxylin (Shandong Chiwell Biotechnology Co., Ltd.) for 6–10 min, the sections were rinsed with running water for ~15 min to obtain blue color. Subsequently, the sections were placed in a 1% hydrochloric acid-ethanol solution for ~5 sec, and were rinsed with running water for 30 sec, incubated in 95% ethanol for 1 min for dehydration, counterstained with eosin stain (Shandong Chiwell Biotechnology Co., Ltd.) for 1.0–1.5 min, and then incubated in 85, 95, 100 and 100% ethanol solutions for 10, 20, 30 sec and 1 min, respectively, for dehydration. After excess alcohol was removed, the sections were soaked in xylene I (20 sec) and II (40 sec) until they became transparent, and sealed with neutral gum. H&E staining was performed at room temperature (~25°C). Secondly, immunohistochemistry was performed on the resected specimens. The resected specimens were fixed with 10% formaldehyde, embedded in paraffin, sliced (~4 µm thick), dewaxed and rehydrated as aforementioned. The sections were rinsed with purified water three times (5 min each) to remove the ethanol, placed in preheated 0.50 M EDTA buffer (pH 8.0) in a boiling water bath for 20 min, and naturally cooled down to room temperature. The slides were rinsed with purified water three times (5 min each) to remove the EDTA buffer, and subsequently placed in 3% hydrogen peroxide at room temperature (5 min) to block the endogenous peroxidases. After washing three times with PBS (pH 7.2–7.4; 5 min each), primary antibodies from Shanghai Jiehao Biotechnology Co., Ltd., were added to the sections (diluted in PBS) and incubated at 37°C for 60 min. The detailed information of the primary antibodies used in the present study is as follows: Cytokeratin (CK)20 (1:100; cat. no. CRM-0632); CK5/6 (1:100; cat. no. CM-0531); CK7 (1:100; cat. no. CM-0541); GATA-3 (1:100; cat. no. GM-0091); p40 (1:100; cat. no. PRM-0271); p53 (1:100; cat. no. PM-0051); Ki-67 (1:100; cat. no. KM-0021); α-smooth muscle actin (α-SMA; 1:100; cat. no. AM-0051); CD117 (1:100; cat. no. CRM-0421); transcription factor E3 (TFE-3; 1:100; cat. no. TRM-0141); CK(Pan) (1:100; cat. no. CM-0641); CD34 (1:100; cat. no. CM-0271); PAX-8 (1:100; cat. no. PRM-0291); vimentin (1:100; cat. no. VM-0031); epithelial membrane antigen (EMA; 1:100; cat. no. EM-0041); and carbonic anhydrase 9 (CA-9; 1:100; cat. no. CR-0811). After washing three times with PBS (pH 7.2–7.4; 5 min each), the secondary antibody (anti-mouse/rabbit IgG peroxidase polymer; 1:20, cat. no. KY-202; Shanghai Jiehao Biotechnology Co., Ltd.) was added and incubated at room temperature for 30 min. 3,3′-Diaminobenzidine was used for color development and hematoxylin was used for counterstaining for 8 min at room temperature. After ethanol dehydration, the slides were sealed with resin. The pathological sections were observed using a light microscope (DM1000; Leica Microsystems, Inc.). The immunohistochemistry results were as follows: CK20(+) (Fig. 2B), CK5/6(−) (Fig. 2C), CK7(+) (Fig. 2D), GATA-3(+) (Fig. 2E), p40(−) (Fig. 2F), p53(+, mutant) (Fig. 2G), Ki-67(+, 30%) (Fig. 2H) and α-SMA(+) (Fig. 2I). H&E results showed high-grade cancer with cells exhibiting disordered polarity (the long axis of the nucleus is not perpendicular to the fibrovascular axis; a), enlarged nuclei (>3 times larger than the normal size; b), chromatin condensation (c), nipple fusion (d) and low intercellular connectivity (e) (Fig. 2A). SMA is part of the microfilament system of cytoskeletal proteins and is present in the smooth muscle, muscularis and muscularis propria of the vascular wall (10). The present immunohistochemical results showed a α-SMA(+) phenotype (Fig. 2I); therefore, this was considered to be a muscle-invasive carcinoma. CK20, CK7 and GATA-3 are markers for the joint diagnosis of UC. The pathological results were all positive (Fig. 2B, D and E); therefore, a diagnosis of UC was made. TP53 is a tumor suppressor gene that is mutated in half of all human cancers (11). p53 expression is upregulated in urothelial carcinoma tissue compared with normal urothelial tissue, and high p53 expression predicts shorter survival in patients with non-muscle-invasive bladder cancer, but is not associated with prognosis in the muscle-invasive group (12). The present result was p53(+, mutant), which further confirmed the diagnosis of UC. Since the specimen was bladder tissue, a diagnosis of bUC was considered. Other possible diagnoses were excluded as follows: i) Squamous cell carcinoma was excluded, as there was no urothelial component, predominantly basal cell or clear cell features (if a urothelial component is present, UC with squamous differentiation can be considered); and ii) adenocarcinoma was excluded, as there was no urothelial differentiation with true glandular elements (mucus-secreting ductules or intestinal glands) in the tumor (if adenocarcinoma is mixed with UC, UC with glandular differentiation is considered) (13). If there was no metastasis, combined with the patient's good condition at the time and the presence of a right kidney tumor, radical cystectomy and partial right nephrectomy could be performed simultaneously. The patient was recommended to undergo a whole-body single-photon emission computed tomography (SPECT) examination to determine whether there was metastasis. However, the patient refused to undergo a total cystectomy and therefore requested a partial right nephrectomy only.
A total of 9 days later, a laparoscopic right partial nephrectomy was performed to remove the right renal mass completely. Pathological examination of the specimen revealed a ccRCC in the right kidney with clean resection margins. The immunohistochemistry results were as follows: CK20(−) (Fig. 3B), CK7(−) (Fig. 3C), GATA-3(−) (Fig. 3D), CD117(−) (Fig. 3E), TFE-3(−) (Fig. 3F), CK(+) (Fig. 3G), CD34(+) (Fig. 3H), PAX-8(+) (Fig. 3I), vimentin(+) (Fig. 3J), EMA(focal +) (Fig. 3K) and Ki-67(+, <1%) (Fig. 3L). H&E results revealed ccRCC with tumor cells arranged in nests and alveoli (a; Fig. 3A). The tumor cells were round (b) or polygonal (c) and relatively large, with transparent cytoplasm (d). The nuclei were centrally located (e), round and uniform in size, and the interstitium contained a network of small, thin-walled sinusoidal vessels (f; Fig. 3A). CD34 immunohistochemical images showed typical ‘chicken cage-like’ changes (grid-like changes in blood vessels; Fig. 3H). The immunohistochemical results of CK20 and GATA-3 were negative thus excluding UC (14), the results for CD117 and CK7 were negative thus excluding chromophobe cell carcinoma (15), and the PAX-8 result was positive, as found in both renal tumors (16) and UC (17). EMA is expressed in several tumors, therefore its diagnostic value is not high and it needs to be used in combination with specific epithelial differentiation markers (18); however, the aforementioned immunohistochemical results showed that CK and vimentin were strongly expressed in renal tubular epithelial cells, suggesting renal carcinoma. No tumor cells were found on the pathological section resection margins; therefore, the resection margins were considered clean. Other possible diagnoses were excluded as follows: i) In chromophobe RCC, the tumor cell membrane is thick and clear, the cytoplasm is rich, the nuclei are shrunken, the interstitial blood vessels are mostly thick-walled, and CD117 and CK7 are diffusely positive (15); and ii) in clear cell papillary RCC, the tumor cell cytoplasm is clear, the cell nuclei are arranged linearly away from the basement membrane, there are various growth patterns, such as cystic, tubular, papillary and solid, and CK7 is diffusely positive (19). According to the TNM system of the American Joint Committee on Cancer (AJCC) (20) and the clinical staging of renal cancer (21), the pathological stage was T1a. However, confirmation of the presence or absence of lymph node metastasis and distant metastasis requires further whole-body SPECT examination. The patient refused SPECT and requested to discuss with their family whether to undergo radical cystectomy.
After surgery (laparoscopic right partial nephrectomy), the patient received regular intravesical instillations of epirubicin (50 mg per week for 2 months). At 2 months after the surgery, the patient developed an intermittent fever (maximum temperature, 39.1°C) and urinary tract infections caused by Klebsiella pneumoniae and Pantoea agglomerans (bacterial detection was performed using the MA-120 microbial identification and drug sensitivity analysis system; Zhuhai Meihua Medical Technology Co., Ltd.). The patient was then treated with sulbactam [0.5 g; every 12 h (q12 h)], cefoperazone (1 g; q12 h) and nitrofurantoin (50 mg; three times a day) for 5 days. The patient finally agreed to undergo a radical cystectomy. A SPECT scan was performed on the patient in September 2021. The patient was intravenously injected with 25 mCi of technetium (99mTc) methylenediphosphonate injection contrast agent 2–4 h before the examination. After emptying their bladder, the patient laid flat on the SPECT scanning bed (Symbia T16 SPECT/CT; Siemens Healthineers) and underwent whole-body bone imaging, cervical and pelvic SPECT, and CT enhanced scanning. The following SPECT parameters were used: Acquisition angle, 6°/frame; acquisition time, 15 sec/frame; matrix, 128×128; and rotation, 360°. The CT scanning parameters were as follows: Tube voltage, 110 kV; tube current, 160 mA; and slice thickness, 1.5 mm. Image fusion was performed using the dedicated software Syngo MI VA70A (Syngo MI Applications VA70A; Siemens AG) for the image post-processing workstation. SPECT showed postoperative changes without distant or lymph node metastasis (Fig. 1G-K). According to the AJCC TNM system and clinical staging (21), the pathological stage of ccRCC was pT1aN0M0 and the clinical stage was I, with the right renal tumor being ~2 cm in size.
Combined with the results of the SPECT examination and previous bladder pathological examination, according to the TNM system of the AJCC and the clinical staging of bladder cancer (22), the pathological stage of bladder cancer was T2 and the clinical stage was II. However, the specific pathological staging needs to be determined by pathological examination after radical cystectomy. According to the guidelines for the diagnosis and treatment of bladder cancer (22), radical cystectomy is recommended for T2 MIBC without lymph node metastasis.
In October 2021, a laparoscopic radical resection of the bladder, prostate, seminal vesicle and distal ureter, a pelvic lymph node dissection and bilateral cutaneous ureterostomies were performed. The pathological results of H&E staining performed according to the aforementioned method revealed high-grade invasive bUC that had infiltrated the entire bladder (Fig. S1A). The bilateral seminal vesicles (Fig. S1B and C), upper bladder resection margin (Fig. S1D), lymph nodes (Fig. S1E and F), junction of the prostate and bladder (Fig. S1G), vas deferens (Fig. S1H and I), prostate (Fig. S1J) and ureters (Fig. S1K and L) were not invaded. Bladder cancer was evaluated according to the AJCC TNM and aforementioned clinical staging (22), and it was confirmed that the pathological stage of bladder cancer was pT2N0M0 and the clinical stage was II. The pathological results of this case showed that the tumor invaded the entire bladder layer (Fig. S1A), but did not invade the perivesical fat tissue (Fig. S1D), and no distant metastasis was found.
After the diagnosis of dual cancer, it was recommended that the patient and their family undergo genetic testing to exclude, or prevent in advance, any gene-related diseases. However, the patient and their family refused for financial reasons, and as some patients do not believe in the concept of preventing diseases before their occurrence.
Postoperative chemotherapy and regular follow-up were recommended according to the postoperative pathology findings suggestive of MIBC. However, the patient refused chemotherapy and regular review, and only underwent bilateral ureteral single J tube replacement in the outpatient clinic every 3 months. Abdominal X-ray showed bilateral ureteral single J tubes exiting from the right abdominal wall (Fig. 4A). In September 2022, the patient visited the Outpatient Department of the Huanghe Sanmenxia Hospital Affiliated to Henan University of Science and Technology for the treatment of hoarseness, cough while drinking water and dyspnea. Physical examination revealed multiple swollen lymph nodes in the neck and armpits on both sides, the largest of which was ~20 mm and was located at level IV of the right side of the neck. SPECT examination results in September 2022 showed no tumor recurrence in the right kidney and pelvis, and a 19×24×23-mm mass was observed in the lower pole of the left kidney (Fig. 4B and E); multiple swollen lymph nodes were observed in the bilateral neck (Fig. 4F), mediastinum (Fig. 4C), axilla and portal vein (data not shown), considering the possibility of metastasis; and nodules with a diameter of ~5 mm were observed in the S6 segment of the liver (Fig. 4D), indicating a potential metastasis.
A right neck lymph node biopsy was performed in October 2022. Lymph node pathology results suggested metastatic UC. The immunohistochemistry results were as follows: CK5/6(+) (Fig. 5B), CK7(+) (Fig. 5C), GATA-3(+) (Fig. 5D), PAX-8(+) (Fig. 5E), Ki-67(+, 80%) (Fig. 5F), p40(focal +) (Fig. 5G), CA-9(−) (Fig. 5H) and CK20(−) (Fig. 5I). H&E staining images showed tumor cell infiltration (Fig. 5A). Positive expression of PAX-8 indicates that the tumor originates from the kidney or urothelial tissue (Fig. 5E). CA-9 is a specific tumor marker for metastatic renal cancer, and negative expression excludes renal cancer metastasis (Fig. 5H) (23). p40 positivity indicates squamous cell cancer, but in this case the expression was focal and had no practical significance (Fig. 5G) (24). CK5/6, CK7, GATA-3 and CK20 are all epithelial tissue tumor markers, which are used together for the diagnosis of UC, among which the relative specificity of GATA-3 is 86% (14,25). In this case, the pathological results showed that CK5/6 (Fig. 5B), CK7 (Fig. 5C) and GATA-3 (Fig. 5D) were all positive, and CK20 (Fig. 5I) was negative; therefore, the lymph node tissue was invaded with metastatic bUC. Bladder cancer was evaluated based on the AJCC TNM and clinical staging. The patient had distant lymph node metastasis, the pathological stage was M1, and the clinical stage was IV.
It was recommended that the patient undergo a liver and left kidney biopsy to clarify the pathological type and assist in further diagnosis and treatment. The patient rejected these suggestions as they already had multiple tumors and had been confirmed with UC with lymph node metastasis. Regardless of the results of the pathological examination of the liver and left kidney, the patient was already in the late stage of cancer; therefore, they did not wish to experience further pain from biopsy punctures, surgery, radiotherapy and chemotherapy. The only treatment they would accept was oral medication to relieve the current pain.
Combined with the patient's clinical data, empirical analysis suggested that the left renal mass may be a recurrence of ccRCC. Firstly, Fig. 4G shows bilateral renal SPECT scans. SPECT examination results showed that the tumor was unevenly enhanced during the cortical phase (Fig. 4H); the tumor disappeared rapidly during the excretory phase, with a density lower than that of normal renal parenchyma, and the tumor was observed to compress the renal pelvis (Fig. 4I). Secondly, the ‘Guidelines for the Diagnosis and Treatment of Urological and Men's Diseases in China (2022 Edition)’ (26) mentioned that metastatic renal cancer caused by other cancers is relatively rare, and its clinical characteristics are bilateral renal metastasis and multiple metastatic lesions. The patient only had a single tumor in the lower pole of the left kidney, which did not meet the clinical characteristics of renal metastatic carcinoma, and they had a history of right-sided ccRCC; therefore, it was more likely that the left kidney may be a recurrence of ccRCC.
For liver tumors, since both bUC and ccRCC can metastasize to the liver, it is impossible to clearly determine their pathological type. According to the AJCC bladder cancer staging (22), the following assumptions can be made: If the liver metastasis comes from UC, the pathological stage is M1b and the clinical stage is IVB; if the metastasis comes from ccRCC, the pathological stage is M1a and the clinical stage is IVA. Therefore, the patient was diagnosed with metastatic UC, with pathological stage M1 and clinical stage IV. The patient and their family refused further radiotherapy and chemotherapy, as they believed that the side effects of chemotherapy and radiotherapy would outweigh the therapeutic effects to the disease itself.
Sunitinib is a multi-targeted receptor tyrosine kinase inhibitor (TKI) that inhibits tumor cell proliferation and antitumor angiogenesis by acting on targets such as vascular endothelial growth factor receptors 1–3 (VEGFR1-3), c-KIT, platelet-derived growth factor receptor-α and -β and FMS-like tyrosine kinase 3 (27). Both the United States Food and Drug Administration (FDA) (21) and the Chinese FDA (28) have approved sunitinib for the treatment of metastatic RCC. Tislelizumab, a programmed cell death protein 1 (PD-1) inhibitor originally developed in China, is specifically designed to minimize Fcγ receptor binding of anti-PD-1 antibodies, thereby limiting antibody-dependent phagocytosis. Tislelizumab has higher affinity than pembrolizumab or nivolizumab, all of which provide a potential mechanism of resistance to anti-PD-1 therapies (29). Tislelizumab was approved by the China National Medical Products Administration for the treatment of locally advanced or metastatic UC (30). The antitumor mechanisms of pembrolizumab, nivolizumab and tislelizumab are similar. The present patient had both ccRCC and bUC, and there is currently no unified guideline for this type of patient. The use of tislelizumab + sunitinib is empirically recommended to treat patients, aiming to maximize the benefits to patients through dual antitumor mechanisms. The reason for choosing tislelizumab instead of pembrolizumab or nivolizumab is that the target affinity of tislelizumab is 35–60 times higher than that of pembrolizumab or nivolizumab (31).
After communicating with the patient and their family, a regimen of tislelizumab (200 mg once every 3 weeks; BeiGene, Ltd.) + sunitinib (50 mg/day; administered for 4 weeks with a 2-week interval) was adopted to control disease progression for 2 months. In January 2023, the patient died of tumor metastasis, and no autopsy was performed.
Discussion
From the establishment of the databases to May 19, 2024, a comprehensive literature search was conducted in the China National Knowledge Infrastructure database (https://www.cnki.net/) and Wanfang Data (https://wanfangdata.com.cn/) using ‘clear cell renal cell carcinoma’ and ‘bladder urothelial carcinoma’ as Chinese search terms. In addition, relevant English studies were searched in Web of Science (webofscience.com) and PubMed (https://pubmed.ncbi.nlm.nih.gov) using the search terms ‘clear cell renal cell carcinoma’ and ‘bladder urothelial carcinoma’ from the inception of the databases to May 19, 2024. The initial search identified 3,656 studies. The inclusion criteria were as follows: i) Case reports or case series of ccRCC combined with bUC or TCC; ii) all included cases had clear pathological types; iii) the included studies had available full texts; and iv) the included studies presented patient information, such as sex, age, smoking, previous history, diagnosis time of renal cancer and bUC, and follow-up status. The exclusion criteria were as follows: i) Irrelevant studies; ii) unable to download full text; and iii) incomplete patient information. Two researchers independently screened the studies according to the inclusion criteria and a third researcher was involved in the decision-making process for study inclusion. When reading the references of the 31 included studies, three further studies met the inclusion criteria, and ultimately 34 studies were included in the literature review. There were 7 articles in Chinese (to ensure high quality of evidence, only core journals were included, because core journals usually have stricter review processes, more authentic information and greater academic influence), 11 articles in Japanese (indexed by PubMed or Web of Science) and 16 articles in English. Japanese articles could be read using Google Translate (https://translate.google.com). The literature screening process is illustrated in Fig. 6.
The relevant survival analyses were performed using the data extracted in Table SI. For patients with multiple primary cancers associated with ccRCC and bUC, the Kaplan-Meier method in GraphPad Prism 5 software (Dotmatics) was used to evaluate the effects of the tumor onset time interval and ccRCC and bUC pathological stage on survival, and the log-rank test was used to test the differences between the survival curves. P<0.05 was considered to indicate a statistically significant difference.
A total of 35 patients were included in 34 articles, and together with the present case, a cohort of 36 patients diagnosed with ccRCC complicated by bUC was included in the literature review. The clinical characteristics of all the cases reviewed in the literature are presented in Tables SI and SII. The median age at first cancer diagnosis was 56.5 years (range, 31–82 years). Most cases occurred in males, with a male-to-female ratio of 6:1. A total of 16 (44.4%) patients had a history of smoking. However, only 11.1% (4 cases) of the patients had a family history of cancer. Regardless of whether renal or bladder cancer is the first type of cancer, the first symptom in most patients is hematuria, which may be intermittent, continuous, macroscopic or microscopic. A small number of patients (11.1%) have symptoms of prostatitis, such as difficulty in urination, frequent urination, urgency and incomplete urination. Few patients with renal cancer (5.6%) as the primary cancer experience lower back or hip pain. A total of 9 patients had dual primary cancers of the urinary system (including ccRCC and bUC) (32–39). A total of 11 patients were diagnosed with triple primary cancers of the urinary tract, including prostate cancer, ccRCC and bUC (40–50). The remaining 16 patients also had other types of cancer, such as von Hippel-Lindau disease (51), uterine cancer (52), renal UC (53), renal pelvic cancer (54), ureteral UC (55), renal pelvic and ureteral TCC (32,56,57), hepatic carcinoma (58), metastatic clear cell carcinoma (59), tubular cystic RCC (60), ureteral inverted papilloma cancer (61), esophageal cancer (62), ureteral fibroepithelial polyps (63), neuroendocrine tumor (64), rectal adenocarcinoma (65), and metastatic UC (present case).
In published reports on multiple primary urinary tract cancers, ccRCC was mainly in stages T1 (32,34–38,40,45–49, 54,56,60,62) (present case) and T2 (33,39,41,44,51–55,57,64,65), accounting for 47.2 and 33.3% of the cases, respectively. A total of 20 patients (55.6%) underwent total (33,36,37,39,40,43,45,51,53,58,59) or partial (44,48,49,52,54,60,62,63) (present case) nephrectomy as the primary treatment, and 8 patients underwent nephroureterectomy (41,54,57) or nephroureter and partial cystectomy (32,34,47,56,61) according to their clinical stage and condition. A total of 3 patients with concurrent bladder cancer underwent nephroureterectomy and cystectomy simultaneously (43,46,53). To prevent recurrence or progression of renal cancer after surgery, certain patients receive chemotherapy with fluorouracil (54), and others use immunosuppressants, such as interferon (41,42,44), interleukin-2 (44), nivolumab (49), ipilimumab (49), tislelizumab and sunitinib (present case). A patient who had previously been receiving hemodialysis for renal failure was found to have bladder, kidney and ureteral tumors and continued to receive hemodialysis treatment after surgery (57).
Among the multiple primary urinary tract cancers in the present review, the pathological stages of bUC were mainly T1 (32–35,38–42,44–46,48,49,51,53,54,57,59,63,64) and T2 (37,38,43,47,60,65) (present case), accounting for 58.3 and 19.4% of cases, respectively, including 1 case (52) in the T3 stage and 1 case (55) in the T4 stage. The main surgical methods for bUC were TURBT (63.9%) (32–35,38–44,48–51,54,56–59,61,62) and radical cystectomy (30.6%) (36,45,46,52,53,60), among which 13.9% of the patients underwent radical cystectomy after being diagnosed with bladder cancer by TURBT (37,47,64,65) (present case). Intravesical chemotherapy (35,37,38,41,50,55,61,62,65) and Bacillus Calmette-Guérin (39) therapy were the main treatments after TURBT.
Based on the different onset times of ccRCC and bUC-related multiple cancers, they can be divided into synchronous multiple primary malignant neoplasms (SMPMN; ≤6 months) and metachronous MPMN (MMPMN; >6 months). In the present review, 20 patients had SMPMN (34,35,37–39,42,43,45–47,49–51,53,54,57,59,60,64) (present case) and 16 patients had MMPMN (32,33,36,38,40,41,44,48,52,55,56,58,61–63,65). The median survival or follow-up time since the last cancer diagnosis was 20 and 48 months in the SMPMN and MMPMN groups, respectively.
For patients with multiple primary cancers associated with ccRCC and bUC, the tumor onset time interval (P=0.533; Fig. 7A) and ccRCC pathological stage (P=0.455; Fig. 7B) had no significant effect on the survival rate; however, the bUC pathological stage had a significant effect on the survival rate (P=0.021; Fig. 7C).
Bladder cancer is currently the 9th most common malignant tumor worldwide (1). According to statistics in 2022, there were ~614,000 new cases of bladder cancer and 220,000 deaths worldwide (1). The incidence and mortality rates in men were higher than those in women (1). Bladder cancer is the sixth most common cancer in men and the ninth leading cause of cancer death (1). bUC accounts for >90% of all bladder cancer cases (5). Smoking is the most common risk factor, while other risk factors include occupational factors, such as exposure to paint, rubber, petroleum, dyes and coal, and iatrogenic factors, such as pelvic radiotherapy, chemotherapy, long-term indwelling catheterization, chronic inflammatory stimulation and schistosomiasis infection, associated with geographical or socioeconomic reasons (6,66). The main clinical manifestation in most patients is painless gross hematuria; however, if lower urinary tract symptoms are present, such as frequency, urgency and difficulty in urination, bladder cancer should be suspected (6,22,67).
Since the advent of cystoscopy, TURBT has been the main method for the initial diagnosis and staging of bladder cancer, and is also the main method for the treatment of NMIBC (6,22).
The current standard surgical approach for MIBC is radical cystectomy combined with urinary diversion (68). With advancements in technology, the surgical methods of radical cystectomy have evolved from traditional open surgery to laparoscopic or robotic surgery. Khan et al (69) compared the prognosis of patients with bladder cancer who underwent three surgical procedures (open radical cystectomy, laparoscopic radical cystectomy and robotic-assisted radical cystectomy) and found no difference in 90-day complication rates among the three surgeries according to the Clavien-Dindo complication classification system (70).
Griffiths et al (71) confirmed that neoadjuvant chemo- therapy with cisplatin, methotrexate and vinblastine is beneficial for the treatment of MIBC. This view is also supported by the results of a systematic review and meta-analysis of neoadjuvant chemotherapy for invasive bladder cancer (72). Currently, the main treatments for metastatic UC include chemotherapy, such as gemcitabine combined with cisplatin (73,74), immune checkpoint inhibitors, such as avelumab (75) and pembrolizumab (76), and radiotherapy; however, radiotherapy alone has no obvious benefit on overall survival (22).
For patients who are unable or unwilling to undergo radical cystectomy and who clearly understand the risks and need for careful follow-up, the American Urological Association guidelines recommend ‘trimodal therapy’, which is maximal TURBT combined with chemoradiotherapy (77).
New guidelines from the FDA and the European Society for Medical Oncology recommend enfortumab vedotin plus pembrolizumab as the first-line standard treatment for advanced UC, with an advantage shown in terms of patient survival compared with chemotherapy (78,79). Nivolumab plus gemcitabine-cisplatin or platinum plus avelumab are alternative treatments (78).
The prognosis and treatment of bUC mainly depends on histopathology and TNM staging. The degree of muscle layer invasion determines whether a patient is staged as pT1 (NMIBC) or pT2 (MIBC). The 5-year overall survival rates of pT1, pT2 and pT3 bUC are 75, 50 and 20%, respectively (22,67).
According to the recommendations of domestic (26) and international (22) guidelines, the patient in the present report was first diagnosed with bladder cancer through TURBT, and then underwent radical cystectomy combined with urinary diversion. Regular follow-up and treatment were not performed after the operation, which eventually led to the occurrence of metastatic UC. Tislelizumab was administered to treat metastatic bladder cancer, but the patient ultimately had a poor prognosis.
Renal cancer is a growing disease with an estimated 400,000 new cases per year worldwide and an annual mortality rate of nearly 175,000 individuals (80); it accounts for ~3% of adult malignancies (81). ccRCC is the predominant and aggressive histological subtype of adult renal cancer. The NCCN guidelines state that ~85% of renal tumors are RCC, of which ~70% are ccRCC (3). However, Wilms' tumors account for 90% of childhood renal cancer cases (80).
High blood pressure (80,82), smoking (80,83,84), high body mass index, obesity (80), alcohol consumption, lack of exercise and multiple births in women (84) are risk factors for renal cancer.
Most cases of renal cancer are discovered incidentally during abdominal ultrasonography or CT scans. Only a minority (<10%) of patients present with the classic triad of kidney cancer, which includes hematuria, flank pain and a palpable abdominal mass (85). The main treatments for localized renal cancer include partial nephrectomy, total nephrectomy and tumor ablation (85,86). Patients with metastatic renal cancer, which is usually not treatable with surgery, may benefit from immune checkpoint and targeted protease inhibitors (85). Since 2005, protein kinase inhibitors have been used to treat metastatic RCC by targeting growth factor receptors, such as fibroblast growth factor receptor, MET oncogene and VEGFR. Since 2015, PD-1 inhibitors (nivolumab and ipilimumab) have been used to inhibit renal cancer cells. Currently, the standard treatment for most patients with metastatic renal cancer is a combination of immune checkpoint inhibitors and protein TKIs. For patients who cannot tolerate immunosuppressants, single-drug therapy can be used (85,86).
A total of three studies (41,42,44) included in the present review reported the use of interferon and IL-2 alone or in combination for postoperative adjuvant therapy of RCC, all of which were published before 2010. However, it was subsequently confirmed that there was no clinical benefit in the use of interferon-α and/or IL-2 for RCC above stage T2 (87).
Routine preoperative renal mass biopsy of small renal masses is not recommended by the current guidelines (26). The main reasons include inaccurate biopsy results, complications of renal mass biopsies and needle tract implantation (88), which ultimately lead to a high rate of unnecessary nephrectomy/partial nephrectomy for benign renal tumors (18–26%) (89). Gao et al (88) reported that a preoperative renal mass biopsy could reduce the rate of unnecessary partial/radical nephrectomy to 3%.
A partial nephrectomy was performed on the right renal tumor of the present patient in accordance with the guidelines (26). During follow-up, the right renal tumor did not recur, but a mass appeared in the left kidney. After evaluation, it was suspected that the mass in the left kidney could be a recurrence of renal cancer. Sunitinib was administered for treatment, but the patient eventually died of multiple advanced tumors.
The presence of two or more histologically different malignancies in the same individual is known as MPMN. In 1932, Warren (90) proposed diagnostic criteria for MPMN, namely that each tumor must occur in a different site or organ, have its own pathological morphology and be histologically malignant, and that metastasis or recurrence is excluded. According to the literature, the incidence of multiple primary neoplasms in patients with cancer is 2.4–8.0% and can be as high as 17.0% at 20 years of follow-up. The main factors causing their occurrence include the host (genetics, hormones and previous cancer history) and the environment (tobacco and alcohol consumption, geography, pathogens and occupation) (91).
Gul et al (92) showed that the incidence of RCC and bladder cancer is higher in men compared with that in women, and that the higher smoking rate in men is partly responsible for the difference in incidence between men and women; however, hormones, genetics and differences in gene mutation patterns between men and women also play a role. Based on the SEER database, Wu et al (8) studied the clinical and pathological characteristics of 704 patients with RCC and UC, 566 of whom had bUC, with a male-to-female ratio of 4.66:1. The results showed that the risk of co-occurrence of RCC and UC increased in older (>65 years old), male and Caucasian populations. The results of the present review showed that the median age at onset of ccRCC- and bUC-related multiple primary cancers was 56.5 years, the incidence rate in males was six times (30:5) higher than that in females, the incidence rate in smoker was 2.67 times (16:6) higher than that in non-smokers and only 1 female patient was diagnosed with this disease among all smokers. Therefore, we hypothesized that male sex and smoking may be risk factors for the co-occurrence of ccRCC and bUC. This is consistent with previously published results (92). However, only 11.1% of the patients with cancer had a family history of cancer. Therefore, whether a family history of cancer is a risk factor remains to be verified. The patient in the present report was male with a history of smoking and was diagnosed with two types of cancer, which is consistent with previous reports (32,37–39). The patient had no family history of cancer; therefore, whether the patient had a genetic mutation needs to be considered. However, the patient and their family refused genetic testing.
The clinical manifestations of ccRCC- and bUC-related multiple malignancies are similar to those of single ccRCC and bUC. Most patients present with hematuria, which may be accompanied by lower urinary tract irritation or lower back pain. The main clinical manifestation of the current case was hematuria, accompanied by urinary tract irritation symptoms, and no lower back pain.
Wu et al (8) showed that the proportions of pathological stage I/II for RCC and UC were 81.1 and 93.3%, respectively. Most patients with RCC underwent a total or partial nephrectomy, whereas 87.1% of patients with bUC underwent a partial resection and only 1.4% underwent a local tumor resection. In the present review, 80.5% of patients with ccRCC and 77.7% of patients with bUC were in stages T1 and T2; therefore, the current results show that the proportion of renal cancer in the T1/2 stage was consistent with the results reported by Wu et al (8), while the proportion of bladder cancer in the T1/2 stage was different. However, this result may have a certain publication bias, as most patients in the early stage can undergo surgery to obtain clear pathological data, whereas most patients in the late stage do not have the opportunity for surgery (since patients with advanced cancer often have metastasis to distant or surrounding tissues, which usually indicates a poor prognosis) and cannot obtain clear pathological data; therefore, patients in the late stage may be omitted from publications. In the present review, 27.8% of patients underwent nephrectomy, 27.8% underwent partial nephrectomy, 27.8% underwent nephrectomy and/or ureterectomy and/or cystectomy, and only 1 patient underwent renal biopsy for RCC, there was no difference in the proportion of surgical approach for RCC, but for bUC, 63.9% of patients underwent TURBT, 16.7% underwent radical cystectomy and 13.9% underwent radical cystectomy after TURBT. The SEER database only includes cancer data from the United States. The data collected in the present review were from studies performed in China, the United States, Japan, France and other countries, which were mainly case reports or small studies. Differences in the economic, regional and medical levels may explain the differences in the surgical methods used. The patient in the present report underwent partial nephrectomy and radical cystectomy in stages. Initially, the patient was recommended to undergo a whole-body SPECT examination to evaluate their systemic condition. If there was no metastasis to other organs or lymph nodes, a partial nephrectomy and a radical cystectomy would be performed at the same time. However, partial nephrectomy combined with radical cystectomy is more difficult. Because it involves multiple organs of the human body (kidneys, ureters, bladder and prostate) at the same time, it requires superb surgical skills. The surgery time involving multiple organs at the same time is longer than the surgery time for a single organ, and it is also a great challenge for the postoperative recovery of the patient.
Qi et al (9) followed up 27 patients with combined RCC and UC, 17 of whom had both renal cancer and bladder tumors. The study showed no difference in survival between patients who underwent partial nephrectomy and total nephrectomy (9). However, detailed information on the patients of the study by Qi et al (9) could not be obtained; therefore, these patients were not included in the present review. Wu et al (8) demonstrated that the co-occurrence of bladder cancer and RCC was not a risk factor for survival outcomes in RCC. Previous studies have suggested that individuals with papillary RCC have an increased risk of subsequently developing bladder (93,94) or prostate (94) cancer, while another study did not confirm this association (95). The present review demonstrated that the survival rate of ccRCC- and bUC-related multiple primary tumors was not associated with the tumor onset time interval (P=0.533) or the pathological stage of ccRCC (P=0.455), but may be related to the pathological stage of bUC (P=0.021), which is inconsistent with the conclusion by Wu et al (8). The present literature review results showed that the median survival time for ccRCC- and bUC-related multiple primary tumors was 47.5 months, with a median survival of 20 months for SMPMN and 48 months for MMPMN. The follow-up of the present case lasted only 19 months from onset to death, which is consistent with the median survival time of 20 months drawn from the literature review. Due to the low incidence of the disease, more studies are needed in the future to clarify whether the occurrence of bladder cancer or RCC affects the prognosis of patients with ccRCC- and bUC-related multiple primary tumors.
Some cases of multiple primary malignancies associated with gene deletions or mutations are called gene-related syndromes, such as Lynch syndrome. Lynch syndrome, also known as hereditary non-polyposis colorectal cancer, is an autosomal dominant disorder caused by germline mutations in one of the four mismatch repair genes or the EpCAM gene. The clinical manifestations of the syndrome include UTUC (2–20%), colorectal cancer (30–73%), endometrial cancer (30–51%) and other extraintestinal tumors (96). According to Lynch syndrome diagnosis and treatment guidelines, renal and bladder cancers do not belong to Lynch syndrome (97). Results of a systematic review and meta-analysis showed that Lynch syndrome was associated with a significantly increased relative risk of renal and bladder cancer, although the quality of the evidence was assessed as ‘low’ (98). Among the reports included in the present literature review, six involved UTUC or rectal adenocarcinoma in addition to bUC and ccRCC (53–57,65). Therefore, it is important to perform genetic testing in patients with both bUC- and ccRCC-related primary multiple cancers to determine whether they have Lynch syndrome. Although the patient in the present report rejected genetic testing, it is believed that genetic testing is important for further studying this disease.
Currently, there are no uniform clinical guidelines or pieces of prospective experimental evidence for the treatment of patients with multiple primary neoplasms, and most cases are managed based on previous case reports (91). The treatment of ccRCC- and bUC-related multiple primary malignant tumors requires the formulation of a surgical plan that maximizes the patient's own interests based on the actual condition of the patient and the determination of further diagnostic and treatment measures, such as radiotherapy, chemotherapy, targeted therapy or combined therapy, according to changes in the patient's condition.
The present study has certain limitations. First, due to insufficient information from the included literature, it was not possible to analyze whether alcohol consumption, hypertension, diabetes and aristolochic acid exposure history were risk factors for the comorbidity of ccRCC and bUC. Second, certain patients included in the literature review had other cancers besides ccRCC and bUC, such as prostate cancer, UTUC, esophageal cancer and rectal cancer, which may be factors leading to the occurrence of other primary cancers. Third, the present study focused on ccRCC and bUC, and did not include UTUC. According to the study by Wu et al (99), the most common secondary tumors of UTUC in Taiwan are RCC and hepatocellular carcinoma. Patients with UTUC and a history of cancer have a higher risk of developing other primary malignancies (99). Fourth, due to the low incidence of the co-occurrence of bUC and ccRCC, only 36 patients were included for analysis. In the future, a multicenter joint study on this type of patients with multiple primary cancers needs to be conducted to gain a deeper understanding of the disease. Fifth, dual and multiple cancers may be related to gene mutations. Although none of the included cases underwent genetic testing, the importance of genetic testing in identifying multiple cancers cannot be excluded. Last, coexistence of RCC and bUC may be related to Lynch syndrome, but genetic testing has not been performed to verify this, and more cases are needed in the future to supplement the present study.
In summary, ccRCC and bUC comorbidity is a rare phenomenon, and there are no clear epidemiological, therapeutic and prognostic characteristics. Previous studies have reported the comorbidity of ccRCC and bUC; however, these studies were limited by the lack of detailed case data or small sample sizes. The present study comprehensively summarized the typical characteristics of ccRCC- and bUC-related multiple primary malignancies. In conclusion, the risk factors for ccRCC- and bUC-related multiple primary malignancies are male sex and smoking, and whether a family history of tumors is a risk factor remains to be confirmed. The median age at the onset of ccRCC- and bUC-related multiple primary malignancies was 56 years, and the median survival was 47.5 months (SMPMN, 20 months; MMPMN, 48 months). The cumulative survival rate is not related to the interval between tumor onset and the pathological stage of ccRCC, but may be related to the pathological stage of bUC. In the present case, the patient had both ccRCC and bUC, namely SMPMN. After surgery, the patient recovered well but eventually developed cervical lymph node metastasis with a UC origin, suggesting that the pathological stage of bladder cancer is crucial for prognosis. The overall survival rate from disease onset to death was 19 months.