Introduction

Bladder cancer constitutes 7% of cancers in men and 3% of cancers in women all over the world. The male/female incidence rate is 3-4/1, and it is generally detected in the fifth-sixth decade (1). Of bladder cancers, 90-95% are urothelial (transitional cell) carcinoma and 5-10% are non-urothelial (epithelial and/or mesenchymal origin) carcinoma (2). Non-urothelial carcinomas have a worse prognosis than urothelial carcinomas, and they are usually diagnosed at an advanced stage. Its diagnosis, staging, and treatment are generally similar to urothelial carcinomas (3). The largest series on non-urothelial carcinomas in the literature was performed by Cohen et al. (4) in 2.201 patients.

Due to the low incidence rates, our knowledge about the treatment protocols and prognosis of non-urothelial bladder carcinomas is based on retrospective case series and very few prospective studies (3,5). The basic treatment approach is adjuvant chemotherapy (CT)/radiotherapy (RT) applied after radical surgical resection, especially in the locally advanced stage. However, due to the scarcity of randomized studies, adjuvant treatment protocols are still not standardized (3). Since our knowledge about non-urothelial carcinoma was limited, in this study, we aimed to evaluate the clinical and pathological characteristics and oncological results of patients diagnosed in three different centers in our country.

Materials and Methods

The clinical and pathological data and postoperative follow-up findings of 26 patients aged 44-75 years, who were treated and followed up in three different centers between January 2012 and October 2019, and diagnosed as having non-urothelial carcinoma, were retrospectively analyzed. Demographic data of the patients, complaint at presentation, location of the tumor in the bladder, tumor size, cystoscopy findings, transurethral tumor resection of bladder tumor (TUR-BT) pathology, clinical tumor stage, radical cystectomy status, adjuvant treatments applied during the postoperative follow-up period, postoperative follow-up period, local recurrence, progression and survival conditions were recorded. Eastern Cooperative Oncology Group (ECOG) score and Charlson Comorbidity index, which were used to evaluate the morbidity status of the patients during the preoperative period, were found from the patient data and recorded. Radical cystectomy and bilateral expanded pelvic lymph node dissection (LND) were routinely performed in patients undergoing radical surgery. Colonoscopy was performed in all patients with TUR-BT pathology of adenocarcinoma to investigate the primary focus in the colorectal system. American Joint Committee on Cancer tumor-node-metastasis (TNM) staging system was used for staging of tumors (6). In addition, every increase observed in the pathological staging performed after radical cystectomy compared to the clinical TNM stage after TUR-BT was defined as up-staging.

Statistical Analysis

Kaplan-Meier method was used for survival analysis, while differences between patient groups were evaluated using the log rank test. This study was not suitable for the multivariate model due to its small sample size. Analyzes were performed using IBM SPSS Statistics 21 (IBM, Armonk, NY USA) software. Values of p<0.05 were considered statistically significant.

Results

Nineteen (73.1%) of the 26 patients we included in the study were male and 7 (26.9%) were female, and the mean age at diagnosis was 60.77±8.52. The most common presenting complaint was macroscopic hematuria (22 patients, 84.6%), followed by lower urinary tract complaints (irritative voiding symptoms, difficulty urinating) (10 patients, 38.4%). More rarely, abdominal distension (1 patient, 3.8%), abdominal pain (1 patient, 3.8%) and obstructive uropathy (1 patient, 3.8%) were observed.

Tumor types in histopathological examination were as follows: Squamous cell carcinoma (9 patients, 38.4%), adenocarcinoma (8 patients with different histopathological subtypes, including mucinous, signet ring cell, plasmacytoid/signet ring cell mixed variant, and signet ring cell containing osteoclast-like giant cells, 30.8%), small cell carcinoma (3 patients, 11.5%), large cell neuroendocrine carcinoma (2 patients, 7.7%), extra-gastrointestinal stromal tumor (1 patient, 3.8%) and malignant undifferentiated mesenchymal tumor (1 patient, 3.8%) and leiomyosarcoma (2 patients, 7.6%).

In the median 13-month (2-42) follow-up of the 26 patients included in our study, the progression-free survival rate was 61.5%, and the overall survival rate was 46.1%. While radical cystectomy was applied to 14 of 18 patients, whose clinical stage was determined as T2-T4a N0M0, 9 of them underwent adjuvant CT, 1 of them adjuvant RT, 1 of them neoadjuvant CT, and 1of them adjuvant CT + RT. Of these 18 patients, adjuvant CT was applied following complete TUR-BT in 3 patients who did not want radical surgery, while partial cystectomy was performed in the patient with extra-gastrointestinal stromal tumor pathology because the tumor was limited to the bladder dome. In the patient with signet ring cell adenocarcinoma with osteoclast-like giant cells without muscle invasion, only complete TUR-BT was performed surgically. These last 2 patients, who did not have a clear treatment scheme, were followed up without adjuvant treatment because the tumor characteristic was not aggressive. Seven patients who were in the metastatic stage at the time of diagnosis were included in the CT program, while palliative RT was applied in 4 patients who developed pain due to bone metastasis during follow-up.

Fourteen patients who underwent radical cystectomy + bilateral expanded pelvic LND and/or neoadjuvant/adjuvant therapy had a median follow-up of 13 (2-42) months, while progression was observed in 4 (28.5%) cancer-related death was observed in 6 (42.8%). In the median 15-month (10-17) follow-up of 3 patients who underwent adjuvant CT and complete TUR-BT, progression and cancer-related death were observed in 2 (66.6%) of them. While no recurrence or progression was observed in the 22-month follow-up of a single patient who underwent partial cystectomy, despite the CT program of 7 patients who were metastatic at the time of diagnosis, 4 (57.1%) had progression and 6 (85.7%) died at a median 9-month (7-22) follow-up. According to the cystectomy pathologies, 9 (60%) of 15 patients had up-staging, while the patient with small cell carcinoma who underwent radical cystectomy after neoadjuvant CT had down-staging.

When we divided the patients into four classes according to histopathological subtype as squamous cell carcinoma, adenocarcinoma, neuroendocrine tumors and sarcomas, the overall survival rates after multimodal treatments were 77.8%, 25%, 20% and 50%, respectively. Metastasis was seen only in patients with adenocarcinoma (62.5%) or neuroendocrine tumors (40%) at the time of diagnosis. Up-staging after cystectomy was observed in 37.5% of patients with squamous cell carcinomas and in all patients with adenocarcinomas or sarcomas. The characteristics of the patients are shown in Table 1. Demographic and clinical characteristics of patients with and without mortality are shown in Table 2.

In the Kaplan-Meier analysis; while the median survival time of all patients was found to be 16 (9-33) months (Figure 1), in the presence of advanced pathological stage (3-4, p=0.006) and higher ECOG score (≥2, p=0.005), it was observed that overall survival times were shorter (Figure 2,3).

Discussion

Non-urothelial bladder carcinomas constitute approximately 5-10% of all bladder carcinomas. The most common histopathological type in Western population is squamous cell carcinoma (3-5%), followed by adenocarcinoma (0.5-2%), and small cell carcinoma (0.35-0.70%). Other histological types such as neuroendocrine carcinoma, sarcomas, and carcinosarcoma are less common and the incidence has been reported as 0.1-0.5% (7). In our study consisting of 26 patients, the most common type was squamous cell carcinoma, in accordance with the literature.

In all types of non-urothelial bladder carcinomas, the most common risk factor observed was smoking (63%) and the most common complaint at presentation was reported as macroscopic hematuria (64%) (8,9). In these tumors with a male/female incidence rate of 3-4.8/1, the presence of muscle invasion at the time of diagnosis is between 72.2-100% in different series (5,10). In our patient group, male/female ratio was 2.71 and macroscopic hematuria and lower urinary tract symptoms, which were the most common complaints at presentation, were observed with a rate of 84.6% and 38.4%, respectively. Muscle invasion was detected in the TUR-BT specimen in all patients (96.1%) except for signet ring cell adenocarcinoma containing osteoclast-like giant cells. While smoking history was a risk factor in half of our patients, 8 (88.8%) of 9 patients with squamous cell carcinoma had a history of clean intermittent catheterization. In 5 patients, no history that could constitute a risk factor was found.

The majority of patients with non-bilharzial squamous cell carcinoma (62.7%) are seen at younger ages compared to transitional cell carcinoma and they are in stage 3-4 at the time of diagnosis, while the rate of distant metastasis is 8-34%. Five-year survival rate is 25.1-57% in patients who have undergone radical cystectomy (5,11,12,13,14). The most recommended chemotherapeutic agents in adjuvant therapy are gemcitabine and cisplatin (4). While radical cystectomy was performed in 8 of our 9 patients with squamous cell carcinoma, who were at the clinically localized stage at the time of diagnosis, 6 of them were given adjuvant CT and 1 adjuvant RT. In one patient who did not want radical surgery, complete TUR-BT + CT was applied. It was seen that CT protocols used were gemcitabine + cisplatin in 4 patients and MVAC in 3 patients. In the median 17-month (9-42) follow-up of these 9 patients, the overall survival rate was found to be 77.7%.

While patients with adenocarcinoma reported in the literature are mostly diagnosed in the sixth decade and the male/female ratio is 4.8/1 (15). If non-urachal adenocarcinoma, which has a worse prognosis and constitutes approximately 90% of bladder adenocarcinomas, is suspected, other primary tumors in the anatomical regions (colon, prostate, endometrium, cervix, breast, lung, etc.) that are likely to develop adenocarcinoma should be excluded (16,17). Standard treatment in primary, localized non-urachal adenocarcinomas is radical cystectomy + bilateral pelvic LND (18). While adjuvant CT/RT is recommended in advanced stage adenocarcinomas, it is known that the prognosis is worse in patients without radical cystectomy (3). In non-urachal adenocarcinomas, approximately 45.7% of the patients are in stage 4, while the rate of distant metastasis is 16.7-25% (5,15). The five-year survival rate was reported as 13-35% in patients who underwent radical cystectomy (5,8,14). In the median 11-month (4-22 months) follow-up of 8 patients with adenocarcinoma including different histological variants in our study, the progression rate was 37.5% and the overall survival rate was 25%. Although one patient was detected in clinical stage 1 and 2 patients were in clinical stage 2 at the time of diagnosis, up-staging to stage 4 was observed in both patients who underwent cystectomy. Intravesical treatments have no role in the treatment of bladder adenocarcinomas (19). As a matter of fact, no recurrence or progression was detected in the 14-month follow-up of our patient of singlet ring cell adenocarcinoma with osteoclast-like giant cells at T1 stage who underwent only complete TUR-BT.

Ploeg et al. (10) reported that the survival time was significantly lower in squamous cell carcinoma than adenocarcinoma (10 months vs 31.6 months), while Arslan et al. (20) could not find a significant difference (21 months vs 22 months) between the two histological types. On the other hand, in our limited number of patients, we could not find a significant difference between the two groups in terms of overall survival (17 months vs 11.5 months, p=0.149).

Neuroendocrine bladder carcinomas generally constitute 0.45-1.2% of all bladder tumors. In this group, small cell carcinomas, which are the more common subtypes, often have muscle invasion, distant organ metastasis and paraneoplastic syndromes at the time of diagnosis (21). Of the patients, 53% are at pT3-4 stage at the time of diagnosis (22). It is necessary to differentiate bladder urothelial carcinoma from small cell carcinoma of prostate origin, and primary small cell carcinoma of the lung, and screening for another primary focus is important (23). Although there is no agreed clear treatment strategy, since micrometastatic involvement may occur at the time of diagnosis, following radical cystectomy/RT and adjuvant CT (cisplatin + etoposide)/RT is the most recommended scheme (3,4). Despite these combinations of therapy, the five-year survival rate has been reported as 10% (24). In patients in whom radical cystectomy cannot be performed, adjuvant CT+RT combination is required in addition to TUR-BT (25,26). Our patient, who was diagnosed at clinical stage 2 and underwent radical cystectomy following neoadjuvant cisplatin + etoposide in accordance with the information in the literature, was still alive at the 6-month follow-up, and death was observed in a median 10-month (9-11 months) follow-up in 2 patients who were found in the metastatic stage and underwent CT.

Large cell carcinomas of the bladder are another less common subtype of neuroendocrine carcinoma (3). As in small cell carcinoma, it is recommended to investigate the presence of another primary focus for differential diagnosis (27). The most common treatment approach reported for this carcinoma with poor prognosis, which is usually detected at an advanced stage, is the combination of adjuvant cisplatin/carboplatin and etoposide following radical cystectomy. Adjuvant cisplatin and etoposide were administered following TUR-BT in 2 patients who were evaluated as having clinical stage 3 disease at the time of diagnosis and did not want radical cystectomy; however, at a median 12.5-month (10-15 months) follow-up, death due to cancer was observed following progression.

Extra-gastrointestinal stromal tumors originating from the bladder are extremely rare mesenchymal tumors (28). Clinical presentation symptoms are generally non-specific, but patients presenting with macroscopic hematuria have also been reported. There is no specific tumor marker and radiological appearance (29). Complete surgical resection is the most curative treatment approach in this tumor, which is resistant to CT and RT. In our patient, who presented with macroscopic hematuria and abdominal distention without clot, partial cystectomy + ileal resection + partial omentectomy was applied to the mass that originated from the bladder dome and spread to the right adnexal area adjacent to the bladder and invaded the ileum. Our patient, who did not receive any additional treatment other than surgery, was in remission during a follow-up of 22 months.

Sarcomas of the bladder and malignant undifferentiated mesenchymal tumors constitute less than 0.5% of all bladder carcinomas. The most common histopathological type among non-epithelial malignant bladder tumors is leiomyosarcoma (3). In these patients, who mostly present with macroscopic hematuria, the tumor is large and often in advanced stage at the time of diagnosis. While radical cystectomy is recommended in the localized stage, adjuvant CT/RT should be combined in advanced stages. The most commonly used CT protocol is doxorubicin and ifosfamide. Nevertheless, since the number of patients reported in the literature is very low, standardization of treatment has not been achieved and mortality rates are quite high (3,30). Although radical cystectomy + adjuvant CT was applied in our patient with malignant undifferentiated mesenchymal tumor diagnosed at clinical stage 2, mortality was observed within 8 months. While one of our two patients with leiomyosarcoma who underwent radical cystectomy died in the second month postoperatively, in our other patient, no recurrence or progression was observed in the 13-month follow-up after adjuvant RT+CT.

Cohen et al. (4) found that the rate of up-staging was higher in non-urothelial carcinomas compared to urothelial carcinomas after radical cystectomy + bilateral expanded pelvic LND. They also stated that in patients with non-urothelial carcinoma with up-staging, overall survival was lower (32.4% vs 46%), and the highest up-staging rate was observed in patients with squamous cell carcinoma (61.8%). On the other hand, unlike the results of the study by Cohen et al. (4), we observed that the rate of up-staging in adenocarcinomas and sarcomas was higher than in squamous cell carcinomas.

When all non-urothelial carcinomas were evaluated, advanced tumor stage, lymph node involvement, advanced age (>70), poor ECOG score, histological types other than squamous cell carcinoma, presence of positive surgical margins, detection of local recurrence during follow-up were found to be significant factors in predicting overall survival (5,12,13,20). We could not evaluate the effects of these factors on survival, since the number of patients was not sufficient to perform multivariate regression analysis. On the other hand, according to Kaplan-Meier analysis; we observed that overall survival times were shorter as expected in the presence of advanced (stages 3-4) pathological stage and high (≥2) ECOG score.

Study Limitations

Although we shared the results of 3 centers in our study, the retrospective design of our study, the limited number of patients, not being able to make randomization, not being able to perform multivariate regression analysis due to the inadequate number of patients, short follow-up periods, and non-standard CT regimens were the main limiting factors.

Conclusion

When multimodal treatments including radical cystectomy were applied to non-urothelial carcinomas of the bladder, which were rare and had very heterogeneous subtypes, as observed in our patients, overall survival rates increased compared to the bladder-sparing approach. According to our results, while survival rates were higher in squamous cell carcinomas, the rate of metastasis at the time of diagnosis was higher in adenocarcinoma and neuroendocrine tumors. We found higher up-staging rates in adenocarcinomas, sarcomas and squamous cell carcinomas after cystectomy. However, since neoadjuvant or adjuvant treatment protocols standardized according to tumor subtype are still not established; there is a need for better determination of prognostic factors that have an impact on survival. Prospective, randomized, controlled and multi-center studies with a large number of patients and longer follow-up periods are needed.

Acknowledgements

Publication: The results of the study were not published in full or in part in form of abstracts.

Contribution: There is not any contributors who may not be listed as authors.

Conflict of Interest: No conflict of interest was declared by the authors.

Financial Disclosure: The authors declared that this study received no financial support.

Ethics

Ethics Committee Approval: All procedures in our study were conducted in accordance with the ethical standards of the institutional and national research committee including human participants and the principles of the Helsinki Declaration, and since it was a retrospective study, no ethics committee approval was made.

Informed Consent: Each patient was informed before the surgery that oncological follow-up information such as recurrence, metastasis development, and survival analysis can be used in various oncological studies to be performed in the clinic without specifying the patient names and identity information, and the data of patients who did not consent were not used.

Peer-review: Internally peer-reviewed.

Authorship Contributions

Concept: E.O.G., Design: İ.S., Data Collection or Processing: İ.S., M.U.K., Y.Ü., Analysis or Interpretation: İ.S., E.O.G., Y.Ü., İ.T., Literature Search: İ.S., Writing: İ.S.