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Non-urothelial bladder cancer

Non-urothelial bladder cancer
Literature review current through: Jan 2024.
This topic last updated: Jun 05, 2023.

INTRODUCTION — Bladder cancers are the most common genitourinary malignancy in both males and females. They are broadly categorized as urothelial and non-urothelial. (See "Pathology of bladder neoplasms".)

The clinical features and treatment of non-urothelial bladder cancers will be reviewed here. Small cell carcinoma of the bladder is discussed elsewhere, as is an overview of urothelial bladder cancer. (See "Small cell carcinoma of the bladder" and "Overview of the initial approach and management of urothelial bladder cancer".)

EPIDEMIOLOGY — Non-urothelial bladder cancer accounts for less than 5 percent of all bladder tumors [1]. Approximately 90 percent of non-urothelial bladder cancers are epithelial in origin, and these include squamous cell carcinoma, adenocarcinoma, and small cell carcinoma.

Non-epithelial tumors include sarcoma, carcinosarcoma, paraganglioma, melanoma, and lymphoma. Risk factors for non-urothelial bladder cancers are discussed below in specific sections for different tumor types. (See 'Non-epithelial bladder tumors' below.)

PATHOGENESIS AND RISK FACTORS — The pathogenesis of non-urothelial bladder cancers is incompletely understood. Both the development of metaplasia and the presence of chronic infection are believed to be important factors in tumorigenesis. Alternative hypotheses include the development of non-urothelial bladder cancers from preexisting urothelial (transitional cell) carcinomas that undergo metaplasia [2], and tumor development from multipotent stem cells in the bladder.

Tissue metaplasia — Tissue metaplasia develops in response to chronic infection and inflammation, which can lead to the development of either squamous epithelium and leukoplakia or mucinous and glandular epithelium. However, the factors that lead to neoplastic transformation are not known.

Squamous cell carcinoma is often associated with squamous metaplasia and is seen in 16 to 28 percent of patients with leukoplakia [3,4].

Two patterns of metaplasia have been associated with adenocarcinoma. Cystitis cystica refers to the invagination of hyperplastic epithelial buds into the lamina propria, which may undergo further metaplasia to cystitis glandularis and is associated with vesical adenocarcinoma. A second pattern involves hyperplasia of the epithelial buds but does not involve invagination into the lamina propria.

Chronic urinary tract infection — Chronic urinary tract infections (UTIs) are associated with both non-schistosomal and schistosomal bladder cancers. Infection may contribute to the development of bladder cancer through multiple mechanisms:

Predisposing patients to metaplasia, the initial step in carcinogenesis.

Gram-negative bacteria such as Escherichia coli and Proteus mirabilis produce nitrosamines, whose metabolites are highly carcinogenic. Carcinogenesis results from DNA adduct formation and possibly from other mechanisms [5-10].

Production of reactive oxygen species by inflammatory cells responding to infection, leading to DNA damage and activation of other carcinogens.

CLINICAL PRESENTATION — Like urothelial carcinomas, patients with non-urothelial bladder cancer typically present with painless hematuria (grossly visible or microscopic), although irritative voiding symptoms (frequency, urgency, dysuria) can be the initial manifestation. (See "Clinical presentation, diagnosis, and staging of bladder cancer", section on 'Clinical presentation'.)

Less common presentations more commonly observed with non-urothelial bladder cancers include:

Mucusuria – Mucusuria has been described with bladder adenocarcinomas and is more common with urachal adenocarcinomas compared with the non-urachal adenocarcinomas.

Abdominal mass – The presence of an abdominal mass is more commonly associated with urachal adenocarcinoma compared with non-urachal adenocarcinomas. (See 'Adenocarcinoma' below.)

DIAGNOSTIC EVALUATION — Cystoscopy is the gold standard for the diagnostic evaluation of a patient with suspected bladder neoplasm, and cystoscopic biopsy generally provides tissue for a definitive diagnosis. Compared with urothelial cancers, non-urothelial tumors are more likely to be muscle invasive at diagnosis and more likely to be upstaged when definitive pathologic staging from surgery is available. Hence, as a group, non-urothelial tumors present at a later stage, contributing to a poorer prognosis compared with urothelial cancers [11]; however, one interesting observation is that urachal cancers tend to have a better prognosis than urothelial cancers of a similar stage at presentation [12]. (See "Clinical presentation, diagnosis, and staging of bladder cancer", section on 'Initial evaluation'.)

OVERVIEW OF TREATMENT APPROACH — Because of the rarity and heterogeneity of non-urothelial bladder tumors, the approach to the treatment of these tumors is largely based upon retrospective series and small trials. Therefore, treatment is usually extrapolated from the approach to patients with urothelial bladder cancers. (See "Overview of the initial approach and management of urothelial bladder cancer".)

For patients who present with localized disease, the primary treatment is cystectomy. For patients with squamous carcinoma, adenocarcinoma, or schistosomal bladder cancer (regardless of histology), this should include a lymph node dissection along with radical cystectomy.

Because these tumors appear to be less responsive to chemotherapy compared with urothelial carcinoma and because these tumors were not included in phase III trials, we do not recommend pre- or postoperative chemotherapy for non-urothelial cancers of the bladders, ureter, or renal pelvis.

Pre-cystectomy radiation therapy (RT) may have a role in schistosomal bladder cancer, but it is not part of the standard treatment approach for other bladder tumors [13,14]. There are no high-quality data to inform the role of chemotherapy and/or RT as adjuvant treatment.

For patients with advanced non-urothelial bladder cancer who are not candidates for surgery, including those with metastatic disease, treatment options include palliative care, RT, or chemotherapy. Whenever possible, such patients should participate in clinical trials. Given that trials for specific groups of non-urothelial cancers are uncommon, these patients are generally candidates for early phase clinical trials and "basket studies" that permit enrolment of tumors with specific mutations that are considered "actionable" by the drug being offered in the trial. Case reports suggest that non-urothelial cancers can respond to targeted agents detected by molecular profiling techniques, such as next-generation sequencing [15,16]. Where possible, patients whose tumors contain potentially actionable mutations should be accrued to clinical trials that prospectively capture molecular, response, and outcome data [17,18].

Management decisions about therapy should take into account that prospective data are limited for the risks and benefits of treatment. (See "Treatment of metastatic urothelial carcinoma of the bladder and urinary tract" and "Benefits, services, and models of subspecialty palliative care".)

SQUAMOUS CELL CARCINOMA

Epidemiology and risk factors — Squamous cell carcinoma accounts for 3 to 5 percent of bladder cancers in North America and Europe and up to 75 percent of bladder cancers in areas where Schistosoma haematobium infection is endemic. (See 'Schistosomal bladder cancer' below.)

In addition to schistosomal infection, reported risk factors associated with the development of squamous cell carcinoma include chronic or recurrent urinary tract infections (UTIs), bladder calculi, pelvic radiation therapy (RT), antecedent intravesical Bacillus Calmette-Guerin (BCG) treatment, and prolonged exposure to cyclophosphamide, particularly when complicated by hemorrhagic cystitis [1]. Although the risk of squamous cell carcinoma has also been linked to smoking [19,20], one observational study with extended follow-up suggested that patients with pure squamous cell carcinoma are more likely to be female and never smokers compared to those with urothelial carcinoma [21].

Chronic indwelling catheters also have been associated with an increased risk of squamous cell carcinoma in some studies, although the association is controversial. (See "Chronic complications of spinal cord injury and disease" and "Chronic complications of spinal cord injury and disease", section on 'Urinary complications'.)

Two, large, population-based studies in patients with spinal cord injury did not identify an increased risk of bladder cancer, although the design of these studies and the frequency of squamous cell cancer and adenocarcinoma in such patients may have precluded a statistically significant outcome [22,23]. However, the bladder cancers that were identified in patients with neurogenic bladders had increased incidences of muscle invasion, and the investigators favored intermittent catheterization rather than an indwelling catheter [23].

Although periodic screening cystoscopies have been recommended for spinal cord injury patients by some investigators, no studies have demonstrated a benefit from screening, perhaps because of the extremely low incidence of cancer in these patients [24,25]. (See "Complications of urinary bladder catheters and preventive strategies", section on 'General complications'.)

Treatment — The primary treatment for squamous cell carcinoma is surgical. Preoperative RT is reasonable, particularly when the likelihood of complete resection is in doubt due to suspected locally advanced disease.

Support for the role of surgery comes from observational and retrospective data. As an example, a Surveillance, Epidemiology, and End Results (SEER) database analysis of 1422 patients diagnosed between 1988 and 2003 found that the two-year all-cause mortality following cystectomy ranged from 11 percent in males with stage I disease to 72 percent in males with stage IV disease [26]. After adjusting for age, sex, race, and initial therapy, squamous cell carcinoma histology was associated with poorer outcomes compared with urothelial bladder cancer.

The strong tendency of squamous cell carcinoma of the bladder to recur locally following radical cystectomy provides a rationale for either preoperative or postoperative RT with or without concomitant radiosensitizing chemotherapy. Unfortunately, the quality of the available data is limited due to the small number of patients included, biases in patient selection, and the heterogeneity of treatments administered.

Preoperative RT is preferred over postoperative treatment in such cases, due to the risk of bowel toxicity and because it is harder to determine an appropriate RT treatment field after the bladder has been removed. However, a number of retrospective case series have suggested possible benefit for adjuvant or neoadjuvant RT [27-30]. There has been only one prospective trial, which was conducted in the context of schistosomiasis infection, and the results may not be applicable to non-schistosomal squamous cell carcinoma. (See 'Schistosomal bladder cancer' below.)

Postoperative RT is a reasonable alternative for patients with persistent locally advanced squamous cell bladder cancer after radical cystectomy who are ineligible for or decline adjuvant chemotherapy. Evolving data also support its use in those with positive surgical margins [31]. In preliminary results from a randomized phase III trial of 123 patients with locally advanced bladder cancer after radical cystectomy (51 percent with urothelial carcinoma and 49 percent with squamous cell or other carcinoma), compared with adjuvant chemotherapy, postoperative RT improved local control (two-year locoregional-free survival of 92 versus 69 percent, hazard ratio 0.28, 95% CI 0.10-0.82) [32]. Disease-free survival, distant metastasis-free survival, and overall survival were similar between the two treatment arms. A subgroup analysis of the patients with urothelial carcinoma demonstrated similar results [33].

For patients with locally advanced, unresectable squamous cell carcinoma of the bladder, radiation with concomitant radiosensitizing chemotherapy (as done for squamous cell carcinoma of the head and neck, anus, and uterine cervix) represents a reasonable approach, especially since these tumors tend to be locally aggressive. However, there are little prospective data to guide management.

Data from the phase III BC2001 trial show efficacy for fluorouracil and mitomycin given concurrently with RT compared with RT alone in patients with high-grade muscle invasive bladder cancer, with improved local and locoregional control and a trend toward better survival [34]. In this trial, only 2.7 percent of patients had adenocarcinoma or squamous cell carcinoma, with no difference found in outcomes compared with urothelial cancer. A very similar regimen is effective and well tolerated in patients with squamous cell cancer of the anus, so extrapolation to the setting of squamous cell cancer of the bladder may be reasonable, especially in patients who are poor candidates for platinum-containing chemotherapy [35,36].

Limited data suggest that squamous cell carcinoma tends to be locally advanced or worse at diagnosis and is relatively resistant to the chemotherapy regimens used for metastatic urothelial carcinoma [21,37-39]. In light of these findings, we prefer that these patients participate in a prospective clinical trial. Encouraging results with T cell checkpoint inhibitor immunotherapy using atezolizumab or pembrolizumab for advanced urothelial cancer previously treated with a platinum-based regimen [40,41] and results with immunotherapy in patients with squamous cell carcinoma of the lung and head and neck cancer provide a rationale for enrolling patients with squamous cell carcinoma of the bladder in clinical trials, so we continue to seek such trials for these patients.

In the absence of a clinical trial, regimens used to treat metastatic urothelial cancer can be tried. We prefer the combination of carboplatin, gemcitabine, and paclitaxel based on phase II trial data where six patients with squamous cell carcinoma of the bladder were treated with good outcomes, similar to the urothelial cancer patients in the same trial [42]. The experience in this trial has been reproducible in our clinical practice for advanced squamous cell carcinoma of the bladder. (See "Treatment of metastatic urothelial carcinoma of the bladder and urinary tract".)

ADENOCARCINOMA — In North America and Europe, primary adenocarcinoma comprises less than 2 percent of all bladder cancer cases. Glandular, colloid, papillary, signet-ring, and clear-cell types have all been described. The signet-ring variant appears to be associated with a poorer prognosis than other forms of adenocarcinoma [43,44]. (See "Pathology of bladder neoplasms" and "Pathology of bladder neoplasms", section on 'Adenocarcinoma'.)

Unlike squamous cell carcinomas, adenocarcinomas of the bladder frequently metastasize. However, they more commonly relapse locally rather than distantly in contradistinction to urothelial carcinomas. In one study, postoperative radiation therapy (RT) was associated with longer relapse-free survival and a much lower local relapse rate, but the distant relapse rate increased [45]. (See "Pathology of bladder neoplasms", section on 'Adenocarcinoma'.)

Two categories of adenocarcinoma have been described: urachal and non-urachal carcinoma; each has a distinct natural history that can help guide treatment [46].

Urachal adenocarcinoma — The urachus is a fibrous solid cord formed early in embryonic life that connects the urinary bladder to the umbilicus [47]. Urachal adenocarcinoma arises in the urachal remnant and is characterized by its location at the dome of the bladder, usually extending into the prevesical space. A diagnosis of urachal adenocarcinoma is supported by the presence of a patent urachus, an absence of metaplasia (cystitis glandularis), and either no involvement or only secondary involvement of the urothelium [48].

Urachal adenocarcinomas are mucin producing in 90 percent of cases. Although mucusuria is not present in all patients with mucin-producing tumors, its presence is suggestive of urachal adenocarcinoma [49-51]. (See "Pathology of bladder neoplasms", section on 'Urachal adenocarcinoma'.)

Risk factors for the development of urachal adenocarcinoma are poorly defined, and it is unclear whether bladder carcinogens play a role. Urachal adenocarcinoma usually presents with locally advanced disease. Hematuria is common, and patients with urachal adenocarcinoma frequently present with a palpable lower abdominal mass, in contrast to those with other bladder cancers.

A retrospective review identified 420 patients with malignant urachal neoplasms in the Surveillance, Epidemiology, and End Results (SEER) database [52]. Urachal carcinoma was more common in males (59 percent). The five-year overall survival and cancer-specific survival rates were 51 and 57 percent, respectively, with grade and stage at diagnosis being predictive of survival.

Non-urachal adenocarcinoma — Factors associated with an increased risk of non-urachal adenocarcinoma include bladder exstrophy [53] and schistosomiasis. (See 'Schistosomal bladder cancer' below.)

At cystoscopy, non-urachal adenocarcinomas are often papillary or flat-infiltrating lesions with overlying edema. Muscle invasion is almost always present, and diffuse or circumferential bladder wall thickening is usually seen [54]. An alternative diagnosis that needs to be excluded is secondary adenocarcinoma extending to the bladder from the cervix, endometrium, prostate or rectum, or metastatic from a distant primary site.

The survival of patients with non-urachal adenocarcinoma is generally poor, with a five-year overall survival of 35 percent in a series of 1374 patients with non-urachal adenocarcinoma from the SEER database [55]. This poor prognosis is probably due to advanced locoregional disease at diagnosis, with 60 to 65 percent of patients having T3 or T4 disease and one-third having lymph node metastases (table 1).

Treatment — Surgery is the primary treatment for adenocarcinomas. There are no randomized trials of neoadjuvant or adjuvant chemotherapy.

For patients with urachal adenocarcinoma, a partial cystectomy can be an alternative to radical cystoprostatectomy, provided the tumor can be resected with adequate margins. Resection should include an en bloc resection of the bladder dome, urachal ligament, and umbilicus. This should be performed using a closed (ie, laparoscopic or robot-assisted) technique, as these tumors are highly implantable. (See "Radical cystectomy", section on 'Surgical approaches'.)

A retrospective analysis of 66 cases seen at the Mayo Clinic between 1951 and 2004 evaluated the efficacy of treatment [56]. Treatment consisted of partial cystectomy in 70 percent, complete cystectomy in 21 percent, and RT in 9 percent. The overall five-year survival rate was 49 percent. On multivariate analysis, the factors significantly associated with better survival were a low tumor grade and negative surgical margins. Higher pathologic stage and surgical margin involvement are associated with a poor prognosis, emphasizing the need for surgical acumen directed at achieving negative margins where possible [57-59].

For patients with non-urachal adenocarcinoma, partial cystectomy has yielded poor results and is not recommended [60-62]. Attempts to preserve the bladder with conservative treatment of nonsuperficial lesions have been associated with a poor outcome [63].

For patients with locally advanced or metastatic adenocarcinomas, the role for chemotherapy or RT is not clear. One prospective study of ifosfamide, paclitaxel, and cisplatin in males with advanced non-urothelial bladder cancer (11 of 20 with adenocarcinoma, including six with urachal adenocarcinoma) reported a response rate of 36 percent and a median survival of 25 months [38]. A retrospective series of 21 patients, including 14 with adenocarcinoma, had a response rate of 36 percent to first-line cisplatin-containing regimens [64]. A retrospective Turkish series of 35 patients with non-schistosomal adenocarcinoma treated with platinum combination chemotherapy either in the adjuvant or recurrent setting reported a promising median overall survival of 30.3 months [65].

We had previously used cisplatin and fluorouracil as a standard in adenocarcinoma of the bladder for many years. More recently, we have utilized triplet regimens combining cisplatin or carboplatin, gemcitabine, and a taxane or fluorouracil [38,66,67]. We find these combinations tolerable and, in a purely historical and anecdotal sense, more efficacious than cisplatin and fluorouracil. In patients who are not cisplatin eligible, we tend to use fluorouracil, leucovorin, and oxaliplatin (FOLFOX), using a similar dose and schedule as is used for colorectal cancer [68,69]. While significant disease shrinkage and clinical improvement are common, major durable responses are rare, and all patients relapse and eventually die, usually from their cancer. Clinical trials of immunotherapy and targeted agents are good options for eligible patients. A study of pathogenetic and targetable genetic alterations in 70 urachal cancers found programmed cell death ligand 1 (PD-L1) expression in 16 percent and aberrations in intracellular signal transduction pathways (RAS/RAF/PI3K) in 31 percent, with potential implications for anti-EGFR therapy of tumors [70].

SCHISTOSOMAL BLADDER CANCER

Epidemiology — Schistosomiasis (also called bilharziasis) is associated with all types of bladder cancer. As an example, in an Egyptian series of 2720 patients, squamous cell carcinoma, urothelial carcinoma, adenocarcinoma, and mixed or undifferentiated tumors constituted 49, 36, 10, and 5 percent of cases, respectively [71].

Schistosomiasis affects roughly 200 million people worldwide. Infection with Schistosoma haematobium is most prevalent in East Africa and the Middle East, where it is responsible for the high incidence of bladder cancer [72,73]. In these regions, bladder cancer is the most common cancer in males and is second to breast cancer in females [74]. (See "Schistosomiasis: Epidemiology and clinical manifestations".)

In Egypt, where public health measures have led to a dramatic decrease in the prevalence of schistosomiasis, there has been a subsequent decrease in the incidence of schistosomal bladder cancer [75,76]. Thus, the epidemiology of bladder cancer in Egypt has become more similar to that of bladder cancer in Western Europe and the United States, with an older age of onset and a predominance of urothelial carcinoma. The median age at diagnosis of schistosomal bladder cancer is in the forties [77]. Bladder cancer is approximately five times more common in males than females, probably due to agricultural workers' exposure to the pathogen while working in fields.

Clinical presentation — Radiographic evaluation frequently reveals calcification of the bladder and distal ureters. Tumors are usually low to moderate grade. At diagnosis, lymph node metastases are present in approximately 20 percent and distant metastases in 3 percent, possibly due to mural fibrosis causing delayed spread of the tumor [13].

Localized or locally advanced disease — The standard management of patients with non-metastatic schistosomal bladder cancer is radical cystectomy with lymph node dissection. The role of neoadjuvant chemotherapy or radiation therapy (RT) is not clear.

Cystectomy — The outcomes following surgery are illustrated by a series of 2720 consecutive cases of invasive bladder cancer treated with radical cystectomy between 1970 and 2000 [71]. Schistosomal eggs were identified in 82 percent of the cases. At a mean follow-up of 5.5 years, the 5- and 10-year disease-free survival rates with schistosomal bladder cancer were 56 and 50 percent, respectively. In a multivariate analysis, factors associated with improved disease-free survival for patients with schistosomal bladder cancer included a lower tumor stage, well-differentiated tumor, and negative regional lymph nodes.

Radiation therapy — There are limited but consistent data on the role of perioperative RT in patients with schistosomal bladder cancer.

Neoadjuvant RT was studied in a randomized trial in 92 patients using a total RT dose of 20 Gy [13]. Although no statistically significant overall survival benefit was observed, there was a suggestion of benefit in some patient subsets. There are no data from larger neoadjuvant trials.

Postoperative RT was evaluated in a trial in which 236 patients were evaluated [78]. Patients treated with 50 Gy over 5 weeks had significantly improved five-year disease-free survival and five-year local control compared with those not receiving RT (44 versus 25 and 93 versus 50 percent, respectively).

Chemotherapy — The role of neoadjuvant chemotherapy is unclear. Small studies have shown contradictory results:

In one trial, 71 patients with T2 or T3 disease (table 1) were randomly assigned to radical cystectomy alone or to treatment with two cycles of epirubicin before planned radical cystectomy followed by four additional cycles of chemotherapy [79]. Two-year disease-free survival was significantly higher with chemotherapy (74 versus 38 percent with radical cystectomy alone).

In another trial, 114 patients (60 percent with squamous cell carcinoma) were randomly assigned to immediate cystectomy or to gemcitabine plus cisplatin prior to cystectomy [80]. Although 55 percent of patients responded to neoadjuvant chemotherapy, there was no difference in survival.

Chemoradiotherapy — One trial evaluated chemoradiation in 120 patients with pathologic stage IIIB or IVA disease or lymph node involvement who had undergone radical cystectomy, where 53 percent (64 of 120) had urothelial carcinoma and 47 percent (56 of 120) had squamous cell carcinoma [81]. Patients were randomly assigned to treatment using RT with or without four cycles of gemcitabine and cisplatin. Two-year outcomes and overall adjusted hazard ratios (HRs) for chemotherapy plus RT versus chemotherapy alone were 96 versus 69 percent (HR 0.08; 95% CI 0.02-0.39) for local relapse-free survival, 68 versus 56 percent (HR 0.53; 95% CI 0.27-1.06) for disease-free survival, and 71 versus 60 percent (HR 0.61; 95% CI 0.33-1.11) for overall survival. The morbidity of the addition of chemotherapy to RT was low, thus chemotherapy plus RT should be considered in patients with locally advanced schistosomal bladder cancer.

Advanced or metastatic disease — Patients with unresectable or metastatic disease should be referred for palliative care, given the unclear benefits of medical therapy. However, patients with a good performance status who are candidates for chemotherapy may be offered a trial of systemic chemotherapy. Patients should understand that there is a lack of high-quality data to inform the benefits of treatment in the face of significant toxicity risks. Therefore, patients who desire treatment should be referred for participation in a clinical trial whenever possible.

For those who desire a trial of chemotherapy, we prefer to administer gemcitabine plus cisplatin, although the data to support this combination are limited. In one study of 37 patients, this combination resulted in a 55 percent response rate, although it was also associated with moderate toxicity [82]. These response rates are similar to those seen in urothelial bladder cancers. (See "Treatment of metastatic urothelial carcinoma of the bladder and urinary tract", section on 'Initial therapy'.)

SARCOMATOID CARCINOMA — Sarcomatoid carcinoma of urothelial origin is a rare biphasic malignant neoplasm that demonstrates both epithelial and mesenchymal differentiation on histopathology [83]. Further details on sarcomatoid carcinoma are discussed separately. (See "Pathology of bladder neoplasms", section on 'Sarcomatoid subtype'.)

NON-EPITHELIAL BLADDER TUMORS — Non-epithelial tumors involving the bladder are very rare. A summary is provided below.

Bladder sarcoma – Bladder sarcoma is a malignant mesenchymal tumor [84]. The diagnosis is most frequently made between the ages of 50 and 60, with a slight male predominance. One-half of bladder sarcomas are leiomyosarcomas, and approximately 20 percent are rhabdomyosarcomas. Risk factors include a history of local irradiation, prior cyclophosphamide treatment, and schistosomiasis.

The prognosis depends upon the patient's age and the extent, rather than the type, of tumor. Five-year overall survival ranged from 60 to 80 percent in small series [85-87]. The management of these patients is similar to the approach to patients with soft tissue sarcoma. (See "Overview of the initial treatment of metastatic soft tissue sarcoma" and "Clinical presentation and diagnosis of retroperitoneal soft tissue sarcoma".)

Paraganglioma – Paraganglioma account for less than 0.05 percent of non-urothelial bladder cancers and 10 percent of extra-adrenal pheochromocytomas; approximately 15 percent are malignant. Bladder paragangliomas demonstrate a slight female predominance [88]. Paragangliomas are thought to arise from embryonic nests of chromaffin cells in the sympathetic plexus of the detrusor muscle. Release of catecholamines can be triggered by voiding, bladder distention, defecation, or sexual intercourse. Typical symptoms include diaphoresis, paroxysmal hypertension, palpitations, headaches, and syncope [88]. If a bladder paraganglioma is suspected, cystoscopy should be accompanied by adrenergic blockade. Biopsy should be avoided since these tumors are vascular and are often covered by intact urothelium [1]. (See "Paragangliomas: Epidemiology, clinical presentation, diagnosis, and histology" and "Paragangliomas: Treatment of locoregional disease".)

Melanoma – Most melanomas identified in the bladder are metastatic from another site. A review of the literature identified only 11 cases of primary bladder melanoma, most frequently arising in the bladder or female urethra [89]. The postulated cells of origin are neural crest cells. The prognosis is guarded [1].

Primary lymphoma – Primary lymphoma of the bladder is rare, with fewer than 100 cases reported [90,91]. It is more common in females (3:1 ratio females to males) [92]. Around 80 percent are mucosa-associated lymphoid tissue (MALT; marginal zone) lymphomas. MALT tumors are thought to result from chronic inflammation; in one series, two-thirds of patients had chronic cystitis [90]. The disease is usually localized at diagnosis and most often adequately treated with transurethral resection, antibiotic therapy directed at Helicobacter pylori, and cystoscopic surveillance. The remaining 20 percent of cases are most often diffuse large B cell lymphomas (DLBCL) or other more-aggressive non-Hodgkin lymphoma variants, where standard treatment consists of chemotherapy or radiation as used for lymphomas occurring at other sites. The prognosis is excellent, with attributed mortality from cases of primary bladder lymphoma being less than 5 percent [93]. (See "Clinical manifestations, pathologic features, and diagnosis of extranodal marginal zone lymphoma of mucosa associated lymphoid tissue (MALT)" and "Splenic marginal zone lymphoma" and "Treatment of extranodal marginal zone lymphoma of mucosa associated lymphoid tissue (MALT lymphoma)" and "Initial treatment of advanced stage diffuse large B cell lymphoma" and "Initial treatment of limited stage diffuse large B cell lymphoma".)

Lymphoepithelioma-like carcinoma – Lymphoepithelioma-like carcinoma of the urinary bladder is a rare epithelial tumor characterized by a lymphoid infiltrate suggestive of lymphoma. Fewer than 50 cases have been reported in the literature. It is usually muscle invasive at the time of diagnosis but appears to have a better prognosis than other primary bladder cancers. The small number of patients identified precludes definitive treatment recommendations, but long-term survival has been reported after transurethral resection, partial cystectomy, or radical cystectomy, with or without adjuvant chemotherapy or RT [94,95].

Other variant histologies – Other variant histologies, including plasmacytoid and micropapillary variants, are discussed separately. (See "Pathology of bladder neoplasms", section on 'Micropapillary subtype' and "Pathology of bladder neoplasms", section on 'Plasmacytoid subtype'.)

Metastatic disease – The most common cancers to metastasize to the bladder are melanoma and lymphoma. Other common primary sites include the stomach, breast, kidney, lung, and pancreas. The management of these patients depends on the primary tumor.

In addition, direct extension of cancer into the bladder can occur from the colon, rectum, prostate, or uterus.

PROGNOSIS — Whether the prognosis is worse for non-urothelial bladder tumors is unclear, particularly after controlling for stage and grade. One multi-institutional study of 1131 consecutive patients (including 1042 with urothelial carcinomas and 89 with non-urothelial bladder cancers) reported no difference in five-year survival following radical cystectomy after controlling for sex, stage, and grade [96].

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Bladder cancer".)

SUMMARY AND RECOMMENDATIONS

Bladder cancers are categorized as urothelial and non-urothelial types. Non-urothelial bladder cancers are further classified as epithelial or non-epithelial. Approximately 90 percent of these cancers are epithelial in origin, including squamous cell carcinomas, adenocarcinomas, and small cell (neuroendocrine) tumors. Non-epithelial cancers are rare and include sarcomas, carcinosarcoma, paraganglioma, melanomas, and lymphomas. (See 'Introduction' above.)

The pathogenesis of non-urothelial bladder cancers is incompletely understood. Both the development of metaplasia and the presence of chronic infection and inflammation are believed to be important factors in tumorigenesis. (See 'Pathogenesis and risk factors' above.)

Like urothelial carcinomas, non-urothelial bladder cancers commonly present with hematuria and bladder irritation. Mucusuria has been described with bladder adenocarcinomas and is more common with urachal types than non-urachal adenocarcinoma. The presence of an abdominal mass may also point to the diagnosis of urachal adenocarcinoma. (See 'Clinical presentation' above.)

Infection with Schistosoma haematobium is associated with squamous cell carcinoma, urothelial carcinoma, and adenocarcinoma of the bladder. In areas where such infections are endemic, non-urothelial bladder cancers comprise up to 80 percent of bladder cancer cases. (See 'Schistosomal bladder cancer' above.)

For most patients with non-metastatic, non-urothelial bladder carcinoma, we recommend surgery (Grade 1B). There is no defined role for adjuvant treatment in most of these patients, but certain patients may benefit from neoadjuvant or adjuvant radiation therapy, and patients with schistosomal bladder cancer have benefit from adjuvant chemoradiation. (See 'Overview of treatment approach' above.)

For patients with advanced bladder cancer who are not candidates for surgery, we suggest palliative care (Grade 2C). However, a trial of chemotherapy is reasonable for patients with a good performance status who are otherwise candidates for chemotherapy. Decisions on treatment should take into account the lack of prospective data to inform the benefits of treatment in light of the risks associated with therapy. (See 'Overview of treatment approach' above.)

For patients with non-epithelial, non-urothelial bladder cancer, we use the therapies that are most appropriate for these tumor types when they occur in other locations in the absence of any better evidence. However, it is important to ensure that metastatic disease is ruled out. (See 'Non-epithelial bladder tumors' above.)

ACKNOWLEDGMENTS — The UpToDate editorial staff acknowledges Julia Hayes, MD, Timothy Gilligan, MD, and David I Quinn, MBBS (Hons I), PhD, FRACP, FACP, who contributed to earlier versions of this topic review.

  1. Dahm P, Gschwend JE. Malignant non-urothelial neoplasms of the urinary bladder: a review. Eur Urol 2003; 44:672.
  2. Kunze E. Histogenesis of nonurothelial carcinomas in the human and rat urinary bladder. Exp Toxicol Pathol 1998; 50:341.
  3. Ozbey I, Aksoy Y, Polat O, et al. Squamous metaplasia of the bladder: findings in 14 patients and review of the literature. Int Urol Nephrol 1999; 31:457.
  4. Khan MS, Thornhill JA, Gaffney E, et al. Keratinising squamous metaplasia of the bladder: natural history and rationalization of management based on review of 54 years experience. Eur Urol 2002; 42:469.
  5. El-Merzabani MM, El-Aaser AA, Zakhary NI. A study on the aetiological factors of bilharzial bladder cancer in Egypt--1. Nitrosamines and their precursors in urine. Eur J Cancer 1979; 15:287.
  6. Radomski JL, Greenwald D, Hearn WL, et al. Nitrosamine formation in bladder infections and its role in the etiology of bladder cancer. J Urol 1978; 120:48.
  7. Bartsch H, Montesano R. Relevance of nitrosamines to human cancer. Carcinogenesis 1984; 5:1381.
  8. Wogan GN, Hecht SS, Felton JS, et al. Environmental and chemical carcinogenesis. Semin Cancer Biol 2004; 14:473.
  9. Oliveira PA, Colaco A, De la Cruz P LF, Lopes C. Experimental bladder carcinogenesis-rodent models. Exp Oncol 2006; 28:2.
  10. El-Mosalamy H, Salman TM, Ashmawey AM, Osama N. Role of chronic E. coli infection in the process of bladder cancer- an experimental study. Infect Agent Cancer 2012; 7:19.
  11. Deuker M, Martin T, Stolzenbach F, et al. Bladder Cancer: A Comparison Between Non-urothelial Variant Histology and Urothelial Carcinoma Across All Stages and Treatment Modalities. Clin Genitourin Cancer 2021; 19:60.
  12. Cohen AJ, Packiam V, Nottingham C, et al. Upstaging of nonurothelial histology in bladder cancer at the time of surgical treatment in the National Cancer Data Base. Urol Oncol 2017; 35:34.e1.
  13. Ghoneim MA, Ashamallah AK, Awaad HK, Whitmore WF Jr. Randomized trial of cystectomy with or without preoperative radiotherapy for carcinoma of the bilharzial bladder. J Urol 1985; 134:266.
  14. Awwad H, El-Baki HA, El-Bolkainy N, et al. Pre-operative irradiation of T3-carcinoma in bilharzial bladder: a comparison between hyperfractionation and conventional fractionation. Int J Radiat Oncol Biol Phys 1979; 5:787.
  15. Collazo-Lorduy A, Castillo-Martin M, Wang L, et al. Urachal Carcinoma Shares Genomic Alterations with Colorectal Carcinoma and May Respond to Epidermal Growth Factor Inhibition. Eur Urol 2016; 70:771.
  16. Loh KP, Mondo E, Hansen EA, et al. Targeted Therapy Based on Tumor Genomic Analyses in Metastatic Urachal Carcinoma. Clin Genitourin Cancer 2016; 14:e449.
  17. Abrams J, Conley B, Mooney M, et al. National Cancer Institute's Precision Medicine Initiatives for the new National Clinical Trials Network. Am Soc Clin Oncol Educ Book 2014; :71.
  18. Redig AJ, Jänne PA. Basket trials and the evolution of clinical trial design in an era of genomic medicine. J Clin Oncol 2015; 33:975.
  19. Kantor AF, Hartge P, Hoover RN, Fraumeni JF Jr. Epidemiological characteristics of squamous cell carcinoma and adenocarcinoma of the bladder. Cancer Res 1988; 48:3853.
  20. Fortuny J, Kogevinas M, Chang-Claude J, et al. Tobacco, occupation and non-transitional-cell carcinoma of the bladder: an international case-control study. Int J Cancer 1999; 80:44.
  21. Gordetsky JB, Montgomery KW, Giannico GA, et al. The Significance of Squamous Histology on Clinical Outcomes and PD-L1 Expression in Bladder Cancer. Int J Surg Pathol 2022; 30:6.
  22. Subramonian K, Cartwright RA, Harnden P, Harrison SC. Bladder cancer in patients with spinal cord injuries. BJU Int 2004; 93:739.
  23. Pannek J. Transitional cell carcinoma in patients with spinal cord injury: a high risk malignancy? Urology 2002; 59:240.
  24. Hamid R, Bycroft J, Arya M, Shah PJ. Screening cystoscopy and biopsy in patients with neuropathic bladder and chronic suprapubic indwelling catheters: is it valid? J Urol 2003; 170:425.
  25. Yang CC, Clowers DE. Screening cystoscopy in chronically catheterized spinal cord injury patients. Spinal Cord 1999; 37:204.
  26. Scosyrev E, Yao J, Messing E. Urothelial carcinoma versus squamous cell carcinoma of bladder: is survival different with stage adjustment? Urology 2009; 73:822.
  27. Rundle JS, Hart AJ, McGeorge A, et al. Squamous cell carcinoma of bladder. A review of 114 patients. Br J Urol 1982; 54:522.
  28. Swanson DA, Liles A, Zagars GK. Preoperative irradiation and radical cystectomy for stages T2 and T3 squamous cell carcinoma of the bladder. J Urol 1990; 143:37.
  29. Richie JP, Waisman J, Skinner DG, Dretler SP. Squamous carcinoma of the bladder: treatment by radical cystectomy. J Urol 1976; 115:670.
  30. Tannenbaum SI, Carson CC 3rd, Tatum A, Paulson DF. Squamous carcinoma of urinary bladder. Urology 1983; 22:597.
  31. Baumann BC, Zaghloul MS, Sargos P, Murthy V. Adjuvant and Neoadjuvant Radiation Therapy for Locally Advanced Bladder Cancer. Clin Oncol (R Coll Radiol) 2021; 33:391.
  32. Zaghloul MS, Christodouleas JP, Zaghloul T, et al. Randomized trial of adjuvant chemotherapy versus adjuvant radiation therapy for locally advanced bladder cancer after radical cystectomy. J Clin Oncol 2019; 37:4507.
  33. Zaghloul MS, Christodoluleas JP, Zaghloul T, et al. Prospective trial of adjuvant chemotherapy versus adjuvant radiation therapy for locally advanced bladder cancer after radical cystectomy. J Clin Oncol 2020; 38;6S:515.
  34. James ND, Hussain SA, Hall E, et al. Radiotherapy with or without chemotherapy in muscle-invasive bladder cancer. N Engl J Med 2012; 366:1477.
  35. Flam M, John M, Pajak TF, et al. Role of mitomycin in combination with fluorouracil and radiotherapy, and of salvage chemoradiation in the definitive nonsurgical treatment of epidermoid carcinoma of the anal canal: results of a phase III randomized intergroup study. J Clin Oncol 1996; 14:2527.
  36. Ryan DP, Compton CC, Mayer RJ. Carcinoma of the anal canal. N Engl J Med 2000; 342:792.
  37. Serretta V, Pomara G, Piazza F, Gange E. Pure squamous cell carcinoma of the bladder in western countries. Report on 19 consecutive cases. Eur Urol 2000; 37:85.
  38. Galsky MD, Iasonos A, Mironov S, et al. Prospective trial of ifosfamide, paclitaxel, and cisplatin in patients with advanced non-transitional cell carcinoma of the urothelial tract. Urology 2007; 69:255.
  39. Zahoor H, Elson P, Stephenson A, et al. Patient Characteristics, Treatment Patterns and Prognostic Factors in Squamous Cell Bladder Cancer. Clin Genitourin Cancer 2018; 16:e437.
  40. Rosenberg JE, Hoffman-Censits J, Powles T, et al. Atezolizumab in patients with locally advanced and metastatic urothelial carcinoma who have progressed following treatment with platinum-based chemotherapy: a single-arm, multicentre, phase 2 trial. Lancet 2016; 387:1909.
  41. Bellmunt J, de Wit R, Vaughn DJ, et al. Pembrolizumab as Second-Line Therapy for Advanced Urothelial Carcinoma. N Engl J Med 2017; 376:1015.
  42. Hussain M, Vaishampayan U, Du W, et al. Combination paclitaxel, carboplatin, and gemcitabine is an active treatment for advanced urothelial cancer. J Clin Oncol 2001; 19:2527.
  43. Grignon DJ, Ro JY, Ayala AG, et al. Primary adenocarcinoma of the urinary bladder. A clinicopathologic analysis of 72 cases. Cancer 1991; 67:2165.
  44. Fiter L, Gimeno F, Martin L, Gómez Tejeda L. Signet-ring cell adenocarcinoma of bladder. Urology 1993; 41:30.
  45. Zaghloul MS, Nouh A, Nazmy M, et al. Long-term results of primary adenocarcinoma of the urinary bladder: a report on 192 patients. Urol Oncol 2006; 24:13.
  46. Wilson TG, Pritchett TR, Lieskovsky G, et al. Primary adenocarcinoma of bladder. Urology 1991; 38:223.
  47. Binnie JF. Development of the Urachus. JAMA 1906; 47:109.
  48. Manunta A, Vincendeau S, Kiriakou G, et al. Non-transitional cell bladder carcinomas. BJU Int 2005; 95:497.
  49. Johnson DE, Hodge GB, Abdul-Karim FW, Ayala AG. Urachal carcinoma. Urology 1985; 26:218.
  50. Kakizoe T, Matsumoto K, Andoh M, et al. Adenocarcinoma of urachus. Report of 7 cases and review of literature. Urology 1983; 21:360.
  51. Sheldon CA, Clayman RV, Gonzalez R, et al. Malignant urachal lesions. J Urol 1984; 131:1.
  52. Mylonas KS, O Malley P, Ziogas IA, et al. Malignant urachal neoplasms: A population-based study and systematic review of literature. Urol Oncol 2017; 35:33.e11.
  53. CULP DA. THE HISTOLOGY OF THE EXSTROPHIED BLADDER. J Urol 1964; 91:538.
  54. Hughes MJ, Fisher C, Sohaib SA. Imaging features of primary nonurachal adenocarcinoma of the bladder. AJR Am J Roentgenol 2004; 183:1397.
  55. Wright JL, Porter MP, Li CI, et al. Differences in survival among patients with urachal and nonurachal adenocarcinomas of the bladder. Cancer 2006; 107:721.
  56. Ashley RA, Inman BA, Sebo TJ, et al. Urachal carcinoma: clinicopathologic features and long-term outcomes of an aggressive malignancy. Cancer 2006; 107:712.
  57. Dhillon J, Liang Y, Kamat AM, et al. Urachal carcinoma: a pathologic and clinical study of 46 cases. Hum Pathol 2015; 46:1808.
  58. Niedworok C, Panitz M, Szarvas T, et al. Urachal Carcinoma of the Bladder: Impact of Clinical and Immunohistochemical Parameters on Prognosis. J Urol 2016; 195:1690.
  59. Szarvas T, Módos O, Niedworok C, et al. Clinical, prognostic, and therapeutic aspects of urachal carcinoma-A comprehensive review with meta-analysis of 1,010 cases. Urol Oncol 2016; 34:388.
  60. Xiaoxu L, Jianhong L, Jinfeng W, Klotz LH. Bladder adenocarcinoma: 31 reported cases. Can J Urol 2001; 8:1380.
  61. Thomas DG, Ward AM, Williams JL. A study of 52 cases of adenocarcinoma of the bladder. Br J Urol 1971; 43:4.
  62. Abenoza P, Manivel C, Fraley EE. Primary adenocarcinoma of urinary bladder. Clinicopathologic study of 16 cases. Urology 1987; 29:9.
  63. Anderström C, Johansson SL, von Schultz L. Primary adenocarcinoma of the urinary bladder. A clinicopathologic and prognostic study. Cancer 1983; 52:1273.
  64. Hong JY, Choi MK, Uhm JE, et al. Palliative chemotherapy for non-transitional cell carcinomas of the urothelial tract. Med Oncol 2009; 26:186.
  65. Erdem GU, Dogan M, Sakin A, et al. Non-Urothelial Bladder Cancer: Comparison of Clinicopathological and Prognostic Characteristics in Pure Adenocarcinoma and Non-Bilharzial Squamous Cell Carcinoma of the Bladder. Oncol Res Treat 2018; 41:220.
  66. Smith DC, Mackler NJ, Dunn RL, et al. Phase II trial of paclitaxel, carboplatin and gemcitabine in patients with locally advanced carcinoma of the bladder. J Urol 2008; 180:2384.
  67. Pagliaro LC, Williams DL, Daliani D, et al. Neoadjuvant paclitaxel, ifosfamide, and cisplatin chemotherapy for metastatic penile cancer: a phase II study. J Clin Oncol 2010; 28:3851.
  68. Goldberg RM, Sargent DJ, Morton RF, et al. A randomized controlled trial of fluorouracil plus leucovorin, irinotecan, and oxaliplatin combinations in patients with previously untreated metastatic colorectal cancer. J Clin Oncol 2004; 22:23.
  69. Yanagihara Y, Tanji N, Miura N, et al. Modified FOLFOX6 chemotherapy in patients with metastatic urachal cancer. Chemotherapy 2013; 59:402.
  70. Reis H, van der Vos KE, Niedworok C, et al. Pathogenic and targetable genetic alterations in 70 urachal adenocarcinomas. Int J Cancer 2018; 143:1764.
  71. Ghoneim MA, Abdel-Latif M, el-Mekresh M, et al. Radical cystectomy for carcinoma of the bladder: 2,720 consecutive cases 5 years later. J Urol 2008; 180:121.
  72. Mostafa MH, Sheweita SA, O'Connor PJ. Relationship between schistosomiasis and bladder cancer. Clin Microbiol Rev 1999; 12:97.
  73. el-Mawla NG, el-Bolkainy MN, Khaled HM. Bladder cancer in Africa: update. Semin Oncol 2001; 28:174.
  74. Hassan N, Mounir M, El-Basmi A, et al. Statistical Report for NCI. National Cancer Institute; Cairo, 2001.
  75. Salem S, Mitchell RE, El-Alim El-Dorey A, et al. Successful control of schistosomiasis and the changing epidemiology of bladder cancer in Egypt. BJU Int 2011; 107:206.
  76. Gouda I, Mokhtar N, Bilal D, et al. Bilharziasis and bladder cancer: a time trend analysis of 9843 patients. J Egypt Natl Canc Inst 2007; 19:158.
  77. Shokeir AA. Squamous cell carcinoma of the bladder: pathology, diagnosis and treatment. BJU Int 2004; 93:216.
  78. Zaghloul MS, Awwad HK, Akoush HH, et al. Postoperative radiotherapy of carcinoma in bilharzial bladder: improved disease free survival through improving local control. Int J Radiat Oncol Biol Phys 1992; 23:511.
  79. Gad el Mawla N, Mansour MA, Eissa S, et al. A randomized pilot study of high-dose epirubicin as neoadjuvant chemotherapy in the treatment of cancer of the bilharzial bladder. Ann Oncol 1991; 2:137.
  80. Khaled HM, Shafik HE, Zabhloul MS, et al. Gemcitabine and cisplatin as neoadjuvant chemotherapy for invasive transitional and squamous cell carcinoma of the bladder: effect on survival and bladder preservation. Clin Genitourin Cancer 2014; 12:e233.
  81. Zaghloul MS, Christodouleas JP, Smith A, et al. Adjuvant Sandwich Chemotherapy Plus Radiotherapy vs Adjuvant Chemotherapy Alone for Locally Advanced Bladder Cancer After Radical Cystectomy: A Randomized Phase 2 Trial. JAMA Surg 2018; 153:e174591.
  82. Khaled HM, Hamza MR, Mansour O, et al. A phase II study of gemcitabine plus cisplatin chemotherapy in advanced bilharzial bladder carcinoma. Eur J Cancer 2000; 36 Suppl 2:34.
  83. Diamantopoulos LN, Korentzelos D, Alevizakos M, et al. Sarcomatoid Urothelial Carcinoma: A Population-Based Study of Clinicopathologic Characteristics and Survival Outcomes. Clin Genitourin Cancer 2022; 20:139.
  84. Russo P, Singer S, Maki R. Chapter 52: Adult genitourinary soft tissue sarcoma. In: Comprehensive Textbook of Genitourinary Oncology, 4th ed, Scardino PT, Linehan WM, Zelefsky MJ, Vogelzang NJ (Eds), Lippincott Williams & Wilkins, Baltimore 2011.
  85. Parekh DJ, Jung C, O'Conner J, et al. Leiomyosarcoma in urinary bladder after cyclophosphamide therapy for retinoblastoma and review of bladder sarcomas. Urology 2002; 60:164.
  86. Russo P, Brady MS, Conlon K, et al. Adult urological sarcoma. J Urol 1992; 147:1032.
  87. Spiess PE, Kassouf W, Steinberg JR, et al. Review of the M.D. Anderson experience in the treatment of bladder sarcoma. Urol Oncol 2007; 25:38.
  88. Whalen RK, Althausen AF, Daniels GH. Extra-adrenal pheochromocytoma. J Urol 1992; 147:1.
  89. Tainio HM, Kylmälä TM, Haapasalo HK. Primary malignant melanoma of the urinary bladder associated with widespread metastases. Scand J Urol Nephrol 1999; 33:406.
  90. Kempton CL, Kurtin PJ, Inwards DJ, et al. Malignant lymphoma of the bladder: evidence from 36 cases that low-grade lymphoma of the MALT-type is the most common primary bladder lymphoma. Am J Surg Pathol 1997; 21:1324.
  91. Bates AW, Norton AJ, Baithun SI. Malignant lymphoma of the urinary bladder: a clinicopathological study of 11 cases. J Clin Pathol 2000; 53:458.
  92. Al-Maghrabi J, Kamel-Reid S, Jewett M, et al. Primary low-grade B-cell lymphoma of mucosa-associated lymphoid tissue type arising in the urinary bladder: report of 4 cases with molecular genetic analysis. Arch Pathol Lab Med 2001; 125:332.
  93. Abrahamson JS, Michaelson MD. Malignant lymphoma of the genitourinary tract. In: Comprehensive textbook of genitourinary oncology, 4th ed, Scardino PT, Linehan WM, Zelefsky MJ, Vogelzang NJ (Eds), Lippincott Williams & Wilkins, Baltimore 2011. Chapter 53.
  94. Porcaro AB, Gilioli E, Migliorini F, et al. Primary lymphoepithelioma-like carcinoma of the urinary bladder: report of one case with review and update of the literature after a pooled analysis of 43 patients. Int Urol Nephrol 2003; 35:99.
  95. Mayer EK, Beckley I, Winkler MH. Lymphoepithelioma-like carcinoma of the urinary bladder--diagnostic and clinical implications. Nat Clin Pract Urol 2007; 4:167.
  96. Nishiyama H, Habuchi T, Watanabe J, et al. Clinical outcome of a large-scale multi-institutional retrospective study for locally advanced bladder cancer: a survey including 1131 patients treated during 1990-2000 in Japan. Eur Urol 2004; 45:176.
Topic 2964 Version 36.0

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