Overview of Squamous Cell Bladder Carcinoma
Squamous cell carcinoma of the urinary bladder is a malignant neoplasm derived from bladder urothelium with pure squamous phenotype. [1, 2, 3] Squamous cell carcinoma of the bladder is essentially similar to the tumors arising in other organs. Because many urothelial carcinomas contain a minor squamous cell component, a diagnosis of squamous cell carcinoma of the bladder should be rendered only when the tumor is solely composed of a squamous cell component in the absence of a conventional urothelial carcinoma component.
For more information, see Bladder Cancer.
Epidemiology of Squamous Cell Bladder Carcinoma
In the United States, squamous cell carcinoma constitutes around 5% of all urinary bladder carcinomas. [4, 5] Approximately 90-95% of bladder tumors are urothelial carcinomas. The male-to-female incidence ratio is 1:2; this stands in contrast to urothelial carcinoma, which predominantly affects males. Worldwide, the incidence of squamous cell carcinoma of the bladder varies. In certain parts of the African continent, the majority of bladder carcinomas are of the squamous cell type. The highest incidence has been seen in areas where schistosomiasis is endemic, notably Sudan and Egypt, where squamous cell carcinoma ranges from two thirds to three quarters of all malignant tumors of the bladder.
In recent years, a few studies from Egypt have shown a reversal of this trend due to the better control of schistosomiasis in the region, whereas in other parts of Africa the association is unchanged. [6, 7, 8] An increase in the prevalence of smoking in Egypt is also believed to have contributed to the shift toward urothelial carcinoma, as that tumor type has a stronger association with smoking.
Pathogenesis and Etiology
Keratinous squamous metaplasia has been associated with the increased risk of developing squamous cell carcinoma, with approximately one half of the cases arising subsequent to the metaplasia. [3, 9, 10] The majority of cases arise in the context of chronic cystitis.  Chronic irritation secondary to lithiasis, [1, 2] urinary retention, and indwelling catheters has also been linked to the development of squamous cell carcinoma. 
Having bladder diverticula may increase the likelihood that an individual will develop squamous cell carcinoma.  Bladder exstrophy has been associated with the development of squamous cell carcinoma at a younger age than usual. [13, 14, 15, 16] Squamous cell carcinoma may arise in a urachal remnant. [17, 18, 19, 20, 21]
Smoking has a well-recognized role in the development of bladder carcinoma, with smoking duration and intensity directly related to increased risk. [22, 23, 24] The risk of developing bladder carcinoma is 2-6 times higher in smokers than in nonsmokers. Cyclophosphamide chemotherapy has also been reported to increase the incidence of squamous cell carcinoma of the bladder.  Rarely, bacillus Calmette-Guérin (BCG) treatment for carcinoma in situ has been reported to lead to development of squamous cell carcinoma. 
As previously mentioned, schistosomiasis is the major cause of squamous cell carcinoma of the bladder in African countries. Its pathogenetic role is well studied. In one study from Egypt, 82% of patients with bladder carcinoma were found to harbor Schistosoma haematobium eggs in the bladder wall.  The presence of eggs was associated with the development of cancer at a younger age and with a predominance of squamous cell carcinoma, relative to egg-negative cases. A higher degree of adenocarcinoma has also been reported in schistosomal-associated bladder carcinomas. 
Three pathogenic species responsible for the disease in humans are S haematobium, S mansoni, and S japonicum. The eggs reside in the pelvic and mesenteric venous plexus. In the bladder, the deposition of Schistosoma eggs commonly provokes a severe inflammatory response and fibrosis.
The eggs are found embedded in the lamina propria and muscularis propria of the bladder wall; many of the eggs are destroyed by host reaction and become calcified. This results in a granular, yellow-tan surface lesion commonly known as sandy patch. S haematobium total antigen has been reported to increase proliferation, migration, and invasion of Schistosoma and to decrease apoptosis of normal epithelial cells. 
Most squamous cell carcinomas produce no symptoms until they reach an advanced stage. Patients are typically in their sixth or seventh decades when the disease manifests, although patients with obstructive and irritative symptoms are usually diagnosed earlier.
The most common symptom is gross hematuria.  Bacteriuria occurs in about 50% of patients. Less commonly, patients may experience nocturia, dysuria, frequency, and pain.
Squamous cell carcinoma may occur at multiple areas in the bladder, but the lateral wall and trigone are the most common sites. [30, 31] On cystoscopy, the tumor appears nodular and has a plaquelike, irregular surface. There is deep invasion into the muscularis and often involvement of the extravesical organs (see image below). Most of the tumors are large, exophytic, and necrotic and bulge into the bladder cavity. [1, 5]
Less commonly, these tumors may be flat, with irregular borders.  Surface necrosis and keratin debris are usually present, which give it a flaky whitish appearance.
Microscopically, the tumors arise in epithelium and infiltrate in sheets, nests, and islands (see images below); they resemble epidermal tumors, with some combination of individual cell keratinization, keratin pearls, and intercellular bridges. Transurethral resection of bladder tumor (TURBT) biopsies may contain only keratinous debris. Keratinization of cells at the stromal interface is a sign of invasion.
Cells are polygonal with well-defined cell borders and have amphophilic to eosinophilic cytoplasm. The nuclei are pleomorphic, occasionally bizarre, with irregular chromatin and prominent nucleoli. Mitotic figures are easily identifiable. Abundant degenerated cells are also seen in biopsy material. Squamous metaplasia has been seen in 17-60% of nonendemic cases. (See image below.)
Verrucous squamous cell carcinoma
This is a rare variant of squamous cell carcinoma of the bladder, accounting for less than 5% of cases. [32, 33] Most cases are associated with S haematobium infection; few cases have been reported from nonendemic areas. The tumor has an indolent growth pattern and spreads by direct extension. It does not metastasize, although it may develop foci of invasive squamous cell carcinoma. 
Grossly, the tumor is a warty, exophytic mass that projects into the bladder lumen.
Microscopically, it appears as a prominent papillary mass with acanthosis. The tumor grows in bulbous fronds of well-differentiated, acanthotic epithelium. There is minimal atypia and pushing margin without increased mitoses.
Verrucous squamous cell carcinoma may focally resemble condyloma and has been reported to be associated with human papillomavirus (HPV); however, no firm link to HPV infection has been established. [35, 36] Generally, verrucous carcinoma is considered to pose a low risk for progression, but the degree of risk with bladder tumors is difficult to establish due to the relatively small number of cases.
Basaloid squamous cell carcinoma
Only a single case of basaloid squamous cell carcinoma of the bladder has been reported, in a 60-year-old woman with incontinence, intractable urinary tract infections, and flat, cystoscopic lesions.  Microscopically, the tumor was composed of nests of basaloid cells with numerous mitoses, areas of squamous differentiation, and squamous cell carcinoma in situ. Bostwick and Cheng have proposed that the correct terminology should be urothelial carcinoma with basaloid features rather than basaloid squamous cell carcinoma. 
The diagnosis of squamous cell carcinoma of the bladder is based primarily on the morphology. Immunohistochemical stains do not have a substantial role in diagnosing this tumor. CK20 has been seen in majority of urothelial carcinoma; however, in one study, none of the schistosomal-associated squamous cell carcinoma stained. Expression of cyclooxygenase-2 (COX-2) and uroplakin II has not been observed in any of the squamous cell carcinomas of the bladder, but they have been expressed in the majority of urothelial carcinomas. [39, 40]
Molecular and Genetic Aspects
The molecular data for squamous cell carcinoma of the bladder have emerged mostly from the analysis of schistosomal-associated cases. Overrepresentation of 5p, 6p, 7p, 8q, 11q, 17q, and 20q of chromosomal material has been detected by cytogenetic and classic molecular analysis. In addition, deletions at 3p, 4q, 5q, 8p, 13q, 17p, and 18q have also been reported. [41, 42, 43, 44, 45, 46, 47]
As with urothelial carcinoma, p53 positivity has been observed in schistosomal-associated squamous cell carcinoma in a wide range in different studies. [48, 49, 50, 51, 52] In one study, TP53 mutations in schistosomal-associated squamous cell carcinoma included more base transitions at CpG dinucleotides than seen in urothelial carcinomas. 
Other molecular alterations known to occur in urothelial carcinomas, such as HRAS mutations, [53, 54] epidermal growth factor receptor (EGFR) overexpression, and HER2 expression were also found at comparable frequencies in schistosomal-associated squamous cell carcinoma.  Methylation of DNA, as shown by detection of O6-methyldeoxyguanosine, has been found in a high percentage of patients with schistosomiasis-associated cancers in Egypt. [56, 57]
Few sporadic squamous cell carcinoma cases examined by classic cytogenetics and comparative genomic hybridization (GCH) have shown gains at 1q, 8qa, and 20q, as well as losses of 3p, 9p, and 13q. [42, 58, 59, 60]
Tumor Spread and Staging
Like urothelial carcinoma, squamous cell carcinoma of the bladder is staged using the American Joint Committee on Cancer (AJCC) / tumor, node, metastasis (TNM) system.  The tumor spreads by direct extension to the adjacent organs, as well as by lymphovascular invasion. It has been reported that squamous cell carcinoma has less tendency than urothelial carcinoma for nodal and vascular distant metastases. [7, 62]
Grading of squamous cell carcinoma
The tumor is generally graded as well, and moderately or poorly differentiated, depending upon the extent of keratinization and nuclear pleomorphism. [2, 11, 63, 64] However, the grading system is not universally reproducible, as some authors believe that there is no direct correlation between the aggressiveness and the tumor grade.  Others believe that histologic grade influences the tumor stage and clinical outcome. [2, 63] Nuclear tetraploidy and aneuploidy correlate with the grade and stage of squamous cell carcinoma and adversely affects survival. [64, 65]
Prognosis and Predictive Factors
Sex and age have not proved prognostically significant in squamous cell bladder cancer.  Tumor stage, lymph node involvement, and tumor grade have been shown to be of independent prognostic value. [46, 65] Radical surgery appears to result in an improved survival rate as compared to radiation therapy and/or chemotherapy, whereas neoadjuvant radiation improves the outcome in locally advanced tumors. 
Pathologic stage is the most important prognostic factor in the outcome of squamous cell carcinoma of the bladder.  In one relatively larger series of 154 cases, the overall 5-year survival was 56% for pT1 and 68% for pT2 tumors. However, the 5-year survival for pT3 and pT4 tumors was only 19%.
Several studies have demonstrated grading to be a significant morphologic parameter.  In one series, 5-year survival rates for grade 1, 2, and 3 squamous cell carcinoma were 62%, 52%, and 35%, respectively.  In the same study of patients undergoing cystectomy, the investigators suggested that a higher number of newly formed blood vessels predicts unfavorable disease outcome. 
A study by Youssef et al found that fibroblast growth factor overexpression is associated with aggressive pathologic features and worse outcomes after radical cystectomy for squamous cell carcinoma of the urinary bladder. The authors added that this suggested a good prognostic and possible therapeutic role. 
More studies need to be performed to elucidate the impact of genetic changes on the prognosis of squamous cell carcinoma of the bladder. To date, there is no convincing evidence of genetic factors affecting the outcome.