Pathologic Findings in Squamous Cell Bladder Carcinoma Overview of Squamous Cell Carcinoma
Squamous cell carcinoma (SCC) is the second most common cell type associated with bladder cancer in developed countries (urothelial carcinoma is the most common type of bladder cancer [about 90%]), [1, 2] accounting for 2%-5% of bladder neoplasms.  In the United States, an estimated 1%-2% of bladder cancers are squamous cell carcinomas, [2, 4] often associated with spinal cord injury and with the long-term use of an indwelling catheter.  Worldwide, however, squamous cell carcinoma is the most common form of bladder cancer, accounting for up to 73% of cases in developing nations, particularly regions with a high prevalence of schistosomiasis (eg, Middle East, Southeast Asia, South America). [5, 6] Human papillomavirus infection also appears to have an association with squamous cell bladder carcinoma. [7, 8, 9, 10, 11]
For more information, see Bladder Cancer, as well as Pathologic Findings in Small Cell Bladder Carcinoma and Cystoscopy.
Cystoscopically, squamous cell carcinoma appears nodular and has a plaquelike, irregular surface with involvement of multiple bladder sites. The lateral wall and trigone are more commonly involved. [3, 14, 15] Grossly, the tumor seems nodular with deep invasion into the muscularis propria and often involves the extravesical organs. Most of the tumors are large, exophytic, and necrotic and bulge into the bladder cavity. [16, 17] Flat tumors with irregular borders are less common.  Surface necrosis and keratin debris are usually present, which give it a flaky, whitish appearance.
Microscopically, the squamous cell tumors arise in the epithelium and infiltrate in sheets, nests, and islands (see the 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 the cells at the stromal interface is a sign of invasion.
The tumor cells are polygonal with well-defined cell borders and have cytoplasm that is amphophilic to eosinophilic. 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.  There is a 21%-42% risk of the development of bladder cancer once squamous metaplasia occurs. 
Verrucous squamous cell carcinoma is a rare variant of squamous cell carcinoma of the bladder, accounting for less than 5% of the squamous cell carcinomas. [21, 22] Most cases are associated with Schistosoma 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. It 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. [8, 24] Generally, the verrucous carcinoma is considered low risk for progression; however, this is difficult to establish in the bladder because of a relatively fewer number of cases.
A single case of basaloid squamous cell carcinoma of the bladder was reported in a 60-year-old woman with incontinence, intractable urinary tract infections (UTIs), 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 proposed that the correct terminology should be urothelial carcinoma with basaloid features, rather than basaloid squamous cell carcinoma. 
Basaloid squamous cell carcinoma of the bladder has also been reported with small-cell carcinoma.  A 54-year-old male had multiple sclerosis-related neurogenic bladder and chronic UTIs. Histologic findings of a cystoscopic speciment from a large right-bladder tumor was consistent with basaloid squamous cell carcinoma, with invasion of the muscular layer and vascular invasion; histopathologic features from a radical cistectomy specimen confirmed these findings as well as revealed squamous metaplasia, squamous carcinoma in situ, and a 5% small-cell carcinoma feature. 
The diagnosis of squamous cell carcinoma of the bladder is primarily based on the morphology. The immunohistochemical stains do not have a substantial role in diagnosing this tumor. CK20 has been seen in the majority of cases of urothelial carcinoma; however, in one study, none of the schistosomal-associated squamous cell carcinomas stained. COX-2 and uroplakin II expression 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. [27, 28]
The molecular data for the squamous cell carcinoma of the bladder has 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. [29, 30, 31, 32, 33, 34, 35]
As with urothelial carcinoma, a wide range of p53 positivity has been observed in schistosomal-associated squamous cell carcinoma in different studies. [36, 37, 38, 39] 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, [40, 41] epidermal growth factor receptor (EGFR) overexpression, and HER2 expression were also found at comparable frequencies in schistosomal-associated squamous cell carcinomas.  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. [43, 44]
A few sporadic cases of squamous cell carcinoma 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. [30, 45, 46, 47]
The squamous cell tumor is generally graded as well differentiated, moderately differentiated, or poorly differentiated, depending on the extent of keratinization and nuclear pleomorphism. [18, 48, 49, 50] 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. [48, 49] A 2019 propensity analysis of National Cancer Database bladder cancer data (2004-2013) from 3332 patients found that histology had a larger impact on survival than tumor stage.  Nuclear tetraploidy and aneuploidy correlate with the grade and stage of squamous cell carcinoma and adversely affect survival. [50, 51]
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Muhammad T Idrees, MD Associate Professor of Pathology, Indiana University School of Medicine
Disclosure: Nothing to disclose.
Liang Cheng, MD Professor of Pathology and Urology, Department of Pathology and Laboratory Medicine, Indiana University School of Medicine; Chief, Genitourinary Pathology Service, Indiana University Health
Liang Cheng, MD is a member of the following medical societies: American Association for Cancer Research, American Urological Association, College of American Pathologists, United States and Canadian Academy of Pathology, International Society of Urological Pathology, Arthur Purdy Stout Society
Disclosure: Nothing to disclose.
Pathologic Findings in Squamous Cell Bladder Carcinoma Overview of Squamous Cell Carcinoma
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