High-Risk Human Papillomavirus DNA Detected in Primary Squamous Cell Carcinoma of Urinary Bladder

Abstract

Context.-We reported previously that more than onethird (37%) of primary bladder squamous cell carcinomas (SCCs) demonstrate diffuse p16 immunoreactivity independent of gender. This observation made us question whether p16 overexpression in bladder carcinoma is due to human papillomavirus (HPV)-dependent mechanisms.Objective.-To determine whether the presence of highrisk HPV (HR-HPV) DNA could be detected in these tumor cells.Design.-Fourteen cases of primary bladder SCC, which were positive for p16 by immunohistochemistry, were probed for the detection of HR-HPV by in situ hybridization and the signal amplification Invader assay. Samples positive for detection of HR-HPV by Invader assay were amplified by using HR-HPV type-specific primers, and amplification products were DNA sequenced.Results.-Detection of HR-HPV by the in situ hybridization method was negative in all cases (0 of 14). However, in 3 of 14 cases (21.4%), the presence of HR-HPV DNA was detected with the Cervista HPV HR Invader assay, which was followed by identification of genotype. All positive cases were confirmed by using HR-HPV typespecific amplification followed by DNA sequencing. Identified HR-HPV genotypes included HPV 16 (2 cases) and HPV 35 (1 case).Conclusions.-High-risk HPV DNA is detectable in a subset of primary bladder SCCs. Based on the welldocumented carcinogenic potential of HR-HPV, there is a necessity for additional studies to investigate the role of HR-HPV in bladder carcinogenesis.(Arch Pathol Lab Med. 2013;137:1088-1093; doi: 10.5858/arpa.2012-0122-OA) B ladder cancer is the second most common malignancy of the genitourinary tract diagnosed in the United States 1 with approximately 70 000 newly diagnosed cases and 14 000 deaths from disease annually. To date, wellestablished risk factors for the development of bladder squamous cell carcinoma (SCC) include increasing age (peak incidence at 50-70 years), male sex (male to female ratio, 3:1), smoking, exposure to carcinogenic chemicals, and chronic bladder inflammation and/or repeated urinary infections, and molecular/genetic factors. Although the oncogenic role of human papillomavirus (HPV) has been well documented in many epithelial cancers, including most cervical carcinomas, anogenital cancers, and carcinomas of the head and neck, its role in bladder carcinogenesis has been controversial throughout the literature.In gynecologic malignancies, the presence of high-risk HPV (HR-HPV) is often associated with overexpression of p16 protein. Immunohistochemistry for p16 is therefore used to screen for the presence of HR-HPV in primary cervical carcinomas.2 In a recent study, 3 we reported that more than-one third (37%) of primary bladder SCCs demonstrated diffuse p16 immunoreactivity independent of gender or tumor differentiation. From this study, we concluded that in tumors involving the pelvic cavity, the presence of p16 immunoreactivity alone cannot be used to distinguish tumors from gynecologic or urothelial origin. Our observed p16 overexpression in a significant proportion of...

Utility of GATA-3 and Cytokeratin 5/6 Immunostains in Separating Condyloma Acuminatum Arising in the Urinary Tract From Non-Invasive Papillary Urothelial Carcinoma

“…6,7 Similarly, the presence of HPV in a squamous cell lesion does not warrant its classification as condyloma because of the presence of HPV in a subset of primary squamous cell carcinomas of the bladder. 21 The luminal phenotype of most non-invasive papillary urothelial carcinomas [9][10][11] contrasts with the squamous phenotype of condyloma acuminatum, 4,12 and we propose that this is the underlying explanation behind the different characteristic CK5/6 staining patterns observed between these two lesions. Furthermore, we observed slightly different CK5/6 staining patterns in low-grade and high-grade noninvasive papillary urothelial carcinomas, the former demonstrating a continuous pattern of staining limited to the basal cell layer and the latter demonstrating a patchy pattern of staining limited to the basal cell layer.…”

“…6,7 Similarly, the presence of HPV in a squamous cell lesion does not warrant its classification as condyloma because of the presence of HPV in a subset of primary squamous cell carcinomas of the bladder. 21…”

Squamous Dysplasia of the Urinary Bladder

“…This is somewhat in line with the previously described finding that HPV-associated invasive SCC of the bladder frequently arises in the setting of chronic catheterization. 17,18 The squamous dysplasia in the other patient with a history of chronic catheterization had the appearance of head and neck squamous dysplasia and was associated with invasive SCC.…”

Association between Human Papillomavirus and Urological Cancers: An Update

“…Although squamous cell carcinoma of the bladder accounts for 2% of all bladder cancers, scientific interest in its relationship with HPV has persisted due to its histological structure [46]. However, because it is rare cancer, published series are small and studies have yielded conflicting results [47][48][49]. In a recent study by Collins et al investigating the presence of p16 and HR-HPV in 33 patients with squamous cell carcinoma of the bladder using in situ hybridization (ISH), P16 expression was detected in 28% of the patients, while HR-HPV was not detected in any patient [50].…”