Human papillomavirus and p16 expression in inverted papillomas of the urinary bladder
Introduction
Human papillomaviruses (HPV) are double-stranded DNA viruses which infect stratified epithelia of skin and mucosae. HPVs of the α-type have been found associated with benign and malignant growth [1]. This association has allowed to divide the viruses of the α-type in two groups, the high-risk group (mainly types 16, 18, 31 and 33) found in carcinomas of the cervix, and the low-risk group (like types 6, 11) mainly associated with genital warts. In more than 70% of cervical tumors sequences of HPV types 16 and 18 have been identified (for a review see [2]). Besides, HPV5 and 8 of the β-type have been identified in skin tumors of patients with Epidermodysplasia verruciformis. Nevertheless, whether these types are also causal in the development of non-melanoma-skin tumors is presently not clear [3]. Viral sequences have also been found in other types of tumors although the role played in the pathogenesis of these tumors is still under debate [4], [5].
The molecular mechanisms by which HPV proteins modulate cell proliferation have been intensively analyzed in the last decade. Two viral proteins seem to be responsible for the oncogenic potential of the virus: E6, which binds and degrades p53, and E7, which targets members of the retinoblastoma proteins pRB [6].
p16 Is a member of the ink family which inhibits cell cycle progression [7]. Basically, p16 inhibits CDK4 activity, rendering the pRB-E2F-1 complex inactive. In cells expressing the viral E7 protein, degradation of pRB results in p16 accumulation [8]. This has resulted in the use of p16 as a marker of cellular transformation in cervical intraepithelial neoplasias (CIN) where a strong increase in p16 expression has been found. Thus, a correlation has been established between cell proliferation, HPV infection and p16 expression [9].
The urinary bladder is lined by a transitional epithelium, formed by several layers of cells which change their shape according to the filling of the bladder. Whereas an association of papillomavirus infection with urinary tumors’ seems very probably in cattle, controversial results have been published regarding the human urinary tract [10], [11], [12]. One rare tumor of the urinary bladder epithelium is the inverted papilloma which is considered to be of benign nature although some uncertainty remains regarding association with synchronous urothelial carcinomas [13]. In the present study we investigate the presence of HPV sequences in inverted papillomas and whether this presence correlates with increased p16 expression.
Section snippets
Tumors
A total of 23 inverted papillomas of the urinary bladder were recorded at Rush University Medical Center in a period of 24 years. There were 15 male and 8 female patients ranging in age from 17 to 75 years with a mean age of 59. Only 18 tumors yielded DNA of quality high enough to perform PCR experiments. In addition, 15 non-tumor samples (5 transitional cell carcinomas (TCC), 6 cystitis and 4 normal urothelial bladder tissues) were used as controls.
p16 Staining
p16 Staining was performed by an
Histology of the inverted papillomas
Inverted papillomas of the bladder are rare proliferations of the urothelium accounting for less than 1% of all urothelial tumors. These tumors are more common in males than females. The lesions are typically located in the trigone region as single, small, sessile or pedunculated masses with a smooth surface. Histologically, inverted papillomas are composed of an endophytic proliferation of anastomosing islands and trabeculae of urothelial cells (Fig. 1A and C). Two major patterns of growth
Discussion
Human papillomaviruses infect mainly stratified epithelia and need cell differentiation to enter the productive life cycle. Bladder epithelium is a unique identity being transitional and without the differentiation characteristics observed in the skin or in mucosal epithelium. Nevertheless, several reports have been published indicating the presence of HPV sequences in the urinary bladder albeit at a very low incidence [17], [18], [19], [20]. However, the association of HPV with tumor
Conflict of interest statement
We declare no conflicts of interest.
Acknowledgement
This work is dedicated to the memory of Dr. Victor E. Gould.
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