Recent analyses of head and neck squamous cell carcinomas revealed frequent infections by oncogenic human papillomavirus (HPV) type 16 in tonsillar carcinomas. Concerning involvement of risk factors, clinical course of the disease, and prognosis there are strong indications arguing that the HPV-positive tonsillar carcinomas may represent a separate tumor entity. Looking for a surrogate marker, which in further epidemiological studies could replace the laborious and expensive HPV detection and typing we analyzed p16 protein expression in 34 tonsillar carcinoma for correlation to HPV status and load of viral DNA. p16 has been shown to be of diagnostic value for clinical evaluation of cervical dysplasia. We found 53% of the tested tonsillar carcinomas to be HPV-positive. Fifty-six percent of all tumors tested were immunohistochemically positive for the p16 protein. In 16 of 18 of the HPV-positive carcinomas diffuse p16 expression was observed. In contrast, only one of the HPV-negative carcinomas showed focal p16 staining (P < 0.001). As determined by laser-assisted microdissection and quantitative real-time polymerase chain reaction, p16 expression correlated with the presence of HPV-DNA in the individual tumor specimens. Clinical outcome analysis revealed significant correlation of p16 expression with increased disease-free survival (P = 0.02). These data indicate that p16 is a technically simple immunohistological marker, applicable for routine pathological histology, and its prognostic value for survival is fully equivalent to HPV-DNA detection.
Molecular prognostic indicators for oropharyngeal squamous cell carcinoma (OSCC), including HPV-DNA detection, epidermal growth factor receptor (EGFR) and p16 expression, have been suggested in the literature, but none of these are currently used in clinical practice. To compare these predictors, 106 newly diagnosed OSCC for the presence of HPV-DNA and expression of p16 and EGFR were analyzed. The 5-year disease-free survival (DFS) and overall survival (OS) were calculated in relation to these markers and a multivariate Cox analysis was performed. Twentyeight percent of the cases contained oncogenic HPV-DNA and 30% were positive for p16. The p16 expression was highly correlated with the presence of HPV-DNA (p < 0.001). Univariate analysis of the 5-year DFS revealed a significantly better outcome for patients with p16-positive tumors (84% vs. 49%, p 5 0.009). EGFR-negative tumors showed a tendency toward a better prognosis in DFS (74% vs. 47%, p 5 0.084) and OS (70% vs. 45%, p 5 0.100). Remarkable and highly significant was the combination of p16 and EGFR expression status, leading to 5-year DFS of 93% for p161/EGFR2 tumors vs. 39% for p162/EGFR1 tumors (p 5 0.003) and to a 5-year OS of 79% vs. 38%, respectively (p 5 0.010). In multivariate analysis p16 remained a highly significant prognostic marker for DFS (p 5 0.030) showing a 7.5-fold increased risk for relapse in patients with p16-negative tumors. Our data indicate that p16 expression is the most reliable prognostic marker for OSCC and further might be a surrogate marker for HPV-positive OSCC. HPV1/p161 tumors tended to have decreased EGFR expression, but using both immunohistological markers has significant prognostic implications. ' 2007 Wiley-Liss, Inc.
A high prevalence of human papillomavirus (HPV) DNA, particularly in squamous cell skin carcinoma of immunosuppressed but also of immunocompetent patients, has renewed great interest in a possible etiologic role of HPV in nonmelanoma skin cancer. It is difficult, however, to interpret these findings against a background of low-level infections with multiple HPV types from supergroup B (HPV4-related and epidermodysplasia verruciformis [EV] HPV), probably acquired by everyone early in and throughout life. Thus far, no high-risk HPV types have been identified. Because of the low copy numbers of HPV DNA in skin cancers, probably not every tumor cell contains a viral genome, which is compatible with cutaneous HPV being possibly important for tumor initiation and progression, but not for maintenance of the malignant phenotype. The question with regard to high-risk types should, therefore, be readdressed in case-control studies on the basis of serology, which can reveal viral activities over years. The viruses lingering in all people are apparently activated by sunlight (UV) exposure, by immunosuppression, and by hyperproliferation of the epithelium (psoriasis) and/or in the specific genetic background of the host (EV). It is intriguing that most of these factors are established risk factors in skin carcinogenesis. The weak transforming activity of cutaneous HPV in vitro compared with the transforming activity of genital HPV may explain the need for activators and synergistic factors. The antiapoptotic activities of E6 proteins of cutaneous HPV could be relevant to oncogenesis in the interplay with UV exposure. Prospective studies should determine the kinetics of HPV activation relative to tumor development. [
Recent studies suggest a role of cutaneous human papillomaviruses (HPV) in non-melanoma skin cancer (NMSC) development. In this study viral DNA loads of six frequent HPV types were determined by quantitative, type-specific real-time-PCR (Q-PCR) in actinic keratoses (AK, n=26), NMSC (n=31), perilesional tissue (n=22), and metastases of squamous cell carcinomas (SCC) (n=8) which were previously shown to be positive for HPV5, 8, 15, 20, 24, or 36. HPV-DNA loads in AK, (partially microdissected) NMSC, and perilesional skin ranged between one HPV-DNA copy per 0.02 and 14,200 cell equivalents (median: 1 HPV-DNA copy per 344 cell equivalents; n=48). In 32 of the 79 HPV-positive skin biopsies and in seven of the eight metastases viral loads were even below the detection limit of Q-PCR. Low viral loads in NMSC were confirmed by in situ-hybridization showing only a few HPV-DNA-positive nuclei per section. Viral loads in SCC, basal cell carcinomas, and perilesional tissue were similar. But, viral loads found in AK were significantly higher than in SCC (p=0.035). Our data suggest that persistence of HPV is not necessary for the maintenance of the malignant phenotype of individual NMSC cells. Although a passenger state cannot be excluded, the data are compatible with a carcinogenic role of HPV in early steps of tumor development.
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