Article

Begum S, Cao D, Gillison M, et al. Tissue distribution of human papillomavirus 16 DNA integration in patients with tonsillar carcinoma

Department of Molecular Microbiology and Immunology, Johns Hopkins Medicine, Baltimore, Maryland, United States
Clinical Cancer Research (Impact Factor: 8.19). 08/2005; 11(16):5694-9. DOI: 10.1158/1078-0432.CCR-05-0587
Source: PubMed

ABSTRACT Human papillomavirus 16 (HPV-16) has been implicated as a causative agent in a subset of head and neck squamous cell carcinomas (HNSCC). This study was undertaken to discern the distribution and timing of HPV viral integration during tumorigenesis of the upper respiratory tract.
A tissue array was assembled from a consecutive group of 176 patients with HNSCCs. The array was evaluated by HPV-16 in situ hybridization and p16 immunohistochemistry. Patients with HPV-positive tonsillar cancers who had undergone bilateral tonsillectomies were selected for more complete mapping of viral integration.
HPV-16 was detected in 38 of the 176 (22%) cases by in situ hybridization. When stratified by site of origin, HPV-16 was detected in 37 of 45 cancers arising from the oropharynx but in only 1 of 131 tumors arising from nonoropharyngeal sites (82% versus 0.8%, P < 0.00001). P16 expression was associated with the presence of HPV-16: 31 of 38 HPV-positive tumors exhibited p16 expression, whereas only 9 of the 138 HPV-negative tumors were p16-positive (82% versus 6%, P < 0.00001). In the bilateral tonsil sections, hybridization signals were strictly limited to the invasive cancers and associated dysplasias. P16 staining was widely distributed throughout the nonneoplastic crypt epithelium of individuals with and without tonsillar cancer.
HPV-16 is strongly associated with carcinomas arising from the oropharynx, and integration is tightly coupled to the neoplastic process. Viral integration does not occur as a field alteration throughout normal tonsillar epithelium. P16 expression localizes to HPV-positive cancers, and is intrinsic to the specialized epithelium of the tonsillar crypts. For risk assessment, early cancer detection and disease surveillance, evidence of HPV-16 integration may represent a meaningful finding, whereas high p16 expression, by itself, may not.

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    • "Begum et al. [24] undertook p16 IHC and HPV DNA ISH on the contra-lateral uninvolved tonsil in eight patients with primary HPV-related tonsil carcinomas and identified p16 overexpression and ISH positivity in one of eight cases. Interestingly, and in agreement with our findings, p16 over-expression in combination with high-risk HPV DNA by ISH was associated with morphological evidence of epithelial dysplasia [24]. These data suggest that pathologist review of pharyngeal endoscopic biopsies by conventional microscopy is likely to be sufficient to screen for multifocal HPV infection, which can then be confirmed by conventional laboratory testing (p16 IHC and high risk HPV ISH/HPV PCR). "
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    • "Preferably, a test is needed that can detect additional risk factors to increase the PPV, thereby reducing the rate of unnecessary referrals for colposcopy, in combination with a high NPV. Examples of such additional risk factors are a high viral load and viral integration [Klaes et al., 1999; Dalstein et al., 2003; Hopman et al., 2004; Begum et al., 2005]. "
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    • "In oral cancers the integration of HPV DNA into the host's cell genome is probably a less common event [9]. Various HPV types have been identified in patients with oral cancer [10], but clinical and case control studies have not proved a causal relationship between the virus and oral carcinomas beyond any reasonable doubt [8] [9] [11]. HPV DNA detection alone is regarded as insufficient evidence for a causal role in oral cells transformation and is more like a secondary invader [7] [10]. "
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