Expression of p16 Protein Identifies a Distinct Entity of Tonsillar Carcinomas Associated with Human Papillomavirus

Klußmann, Jens Peter; Gültekin, Elif; Weissenborn, Soenke J.; Wieland, Ulrike; Dries, Volker; Dienes, Hans Peter; Eckel, Hans Edmund; Pfister, Herbert; Fuchs, Pawel G.

doi:10.1016/s0002-9440(10)63871-0

Cited by 375 publications

(422 citation statements)

References 36 publications

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“…We noticed that the tumors with the low expression levels of pRb showed the overexpression of p16 INK4A . Accumulation of this latter protein has been strongly associated with the presence of oncogenic HPV in oropharyngeal carcinomas, 7,10,14,15 which was also evident in the underlying study. These HPV16-positive tonsillar squamous cell carcinomas furthermore showed the downregulation of cyclin D1, next to the accumulation of p14 ARF and p21 Cip1/WAF1 .…”

Section: Discussionsupporting

confidence: 61%

“…15 Briefly, sections were deparaffinized and subsequently pretreated with 2% H 2 O 2 in methanol for 30 min to quench endogenous peroxidase activity. Antigen retrieval was carried out by microwave heating in 0.01-M citrate buffer (pH 6.0).…”

Section: Immunohistochemical Stainingmentioning

confidence: 99%

“…10,11 At the molecular level, the functional inactivation of two key tumor suppressor proteins, ie, p53 and pRb by the HPV-derived oncoproteins E6 and E7, often result in the downregulation of p53, pRb, cyclin D1, and a strong upregulation of p16 INK4A in HPVpositive tumors. 5,7,[14][15][16] HPV-negative tumors, in contrast, often show inactivation of p16 INK4A , p53 overexpression as a result of gene mutations, cyclin D1 gene amplification and overexpression, as well as EGFR accumulation. 3,[17][18][19] The literature, however, shows conflicting data with respect to HPV-associated characteristics and clinical outcome of head-and-neck squamous cell carcinomas.…”

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confidence: 99%

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P21Cip1/WAF1 expression is strongly associated with HPV-positive tonsillar carcinoma and a favorable prognosis

et al. 2009

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Human papillomavirus is involved in the carcinogenesis of tonsillar squamous cell carcinomas. Here, we investigated the expression and the prognostic value of key cell cycle proteins in the pRb and p53 pathways in both human papillomavirus type 16-positive and -negative tonsillar squamous cell carcinomas. Using immunohistochemistry, 77 tonsillar squamous cell carcinomas with known human papillomavirus type 16 status and clinical outcome were analyzed for expression of Ki67, p16 INK4A, cyclin D1, pRb, p14 ARF , MDM2, p53, p21 Cip1/WAF1 , and p27 KIP1 . Results were correlated with each other and with clinical and demographic patient data. A total of 35% of tonsillar carcinomas harbored integrated human papillomavirus type 16 DNA and p16 INK4A overexpression, both being considered essential features for human papillomavirus association. These tumors also showed the overexpression of p14 ARF (Po0.0001) and p21 Cip1/WAF1 (P ¼ 0.001), and downregulation of pRb (Po0.0001) and cyclin D1 (P ¼ 0.027) compared with the human papillomavirus-negative cases. Univariate Cox regression analyses revealed a favorable survival rate for non-smokers (P ¼ 0.006), as well as for patients with T1-2 tumors (Po0.0001) or tumors showing low expression of cyclin D1 (P ¼ 0.028), presence of human papillomavirus and overexpression of p16 INK4A (P ¼ 0.01), p14 ARF (P ¼ 0.02) or p21 Cip1/WAF1 (P ¼ 0.004). In multivariate regression analyses, smoking and tumor size, as well as expression of cyclin D1 and p21 Cip1/WAF1 , were found to be independent prognostic markers. We conclude that human papillomavirus positivity in tonsillar squamous cell carcinomas strongly correlates with p21 Cip1/WAF1 and p14 ARF overexpression and downregulation of pRb and cyclin D1. In particular p21 Cip1/WAF1 overexpression is an excellent favorable prognosticator in tonsillar squamous cell carcinomas. Modern Pathology ( Head-and-neck squamous cell carcinoma is the sixth most prevalent malignancy in the world, contributing 6% of new cancer cases annually worldwide. 1,2 These tumors have a 5-year survival rate of approximately 50%, which has not improved in the last two decades. 3 Well-recognized risk factors in the etiology of head-and-neck squamous cell carcinomas are extensive tobacco and alcohol consumption in B90% of cases, as well as oncogenic human papillomaviruses (HPVs), predominantly HPV type 16. 3,4 Interestingly, the association of HPV is strongest for tonsillar squamous cell carcinoma with a prevalence up to 50%. [5][6][7][8]

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Section: Discussionsupporting

confidence: 61%

Section: Immunohistochemical Stainingmentioning

confidence: 99%

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confidence: 99%

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P21Cip1/WAF1 expression is strongly associated with HPV-positive tonsillar carcinoma and a favorable prognosis

et al. 2009

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“…In oropharyngeal cancers, the concordance of p16 and HPV is reported higher and p16 positive and HPV positive tumors have significantly better prognosis. p16 IHC as a surrogate marker for HPV infection has been depicted in several studies (Wittekindt et al, 2005;Lewis et al, 2010;Oguejiofor et al, 2013) and is considered as a molecular hall mark of HPV positive HNSCC (Klussmann et al, 2003;Li et al, 2004).…”

Section: Discussionmentioning

confidence: 99%

Risk Stratification of Early Stage Oral Tongue Cancers Based on HPV Status and p16 Immunoexpression

Ramshankar¹,

Soundara²,

Shyamsundar³

et al. 2014

Asian Pacific Journal of Cancer Prevention

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Background: Recent epidemiological data have implicated human papilloma virus (HPV) infection in the pathogenesis of head and neck cancers, especially oropharyngeal cancers. Although, HPV has been detected in varied amounts in persons with oral dysplasia, leukoplakias and malignancies, its involvement in oral tongue carcinogenesis remains ambiguous. Materials and Methods: HPV DNA prevalence was assessed by PCR with formalin fixed paraffin embedded sections (n=167) of oral tongue squamous cell carcinoma patients and the physical status of the HPV16 DNA was assessed by qPCR. Immunohistochemistry was conducted for p16 evaluation. Results: We found the HPV prevalence in tongue cancers to be 51.2%, HPV 16 being present in 85.2% of the positive cases. A notable finding was a very poor concordance between HPV 16 DNA and p16 IHC findings (kappa<0.2). Further molecular classification of patients based on HPV16 DNA prevalence and p16 overexpression showed that patients with tumours showing p16 overexpression had increased hazard of death (HR=2.395; p=0.005) and disease recurrence (HR=2.581; p=0.002) irrespective of their HPV 16 DNA status. Conclusions: Our study has brought out several key facets which can potentially redefine our understanding of tongue cancer tumorigenesis. It has emphatically shown p16 overexpression to be a single important prognostic variable in defining a high risk group and depicting a poorer prognosis, thus highlighting the need for its routine assessment in tongue cancers. Another significant finding was a very poor concordance between p16 expression and HPV infection suggesting that p16 expression should possibly not be used as a surrogate marker for HPV infection in tongue cancers. Interestingly, the prognostic significance of p16 overexpression is different from that reported in oropharyngeal cancers. The mechanism of HPV independent p16 over expression in oral tongue cancers is possibly a distinct entity and needs to be further studied.

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“…It is overexpressed in HPV-related SCC but is usually deleted or otherwise inactivated in non-HPV-related head and neck SCC [19,20]. p16 expression by immunohistochemistry approaches 100% in HPVpositive oropharyngeal carcinomas in some studies [5,11,21,22] and is indicative of transcriptionally-active HPV. HPV-negative SCCs tend to harbor p53 mutations leading to nuclear accumulation of p53 protein that is detectable by immunohistochemistry.…”

Section: Introductionmentioning

confidence: 99%

Adenosquamous Carcinoma of the Head and Neck: Relationship to Human Papillomavirus and Review of the Literature

Masand

El‐Mofty

et al. 2011

Head and Neck Pathol

133

106

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Adenosquamous carcinoma (ADSC) of the head and neck is an aggressive variant of squamous cell carcinoma (SCC). Certain variants of head and neck SCC are human papillomavirus (HPV)-related and have better prognosis. The relationship of HPV to head and neck ADSC has not been investigated. We searched our files for the term ''adenosquamous'' and head and neck subsites and found cases from 1998 to 2009. The requisite histologic criteria were the presence of SCC combined with distinct gland formation and/or intracellular mucin. DNA in situ hybridization for high-risk HPV, RNA in situ hybridization for high risk HPV E6 and E7 transcripts, and immunohistochemistry for p16 and p53 were performed. The existing literature on ADSC was also reviewed. Of the 18 cases, eight were from the larynx and hypopharynx, four from the oral cavity, three from the oropharynx, and three from the nasal cavity. Three cases (16%) showed both high risk HPV E6 and E7 and p16 expression, one from the nasal cavity and two from the oropharynx. Both oropharyngeal carcinoma patients were alive and disease free at 34 and 103 months, respectively. ADSCs of the head and neck are a heterogeneous group of tumors. A small minority of cases harbor HPV and most of these, particularly those occurring at sites with known high prevalence of HPV, show active viral transcription with detectable E6 and E7 and overexpression of p16. The HPV-related oropharyngeal cases, though rare, appear to do very well clinically, while the remaining cohort of ADSC patients do quite poorly. Head and neck ADSC appears to be a mixed variant that can be further classified according to its HPV status.

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Expression of p16 Protein Identifies a Distinct Entity of Tonsillar Carcinomas Associated with Human Papillomavirus

Cited by 375 publications

References 36 publications

P21Cip1/WAF1 expression is strongly associated with HPV-positive tonsillar carcinoma and a favorable prognosis

P21Cip1/WAF1 expression is strongly associated with HPV-positive tonsillar carcinoma and a favorable prognosis

Risk Stratification of Early Stage Oral Tongue Cancers Based on HPV Status and p16 Immunoexpression

Adenosquamous Carcinoma of the Head and Neck: Relationship to Human Papillomavirus and Review of the Literature

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