HPV Causes Head and Neck Cancers

Human papillomavirus (HPV) in head and neck cancer. An association of HPV 16 with squamous cell carcinoma of Waldeyer's tonsillar ring. IB Paz, N Cook, T Odom-Maryon, Y Xie, SP Wilczynski. Cancer 1997 Feb 1;79(3):595-604. HPV was detected in 25/167 (15%) tumors overall. "With respect to age, gender, and tobacco and alcohol consumption, analysis of clinical data obtained by retrospective review showed no difference between patients with HPV DNA in their tumors and those in which no HPV was detected."

Human papillomavirus and Epstein-Barr virus in epithelial carcinomas of the head and neck region. S Atula, E Auvinen, R Grenman, S Syrjanen. Anticancer Res 1997 Nov-Dec;17(6D):4427-4433. HPV was found in 13/79 (16.5%).

Etiological involvement of oncogenic human papillomavirus in tonsillar squamous cell carcinomas lacking retinoblastoma cell cycle control. T Andl, T Kahn, A Pfuhl, T Nicola, R Erber, C Conradt, W Klein, M Helbig, A Dietz, H Weidauer, FX Bosch. Cancer Res 1998;58(1):5-13. HPV DNA was found in 11/12 pRb-defective tonsillar tumors, versus 0/9 pRb non-defective tumors.

Low prevalence of human papillomavirus in a geographic region with a high incidence of head and neck cancer. RE Miguel, LL Villa, AC Cordeiro, JC Prado, JS Sobrinho, LP Kowalski. Am J Surg 1998 Nov;176(5):428-429. (An anti-smoker study). 5/45 (11%) were HPV positive.

Human papilloma virus (HPV) type 16 and 18 detected in head and neck squamous cell carcinoma. H Mineta, T Ogino, HM Amano, Y Ohkawa, K Araki, S Takebayashi, K Miura. Anticancer Res 1998 Nov-Dec;18(6B):4765-4768. "HPV16-DNA was detected in 23% of all cases (23/98), 31% (8/26) larynx, 16% (3/19) nasal and paranasal sinus, 19% (3/16) hypopharynx, 21% (3/14) oral cavity, 38% (5/13) oropharynx, and 10% (1/10) nasopharynx. HPV18-DNA was detected in 4% of all cases (4/98), 8% (2/26) larynx, and 15% (2/13) oropharynx. 54% (7/13) in oropharynx and 38% (10/26) in larynx showed rather high prevalence in the head and neck. CONCLUSIONS: HPV16 and 18 play an important role in carcinogenesis of the head and neck, especially, in the oropharynx and larynx."

Head and neck cancer in nonsmokers: a distinct clinical and molecular entity. WM Koch, M Lango, D Sewell, M Zahurak, D Sidransky. Laryngoscope 1999 Oct;109(10):1554-1551.

Human papillomavirus in head and neck carcinomas: prevalence, physical status and relationship with clinical/pathological parameters. G Badaracco, A Venuti, R Morello, A Muller, ML Marcante. Anticancer Res 2000 Mar-Apr;20(2B):1301-1305. Of 66 tumors from various sites including 38 oral and 22 laryngeal squamous cell carcinomas, 24 were HPV-positive. "HPV 16 was integrated in 7/12 positive tumours without site-specificity. HPV infection was not related to age, gender, tumour stage, differentiation grade, and use of alcohol and/or tobacco."

Evidence for a causal association between human papillomavirus and a subset of head and neck cancers. ML Gillison, WM Kock, RB Capone, M Spafford, WH Westra, L Wu, ML Zahurak, RW Daniel, M Viglione, DE Symer, KV Shah, D Sidransky. JNCI 2000 May 3;92(9):709-720. "Conclusions: These data extend recent molecular and epidemiologic studies and strongly suggest that HPV-positive oropharyngeal cancers comprise a distinct molecular, clinical, and pathologic disease entity that is likely causally associated with HPV infection and that has a marked improved prognosis."

Caveat: In this study, cancers at nonoropharyngeal sites comprised the vast majority of cancers in both smokers and nonsmokers (193 nonoropharyngeal, 76.3%, versus 60 oropharyngeal, 23.7%). Nevertheless, only the (nonsignificant) results for smoker versus nonsmoker differences at oropharyngeal sites were reported in the abstract, thus creating the false impression that HPV was more likely to be involved in nonsmokers' cancers than in smokers' cancers. In fact, the overall proportion of HPV-positive cancers was virtually identical among smokers, ex-smokers, and nonsmokers (39/167=23.4%, OR=0.81, 95% CI 0.35-1.9; 14/51=27.5%, OR=1.0, 95% CI 0.38-2.7; 9/33=27.3%, OR=1.0, referent). Smokers did not have a disproportionate number of HPV-negative cancers, as would be expected if smoking played an independent causal role. This suggests that increased exposure to HPV is the more likely cause of smokers' increased rates of head and neck cancers, and that alleged smoking risks are the result of confounding.

HPV-16 a possible risk factor for squamous cell carcinoma of the head and neck. Medscape-Reuters Health 2001 Apr 12; Re: Human papillomavirus infection as a risk factor for squamous-cell carcinoma of the head and neck. J Mork, AK Lie, E Glattre, G Hallmans, E Jellum, P Koskela, B Moller, E Pukkala, JT Schiller, L Youngman, M Lehtinen, J Dillner, S Clark, Z Wang. N Engl J Med 2001 Apr 12;344(15):1125-1131.

Caveat: "Adjusting" for smoking is exactly how spurious smoking risks were generated in cervical cancer studies, due to confounding by undetected HPV combined with higher prevalence in smokers. Also, the OR for HPV may have been pulled down because of this procedure.

Human papillomavirus-associated head and neck squamous cell carcinoma: mounting evidence for an etiologic role for human papillomavirus in a subset of head and neck cancers. ML Gillison, KV Shah. Curr Opin Oncol 2001 May;13(3):183-188. Review.

Biological evidence that human papillomaviruses are etiologically involved in a subgroup of head and neck squamous cell carcinomas. VM van Houten, PJ Snijders, MW van den Brekel, JA Kummer, CJ Meijer, B van Leeuwen, F Denkers, LE Smeele, GB Snow, RH Brakenhoff. Int J Cancer 2001 Jul 15;93(2):232-235. 20/84 were HPV+.

Human papillomavirus positive squamous cell carcinoma of the oropharynx: a radiosensitive subgroup of head and neck carcinoma. K Lindel, KT Beer, J Laissue, RH Greiner, DM Aebersold. Cancer 2001 Aug 15;92(4):805-813. 14/99 tumors were HPV positive.

[Relationship between the integration of human papillomavirus and loss of heterozygosity of the P53 gene in squamous cell carcinomas of the head and neck]. A Martinez Ferreras, JP Rodrigo Tapia, MV Gonzalez Meana, I Alvarez Alvarez, E Coto, C Suarez Nieto. Acta Otorrinolaringol Esp 2001 Oct;52(7):546-552. 8/26 (31%) were HPV positive.

Prevalence, distribution, and viral load of human papillomavirus 16 DNA in tonsillar carcinomas. JP Klussmann, SJ Weissenborn, U Wieland, V Dries, J Kolligs, M Jungehuelsing, HE Eckel, HP Dienes, HJ Pfister, PG Fuchs. Cancer 2001 Dec 1;92(11):2875-2884. "Altogether 25 HNSCCs (26%) were found to be HPV positive. Stratified according to the tumor localization, the frequency of HPV positive lesions was 18% in the oral cavity, 45% for oropharynx, 25% for hypopharynx, 8% for nasopharynx, and 7% for larynx. The highest HPV DNA prevalence (58%) was found in tonsillar carcinomas."

[Causal association between human papilloma virus infection and head and neck and esophageal squamous cell carcinoma]. Z Szentirmay, I Szántó, I Bálint, K Pólus, E Remenár, L Tamás, G Szentkúti, Z Melegh, P Nagy, M Kásler. Magy Onkol 2002;46(1):35-41. "Overall, HPV sequences were detected in 61 of 150 specimens. HPV DNA sequences were detected in 16/32 specimens in the oropharyngeal region, in 13/36 specimens in larynx and 32/82 specimens in esophagus. Papillomas contained only the episomal form of HPV 16.In the esophagus, the most common type was HPV 73. In all specimens examined, HPV 6/11 (4/150), HPV 16 (23/150), HPV 35 (1/150), HPV 45 (1/150), HPV 54 (1/150), HPV 58 (1/150), HPV 61 (1/150), HPV 66 (1/150), HPV 68 (2/150), HPV 70 (3/150), HPV 72 (1/150), HPV 73 (16/150), double HPV infection (2/150), and unidentified HPV type (4/150) was detected. Interestingly, HPV was found in all verrucous carcinomas and in 18/22 basaloid squamous cell carcinomas."

Human papillomavirus type 16 and squamous cell carcinoma of the head and neck. E Ringstrom, E Peters, M Hasegawa, M Posner, M Liu, KT Kelsey. Clin Cancer Res 2002 Oct;8(10):3187-3192. 18/89 (20%) had detectable HPV DNA, including 64% of tonsil tumors and 52% of oropharyngeal tumors. "Smoking, clinical stage, tumor grade, and tumor-node-metastasis status were not asociated with HPV-16 presence."

Epstein-Barr virus and human papillomavirus infections and oropharyngeal squamous cell carcinomas. A Szkaradkiewicz, A Kruk-Zagajewska, M Wal, A Jopek, M Wierzbicka, A Kuch. Clin Exp Med 2002 Nov;2(3):137-141. EBV was detected in 86% of palatine tonsil and tongue carcinoma cases.

Human papillomavirus type 16 infection and squamous cell carcinoma of the head and neck in never-smokers: a matched pair analysis. KR Dahlstrom, K Adler-Storthz, CJ Etzel, Z Liu, L Dillon, AK El-Naggar, MR Spitz, JT Schiller, Q Wei, EM Sturgis. Clin Cancer Res 2003 Jul;9(7):2620-2626. "Forty-nine of the 120 case subjects (40.8%) but only 11 (9.2%) of the control subjects tested positive for HPV-16 antibodies (adjusted odds ratio, 6.69; 95% confidence interval, 3.01-14.90). Among cases, HPV-16 seropositivity was more common in those with oropharyngeal cancer (41 of 70, 58.6%) and poorly differentiated tumors (25 of 43, 58.1%). HPV-16 seropositivity was associated with a significantly increased risk of oropharyngeal cancer (adjusted odds ratio, 59.53; 95% confidence interval, 5.71-620.20). Whereas HPV-16 seropositivity was more common in never-smokers with SCCHN than in ever-smokers (43.3% versus 38.3%, respectively), this difference was not statistically significant."

Human papillomavirus-positive tonsillar carcinomas: a different tumor entity? JP Klussmann, SJ Weissenborn, U Wieland, V Dries, HE Eckel, HJ Pfister, PG Fuchs. Med Microbiol Immunol (Berl) 2003 Aug;192(3):129-132. "18% of the oral cavity cancers, 8% of nasopharyngeal cancers, 25% of hypopharyngeal cancers and 7% of laryngeal cancers were HPV DNA positive. In contrast, HPV sequences could be detected in 45% of the oropharyngeal cancers, particularly tonsillar carcinomas (58%)."

Prevalence of human papillomavirus type 16 DNA in squamous cell carcinoma of the palatine tonsil, and not the oral cavity, in young patients: a distinct clinicopathologic and molecular disease entity. SK El-Mofty, DW Lu. Am J Surg Pathol 2003 Nov;27(11):1463-1470. In 33 patients under the age of 40 years, HPV DNA was detected by polymerase chain reaction in 0/15 oral, 10/11 tonsillar, and 2/7 laryngeal tumors. 11/12 HPV-positive tumors were HPV16 and 1 was HPV31.

A subset of head and neck squamous cell carcinomas exhibits integration of HPV 16/18 DNA and overexpression of p16INK4A and p53 in the absence of mutations in p53 exons 5-8. HC Hafkamp, EJ Speel, A Haesevoets, FJ Bot, WN Dinjens, FC Ramaekers, AH Hopman, JJ Manni. Int J Cancer 2003 Nov 10;107(3):394-400. "Ten of the 47 (21%) HNSCC unequivocally exhibited HPV 16 integration, including 8 of 12 (67%) tonsillar carcinomas."

Prevalence and physical status of human papillomavirus in squamous cell carcinomas of the head and neck. WJ Koskinen, RW Chen, I Leivo, A Makitie, L Back, R Kontio, R Suuronen, C Lindqvist, E Auvinen, A Molijn, WG Quint, A Vaheri, LM Aaltonen. Int J Cancer 2003 Nov 10;107(3):401-406. "By the sensitive SPF10 PCR and INNO-LiPA assay, 37 of 61 (61%) samples were positive for HPV. HPV-16 was the most frequently detected type (31 of 37, 84%). Multiple infections were found in 8 of 37 (22%) of the HPV-positive samples, and co-infection by HPV-16 and HPV-33 was predominant. No cutaneous HPV types were detected."

Absence of human papillomavirus in tonsillar squamous cell carcinomas from Chinese patients. W Li, CH Thompson, D Xin, YE Cossart, CJ O'Brien, EB McNeil, K Gao, RA Scolyer, BR Rose. Am J Pathol 2003;163:2185-2189. 0/16 tonsil cancer specimens from Chinese patients were positive for HPV, compared with 31/67 (46%) of Australian tumors.

HPV infections and tonsillar carcinoma. Syrjanen S. J Clin Pathol 2004;57:449–455. Review. "By the end of 2002, 432 TCs had been analysed for HPV DNA. Overall detection rate was 51%, with HPV-16 being the most prevalent (84%). The original proposal that HPV-33 would be the most frequent HPV in TCs has not been confirmed, being present in only 4.6% of cases. HPV copy numbers are similar to those found in genital carcinomas (10-300 copies/cell), although HPV is mainly episomal in TC."

Analysis of human papillomavirus prevalence and TP53 polymorphism in head and neck squamous cell carcinomas. SS Cortezzi, PJ Provazzi, JS Sobrinho, JC Mann-Prado, PM Reis, SE de Freitas, JF Filho, EE Fukuyama, JA Cordeiro, PM Cury, JV Maniglia, LL Villa, EH Tajara, P Rahal. Cancer Genet Cygenet 2004 Apr 1;150(1):44-49. The prevalence of HPV in mouth swabs of 142 controls was 10.6%, and in 50 cancer specimens 16%.

Different risk factors in basaloid and common squamous head and neck cancer. B Kleist, A Bankau, G Lorenz, B Jager, M Poetsch. Laryngoscope 2004 Jun;114(6):1063-1068. HPV was detected in 32.5% of 67 conventional squamous cell carcinomas and 10 basaloid squamous cell carcinomas; "a basaloid morphology of the carcinomas correlated significantly with occurrence of HPV DNA (P =.0001)... Demonstration of viral DNA in the BSCC specimens was not related to tobacco or alcohol consumption. In contrast, cigarette smoking proved as significant characteristic of SCC (P =.0087)."

High frequency of HPV16-associated head and neck squamous cell carcinoma in the Puerto Rican population. A Baez, JI Almodovar, A Cantor, F Celestin, L Cruz-Cruz, S Fonseca, J Trinidad-Pinedo, W Vega. Head Neck 2004 Sep;26(9):778-784. "HPV16 was detected in tumor tissue of 52 patients (44%) with HNSCC... Positivity for HPV16 was independent of the tumor grade, tumor stage, nodal status, and tobacco or alcohol use."

Presence of HPV in head and neck tumours: high prevalence in tonsillar localization. A Venuti, G Badaracco, C Rizzo, B Mafera, S Rahimi, M Vigili. J Exp Clin Cancer Res 2004 Dec;23(4):561-566. "HPV DNA was found in 16 cases (24.6%); the HPV types detected were: HPV16 (10 cases), HPV 6 (3 cases) HPV 33, 35, and 58 (one case each). The tonsil was the location with the highest HPV positivity (6/8, 75%).... HPV status was not related to age, gender, tumour stage or grade, and use of alcohol and/or tobacco."

Altered patterns of the interferon-inducible gene IFI16 expression in head and neck squamous cell carcinoma: immunohistochemical study including correlation with retinoblastoma protein, human papillomavirus infection and proliferation index. B Azzimonti, M Pagano, M Mondini, M De Andrea, G Valente, G Monga, M Tommasino, P Aluffi, S Landolfo, M Gariglio. Histopathology 2004 Dec;45(6):560-572. "HPV DNA was found in 14 of 25 (56%) laryngeal SCCs and in five of nine (56%) tonsillar SCC specimens examined."

Expression of p16 protein is associated with human papillomavirus status in tonsillar carcinomas and has implications on survival. C Wittekindt, E Gultekin, SJ Weissenborn, HP Dienes, HJ Pfister, JP Klussmann. Adv Otorhinolaryngol 2005;62:72-80. 53% of tested tonsillar carcinomas were HPV positive.

The characteristics of human papillomavirus DNA in head and neck cancers and papillomas. T Major, K Szarka, I Sziklai, L Gergely, J Czegledy. J Clin Pathol 2005 Jan;58(1):51-55. "HPV DNA was detected in 13 of 27 cancers and 10 of 10 papillomas. Both low risk HPV-6 and HPV-11 and high risk HPV-16 were present in cancers in low copy numbers, whereas papillomas exclusively harboured low risk HPV-6 and HPV-11. E1E2 PCRs failed to determine the physical state of HPV in cancers except one case where HPV-6 DNA was integrated."

Human papillomavirus types in head and neck squamous cell carcinomas worldwide: a systematic review. AR Kreimer, GM Clifford, P Boyle, S Franceschi. Cancer Epidemiol Biomarkers Prevent 2005 Feb;14(2):467-475. "In the 5,046 HNSCC cancer specimens from 60 studies, the overall HPV prevalence was 25.9% [95% confidence interval (95% CI), 24.7-27.2]. HPV prevalence was significantly higher in oropharyngeal SCCs (35.6% of 969; 95% CI, 32.6-38.7) than oral SCCs (23.5% of 2,642; 95% CI, 21.9-25.1) or laryngeal SCCs (24.0% of 1,435; 95% CI, 21.8-26.3). HPV16 accounted for a larger majority of HPV-positive oropharyngeal SCCs (86.7%; 95% CI, 82.6-90.1) compared with HPV-positive oral SCCs (68.2%; 95% CI, 64.4-71.9) and laryngeal SCCs (69.2%; 95% CI, 64.0-74.0). Conversely, HPV18 was rare in HPV-positive oropharyngeal SCCs (2.8%; 95% CI, 1.3-5.3) compared with other head and neck sites [34.1% (95% CI, 30.4-38.0) of oral SCCs and 17.0% (95% CI, 13.0-21.6) of laryngeal SCCs]. Aside from HPV16 and HPV18, other oncogenic HPVs were rarely detected in HNSCC. Tumor site-specific HPV prevalence was higher among studies from North America compared with Europe and Asia. The high HPV16 prevalence and the lack of HPV18 in oropharyngeal compared with other HNSCCs may point to specific virus-tissue interactions."

Tissue distribution of human papillomavirus 16 DNA integration in patients with tonsillar carcinoma. S Begum, D Cao, M Gillison, M Zahurak, WH Westra. Clin Cancer Res 2005 Aug 15;11(16):5694-5699. "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)."

Strong association between infection with human papillomavirus and oral and oropharyngeal squamous cell carcinoma: a population-based case-control study in southern Sweden. BG Hansson, K Rosenquist, A Antonsson, J Wennerberg, EB Schildt, A Bladstrom, G Andersson. Acta Otolaryngol 2005 Dec;125(12):1337-1344. In 131 patients with oral and oropharyngeal squamous cell carcinoma, infection with high-risk HPV, OR = 63; 95% CI 14-480 (by PCR). "Forty-seven (36%) of the cancer patients had > or =1 specimen that was positive for a high-risk HPV type (81% of which were HPV 16)."

Head and neck squamous cell carcinoma: role of the human papillomavirus in tumour progression. M De Petrini, M Ritta, M Schena, L Chiusa, P Campisi, C Giordano, V Landolfo, G Pecorari, S Landolfo. New Microbiol 2006 Jan;29(1):25-33. In 47 squamous cell carcinomas of the oropharynx and the oral cavity, "HPV DNA was found in 50% of carcinomas of the oropharynx and 36% in those of the oral cavity, the only genotype detected being HPV 16."

Human papillomavirus and head and neck cancer: a systematic review and meta-analysis. CG Hobbs, JA Sterne, M Bailey, RS Heyderman, MA Birchall, SJ Thomas. Clin Otolaryngol 2006 Aug;31(4):259-266. "The association between HPV16 and cancer was strongest for tonsil (OR: 15.1, 95% CI: 6.8-33.7), intermediate for oropharynx (OR: 4.3, 95% CI: 2.1-8.9) and weakest for oral (OR: 2.0, 95% CI: 1.2-3.4) and larynx (OR: 2.0, 95% CI: 1.0-4.2). To investigate heterogeneity, further stratification by method of HPV16 detection, suggested that variation in the magnitude of the HPV-cancer association with cancer site was restricted to studies using ELISA: among studies using PCR, the magnitude of the summary odds ratios was similar across the four sites."

Wart Virus Linked to Head and Neck Squamous Cell Carcinoma: Presented at AHNS. By John Otrompke. Doctor's Guide, Aug. 22, 2006. Presentation title: Frequency and Types of Human Papilloma Virus in Head and neck Squamous Cell Carcinoma. Poster 160, presented at the 2006 annual meeting of the American Head and Neck Society (AHNS), by Jose-Francisco Gallegos-Hernandez. In 118 head and neck cancer patients, HPV was found in 42% of the cases, 70% of which were HPV16. "Fifty percent of patients with laryngeal cancer had HPV, he said. HPV type 16 was present in 20% of those with mouth cancer, 25% of those with cancer of the mucosae, and 66% of those with cancer of the palate, while no other forms of HPV were found in patients with those forms of cancer in the study, the poster said. HPV was found more frequently in patients over 50 years of age and in men."

Molecular and cytogenetic subgroups of oropharyngeal squamous cell carcinoma. F Perrone, S Suardi, E Pastore, P Casieri, M Orsenigo, S Caramuta, G Dagrada, M Losa, L Licitra, P Bossi, S Staurengo, M Oggionni, L Locati, G Cantu, M Squadrelli, A Carbone, MA Pierotti, S Pilotti. Clin Cancer Res 2006 Nov 15;12(22):6643-6651. 19% of 90 head and neck squamous cell carcinomas were HPV positive.

Human papillomavirus as a risk factor for the increase in incidence of tonsillar cancer. L Hammarstedt, D Lindquist, H Dahlstrand, M Romanitan, LO Dahlgren, J Joneberg, N Creson, J Lindholm, W Ye, T Dalianis, E Munck-Wikland. Int J Cancer 2006 Dec 1;119(11):2620-2623. In Stockholm, "The incidence of tonsillar cancer increased 2.8-fold (2.6 in men and 3.5 in women) from 1970 to 2002. During the same period, a significant increase in the proportion of HPV-positive tonsillar cancer cases was observed, as it increased 2.9-fold (p < 0.001). The distribution of HPV-positive cases was 7/30 (23.3%) in the 1970s, 12/42 (29%) in the 1980s, 48/84 (57%) in the 1990s and 32/47 (68%) during 2000-2002." During this period, there was no parallel rise in smoking and alcohol consumption.

Combined analysis of HPV-DNA, p16 and EGFR expression to predict prognosis in oropharyngeal cancer. N Reimers, HU Kasper, SJ Weissenborn, H Stutzer, SF Preuss, TK Hoffmann, EJ Speel, HP Dienes, HJ Pfister, O Guntinas-Lichius, JP Klussmann. Int J Cancer 2007 Jan 18;120(8):1731-1738. 28% of 106 newly diagnosed oropharyngeal squamous cell carcinomas contained oncogenic HPV-DNA.

EGFR mutations and human papillomavirus in squamous cell carcinoma of tongue and tonsil. II Na, HJ Kang, SY Cho, JS Koh, JK Lee, BC Lee, GH Lee, YS Lee, HJ Yoo, BY Ryoo, SH Yang, YS Shim. Eur J Cancer 2007 Feb;43(3):520-526. 108 patients with tongue and tonsil cancer. "Ten patients (9%) were HPV positive and 17 (16%) had EGFR mutations. None of the patients with EGFR mutations were HPV positive. Gender, age (<60 years versus 60 years), and smoking history were not associated with EGFR mutations. A higher percentage of patients with tonsillar cancer were HPV positive than those with tongue cancer (26% and 0%, respectively; P<0.001)."

Human papillomavirus seropositivity and risks of head and neck cancer. EM Smith, JM Ritchie, M Pawlita, LM Rubenstein, TH Haugen, LP Turek, E Hamsikova. Int J Cancer 2007 Feb 15;120(4):825-832. "204 HNC cases and 326 controls evaluated for HPV presence in sera using ELISAs for anti-HPV VLP antibodies and HPV-16 E6 and/or E7 antibodies, and in tumor tissue using PCR and DNA sequencing. Anti-HPV-16 VLP was detected in 33.8% of cases and 22.4% of controls, anti-E6 in 20.6% of cases and 0.9% of controls and anti-E7 in 18.6% of cases and 0.6% of controls. HPV-16 DNA was detected in 26.1% of tumors. The adjusted risk of HNC was elevated among those seropositive for HPV-16 VLP (odds ratio (OR) = 1.7, 1.1-2.5), E6 (OR = 32.8, 9.7-110.8) or E7 (OR = 37.5, 8.7-161.2). Compared to HPV DNA-negative/seronegative cases, tumor HPV-16 cases had increased risk of detection with anti-VLP antibodies (OR = 6.8, 3.1-14.9). The odds were more pronounced among cases seropositive for E6 (OR = 69.0, 19.3-247) or E7 (OR = 50.1, 14.7-171). Antibodies against E6 or E7 were associated with risk of cancer in the oral cavity (OR = 5.1, 1.2-22.4) and oropharynx (OR = 72.8, 16.0-330), and with disease characteristics: stage, grade and nodal status."

HPV integration begins in the tonsillar crypt and leads to the alteration of p16, EGFR and c-myc during tumor formation. SH Kim, BS Koo, S Kang, K Park, H Kim, KR Lee, MJ Lee, JM Kim, EC Choi, NH Cho. Int J Cancer 2007 Apr 1;120(7):1418-1425. "We observed a significant difference in HPV prevalence between 52 TCs and 69 CFTs [tonsillitis] (73.1% vs. 11.6%), and most of the HPVs were type 16 (87.2%) and nonepisomal (94.1%). Most TCs associated with HPV arose from the tonsillar crypts, and tended to be inverted and poorly differentiated."

New evidence for geographic variation in the role of human papillomavirus in tonsillar carcinogenesis. W Li, N Tran, SC Lee, CJ O'Brien, GM Tse, RA Scolyer, A Hong, C Milross, KH Yu, BR Rose. Pathology 2007 Apr;39(2):217-222. "Of the 31 Hong Kong cancers with amplifiable DNA, nine (29%) were HPV positive by PCR compared with 46% from New South Wales and 0% from Jilin Province."

Combined analysis of HPV-DNA, p16 and EGFR expression to predict prognosis in oropharyngeal cancer. N Reimers, HU Kasper, SJ Weissenborn, H Stützer, SF Preuss, TK Hoffmann, EJ Speel, HP Dienes, HJ Pfister, O Guntinas-Lichius, JP Klussmann. Int J Cancer 2007 Apr 15;120(8):1731-1738. 106 newly diagnosed OSCCs. "Twenty-eight percent of the cases contained oncogenic HPV-DNA and 30% were positive for p16," detection method and HPV types found were not specified in the abstract.

[Human papillomavirus: association with head and neck cancer.] JF Gallegos-Hernández, E Paredes-Hernández, R Flores-Díaz, G Minauro-Muñoz, T Apresa-García, DM Hernández-Hernández. Cir Cir 2007 May-Jun;75(3):151-155. "Results: There were 118 patients were HPV positive and oropharyngeal and laryngeal cancer patients were the most frequently affected (55% and 50%, respectively). HPV-16 was most frequently isolated (70%). Laryngeal cancer patients suffered the highest ratio of HPV-16 infection (68.7%). Factors associated with HPV (univariate analysis) were age >50 years, tobacco/alcohol consumption and male gender. In multivariate analysis, none of the variables showed importance (p >0.5); HPV infection was more frequent in patients with history of alcohol/tobacco consumption (p = 0.6)."

Case–control study of human papillomavirus and oropharyngeal cancer. G D'Souza, AR Kreimer, R Viscidi, M Pawlita, C Fakhry, WM Koch, WH Westra, ML Gillison. New Engl J Med 2007 May 10;356(19):1944-1956. 100 patients with newly diagnosed oropharyngeal cancer and 200 control patients without cancer; tumor sites were: tonsil 54, base of tongue or lingual tonsil 36, other 10. "Oropharyngeal cancer was significantly associated with oral HPV type 16 (HPV-16) infection (odds ratio, 14.6; 95% CI, 6.3 to 36.6), oral infection with any of 37 types of HPV (odds ratio, 12.3; 95% CI, 5.4 to 26.4), and seropositivity for the HPV-16 L1 capsid protein (odds ratio, 32.2; 95% CI, 14.6 to 71.3). HPV-16 DNA was detected in 72% (95% CI, 62 to 81) of 100 paraffin-embedded tumor specimens, and 64% of patients with cancer were seropositive for the HPV-16 oncoprotein E6, E7, or both.... Moreover, when the analysis was restricted to patients who were seropositive for the HPV-16 L1 protein, the odds of oropharyngeal cancer were not increased among heavy users of tobacco or alcohol." [Note: Other analyses using supposedly HPV-negative patients likely include false negatives, which produce confounded results which falsely implicate tobacco use.]

Human papillomavirus 16 and head and neck squamous cell carcinoma. CS Furniss, MD McClean, JF Smith, J Bryan, HH Nelson, ES Peters, MR Posner, JR Clark, EA Eisen, KT Kelsey. Int J Cancer 2007 Jun 1;120(11):2386-2392. In a case-control study of approximately 1,000 individuals,... HPV16 seropositivity was associated with 1.5- and 6-fold risks for tumors of the oral cavity and pharynx, respectively. There was a dose response trend for HPV16 titer and increasing risk of HNSCC (p < 0.0001) and HPV16 tumor DNA (p < 0.0001). In cases, HPV16 DNA and seropositivity were significantly associated with sexual activity; odds ratios (ORs) of 12.8 and 3.7 were observed for more than 10 oral sexual partners and ORs of 4.5 and 3.2 were associated with a high number of lifetime sexual partners, respectively."

Studies on interplay between human papilloma virus infection and p53 gene alterations in head and neck squamous cell carcinoma of an Indian patient population. S Mitra, S Banerjee, C Misra, RK Singh, A Roy, A Sengupta, CK Panda, S Roychoudhury. J Clin Pathol 2007 Sep;60(9):1040-1047. 69% of 92 head and neck squamous cell carcinomas were HPV positive.

Human Papillomavirus and Oropharyngeal Cancer. Correspondence re D'Souza 2007. New Engl J Med 2007 Sep 13;357(11):1156-1158. "Although viral integration occurs in the majority of cervical cancers, it is neither necessary for nor specific to invasive carcinoma. Increased expression and stability of viral oncogene transcripts occur as a consequence of viral integration. Analogous deregulation of viral oncogene expression may occur in episomal virus through methylation or mutation of the viral upstream regulatory region. Although we agree with Ukpo et al. that patterns of in situ hybridization and RT-PCR are indirect measures of integration, analysis of restriction-fragment–length polymorphisms by Southern blot hybridization is a direct measure. Viral integration into the genome of head-and-neck squamous-cell carcinoma has been demonstrated by this method and through the cloning of viral-cell genome fusion sites, albeit in few cases."

Gene expression profiles in HPV-infected head and neck cancer. NF Schlecht, RD Burk, L Adrien, A Dunne, N Kawachi, C Sarta, Q Chen, M Brandwein-Gensler, MB Prystowsky, G Childs, RV Smith, TJ Belbin. J Pathol 2007 Nov;213(3):283-293. "Total DNA and RNA were extracted and purified from frozen tumour samples and gene expression levels were compared to a universal human reference RNA standard using a 27 323 cDNA microarray chip. HPV detection and genotyping were performed using an MY09/11-PCR system and RT-PCR. HPV was detected in 29% of HNSCC tumours. Most harboured only HPV16 and expressed the HPV16-E6 oncogene. HPV prevalence was highest in pharyngeal tumours (45%).... Focusing on never-smokers, we further identified a distinct subset of 123 genes that were specifically dysregulated in HPV16-positive HNSCC...."

Lack of association of alcohol and tobacco with HPV16-associated head and neck cancer. KM Applebaum, CS Furniss, A Zeka, MR Posner, JF Smith, J Bryan, EA Eisen, ES Peters, MD McClean, KT Kelsey. J Natl Cancer Inst 2007 Dec 5;99(23):1801-1810. 722 cases. A sorry excuse for a study from the Harvard School of Public Health, which is clearly reluctant to adopt modern scientific techniques. They used serology to determine HPV infection status, a method which fails to identify about half of known-infected cervical cancer cases, and they only tested for HPV16. They admit that "The presence of serum antibodies to the virus may be a poor surrogate for viral infection at the cancer site." They did determine that smoking and drinking were not associated with the risk of head and neck squamous cell carcinoma among those whose blood tested positive for HPV16. And, that "The relationships among pharyngeal cancer risk, HPV16 status, and alcohol and smoking were essentially unchanged when HPV16 DNA detection in tumors was used to determine HPV16 status. There was no dose–response relationship between either alcohol or tobacco use and pharyngeal cancer risk in case subjects with detectable HPV16 DNA in tumors compared with the control subjects," data not shown. This finding indicates that the supposed risks from smoking and drinking are spurious and due to confounding by undetected HPV infection, and so their claim that "HPV16 serology was not a strong confounder for associations of HNSCC risk and cigarette smoking and alcohol consumption" (based upon playing around with regression lines) is false.

Lower prevalence but favorable survival for human papillomavirus-related squamous cell carcinoma of tonsil in Taiwan. CY Chien, CY Su, FM Fang, HY Huang, HC Chuang, CM Chen, CC Huang. Oral Oncol 2008 Feb;44(2):174-179. 12.6 % of 111 squamous cell carcinoma of tonsil samples were positive for HPV; types not specified in abstract.

Two types of squamous cell carcinoma of the palatine tonsil characterized by distinct etiology, molecular features and outcome. L Charfi, T Jouffroy, P de Cremoux, N Le Peltier, M Thioux, P Fréneaux, D Point, A Girod, J Rodriguez, X Sastre-Garau. Cancer Lett 2008 Feb 18;260(1-2):72-78. "HPV DNA was found in 32/52 (62%) cases, (HPV16 genotype in 27). All patients with no history of tobacco-alcohol exposure presented HPV positive tumor (p=0.0008). A strong correlation was observed between positive HPV status, decrease in pRB and increase in p16 expression level. 5 year overall survival rate was higher in HPV16 positive patients than in HPV negative (71% versus 36%; p=0.023). HPV status remained a significant prognostic factor in multivariate analysis."

Distinct risk factor profiles for human papillomavirus type 16-positive and human papillomavirus type 16-negative head and neck cancers. ML Gillison, G D'Souza, W Westra, E Sugar, W Xiao, S Begum, R Viscidi. J Natl Cancer Inst 2008 Mar 19;100(6):407-420. HPV-16 was detected in 92 of 240 (38%) HNSCC cases at the Johns Hopkins Hospital from 2000 through 2006. Only one type of HPV was tested for, and the method used would fail to detect some positive cases.

Human papillomavirus infection and oral cancer: a case-control study in Montreal, Canada. J Pintos, MJ Black, N Sadeghi, P Ghadirian, AG Zeitouni, RP Viscidi, R Herrero, F Coutlée, EL Franco. Oral Oncol 2008 Mar;44(3):242-250. HPV DNA was detected in 19% of cases (14 out of 72), and 5% of controls (six out of 129), by the PGMY09/11 polymerase chain reaction protocol. "Among tonsil-related cancers (palatine tonsil and base of tongue) viral DNA was detected in 43% of cases (nine out of 21). The OR for tonsil-related cancers for high-risk HPV types was 19.32 (95%CI: 2.3-159.5), after adjustment for socio-demographic characteristics, tobacco, and alcohol consumption. The equivalent OR for HPV 16 seropositivity was 31.51 (95%CI: 4.5-219.7). The ORs of non-tonsillar oral cancers for high risk HPV DNA in oral cells and for seropositivity were 2.14 (95%CI: 0.4-13.0) and 3.16 (95%CI: 0.8-13.0), respectively."

p53 codon 72 polymorphism associated with risk of human papillomavirus-associated squamous cell carcinoma of the oropharynx in never-smokers. X Ji, AS Neumann, EM Sturgis, K Adler-Storthz, KR Dahlstrom, JT Schiller, Q Wei, G Li. Carcinogenesis 2008 Apr;29(4):875-879. 188 newly diagnosed squamous cell carcinomas of the oropharynx, versus 342 cancer-free control subjects frequency matched by age (+/-5 years), sex, tobacco smoking status and alcohol drinking status. "We found that HPV16 seropositivity was associated with an increased risk of SCCOP [adjusted odds ratio (OR), 5.7; 95% confidence interval (CI), 3.7-8.7], especially among never-smokers (adjusted OR, 14.1; 95% CI, 6.0-32.9) and among subjects with the p53 codon 72 variant genotypes [Arginine (Arg)/Proline (Pro) and Pro/Pro] (adjusted OR, 9.2; 95% CI, 4.7-17.7). A significant multiplicative interaction on the risk of SCCOP was also found between the p53 codon 72 polymorphism and HPV16 seropositivity (P = 0.05). Among never-smokers, the risk of SCCOP for those who had both HPV16 seropositivity and p53 codon 72 variant genotypes (Arg/Pro + Pro/Pro) was particularly high (adjusted OR, 22.5; 95% CI, 4.8-106.2)."

The biomarkers of human papillomavirus infection in tonsillar squamous cell carcinoma-molecular basis and predicting favorable outcome. KT Kuo, CH Hsiao, CH Lin, LT Kuo, SH Huang, MC Lin. Mod Pathol 2008 Apr;21(4):376-386. 92 patients with primary tonsillar squamous cell carcinoma diagnosed or treated in National Taiwan University Hospital. The percentage positive varied by method: "The positive rates of nested PCR-based genechips, overexpression of p16(INK4A), and high-risk HPV in situ hybridization were 75% (69/92), 53% (49/92), and 44% (40/92), respectively. Both overexpression of P16(INK4A) and high-risk HPV in situ hybridization positivity were associated with favorable prognoses (P=0.004 and 0.001, respectively) and also independent prognostic factors in multivariate analyses (P=0.01 and 0.01, respectively)."

High Incidence of HPV in Patients With Head and Neck Squamous Cell Carcinoma Suggests Benefit From Routine Testing and Vaccination in Both Genders: Presented at IM. By Crina Frincu-Mallos, Ph.D. Re: The Incidence of Human Papillomavirus in Head and Neck Squamous Cell Carcinomas. Abstract PR#6. Reported at the 2008 Internal Medicine Annual Scientific Meeting, May 20, 2008. Lead author Payal C. Desai. 34 men and 7 women, all smokers. 12 of 41 (29%) were HPV-positive. 11 samples were positive by both PCR and p16 staining, 1 was positive by PCR only, while 4 more samples were positive by p16 staining only. 10 were infected by HPV 16, and 2 by HPV 33 and HPV 45. "Since HPV was found to be a prognostic factor for HNSCC, regardless of gender, testing and vaccination of both genders should be considered."

Human papillomavirus frequency in oral and oropharyngeal cancer in Greece. M Romanitan, A Näsman, T Ramqvist, H Dahlstrand, L Polykretis, P Vogiatzis, P Vamvakas, G Tasopoulos, C Valavanis, P Arapantoni-Dadioti, K Banis, T Dalianis. Anticancer Res 2008 Jul-Aug;28(4B):2077-2080. "13/103 (13%) tumours were HPV-positive and the majority of these were HPV-16-positive. Of the tonsillar cancer samples, 12/28 (43%) were HPV-positive and, notably, 1/6 (17%) collected between 1992-1998 and 11/22 (50%) collected between 2000-2007 were HPV-positive. Of the tongue cancer samples, 1/38 (3%) were HPV-positive, while none of the 41 oral cavity cancer samples was HPV-positive."

Does pretreatment seropositivity to human papillomavirus have prognostic significance for head and neck cancers? EM Smith, LM Rubenstein, JM Ritchie, JH Lee, TH Haugen, E Hamsikova, LP Turek. Cancer Epidemiol Biomarkers Prev 2008 Aug;17(8):2087-2096. "Sera from 156 HNC patients were tested for antibodies to HPV-16-derived antigens using ELISA. HPV-16 in tumors was evaluated by PCR and DNA sequencing. RESULTS: HPV-16 antibodies were found in 33% with HPV-16 VLP, 21% with HPV-16 E6, and 21% with E7. HPV-16 was detected in 26% of tumors. There was a strong correlation between detection of HPV-16 tumor DNA and antibodies to HPV-16 E6 or E7 (kappa = 0.7) but not to HPV-16 VLP (kappa = 0.4). Multivariate analyses showed significantly better disease-specific survival in seropositive HPV-16 VLP [hazard ratio (HR), 0.4; 95% confidence interval (95% CI), 0.1-0.9], HPV-16 E6 (HR, 0.1; 95% CI, 0.02-0.5), and HPV-16 E7 (HR, 0.3; 95% CI, 0.1-0.9) cases. Less disease recurrence occurred among those with antibodies to both E6 and E7 compared with those negative to both (P = 0.003). There was better disease-specific survival in patients who were E6 positive at baseline and remained positive at follow-up compared with individuals who were E6 negative at both time points (P = 0.03; kappa = 0.9)."

Human papillomavirus 6 seropositivity is associated with risk of head and neck squamous cell carcinoma, independent of tobacco and alcohol use. CS Furniss, MD McClean, JF Smith, J Bryan, KM Applebaum, HH Nelson, MR Posner, KT Kelsey. Ann Oncol 2009 Mar;20(3):534-541. Sera from 486 incident HNSCCs and 548 population controls tested for antibodies to human papillomavirus (HPV)6, HPV11, HPV16, and HPV18 L1. "HPV6 antibodies were associated with an increased risk of pharyngeal cancer [odds ratio (OR)=1.6, 1.0-2.5], controlling for smoking, drinking, and HPV16 seropositivity. In HPV16-seronegative subjects, high HPV6 titer was associated with an increased risk of pharyngeal cancer (OR=2.3, 1.1-4.8) and oral cancer (OR=1.9, 1.0-3.6), suggesting that the cancer risk associated with HPV6 is independent of HPV16."

Expression of p16 in benign and malignant cystic squamous lesions of the neck. D Cao, S Begum, SZ Ali, WH Westra. Hum Pathol Hum Pathol 2010 Apr;41(4):535-539. "Human papillomavirus 16 was detected in the 3 p16-positive cystic squamous cell carcinomas but in none of the p16-positive benign lymphoepithelial cysts."

HPV-positive/p16-positive/EBV-negative nasopharyngeal carcinoma in white North Americans. JH Maxwell, B Kumar, FY Feng, JB McHugh, KG Cordell, A Eisbruch, FP Worden, GT Wolf, ME Prince, JS Moyer, TN Teknos, DB Chepeha, J Stoerker, H Walline, TE Carey, CR Bradford. Head Neck 2010 May;32(5):562-567. 5 patients with nasopharyngeal cancer were positive for HPV and negative for EBER.

See also:

Confounding By Infection - why studies that don't include full detection of HPV (and other causal infections) are defective, and falsely blame smoking and other non-causal associations.

The Lie That p53 Mutations Are the Mechanism Behind Lung Cancer - this is because p53 mutations happen after maligancy has occurred, and the point is relevant to other cancers as well.

cast 04-17-10