HPV Causes Oral Cancer

Morphological and immunohistochemical evidence suggesting human papillomavirus (HPV) involvement in oral squamous cell carcinogenesis. K Syrjanen, S Syrjanen, M Lamberg, S Pyrhonen, J Nuutinen. Int J Oral Surg 1983 Dec;12(6):418-424. 4/40 OSCCs were HPV positive.

Papillomavirus DNA in human tongue carcinomas. E-M de Villiers, H Weidauer, H Otto, H zur Hausen. Int J Cancer 1985 Nov 15;36(5):575-578. 3/7 carcinomas of the tongue were HPV positive.

Local immunoreactivity and human papillomavirus (HPV) in oral precancer and cancer lesions. PO Lind, SM Syrjanen, KJ Syrjanen, HS Koppang, E Aas. Scand J Dent Res 1986 Oct;94(5):419-426. An observation of 20 oral leukoplakia patients, 10 of whom developed cancer: "Preceding the malignant tranformation by 12 to 15 months, however, a remarkable shift from IgA to IgG plasma cell predominance was noticed in the biopsies of the cancer series, not detectable in the non-cancer group." 7/10 of the cancer group and 6/10 of the non-cancer group were positive for HPV.

Presence of human papillomavirus DNA in benign and precancerous oral leukoplakias and squamous cell carcinomas. A Gassenmaier, OP Hornstein. Dermatologica 1988;176(5):224-233. 56/373 (15%) specimens were HPV positive.

Detection of human papillomavirus DNA in oral mucosal lesions using in situ DNA-hybridization applied on paraffin sections. SM Syrjänen, KJ Syrjänen, MA Lamberg. Oral Surg Oral Med Oral Pathol 1986 Dec;62(6):660-667. HPV antigens "were found in 4 of 7 squamous cell papillomas, in 2 of 2 classic condylomas, in 2 of 10 papillary hyperplasias, and in 2 of 3 leukoplakia lesions. Two of the squamous cell papillomas contained HPV 6 DNA, and 4 additional lesions were positive for HPV 11 DNA. In one of the condylomas, a double infection by HPV 6 and 11 was found, while the second was positive for HPV 11 alone. Both the HPV antigen-positive papillary hyperplasias contained HPV 6 DNA, as did the HPV antigen-positive leukoplakia lesions. Of the latter, one was infected by HPV 6 and 11. DNA of the "high-risk" HPV 16 was contained in two lesions: one lichen planus lesion and one of the two squamous cell carcinomas."

Human papillomavirus (HPV) DNA sequences in oral precancerous lesions and squamous cell carcinoma demonstrated by in situ hybridization. SM Syrjanen, KJ Syrjanen, RP Happonen. J Oral Pathol 1988 Jul; 17(6):273-278. 6/51 (11.8%) oral SCCs contained HPV DNA.

Detection of human papillomavirus genes in human oral tissue biopsies and cultures by polymerase chain reaction. NJ Maitland, T Bromidge, MF Cox, IJ Crane, SS Prime, C Scully. Br J Cancer 1989 May;59(5):698-703. Their main subject is the PCR process; however, they speak of "unequivocally positive results, in almost 50% of oral carcinomas tested." This work was supported by the Cancer Research Campaign.

High prevalence of human papillomavirus infection and possible association with betel quid chewing and smoking in oral epidermoid carcinomas in Taiwan. KW Chang, CS Chang, KS Lai, MJ Chou, KB Choo. J Med Virol 1989 May;28(1):57-61. HPV was detected in 76.4% of 17 oral epidermoid (squamous) carcinomas.

Detection of human papillomavirus (HPV) DNA in oral squamous cell carcinomas by in situ hybridization and ploymerase chain reaction. F Chang, S Syrjanen, J Nuutinen, J Karja, K Syrjanen. Arch Dermatol Res 1990;282(8):493-497. 11/40 oral squamous cell carcinoma surgical samples contained HPV DNA. HPV was also found in adjacent precursor lesions, but not from the margins.

Detection of human papillomavirus-genomic DNA in oral epithelial dysplasias, oral smokeless tobacco-associated leukoplakias, and epithelial malignancies. RO Greer Jr, LR Eversole, LK Crosby. J Oral Maxillofac Surg 1990;48:1201-1205. 3/50 (6%) oral SCCs were positive for HPV. This work was supported by the Smokeless Tobacco Research Council and the Sands House Foundation.

Human papillomavirus DNA types in squamous cell carcinomas of the head and neck. SL Watts, EE Brewer, TL Fry. Oral Surg Oral Med Oral Pathol 1991 Jun;71(6):701-707. 27/30 (90%) oral squamous cell carcinomas were HPV positive by PCR, and 31/49 (63%) by Southern Blot. This work was supported by the US Public Health Service and NIH.

Detection of human papillomavirus DNA by in situ DNA hybridization and polymerase chain reaction in premalignant and malignant oral lesions. KR Shroyer, RO Greer Jr. Oral Surg Oral Med Oral Pathol 1991 Jun;71(6):708-713. 1/10 (10%) oral squamous cell carcinomas were HPV positive, as well as 4/24 epithelial dysplasias (17%). This work was supported by the Smokeless Tobacco Research Council.

In situ hybridization analysis of human papillomavirus DNA in oral muosal lesions. MS Zeuss, CS Miller, DK White. Oral Surg Oral Med Oral Pathol 1991 Jun;71(6):714-720. HPV DNA was found in benign lesions but not in 15 oral squamous cell carcinomas. This work was supported by the University of Kentucky Medical Center Research Fund.

Detection of human papillomavirus in head and neck tumors with DNA hybridization and immunohistochemical analysis. H Tsuchiya, Y Tomita, H Shirasawa, H Tanzawa, K Sato, B Simizu. Oral Surg Oral Med Oral Pathol 1991 Jun;71(6):721-725. HPV was found in 3/23 oral SCCs.

In situ DNA hybridization analysis of oral papillomas, leukoplakias, and carcinomas for human papillomavirus. SK Young, KW Min. Oral Surg Oral Med Oral Pathol 1991 Jun;71(6):726-729. HPV identified in 0/17 oral squamous cell carcinomas. This work was supported by the Presbyterian Health Foundation.

Study of human papillomavirus in oral epithelial dysplasia and epidermoid carcinoma in the absence of tobacco and alcohol use. RA Abdelsayed. Oral Surg Oral Med Oral Pathol 1991 Jun;71(6):730-732. HPV was found in 0/18 carcinomas of patients who were nonusers of tobacco.

Prevalence and expression of human papillomavirus in tonsillar carcinomas, indicating a possible viral etiology. PJ Snijders, FV Cromme, AJ van den Brule, HF Schrijnemakers, GB Snow, CJ Meijer, JM Walboomers. Int J Cancer 1992 Jul 30;51(6):845-850. Of 10 biopsies of tonsillar carcinomas, 4 contained HPV-16 DNA, 4 contained HPV-33 DNA, and 1 contained HPV-16/33 double infection. "All carcinomas appeared HPV-positive, whereas all cases of tonsillitis [n=7] were HPV-negative."

Association between malignancies of the upper aerodigestive tract and uterine cervix. MR Spitz, JG Sider, SP Schantz, GR Newell. Head Neck 1992 Sep-Oct;14(5):347-351. Elevated risks were found for cervical cancer after having cancer of the mouth; and for cancers of the mouth after having cervical cancer, with HPV suspected as the reason behind this paired occurrence.

Non radioactive in situ hybridization for detection of human papilloma virus DNA in squamous cell carcinoma of tongue. JF Honig. Bull Group Int Rech Sci Stomatol Odontol 1992 Sep-Dec;35(3-4):107-115. 60% of 12 squamous cell carcinomas of the tongue "not related to tobacco or alcohol use" were positive for HPV DNA.

Analysis of human papillomavirus DNA in oral squamous cell carcinomas. KV Woods, EJ Shilltoe, MR Spitz, SP Schantz, K Adler-Storthz. J Oral Pathol 1993 Mar;22(3):101-108. "Fourteen (78%) of 18 primary tumors, 6 (67%) of 9 normal epithelial tissues from the patients and 5 (100%) of 5 neck metastases were HPV DNA-positive... There was no significant association between HPV presence and any of 12 factors or patient characteristics studied."

Human papillomavirus (HPV) infections in carcinogenesis of the upper aerodigestive tract. K Syrjanen & Kuopio Papillomavirus Research Group (S Syrjanen, R Mantyjarva, S Saarikoski, F Chang, S Parkkinen, M Yliskoski, T Nurmi, V Kataja, J Kellokoski, M Hippelainen, A Tervahauta, J Janne, L Albonen). Research proposal to the Council for Tobacco Research, estimated date 1993.

Correlation of mitotic abnormalities and the presence of human papillomavirus antigens in squamous cell carcinomas of the oral cavity. D Mukhopadhyay, R Chatterjee, RN Chakraborty. Cancer Lett 1993 Oct 15;74(1-2):51-56. 16/19 (84%) with abnormal and 15/25 lesions (60%) with normal mitotic figures were HPV positive.

[p53 alterations and HPV status in oral squamous cell carcinomas] M Barten, C Ostwald, P Muller, T Loning, K Milde-Langosch, Y Wukasch. Verh Dtsch Ges Pathol 1994;78:255-259. 28/40 (70%) oral carcinomas contained HPV-16 or 18.

Detection of HPV DNA in oral carcinoma using polymerase chain reaction together with in situ hybridization. CS Miller, MS Zeuss, DK White. Oral Surg Oral Med Oral Pathol 1994 May;77(5):480-486. HPV was detected in 20/30 specimens (66.7%).

Human papillomavirus DNA in oral squamous cell carcinomas and normal mucosa. C Ostwald, P Muller, M Barten, K Rutsatz, M Sonnenberg, K Milde-Langosch, T Loning. J Oral Pathol Med 1994 May;23(5):220-225. 16/26 (61.5%) OSCCs were positive, and "The frequency of HPV detection in non-neoplastic mucosa of tumor patients decreased claerly with increasing distance from the tumor... In contrast, normal buccal mucosa of a group of healthy volunteers contained HPV DNA only in 1% (1/97)."

H-ras oncogene mutation and human papillomavirus infection in oral carcinomas. JA Anderson, JC Irish, CM McLachlin, BY Ngan. Arch Otolaryngol Head Neck Surg 1994 Jul;120(7):755-760. 6/27 OSCCs (22%) were positive for HPV DNA.

HPV detection using "hot start" polymerase chain reaction in patients with oral cancer: a clinicopathological study of 64 patients. M Brandwein, J Zeitlin, GJ Nuovo, P MacConnell, C Bodian, M Urken, H Biller. Mod Pathol 1994 Sep;7(7):720-727. 16 of 64 intraoral cancers were positive for HPV. "Three of 16 HPV+ patients (19%) had never smoked cigarettes; however, 16% of the HPV- group had also never smoked."

Detection of HPV DNA by in situ hybridization in benign, premalignant and malignant lesions of the oral mucosa. MA Gonzalez-Moles, I Ruiz-Avila, S Gonzalez-Moles, I Martinez, A Ceballos, F Nogales. Bull Group Int Rech Sci Stomatol Odontol 1994 Sep-Dec;37(3-4):79-85. HPV was found in 37% of 27 oral squamous cell carcinomas.

Presence of human papillomavirus sequences in tumour-derived human oral keratinocytes expressing mutant p53. WA Yeudall, IC Paterson, V Patel, SS Prime. Oral Oncol, Eur J Cancer 1995 Mar;31B(2):136-143. 2/8 OSCC early passaged cell lines were positive for HPV-16. "HPV sequences were undetectable in cells at later passage (12-15), suggesting that viral sequences had been lost during growth in vitro, or that negative selection of HPV-containing cells had occurred."

Human papillomavirus in 91 oral cancers from Indian betel quid chewers -- high prevalence and multiplicity of infections. P Balaram, KR Nalinnakumari, E Abraham, A Balan, NK Hareendran, HU Bernard, SY Chan. Int J Cancer 1995 May 16;61(4):450-454. "HPV DNA was detected in 74% of these lesions, of which 41% had multiple HPV infections," and 9/11 (81%) of tongue lesions were HPV positive.

Detection of human papillomavirus DNA sequences in oral squamous cell carcinomas and their relation to p53 and proliferating cell nuclear antigen expression. M Shindoh, I Chiba, M Yasuda, T Saito, K Funaoka, T Kohgo, A Amemiya, Y Sawada, K Fujinaga. Cancer 1995 Nov 1;76(9):1513-1521. 23/77 (30%) OSCCs were positive for HPV.

Age-dependence of human papillomavirus DNA presence in oral squamous cell carcinomas. IB Cruz, PJ Snijders, RD Steenbergen, CJ Meijer, GB Snow, JM Walboomers, I van der Waal. Eur J Cancer B Oral Oncol 1996 Jan;32B(1):55-62. 54.3% of 35 OSCCs were positive for HPV, and the prevalence of the virus was higher in patients less than 60 years old.

Mutations in the p53 gene and human papillomavirus infection as significant prognostic factors in squamous cell carcinomas of the oral cavity. I Chiba, M Shindoh, M Yasuda, Y Yamazaki, A Amemiya, Y Sato, K Fujinaga, K Notani, H Fukuda. Oncogene 1996 Apr 18;12(8):1663-1668. 8/38 cases (21%) were positive for HPV-16.

Human papillomavirus and cancers of the upper aerodigestive tract: a review of epidemiological and experimental evidence. S Franceschi, N Munoz, XF Bosch, PJ Snijders, JM Walboomers. Cancer Epidemiol Biomarkers Prev 1996 Jul;5(7):567-575. "Largest and most accurate case series ) i.e., >15 UADT cancer cases, based on best HPV detection techniques) showed HPV in 46% of cancers of the oral cavity and pharynx, 15% of cancers of the esophagus, and 24% of cancers of the larynx, with, however, great discrepancies from one study to another. An additional 14 case series with a comparison group of noncancer patients revealed approximately a 4-fold higher HPV prevalence in UADT cancer tissues than in normal ones."

Loss of the adenomatous polyposis coli gene and human papillomavirus infection in oral carcinogenesis. EJ Mao, D Oda, WG Haigh, AM Beckmann. Eur J Cancer B Oral Oncol 1996 Jul;32B(4):260-263. "More than half of the carcinoma cases were found to contain both LOH of APC and HPV infection."

Increase of proliferating cell nuclear antigen (PCNA) expression in HPV-18 positive oral squamous cell carcinomas. MA Gonzalez-Moles, A Rodriguez-Archilla, I Ruiz-Avila, S Gonzalez-Moles, R Marfil-Alvarez. Acta Stomatol Belg 1996 Sep;93(3):113-118. 7/37 OSCCs (19.1%) were positive for HPV-18, and PCNA expression (a marker of cell proliferation) was greater in these tumors.

[Study of HPV in oral squamous cell carcinoma.] L Lei, H Li, Y Sun. Zhonghua Kou Qiang Yi Xue Za Zhi 1996 Nov;31(6):375-377. 11/23 OSCCs (47.8%) were positive for HPV, versus 20% of normal tissue (source not specified).

Detection and analysis of human papillomavirus 16 and 18 homologous DNA sequences in oral lesions. S Wen, T Tsuji, X Li, Y Mizugaki, Y Hayatsu, F Shinozaki. Anticancer Res 1997 Jan-Feb;17(1A):307-311. 14/45 OSCCs (31.1%) were positive for HPV-16 and/or -18..

Association of human papillomavirus type 11 DNA with squamous cell carcinoma of the tongue. KH Fife, L Fan, MH Fritsch, J Bryan, DR Brown. Arch Otolaryngol Head Neck Surg 1996 Dec;122(12):1404-1408. Case report.

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. 9/165 (60%) of tumors of Waldeyer's tonsillar ring were positive for HPV.

Mutated and wild-type p53 expression and HPV integration in proliferative verrucous leukoplakia and oral squamous cell carcinoma. R Gopalakrishnan, CM Weghorst, TA Lehman, RJ Calvert, G Bijur, CL Sabourin, SR Mallory, DE Schuller, GD Stoner. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 1997 Apr;83(4):471-477. 2/7 OSCCs (29%) were positive for HPV.

[The presence of Human Papillomavirus (HPV) in microinvasive in situ spinocellular carcinoma of the oral cavity. Preliminary report.] MD Mignogna, R Duraccio, R Carbone, RE Mignogna, L Lo Muzio. Minerva Stomatol 1997 Jun;46(6):287-291. A variety of HPV types were found in 9 of 15 cases (60%).

Human papillomavirus expression and p53 gene mutations in squamous cell carcinoma. LG Portugal, JD Goldenberg, BL Wenig, KT Ferrer, E Nodzenski, JB Sabnani, C Javier, RR Weichselbaum, EE Vokes. Arch Otolaryngol Head Neck Surg 1997 Nov;123(11):1230-1234. 11/100 patients with oral (58) and tonsillar (42) squamous cell carcinoma were positive for HPV.

Low detection rate of HPV in oral and laryngeal carcinomas. T Matzow, M Boysen, M Kalantari, B Johansson, B Hagmar. Acta Oncol 1998;37(1):73-76. HPV was found in only 1/38 (2.6%) oral carcinomas.

p53 alterations and HPV infections are common in oral SCC: p53 gene mutations correlate with the absence of HPV 16-E6 DNA. J Penhallow, H Steingrimsdottir, F Elamin, S Warnakulasuriya, F Farzaneh, N Johnson, M Tavassoli. Int J Oncol 1998 Jan;12(1):59-68. "HPV 6 and HPV 16 were detected in 14/28 (50%) oral SCC and 4 of 12 (33%) precancerous lesions, 7 tumours harboured both types."

Prevalence of human papillomavirus infection in premalignant and malignant lesions of the oral cavity in U.K. subjects: a novel method of detection. F Elamin, H Steingrimsdottir, S Wanakulasuriya, N Johnson, M Tavassoli. Oral Oncol 1998 May;34(3):191-197. HPV was detected in 14/28 oral carcinomas (50%); "HPV 6 and HPV 16 were the only HPV types detected and seven tumours harboured both types."

p53 mutations and human papillomavirus DNA in oral squamous cell carcinoma: correlation with apoptosis. JY Koh, NP Cho, G Kong, JD Lee, K Yoon. Br J Cancer 1998 Aug;78(3):354-359. "HPV DNAs were detected from 22 out of 42 SCCs (52%) with predominance of HPV-16 (68%)."

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. HPV was present in 3/14 (21%) oral cavity carcinomas.

Oral cancer risk in relation to sexual history and evidence of human papillomavirus infection. SM Schwartz, JR Daling, DR Doody, GC Wipf, JJ Carter, MM Madeleine, EJ Mao, ED Fitzgibbons, S Huang, AM Beckmann, JK McDougall, DA Galloway. J Natl Cancer Inst 1998 Nov 4;90(21):1626-1636. 284 oral SCC patients; OR 6.8 (95% CI = 3.0-15.2) for oral SCCs containing HPV type 16 DNA.

Detection of the E7 transform gene of human papilloma virus type 16 in human oral squamous cell carcinoma. J Wang, J Li, H Huang, Y Fu. Chin J Dent Res 1998 Dec;1(3):35-37. "HPV 16 was detected in 36.7% (11/30) of oral squamous cell carcinoma patients and 11.1% (4/30) controls."

Human papilloma virus DNA detection in oral lesions in the Greek population. EP Aggelopoulou, D Skarlos, C Papadimitriou, C Kittas, C Troungos. Anticancer Res 1999 Mar-Apr;19(2B):1391-1395. 49% (50/102) samples including both carcinomas and papillomatous hyperplasias were HPV positive; "HPV-18 was detected only in carcinomas, while HPV-16 was more abundant in papillomatous hyperplasias and in a small percentage of carcinomas."

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 squamous cell carcinomas of the oral cavity, 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."

"High risk" HPV types are frequently detected in potentially malignant and malignant oral lesions, but not in normal oral mucosa. M Bouda, VG Gorgoulis, NG Kastrinakis, A Giannoudis, E Tsoli, D Danassi-Afentaki, P Foukas, A Kyroudi, G Laskaris, CS Herrington, C Kittas. Mod Pathol 2000 Jun;13(6):644-653. "Nested PCR revealed the presence of HPV DNA in 48 of the 53 (91%) pathologic samples analyzed, whereas none (0%) of the normal specimens [derived from healthy individuals] was found to be infected. Positivity for HPV was independent of histology and the smoking habits of the analyzed group of patients." The series included 19 oral squamous cell carcinomas.

Incidence of human papillomavirus 16 and 18 infection and p53 mutation in patients with oral squamous cell carcinoma in Japan. K Shima, I Kobayashi, I Saito, T Kiyoshima, K Matsuo, S Ozeki, M Ohishi, H Sakai. Br J Oral Maxillofac Surg 2000 Oct;38(5):445-450. "HPV16 and 18 E6/E7 DNA was detected in 9 (20%) and 25 (54%) of 36 samples."

Human papillomavirus infection and p53 alterations in oral squamous cell carcinoma. J Cao, ZY Zhang, Patima, YX Zhang, WT Chen. Chin J Dent Res 2000 Nov;3(3):44-49. 29/40 (72.5%) oral squamous cell carcinomas were positive for HPV.

Detection of HPV in Japanese and Chinese oral carcinomas by in situ PCR. K Uobe, K Masuno, YR Fang, LJ Li, YM Wen, Y Ueda, A Tanaka. Oral Oncol 2001 Feb;37(2):146-152. "Analysis revealed the specific presence of HPV DNA in all cases of SCC in our Japanese (10/10) and Chinese (10/10) population samples."

[Research on expression of human papillomavirus type 16 and telomerase in oral lesions.] Patiman, Z Zhang, J Cao. Zhonghua Kou Qiang Yi Xue Za Zhi 2001 Mar;36(2):119-121. "HPV16DNA was positive in 14.3% (1/7) of normal oral mucosa, 42.9% (3/7) of hyperplasia lesions, 66.6% (20/30) of dysplasia lesions and 81.6% (31/35) of OSCCs."

Human papillomavirus as a risk factor for oral squamous cell carcinoma: A meta-analysis, 1982-1997. CS Miller, BM Johnstone. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2001 Jun;91(6):622-635. In a meta-analysis of 94 reports, "The pooled odds ratio for the subset of studies directly comparing the prevalence of HPV in normal mucosa and OSCC was 5.37... The findings provide further quantitative evidence that oral infection with HPV, particularly with high-risk genotypes, is a significant independent risk factor for OSCC." The authors also noted that differences in assay sensitivity indicate that these estimates may be conservative.

High risk human papillomavirus in oral squamous carcinoma: evidence of risk factors in a Venezuelan rural population. Peliminary report. G Premoli-De-Percoco, JL Ramirez. J Oral Pathol Med 2001 Jul;30(6):355-361. 60% (30/50) oral squamous cell carcinomas were positive for HPV.

Human papillomavirus infection and survival in oral squamous cell cancer: a population-based study. SR Schwartz, B Yueh, JK McDougall, JR Daling, SM Schwartz. Otolaryngol Head Neck Surg 2001 Jul;125(1):1-9. 15.1% of 254 tumors were HPV positive.

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 (11 HPV16, 1 HPV33, 1 HPV35, and 1 HPV45). "Human papillomavirus positivity was closely linked to female gender (odds ratio [OR], 5.75; P = 0.004), age older than 56 years (OR, 7.42; P = 0.012), nonsmokers (OR, 21.33; P = 0.00001), and alcohol abstainers (OR, 5.35; P = 0.012)." [It is very peculiar that HPV-related squamous cell carcinomas of the oropharynx would be most likely among those who are the least likely to have been exposed to HPV! -cast] They admit that "Because of the selection of patients undergoing curative radiotherapy, individuals of our study population had advanced tumor classifications in most cases (88% T3/4). This bias may have contributed to the low prevalence of HPV positive tumors in our study."

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."

Prevalence of high-risk human papilloma virus types and its association with P53 codon 72 polymorphism in tobacco addicted oral squamous cell carcinoma (OSCC) patients of Eastern India. JK Nagpal, S Patnaik, BR Das. Int J Cancer 2002 Feb 10;97(5):649-653. 37/110 (33.6%) of oral squamous cell carcinomas were HPV positive.

Squamous cell carcinoma of the tonsils. SE Strome, A Savva, AE Brissett, BS Gostout, J Lewis, AC Clayton, R McGovern, AL Weaver, D Persing, JL Kasperbauer. Clin Cancer Res 2002 Apr;8(4):1093-110. HPV DNA was found in 46% of 51 tumors.

Risk of oral cancer associated with human papillomavirus infection, betel quid chewing, and cigarette smoking in Taiwan--an integrated molecular and epidemiological study of 58 cases. PC Chen, C Kuo, CC Pan, MY Chou. J Oral Pathol Med 2002 Jul;31(6):317-322. In situ PCR ISH on tumor specimens from 29 patients with OSCC and oral mucosal specimens from 29 patients without OSCC. HPV16 infection, adjusted odds ratio = 11.20.

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. "Of the 89 patients, 18 (20%) had detectable HPV 16 in their tumor samples. HPV 16 was detected in 64% of tonsil tumors, 52% oropharyngeal tumors, and 5% oral cavity tumors." Smoking was not associated with HPV 16 presence.

Expression of p16 protein identifies a distinct entity of tonsillar carcinomas associated with human papillomavirus. JP Klussmann, E Gultekin, SJ Weissenborn, U Wieland, V Dries, HP Dienes, HE Eckel, HJ Pfister, PG Fuchs. Am J Pathol 2003 Mar;162(3):747-753. "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)."

Human papillomavirus infection as a prognostic factor in carcinomas of the oral cavity and oropharynx. JM Ritchie, EM Smith, KF Summersgill, HT Hoffman, D Wang, JP Klussmann, LP Turek, TH Haugen. Int J Cancer 2003 Apr 10;104(3):336-344. HPVs were detected in 21% of 139 tumors; 83% were HPV-16.

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%)."

Human papillomavirus 6/11, 16 and 18 in oral carcinomas and benign oral lesions. C Ostwald, K Rutsatz, J Schweder, W Schmidt, K Gundlach, M Barten. Med Microbiol Immunol 2003 Aug;192(3):145-148. "HPV DNA were found in 51/118 carcinomas (43.2%), in 16/72 (22.2%) leukoplakias, 3/12 (25.0%) cheilitic lesions and 10/65 (15.4%) lichen planus cases. These differences were even stronger when analyzing separately for the high-risk types HPV 16 and 18 as compared to low-risk types 6/11. HPV 16 and 18 DNA were present in 41/118 (34.7%) oral carcinomas, 12/72 (16.7%) leukoplakias, 2/12 (16.7%) cheilitic lesions and 6/65 (9.2%) lichen planus."

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.

Human Papillomavirus and Oral Cancer: The International Agency for Research on Cancer Multicenter Study. R Herrero, X Castellsague, M Pawlita, J Lissowska, F Kee, P Balaram, T Rajkumar, H Sridhar, B Rose, J Pintos, L Fernandez, A Idris, M Jose Sanchez, A Nieto, R Talamini, A Tavani, FX Bosch, U Reidel, PJF Snijders, CJLM Meijer, R Viscidi, N Munoz, S Franceschi, for the IARC Multicenter Oral Cancer Study Group. JNCI 2003 Dec 3;95(23):1772-1783. 1670 cases (1415 with cancer of the oral cavity and 255 with cancer of the oropharynx) and 1732 controls. HPV-16 was detected in 3.9% of 766 cancers of the oral cavity, and 18.3% of 142 cancers of the oropharynx. "HPV16 was the only HPV type found in biopsies of 89.3% of HPV DNA-positive case patients, and HPV16 was present with HPV18 in an additional 5.4%, for a total of 94.7% HPV16 among positive case patients (data not shown). One case patient had HPV18 alone, one had HPV33 and HPV35, and one had HPV35 alone." The highest ORs were found with either or both HPV16 E6 or E7 positive and cancer of the oropharynx (OR 64.5 (18.3 to 226.7) in nonsmokers, 56.2 (22.5 to 140.4) in smokers), Table 6. "HPV16 E6 and E7 antibodies are generally considered markers of invasive HPV16-transformed tumors, possibly generated after antigen exposure, after development of a tumor vascular bed, or after necrosis has occurred," however, only a small percentage of patients develop them.

Age, sexual behavior and human papillomavirus infection in oral cavity and oropharyngeal cancers. EM Smith, JM Ritchie, KF Summersgill, JP Klussmann, JH Lee, D Wang, TH Haugen, LP Turek. Int J Cancer 2004 Feb 20;108(5):766-772. "The prevalence of HPV high-risk (HR) types was 20% in cancer cases. Three types were identified: HPV-16 (87%), HPV-18 (3%) and HPV-33 (11%). Risk factors for HPV-HR included younger age (< or = 55 years vs. > 55 years; adjusted OR = 3.4; 95% CI = 1.6-7.3) and younger-age cases who had more lifetime sex partners (adjusted OR = 3.8; 95% CI = 1.4-10.1), practiced oral-genital sex (adjusted OR = 4.3; 95% CI = 1.8-10.4) or oral-anal sex (adjusted OR = 19.5; 95% CI = 3.4-113)."

HPV infections and tonsillar carcinoma. S Syrjanen. J Clin Pathol 2004;57(5):449-455. Review. As of Feb. 2003, the world literature on HPV in tonsillar squamous cell carcinomas consisted of 432 lesions, with HPV detected in 221 (51%). Around 84% of these were HPV-16. "The HPV detection rate of 51% is among the highest in any extragenital human malignancy."

Human papillomavirus in oral exfoliated cells and risk of head and neck cancer. EM Smith, JM Ritchie, KF Summersgill, HT Hoffman, DH Wang, TH Haugen, LP Turek. JNCI 2004 Mar 17;96(6):449-455. 201 patients (186 SCC and 15 other types), from all sites in the oral cavity and oropharynx; and 333 controls (oral rinse samples). HPV was detected in 15% of oral cavity cancers and in 38% of oropharyngeal cancers. OR = 2.6 (95% CI = 1.5 to 4.2) for high-risk HPV, "adjusted for age, tobacco pack-years, and number of alcoholic drinks per week," which may adjust-out the actual cause and falsely implicate non-causal associations. Odds ratio not "adjusted" for tobacco and alcohol, 11.5 (5.2 to 25.7) for high-risk HPV (Table 4).

Genetic patterns in head and neck cancers that contain or lack transcriptionally active human papillomavirus. BJ Braakhuis, PJ Snijders, WJ Keune, CJ Meijer, HJ Ruijter-Schippers, CR Leemans, RH Brakenhoff. J Natl Cancer Inst 2004 Jul 7;96(13):998-1006. 143 consecutive HNSCCs (106 of the oral cavity and 37 of the oropharynx). "Twenty-four (16.7%) of the 143 HNSCCs were positive for HPV16 DNA, and 12 of these HNSCCs (8.4% of total number) expressed E6 and E7 mRNAs. None of the HPV DNA–and E6/E7 mRNA–positive tumors had TP53 gene mutations, whereas nine (75%) of the 12 HPV DNA–negative tumors had such mutations (P<.001).... CONCLUSIONS: HNSCCs with transcriptionally active HPV16 DNA are characterized by occasional chromosomal loss, whereas HNSCCs lacking HPV DNA are characterized by gross deletions that involve whole or large parts of chromosomal arms and that already occur early in HNSCC development. These distinct patterns of genetic alterations suggest that HPV16 infection is an early event in HNSCC development."

[Meta analysis of the relationship between tumorigenesis of oral squamous cell carcinoma and human papillomavirus infection] AX Wang, HS Xu, KQ Lia, XL Zhong. Ai Zheng 2004 Sep;23(9):1077-1080. Meta-analysis of 44 Chinese studies. "[T]he combined odds ratioes (ORc) for HPV, and HPV16 infection of OSCC were 8.89 (3.62-21.80), and 6.81 (2.18-21.32) times that of normal oral mucosa."

Human papillomavirus is more common in base of tongue than in mobile tongue cancer and is a favorable prognostic factor in base of tongue cancer patients. L Dahlgren, HM Dahlstrand, D Lindquist, A Hogmo, L Bjornestal, J Lindholm, B Lundberg, T Dalianis, E Munck-Wikland. Int J Cancer 2004 Dec 20;112(6):1015-1019. "Twelve of 110 (10.9%) samples were HPV-positive; 9 for HPV-16, 1 for HPV-33, 1 for HPV-35 and 1 could not be analyzed because of shortage of DNA. HPV was significantly more common in base of tongue tumors (10/25, 40.0%) compared to tumors of the mobile tongue (2/85, 2.3%)."

Risk factors in oral and oropharyngeal squamous cell carcinoma: a population-based case-control study in southern Sweden. K Rosenquist. Swed Dent J Suppl 2005;(179):1-66. In 128 cases and 320 controls: "There was a significant relationship between high-risk human papillomavirus (HPV) infection and OOSCC (OR 63; 95% CI 14-280). Forty-seven of the cases (36%) were high-risk HPV infected and 7 (5.3%) were low-risk HPV infected in the specimens collected from the oral cavity. The corresponding figures for the controls were 3 (0.94%) and 13 (4.1%), respectively. The high-risk HPV types found in the oral cavity were the same types as observed in cervical cancer." [The odds ratio of sixty-three for high-risk HPV makes it likely that the OR of 2.4 (95% CI 1.3-4.1) claimed for 11-20 cigarettes per day is the result of confounding].

Human papillomavirus (HPV) in head and neck cancer. S Syrjanen. J Clin Virol 2005 Mar;32 Suppl 1:S59-66. Review. "The latest meta-analyses of the epidemiological studies as well as the multi-centre case-control studies have confirmed HPV as an independent risk factor for oral cancer, with a range of odds ratios (OR) between 3.7 and 5.4. Until 2002, 4768 oral carcinomas have been analysed for HPV DNA, and 22% were reported to contain HPV by any of the detection techniques. Of all non-genital cancers, tonsillar carcinomas appear to have the highest prevalence of HPV. By the end of 2002, 422 cases of tonsillar carcinoma have been analyzed for the presence of HPV DNA, with the overall detection rate of 51%. HPV 16 is the most prevalent HPV type found in 84% of HPV DNA-positive tumours."

Identification of human papillomaviruses in tumors of the oral cavity in an Indian community. P Koppikar, EM deVilliers, R Mulherkar. Int J Cancer 2005 Mar 1;113(6):946-950. "HPV was detected in 32 out of 102 patients (31%), in either the tumor or the adjacent normal mucosa, while 5% (5/102) of the comparative group were found to be HPV-positive. Sequence analysis revealed a number of cutaneous HPVs, predominantly HPV types of the genus Beta-Papillomavirus, in the oral cavity. Multiple HPV infections were also commonly observed in patients (14/102; 14%). HPV 16 and 18 were each detected in 6 patients (6/102; 6%)."

Human papilloma virus in oral squamous cell carcinoma in a Mexican population. BR Ibieta, M Lizano, M Fras-Mendivil, JL Barrera, A Carrillo, L Ma Ruz-Godoy, A Mohar. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2005 Mar;99(3):311-315. In 51 patients, "21 (42%) cases were HPV-positive, and 14/21 were positive for HPV-16. We found more samples positive in men than in women (71% vs 29%). No differences were observed between HPV-positive and -negative patients in relation to smoking and drinking habits (81% vs 79%)."

Sensitive detection of human papillomavirus in cervical, head/neck, and schistosomiasis-associated bladder malignancies. H Yang, K Yang, A Khafagi, Y Tang, TE Carey, AW Opipari, R. Lieberman, PA Oeth, W Lancaster, HP Klinger, AO Kaseb, A. Metwally, H Khaled, DM Kurnit. PNAS 2005 May 24;102(21):7683-7688. HPV 16/18 was detected in 13/16 oral cancers.

HPV16 semiquantitative viral load and serologic biomarkers in oral and oropharyngeal squamous cell carcinomas. AR Kreimer, GM Clifford, PJ Snijders, X Castellsague, CJ Meijer, M Pawlita, R Viscidi, R Herrero, S Franceschi; International Agency for Research on Cancer (IARC) Multicenter Oral Cancer Study Group. Int J Cancer 2005 Jun 10;115(2):329-332.

Expression of cell cycle markers and human papillomavirus infection in oral squamous cell carcinoma: use of fuzzy neural networks. L Lo Muzio, M D'Angelo, M Procaccini, F Bambini, F Calvino, AM Florena, V Franco, L Giovannelli, P Ammatuna, G Campisi. Int J Cancer 2005 Jul 10;115(5):717-723. "HPV DNA was found in 9/18 OSCCs (50.0 %) without any significant higher risk of HPV infection with respect to the sociodemographic variables considered (p > 0.2), apart from tobacco smoking, reported in 44.4% of OSCC HPV-positive vs. 100% HPV-negative subjects (p = 0.029)."

p53 mutations and human papillomavirus infection in oral squamous cell carcinomas: correlation with overall survival. R Kozomara, N Jovic, Z Magic, M Brankovic-Magic, V Minic. J Craniomaxillofac Surg 2005 Oct;33(5):342-348. "HPV infection was detected in 32/50 cases, mostly HPV16 (10/32), HPV18 and HPV31 (6/32). A significantly higher incidence of HPV infection was found among smokers (p<0.05) and among patients with poor oral hygiene (p<0.01)."

Analysis of the effect of DNA purification on detection of human papillomavirus in oral rinse samples by PCR. G D'Souza, E Sugar, W Ruby, P Gravitt, and M Gillison J Clin Microbiol 2005 Nov;43(11):5526-5535. "Puregene-purified samples had higher human DNA yields and purities, and Puregene purification detected the greatest number of HPV-positive subjects and total HPV infections in comparison to the numbers detected by all other methods. The total number of HPV infections and HPV prevalence estimates were also higher for Puregene-processed oral rinse samples when a fixed volume (10 µl) rather than a fixed cell number (50,000 cells) was used for PCR amplification.The method of DNA purification significantly affects the detection of HPV genomic DNA from oral rinse samples and may result in exposure misclassification that could contribute to the inconsistent associations reported in the literature [emphasis added]."

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."

HPV and other risk factors of oral cavity/oropharyngeal cancer in the Czech Republic. R Tachezy, J Klozar, M Salakova, E Smith, L Turek, J Betka, R Kodet, E Hamsikova. Oral Dis 2005 May;11(3):181-185. "The HPV DNA was detected in 51.5% of samples tested. Among the HPV DNA positive tumours, 80% contained HPV16. In the analysed group there were 54 men and 14 women. The prevalence of HPV DNA was lower in oral (25%) than in oropharyngeal (57%) tumours, and higher in never smokers (100%) and never drinkers (68.8%)."

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."

Biopsy vs. superficial scraping: detection of human papillomavirus 6, 11, 16, and 18 in potentially malignant and malignant oral lesions. VE Furrer, MB Benitez, M Furnes, HE Lanfranchi, NM Modesti. J Oral Pathol Med 2006 Jul;35(6):338-344. "From 22 patients with potentially malignant and malignant lesions analyzed, 41% of the biopsies were HPV DNA positive, whereas 95-100% of the superficial scrapes were positive (McNemar, P < 0.0001). Clinical presumption of HPV infection detected 67% (P < 0.0001) of the HPV DNA positive cases compared with 48% (P < 0.0001) determined by cytology and histopathology. The prevalence of HPV 6, 11, 16 and 18 in the oral mucosa was studied in 59 individuals. While 9% of normal controls were HPV DNA positive, 100% of the patients with potentially malignant and malignant lesions were HPV DNA positive, and the prevailing genotype was HPV 16 followed by HPV 18. CONCLUSIONS: The higher HPV DNA detection rate in superficial oral scrapes than in biopsies suggests that accurate epidemiological information on oral HPV infection/oral carcinogenesis depends not only on the DNA detection technique, but also on the tissue/cell sampling procedure."

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." Published as: [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. "HPV infection was more frequent in patients with history of alcohol/tobacco consumption (p = 0.6)."

Expression of p16(INK4A), p53, and Rb proteins are independent from the presence of human papillomavirus genes in oral squamous cell carcinoma. JA Nemes, L Deli, Z Nemes, IJ Márton. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2006 Sep;102(3):344-52. 79 oral squamous cell carcinoma cases were studied by immunohistochemistry and polymerase chain reaction (PCR). "Thirty-three cases were HPV positive for high-risk HPV (HR-HPV) types, of which 27 harbored HPV16. In 25 of 27 HPV16-positive tumors, the HPV16 genome was fully integrated into the host genome, as evidenced by the lack of PCR-amplifiable E2 gene sequences."

[Oral squamous cell carcinoma in north-eastern Hungary. II. Etiological factors] J Nemes, R Boda, P Redl, I Márton. Fogorv Sz 2006 Oct;99(5):179-185. High-risk HPV types were detected in 42.8% of 119 oral squamous cell carcinomas in Hungary.

Brushing of oral mucosa for diagnosis of HPV infection in patients with potentially malignant and malignant oral lesions. L Giovannelli, G Campisi, G Colella, G Capra, C Di Liberto, MP Caleca, D Matranga, M D'Angelo, L Lo Muzio, P Ammatuna. Mol Diagn Ther 2006;10(1):49-55. 50 patients with oral leukoplakia (OL), 49 with oral lichen planus (OLP), and 17 with oral squamous cell carcinoma (OSCC). "HPV DNA was detected in 22% of samples from lesion sites and in 16% of samples from adjacent sites (p = 0.22) in patients with OL, in 24.5% and 22.4% of samples from lesion and adjacent sites, respectively, in patients with OLP (p = 0.40), and in 35.3% and 41.2% of samples from lesion and adjacent sites, respectively, in patients with OSCC (p = 0.36). Lesions adjacent to HPV-positive normal sites had an increased rate of HPV detection (OR = 30; 95% CI 9.57, 94.1). HPV-18 was the most frequent genotype, followed by HPV-6, -16, -33, and -53. HPV prevalence was reduced in lesions at keratinized sites (14.5%) compared with non-keratinized sites (34.4%; p = 0.007; OR = 0.32; 95% CI 0.13, 0.81)."

Differential expression and activation of NF-kappaB family proteins during oral carcinogenesis: Role of high risk human papillomavirus infection. A Mishra, AC Bharti, P Varghese, D Saluja, BC Das. Int J Cancer 2006 Dec 15;119(12):2840-2850. 110 fresh oral tissue biopsies were collected comprising 10 normal controls, 34 precancer and 66 oral cancer lesions prior to chemotherapy/radiotherapy. "Diagnosis of HPV was done by both consensus and type-specific PCR.... Twenty seven percent (18/66) of the oral cancer biopsies showed the presence of HPV infection exclusively of high risk HPV type 16, which was primarily associated with the well differentiated squamous cell carcinomas (WDSCC)."

High-risk human papillomavirus affects prognosis in patients with surgically treated oropharyngeal squamous cell carcinoma. L Licitra, F Perrone, P Bossi, S Suardi, L Mariani, R Artusi, M Oggionni, C Rossini, G Cantu, M Squadrelli, P Quattrone, LD Locati, C Bergamini, P Olmi, MA Pierotti, S Pilotti. J Clin Oncol 2006 Dec 20;24(36):5630-6. 90 consecutive oropharyngeal cancer patients. "Seventeen (19%) patients showed integrated HPV 16 DNA (HPV positive), wt TP53 in all but two patients, normal p16INK4a in 15 assessable patients, and p16 expression in all 17 patients."

Highly sensitive detection of HPV-DNA in paraffin sections of human oral carcinomas. K Koyama, K Uobe, A Tanaka. J Oral Pathol Med 2007 Jan;36(1):18-24. 20 cases. "We developed highly sensitive detection methods for HPV to elucidate the prevalence and localization of HPV in paraffin sections from human oral SCC using modified in situ polymerase chain reaction (PCR) and in situ hybridization AT tailing (ISH-AT). Analyses revealed a high prevalence of several HPV types (HPV-16, -18, -22, -38 and -70) under optimal conditions."

High-risk human papillomavirus type 16 E7 oncogene associates with Cdc25A over-expression in oral squamous cell carcinoma. UK Bhawal, M Sugiyama, Y Nomura, M Sawajiri, K Tsukinoki, MA Ikeda, H Kuniyasu. Virchows Arch 2007 Jan;450(1):65-71. "HPV-16 E7 was not found in non-neoplastic oral tissues, whereas it was observed in eight (36%) of 22 oral carcinomas.... This study suggests that Cdc25A is likely to be an important mediator in the progression of oral tumors, and HPV-16 E7 may be a sensitive indicator of the involvement of viral oncogenes in oral carcinogenesis."

Human papillomaviruses in oral squamous cell carcinoma and pre-cancerous lesions detected by PCR-based gene-chip array. CW Luo, CH Roan, CJ Liu. Int J Oral Maxillofac Surg 2007 Feb;36(2):153-158. "DNA samples were collected by cytobrushing from 51 patients with OSCC, 46 with oral pre-cancerous lesions and 90 normal controls... In pre-cancerous lesions, there was a higher frequency of HPV of any type (14/46, OR = 2.844, CI = 1.186-6.816, P = 0.0216) and of low-risk HPV types (9/46, OR = 5.529, CI = 1.597-19.14, P = 0.0096) than in control samples. The prevalence of high-risk types was significantly higher in OSCC than in control lesions (11/51 vs 8/90, OR = 2.819, CI = 1.051-7.558, P = 0.0420) but this was not the case for HPV of any type (13/51 vs 12/90, OR = 2.244, CI = 0.9266-5.337, P = 0.1066)."

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."

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."

Prevalence of human papillomavirus in squamous cell carcinoma of the tongue. CE Silva, ID Silva, A Cerri, LL Weckx. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2007 Oct;104(4):497-500. Fifty white male smokers with squamous cell carcinoma (SCC) of the tongue, versus 10 matched patients with no clinical evidence of tongue lesions. "Thirty-seven patients (74%) had a positive PCR for oncogenic papillomavirus, and only 1 specimen (10%) of the control group was positive for nononcogenic papillomavirus."

Human papillomavirus in oral squamous cells carcinoma in a population of 75 Brazilian patients. RC Soares, MC Oliveira, LB Souza, AL Costa, SR Medeiros, LP Pinto. Am J Otolaryngol 2007 Nov-Dec;28(6):397-400. From paraffin-embedded tissue, "Human papillomavirus DNA was detected in 18 (24%) of the 75 cases positive for the human beta-globin gene. No significant association was observed between HPV and age, sex, or anatomical location of the tumor. The most prevalent viral type was HPV-18 (77,8%)."

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. 485 cases (187 tumors of the oral cavity) and 549 controls. 85.6% of oral cancer patients were negative for HPV16 by serology, which is neither reliable nor complete. Four of the authors were from the Harvard School of Public Health, and it was funded by the National Institutes of Health.

Inverse relationship between human papillomavirus-16 infection and disruptive p53 gene mutations in squamous cell carcinoma of the head and neck. WH Westra, JM Taube, ML Poeta, S Begum, D Sidransky, WM Koch. Clin Cancer Res 2008 Jan 15;14(2):366-369. By in situ hybridization, "HPV16 was detected in 12 of 89 (13%) HNSCCs. By tumor site, HPV16 was detected in 12 of 21 (57%) tumors from the palatine/lingual tonsils, but in none of 68 tumors from nontonsillar sites (P < 0.00001). Both HPV16-positive and HPV16-negative HNSCCs harbored p53 mutations (25% versus 52%), but disruptive mutations were only encountered in HPV16-negative carcinomas. Of seven tonsillar carcinomas with disruptive p53 mutations, none were HPV16 positive, in contrast to HPV16-positive tonsillar carcinomas without disruptive p53 mutations (0% versus 57%; P = 0.008)."

High association of human papillomavirus infection with oral cancer: a case-control study. G Anaya-Saavedra, V Ramírez-Amador, ME Irigoyen-Camacho, CM García-Cuellar, M Guido-Jiménez, R Méndez-Martínez, A García-Carrancá. Arch Med Res 2008 Feb;39(2):189-197. "Sixty two cases and 248 controls (53.2% males), median age 62 years (Q(1)-Q(3) = 54-72 years) were included. HPV prevalence was 43.5% in cases and 17.3% in controls (HR-HPV: 37.1% cases, 9.7% controls). The most frequent types in cases were HPV-16 and HPV-18 (55.6 and 18.5%). The presence of HR-HPV was associated with OSCC (OR = 6.2; 95% CI: 2.98-12.97) controlling for the most common risk factors. An interaction between smoking and drinking was detected, and family history of cancer was also significant (OR: 3.61; 95% CI = 1.44-8.99). Early age at first sexual intercourse and large number of lifetime sexual partners showed an association with HR-HPV (p = 0.019 and p = 0.033, respectively)."

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. 52 cases. "Forty patients reported tobacco/alcohol exposure, 10 reported no exposure. 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)."

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. "Oral exfoliated cells were tested for detection of HPV DNA by the PGMY09/11 polymerase chain reaction protocol. Serum antibodies against HPV 16, 18, and 31 viral capsids were detected using an immunoassay technique.... 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." [Unwarranted "adjustment" for the non-causal factors listed may have weakened the association -cast]

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, K Dahlstrom, JT Schiller, Q Wei, G Li. Carcinogenesis 2008 Apr;29(4):875-879. "[A] hospital-based case-control study of 188 non-Hispanic white patients with newly diagnosed SCCOP and 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 (Arg/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. "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."

Prevalence and significance of human papillomavirus in oral tongue cancer: the Mayo Clinic experience. XH Liang, J Lewis, R Foote, D Smith, D Kademani. J Oral Maxillofac Surg 2008 Sep;66(9):1875-1880. 1 /51 (1.96%) were positive for HPV-16.

HPV in oral squamous cell carcinoma vs head and neck squamous cell carcinoma biopsies: a meta-analysis (1988-2007). N Termine, V Panzarella, S Falaschini, A Russo, D Matranga, L Lo Muzio, G Campisi. Ann Oncol 2008 Oct;19(10):1681-1690. 62 studies studies examining paraffin-embedded (PE) biopsies of HNSCC and OSCC. "The pooled prevalence of HPV DNA in the overall samples (Sigma: 4852) was 34.5%, in OSCC it was 38.1% and in the not site-specific HNSCC was 24.1%. With regard to the detection method, PCR-based studies reported a higher prevalence rate than ISH-based rates (34.8, versus 32.9%) especially in the OSCC subgroup (OSCC PCR based: 39.9%). CONCLUSION: These findings support the assumption that a correct distinction of HNSCC by site, together with the use of more sensitive HPV DNA detection methods, should be considered as essential prerogatives in designing future investigations into viral prevalence in head and neck tumors."

Use of in situ hybridization to detect human papillomavirus in head and neck squamous cell carcinoma patients without a history of alcohol or tobacco use. WT Lee, RR Tubbs, AM Teker, J Scharpf, M Strome, B Wood, RR Lorenz, J Hunt. Arch Pathol Lab Med 2008 Oct;132(10):1653-1656. 22 patients who did not use alcohol or tobacco, 14 male, 8 female; tongue (n = 8), tonsil (n = 7), and larynx (n = 7). "Only 2 cases were positive for high-risk HPV, and both demonstrated an integrated pattern. Both cases were tumors of the tonsil. No cases were positive for low-risk HPV."

Detection of HPV in mouth floor squamous cell carcinoma and its correlation with clinicopathologic variables, risk factors and survival. LE Simonato, JF Garcia, ML Sundefeld, NJ Mattar, LA Veronese, GI Miyahara. J Oral Pathol Med 2008 Nov;37(10):593-598. By nested polymerase chain reaction in 29 paraffin-embedded specimens of mouth floor squamous cell carcinoma, "HPV DNA was detected in 17.2% (5 of 29) of the specimens; the highest prevalence was observed in non-smoking patients over the age of 60 years."

No high-risk HPV detected in SCC of the oral tongue in the absolute absence of tobacco and alcohol-a case study of seven patients. TJ Siebers, MA Merkx, PJ Slootweg, WJ Melchers, P van Cleef, PC de Wilde. Oral Maxillofac Surg 2008 Dec;12(4):185-188. No HPV found using in situ hybridization and SPF(10)Line Blot 25 polymerase chain reaction assays.

p73 G4C14-to-A4T14 polymorphism and risk of human papillomavirus-associated squamous cell carcinoma of the oropharynx in never smokers and never drinkers. X Chen, EM Sturgis, CJ Etzel, Q Wei, G Li. Cancer 2008 Dec 15;113(12):3307-3314. 188 non-Hispanic white patients with newly diagnosed SCCOP and a control group of 349 healthy individuals. "HPV-16 seropositivity was associated with an increased risk of SCCOP (adjusted OR, 5.98; 95% CI, 3.89-9.20), especially among never smokers (adjusted OR, 13.8; 95% CI, 5.91-32.1), never drinkers (adjusted OR, 14.9; 95% CI, 5.24-42.4), and individuals with p73 variant genotypes (GC/AT and AT/AT; adjusted OR, 7.96; 95% CI, 3.83-16.5). Moreover, the risk of HPV-16-associated SCCOP for individuals who had p73 variant genotypes was particularly high in never smokers and never drinkers."

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."

Prevalence of human papillomavirus and other risk factors in Lithuanian patients with head and neck cancer. Z Gudleviciene, G Smailyte, A Mickonas, A Pikelis. Oncology 2009;76(3):205-208. 13/48 (27.1%) patients with primary diagnosed HNSCC carcinoma had detectable HPV; only 4 (30.1%) were HPV16. "There were no differences regarding the other risk factors (smoking, alcohol consumption and occupational history) between HPV-positive and HPV-negative patients with head and neck cancer in our study."

Genomewide gene expression profiles of HPV-positive and HPV-negative oropharyngeal cancer: potential implications for treatment choices. P Lohavanichbutr, J Houck, W Fan, B Yueh, E Mendez, N Futran, DR Doody, MP Upton, DG Farwell, SM Schwartz, LP Zhao, C Chen. Arch Otolaryngol Head Neck Surg 2009 Feb;135(2):180-188. Tumor tissue from 119 primary OSCC patients and normal oral tissue from 35 patients without cancer. "HPV DNA was found in 41 of 119 (34.5%) tumors and 2 of 35 (5.7%) normal tissue samples, with 39 of 43 HPV being HPV type 16; there was a higher prevalence of HPV DNA in oropharyngeal cancer (23 of 31) than in oral cavity cancer (18 of 88)." Tested for 37 types of HPV.

Low prevalence of human papillomavirus in squamous-cell carcinoma limited to oral cavity proper. L Scapoli, A Palmieri, C Rubini, M Martinelli, G Spinelli, F Ionna, F Carinci. Mod Pathol 2009 Mar;22(3):366-372. "314 squamous-cell carcinoma limited to oral cavity proper, indicated that the prevalence of high-risk human papillomavirus was as low as 2% (CI 0.6-3)."

Chronic periodontitis-human papillomavirus synergy in base of tongue cancers. M Tezal, M Sullivan Nasca, DL Stoler, T Melendy, A Hyland, PJ Smaldino, NR Rigual, TR Loree. Arch Otolaryngol Head Neck Surg 2009 Apr;135(4):391-396. 21 / 30 (70%) of newly diagnosed base of tongue squamous cell carcinoma tumors were positive for HPV-16; none were positive for HPV-18. Patients with HPV-positive tumors had significantly higher mean alveolar bone loss.

Oropharyngeal carcinoma in non-smokers and non-drinkers: A role for HPV. E Andrews, WT Seaman, J Webster-Cyriaque. Oral Oncol 2009 Jun;45(6):486-91. 40 OSCCs in non-smoker/non-drinkers. "[C]ases were 6.1 (OR 95% CI, 1.3-28) times more likely to have HPV infection in their tumors than controls. High-risk HPV-DNA was readily detected in the tonsils and base of tongue (oropharynx) of 14/18 cases and 6/22 controls by both consensus and real-time PCR."

Human papillomavirus (HPV)-positive tonsillar carcinomas are frequent and have a favourable prognosis in males in Norway. K Hannisdal, A Schjølberg, PM De Angelis, M Boysen, OP Clausen. Acta Otolaryngol 2009 Aug 13:1-7. 71 / 137 (52%) of tonsillar tumors were HPV-positive; 87% were HPV-16.

High-risk human papillomavirus (HPV) is not associated with p53 and bcl-2 expression in oral squamous cell carcinomas. MC Oliveira, RC Soares, LP Pinto, LB Souza, SR Medeiros, L Costa Ade. Auris Nasus Larynx 2009 Aug;36(4):450-456. "Twenty-six cases (29.5%) were positive for the virus by PCR. Dot blot hybridization identified HPV 18 in 21 (80.8%) cases, HPV 16 in one (3.8%) case and a combination of the two types in the four (15.4%) remaining cases. No other type of HPV was detected in the sample."

Progressive increase of human papillomavirus carriage rates in potentially malignant and malignant oral disorders with increasing malignant potential. K Szarka, I Tar, E Fehér, T Gáll, A Kis, ED Tóth, R Boda, I Márton, L Gergely. Oral Microbiol Immunol 2009 Aug;24(4):314-318. 65 OSCC tumor samples, 44 oral leukoplakia patients, 119 patients with oral lichen planus, and 72 healthy controls. "We detected HPVs significantly more frequently in lesions than in controls (P < or = 0.001 in all comparisons). HPV prevalence increased gradually with increasing severity of lesions (32.8, 40.9, and 47.7% in OLP, OL, and OSCC, respectively)."

Human papillomavirus in metastatic squamous carcinomas from unknown primaries: A retrospective 7 year study. PC Desai, MV Jaglal, P Gopal, SJ Ghim, DM Miller, H Farghaly, AB Jenson. Exp Mol Pathol 2009 Oct;87(2):94-8. 41 samples, all smokers. 11/41 (27%) were positive for HPV, strain(s) not specified (9/34 males and 2/7 females). "HPV (+) carcinomas appeared to arise from multiple sites in the oropharynx, particularly the tonsils and tongues, including unknown primaries. By histological exam, most metastatic HPV(+) squamous carcinomas were poorly differentiated (basaloid) microscopically and grossly cystic."

Prevalence, morphology, and prognosis of human papillomavirus in tonsillar cancer. A Luginbuhl, M Sanders, JD Spiro. Ann Otol Rhinol Laryngol 2009 Oct;118(10):742-749. 35% of 48 tonsillar carcinomas were HPV-positive by ISH. "Morphologically, we found that HPV-positive tumors had their origin in the tonsillar crypts, whereas HPV-negative tumors arose from the surface epithelium."

Sensitive HPV detection in oropharyngeal cancers. DM Winder, SL Ball K Vaughan, N Hanna, YL Woo, JT Fränzer, JC Sterling, MA Stanley, H Sudhoff, PK Goon. BMC Cancer 2009 Dec 15;9:440. "We compared PGMY09/11, MY09/11 and GP5+/6+ primers sets in PCRs of 34 clinically diagnosed samples of genital warts, cervical brushings (with associated histological diagnosis) and vulval biopsies. All negative samples were subsequently tested using the previously reported PGMY/GP PCR method and amplicons directly sequenced for confirmation and typing. An optimised PCR protocol was then compared to a line blot assay for detection of HPV in 15 oropharyngeal cancer samples. RESULTS: PGMY09/11 primers detected HPV presence in more cervical brushing (100%) and genital wart (92.9%) samples compared to MY09/11 (90% and 64.3%) and GP5+/6+ (80% and 64.3%) primer sets, respectively. From vulval biopsies, HPV detection rates were: MY09/11 (63.6%), GP5+/6+ (54.5%) and PGMY09/11 (54.5%). PGMY/GP nested PCR demonstrated that HPV was present, and direct sequencing confirmed genotypes. This nested PCR protocol showed detection of HPV in 10/15 (66.7%) of oropharyngeal cancer samples."

BUBR1 expression in benign oral lesions and squamous cell carcinomas: correlation with human papillomavirus. RC Lira, FA Miranda, MC Guimarães, RT Simões, EA Donadi, CP Soares, EG Soares. Oncol Rep 2010 Apr;23(4):1027-1036. 70 OSCC biopsies, 16 non-malignant oral lesions. "Ninety percent of OSCC and 100% of benign lesions were HPV positive. HPV16 and HVP18 were present in 13 and 24% of HPV-positive OSCC samples, respectively. HPV was more prevalent (76%) in samples with a high BUBR1 expression and the absence of viral DNA had no influence on BUBR1 expression."

Squamous cell carcinoma of the oropharynx in Australian males induced by human papillomavirus vaccine targets. AM Hong, AE Grulich, D Jones, CS Lee, SM Garland, TA Dobbins, JR Clark, GB Harnett, CG Milross, CJ O'Brien, BR Rose. Vaccine 2010 Apr 26;28(19):3269-3272. 302 oropharyngeal cancers diagnosed between 1987 and 2006. "The overall HPV-positivity rate was 36% (94% types 16 and 18). HPV-related cancer increased from 19% (1987-1990) to 47% (2001-2005)."

Relevance of human papilloma virus (HPV) infection to carcinogenesis of oral tongue cancer. SY Lee, NH Cho, EC Choi, SJ Baek, WS Kim, DH Shin, SH Kim. Int J Oral Maxillofac Surg 2010 Jul;39(7):678-683. 36 patients with oral tongue cancer and 25 normal controls. "HPV was detected in 36% (13/36) of oral tongue cancer patients, compared with 4% (1/25) of the control. In the HPV-positive group of oral tongue cancers, HPV-16 was the most common type and its prevalence rate was 85% (11/13). Of the HPV-16 infected oral tongue cancers, the integration rate of HPV-16 was 55% (6/11)."

Human papillomavirus and survival in patients with base of tongue cancer. P Attner, J Du, A Näsman, L Hammarstedt, T Ramqvist, J Lindholm, L Marklund, T Dalianis, E Munck-Wikland. Int J Cancer 2010 Aug 19 [Epub ahead of print]. Biopsies of 68 / 87 (78%) patients wirh base of tongue cancer were positive for HPV.

Frequency and Role of HPV in the Progression of Epithelial Dysplasia to Oral Cancer. F Angiero, LB Gatta, R Seramondi, A Berenzi, A Benetti, S Magistro, P Ordesi, P Grigolato, E Dessy. Anticancer Res 2010 Sep;30(9):3435-3440. "Five out of 14 of group 2 [moderate and severe dysplasia] cases (35.71%) and 3/11 (27.27%) of group 3 [invasive squamous cell carcinomas] were HPV DNA positive. The HPVs detected were of both high-risk and low-risk genotype. The analysis of the relationship between HPV and p16 protein expression revealed that all the group 2 and 3 samples with HPV DNA, overexpressed p16 protein."

Presence of human papilloma virus, herpes simplex virus and Epstein-Barr virus DNA in oral biopsies from Sudanese patients with regard to toombak use. J Jalouli, SO Ibrahim, D Sapkota, MM Jalouli, EN Vasstrand, JM Hirsch, PA Larsson. J Oral Pathol Med 2010 Sep;39(8):599-604. "The formalin-fixed samples with oral dysplasias were all negative for HPV. In the 145 oral cancer samples from toombak users, HPV was detected in 39 (27%), HSV in 15 (10%) and EBV in 53 (37%) of the samples. The corresponding figures for the samples from non-users were 15 (21%) positive for HPV, 5 (7%) for HSV and 16 (22%) for EBV."

Prevalence of viral (HPV, EBV, HSV) infections in oral submucous fibrosis and oral cancer from India. J Jalouli, SO Ibrahim, R Mehrotra, MM Jalouli, D Sapkota, PA Larsson, JM Hirsch. Acta Otolaryngol 2010 Nov;130(11):1306-1311. "HPV DNA, HSV DNA, and EBV DNA were detected in 11 (91%), 1 (8%), and 3 (25%) of the 12 samples from patients with OSMF compared with 15 (24%), 3 (5%), and 18 (29%), respectively, from 62 patients with OSCC. HPV 16 and 18 DNA was detected in 8/12 (67%) in the OSMF group and 10/62 (16%) in the OSCC group."

Assessing for primary oropharyngeal or nasopharyngeal squamous cell carcinoma from fine needle aspiration of cervical lymph node metastases. S Jannapureddy, C Cohen, S Lau, JJ Beitler, MT Siddiqui. Diagn Cytopathol 2010 Nov;38(11):795-800. "Seven (63.6%) oropharyngeal SCC were positive for HPV ISH and negative for EBV; one nasopharyngeal SCC (50%) was EBER positive and HPV negative."

Significant association of high-risk human papillomavirus (HPV) but not of p53 polymorphisms with oral squamous cell carcinomas in Malaysia. R Saini, TH Tang, RB Zain, SC Cheong, KI Musa, D Saini, AR Ismail, MT Abraham, WM Mustafa, J Santhanam. J Cancer Res Clin Oncol 2011 Feb;137(2):311-320. Samples from 105 OSCCs and 105 healthy controls. "HPV DNA was detected in 51.4% OSCC samples, while 24.8% controls were found to be HPV positive. HPV was found to be significantly associated with OSCC (P < 0.001, OR = 4.3 after adjustment for habits) when compared to controls. High-risk HPV was found to be significantly associated with OSCC cases (P < 0.05). Demographic profiles of age, gender, race and habits were not associated with HPV presence in cases and controls. However, significantly less HPV positivity was seen in poorly differentiated compared to well-differentiated OSCCs."

Low human papillomavirus prevalence in head and neck cancer: results from two large case-control studies in high-incidence regions. KB Ribeiro, JE Levi, M Pawlita, S Koifman, E Matos, J Eluf-Neto, V Wunsch-Filho, MP Curado, O Shangina, D Zaridze, N Szeszenia-Dabrowska, J Lissowska, A Daudt, A Menezes, V Bencko, D Mates, L Fernandez, E Fabianova, T Gheit, M Tommasino, P Boffetta, P Brennan, T Waterboer. Int J Epidemiol 2011 Apr;40(2):489-502. From two separate populations, in Central Europe and Latin America. "HPV16 E7 DNA prevalence among cases was 3.1% (6/196), including 4.4% in the oropharynx (3/68), 3.8% in the hypopharynx/larynx (3/78) and 0% among 50 cases of oral cavity carcinomas. Positivity for both HPV16 E6 and E7 antibodies was associated with a very high risk of oropharyngeal cancer (OR = 179, 95% CI 35.8-899) and hypopharyngeal/laryngeal cancer (OR = 14.9, 95% CI 2.92-76.1)."

Evaluation of human papillomavirus testing for squamous cell carcinoma of the tonsil in clinical practice. S Thavaraj, A Stokes, E Guerra, J Bible, E Halligan, A Long, A Okpokam, P Sloan, E Odell, M Robinson. J Clin Pathol 2011 Apr;64(4):308-312. 142 tonsil squamous cell carcinomas. "There were high levels of agreement between pathologists for p16 IHC and HPV ISH scoring; however, around 10% of HPV ISH cases showed some interobserver discrepancy that was resolved by slide review. The combination of p16 IHC and HPV ISH classified 53% of the samples as HPV-positive, whereas the combination of p16 IHC and HPV PCR classified 61% of the samples as HPV-positive. By employing a three-tiered, staged algorithm (p16 IHC/HPV ISH/HPV PCR), the authors were able to classify 98% of the cases as either HPV-positive (p16 IHC+/HPV DNA+; 62%) or HPV-negative (p16 IHC-/HPV DNA-; 35%)."

Mechanisms

Human papillomavirus-16 DNA methylation patterns support a causal association of the virus with oral squamous cell carcinomas. A Balderas-Loaeza, G Anaya-Saavedra, VA Ramirez-Amador, MC Guido-Jimenez, M Kalantari, IE Calleja-Macias, HU Bernard, A Garcia-Carranca. Int J Cancer 2007 May 15;120(10):2165-2169. "Our previous investigations of HPV-16 DNA methylation in anogenital sites have identified hypermethylation of the L1 gene and part of the long control region in many malignant lesions, but rarely in asymptomatic infections and low-grade precancerous lesions. Here, we report hypermethylation of this diagnostically important segment of the viral DNA in 10 out of 12 HPV-16 positive oral carcinomas from Mexican patients. These data indicate epigenetic changes of HPV-16 in oral carcinomas similar to those in anogenital carcinomas, suggesting carcinogenic processes under the influence of HPV-16 in most if not all of these oral malignant lesions."

Men's beliefs about HPV-related disease. NT Brewer, TW Ng, AL McRee, PL Reiter. J Behav Med 2010 Aug;33(4):274-81. Results of an online survey of 312 gay or bisexual men and 296 heterosexual men in January 2009. "The response rate was 70%. Fewer than half of men knew that HPV can cause genital warts (41%), anal cancer (24%), and oral cancers (23%). However, gay and bisexual men typically knew more than heterosexual men about these topics. Overall, most men believed that sexual behavior causes genital warts (70%) and anal cancer (54%), and tobacco use causes oral cancer (89%)."

Human Papillomavirus (HPV)-16 Genomes Integrated in Head and Neck Cancers and in HPV-16-immortalized Human Keratinocyte Clones Express Chimeric Virus-cell mRNAs Similar to Those Found in Cervical Cancers. MJ Lace, JR Anson, JP Klussmann, DH Wang, EM Smith, TH Haugen, LP Turek. J Virol 2011 Feb;85(4):1645-1654. "Three of nine HNC tumors and epithelial clones containing unintegrated HPV-16 genomes expressed mRNAs spliced from HPV-16 SD880 to SA3358 and terminating at the viral early gene p(A) signal. In contrast, most integrated HPV genomes in six HNCs and a set of thirty-one keratinocyte clones expressed HPV-16 major early promoter (MEP)-initiated mRNAs spliced from the viral SD880 directly to diverse cellular sequences with a minority spliced to SA3358 followed by a cellular DNA junction. Sequence analysis of chimeric virus-cell mRNAs from HNC tumors and keratinocyte clones identified viral integration sites in a variety of chromosomes with some located in or near growth control genes, including the c-myc protooncogene and FAP-1 phosphatase."

Immortalization of oral keratinocytes by functional inactivation of the p53 and pRb pathways. SJ Smeets, M van der Plas, TB Schaaij-Visser, EA van Veen, J van Meerloo, BJ Braakhuis, RD Steenbergen, RH Brakenhoff. Int J Cancer 2011 Apr 1;128(7):1596-605. "Expression of HPV16 E6 caused an extended life span similar to expression of mutant p53R(175)H or p53 knockdown. Expression of mutant p53R(175)H seemed to cause additional activation of the hypoxia and WNT signaling pathways. HPV16 E7 expression had no direct effect on lifespan, similar to p16 knockdown or cyclinD1 expression. In combination with HPV16 E6 or other functional inactivations of p53, abrogation of the pRb-pathway by either HPV16 E7 or other manipulations caused an immortal phenotype. Our data show the causative role of HPV16 E6/E7 in early squamous carcinogenesis. Activity of each gene could be mimicked by other genetic events frequently found in HNSCC without HPV. This data provides the experimental proof of causal association of HPV in HNSCC carcinogenesis and further support the crucial role of the p53- and pRb-pathways."

A possible role for EBV

More studies that observe interactions are needed, rather than studying each virus separately. In comparison, see how much effort has been expended in dead-end investigations of p53 mutations.

Prevalence of Epstein-Barr virus in oral squamous cell carcinomas, premalignant lesions and normal mucosa -- a study using the polymerase chain reaction. I Cruz, AJ Van den Brule, RD Steenbergen, PJ Snijders, CJ Meijer, JM Walboomers, GB Snow, I Van der Waal. Oral Oncol 1997 May;33(3):182-188. "EBV was found in 100% of OSCCs, in 77.8% of premalignant lesions and in 8.3% of clinically normal oral mucosa (P=0.0001)."

Comparative study of oral squamous cell carcinoma in Okinawa, Southern Japan and Sapporo in Hokkaido, Northern Japan; with special reference to human papillomavirus and Epstein-Barr virus infection. K Tsuhako, I Nakazato, J Miyagi, T Iwamasa, A Arasaki, H Hiratsuka, H Sunakawa, G Kohama, T Abo. J Oral Pathol Med 2000 Feb;29(2):70-79. In 60 OSCCs from Okinawa, 78% were positive for HPV and 76.6% for EBV; in 42 from Sapporo (a lower incidence area), 26.2% and 38.1% were positive respectively.

No direct role for Epstein-Barr virus in oral carcinogenesis: a study at the DNA, RNA and protein levels. I Cruz, AJ Van Den Brule, AA Brink, PJ Snijders, JM Walboomers, I Van Der Waal, CJ Meijer. Int J Cancer 2000 May 1;86(3):356-361. Study established that transciption was not occurring.

Demonstration of Epstein-Barr virus in odontogenic and nonodontogenic tumors by the polymerase chain reaction (PCR). HS Jang, JO Cho, CY Yoon, HJ Kim, JC Park. J Oral Pathol Med 2001 Nov;30(10):603-610. "Fifty-three percent (17/32) of nonodontogenic tumors, forty-eight percent (8/17) of ameloblastomas, and ninety-two percent (11/12) of normal oral tissues were positive for EBV-DNA. Of the EBV-DNA, BMLF1 demonstrated the strongest reactivity in the nonodontogenic tumors, and BamC demonstrated the strongest reactivity in the ameloblastomas and normal oral mucosae."

Epstein-Barr virus prevalence in oral squamous cell cancer and in potentially malignant oral disorders in an eastern Hungarian population. A Kis, E Fehér, T Gáll, I Tar, R Boda, ED Tóth, G Méhes, L Gergely, K Szarka. Eur J Oral Sci 2009 Oct;117(5):536-540. 65, 44, and 116 patients with oral squamous cell cancer (OSCC), oral leukoplakia (OL), and oral lichen planus (OLP) versus 68 age-matched controls. "The prevalence of EBV in the controls and in OSCC, OL, and OLP lesions was 19.1%, 73.8%, 29.5%, and 46.6%, respectively, and 66.2%, 22.7%, and 31.9% in the healthy mucosa of patients, respectively."

High-risk human papillomavirus in nasopharyngeal carcinoma. AD Singhi, J Califano, WH Westra. Head Neck 2011 Apr 11 doi: 10.1002/hed.21714 [Epub ahead of print]. "Thirty-four (76%) carcinomas were EBV-positive/HPV-negative, 7 (16%) were EBV-negative/HPV-negative, and 4 (9%) were EBV-negative/HPV-positive. HPV was more likely to be detected in carcinomas from white patients than non-white patients (16% vs 0%; p = .03). Of the 3 patients with HPV-positive carcinomas and available staging information, all were found to have extension into the oropharynx. All HPV-positive carcinomas were p16 positive, but none of the HPV-negative carcinomas were p16 positive (p < .001)."

A possible role of oral lichenoid lesions

The possible premalignant character of oral lichen planus and oral lichenoid lesions: a prospective five-year follow-up study of 192 patients. EH van der Meij, H Mast, I van der Waal. Oral Oncol 2007 Sep;43(8):742-748. 67 patients with oral lichen planus and 125 patients with with OLL, according to revised World Health Organization diagnostic criteria. "Four out of 192 patients, two men and two women, developed a squamous cell carcinoma of the oral mucosa during follow-up. All malignant transformations occurred in the OLL group. The malignant transformation of the OLL group, based on a mean follow-up of 53.8 months, was calculated at 0.71% per year. A comparison of the expected against actual figures for the development of carcinomas revealed no increase in patients with OLP and a 142-fold increase in patients with OLL, the latter being statistically significant, with a p-value of 0.044."

Incidence

Tongue Cancer Rates Increase: Head and neck cancer incidence trends in young Americans, 1973-1997, with a special analysis for tongue cancer. SP Schantz, GP Yu. Arch Otolaryngol Head Neck Surg 2002 Mar;128(3):268-274. "The incidence of head and neck cancer remained stable in groups older than 40 years comparing the 1973-1984 and 1985-1997 data. In contrast, tongue cancer in adults younger than 40 years increased approximately 60% during the same period. We detected a significant increase until 1985, the estimated annual percentage change being 6.7% (95% confidence interval, 2.7%-10.8%; P<.001). After 1985, incidence rates stopped rising but remained steadily high. The change in tongue cancer incidence rates for young adults was related to birth cohorts between 1938 and 1948." Also: Oral and tongue cancer rates rise among young Americans. News Release, American Head and Neck Society, Mar. 2, 2002. The data base of this study covered 10% of the US population. "Tongue cancer among young Americans ranked second to salivary gland cancers in all head and neck cancers and increased 62 percent when comparing 1985-1997 to 1973-1984. Laryngeal cancer showed no significant change in incidence during the two time periods.... Conclusions: The increase in tongue cancer in individuals born after 1938 and its association with improved survival suggest the emergence of a distinct disease process independent of tobacco and alcohol use."

Trends in palatine tonsillar cancer incidence and mortality rates in the United States. SM Golas. Community Dent Oral Epidemiol 2007 Apr;35(2):98-108. From the NCI SEER database. "The highest incidence of palatine tonsillar cancer occurred in black males, followed by white males with SCC. For age 40-64 years, palatine tonsillar incidence rates significantly declined for white females and black females, rose and then declined for black males, but increased from 1988 for white males. For age 65+ years, incidence significantly declined among white males. Palatine tonsillar cancer mortality rates for age 40-64 years significantly declined for white females. Rates also declined for black females (1981-2001) and black males (1985-2001) in this age group while rates for white males declined significantly from 1969 to 1987, but stabilized at nearly 0.4 through 2001. Mortality for the age group, 65+, significantly rose and fell for white females and declined for white males."

Rising Incidence of Oropharyngeal Cancer and the Role of Oncogenic Human PapillomaVirus. JA Ernster, CG Sciotto, MM O'brien, JL Finch, LJ Robinson, T Willson, M Mathews. Laryngoscope 2007 Dec;117(12):2115-28. "The average annual age-adjusted incidence of OP cancer in males in Colorado increased from 2.54 per 100,000 to 3.47 (P < .05) or 36.6%, whereas the U.S. rate increased from 4.34 to 4.81 (P < .05) or 10.8%. The rates in females and the rates of non-OP head and neck cancer decreased. Of the 72 cases, 50 (69%) were positive for HPV subtype 16."

Incidence trends for human papillomavirus-related and -unrelated oral squamous cell carcinomas in the United States. AK Chaturvedi, EA Engels, WF Anderson, ML Gillison. J Clin Oncol 2008 Feb 1;26(4):612-619. 17,625 potentially HPV-related and 28,144 HPV-unrelated diagnoses from nine Surveillance, Epidemiology, and End Results program registries (1973 to 2004). "HPV-related OSCCs were diagnosed at younger ages than HPV-unrelated OSCCs (mean ages at diagnosis, 61.0 and 63.8 years, respectively; P < .001). Incidence increased significantly for HPV-related OSCC from 1973 to 2004 (annual percentage change [APC] = 0.80; P < .001), particularly among white men and at younger ages. By contrast, incidence for HPV-unrelated OSCC was stable through 1982 (APC = 0.82; P = .186) and declined significantly during 1983 to 2004 (APC = -1.85; P < .001)." [caveat - they do not explain in the abstract how they determined whether tumors were HPV-related or not]

Sexual behaviours and the risk of head and neck cancers: a pooled analysis in the International Head and Neck Cancer Epidemiology (INHANCE) consortium. JE Heck, J Berthiller, S Vaccarella, DM Winn, EM Smith, O Shan'gina, SM Schwartz, MP Purdue, A Pilarska, J Eluf-Neto, A Menezes, MD McClean, E Matos, S Koifman, KT Kelsey, R Herrero, RB Hayes, S Franceschi, V Wünsch-Filho, L Fernández, AW Daudt, MP Curado, C Chen, X Castellsagué, G Ferro, P Brennan, P Boffetta, M Hashibe. Int J Epidemiol 2010;39(1):166-181. "Cancer of the oropharynx was associated with having a history of six or more lifetime sexual partners [OR = 1.25, 95% confidence interval (CI) 1.01, 1.54] and four or more lifetime oral sex partners (OR = 2.25, 95% CI 1.42, 3.58). Cancer of the tonsil was associated with four or more lifetime oral sex partners (OR = 3.36, 95 % CI 1.32, 8.53), and, among men, with ever having oral sex (OR = 1.59, 95% CI 1.09, 2.33) and with an earlier age at sexual debut (OR = 2.36, 95% CI 1.37, 5.05). Cancer of the base of the tongue was associated with ever having oral sex among women (OR = 4.32, 95% CI 1.06, 17.6), having two sexual partners in comparison with only one (OR = 2.02, 95% CI 1.19, 3.46) and, among men, with a history of same-sex sexual contact (OR = 8.89, 95% CI 2.14, 36.8)."

The role of human papillomavirus in the increased incidence of base of tongue cancer. P Attner, J Du, A Näsman, L Hammarstedt, T Ramqvist, J Lindholm, L Marklund, T Dalianis, E Munck-Wikland. Int J Cancer 2010 Jun 15;126(12):2879-84. 95 samples of base of tongue cancer. "An overall increase in the incidence of base of tongue cancer from 0.15/100,000 person-years during 1970-1974 to 0.47/100,000 person-years during 2005-2007 was found in Sweden. The prevalence of HPV in base of tongue cancer in Stockholm county increased from 58% during 1998-2001 to 84% during 2004-2007 (p < 0.05). In the HPV-positive tumors, HPV-16 dominated (86%) but interestingly, HPV33 was detected in as many as 10%. E6 and/or E7 RNA were found in 85% of the samples tested."

The epidemiology of oral HPV infection among a multinational sample of healthy men. AR Kreimer, A Villa, AG Nyitray, M Abrahamsen, M Papenfuss, D Smith, A Hildesheim, LL Villa, E Lazcano-Ponce, AR Giuliano. Cancer Epidemiol Biomarkers Prev 2011 Jan;20(1):172-182. "Oral HPV DNA was detected in 67 of 1,680 (4.0%, 95% CI = 3.1%-5.0%) β-globin-positive specimens; carcinogenic HPVs were detected in 1.3% (95% CI = 0.8%-2.0%; n = 22) and HPV16 was the most commonly detected carcinogenic HPV type (0.6%, 95% CI = 0.2%-1.1%; n = 10). The prevalence of oral HPV infection was similar by country except for HPV55, which had notably higher prevalence in Mexico (3.0%) than Brazil (0%) or the United States (0.2%). Oral HPV prevalence nonsignificantly increased over increasing age categories (P(trend) = 0.096). The strongest predictor of oral HPV was current tobacco use, which increased the odds 2.5-fold (95% CI = 1.4-4.4). Oral sexual behaviors were not associated with oral HPV infection."

Increased Tongue Cancer Among Patients With Systemic Sclerosis

Increased incidence of carcinoma of the tongue in patients with systemic sclerosis. Derk CT, Rasheed M, Spiegel JR, Jimenez SA. J Rheumatol 2005 Apr;32(4):637-641. In a prospective study, 9 out of 769 patients with SSc (392 diffuse cutaneous and 377 limited cutaneous) were diagnosed with oral cavity and pharyngeal carcinomas, six of whom had squamous cell carcinoma of the tongue. "The standardized incidence ratio of squamous cell carcinoma of the tongue observed in this cohort of patients with SSc was 25-fold higher than that expected in an age adjusted population from the SEER cancer registries." All of the patients who developed oral cancer had the diffuse form of systemic sclerosis.

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 05-01-11