HPV is implicated in laryngeal cancer

Human papillomavirus (HPV) infection interferes with DNA repair and the destruction of cells with unrepairable defective DNA. This means that mutated cells survive to become cancers, instead of being eliminated. The virus also directly disrupts the cell nucleus. HPV has been found in a proportion of laryngeal cancers, an alleged smoking-related cancer. As was the case with cervical cancer, it is likely that as methodology improves, the proportion of laryngeal cancer in which HPV is implicated will increase with time. The majority of this work has only been performed since 1996, and the US health establishment has had relatively little involvement.

The tobacco industry funded some of the pioneering investigations of Syrjanen and Syrjanen. The absence of interest and support from the health establishment accounts for their seeking support from this source. History now shows that the Syrjanens were right to suspect a role for HPV. In 1989, a research analyst for Shook, Hardy & Bacon noted that the industry position paper on cancer of the larynx ignored HPV ("The one theory of causation which is noticeably absent from Mr. Goold's paper is that of human papillomavirus (HPV) as an etiologic agent for some squamous cell carcinomas of the larynx..."). But, despite ironclad proof that the anti-smokers falsely blamed smoking for cervical cancer that was actually caused by HPV, the tobacco lawyers have never uttered so much as a word about this subject. This is conspiracy. at the Minnesota tobacco trial, the tobacco industry said nothing about HPV. For obvious reasons, neither did Jonathan Samet, the anti-smokers' star perjuror about smoking and health. Furthermore, these facts cast a whole different light on those demonstrations against the tobacco companies that the anti-smoking demagogues arranged: The anti-smokers are to blame for their misfortune, because they are the ones who obstructed the truth!

Histological evidence for the presence of condylomatous epithelial lesions in association with laryngeal squamous cell carcinoma. KJ Syrjanen, SM Syrjanen. ORL J Otorhinolaryngol Relat Spec 1981;43(4):181-194. "The role of HPV in the development of these lesions is discussed, and the possibility is raised that HPV might be the agent responsible for contributing to the development of squamous cell carcinoma of the larynx in man."

Analysis of prevalence of human papillomavirus in laryngeal carcinomas. Study of 40 cases using polymerase chain reaction and consensus primers. MS Brandwein, GJ Nuovo, H Biller. Ann Otol Rhinol Laryngol 1993 Apr;102(4 Pt 1):309-313. 3 of 40 patients (8%) had detectable HPV DNA, by polymerase chain reaction (PCR) with the "hot start" modification and consensus primers that can detect over 30 distinct HPV types.

High frequency of p53 abnormality in laryngeal cancers of heavy smokers and its relation to human papillomavirus infection. T Suzuki, K Shidara, F Hara, T Nakajima. Jpn J Cancer Res 1994 Nov;85(11):1087-1093. 11/41 (27%) laryngeal cancers were positive for HPV 16/18.

Prevalence of human papillomaviruses (HPV) in benign and malignant tumors of the upper respiratory tract. J Shen, JE Tate, CP Crum, ML Goodman. Mod Pathol 1996 Jan;9(1):15-20. 3/32 (9%) laryngeal squamous cell carcinomas were positive for HPV types 6 and 11.

Detection of human papillomavirus DNA in laryngeal squamous cell carcinoma by polymerase chain reaction. G Almadori, G Cadoni, P Cattani, P Posteraro, E Scarano, F Ottaviani, G Paludetti, M Maurizi. Eur J Cancer 1996 May;32A(5):783-788. Nine (20%) of 45 patients were positive, by PCR with consensus primers that detect HPV types 6, 11, 16 and 18.

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. "Increased risk of cancer of the oral cavity, pharynx, and larynx subsequent to the occurrence of cancer of the cervix has been found and suggests common etiological factors besides smoking. HPV has been found in a substantial proportion of benign UADT lesions, most notably laryngeal papillomas and oral verrucal-papillary lesions. Largest and most accurate case series (i.e., > 15 UADT cancer cases, based on best HPV detection techniques) showed HPV DNA 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."

Presence of human papillomavirus in squamous cell laryngeal carcinomas. A study of thirty-nine cases using polymerase chain reaction and in situ hybridization. ES Lie, F Karison, R Holm. Acta Otolaryngol 1996 Nov;116(6):900-905. 3/39 (8%) were positive for HPV, with specific PCR primers for HPV 6, 11, 16, 18, 31, 33 and 35 and with in situ hybridization (ISH). One was HPV 16 and the other two " type related to HPV 6/11."

[The detection of human papillomavirus in papillomas of the larynx and tonsils through immunohistochemistry and DNA in situ hybridization]. M Lopez Amado, T Garcia Caballero, A Lozano Ramirez, T Labella Caballero. An Otorrinolaringol Ibero Am 1997;24(3):269-280. 5/10 laryngeal papillomas were HPV-positive; two of these patients later developed a laryngeal carcinoma.

[A preliminary study on p53 gene expression and infection of human papilloma virus in laryngeal squamous cell carcinoma]. M Xie, J Xiao, Z Tao, J Luo. Hunan I Ko Ta Hsueh Hsueh Pao 1997;22(3):209-211. 3/13 (23.1%) laryngeal squamous cell carcinomas were positive for HPV type 16; no HPV 18 reported.

[Study on the relation between HPV and tumors of the throat and larynx]. J Ren, X Wang, Q Zhu. Lin Chuong Erh Pi Yen Hou Ko Tsa Chih 1997 Apr;11(4):157-159. 6/22 (27.3%) of laryngeal squamous cell carcinomas were positive for HPV DNA (HPV types 6, 11, 16, or 18).

[Detection of human papillomavirus gene sequences in laryngeal tumors and premalignant changes by polymerase chain reaction]. J Czegledy, T Major, A Juhasz, G Repassy, L Gergely. Orv Hetil 1997 Jul 27;138(30):1891-1895. "In the squamous cell carcinomas, papillomas and precancerous lesions the presence of human papillomavirus gene sequences was significantly higher than in the control group." (HPV types 6, 11, 16 and 18).

Using polymerase chain reaction to human papillomavirus in oral and pharyngolaryngeal carcinomas. I Alvarez Alvarez, P Sanchez Lazo, S Ramos Gonzalez, JP Rodrigo Tapia, F Nunez Batalla, C Suarez Nieto. Am J Otolaryngol 1997 Nov-Dec;18(6):375-381. "HPV E6 DNA of the 6b and 16 types was detected in 14 patients (25%)," but not HPV 18.

Localization of p53 protein and human papillomavirus in laryngeal squamous lesions. ML Caruso, AM Valentini. Anticancer Res 1997 Nov-Dec;17(6D):4671-4675. 1/12 (8%) laryngeal squamous cell carcinomas was positive for HPV16 or 18.

[Study on HPV infection and p53 protein expression in laryngeal carcinoma]. Z Qin, M Dong. Lin Chuang Erh Pi Yen Hou Ko Tsa Chih 1997 Dec;11(12):546-549. 19/44 (43.2%) of laryngeal squamous cell carcinomas were positive for HPV 16/18.

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. 3/16 (19%) laryngeal carcinomas and dysplasias were positive for HPV.

Human papillomavirus DNA sequences and p53 over-expression in laryngeal squamous cell carcinomas in Northeast China. XL Ma, K Ueno, ZM Pan, sz Hi, M Ohyama, Y Eizuru. J Med Virol 1998 Mar;54(3):186-191. 60/102 (58.8%) were positive for HPV types 16, 18, 6, 11 or 33.

Malignant transformation of recurrent respiratory papillomatosis associated with integrated human papillomavirus type 11 DNA and mutation of p53. PL Rady, VJ Schnadig, RL Weiss, TK Hughes, SK Tyring. Laryngoscope 1998 May;108(5):735-740. "[T]he p53 genetic mutation was associated with integration of HPV-11 in histologically malignant lesions."

Detection and typing of human papillomavirus DNA in benign and malignant tumours of laryngeal epithelium. R García-Milián, H Hernández, L Panadé, C Rodríguez, N González, C Valenzuela, MD Araña, SE Perea. Acta Otolaryngol 1998 Sep;118(5):754-758. "Four normal laryngeal samples (16%) were positive for HPV DNA against the 24 samples (82%) (p < 0.001) found for laryngeal papilloma and 16 (48.5%) (p < 0.05) found for laryngeal squamous cell carcinoma. HPV 16 was the type most frequently found in laryngeal carcinoma samples. Our results support an etiologic role for this type of HPV in the pathogenesis of laryngeal carcinoma."

Association between cyclin D1 (CCND1) gene amplification and human papillomavirus infection in human laryngeal squamous cell carcinoma. P Cattani, S Hohaus, A Bellacosa, M Genuardi, S Cavallo, V Rovella, G Almadori, G Cadoni, J Galli, M Maurizi, G Fadda, G Neri. Clin Cancer Res 1998 Nov;4(11):2585-2589. "HPV DNA was detected in 22 of 75 (29.3%) tumors, and it belonged almost exclusively to the highly oncogenic HPV-16, HPV-18, and HPV-33."

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. 10/26 (38%) laryngeal squamous cell carcinomas were positive for HPV16/18.

Human papilloma virus (HPV) is possibly involved in laryngeal but not in lung carcinogenesis. VG Gorgoulis, P Zacharatos, A Kotsinas, A Kyroudi, AN Rassidakis, JA Ikonomopoulos, C Barbatis, CS Herrington, C Kittas. Hum Pathol 1999 Mar;30(3):274-283. HPV DNA was found in 19/91 (21%) laryngeal squamous cell carcinomas.

Detection of human papillomavirus (HPV) in laryngeal carcinoma lines provides evidence for a heterogeneic cell population. S Atula, R Grenman, H Kujari, S Syrjanen. Eur J Cancer 1999 May;35(5):825-832. 7/27 (26%) cell lines and 7/12 (58%) tumor samples were positive for high-risk types of HPV.

Demonstration of multiple HPV types in laryngeal premalignant lesions using polymerase chain reaction and immunohistochemistry. B Azzimonti, L Hertel, P Aluffi, F Pia, G Monga, M Zocchi, S Landolfo, M Gariglio. J Med Virol 1999 Sep;59(1):110-116. "The presence of HPV DNA was detected in 28 of 50 specimens (56%), including 9/12 cases with mild dysplasia (75%), 3/6 cases with moderate dysplasia (50%), and 7/11 cases with severe dysplasia (64%). Multiple HPV infections, containing two or three types, were detected in 17 of the 28 HPV-positive lesions (60%). Of 21 cases with keratosis and no dysplasia, 11 were positive for HPV DNA (52%) and 4 showed L1 staining (36%). By contrast, L1 positivity was revealed only in two lesions with moderate dysplasia, confirming that fully productive HPV infection is strictly dependent on epithelial differentiation and surface keratinization. The probability that HPV is a cofactor in the malignant progression of these lesions is suggested by the fact that 3/4 patients who developed cancer within 50 months were positive for HPV DNA."

Laryngeal cancer and human papillomavirus: HPV is absent in the majority of laryngeal carcinomas. H Lindeberg, A Krogdahl. Cancer Lett 1999 Nov 1;146(1):9-13. 1/30 laryngeal carcinomas from patients without pre-existing recurrent laryngeal papillomatosis were HPV+. "The HPV type present could not be determined, but it was not type 6, 11, 13, 16, 18, 30, 31, 33, 35 or 45."

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 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."

Physical state and expression of human papillomavirus in laryngeal carcinoma and surrounding normal mucosa. A Venuti, V Manni, R Morello, F De Marco, F Marzetti, ML Marcante. J Med Virol 2000 Apr;60(4):396-402. 13/25 (52%) were HPV-positive: 7 for HPV-16, 5 for HPV-6, and 1 for HPV-45.

[Human papillomavirus (HPV) in the laryngeal carcinoma]. W Makowska, M Malejczyk, D Kapiszewska, J Nyckowska, E Wojcikiewicz, B Wroblewska. Otolaryngol Pol 2001;55(3):263-266. 10/23 (43.5%) were positive for HPV.

Prevalence of human papillomavirus (HPV) DNA in larynx and lung carcinomas. H Kaya, E Kotlioglu, S Inanli, G Ekicioglu, SU Bozkurt, A Tutkun, S Kullu. Pathologica 2001 Oct;93(5):531-534. 10/21 (47.6%) laryngeal SCCs were positive for HPV. "Typing showed signals of HPV 6/11, 16/18 and 31/33 infection in 80%, 40%, 30% of the laryngeal carcinomas, respectively."

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."

Human papillomavirus infection and epidermal growth factor receptor expression in primary laryngeal squamous cell carcinoma. G Almadori, G Cadoni, P Cattani, J Galli, F Bussu, G Ferrandina, G Scambia, G Fadda, M Maurizi. Clin Cancer Res 2001 Dec;7(12):3988-3993. HPV DNA was found in 15/42 (35.7%), nearly all of high-risk types HPV-16, HPV-18, and HPV-33. "At analysis by Mann-Whitney nonparametric statistical test, EGFR level was found to be significantly higher in HPV-infected than in HPV-negative cases (T = 440; P = 0.002). EGFR overexpression (EGFR-positive status >6 fmol/mg protein, the arbitrary cutoff value chosen) was found in 20 of 42 (47.6%) tumors, and it was associated with HPV infection in a statistically significant extent (2 = 4.686; P = 0.03). Conclusions: Viral oncoproteins have been shown to induce a perturbation of the cell response to signals for growth and differentiation; these findings confirm that enhanced EGFR expression and activation in laryngeal squamous cell carcinoma may occur also as a consequence of HPV infection and support the hypothesis of an involvement of HPV infection in laryngeal carcinogenesis."

[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."

Cellular manifestations of human papillomavirus infection in laryngeal tissues. SE Jacob, S Sreevidya, E Chacko, MR Pillai. J Surg Oncol 2002 Mar;79(3):142-150. 15/44 (34%) invasive cancers were HPV positive.

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. 25% of hypopharyngeal cancers and 7% of laryngeal cancers were HPV DNA positive.

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 systematic review of case-control studies of human papillomavirus infection in laryngeal squamous cell carcinoma. L Rees, M Birchall, M Bailey, S Thomas. Clin Otolaryngol Allied Sci 2004 Aug;29(4):301-306. Review. "The studies are heterogeneous in the methods used to harvest tissue samples and techniques for detecting the virus within the tissue. HPV-16 positivity among cases ranged from 2.7% to 46.9% and 0-5.7% among controls. Two studies showed a significantly increased risk of LSCC if HPV-16 was present (OR 18.5, 95% CI 2.2-154.8, OR 2.6, 95% CI 1.1-6.0)."

Integration of human papillomavirus type 11 in recurrent respiratory papilloma-associated cancer. PM Reidy, HH Dedo, R Rabah, JB Field, RH Mathog, L Gregoire, WD Lancaster. Laryngoscope 2004 Nov;114(11):1906-1909. "HPV-11 but not HPV-6, 16, or 18 was found in all of the laryngeal and bronchogenic cancers in patients with a history of early onset RRP in this study.... HPV type 6 and 11 are considered "low-risk" viruses and are not associated with genital cancers, as are HPV types 16 and 18. However, our data suggests that HPV type 11 is an aggressive virus in laryngeal papilloma that should be monitored in patients with RRP."

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."

High co-prevalence of genogroup 1 TT virus and human papillomavirus is associated with poor clinical outcome of laryngeal carcinoma. G Szladek, A Juhasz, G Kardos, K Szoke, T Major, I Sziklai, I Tar, I Marton, J Konya, L Gergely, K Szarka. J Clin Pathol 2005 Apr;58(4):402-405. 40 healthy individuals, 10 patients with recurrent papillomatosis, five patients with papillomatosis with malignant transformation, and 25 patients with laryngeal carcinoma. "In the 11 patients with carcinoma who had metastasis or relapse there was a high rate of coinfection with genogroup 1 TTV and HPV (eight of 11), whereas in the 14 without tumour progression no coinfection was found. Coinfection was associated with significantly lower tumour free survival in patients with carcinoma (p < 0.001). Furthermore, four of five patients who had papillomatosis with malignant transformation were coinfected with genogroup 1 TTV and HPV."

Molecular detection and typing of human papillomavirus in laryngeal carcinoma specimens. MC Torrente, S Ampuero, M Abud, JM Ojeda. Acta Otolaryngol 2005 Aug;125(8):888-893. "Ten of the 31 samples (32%) were positive for HPV DNA and all of the samples were positive for human beta-globin. The genotypes identified were HPV 16 (n=3), HPV 58 (n=2) and HPV 39, 45, 51, 59, 66 and 69 (n=1 for each). The three samples positive for HPV 16 had lost region E2, meaning that the viral DNA had been integrated into the host genome."

[The prevalence of E6/E7 HPV type 16 in laryngeal cancer and in normal mucosa] K Morshed, M Polz-Dacewicz, B Rajtar, M Szymanski, M Ziaja-Soltys, W Golabek. Pol Merkur Lekarski 2005 Sep;19(111):291-293. HPV 16 DNA was found in 26 (36.1%) of 72 samples of laryngeal squamous cell carcinoma.

Immunohistochemical demonstration of multiple HPV types in laryngeal squamous cell carcinoma. K Morshed, E Korobowicz, M Szymanski, D Skomra, W Golabek. Eur Arch Otorhinolaryngol 2005 Nov;262(11):917-920. 6/40 (15%) of laryngeal squamous cell carcinoma patients were positive for HPV, versus zero of 33 controls with with non-neoplastic laryngeal lesions or laryngeal nodules. "Five (83.4%) of six patients with HPV positive tumors had G2 (moderately differentiated), one patient (16.6%) had G3 (poorly differentiated), and no patient with HPV positive tumor had a G1 (well-differentiated) tumor. Four (66.6%) of the six HPV positive tumors were in the supraglottic region, one (16.6%) tumor was located in the glottis, and one (16.6%) HPV positive tumor was in the subglotic region."

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."

Human papillomavirus and Epstein-Barr virus infection, p53 expression, and cellular proliferation in laryngeal carcinoma. DE de Oliveira, MM Bacchi, RS Macarenco, JV Tagliarini, RC Cordeiro, CE Bacchi. Am J Clin Pathol 2006 Aug;126(2):284-293. In 110 squamous cell carcinomas of the larynx, "High-grade HPV was found in 37.3% of cases, and none had demonstrable EBV infection."

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."

Detection of human papillomavirus and relevant tumor suppressors and oncoproteins in laryngeal tumors. ME Manjarrez, R Ocadiz, L Valle, C Pacheco, A Marroquin, C De la Torre, M Selman, P Gariglio. Clin Cancer Res 2006 Dec 1;12(23):6946-6951. 16 laryngeal carcinomas versus 13 individuals who died of nonmalignant causes. "Most laryngeal papillomatosis samples contained low-risk HPV determined by both techniques. However, 25% of laryngeal carcinoma samples were positive for HPV employing PCR or in situ PCR." "In laryngeal cancer, we found that in situ PCR was more sensitive than in vitro PCR, detecting HPV-DNA in 25% of the samples as compared with 12.5% when in vitro PCR was employed. The large difference in the percentages reported by other authors can be explained partly by the different detection methods used." "Two cases with laryngeal cancer showed high-risk and low-risk HPV whereas the other two contained either low-risk HPV or high-risk HPV, suggesting that both low-risk and high-risk HPV might be involved in the development of laryngeal malignant tumors in a subset of patients, and that these viruses may be a synergistic risk factor for malignant development." Low-risk HPV was present in all papillomatosis patients.

[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)."

Human papilloma virus prevalence in laryngeal squamous cell carcinoma. A Gungor, H Cincik, H Baloglu, E Cekin, S Dogru, E Dursun. J Laryngol Otol 2007 Aug;121(8):772-774. "Human papilloma virus deoxyribonucleic acid was detected in seven of 95 cases of laryngeal squamous cell carcinoma (7.36 per cent). Human papilloma virus genotyping revealed double human papilloma virus infection in three cases and single human papilloma virus infection in the remaining four cases. The human papilloma virus genotypes detected were 6, 11 and 16 (the latter detected in only one case)."

Alcohol, smoking and human papillomavirus in laryngeal carcinoma: a Nordic prospective multicenter study. WJ Koskinen, K Brøndbo, H Mellin Dahlstrand, T Luostarinen, T Hakulinen, I Leivo, A Molijn, WG Quint, T Røysland, E Munck-Wikland, AA Mäkitie, I Pyykkö, J Dillner, A Vaheri, LM Aaltonen. J Cancer Res Clin Oncol 2007 Sep;133(9):673-678. Fresh-frozen laryngeal cancer biopsies from 108 patients in Finland, Norway, and Sweden. Four (3.3%) were positive for HPV, type(s) not specified in abstract.

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 (93 laryngeal tumors) and 549 controls. 80.7% of laryngeal 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.

High incidence of malignant transformation of laryngeal papilloma in Taiwan. LA Lee, AJ Cheng, TJ Fang, CG Huang, CT Liao, JT Chang, HY Li. Laryngoscope 2008 Jan;118(1):50-55. 26 consecutive laryngeal papilloma patients. "During 237 person-years of follow-up, six new, pathologically confirmed cases of laryngeal carcinoma were ascertained (incidence 2.5/100 person-years), and all were associated with HPV-6 or HPV-11. Malignant transformation revealed no correlation with the following: age less than 3 years at diagnosis, sex, history of tobacco use, history of alcohol consumption, family history of laryngeal cancer, or type of laryngeal papilloma. Laryngeal papilloma without demonstrable HPV DNA was the only significant risk factor for malignant transformation (P < .05). The cumulative risk of malignant transformation in subjects without demonstrable HPV DNA was significantly higher than that in HPV-positive patients (relative risk, 8.0; 95% confidence interval, 1.1-60.3; P = .05)."

Short-fragment PCR assay for highly sensitive broad-spectrum detection of human papillomaviruses in laryngeal squamous cell carcinoma and normal mucosa: clinico-pathological evaluation. K Morshed, M Polz-Dacewicz, M Szymański, D Polz. Eur Arch Otorhinolaryngol 2008 Jul;265 Suppl 1:S89-96. 93 primary laryngeal squamous cell carcinomas, 49 specimens of normal mucosa, and 22 specimens of laryngeal nodules serving as controls. By SPF(10) HPV DNA test, PCR/DEIA method and INNO-LiPA genotyping assay, "Human papillomavirus was detected in 33 (35.5%) of the 93 samples from LSCC, in 4 (8.2%) of 49 samples of the normal mucosa and it was not detected in any of the sample from the control group. Twenty-eight of 33 (81.8%) were positive for HPV-16, 6 of 33 (18.2%) were positive for HPV-18 and 5 of 33 (15.1%) were positive for HPV-33. Multiple infection was found in 5 of 33 (15.1%); 3 samples were positive for HPV-16 and HPV-33, 2 samples for HPV-16 and HPV-18." "The difference between the presence of HPV in squamous cell carcinoma tumors and in control group samples was statistically significant (χ² = 8.13; P = 0.004). The difference between the presence of HPV in squamous cell carcinoma tumors and in normal mucosa from the surgical margin in patients with LSCC samples was statistically significant (χ² = 3.78; P = 0.05)." In Table 1, 32.5% of carcinomas in smokers were HPV-positive, versus 36.4% in non-smokers (P = 0.48).

Retraction: WITHDRAWN: Human papillomavirus detection and genotyping in squamous cell carcinomas of the larynx. AM Silva, CA Vilanova-Costa, SF de Oliveira, CC da Silva, MP Curado, AD da Cruz. J Virol Methods 2009 May;157(2):231. In 20 cases, "HPV DNA was amplified in 25% of cases, and the amplified products from the first PCR were genotyped using specific primers for HPVs 6, 11, 16, 18, 33, 35, 45 and 58. HPV33 genome was found in three samples and HPV45 in two samples as the viral types associated most frequently with laryngeal cancer. HPVs 11, 16, and 18 were also genotyped. Three patients had two viral types simultaneously, suggesting that co-infection may play an important role in the etiology of cancer of the larynx."

Detection of HHV-8 and HPV in laryngeal carcinoma. MG Güvenç, K Midilli, A Ozdoğan, E Inci, R Tahamiler, O Enver, G Sirin, S Ergin, M Kuşkucu, EO Divanoğlu, G Yilmaz, K Altas. Auris Nasus Larynx 2008 Sep;35(3):357-362. 47 squamous cell carcinomas (SCC) and 3 verrucous carcinomas. "HPV DNA was detected in seven patients (7/50; 14%) (5 out of 47 patients with SCC (5/47; 10.6%) and two out of three patients with verrucous carcinoma). HHV-8 DNA was detected in five patients and they all had SCC (5/47; 10.6%). One case had both HHV-8 and HPV DNA. None of the control samples from cadavers harbored HHV-8 DNA, or HPV DNA. There was a statistically significant correlation between HHV-8 DNA and HPV DNA positivity and laryngeal SCC (Fisher exact test; p=0.023 for each). No statistically significant correlations were found between the presence of HHV-8 and/or HPV and age, gender, tumor stage, differentiation, the site of the tumor, smoking and alcohol use."

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."

Galectin-3 overexpression in invasive laryngeal carcinoma, assessed by computer-assisted analysis. FA Miranda, MK Hassumi, MC Guimarães, RT Simões, TG Silva, RC Lira, AM Rocha, CT Mendes Jr, EA Donadi, CP Soares, EG Soares. J Histochem Cytochem 2009 Jul;57(7):665-673. "[P]araffin-embedded larynx biopsies from 65 patients, 10 in situ laryngeal carcinomas, 27 laryngeal carcinomas without metastases, and 28 with metastases. Twenty-eight cervical lymph nodes from patients with metastatic lesions were also evaluated." 7 (12.7%) out of 55 patients were HPV positive.

Human papillomavirus in early laryngeal carcinoma. JL Baumann, S Cohen, AN Evjen, JH Law, S Vadivelu, A Attia, JS Schindler, CH Chung, PS Wirth, CJ Meijer, PJ Snijders, WG Yarbrough, RJ Slebos. Laryngoscope 2009 Aug;119(8):1531-1537. 38 cases of T1 or carcinoma in situ (CIS) laryngeal lesions by PCR for 37 HPV subtypes. "HPV DNA was detected in 6 (16%) of the 38 lesions, representing HPV types 16, 26, 31, 39, and 52,... This HPV prevalence is higher than that noted in many previous laryngeal cancer studies, possibly due to the relatively large panel of subtypes screened for in this study."

Papillary squamous cell carcinoma of the head and neck: frequent association with human papillomavirus infection and invasive carcinoma. VY Jo, SE Mills, MH Stoler, EB Stelow. Am J Surg Pathol 2009 Nov;33(11):1720-1724. 33% of laryngeal tumors were HPV-positive by ISH.

Prevalence of high-risk human papillomavirus types (HPV-16, HPV-18) and their physical status in primary laryngeal squamous cell carcinoma. B Liu, Z Lu, P Wang, Z Basang, X Rao. Neoplasma 2010;57(6):594-600. "Using HPV L1 general primer amplification, HPV DNA was detected in 23 (27.4%) of the 84 LSCC samples. When PCR products were cloned and sequenced, HPV16 were found in all 23 L1 positive samples. However, when specific primers for HPV- 16 or -18 were used to amplify E6 and E7 in all samples, 29 cases (34.5%) were positive for HPV-16, while 6 cases (7.1%) were positive for HPV 18. Coinfection of HPV-16 and -18 were found in 4 cases (4.8%). In addition, qRT-PCR assay found that HPV-16 was characterized as episomal in 51.7% of cases, mixed (i.e., episomal and integrated) in 34.5%, and integrated in 13.8%, while HPV-18 was similarly characterized as episomal in 83.3% of cases and mixed in 16.7%. In the present study, about 36.9% of patients with LSCC were found to be infected with HPV-16 and -18 and integration of HPV-16 and -18 DNA into the host genome was found."

Usefulness and efficiency of formalin-fixed paraffin-embedded specimens from laryngeal squamous cell carcinoma in HPV detection by IHC and PCR/DEIA. K Morshed, M Polz-Dacewicz, M Szymański, A Smoleń. Folia Histochem Cytobiol 2010 Sep 30;48(3):398-402. "HPV was detected by two methods (SPF10 PCR/DEIA and IHC) in 14 (25.92%) out of 54 specimens from FFPE. Significant differences were found between the HPV detection using PCR/DEIA method and IHC method in FFPE tissues. The comparative analysis of the 54 samples after assuming PCR method in FFPE tissues showed accuracy of 92.6%, sensitivity of 90.5% and specificity of 93.9%."

Detection of novel Human papilloma virus type 82 in laryngeal cancer: case report. G Pannone, F Sanguedolce, A Santoro, P Fierro, M Panetti, D Fierro, F Maiello, S De Maria, A Giannattasio, R Serpico, L Lo Muzio, S Metafora, P Bufo. Auris Nasus Larynx 2010 Oct;37(5):648-650. "We report the case of a 51-year-old man affected by laryngeal squamous cell carcinoma; analysis of DNA extracted by cancer cells by an innovative molecular virology assay (INNO-LiPA HPV Genotyping Extra) showed the presence of two high-risk HPV genotypes, HPV-73 and -82. Immunohistochemical examination confirmed positivity for both capsid protein and viral oncogenic protein E7."

Human papillomavirus infections in laryngeal cancer. MC Torrente, JP Rodrigo, M Haigentz Jr, FG Dikkers, A Rinaldo, RP Takes, J Olofsson, A Ferlito. Head Neck 2011 Apr;33(4):581-586. Review. "[A]pproximately 25% of laryngeal squamous cell carcinomas harbor HPV infections on meta-analysis, with common involvement of high-risk HPV types 16 (highest frequency) and 18. Preliminary results suggest that these high-risk HPV infections seem to be biologically relevant in laryngeal carcinogenesis, manifested as having viral DNA integration in the cancer cell genome and increased expression of the p16 protein."

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)."

Human Papillomavirus Outcomes in an Access-to-Care Laryngeal Cancer Cohort. JK Stephen, KM Chen, V Shah, S Havard, M Lu, VP Schweitzer, G Gardner, MJ Worsham. Otolaryngol Head Neck Surg 2012 May;146(5):730-738. 79 patients with primary LSCC. HPV16 was detected in 27% of LSCC patients. There were no differences in survival between HPV-positive and HPV-negative patients.

Possible implication of Mdm2 as a prognostic marker in invasive laryngeal carcinoma. MK Hassumi-Fukasawa, FA Miranda-Camargo, MC Guimarães, RT Simões, EA Donadi, CP Soares, EG Soares. Eur Arch Otorhinolaryngol 2012 Jul;269(7):1795-1804. 7 (13.2%) out of 53 patients were positive for HPV 6, 11, 16, 18, 31 or 33 by PCR.

Human Papillomavirus Infection and Laryngeal Cancer Risk: A systematic review and meta-analysis. X Li, H Li, J Gao, Y Yang, F Zhou, C Gao, M Li, Q Jin, L Gao. J Infect Dis 2013 Feb 1;207(3):479-488. 55 eligible studies. "The overall HPV prevalence in laryngeal cancer tissues was 28.0% (95% confidence interval [CI], 23.5%-32.9%). There were 26.6% laryngeal cancer patients were infected with high-risk types only, and HPV-16 was most frequently observed with a prevalence of 19.8% (95% CI, 15.7%-24.6%). The meta-analysis based on 12 eligible case-control studies suggests a strong association between HPV infection and laryngeal squamous cell carcinoma with a summarized odds ratio (OR) of 5.39 (95% CI, 3.25-8.94). Different magnitude of the association was observed for HPV-16 (OR=6.07, 95% CI: 3.44-10.70) and HPV-18 (OR=4.16, 95% CI: 0.87-20.04) (p<0.01)."

The role of human papillomavirus in head and neck cancer in Senegal. C Ndiaye, L Alemany, Y Diop, N Ndiaye, MJ Diémé, S Tous, JE Klaustermeier, M Alejo, X Castellsagué, FX Bosch, H Trottier, S Sanjosé. Infect Agent Cancer 2013 Apr 17;8(1):14. [Epub ahead of print]. 3 of 25 (8.6%) laryngeal cancers were positive for HPV (Table 2).

Methodology

Correlation of histology, human papillomavirus, and viral load in laryngeal papillomas of childhood. G Sharma, J DeHart, GJ Nuovo. Diagn Mol Pathol 2005 Dec;14(4):230-236. 29 of 47 (62%) of cases were positive for HPV, types 6 and 11, by ISH. There were less than 20 HPV-positive cells per tissue. 38 of 47 (81%) were positive by RT in situ PCR using primers specific for HPVs 6 and 11, in lesions negative by ISH.

Differential Diagnosis

Laryngeal zoster mimicking a laryngeal cancer. E Higuchi, Y Nakamaru, R Ohwatari, T Sakashita, Y Mesuda, A Homma, Y Furuta, S Fukuda. Otolaryngol Head and Neck Surgery 2005 Oct;133(4):1-3. The patient had a white ulcerated lesion on the left arytenoid and the epiglottis, and paralysis of the left vocal cord. Pathological examination showed "moderate to severe dysplasia highly suggestive of squamous cell carcinoma. However, severe inflammation precluded definitive pathological diagnosis, and rebiopsy was recommended. At this point, the most likely diagnosis was thought to be cancer of the larynx."

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 04-29-13