Herpes Viruses and Oral Cavity Cancer

Detection of Epstein-Barr virus (EBV) DNA by the polymerase chain reaction (PCR) in oral smears from healthy individuals and patients with squamous cell carcinoma. EJ Mao, CJ Smith. J Oral Pathol Med 1993 Jan;22(1):12-17. 20 oral cancer patients and 60 healthy adults. EBV DNA was found in 10 out of 20 oral cancer patients (50%), though in only 7 (35%) of the lesions, versus 15/60 (25%) controls.

Mao - J Oral Pathol Med 1993 abstract / PubMed

Human herpes simplex-1 and papillomavirus type 16 homologous DNA sequences in normal, potentially malignant and malignant oral mucosa. M Cox, N Maitland, C Scully. Eur J Cancer B Oral Oncol 1993 Jul;29B(3):215-219. "The results show that: (1) 2/4 patients with lichen planus, 2/4 patients with non-specific keratosis, 1/8 patients with oral carcinoma and 3/5 biopsy specimens of normal oral mucosa contained DNA sequences homologous to the HSV-1, Bam HI-G fragment. (2) HPV-16 homologous DNA sequences were detected in 3/4 patients with lichen planus, 4/4 non-specific keratosis, 4/8 oral carcinomas and in 3/5 biopsy specimens of normal oral mucosa. (3) Overall, only 5 patient biopsy specimens were positive for both HSV-1 and HPV-16 homologous DNA sequences; 2 lichen planus, 2 non-specific keratosis and 1 normal. The data cannot exclude a "hit and run" oncogenic mechanism for HSV but suggest that if HSV-1 and HPV-16 play a synergistic role in the development of oral cancer this may be an early event. Indeed, the data suggest HSV might be more frequently found in potentially malignant lesions than in carcinoma."

Cox - Eur J Cancer B Oral Oncol 1993 abstract / PubMed

Epstein-Barr virus in tobacco-induced oral cancers and oral lesions in patients from India. J D'Costa, D Saranath, V Sanghvi, AR Mehta. J Oral Pathol Med 1998 Feb;27(2):78-82. 103 oral squamous cell carcinomas (OSCC), 100 oral lesions primarily leukoplakia (82 cases), and 76 clinically normal mucosa specimens. BamHIL by PCR, followed by Southern blot. "We detected EBV in 25 of 103 (25%) OSCC, 13 of 100 (13%) oral lesions, 3 of 76 (4%) clinically normal mucosa samples and 10 of 141 (7%) PBC."

D'Costa - J Oral Pathol Med 1998 abstract / PubMed

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)."

Cruz - Oral Oncol 1997 abstract / PubMed

Epstein-Barr virus and oral squamous cell carcinoma in patients without HIV infection: viral detection by polymerase chain reaction. M González-Moles, J Gutiérrez, I Ruiz, JA Fernández, M Rodriguez, J Aneiros. Microbios 1998;96(383):23-31. 108 OSCC patients without HIV. EBV DNA was detected in 17.59% of the tumours... Results revealed that 63.1% of the tumours (12 cases) were DNA positive affecting the lateral margin of the tongue."

González-Moles - Microbios 1998 abstract / PubMed

Prevalence of Epstein-Barr virus in oral squamous cell carcinoma. I Kobayashi, K Shima, I Saito, T Kiyoshima, K Matsuo, S Ozeki, M Ohishi, H Sakai. J Pathol 1999 Sep;189(1):34-39. 7/46 (15.2%) OSCCs were positive by a combination of PCR and Southern blot hybridization. 6 expressed LMP1, but none expressed EBER-1 by ISH.

Kobayashi - J Pathol 1999 abstract / PubMed

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.

Tsuhako - J Oral Pathol Med 2000 abstract / PubMed

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. "EBER transcripts were investigated by RNA in situ hybridisation. EBNA-1, EBNA-2, LMP-1, LMP-2, BHRF1 and BARF0 transcripts were investigated by RT-PCR and/or NASBA. EBNA-1, LMP-1 and ZEBRA protein expressions were investigated by immunohistochemistry. All 36 OSCCs were positive for EBV DNA, using the highly sensitive BamHI W PCR, and 18 of these (50%) were positive using the less-sensitive PCR, which targets BNLF-1. However, virtually all OSCCs tested failed to reveal EBV transcripts, including EBERs and EBNA-1 transcripts. No ZEBRA and LMP-1 proteins were found in the neoplastic or any other cells of the OSCCs investigated." Study established that transciption was not occurring.

Cruz - Int J Cancer 2000 abstract / PubMed

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."

Jang - J Oral Pathol Med 2001 abstract / PubMed

Epstein-Barr virus latent membrane protein-1 (LMP-1) expression in oral squamous cell carcinoma. MA Gonzalez-Moles, J Gutierrez, MJ Rodriguez, I Ruiz-Avila, A Rodriguez-Archilla. Laryngoscope 2002 Mar;112(3):482-487. 78 OSCCs. By PCR, IHC, and ISH. "EBV DNA was detected in 19.2% of the cases. Expression of LMP-1 in neoplastic cells was found in 85.7% of the EBV-positive OSCCs. EBV presence was significantly more frequent (P <.05) in OSCCs localized on the lateral tongue. EBV-positive OSCCs more frequently presented (P <.05) greater nuclear atypia."

Gonzalez-Moles - Laryngoscope 2002 abstract / PubMed

Association of Epstein-Barr virus with oral cancers. M Shimakage, K Horii, A Tempaku, K Kakudo, T Shirasaka, T Sasagawa. Hum Pathol 2002 Jun;33(6):608-614. 28 tongues and 9 other oral cancers, all squamous cell carcinomas. "RNA in situ hybridization using an EBER1 probe detected RNAs in 16 out of 24 cancers. Also, mRNA in situ hybridization using a probe of the EBV-determined nuclear antigen-2 (EBNA2) region detected positive signals in 9 out of 12 cancers. Furthermore, EBNA2, latent membrane protein-1 (LMP1) and BZLF1 were detected in these cancers by immunofluorescence staining, but were not detected in any of the epithelial cells of the normal tissues. Four out of 6 metastatic tissues showed stronger fluorescence than that in the primary tissues. RT-PCR analysis also showed EBER1 expression in 1 of the 3 tongue cancers. PCR detected the BamHIW sequence of EBV DNA in all cases, including the normal tissues tested."

Shimakage - Hum Pathol 2002 abstract / PubMed

Prevalence of Epstein-Barr virus in oral squamous cell carcinoma, oral lichen planus, and normal oral mucosa. LP Sand, J Jalouli, PA Larsson, JM Hirsch. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2002 May;93(5):586-592. 29 patients with OSCC, 23 with OLP, and 67 healthy controls. "Of the OSCC patients, 37.9% were EBV positive; and of the OLP patients, 26.1% were EBV positive. Both percentages were statistically significant compared with that of control patients (7.3%)."

Sand - Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2002 abstract / PubMed

Detection of Epstein-Barr virus-derived latent membrane protein-1 gene in various head and neck cancers: is it specific for nasopharyngeal carcinoma? NM Tsang, KP Chang, SY Lin, SP Hao, CK Tseng, TT Kuo, MH Tsai, TC Chung. Laryngoscope 2003 Jun;113(6):1050-1054. LMP-1 was found in 0/26 oral cavity carcinomas and 1 tonsillar carcinoma.

Tsang - Laryngoscope 2003 abstract / PubMed

Epstein-Barr virus (EBV)-related oral squamous cell carcinoma in Okinawa, a subtropical island, in southern Japan--simultaneously infected with human papillomavirus (HPV). M Higa, T Kinjo, K Kamiyama, K Chinen, T Iwamasa, A Arasaki, H Sunakawa. Oral Oncol 2003 Jun;39(4):405-414. 188 oral tumors, 177 (94%) squamous cell carcinomas. 72% of OSCCs were positive for EBV and 78% for HPV. Different strains prevailed in Okinawa versus the mainland. Most mainland cases were negative for EBV and/or HPV.

Higa - Oral Oncol 2003 abstract / PubMed

Co-expression of p53 and Ki67 and lack of EBV expression in oral squamous cell carcinoma. A Iamaroon, U Khemaleelakul, S Pongsiriwet, J Pintong. J Oral Pathol Med 2004 Jan;33(1):30-36. "None of OSCC cases [24] expressed EBV-encoded RNA (EBER) transcripts."

Iamaroon - J Oral Pathol Med 2004 abstract / PubMed

Involvement of viral and chemical factors with oral cancer in Taiwan. YY Yang, LW Koh, JH Tsai, CH Tsai, EF Wong, SJ Lin, CC Yang. Jpn J Clin Oncol 2004 Apr;34(4):176-183. 37 oral cancer biopsies and 36 normal specimens, with PCR for HPV, CMV, EBV, HSV-1, HSV-2 and HHV-8. Two (5.4%) were HSV-1-positive and four (10.8%) were HPV-positive.

Yang - Jpn J Clin Oncol 2004 abstract / PubMed

Detection of EBV infection and gene expression in oral cancer from patients in Taiwan by microarray analysis. CY Yen, MC Lu, CC Tzeng, JY Huang, HW Chang, RS Chen, SY Liu, ST Liu, B Shieh, C Li. J Biomed Biotechnol 2009;2009:904589. 57 oral squamous cell carcinoma biopsies. "The majority of the specimens (82.5%) were EBV-positive that probably expressed coincidently the genes for EBNAs, LMP2A and 2B, and certain structural proteins. Importantly, the genes fabricated at the spots 61 (BBRF1, BBRF2, and BBRF3) and 68 (BDLF4 and BDRF1) on EBV-chip were actively expressed in a significantly greater number of OSCC exhibiting exophytic morphology or ulceration than those tissues with deep invasive lesions (P = .0265 and .0141, resp.)."

Yen - J Biomed Biotechnol 2009 full article / PubMed Central
Yen / J Biomed Biotechnol 2009 full article

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."

Kis - Eur J Oral Sci 2009 abstract / PubMed

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."

Jalouli - J Oral Pathol Med 2010 abstract / PubMed

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."

Jalouli - Acta Otolaryngol 2010 abstract / PubMed

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."

Jannapureddy - Diagn Cytopathol 2010 abstract / PubMed

High-risk human papillomavirus in nasopharyngeal carcinoma. AD Singhi, J Califano, WH Westra. Head Neck 2012 Feb;34(2):213-218. "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)."

Singhi - Head Neck 2012 abstract / PubMed

Oral dysplasia and squamous cell carcinoma: Correlation between increased expression of CD21, Epstein-Barr virus and CK19. R Jiang, X Gu, TN Moore-Medlin, CA Nathan, LM Hutt-Fletcher. Oral Oncol 2012 Sep;48(9):836-841. "[E]xpression of CD21 increases in frequency and intensity as oral epithelial cells become more dysplastic and that expression correlates with an increase in infection by EBV. Tumors or dysplastic lesions that carry EBV also generally express higher levels of CK19 than those that do not... The findings suggest that dysplasia may make cells more susceptible to infection by EBV and that infection by the virus may alter the phenotype of the infected cell in a manner which could affect prognosis."

Jiang - Oral Oncol 2012 abstract / PubMed

Squamous cell carcinoma of the oral tongue in young non-smokers is genomically similar to tumors in older smokers. CR Pickering, J Zhang, DM Neskey, M Zhao, SA Jasser, J Wang, A Ward, CJ Tsai, MV Ortega Alves, JH Zhou, J Drummond, AK El-Naggar, R Gibbs, JN Weinstein, DA Wheeler, J Wang, MJ Frederick, JN Myers. Clin Cancer Res 2014 Jul 15;20(14):3842-3848. 16 young (<45 yrs, non-smokers) and 28 old (>45 yrs) tongue cancer patients. "[W]e found that gene-specific mutation and copy-number alteration frequencies were similar between young and old patients with SCCOT in two independent cohorts. Likewise, the types of base changes observed in the young cohort were similar to those in the old cohort even though they differed in smoking history. TCGA data also demonstrate that the genomic effects of smoking are tumor site-specific, and we find that smoking has only a minor impact on the types of mutations observed in SCCOT."

Pickering - Clin Cancer Res 2014 full article / PubMed Central
Pickering / Clin Cancer Res 2014 full article

Human papillomavirus promotes Epstein-Barr virus maintenance and lytic reactivation in immortalized oral keratinocytes. KR Makielski, D Lee, LD Lorenz, DM Nawandar, YF Chiu, SC Kenney, PF Lambert. Virology 2016 May 11;495:52-62. "Our results indicate that HPV increases maintenance of the EBV genome in the co-infected cells and promotes lytic reactivation of EBV in upper layers of stratified epithelium. Expression of the HPV oncogenes E6 and E7 were found to be necessary and sufficient to account for HPV-mediated lytic reactivation of EBV. Our findings indicate that HPV increases the capacity of epithelial cells to support the EBV life cycle, which could in turn increase EBV-mediated pathogenesis in the oral cavity."

Makielski - Virology 2016 abstract / PubMed

Thymidylate synthase

The cytostatic activity of 5-(1-azidovinyl)-2'-deoxyuridine (AzVDU) against herpes simplex virus thymidine kinase gene-transfected FM3A cells is due to inhibition of thymidylate synthase and enhanced by UV light (lambda = 254 nm) exposure. J Balzarini, G Andrei, R Kumar, EE Knaus, LI Wiebe, E De Clercq. FEBS Lett 1995 Oct 2;373(1):41-44.

Balzarini - FEBS Lett 1995 abstract / PubMed

Human herpesvirus 8 gene encodes a functional thymidylate synthase. G Gáspár, E De Clercq, J Neyts. J Virol 2002 Oct;76(20):10530-10532. "The enzyme is a key target for the action of antitumoral drugs. HVS and varicella-zoster virus (VZV) have been previously reported to encode a functional TS (9, 22). Human cytomegalovirus, a virus that belongs to the betaherpesvirus family, does not encode a TS but markedly stimulates cellular TS activity in infected human embryonic lung cells." It influences the regulation of p53 expression.

Gáspár - J Virol 2002 full article / PubMedCentral
Gáspár - J Virol 2002 full article

Human cytomegalovirus requires cellular deoxycytidylate deaminase for replication in quiescent cells. G Gribaudo, L Riera, P Caposio, F Maley, S Landolfo. J Gen Virol 2003 Jun;84(Pt 6):1437-1441. "Here, we have demonstrated that HCMV increases expression of the cellular deoxycytidylate deaminase (dCMP deaminase), which provides the substrate for TS by converting dCMP to dUMP. We observed an increase in dCMP deaminase protein levels, whereas deoxyuridine triphosphatase (dUTPase), another cellular enzyme that may provide dUMP by hydrolysing dUTP, was undetectable. The essential requirement of cellular dCMP deaminase for productive HCMV replication was further emphasized by showing that a precursor of a potent dCMP deaminase inhibitor, zebularine, suppressed virus replication and DNA synthesis. These results suggest that HCMV exploits the host's dCMP deaminase activity to replicate in quiescent cells."

Gribaudo / J Gen Virol 2003 full article

[The clinical significance of thymidylate synthase expression in human papillomavirus-related oropharyngeal squamous carcinoma]. H Kato, T Yui, N Yamamoto, T Okada, M Urano, K Sakurai, K Naito. Nihon Jibiinkoka Gakkai Kaiho 2012 Nov;115(11):957-964. 22 / 54 (40.7%) were positive for HPV, (21 HPV 16 and 1 HPV 58). "TS was overexpressed in 25 (46.3%) of 54 samples. Of these, 19 (76.0%) had an HPV-negative status and 21 (84.0%) were heavy smokers. TS over-expression was associated with the patients with HPV-negative tumors (P = 0.02) and heavy smokers (p = 0.012)."

Kato - Nihon Jibiinkoka Gakkai Kaiho 2012 abstract / PubMed

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."

van der Meij - Oral Oncol 2007 abstract / PubMed

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.

Derk - J Rheumatol 2005 abstract / PubMed

Progression of Leukoplakia

Gene expression profiling predicts the development of oral cancer. P Saintigny, L Zhang, YH Fan, AK El-Naggar, VA Papadimitrakopoulou, L Feng, JJ Lee, ES Kim, W Ki Hong, L Mao. Cancer Prev Res (Phila) 2011 Feb;4(2):218-229.) 35 oral cancers among 86 oral preneoplastic lesion patients enrolled in a chemoprevention trial (which had no effect on outcome) over approximately 6 years of followup. From analysis of the supplementary material, 6/56 = 10.7% current smokers; 20/65 = 30.8% former smokers (or 26/121 = 21.5% of current plus former smokers), versus 9/41 = 22.0% never smokers developed oral cancer. Of the 4 cases from the prevention trial not included, if these had all been among current and/or former smokers, results would be 30/121 = 24.8%; while if those 4 were all among never smokers, 13/41 = 31.7%.

Saintigny - Cancer Prev Res (Phila) 2011 author manuscript / PubMed Central

Urban legends series: oral leukoplakia. PG Arduino, J Bagan, AK El-Naggar, M Carrozzo. Oral Dis 2013 Oct;19(7):642-659. "Results of extensive literature search suggest that (i) no definitive evidence for direct causal relationship between smoked tobacco and alcohol as causative factors of OLs, (ii and iii) the vast majority of OLs follow a benign course and do not progress into a cancer, and no widely accepted and/or validated clinical and/or biological factors can predict malignant transformation, and (iv) the distinction between multifocal/multiple leukoplakias and [proliferative verrucous leukoplakia] in their early presentation is impossible; the temporal clinical progression and the high rate of recurrences and development of cancer of PVL are the most reliable features for diagnosis."

Arduino - Oral Dis 2013 abstract / PubMed

See Also:

HPV Causes Oral Cancer
Viruses Cause Salivary Gland Cancers
Epstein-Barr Virus Causes Nasopharyngeal Cancer


cast 05-15-16