Basic consideration of research strategies for head and neck cancer

Abstract

Head and neck cancer (HNC) consists of a group of malignancies affecting closely related anatomical regions of the upper aerodigestive tract (UADT), including the oral cavity, salivary glands, upper and lower jaw bones and facial skin; the nasal cavity, paranasal sinuses, pharynx, larynx and thyroid gland (although the latter is often excluded and considered as part of endocrine neoplasms). Of these, 90% of HNCs are histologically squamous cell carcinomas originating from the mucosal lining. These malignancies are strongly associated with certain environmental and life-style risk factors, principally tobacco in both smoked and smokeless forms, excessive alcohol consumption, diets poor in antioxidants and essential micronutrients, UV light, chemicals used in certain workplaces, and viruses, principally certain strains of human papillomavirus (HPV) and Epstein-Barr virus (EBV). These cancers are frequently aggressive in their biological behaviour with local invasion and metastasis to lymph nodes in the neck. Since most patients are already at late stages of disease at the time of diagnosis, the desirable practice of early diagnosis (first sign of the malignant lesion at an initial stage ) and early treatment, a critical priority to save lives and retain quality of life, is difficult to implement. Thus, primary prevention has been set as a key goal. This article aims to reinforce the basic knowledge of aetiology, key risk factors related to the development of head and neck cancer, basic features of clinical appearance of this group of cancers, and strategies for prevention and early detection. We also suggest basic research strategies on the basis of current knowledge, which should ultimately lead to the improvement of clinical management.

Keywords

clinical management / head and neck cancer / prevention and early detection / research strategies / risk factors

References

[1] Jemal A, Siegel R, Xu J, Ward E. Cancer statistics 2010. CA: A Cancer J Clin2010;60:277-300. Erratum in: CA: A Cancer J Clin2011;61(2):133-134

[2] Shah JP, Johnson NW, Batsakis JG. Oral Cancer. MD Martin Dunitz Taylor & Francis Group, 2003:20-32, 77-128

[3] Johnson NW, Jayasekara P, Amarasinghe AA. Squamous cell carcinoma and precursor lesions of the oral cavity: epidemiology and aetiology. Periodontol 20002011; 57(1): 19-37

[4] Forastiere A, Koch W, Trotti A, Sidransky D. Head and neck cancer. N Engl J Med2001; 345(26): 1890-1900

[5] Cooper JS, Pajak TF, Rubin P, Tupchong L, Brady LW, Leibel SA, Laramore GE, Marcial VA, Davis LW, Cox JD. Second malignancies in patients who have head and neck cancer: incidence, effect on survival and implications based on the RTOG experience. Int J Radiat Oncol Biol Phys1989; 17(3): 449-456

[6] Papaspyrou G, Hoch S, Rinaldo A, Rodrigo JP, Takes RP, van Herpen C, Werner JA, Ferlito A. Chemotherapy and targeted therapy in adenoid cystic carcinoma of the head and neck: a review. Head Neck2011; 33(6): 905-911

[7] Kumar V, Abbas AK, Fausto N. Robbins and Cotran- Pathologic basis of disease. 7th Ed. Elsevier Saunders, 2005:335

[8] Iro H, Waldfahrer F. Evaluation of the newly updated TNM classification of head and neck carcinoma with data from 3247 patients. Cancer1998; 83(10): 2201-2207

[9] Takes RP, Rinaldo A, Silver CE, Piccirillo JF, Haigentz M Jr, Suárez C, Van der Poorten V, Hermans R, Rodrigo JP, Devaney KO, Ferlito A. Future of the TNM classification and staging system in head and neck cancer. Head Neck2010; 32(12): 1693-1711

[10] Ferlay J, Shin HR, Bray F, Forman D, Mathers C, Parkin DM. Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008. Int J Cancer2010; 127(12): 2893-2917

[11] Johnson NW, Warnakulasuriya S, Gupta PC, Dimba E, Chindia M, Otoh EC, Sankaranarayanan R, Califano J, Kowalski L. Global oral health inequalities in incidence and outcomes for oral cancer: causes and solutions. Adv Dent Res2011; 23(2): 237-246

[12] Globocan. Globocan 2008: World Health Organisation. http://globocan.iarc.fr (Accessed on <month>January</month><day>5</day>, 2012)

[13] Chen K, Song FS, He M, Li H, Qian B, Zhang W, Wei Q, Hao X. Trends in head and neck cancer incidence in Tianjin, China, between 1981 and 2002. Head Neck2009; 31(2): 175-182

[14] Gao N, Li Y, Li LJ, Wen YM. Clinical analysis of head and neck cancer cases in south-west China 1953-2002. J Int Med Res2009; 37(1): 189-197

[15] Yang L, Parkin DM, Li LD, Chen YD, Bray F. Estimation and projection of the national profile of cancer mortality in China: 1991-2005. Br J Cancer2004; 90(11): 2157-2166

[16] Hobdell MH, Oliveira ER, Bautista R, Myburgh NG, Lalloo R, Narendran S, Johnson NW. Oral diseases and socio-economic status (SES). Br Dent J2003; 194(2): 91-96, discussion 88

[17] Warnakulasuriya S. Significant oral cancer risk associated with low socioeconomic status. Evid Based Dent2009; 10(1): 4-5

[18] Ogden GR. Alcohol and oral cancer. Alcohol2005; 35(3): 169-173

[19] Morse DE, Psoter WJ, Cleveland D, Cohen D, Mohit-Tabatabai M, Kosis DL, Eisenberg E. Smoking and drinking in relation to oral cancer and oral epithelial dysplasia. Cancer Causes Control2007; 18(9): 919-929

[20] Wu M, Zhao JK, Zhang ZF, Han RQ, Yang J, Zhou JY, Wang XS, Zhang XF, Liu AM, van’ t Veer P, Kok FJ, Kampman E. Smoking and alcohol drinking increased the risk of esophageal cancer among Chinese men but not women in a high-risk population. Cancer Causes Control2011; 22(4): 649-657

[21] Gangane N, Chawla S, Anshu, Gupta SS, Sharma SM. Reassessment of risk factors for oral cancer. Asian Pac J Cancer Prev2007; 8(2): 243-248

[22] Yen TT, Lin WD, Wang CP, Wang CC, Liu SA. The association of smoking, alcoholic consumption, betel quid chewing and oral cavity cancer: a cohort study. Eur Arch Otorhinolaryngol2008; 265(11): 1403-1407

[23] Szymańska K, Hung RJ, Wünsch-Filho V, Eluf-Neto J, Curado MP, Koifman S, Matos E, Menezes A, Fernandez L, Daudt AW, Boffetta P, Brennan P. Alcohol and tobacco, and the risk of cancers of the upper aerodigestive tract in Latin America: a case-control study. Cancer Causes Control2011; 22(7): 1037-1046

[24] Accortt NA, Waterbor JW, Beall C, Howard G. Cancer incidence among a cohort of smokeless tobacco users (United States). Cancer Causes Control2005; 16(9): 1107-1115

[25] Schlecht NF, Franco EL, Pintos J, Kowalski LP. Effect of smoking cessation and tobacco type on the risk of cancers of the upper aero-digestive tract in Brazil. Epidemiology1999; 10(4): 412-418

[26] Menvielle G, Luce D, Goldberg P, Bugel I, Leclerc A. Smoking, alcohol drinking and cancer risk for various sites of the larynx and hypopharynx. A case-control study in France. Eur J Cancer Prev2004; 13(3): 165-172

[27] Muscat JE, Ahn K, Richie JP Jr, Stellman SD. Nicotine dependence phenotype, time to first cigarette, and risk of head and neck cancer. Cancer2011; 117(23): 5377-5382

[28] Jeng JH, Chang MC, Hahn LJ. Role of areca nut in betel quid-associated chemical carcinogenesis: current awareness and future perspectives. Oral Oncol2001; 37(6): 477-492

[29] Gupta PC, Warnakulasuriya S. Global epidemiology of areca nut usage. Addict Biol2002; 7(1): 77-83

[30] Muwonge R, Ramadas K, Sankila R, Thara S, Thomas G, Vinoda J, Sankaranarayanan R. Role of tobacco smoking, chewing and alcohol drinking in the risk of oral cancer in Trivandrum, India: a nested case-control design using incident cancer cases. Oral Oncol2008; 44(5): 446-454

[31] Secretan B, Straif K, Baan R, Grosse Y, El Ghissassi F, Bouvard V, Benbrahim-Tallaa L, Guha N, Freeman C, Galichet L, Cogliano V; WHO International Agency for Research on Cancer Monograph Working Group. A review of human carcinogens- Part E: tobacco, areca nut, alcohol, coal smoke, and salted fish. Lancet Oncol2009; 10(11): 1033-1034

[32] Rosenblatt KA, Daling JR, Chen C, Sherman KJ, Schwartz SM. Marijuana use and risk of oral squamous cell carcinoma. Cancer Res2004; 64(11): 4049-4054

[33] Liang C, McClean MD, Marsit C, Christensen B, Peters E, Nelson HH, Kelsey KT. A population-based case-control study of marijuana use and head and neck squamous cell carcinoma. Cancer Prev Res (Phila)2009; 2(8): 759-768

[34] Cho CM, Hirsch R, Johnstone S. General and oral health implications of cannabis use. Aust Dent J2005; 50(2): 70-74

[35] Levi F, Pasche C, La Vecchia C, Lucchini F, Franceschi S, Monnier P. Food groups and risk of oral and pharyngeal cancer. Int J Cancer1998; 77(5): 705-709

[36] Pavia M, Pileggi C, Nobile CG, Angelillo IF. Association between fruit and vegetable consumption and oral cancer: a meta-analysis of observational studies. Am J Clin Nutr2006; 83(5): 1126-1134

[37] Lubin JH, Gaudet MM, Olshan AF, Kelsey K, Boffetta P, Brennan P, Castellsague X, Chen C, Curado MP, Dal Maso L, Daudt AW, Fabianova E, Fernandez L, Wünsch-Filho V, Franceschi S, Herrero R, Koifman S, La Vecchia C, Lazarus P, Levi F, Lissowska J, Mates IN, Matos E, McClean M, Menezes A, Morgenstern H, Muscat J, Eluf Neto J, Purdue MP, Rudnai P, Schwartz SM, Shangina O, Sturgis EM, Szeszenia-Dabrowska N, Talamini R, Wei Q, Winn D, Zhang ZF, Hashibe M, Hayes RB. Body mass index, cigarette smoking, and alcohol consumption and cancers of the oral cavity, pharynx, and larynx: modeling odds ratios in pooled case-control data. Am J Epidemiol2010; 171(12): 1250-1261

[38] Guha N, Boffetta P, Wünsch Filho V, Eluf Neto J, Shangina O, Zaridze D, Curado MP, Koifman S, Matos E, Menezes A, Szeszenia-Dabrowska N, Fernandez L, Mates D, Daudt AW, Lissowska J, Dikshit R, Brennan P. Oral health and risk of squamous cell carcinoma of the head and neck and esophagus: results of two multicentric case-control studies. Am J Epidemiol2007; 166(10): 1159-1173

[39] Behnoud F, Torabian S, Zargaran M. Relationship between oral poor hygiene and broken teeth with oral tongue squamous cell carcinoma. Acta Med Iran2011; 49(3): 159-162

[40] Wee JT, Ha TC, Loong SL, Qian CN. Is nasopharyngeal cancer really a “Cantonese cancer”? Chin J Cancer2010; 29(5): 517-526

[41] Jia WH, Luo XY, Feng BJ, Ruan HL, Bei JX, Liu WS, Qin HD, Feng QS, Chen LZ, Yao SY, Zeng YX. Traditional Cantonese diet and nasopharyngeal carcinoma risk: a large-scale case-control study in Guangdong, China. BMC Cancer2010; 10(1): 446-452

[42] Paz IB, Cook N, Odom-Maryon T, Xie Y, Wilczynski SP. Human papillomavirus (HPV) in head and neck cancer. An association of HPV 16 with squamous cell carcinoma of Waldeyer’s tonsillar ring. Cancer1997; 79(3): 595-604

[43] Kreimer AR, Clifford GM, Boyle P, Franceschi S. Human papillomavirus types in head and neck squamous cell carcinomas worldwide: a systematic review. Cancer Epidemiol Biomarkers Prev2005; 14(2): 467-475

[44] D’Souza G, Kreimer AR, Viscidi R, Pawlita M, Fakhry C, Koch WM, Westra WH, Gillison ML. Case-control study of human papillomavirus and oropharyngeal cancer. N Engl J Med2007; 356(19): 1944-1956

[45] Torrente MC, Rodrigo JP, Haigentz M Jr, Dikkers FG, Rinaldo A, Takes RP, Olofsson J, Ferlito A. Human papillomavirus infections in laryngeal cancer. Head Neck2011; 33(4): 581-586

[46] Leemans CR, Braakhuis BJ, Brakenhoff RH. The molecular biology of head and neck cancer. Nat Rev Cancer2011; 11(1): 9-22

[47] Agrawal N, Frederick MJ, Pickering CR, Bettegowda C, Chang K, Li RJ, Fakhry C, Xie TX, Zhang J, Wang J, Zhang N, El-Naggar AK, Jasser SA, Weinstein JN, Treviño L, Drummond JA, Muzny DM, Wu Y, Wood LD, Hruban RH, Westra WH, Koch WM, Califano JA, Gibbs RA, Sidransky D, Vogelstein B, Velculescu VE, Papadopoulos N, Wheeler DA, Kinzler KW, Myers JN. Exome sequencing of head and neck squamous cell carcinoma reveals inactivating mutations in NOTCH1. Science2011; 333(6046): 1154-1157

[48] Stransky N, Egloff AM, Tward AD, Kostic AD, Cibulskis K, Sivachenko A, Kryukov GV, Lawrence MS, Sougnez C, McKenna A, Shefler E, Ramos AH, Stojanov P, Carter SL, Voet D, Cortés ML, Auclair D, Berger MF, Saksena G, Guiducci C, Onofrio RC, Parkin M, Romkes M, Weissfeld JL, Seethala RR, Wang L, Rangel-Escareño C, Fernandez-Lopez JC, Hidalgo-Miranda A, Melendez-Zajgla J, Winckler W, Ardlie K, Gabriel SB, Meyerson M, Lander ES, Getz G, Golub TR, Garraway LA, Grandis JR. The mutational landscape of head and neck squamous cell carcinoma. Science2011; 333(6046): 1157-1160

[49] Kondo S, Wakisaka N, Muramatsu M, Zen Y, Endo K, Murono S, Sugimoto H, Yamaoka S, Pagano JS, Yoshizaki T. Epstein-Barr virus latent membrane protein 1 induces cancer stem/progenitor-like cells in nasopharyngeal epithelial cell lines. J Virol2011; 85(21): 11255-11264

[50] Liu P, Fang X, Feng Z, Guo YM, Peng RJ, Liu T, Huang Z, Feng Y, Sun X, Xiong Z, Guo X, Pang SS, Wang B, Lv X, Feng FT, Li DJ, Chen LZ, Feng QS, Huang WL, Zeng MS, Bei JX, Zhang Y, Zeng YX. Direct sequencing and characterization of a clinical isolate of Epstein-Barr virus from nasopharyngeal carcinoma tissue by using next-generation sequencing technology. J Virol2011; 85(21): 11291-11299

[51] Mercante G, Bacciu A, Ferri T, Bacciu S. Gastroesophageal reflux as a possible co-promoting factor in the development of the squamous-cell carcinoma of the oral cavity, of the larynx and of the pharynx. Acta Otorhinolaryngol Belg2003; 57(2): 113-117

[52] Bairati I, Meyer F, Gélinas M, Fortin A, Nabid A, Brochet F, Mercier JP, Têtu B, Harel F, Mâsse B, Vigneault E, Vass S, del Vecchio P, Roy J. A randomized trial of antioxidant vitamins to prevent second primary cancers in head and neck cancer patients. J Natl Cancer Inst2005; 97(7): 481-488

[53] International Agency for Research on Cancer. World Cancer Report 2008. Diet, obesity and physical activity. Edited by Boyle P and Levin B. Lyon: IARC, 2008:154-158 (Accessed on <month>January</month><day>5</day>, 2012)

[54] Maserejian NN, Giovannucci E, Rosner B, Joshipura K. Prospective study of vitamins C, E, and A and carotenoids and risk of oral premalignant lesions in men. Int J Cancer2007; 120(5): 970-977

[55] Yan X, Shen H, Jiang H, Zhang C, Hu D, Wang J, Wu X. External Qi of Yan Xin Qigong differentially regulates the Akt and extracellular signal-regulated kinase pathways and is cytotoxic to cancer cells but not to normal cells. Int J Biochem Cell Biol2006; 38(12): 2102-2113

[56] Oh B, Butow P, Mullan B, Hale A, Lee MS, Guo X, Clarke S. A criticial review of the effects of medical Qigong on quality of life, immune function, and survival in cancer patients. Integr Cancer Ther2012; 11(2):101-110

[57] Kong QL, Hu LJ, Cao JY, Huang YJ, Xu LH, Liang Y, Xiong D, Guan S, Guo BH, Mai HQ, Chen QY, Zhang X, Li MZ, Shao JY, Qian CN, Xia YF, Song LB, Zeng YX, Zeng MS. Epstein-Barr virus-encoded LMP2A induces an epithelial-mesenchymal transition and increases the number of side population stem-like cancer cells in nasopharyngeal carcinoma. PLoS Pathog2010; 6(6): e1000940

[58] Lutzky VP, Corban M, Heslop L, Morrison LE, Crooks P, Hall DF, Coman WB, Thomson SA, Moss DJ. Novel approach to the formulation of an Epstein-Barr virus antigen-based nasopharyngeal carcinoma vaccine. J Virol2010; 84(1): 407-417

[59] Tanuma J, Shisa H, Hiai H, Higashi S, Yamada Y, Kamoto T, Hirayama Y, Matsuuchi H, Kitano M. Quantitative trait loci affecting 4-nitroquinoline 1-oxide-induced tongue carcinogenesis in the rat. Cancer Res1998; 58(8): 1660-1664

[60] Culp SJ, Gaylor DW, Sheldon WG, Goldstein LS, Beland FA. A comparison of the tumors induced by coal tar and benzo[a]pyrene in a 2-year bioassay. Carcinogenesis1998; 19(1): 117-124

[61] Shklar G. Development of experimental oral carcinogenesis and its impact on current oral cancer research. J Dent Res1999; 78(12): 1768-1772

[62] Opitz OG, Harada H, Suliman Y, Rhoades B, Sharpless NE, Kent R, Kopelovich L, Nakagawa H, Rustgi AK. A mouse model of human oral-esophageal cancer. J Clin Invest2002; 110(6): 761-769

[63] Lu SL, Herrington H, Reh D, Weber S, Bornstein S, Wang D, Li AG, Tang CF, Siddiqui Y, Nord J, Andersen P, Corless CL, Wang XJ. Loss of transforming growth factor-beta type II receptor promotes metastatic head-and-neck squamous cell carcinoma. Genes Dev2006; 20(10): 1331-1342

[64] Bornstein S, White R, Malkoski S, Oka M, Han G, Cleaver T, Reh D, Andersen P, Gross N, Olson S, Deng C, Lu SL, Wang XJ. Smad4 loss in mice causes spontaneous head and neck cancer with increased genomic instability and inflammation. J Clin Invest2009; 119(11): 3408-3419

[65] Oh SH, Kim WY, Lee OH, Kang JH, Woo JK, Kim JH, Glisson B, Lee HY. IGFBP-3 suppresses VEGF expression and tumor angiogenesis in head and neck squamous cell carcinoma. Cancer Sci 2012 Apr 12. [Epub ahead of print]

[66] Chen SF, Chang YC, Nieh S, Liu CL, Yang CY, Lin YS. Nonadhesive culture system as a model of rapid sphere formation with cancer stem cell properties. PLoS ONE2012; 7(2): e31864

[67] Day TA, Chi A, Neville B, Hebert JR. Prevention of head and neck cancer. Curr Oncol Rep2005; 7(2): 145-153

[68] Evans SJ, Langdon JD, Rapidis AD, Johnson NW. Prognostic significance of STNMP and velocity of tumor growth in oral cancer. Cancer1982; 49(4): 773-776

[69] D’Souza G, Dempsey A. The role of HPV in head and neck cancer and review of the HPV vaccine. Prev Med2011; 53(Suppl 1): S5-S11

[70] de Kok IM, Habbema JD, van Rosmalen J, van Ballegooijen M. Would the effect of HPV vaccination on non-cervical HPV-positive cancers make the difference for its cost-effectiveness? Eur J Cancer2011; 47(3): 428-435

[71] McRee AL, Reiter PL, Chantala K, Brewer NT. Does framing human papillomavirus vaccine as preventing cancer in men increase vaccine acceptability? Cancer Epidemiol Biomarkers Prev2010; 19(8): 1937-1944

[72] Warnakulasuriya S, Kashyap R, Dasanayake AP. Is workplace screening for potentially malignant oral disorders feasible in India? J Oral Pathol Med2010; 39(9): 672-676

[73] Rethman MP, Carpenter W, Cohen EE, Epstein J, Evans CA, Flaitz CM, Graham FJ, Hujoel PP, Kalmar JR, Koch WM, Lambert PM, Lingen MW, Oettmeier BW Jr, Patton LL, Perkins D, Reid BC, Sciubba JJ, Tomar SL, Wyatt AD Jr, Aravamudhan K, Frantsve-Hawley J, Cleveland JL, Meyer DM; American Dental Association Council on Scientific Affairs Expert Panel on Screening for Oral Squamous Cell Carcinomas. Evidence-based clinical recommendations regarding screening for oral squamous cell carcinomas. J Am Dent Assoc2010; 141(5): 509-520

[74] Liu C, Geva E, Mauk M, Qiu X, Abrams WR, Malamud D, Curtis K, Owen SM, Bau HH. An isothemal amplification reactor with an integrated isolation membrane for point-of-are detection of infectious diseases. Analyst (Lond)2011; 136(10): 2069-2076

[75] Gómez I, Warnakulasuriya S, Varela-Centelles PI, López-Jornet P, Suárez-Cunqueiro M, Diz-Dios P, Seoane J. Is early diagnosis of oral cancer a feasible objective? Who is to blame for diagnostic delay? Oral Dis2010; 16(4): 333-342

[76] Ang KK, Harris J, Wheeler R, Weber R, Rosenthal DI, Nguyen-Tân PF, Westra WH, Chung CH, Jordan RC, Lu C, Kim H, Axelrod R, Silverman CC, Redmond KP, Gillison ML. Human papillomavirus and survival of patients with oropharyngeal cancer. N Engl J Med 2010; 363(1): 24-35

[77] Pitiyage G, Tilakaratne WM, Tavassoli M, Warnakulasuriya S. Molecular markers in oral epithelial dysplasia: review. J Oral Pathol Med2009; 38(10): 737-752

[78] Amarasinghe HK, Johnson NW, Lalloo R, Kumaraarachchi M, Warnakulasuriya S. Derivation and validation of a risk-factor model for detection of oral potentially malignant disorders in populations with high prevalence. Br J Cancer2010; 103(3): 303-309

[79] Clarke MF, Dick JE, Dirks PB, Eaves CJ, Jamieson CH, Jones DL, Visvader J, Weissman IL, Wahl GM. Cancer stem cells—perspectives on current status and future directions: AACR Workshop on cancer stem cells. Cancer Res2006; 66(19): 9339-9344

[80] Liang Y, Zhong Z, Huang Y, Deng W, Cao J, Tsao G, Liu Q, Pei D, Kang T, Zeng YX. Stem-like cancer cells are inducible by increasing genomic instability in cancer cells. J Biol Chem2010; 285(7): 4931-4940

[81] Biddle A, Liang X, Gammon L, Fazil B, Harper LJ, Emich H, Costea DE, Mackenzie IC. Cancer stem cells in squamous cell carcinoma switch between two distinct phenotypes that are preferentially migratory or proliferative. Cancer Res2011; 71(15): 5317-5326

[82] Qiao B, Johnson NW, Chen XH, Li RY, Tao Q, Gao J. Disclosure of a stem cell phenotype in an oral squamous cell carcinoma cell line induced by BMP-4 via an epithelial-mesenchymal transition. Oncol Rep2011; 26(2): 455-461

[83] Prince ME, Sivanandan R, Kaczorowski A, Wolf GT, Kaplan MJ, Dalerba P, Weissman IL, Clarke MF, Ailles LE. Identification of a subpopulation of cells with cancer stem cell properties in HNSCC. Proc Natl Acad Sci USA2007; 104(3): 973-978

[84] Rajarajan A, Stokes A, Bloor BK, Ceder R, Desai H, Grafström RC, Odell EW. CD44 expression in oro-pharyngeal carcinoma tissues and cell lines. PLoS ONE2012; 7(1): e28776

[85] Lee DG, Lee JH, Choi BK, Kim MJ, Kim SM, Kim KS, Chang K, Park SH, Bae YS, Kwon BSH. H⁺-myo-inositol transporter SLC2A13 as a potential marker for cancer stem cells in an oral squamous cell carcinoma. Curr Cancer Drug Targets2011; 11(8): 966-975

[86] Renkonen S, Häyry V, Heikkilä P, Leivo I, Haglund C, Mäkitie AA, Hagström J. Stem cell-related proteins C-KIT, C-MYC and BMI-1 in juvenile nasopharyngeal angiofibroma—do they have a role? Virchows Arch2011; 458(2): 189-195

[87] Wiercinska E, Naber HP, Pardali E, van der Pluijm G, van Dam H, Ten Dijke P. The TGF-beta/Smad pathway induces breast cancer cell invasion through the up-regulation of MMP2 and 9 in a spheroid invasion model system. Breast Cancer Res Treat2011; 128(3): 657-666

[88] Clay MR, Tabor M, Owen JH, Carey TE, Bradford CR, Wolf GT, Wicha MS, Prince ME. Single marker identification of HNSCC stem cells with aldehyde dehydrogenase. Head Neck2010; 32(9): 1195-1201

[89] Han G, Wang XJ. Roles of TGFβ signaling Smads in squamous cell carcinoma. Cell Biosci2011; 1(1): 41-48

[90] Cipriano R, Kan CE, Graham J, Danielpour D, Stampfer M, Jackson MW. TGF-β signaling engages an ATM-CHK2-p53-independent RAS-induced senescence and prevents malignant transformation in human mammary epithelial cells. Proc Natl Acad Sci USA2011; 108(21): 8668-8673

[91] Bian Y, Hall B, Sun ZJ, Molinolo A, Chen W, Gutkind JS, Waes CV, Kulkarni AB. Loss of TGF-β signaling and PTEN promotes head and neck squamous cell carcinoma through cellular senescence evasion and cancer-related inflammation. Oncogene2012; 31(28):3322-3332

[92] Carbone A, Gloghini A, Rinaldo A, Devaney KO, Tubbs R, Ferlito A. True identity by immunohistochemistry and molecular morphology of undifferentiated malignancies of the head and neck. Head Neck2009; 31(7): 949-961

[93] Conway DI, Petticrew M, Marlborough H, Berthiller J, Hashibe M, Macpherson LM. Socioeconomic inequalities and oral cancer risk: a systematic review and meta-analysis of case-control studies. Int J Cancer2008; 122(12): 2811-2819

[94] Warnakulasuriya S. Food, nutrition and oral cancer. In: Food constituents and oral health. Wilson M, editor. Oxford, UK: Woodhead Publishing Limited, 2009: 273-295

[95] Liu W, Wang YF, Zhou HW, Shi P, Zhou ZT, Tang GY. Malignant transformation of oral leukoplakia: a retrospective cohort study of 218 Chinese patients. BMC Cancer2010; 10(1): 685-690

[96] Rodrigo JP, Shah JP, Silver CE, Medina JE, Takes RP, Robbins KT, Rinaldo A, Werner JA, Ferlito A. Management of the clinically negative neck in early-stage head and neck cancers after transoral resection. Head Neck2011; 33(8): 1210-1219

[97] Ferlito A, Silver CE, Rinaldo A. Neck dissection: present and future? Eur Arch Otorhinolaryngol2008; 265(6): 621-626

[98] Karni RJ, Rich JT, Sinha P, Haughey BH. Transoral laser microsurgery: a new approach for unknown primaries of the head and neck. Laryngoscope2011; 121(6): 1194-1201

[99] Bonner JA, Harari PM, Giralt J, Azarnia N, Shin DM, Cohen RB, Jones CU, Sur R, Raben D, Jassem J, Ove R, Kies MS, Baselga J, Youssoufian H, Amellal N, Rowinsky EK, Ang KK. Radiotherapy plus cetuximab for squamous-cell carcinoma of the head and neck. N Engl J Med2006; 354(6): 567-578

[100] Lin JT, Lai GM, Chang TH, Liu MT, Bi CP, Wang JW, Chen MK.Chemotherapy with modified docetaxel, cisplatin, and 5-fluorouracil in patients with metastatic head and neck cancer. Adv Ther2012; 29(1):71-77

[101] Jerjes W, Upile T, Hamdoon Z, Alexander Mosse C, Morcos M, Hopper C. Photodynamic therapy outcome for T1/T2 N0 oral squamous cell carcinoma. Lasers Surg Med2011; 43(6): 463-469

[102] Burtness B, Goldwasser MA, Flood W, Mattar B, Forastiere AA; Eastern Cooperative Oncology Group. Phase III randomized trial of cisplatin plus placebo compared with cisplatin plus cetuximab in metastatic/recurrent head and neck cancer: an Eastern Cooperative Oncology Group study. J Clin Oncol2005; 23(34): 8646-8654

[103] Specenier P, Vermorken JB. Advances in the systemic treatment of head and neck cancers. Curr Opin Oncol2010; 22(3): 200-205

[104] Soulieres D, Senzer NN, Vokes EE, Hidalgo M, Agarwala SS, Siu LL. Multicenter phase II study of erlotinib, an oral epidermal growth factor receptor tyrosine kinase inhibitor, in patients with recurrent or metastatic squamous cell cancer of the head and neck. J Clin Oncol2004; 22(1): 77-85

[105] Brook I. Neck cancer: a physician’s personal experience. Arch Otolaryngol Head Neck Surg2009; 135(2): 118-118

[106] Rodriguez-Bruno K, Ali MJ, Wang SJ. Role of panendoscopy to identify synchronous second primary malignancies in patients with oral cavity and oropharyngeal squamous cell carcinoma. Head Neck2011; 33(7): 949-953

[107] Jones AS, Morar P, Phillips DE, Field JK, Husband D, Helliwell TR. Second primary tumors in patients with head and neck squamous cell carcinoma. Cancer1995; 75(6): 1343-1353

[108] Bosetti C, Scelo G, Chuang SC, Tonita JM, Tamaro S, Jonasson JG, Kliewer EV, Hemminki K, Weiderpass E, Pukkala E, Tracey E, Olsen JH, Pompe-Kirn V, Brewster DH, Martos C, Chia KS, Brennan P, Hashibe M, Levi F, La Vecchia C, Boffetta P. High constant incidence rates of second primary cancers of the head and neck: a pooled analysis of 13 cancer registries. Int J Cancer2011; 129(1): 173-179

[109] Wang J, Lippman SM, Lee JJ, Yang H, Khuri FR, Kim E, Lin J, Chang DW, Lotan R, Hong WK, Wu X. Genetic variations in regulator of G-protein signaling genes as susceptibility loci for second primary tumor/recurrence in head and neck squamous cell carcinoma. Carcinogenesis2010; 31(10): 1755-1761

[110] Dequanter D, Shahla M, Lardinois I, Gilbert O, Hanquet O, Tragas G, Van Meerhæghe A, Lothaire P. Second primary lung malignancy in head and neck cancer patients. Eur Ann Otorhinolaryngol Head Neck Dis2011; 128(1): 11-13

[111] Gao M. Progresses and strategies in diagnosis and treatment of thyroid carcinoma. Chin J Otorhinolaryngol Head Neck Surg (Zhonghua Er Bi Yan Hou Tou Jing Wai Ke Za Zhi)2010; 45(11): 887-890 (in Chinese )

[112] Al-Sarraf M. Treatment of locally advanced head and neck cancer: historical and critical review. Cancer Control2002; 9(5): 387-399

[113] Haughey BH, Hinni ML, Salassa JR, Hayden RE, Grant DG, Rich JT, Milov S, Lewis JS Jr, Krishna M. Transoral laser microsurgery as primary treatment of advanced stage oropharynx cancer: A United States multicenter study. Head Neck2011;33(12):1683-1694

[114] Liu Y, Chen XQ, Liang HX, Zhang FX, Zhang B, Jin J, Chen YL, Cheng YX, Zhou GB. Small compound 6-O-angeloylplenolin induces mitotic arrest and exhibits therapeutic potentials in multiple myeloma. PLoS ONE2011; 6(7): e21930

[115] Yu XJ, Han QB, Wen ZS, Ma L, Gao J, Zhou GB. Gambogenic acid induces G1 arrest via GSK3β-dependent cyclin D1 degradation and triggers autophagy in lung cancer cells. Cancer Lett2012; 322(2): 185-194

[116] Carmady B, Smith CA. Use of Chinese medicine by cancer patients: a review of surveys. Chin Med2011; 6(1): 22-29

[117] Savage N. Early detection: Spotting the first signs. Nature2011; 471(7339): S14-S15

Acknowledgements

We appreciated Dr. Moustafa El-Housiny (postgraduate at James Cook University) who drew Fig. 1, and Dr. Songfeng Wei (Cancer Hospital, Tianjin Medical University) who generously provided Fig. 2. Our appreciation also extended to Dr. Rui Gao (a General Practitioner in Dentistry, Queensland, Australia) who contributed to the proof reading of this manuscript.

Conflict of interest The authors declared to have no conflict of interest.

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