Official reprint from UpToDate®
www.uptodate.com ©2017 UpToDate, Inc. and/or its affiliates. All Rights Reserved.

Second primary malignancies in patients with head and neck cancers

Stephen Kang, MD
Theodoros N Teknos, MD
Section Editors
Marshall R Posner, MD
Bruce E Brockstein, MD
David M Brizel, MD
Marvin P Fried, MD, FACS
Deputy Editor
Michael E Ross, MD


Patients with head and neck squamous cell carcinoma (HNSCC) are at increased risk for the development of a second primary malignancy (SPM), which is defined as a second malignancy that presents either simultaneously or after the diagnosis of an index tumor. A synchronous SPM is diagnosed simultaneously or within six months of the index tumor, while a metachronous SPM is diagnosed greater than six months after the index tumor. SPMs need to be distinguished from local recurrences or metastasis of the primary tumor.

Second primary malignancies represent the second leading cause of death in patients with HNSCC [1]. One-quarter to one-third of deaths in these patients are attributable to SPM [1-3], highlighting the importance of SPM in the successful management of HNSCC.

The classification, epidemiology, etiology, diagnosis, and management of SPMs of the upper aerodigestive tract after treatment of an initial head and neck cancer will be reviewed here. Surveillance for an SPM or locally recurrent disease and the management of head and neck cancer in patients who have already been treated once are discussed separately. (See "Posttreatment surveillance of squamous cell carcinoma of the head and neck" and "Treatment of locally recurrent squamous cell carcinoma of the head and neck".)


The concept of field cancerization has been used to explain the occurrence of SPMs, especially in the oral cavity. This concept was introduced by Slaughter et al [4], who discovered that in oral cancers, the epithelium beyond the boundaries of tumor possessed histologic changes. The classic view of the term "field cancerization" hypothesized that large areas of head and neck mucosa are affected by carcinogen exposure, resulting in a wide field of premalignant disease that gives rise to multiple independent primary tumors. (See "Head and neck squamous cell carcinogenesis: Molecular and genetic alterations", section on 'Field cancerization'.)

Some but not all studies have found that putative SPMs share a genetic pattern with the primary tumor, with both tumors originating from a common clone [5,6].

To continue reading this article, you must log in with your personal, hospital, or group practice subscription. For more information on subscription options, click below on the option that best describes you:

Subscribers log in here

Literature review current through: Nov 2017. | This topic last updated: Aug 03, 2016.
The content on the UpToDate website is not intended nor recommended as a substitute for medical advice, diagnosis, or treatment. Always seek the advice of your own physician or other qualified health care professional regarding any medical questions or conditions. The use of this website is governed by the UpToDate Terms of Use ©2017 UpToDate, Inc.
  1. Baxi SS, Pinheiro LC, Patil SM, et al. Causes of death in long-term survivors of head and neck cancer. Cancer 2014; 120:1507.
  2. Sturgis EM, Miller RH. Second primary malignancies in the head and neck cancer patient. Ann Otol Rhinol Laryngol 1995; 104:946.
  3. León X, Del Prado Venegas M, Orús C, et al. Metachronous second primary tumours in the aerodigestive tract in patients with early stage head and neck squamous cell carcinomas. Eur Arch Otorhinolaryngol 2005; 262:905.
  4. SLAUGHTER DP, SOUTHWICK HW, SMEJKAL W. Field cancerization in oral stratified squamous epithelium; clinical implications of multicentric origin. Cancer 1953; 6:963.
  5. Scholes AG, Woolgar JA, Boyle MA, et al. Synchronous oral carcinomas: independent or common clonal origin? Cancer Res 1998; 58:2003.
  6. Braakhuis BJ, Tabor MP, Leemans CR, et al. Second primary tumors and field cancerization in oral and oropharyngeal cancer: molecular techniques provide new insights and definitions. Head Neck 2002; 24:198.
  7. Worsham MJ, Wolman SR, Carey TE, et al. Common clonal origin of synchronous primary head and neck squamous cell carcinomas: analysis by tumor karyotypes and fluorescence in situ hybridization. Hum Pathol 1995; 26:251.
  8. Ribeiro U, Safatle-Ribeiro AV, Posner MC, et al. Comparative p53 mutational analysis of multiple primary cancers of the upper aerodigestive tract. Surgery 1996; 120:45.
  9. Warren S, Gates O. Multiple primary malignant tumors. A survey of the literature and a statistical study. Am J Cancer 1932; 16:1358.
  10. Schwartz LH, Ozsahin M, Zhang GN, et al. Synchronous and metachronous head and neck carcinomas. Cancer 1994; 74:1933.
  11. Morris LG, Sikora AG, Patel SG, et al. Second primary cancers after an index head and neck cancer: subsite-specific trends in the era of human papillomavirus-associated oropharyngeal cancer. J Clin Oncol 2011; 29:739.
  12. Leong PP, Rezai B, Koch WM, et al. Distinguishing second primary tumors from lung metastases in patients with head and neck squamous cell carcinoma. J Natl Cancer Inst 1998; 90:972.
  13. van Oijen MG, Leppers Vd Straat FG, Tilanus MG, Slootweg PJ. The origins of multiple squamous cell carcinomas in the aerodigestive tract. Cancer 2000; 88:884.
  14. Kim SY, Roh JL, Yeo NK, et al. Combined 18F-fluorodeoxyglucose-positron emission tomography and computed tomography as a primary screening method for detecting second primary cancers and distant metastases in patients with head and neck cancer. Ann Oncol 2007; 18:1698.
  15. Gan SJ, Dahlstrom KR, Peck BW, et al. Incidence and pattern of second primary malignancies in patients with index oropharyngeal cancers versus index nonoropharyngeal head and neck cancers. Cancer 2013; 119:2593.
  16. Lee DH, Roh JL, Baek S, et al. Second cancer incidence, risk factor, and specific mortality in head and neck squamous cell carcinoma. Otolaryngol Head Neck Surg 2013; 149:579.
  17. Chuang SC, Scelo G, Tonita JM, et al. Risk of second primary cancer among patients with head and neck cancers: A pooled analysis of 13 cancer registries. Int J Cancer 2008; 123:2390.
  18. Schoenberg BS, Myers MH. Statistical methods for studying multiple primary malignant neoplasms. Cancer 1977; 40:1892.
  19. Begg CB, Zhang ZF, Sun M, et al. Methodology for evaluating the incidence of second primary cancers with application to smoking-related cancers from the Surveillance, Epidemiology, and End Results (SEER) program. Am J Epidemiol 1995; 142:653.
  20. Peck BW, Dahlstrom KR, Gan SJ, et al. Low risk of second primary malignancies among never smokers with human papillomavirus-associated index oropharyngeal cancers. Head Neck 2013; 35:794.
  21. Lin K, Patel SG, Chu PY, et al. Second primary malignancy of the aerodigestive tract in patients treated for cancer of the oral cavity and larynx. Head Neck 2005; 27:1042.
  22. Chen MC, Chen PT, Chan CH, et al. Second primary esophageal or lung cancer in patients with head and neck carcinoma in Taiwan: incidence and risk in relation to primary index tumor site. J Cancer Res Clin Oncol 2011; 137:115.
  23. Chu PY, Chang SY, Huang JL, Tai SK. Different patterns of second primary malignancy in patients with squamous cell carcinoma of larynx and hypopharynx. Am J Otolaryngol 2010; 31:168.
  24. Rennemo E, Zätterström U, Boysen M. Impact of second primary tumors on survival in head and neck cancer: an analysis of 2,063 cases. Laryngoscope 2008; 118:1350.
  25. Rusthoven K, Chen C, Raben D, Kavanagh B. Use of external beam radiotherapy is associated with reduced incidence of second primary head and neck cancer: a SEER database analysis. Int J Radiat Oncol Biol Phys 2008; 71:192.
  26. Miyahara H, Sato T, Yoshino K. Radiation-induced cancers of the head and neck region. Acta Otolaryngol Suppl 1998; 533:60.
  27. Haughey BH, Gates GA, Arfken CL, Harvey J. Meta-analysis of second malignant tumors in head and neck cancer: the case for an endoscopic screening protocol. Ann Otol Rhinol Laryngol 1992; 101:105.
  28. Davidson J, Gilbert R, Irish J, et al. The role of panendoscopy in the management of mucosal head and neck malignancy-a prospective evaluation. Head Neck 2000; 22:449.
  29. 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 Neck 2011; 33:949.
  30. Hujala K, Sipilä J, Grenman R. Panendoscopy and synchronous second primary tumors in head and neck cancer patients. Eur Arch Otorhinolaryngol 2005; 262:17.
  31. http://www.nccn.org/professionals/physician_gls/pdf/head-and-neck.pdf (Accessed on October 14, 2014).
  32. Strojan P, Corry J, Eisbruch A, et al. Recurrent and second primary squamous cell carcinoma of the head and neck: when and how to reirradiate. Head Neck 2015; 37:134.
  33. Stewart FA. Re-treatment after full-course radiotherapy: is it a viable option? Acta Oncol 1999; 38:855.
  34. Duprez F, Madani I, Bonte K, et al. Intensity-modulated radiotherapy for recurrent and second primary head and neck cancer in previously irradiated territory. Radiother Oncol 2009; 93:563.
  35. Aziz TM, Saad RA, Glasser J, et al. The management of second primary lung cancers. A single centre experience in 15 years. Eur J Cardiothorac Surg 2002; 21:527.
  36. Jones AS, Morar P, Phillips DE, et al. Second primary tumors in patients with head and neck squamous cell carcinoma. Cancer 1995; 75:1343.
  37. Chen MC, Huang WC, Chan CH, et al. Impact of second primary esophageal or lung cancer on survival of patients with head and neck cancer. Oral Oncol 2010; 46:249.
  38. Jayaprakash V, Cheng C, Reid M, et al. Previous head and neck cancers portend poor prognoses in lung cancer patients. Ann Thorac Surg 2011; 92:1056.
  39. Di Martino E, Sellhaus B, Hausmann R, et al. Survival in second primary malignancies of patients with head and neck cancer. J Laryngol Otol 2002; 116:831.
  40. Dequanter D, Shahla M, Lardinois I, et al. Second primary lung malignancy in head and neck cancer patients. Eur Ann Otorhinolaryngol Head Neck Dis 2011; 128:11.