Management of Unknown Primary Cancer of the Head and Neck

  • Jennifer Christenson
  • Ryan J. LiEmail author
Part of the Difficult Decisions in Surgery: An Evidence-Based Approach book series (DDSURGERY)


Head and neck cancer with an unknown primary site (CUP) often presents as an asymptomatic, enlarging neck mass, which is then confirmed to represent metastatic nodal disease. These cancers are encountered with increasing frequency in many head and neck surgical oncology practices. The majority of CUP occurs in patients over age 40 years, and is most frequently suspected as having an oropharyngeal primary site, and a causal association with high-risk human papillomavirus infection. The majority of patients diagnosed with CUP on initial presentation, will have a detectable primary tumor after thorough diagnostic evaluation, either within the tongue base or palatine tonsil. A comprehensive diagnostic evaluation and understanding of the advantages and disadvantages of treatment options is essential to serve patients with the best oncologic outcomes and least morbidity possible. In this chapter, we review contemporary research advancing the evaluation and management of CUP. As head and neck squamous cell carcinoma is the most commonly encountered histopathology of CUP, the majority of this chapter focuses on this form of cancer.


Unknown primary Head and neck cancer Human papillomavirus Oropharyngeal cancer Tonsil cancer Tongue base cancer Transoral cancer surgery 


  1. 1.
    Grau C, Johansen LV, Jakobsen J, Geertsen P, Andersen E, Jensen BB. Cervical lymph node metastases from unknown primary tumours. Results from a national survey by the Danish Society for Head and Neck Oncology. Radiother Oncol. 2000;55(2):121–9.CrossRefGoogle Scholar
  2. 2.
    Network NCC. NCCN Clinical Practice Guidelines in Oncology (Head and Neck Cancers). 2018;Version 1.2018.Google Scholar
  3. 3.
    Keller LM, Galloway TJ, Holdbrook T, et al. p16 status, pathologic and clinical characteristics, biomolecular signature, and long-term outcomes in head and neck squamous cell carcinomas of unknown primary. Head Neck. 2014;36(12):1677–84.CrossRefGoogle Scholar
  4. 4.
    Motz K, Qualliotine JR, Rettig E, Richmon JD, Eisele DW, Fakhry C. Changes in unknown primary squamous cell carcinoma of the head and neck at initial presentation in the era of human papillomavirus. JAMA Otolaryngol Head Neck Surg. 2016;142(3):223–8.CrossRefGoogle Scholar
  5. 5.
    Nieder C, Gregoire V, Ang KK. Cervical lymph node metastases from occult squamous cell carcinoma: cut down a tree to get an apple? Int J Radiat Oncol Biol Phys. 2001;50(3):727–33.CrossRefGoogle Scholar
  6. 6.
    Mizuta M, Kitamura M, Tateya I, et al. Unknown primary squamous cell carcinoma of the head and neck: retrospective analysis of 80 cases. Acta Otolaryngol. 2018;138(6):590–6.CrossRefGoogle Scholar
  7. 7.
    Balaker AE, Abemayor E, Elashoff D, St John MA. Cancer of unknown primary: does treatment modality make a difference? Laryngoscope. 2012;122(6):1279–82.CrossRefGoogle Scholar
  8. 8.
    Kamal M, Mohamed ASR, Fuller CD, et al. Outcomes of patients diagnosed with carcinoma metastatic to the neck from an unknown primary source and treated with intensity-modulated radiation therapy. Cancer. 2018;124(7):1415–27.CrossRefGoogle Scholar
  9. 9.
    Wallace A, Richards GM, Harari PM, et al. Head and neck squamous cell carcinoma from an unknown primary site. Am J Otolaryngol. 2011;32(4):286–90.CrossRefGoogle Scholar
  10. 10.
    Aslani M, Sultanem K, Voung T, Hier M, Niazi T, Shenouda G. Metastatic carcinoma to the cervical nodes from an unknown head and neck primary site: is there a need for neck dissection? Head Neck. 2007;29(6):585–90.CrossRefGoogle Scholar
  11. 11.
    Chen AM, Meshman J, Hsu S, Yoshizaki T, Abemayor E, John MS. Oropharynx-directed ipsilateral irradiation for p16-positive squamous cell carcinoma involving the cervical lymph nodes of unknown primary origin. Head Neck. 2018;40(2):227–32.CrossRefGoogle Scholar
  12. 12.
    Galloway TJ, Ridge JA. Management of squamous cancer metastatic to cervical nodes with an unknown primary site. J Clin Oncol. 2015;33(29):3328–37.CrossRefGoogle Scholar
  13. 13.
    Muraki AS, Mancuso AA, Harnsberger HR. Metastatic cervical adenopathy from tumors of unknown origin: the role of CT. Radiology. 1984;152(3):749–53.CrossRefGoogle Scholar
  14. 14.
    Nakamoto Y, Tatsumi M, Hammoud D, Cohade C, Osman MM, Wahl RL. Normal FDG distribution patterns in the head and neck: PET/CT evaluation. Radiology. 2005;234(3):879–85.CrossRefGoogle Scholar
  15. 15.
    Cianchetti M, Mancuso AA, Amdur RJ, et al. Diagnostic evaluation of squamous cell carcinoma metastatic to cervical lymph nodes from an unknown head and neck primary site. Laryngoscope. 2009;119(12):2348–54.CrossRefGoogle Scholar
  16. 16.
    Keller F, Psychogios G, Linke R, et al. Carcinoma of unknown primary in the head and neck: comparison between positron emission tomography (PET) and PET/CT. Head Neck. 2011;33(11):1569–75.CrossRefGoogle Scholar
  17. 17.
    Rudmik L, Lau HY, Matthews TW, et al. Clinical utility of PET/CT in the evaluation of head and neck squamous cell carcinoma with an unknown primary: a prospective clinical trial. Head Neck. 2011;33(7):935–40.CrossRefGoogle Scholar
  18. 18.
    Patel SA, Magnuson JS, Holsinger FC, et al. Robotic surgery for primary head and neck squamous cell carcinoma of unknown site. JAMA Otolaryngol Head Neck Surg. 2013;139(11):1203–11.CrossRefGoogle Scholar
  19. 19.
    Kuta V, Williams B, Rigby M, et al. Management of head and neck primary unknown squamous cell carcinoma using combined positron emission tomography-computed tomography and transoral laser microsurgery. Laryngoscope. 2018;128(10):2307–11.CrossRefGoogle Scholar
  20. 20.
    Kobayashi K, Saito Y, Omura G, et al. Clinical features of human papilloma virus-related head and neck squamous cell carcinoma of an unknown primary site. ORL J Otorhinolaryngol Relat Spec. 2014;76(3):137–46.CrossRefGoogle Scholar
  21. 21.
    Jensen DH, Hedback N, Specht L, et al. Human papillomavirus in head and neck squamous cell carcinoma of unknown primary is a common event and a strong predictor of survival. PLoS One. 2014;9(11):e110456.CrossRefGoogle Scholar
  22. 22.
    Conscience I, Jovenin N, Coissard C, et al. P16 is overexpressed in cutaneous carcinomas located on sun-exposed areas. Eur J Dermatol. 2006;16(5):518–22.PubMedGoogle Scholar
  23. 23.
    Maxwell JH, Kumar B, Feng FY, et al. HPV-positive/p16-positive/EBV-negative nasopharyngeal carcinoma in white North Americans. Head Neck. 2010;32(5):562–7.PubMedPubMedCentralGoogle Scholar
  24. 24.
    Jannapureddy S, Cohen C, Lau S, Beitler JJ, Siddiqui MT. Assessing for primary oropharyngeal or nasopharyngeal squamous cell carcinoma from fine needle aspiration of cervical lymph node metastases. Diagn Cytopathol. 2010;38(11):795–800.CrossRefGoogle Scholar
  25. 25.
    Beadle BM, William WN Jr, McLemore MS, Sturgis EM, Williams MD. p16 expression in cutaneous squamous carcinomas with neck metastases: a potential pitfall in identifying unknown primaries of the head and neck. Head Neck. 2013;35(11):1527–33.CrossRefGoogle Scholar
  26. 26.
    Coster JR, Foote RL, Olsen KD, Jack SM, Schaid DJ, DeSanto LW. Cervical nodal metastasis of squamous cell carcinoma of unknown origin: indications for withholding radiation therapy. Int J Radiat Oncol Biol Phys. 1992;23(4):743–9.CrossRefGoogle Scholar
  27. 27.
    3311 E. Phase II randomized trial of transoral surgical resection followed by low-dose or standard-dose IMRT in resectable p16+ locally advanced oropharynx cancer (E3311).Google Scholar
  28. 28.
    Patel SA, Parvathaneni A, Parvathaneni U, et al. Post-operative therapy following transoral robotic surgery for unknown primary cancers of the head and neck. Oral Oncol. 2017;72:150–6.CrossRefGoogle Scholar
  29. 29.
    Geltzeiler M, Doerfler S, Turner M, et al. Transoral robotic surgery for management of cervical unknown primary squamous cell carcinoma: updates on efficacy, surgical technique and margin status. Oral Oncol. 2017;66:9–13.CrossRefGoogle Scholar
  30. 30.
    Mehta V, Johnson P, Tassler A, et al. A new paradigm for the diagnosis and management of unknown primary tumors of the head and neck: a role for transoral robotic surgery. Laryngoscope. 2013;123(1):146–51.CrossRefGoogle Scholar
  31. 31.
    Nagel TH, Hinni ML, Hayden RE, Lott DG. Transoral laser microsurgery for the unknown primary: role for lingual tonsillectomy. Head Neck. 2014;36(7):942–6.CrossRefGoogle Scholar
  32. 32.
    Graboyes EM, Sinha P, Thorstad WL, Rich JT, Haughey BH. Management of human papillomavirus-related unknown primaries of the head and neck with a transoral surgical approach. Head Neck. 2015;37(11):1603–11.CrossRefGoogle Scholar
  33. 33.
    Durmus K, Rangarajan SV, Old MO, Agrawal A, Teknos TN, Ozer E. Transoral robotic approach to carcinoma of unknown primary. Head Neck. 2014;36(6):848–52.CrossRefGoogle Scholar
  34. 34.
    Jesse RH, Perez CA, Fletcher GH. Cervical lymph node metastasis: unknown primary cancer. Cancer. 1973;31(4):854–9.CrossRefGoogle Scholar
  35. 35.
    Mourad WF, Hu KS, Shasha D, et al. Initial experience with oropharynx-targeted radiation therapy for metastatic squamous cell carcinoma of unknown primary of the head and neck. Anticancer Res. 2014;34(1):243–8.PubMedGoogle Scholar
  36. 36.
    Colletier PJ, Garden AS, Morrison WH, Goepfert H, Geara F, Ang KK. Postoperative radiation for squamous cell carcinoma metastatic to cervical lymph nodes from an unknown primary site: outcomes and patterns of failure. Head Neck. 1998;20(8):674–81.CrossRefGoogle Scholar
  37. 37.
    Reddy SP, Marks JE. Metastatic carcinoma in the cervical lymph nodes from an unknown primary site: results of bilateral neck plus mucosal irradiation vs. ipsilateral neck irradiation. Int J Radiat Oncol Biol Phys. 1997;37(4):797–802.CrossRefGoogle Scholar
  38. 38.
    Perkins SM, Spencer CR, Chernock RD, et al. Radiotherapeutic management of cervical lymph node metastases from an unknown primary site. Arch Otolaryngol Head Neck Surg. 2012;138(7):656–61.CrossRefGoogle Scholar
  39. 39.
    Marcial-Vega VA, Cardenes H, Perez CA, et al. Cervical metastases from unknown primaries: radiotherapeutic management and appearance of subsequent primaries. Int J Radiat Oncol Biol Phys. 1990;19(4):919–28.CrossRefGoogle Scholar
  40. 40.
    Sinnathamby K, Peters LJ, Laidlaw C, Hughes PG. The occult head and neck primary: to treat or not to treat? Clin Oncol (R Coll Radiol). 1997;9(5):322–9.CrossRefGoogle Scholar
  41. 41.
    Glynne-Jones RG, Anand AK, Young TE, Berry RJ. Metastatic carcinoma in the cervical lymph nodes from an occult primary: a conservative approach to the role of radiotherapy. Int J Radiat Oncol Biol Phys. 1990;18(2):289–94.CrossRefGoogle Scholar
  42. 42.
    Weir L, Keane T, Cummings B, et al. Radiation treatment of cervical lymph node metastases from an unknown primary: an analysis of outcome by treatment volume and other prognostic factors. Radiother Oncol. 1995;35(3):206–11.CrossRefGoogle Scholar
  43. 43.
    Ross RB, Koyfman SA, Reddy CA, et al. A matched comparison of human papillomavirus-induced squamous cancer of unknown primary with early oropharynx cancer. Laryngoscope. 2018;128(6):1379–85.CrossRefGoogle Scholar
  44. 44.
    Ozbay I, Yumusakhuylu AC, Sethia R, et al. One-year quality of life and functional outcomes of transoral robotic surgery for carcinoma of unknown primary. Head Neck. 2017;39(8):1596–602.CrossRefGoogle Scholar
  45. 45.
    Rusthoven KE, Koshy M, Paulino AC. The role of fluorodeoxyglucose positron emission tomography in cervical lymph node metastases from an unknown primary tumor. Cancer. 2004;101(11):2641–9.CrossRefGoogle Scholar
  46. 46.
    A. Argiris, (2003) Concurrent chemoradiotherapy for N2 or N3 squamous cell carcinoma of the head and neck from an occult primary. Annals of Oncology 14(8):1306–11.Google Scholar
  47. 47.
    Demiroz C, Vainshtein JM, Koukourakis GV, et al. Head & Neck Squamous Cell Carcinoma of Unknown Primary: Neck Dissection and Radiotherapy or Definitive Radiotherapy. Head&Neck. 2014; 36(11): 1589–95.Google Scholar
  48. 48.
    Michael Huo, Benedict Panizza, Anne Bernard, Sandro V. Porceddu, (2018) Head and neck squamous cell carcinoma of unknown primary: Outcomes of a pre-defined institutional treatment policy in a region with a high prevalence of skin cancer. Oral Oncology 77:43–48.Google Scholar
  49. 49.
    De Ridder M, Klop M, Hamming-Vrieze O, et al. Unknown primary head and neck squamous cell carcinoma in the era of fluorodeoxyglucosepositron emission tomography/ CT and intensity-modulated radiotherapy. Head & Neck. 2017;39:1382–91.Google Scholar
  50. 50.
    Lachlan J. McDowell, Richard J. Young, Meredith L. Johnston, Tze-Jian Tan, Stephen Kleid, Chen S. Liu, Mathias Bressel, Vanessa Estall, Danny Rischin, Benjamin Solomon, June Corry, (2016) p16-positive lymph node metastases from cutaneous head and neck squamous cell carcinoma: No association with high-risk human papillomavirus or prognosis and implications for the workup of the unknown primary. Cancer 122 (8):1201–08.Google Scholar
  51. 51.
    John Cuaron, Shyam Rao, Suzanne Wolden, Michael Zelefsky, Karen Schupak, Borys Mychalczak, Nancy Lee, (2016) Patterns of failure in patients with head and neck carcinoma of unknown primary treated with radiation therapy. Head & Neck 38 (S1):E426-E431.Google Scholar
  52. 52.
    Hatten KM, O’Malley BW Jr, Bur AM, et al. Transoral robotic surgery-assisted endoscopy with primary site detection and treatment in occult mucosal primaries. JAMA Otolaryngol Head Neck Surg. 2017;143(3):267–73.Google Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  1. 1.Department of Head and Neck SurgeryOrlando Health UF Health Cancer CenterOrlandoUSA
  2. 2.Department of Otolaryngology—Head and Neck SurgeryOregon Health & Science UniversityPortlandUSA

Personalised recommendations