Head and neck squamous cell carcinoma of unknown primary
- Benjamin E Saltman, MD
Benjamin E Saltman, MD
- Assistant Professor of Otolaryngology
- Division of Head and Neck Surgery
- Hofstra North Shore LIJ School of Medicine
- Sue S Yom, MD, PhD, MAS
Sue S Yom, MD, PhD, MAS
- Associate Professor
- Departments of Radiation
- Oncology and Otolaryngology
- Head and Neck Surgery
- University of California, San Francisco School of Medicine
- Section Editors
- Marshall R Posner, MD
Marshall R Posner, MD
- Section Editor — Cancer of the Head and Neck
- Professor of Gene and Cell Medicine
- The Tisch Cancer Institute
- Icahn School of Medicine at Mount Sinai
- Bruce E Brockstein, MD
Bruce E Brockstein, MD
- Section Editor — Cancer of the Head and Neck
- Clinical Professor of Medicine
- University of Chicago Pritzker School of Medicine
- David M Brizel, MD
David M Brizel, MD
- Section Editor — Radiation Therapy
- Leonard R Prosnitz Professor of Radiation Oncology
- Professor of Otolaryngology Head & Neck Surgery
- Duke University Cancer Institute
- Marvin P Fried, MD, FACS
Marvin P Fried, MD, FACS
- Section Editor — Head and Neck Surgery
- Professor and University Chairman, Department of Otorhinolaryngology - Head and Neck Surgery
- Montefiore Medical Center, Albert Einstein College of Medicine
Head and neck squamous cell carcinoma (SCC) of unknown primary is defined as the presence of SCC in one or more lymph nodes within the head and neck region that are not solely in the supraclavicular region, without an identifiable primary tumor. While many head and neck cancer patients initially present with a neck mass, the mucosally based primary site of origin is usually identified over the course of the subsequent workup.
Thus, SCC of a truly unknown primary origin is a relatively rare entity in the head and neck region; retrospective studies suggest that it represents between 1 and 3 percent of new cases of head and neck SCC . It is commonly thought that many SCC of unknown primary may represent clinically occult oropharyngeal cancers. A contemporary single institution series of 75 patients with SCC of unknown primary found that 69 (90.5 percent) were positive for human papilloma virus (HPV) by either p16 positivity or in situ hybridization , although some older series have reported a lower incidence .
The special case of isolated supraclavicular lymphadenopathy, including those of squamous cell origin, almost always originates from cancer in the skin or a primary site beneath the clavicles (ie, lung, breast, colon, prostate, esophagus, cervix, ureteral, and lymphoma primaries) . These cancers are associated with a different natural history and prognosis than cancers originating from the head and neck.
The management of head and neck SCC of unknown primary is directed at cure for most patients; cervical lymphadenopathy represents disease that is locoregionally advanced but is not distantly metastatic in most patients. This is in sharp distinction to cancers of unknown primary originating from below the clavicles, for which supraclavicular adenopathy may represent incurable distant metastasis.
The diagnosis and management of patients with SCC of unknown primary presumed to originate from the head and neck are presented here. The initial evaluation of a neck mass and the general approach to neoplasms of unknown primary origin are discussed separately.
- Syrjänen S. Human papillomaviruses in head and neck carcinomas. N Engl J Med 2007; 356:1993.
- Motz K, Qualliotine JR, Rettig E, et al. 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; 142:223.
- 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; 36:1677.
- Gupta RK, Naran S, Lallu S, Fauck R. The diagnostic value of fine needle aspiration cytology (FNAC) in the assessment of palpable supraclavicular lymph nodes: a study of 218 cases. Cytopathology 2003; 14:201.
- Conscience I, Jovenin N, Coissard C, et al. P16 is overexpressed in cutaneous carcinomas located on sun-exposed areas. Eur J Dermatol 2006; 16:518.
- McDowell LJ, Young RJ, Johnston ML, et al. 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 2016; 122:1201.
- 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; 101:2641.
- Johansen J, Buus S, Loft A, et al. Prospective study of 18FDG-PET in the detection and management of patients with lymph node metastases to the neck from an unknown primary tumor. Results from the DAHANCA-13 study. Head Neck 2008; 30:471.
- 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; 33:935.
- Yabuki K, Tsukuda M, Horiuchi C, et al. Role of 18F-FDG PET in detecting primary site in the patient with primary unknown carcinoma. Eur Arch Otorhinolaryngol 2010; 267:1785.
- Miller FR, Karnad AB, Eng T, et al. Management of the unknown primary carcinoma: long-term follow-up on a negative PET scan and negative panendoscopy. Head Neck 2008; 30:28.
- 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; 33:1569.
- Lapeyre M, Malissard L, Peiffert D, et al. Cervical lymph node metastasis from an unknown primary: is a tonsillectomy necessary? Int J Radiat Oncol Biol Phys 1997; 39:291.
- Mendenhall WM, Mancuso AA, Amdur RJ, et al. Squamous cell carcinoma metastatic to the neck from an unknown head and neck primary site. Am J Otolaryngol 2001; 22:261.
- Waltonen JD, Ozer E, Schuller DE, Agrawal A. Tonsillectomy vs. deep tonsil biopsies in detecting occult tonsil tumors. Laryngoscope 2009; 119:102.
- Koch WM, Bhatti N, Williams MF, Eisele DW. Oncologic rationale for bilateral tonsillectomy in head and neck squamous cell carcinoma of unknown primary source. Otolaryngol Head Neck Surg 2001; 124:331.
- Lindberg R. Distribution of cervical lymph node metastases from squamous cell carcinoma of the upper respiratory and digestive tracts. Cancer 1972; 29:1446.
- Nagel TH, Hinni ML, Hayden RE, Lott DG. Transoral laser microsurgery for the unknown primary: role for lingual tonsillectomy. Head Neck 2014; 36:942.
- 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; 123:146.
- Durmus K, Rangarajan SV, Old MO, et al. Transoral robotic approach to carcinoma of unknown primary. Head Neck 2014; 36:848.
- 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; 139:1203.
- Graboyes EM, Sinha P, Thorstad WL, et al. Management of human papillomavirus-related unknown primaries of the head and neck with a transoral surgical approach. Head Neck 2015; 37:1603.
- Chaturvedi AK, Engels EA, Pfeiffer RM, et al. Human papillomavirus and rising oropharyngeal cancer incidence in the United States. J Clin Oncol 2011; 29:4294.
- Jannapureddy S, Cohen C, Lau S, et al. Assessing for primary oropharyngeal or nasopharyngeal squamous cell carcinoma from fine needle aspiration of cervical lymph node metastases. Diagn Cytopathol 2010; 38:795.
- Meier JD, Xie H, Sun Y, et al. Time-resolved laser-induced fluorescence spectroscopy as a diagnostic instrument in head and neck carcinoma. Otolaryngol Head Neck Surg 2010; 142:838.
- Balaker AE, Abemayor E, Elashoff D, St John MA. Cancer of unknown primary: does treatment modality make a difference? Laryngoscope 2012; 122:1279.
- Strojan P, Ferlito A, Langendijk JA, et al. Contemporary management of lymph node metastases from an unknown primary to the neck: II. a review of therapeutic options. Head Neck 2013; 35:286.
- Galloway TJ, Ridge JA. Management of Squamous Cancer Metastatic to Cervical Nodes With an Unknown Primary Site. J Clin Oncol 2015; 33:3328.
- Coster JR, Foote RL, Olsen KD, et al. Cervical nodal metastasis of squamous cell carcinoma of unknown origin: indications for withholding radiation therapy. Int J Radiat Oncol Biol Phys 1992; 23:743.
- Iganej S, Kagan R, Anderson P, et al. Metastatic squamous cell carcinoma of the neck from an unknown primary: management options and patterns of relapse. Head Neck 2002; 24:236.
- Patel RS, Clark J, Wyten R, et al. Squamous cell carcinoma from an unknown head and neck primary site: a "selective treatment" approach. Arch Otolaryngol Head Neck Surg 2007; 133:1282.
- 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; 50:727.
- Argiris A, Smith SM, Stenson K, et al. Concurrent chemoradiotherapy for N2 or N3 squamous cell carcinoma of the head and neck from an occult primary. Ann Oncol 2003; 14:1306.
- Shehadeh NJ, Ensley JF, Kucuk O, et al. Benefit of postoperative chemoradiotherapy for patients with unknown primary squamous cell carcinoma of the head and neck. Head Neck 2006; 28:1090.
- Nutting CM, Morden JP, Harrington KJ, et al. Parotid-sparing intensity modulated versus conventional radiotherapy in head and neck cancer (PARSPORT): a phase 3 multicentre randomised controlled trial. Lancet Oncol 2011; 12:127.
- Pow EH, Kwong DL, McMillan AS, et al. Xerostomia and quality of life after intensity-modulated radiotherapy vs. conventional radiotherapy for early-stage nasopharyngeal carcinoma: initial report on a randomized controlled clinical trial. Int J Radiat Oncol Biol Phys 2006; 66:981.
- Kam MK, Leung SF, Zee B, et al. Prospective randomized study of intensity-modulated radiotherapy on salivary gland function in early-stage nasopharyngeal carcinoma patients. J Clin Oncol 2007; 25:4873.
- Grau C, Johansen LV, Jakobsen J, et al. 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; 55:121.
- Sher DJ, Balboni TA, Haddad RI, et al. Efficacy and toxicity of chemoradiotherapy using intensity-modulated radiotherapy for unknown primary of head and neck. Int J Radiat Oncol Biol Phys 2011; 80:1405.
- Frank SJ, Rosenthal DI, Petsuksiri J, et al. Intensity-modulated radiotherapy for cervical node squamous cell carcinoma metastases from unknown head-and-neck primary site: M. D. Anderson Cancer Center outcomes and patterns of failure. Int J Radiat Oncol Biol Phys 2010; 78:1005.
- Klem ML, Mechalakos JG, Wolden SL, et al. Intensity-modulated radiotherapy for head and neck cancer of unknown primary: toxicity and preliminary efficacy. Int J Radiat Oncol Biol Phys 2008; 70:1100.
- Villeneuve H, Després P, Fortin B, et al. Cervical lymph node metastases from unknown primary cancer: a single-institution experience with intensity-modulated radiotherapy. Int J Radiat Oncol Biol Phys 2012; 82:1866.
- Shoushtari A, Saylor D, Kerr KL, et al. Outcomes of patients with head-and-neck cancer of unknown primary origin treated with intensity-modulated radiotherapy. Int J Radiat Oncol Biol Phys 2011; 81:e83.
- 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; 34:243.