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Metastatic Squamous Neck Cancer With Occult Primary Treatment (PDQ®)–Health Professional Version

General Information About Metastatic Squamous Neck Cancer With Occult Primary


The diagnosis of an occult primary tumor is made only when no primary tumor is detected after careful search and when a primary tumor does not appear during therapy. Patients with cervical lymph node metastases histologically related to a previously treated primary tumor and patients with lymphomas and adenocarcinoma are excluded. If the biopsy is an undifferentiated carcinoma (in particular, a lymphoepithelioma), the most probable primary site is in Waldeyer ring; for example, the nasopharynx, base of tongue, or tonsil. Most epidermoid carcinomas metastatic to lymph nodes of the upper half of the neck will originate from a head and neck primary site. Squamous carcinomas metastatic to the lower neck may represent a primary site in the head and neck, esophagus, lung, or genitourinary tract. A search for primaries in these areas must be undertaken before assuming that the primary is occult. Primary tumors arising in the nasopharynx may be secondary to Epstein-Barr virus (EBV) infection, and EBV genomic material may be detectable in cervical nodal tissue after DNA amplification using the polymerase chain reaction. Such a finding should lead to an in-depth search for a primary in the nasopharynx.[1]

The extent of investigation and type of treatment must be individualized depending on the patient's age and wishes, and on the site, histology, and extent of metastatic lymph node involvement of the tumor. When a patient qualifies as having squamous carcinoma of the neck with occult primary, he or she should be checked for other obvious metastatic disease, such as lung, liver, or bone, because this would affect the locoregional approach to therapy.[2]


Three-year disease-free survival rates following surgery and/or radiation therapy for unknown squamous primaries range from 40% to 50% in patients with N1 disease, to 38% and 26% for patients with N2 and N3 disease, respectively. Patients who later develop primary lesions have poor survival rates compared with patients whose primaries remain occult, for example 30% versus 60%.


Patients with neck metastases from an undetectable primary should be given the benefit of definitive treatment. Despite the ominous situation of an undiscovered primary, a significant number of patients do achieve cure by both surgical and radiotherapeutic approaches. In some patients, long-term repeat examinations will eventually disclose the primary tumor, and at a treatable stage.

  1. Feinmesser R, Miyazaki I, Cheung R, et al.: Diagnosis of nasopharyngeal carcinoma by DNA amplification of tissue obtained by fine-needle aspiration. N Engl J Med 326 (1): 17-21, 1992. [PUBMED Abstract]
  2. de Braud F, al-Sarraf M: Diagnosis and management of squamous cell carcinoma of unknown primary tumor site of the neck. Semin Oncol 20 (3): 273-8, 1993. [PUBMED Abstract]

Cellular Classification of Metastatic Squamous Neck Cancer With Occult Primary

This section helps lead the clinician and pathologist through a differential diagnosis for an unknown primary presenting with cervical node metastases. The therapeutic section, however, relates only to squamous carcinoma and assumes that the primary physician has worked with the pathologist as described below to eliminate other possibilities that would require alternative therapies.

The pathologist plays a central role in evaluating an occult primary tumor. A thorough evaluation of an adequate specimen through histological or immunohistochemical techniques, and, when appropriate, electron microscopy (EM) provides guidance for the clinical evaluation that ensues. A critical interaction should exist between the pathologist, oncologist, and primary physician.

The complexity of the pathological evaluation tends to be inversely related to the degree of differentiation of the tumor. For instance, for well or moderately differentiated tumors, the pathological diagnosis of an epithelial cancer is often readily apparent, in contrast to lymphoma, sarcoma, melanoma, or a germ cell tumor. Commonly used stains such as mucicarmine or diastase-sensitive Periodic Acid Schiff can be important in confirming the diagnosis of certain tumors of gastrointestinal or renal origin.

If the clinician is faced with a male patient younger than 50 years with a poorly differentiated tumor, serum levels of beta-human chorionic gonadotropin (beta-hCG) and alpha-fetoprotein (AFP) should be obtained and specimens should be evaluated with immunohistochemical stains for beta-hCG and AFP. Some of these tumors respond to platinum-based combination chemotherapy in a manner similar to extragonadal germ cell malignancies, and this group of patients should be so treated unless other alternative diagnoses are made.[1]

Special studies can help in differentiating more poorly differentiated tumors. Often, a generic distinction is important between a poorly differentiated tumor of epithelial, hematopoietic, neuroendocrine, or neuroectodermal origin (i.e., melanoma).

  • Immunohistochemical:

    Immunohistochemical studies can be important in making these broad distinctions, in particular, studies that evaluate staining for keratins, leukocyte common antigen, and S-100, a neuroectodermal antigen expressed in melanomas.[2]

  • Polymerase chain reaction:

    In patients with suspected nasopharyngeal carcinoma, DNA amplification of Epstein-Barr virus (EBV) genomes can be used for diagnosis with tissue provided by fine-needle aspiration biopsy. The presence of EBV in metastases from an occult primary tumor suggests the development of overt nasopharyngeal carcinoma.[3]

    Acinar spaces and microacini are seen with adenocarcinomas. Electron dense secretory granules are seen in tumors of neuroectodermal origin. Premelanosomes can be found in most amelanotic melanomas. But these features are generally associated with differentiation along a particular line. Often poorly differentiated tumors do not display such characteristics, and EM evaluation would be of little value. The use of EM may aid in distinguishing a primary diagnosis not obtained by light microscopy approximately 10% of the time.[4-6]

  1. Hainsworth JD, Wright EP, Gray GF, et al.: Poorly differentiated carcinoma of unknown primary site: correlation of light microscopic findings with response to cisplatin-based combination chemotherapy. J Clin Oncol 5 (8): 1275-80, 1987. [PUBMED Abstract]
  2. Battifora H: Recent progress in the immunohistochemistry of solid tumors. Semin Diagn Pathol 1 (4): 251-71, 1984. [PUBMED Abstract]
  3. Feinmesser R, Miyazaki I, Cheung R, et al.: Diagnosis of nasopharyngeal carcinoma by DNA amplification of tissue obtained by fine-needle aspiration. N Engl J Med 326 (1): 17-21, 1992. [PUBMED Abstract]
  4. Hanna W, Kahn HJ: The ultrastructure of metastatic adenocarcinoma in serous fluids. An aid in identification of the primary site of the neoplasm. Acta Cytol 29 (3): 202-10, 1985 May-Jun. [PUBMED Abstract]
  5. Herrera GA, Reimann BE: Electron microscopy in determining origin of metastatic adenocarcinomas. South Med J 77 (12): 1557-66, 1984. [PUBMED Abstract]
  6. Mackay B, Ordonez NG: The role of the pathologist in the evaluation of poorly differentiated tumors. Semin Oncol 9 (4): 396-415, 1982. [PUBMED Abstract]

Stage Information for Metastatic Squamous Neck Cancer With Occult Primary

American Joint Committee on Cancer (AJCC) Stage Groupings and TNM Definitions

For metastatic squamous neck cancer with occult primary, the patient's human papilloma virus (HPV) p16 status or Epstein-Barr virus (EBV) status is used to determine which AJCC staging system is used, as follows:

Treatment of Untreated Metastatic Squamous Neck Cancer With Occult Primary

Untreated metastatic squamous neck cancer with occult primary means that a patient is newly diagnosed and has had no previous treatment except supportive care. Patients with neck nodes from a presumed unknown primary tumor should be evaluated as follows:

  1. Surgical biopsy or excision to establish a histological diagnosis, but only after an aerodigestive tract primary has been carefully ruled out as in the following procedures:
    • Direct nasopharyngoscopy, laryngoscopy, bronchoscopy, and esophagoscopy, with biopsy of any suspicious area.
      • If no suspicious lesions are found, random biopsies of the nasopharynx, base of tongue, tonsil, and pyriform sinus on the side of the lesion should be performed.
      • If the tonsil is not present, biopsy of the tonsillar fossa should be performed.
      • Sinus x-rays are probably indicated; if an abnormality is found, it should be biopsied as well.
  2. Selected other studies if indicated. In the detection of head and neck tumors and in the distinction of lymph nodes from blood vessels, magnetic resonance imaging offers an advantage over computed tomography scans and should be considered in the initial evaluation of the patient with metastatic squamous cell cancer in cervical lymph nodes.[1] Positron emission tomography may be helpful in determining the primary site.[2]

    Patients should be managed with either a full course of radiation therapy or adequate neck dissection, when possible. In cases of massive homolateral adenopathy that is fixed or bilateral nodes, radiation therapy should be administered first. The radiation fields should also include the nasopharynx, base of tongue, and pyriform sinuses. If radiation therapy is the primary mode of treatment and the neck mass persists upon completion of radiation therapy, cervical lymph node dissection should be performed. Patients with metastatic carcinoma in the supraclavicular region are best managed with a full course of radiation therapy followed by surgical dissection if palpable tumor persists. Careful continued follow-up of these patients is of utmost importance. Depending on the likely site of origin and histology, chemotherapy appropriate to the most treatable site may be indicated.

    Accumulating evidence has demonstrated a high incidence (>30%–40%) of hypothyroidism in patients who received external-beam radiation therapy to the entire thyroid gland or the pituitary gland. Thyroid function testing of patients should be considered before therapy and as part of posttreatment follow-up.[3,4]

Treatment options:

  1. Radical neck dissection.
  2. Radiation therapy.[5,6] Intensity-modulated radiation therapy may have less short- and long-term toxicity than conventional radiation therapy in terms of xerostomia, acute dysphagia, and skin fibrosis.[7,8]
  3. Combined surgery and radiation therapy.[9]
  4. Chemotherapy followed by radiation therapy (under clinical evaluation).[10]
  5. Simultaneous chemotherapy and hyperfractionated radiation therapy (under clinical evaluation).[11]
  6. Clinical trials for advanced tumors should be considered.

Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.

  1. Consensus conference. Magnetic resonance imaging. JAMA 259 (14): 2132-8, 1988. [PUBMED Abstract]
  2. Rege S, Maass A, Chaiken L, et al.: Use of positron emission tomography with fluorodeoxyglucose in patients with extracranial head and neck cancers. Cancer 73 (12): 3047-58, 1994. [PUBMED Abstract]
  3. Turner SL, Tiver KW, Boyages SC: Thyroid dysfunction following radiotherapy for head and neck cancer. Int J Radiat Oncol Biol Phys 31 (2): 279-83, 1995. [PUBMED Abstract]
  4. Constine LS: What else don't we know about the late effects of radiation in patients treated for head and neck cancer? Int J Radiat Oncol Biol Phys 31 (2): 427-9, 1995. [PUBMED Abstract]
  5. Carlson LS, Fletcher GH, Oswald MJ: Guidelines for radiotherapeutic techniques for cervical metastases from an unknown primary. Int J Radiat Oncol Biol Phys 12 (12): 2101-10, 1986. [PUBMED Abstract]
  6. Mack Y, Parsons JT, Mendenhall WM, et al.: Squamous cell carcinoma of the head and neck: management after excisional biopsy of a solitary metastatic neck node. Int J Radiat Oncol Biol Phys 25 (4): 619-22, 1993. [PUBMED Abstract]
  7. Madani I, Vakaet L, Bonte K, et al.: Intensity-modulated radiotherapy for cervical lymph node metastases from unknown primary cancer. Int J Radiat Oncol Biol Phys 71 (4): 1158-66, 2008. [PUBMED Abstract]
  8. 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 80 (5): 1405-11, 2011. [PUBMED Abstract]
  9. Maulard C, Housset M, Brunel P, et al.: Postoperative radiation therapy for cervical lymph node metastases from an occult squamous cell carcinoma. Laryngoscope 102 (8): 884-90, 1992. [PUBMED Abstract]
  10. Thyss A, Schneider M, Santini J, et al.: Induction chemotherapy with cis-platinum and 5-fluorouracil for squamous cell carcinoma of the head and neck. Br J Cancer 54 (5): 755-60, 1986. [PUBMED Abstract]
  11. Weissler MC, Melin S, Sailer SL, et al.: Simultaneous chemoradiation in the treatment of advanced head and neck cancer. Arch Otolaryngol Head Neck Surg 118 (8): 806-10, 1992. [PUBMED Abstract]

Treatment of Recurrent Metastatic Squamous Neck Cancer With Occult Primary

The prognosis for most treated patients with progressing, recurring, or relapsing cancer is poor, regardless of cell type or stage. Deciding on further treatment depends on many factors, including the specific cancer, previous treatment, site of recurrence, as well as individual patient considerations. Treatments that are under clinical evaluation are appropriate and should be considered when possible.

Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.

Latest Updates to This Summary (09/05/2023)

The PDQ cancer information summaries are reviewed regularly and updated as new information becomes available. This section describes the latest changes made to this summary as of the date above.

Editorial changes were made to this summary.

This summary is written and maintained by the PDQ Adult Treatment Editorial Board, which is editorially independent of NCI. The summary reflects an independent review of the literature and does not represent a policy statement of NCI or NIH. More information about summary policies and the role of the PDQ Editorial Boards in maintaining the PDQ summaries can be found on the About This PDQ Summary and PDQ® Cancer Information for Health Professionals pages.

About This PDQ Summary

Purpose of This Summary

This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the treatment of adult metastatic squamous neck cancer with occult primary. It is intended as a resource to inform and assist clinicians in the care of their patients. It does not provide formal guidelines or recommendations for making health care decisions.

Reviewers and Updates

This summary is reviewed regularly and updated as necessary by the PDQ Adult Treatment Editorial Board, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).

Board members review recently published articles each month to determine whether an article should:

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Changes to the summaries are made through a consensus process in which Board members evaluate the strength of the evidence in the published articles and determine how the article should be included in the summary.

The lead reviewers for Metastatic Squamous Neck Cancer With Occult Primary Treatment are:

  • Andrea Bonetti, MD (Azienda ULSS 9 of the Veneto Region)
  • Ann W. Gramza, MD (Georgetown Lombardi Comprehensive Cancer Center)
  • Monaliben Patel, MD (University of Rochester Medical Center)
  • Minh Tam Truong, MD (Boston University Medical Center)

Any comments or questions about the summary content should be submitted to through the NCI website's Email Us. Do not contact the individual Board Members with questions or comments about the summaries. Board members will not respond to individual inquiries.

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PDQ® Adult Treatment Editorial Board. PDQ Metastatic Squamous Neck Cancer With Occult Primary Treatment. Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at: Accessed <MM/DD/YYYY>. [PMID: 26389364]

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