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Unknown Primary Squamous Cell Cancer (Evaluation and Management)

last modified on: Fri, 03/29/2024 - 09:56

General Considerations

  1. Definition
    1. The "unknown primary" refers to cancer identified in the neck suspected to represent metastasis from a primary site not readily determined. This discussion is limited to squamous cell carcinoma.
  2. Incidence
    1. Unknown primary represents about 1-2% of head and neck squamous cell cancers.
    2. The incidence of unknown primary cancers has diminished with the advent of advanced radiographic imaging (CT, MRI, PET) and routing use of flexible fiberoptic endoscopic examination in the clinic. The patterns of presentation have similarly changed with expanded use of this improved technology.
    3. With increased incidence and recognition of the impact of human papillomavirus (HPV), unknown primary cancers are increasingly identified as oropharygneal tumors.


  1. History
    1. Identify risk factors for malignancy
      1. Age, tobacco use, alcohol use, associated symptoms
      2. Previous cancer or previous irradiation
      3. Family history
    2. Identify duration of neck mass
    3. Identify presence of other localizing head and neck symptoms
  2. Physical Examination
    1. Examine all mucosal surfaces of the upper aerodigestive tract
    2. Perform flexible fiberoptic nasopharyngoscopy and laryngoscopy
    3. Examine skin surfaces (including scalp)
    4. Location of an isolated neck mass may predict the location of the primary site based on lymph drainage
      1. Level I: oral cavity, skin
      2. Level II: oral cavity, oropharynx, supraglottic larynx, hypopharyn, or nasopharynx
      3. Level III: larynx, hypopharynx
      4. Level IV: subglottic larynx, cervical esophagus, infraclavicular regions (lung, GI tract)
      5. Level V: nasopharynx
  3. Consider a single empiric trial of antibiotics
    1. The working diagnosis is cervical lymphadenitis
    2. Take this approach only if history and physical exam strongly support infectious etiology
    3. Persistence after single course of antibiotics warrants pathologic assessment
  4. Blood studies
    1. Provides little value in initial evaluation
    2. General evaluation includes
      1. General screen (electrolytes, LFTs, renal function)
      2. CBC and coagulation profile
  5. Fine needle aspiration biopsy
    1. May be an initial step following history and physical or may defer to radiographic imaging
    2. Radiographic imaging may help determine need for FNA and direct it anatomically
  6. Radiographic imaging
    1. Ultrasound (USG) may be helpful for selected masses
      1. Ultrasound can be done in conjunction with FNA
      2. Disadvantage: USG is a dynamic study, therefore the permanent images provided are difficult to interpret for all but the radiologist performing the exination
      3. USG is not as comprehensive or definitive as CT or MRI
    2. CT or MRI
      1. Perform with and without contrast
      2. Request imaging: "skull base to clavicles... with focus on..." depending on site of lesion; either MRI or CT is usually sufficient for initial evaluation
      3. MRI is better for salivary gland, soft tissue detail
      4. CT is better for bone detail, also (currently) better for cervical adenopathy
    3. PET
      1. Due to the limited spatial resolution of PET, CT and MRI are preferred for determining tumor extent and staging
      2. PET may help identify the primary site in one fourth to one third of patients with cancer of unknown primary, but the false positive rate is also high (40% in Wong 2008).
      3. Because post-surgical inflammation can complicate the PET interpretation, the PET scan is ideally performed before directed biopsies.
  7. Pathologic considerations
    1. The FNA diagnosis of squamous cell carcinoma is generally uncomplicated
    2. Open biopsy of a neck mass may be indicated to determine definitive histopathology. The dictum against open biopsy of SCC has been modified.
      1. It remains good practice to avoid an open biopsy of a neck mass as an initial step in the evaluation
      2. It is not clear that an open biopsy of a neck mass harboring squamous cell carcinoma comprises survival as long as timely and appropriate subsequent measures are taken
      3. Following a detailed history and physical examination, an indeterminate FNA, adequate radiographic imaging, and a full survey of the upper aerodigestive tract mucosa, an open biopsy of a neck mass may be warranted (eg. to rule out lymphoma)
    3. The key to successful treatment is expeditious and comprehensive management immediately following the open biopsy if squamous cell carcinoma is identified
  8. Consultations
    1. Radiation oncology
    2. Internal medicine
      1. If needed to help address co-existing illnesses that are common in the group of patients with squamous cell carcinoma
    3. Dentistry
      1. To coordinate dental care and timing of extractions if irradiation is part of the management plan
  9. Panedoscopy is indicated before treatment (see Panendoscopy protocol)
    1. "Pan" (everywhere) refers to:
      1. Nasopharyngoscopy and rhinoscopy
        1. May actually visualize these sites better in the clinic with flexible fiberoptic endoscopy
      2. Direct laryngoscopy
        1. Includes oropharynx in survey
        2. Yield highest in piriform sinuses, post-cricoid region, supraglottic larynx, and base of tongue
      3. Esophagoscopy
        1. Cervical esophagoscopy done to identify poential site for neck metastasis
        2. Thoracic esophagoscopy done to survey for synchronous second primary (most commonly in lower esophagus)
      4. Bronchoscopy
        1. Done with washings if symptoms or radiographic imaging support pulmonary abnormality
      5. Inspection and palpating bimanually of the oral cavity and neck
        1. Deep palpation of the base of tongue
    2. Directed (not "blind") biopsies are done to sites most likely to harbor an occult neoplasm
      1. Bilateral tonsillectomy
        1. Unilateral tonsillectomy leaves asymmetry tto the oropharynx that may be percieved as a pathologic abnormality later
        2. 10% of patients with an occult malignancy may be contralatertal or bilateral disease
      2. Bilateral or unilateral nasopharyngeal biopsies
        1. Fossa of Rosenmuller
      3. Ipsilatereal base of tongue biopsy
        1. Consider piriform sinus biopsy


  1. Assume that, despite an appropriately intense evaluation in the clinical setting, the primary tumor remains elusive
    1. The diagnosis of squamous cell carcinoma is made through FNA of neck mass
      1. Under general anesthesia, perform panendoscopy with directed biopsies and neck dissection
      2. Usual practice at the University of Iowa: If the primary site if sound, it is likely to be classified T1 and hence may receive radiation or transoral resection as definitive therapy. If treated with resection, surgical planning may be done to determine surgical exposure and margins. If radiation is chosen, identification of the primary site helps to limit the extent of irradiation. If the primary site is not found, the neck and mucosa of the entire upper aerodigestive tract is irradiated.
      3. Alternatives: if the primary site is not found despite appropriate biopsies
        1. The neck disease demonstrates extracapsular spread or multiple nodes at multiple levels: consider XRT to the neck following neck dissection, sparing irradiation of upper aerodigestive tract mucosal surfaces
        2. The neck disease is small without extracapsular spread (ie. one or two lymph nodes): consider treatment with neck dissection only and no irradiation
    2. The diagnosis was made elsewhere through open biopsy with resection of all gross residual disease as documented by subsequent CT imaging, but without a formal neck dissection
      1. Under general anesthesia, perform panendoscopy with directed biopsies
      2. Consider neck dissection under the same anesthetic
        1. May be followed either with or without postoperative irradiation depending on pathologic findings
        2. May alternatively consider treatment with irradiation without neck dissection depending on pathologic findings from the resected specimen


Collins MS. Controversies in management of cancer in the neck. In: Thawley SE, Panje WR, Batsakis JG, Lindberg RD, eds. Comprehensive Management of Head and Neck Tumors, Vol 2. 2nd ed. Philadelphia, PA. WB Saunders Co; 1999: 1479-1563.

Gluckman JL, Robbins KT, Fried MP. Cervical metastatic squamous cell carcinoma of unknown or occult primary source. Head Neck 1990; 12: 440-443.

Lindberg RD, Paris KJ, Fletcher GH. Radiation therapy of tumors of the neck. n: Thawley SE, Panje WR, Batsakis JG, Lindberg RD, eds. Comprehensive Management of Head and Neck Tumors, Vol 2. 2nd ed. Philadelphia, PA. WB Saunders Co; 1999:1450-1477.

McGuirt WF, McCabe BF. Significance of node biopsy before definitive treatment of cervical metastatic carcinoma. Laryngoscope 1978; 88: 594-597.

Neel HB. Nasopharyngeal carcinoma: diagnosis, staging, and management. Oncology. 1992; 6:87-95.

Razack MS, Sako K, Marcheeta FC. Influence of initial neck node biopsy on the incidence of recurrence in the neck and survival in patients who subsequently undergo curative resectional surgery. J Surg Oncol. 1977; 9: 347.

Robbins KT. Detrimental effects of diagnostic cervical node biopsy: dogma vs. science. Head Neck 1991; 13: 175-176.

Wang RC, Goepfert H, Barber A, Wolf P. Squamous cell carcinoma metastatic tot he neck from an unknown primary site. In: Lorson DL, Ballantyne AS, Guillamondequi OM, eds. Cancer in the Neck-- Evaluation and Treatment. New York, NY. Macmillan Publishing Co; 1986.

Young T, Gluckman J. Tumors of the upper aerodigestive tract: neck metastases-- unknown primary. In: Medina J, ed. Clinical Practice Guidelines for the Diagnosis and Management of Cacner of the Head and Neck. Pittsburgh PA. American Society for Head and Neck Surgery and the Society for Head and Neck Surgeons; 1996: 49-53.