Neck Cancer With Unknown Primary Site Treatment & Management

Updated: Mar 04, 2021
  • Author: Philip E Zapanta, MD, FACS; Chief Editor: Arlen D Meyers, MD, MBA  more...
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Medical Therapy

This section targets the treatment of patients without an identifiable primary lesion of the head and neck after a thorough examination of the head and neck, a panendoscopy, and possible neck dissection. Jesse et al demonstrated the added advantage of radiation therapy to locoregional control following the surgical removal of cervical metastases. Patients with metastatic cervical lymphadenopathy (N1-N3) had a locoregional failure rate of 13-32% when treated with surgery alone. Compare this with the locoregional failure rate of 0-18% associated with primary surgery (neck dissection) followed by adjuvant external beam radiotherapy. The research following this study further demonstrated the improvement in locoregional control of patients with occult primary squamous cell carcinoma. [28]

Although the value of radiation therapy has been confirmed, the field to be covered by the radiation therapy is controversial. Grau et al demonstrated the improvement of locoregional control of cancer with bilateral neck irradiation versus ipsilateral irradiation. Patients treated with ipsilateral irradiation had a relative risk of recurrence in the head and neck of 1.9 compared with patients treated with bilateral irradiation. With further research, bilateral cervical irradiation with surgical therapy improves locoregional control of cancer and is accepted as the standard of care for patients with advanced cervical disease (>N2). [29, 30]

The entire pharyngeal axis is generally accepted as the mucosal sites to be included in the radiation field in patients with occult primary lesions. Theoretically, this should prevent the occurrence of the primary lesion. In order to decrease the morbidity of radiation induced xerostomia, some practitioners would not include the nasopharynx within the radiation field if the results of the endoscopy and the findings on imaging studies are negative. [6]

Chemotherapy is generally reserved for patients with clinical or pathologic indicators of aggressive disease or primary nasopharyngeal carcinoma. Patients with extensive lymphadenopathy (>N2C), pathologic evidence of extracapsular spread of the carcinoma outside of individual lymph nodes, unresectable local disease, or distant metastatic spread of the carcinoma often undergo chemotherapy for curative intent or palliative treatment.

Aggressive medical management consisting of both chemotherapy and radiation is reserved for advanced disease in patients who are deemed poor candidates for surgery or inoperable or in whom palliation is employed. A study reported that concurrent chemoradiotherapy of N2 and N3 nodal disease from an unknown primary was able to give patients a 5-year survival rate and control rate of 75% and 87%, respectively. [31] Also, patients with nasopharyngeal carcinoma are treated with combined chemoradiation therapy without surgery.

In a single-institution series of 24 patients reported by Sher et al, chemoradiotherapy treatment of head and neck squamous cell carcinoma of an unknown primary using intensity-modulated radiotherapy (IMRT) achieved excellent good locoregional control and overall survival. Xerostomia (grade 2) rates were 25%, but the aggressive therapy left a significant number of patients with esophageal stenosis and 46% of patients required dilatation. [32]

A study sought to determine whether the addition of cisplatin-based concurrent chemotherapy to radiation therapy would influence patients treated for head and neck cancer of unknown primary origin. Results showed concurrent chemoradiation provides no clear advantage to overall survival and imparted significant added toxicity. Further study is needed to make any firm conclusions regarding the study aim. [33]

See Cancer of Unknown Primary Treatment Protocols for summarized information.


Surgical Therapy

Panendoscopy is the primary surgical therapy used to discover an occult primary lesion. The procedure begins with nasal endoscopy using a 0° rigid endoscope to examine the nasopharynx. Generous biopsy samples of the nasopharynx are obtained for both frozen sectioning and permanent sectioning. Frozen sectioning of the nasopharynx is the first portion of the endoscopy. If the results are positive for carcinoma, the procedure is halted because definitive treatment of nasopharyngeal carcinoma is radiation and chemotherapy. By performing this aspect of the procedure first and by obtaining results that are positive, the patient is spared both the additional morbidity of alternate biopsies of the site and the probable surgical treatment of the cervical lymphadenopathy.

If the results from the frozen sections of the nasopharynx are negative, the oral cavity, oropharynx, hypopharynx, and larynx are inspected and palpated. These areas can be evaluated with a laryngoscope. Next, a rigid cervical esophagoscope is used to examine the esophagus. If any suspicious lesions are present, biopsy samples are obtained and sent for permanent sectioning.

After thoroughly palpating the base of the tongue, the examiner obtains biopsy samples. The tonsillar fossa is then inspected. Considerable controversy surrounds the proper sampling technique of a tonsil. Some clinicians obtain biopsy samples of any suspicious sites found on the tonsil. Others perform elective tonsillectomy to eliminate sampling errors. A literature review by Di Maio et al supported palatine tonsillectomy as an effective means of identifying the primary lesion site in patients with head and neck squamous cell carcinoma of unknown primary origin. The report revealed that out of 416 palatine tonsillectomies in such patients, 140 occult tonsillar cancers were found, including 124 (89%) that were ipsilateral, 2 (1%) that were contralateral, and 14 (10%) that were synchronous bilateral. [34]

The unilateral tonsillectomy adds little morbidity and allows thorough sampling of a suspicious site. Others argue that bilateral tonsillectomy also adds little morbidity and decreases confusion of asymmetric tonsils in follow-up examination. Koch et al reported a 10% spread of metastatic cancer from the contralateral tonsil; therefore, they recommended a bilateral tonsillectomy. [35] The only clinical situation that apparently justifies a bilateral tonsillectomy is the presence of bilateral metastatic cervical lymphadenopathy. [36, 37]

Depending on the results of the panendoscopy, either the newly found primary lesion (other than the nasopharynx) is addressed surgically along with the cervical lymphadenopathy or the lymphadenopathy is addressed separately with the appropriate neck dissection. [38, 39]

Patel et al studied the efficacy of transoral robotic surgery (TORS) in identifying unknown primary sites in head and neck squamous cell carcinoma and concluded that it is a useful approach. [40, 41, 42]  A literature review by Meccariello et al reported that TORS identified 70.8% of primary tumors in head and neck unknown primary cancers. [43]


Preoperative Details

As stated above, the panendoscopy requires use of frozen sectioning. The clinician should ensure the availability of a pathologist skilled in the use of frozen sections.


Postoperative Details

Postoperative details are unchanged when compared to patients with squamous cell carcinoma from a known primary lesion.



The usual postoperative care following a neck dissection is administered. The workup required for patients with cancer from an unknown primary site does not necessitate any upgrade in the level or complexity of the care.

Long-term follow-up care of this patient population consists of thorough examinations of the head and neck and does not differ when compared to the other patient groups with squamous cell carcinoma of the head and neck.



The number and the type of complications generated by the surgical workup of patients with an unknown primary lesion are not significantly different from those associated with the surgical treatment of patients with a known primary lesion and metastatic cervical lymphadenopathy. Complications of panendoscopy include the following:

  • Chipped teeth (most common)

  • Hemorrhage from site of biopsy (ie, same incidence of tonsillar fossa hemorrhage with panendoscopy as with primary tonsillectomy)

  • Pharyngeal and/or esophageal puncture/rupture from endoscopy (rare)


Outcome and Prognosis

Patients with metastatic squamous cell carcinoma of the head and neck from occult primary lesions have clinical features and prognosis similar to those patients with carcinoma from known primary sites. With multimodality treatment, locoregional control of the cancer has improved in this patient population, but little improvement has occurred in overall disease-free survival. The 3- and 5-year disease-free survival rates are 40-60% and 10-25%, respectively. Prognostic factors include nodal stage at presentation, extracapsular spread, and tumor differentiation. [29, 30, 44]


Future and Controversies

The treatment of cervical lymphadenopathy from metastatic squamous cell carcinoma with an occult primary lesion is in flux. Large institutional studies are currently evaluating the efficacy of chemoradiation therapy as the sole treatment modality. This treatment regimen will be compared against the traditional combined modality treatment of neck dissection followed by radiation and/or chemotherapy.

In addition to comparing different treatment modalities, advances in science allow the use of oncogenes and microarray complementary deoxyribonucleic acid (cDNA) technology to determine which patients will respond to specific treatments.