Unknown Head and Neck Primary Site

Key Points

Incidence

Carcinoma of an unknown primary tumor (CUP) in the head and neck describes a patient with cervical node metastases without a physically or radiologically identifiable primary tumor site. Approximately 3% of patients with head and neck squamous cell carcinomas have a CUP.

Biologic Characteristics

Biologic characteristics are similar to head and neck mucosal squamous cell carcinomas with known primary sites. Most CUPs are thought to be of tonsillar fossa or tongue base origin and behave similarly.

Staging Evaluation

Evaluation begins with a history and complete head and neck physical examination, including palpation of the tonsils and base of tongue. This is followed by in-office flexible laryngoscopy. Imaging studies should be ordered next and include computed tomography (CT) of the neck and chest with contrast or positron emission tomography (PET)-CT with a diagnostic neck CT with contrast. A problem with PET-CT is that there is a 30% false–positive rate in the oropharynx, the most likely site of the primary tumor. After imaging, a trip to the operating room (OR) is necessary to perform panendoscopy, tonsillectomies, and base of tongue biopsies or lingual tonsillectomy. Directed nasopharyngeal and hypopharyngeal biopsies are not typically necessary unless there is a suspicion of cancer at these sites.

Primary Therapy and Results

Treatment philosophies are either surgery-based or radiotherapy (RT)-based. Surgery-based approaches include panendoscopy, direct biopsies to suspicious sites, palatine and lingual tonsillectomies as well as neck dissection(s). This is followed by RT or chemoradiation therapy (CRT). RT-based treatments involve treating the affected neck with or without elective treatment of the contralateral neck as well as wide-field RT to the oropharynx plus or minus nasopharynx. Because the tongue base has a high likelihood of harboring the primary tumor site and exhibits lymphatic drainage to both sides of the neck, both sides of the neck are usually irradiated.

Adjuvant Therapy

Concomitant cisplatin chemotherapy is administered for N2 and N3 neck disease and for close and positive margins or extracapsular extension following an initial neck dissection.

Locally Advanced Disease

Radiotherapy is administered to the oropharynx, nasopharynx, and both sides of the neck with concomitant chemotherapy followed by evaluation for a neck dissection.

Palliation

Moderate-dose RT (30 Gy/10 fractions or 20 Gy/2 fractions with a 1-week interfraction interval) is administered to the involved neck.

In 25% to 50% of patients with squamous cell carcinoma metastatic to the cervical lymph nodes, the primary lesion cannot be found, even after an extensive evaluation. Patients with metastatic adenopathy in the upper neck have a good prognosis when treated aggressively, compared with those with metastatic lymph nodes in the level IV nodes or supraclavicular fossa. The latter group is more likely to have a primary lesion located below the clavicles, and the probability of cure is remote. Most patients have either squamous cell carcinoma or poorly differentiated carcinoma. Patients with adenocarcinoma almost always have a primary lesion below the clavicles; however, if the nodes are located in the upper neck, a salivary gland, thyroid, or parathyroid primary tumor cannot be excluded.

This chapter addresses the treatment of patients presenting with squamous cell or poorly differentiated carcinoma in the upper or middle neck. Squamous cell carcinoma presenting in a parotid area lymph node is almost always metastatic from a cutaneous primary site and will not be addressed.

Diagnostic Evaluation

A complete head and neck examination with thorough evaluation of the oropharynx and nasopharynx is performed. The tonsils and base of tongue should be palpated with a gloved finger, despite patient discomfort and gagging. The oropharynx may be sprayed with lidocaine to help the patient tolerate the examination. Flexible laryngoscopy will provide visualization of the nasopharynx and larynx/hypopharynx.

A fine-needle aspirate (FNA) biopsy of the lymph node should be performed under ultrasound guidance; multiple samples should be taken and sent for cytology, p16/human papilloma virus (HPV) testing, and Epstein-Barr virus testing. Epstein-Barr virus detection is useful for finding a nasopharyngeal primary tumor in geographic areas where this malignancy is prevalent. Most occult primary cancers in the United States will be of oropharyngeal origin.

Imaging is the next step and should include CT of the neck and chest with contrast or a PET-CT with a diagnostic CT neck with contrast. The recommended diagnostic algorithm is depicted in Box 45.1 .

Box 45.1

From Mendenhall WM, Parsons JT, Mancuso AA, et al. Head and neck: management of the neck. In: Perez CA, Brady LW, eds. Principles and Practice of Radiation Oncology , 3d ed. Philadelphia: JB Lippincott; 1998:1135–1156 (Table 44.20, p 1152).

Diagnostic Algorithm

General

History
Physical examination
Careful examination of the neck and supraclavicular regions
Examination of oral cavity, pharynx, and larynx (indirect laryngoscopy with a flexible endoscope)

Radiographic Studies

Chest roentgenogram
Computed tomography or magnetic resonance imaging (MRI) scans of head and neck (special attention to nasopharynx, pharynx, and larynx)

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