Key Points
- Management decisions for squamous cell carcinoma of unknown primary (SCCUP) are best decided in the context of a multidisciplinary tumor board and with careful consideration of human papillomavirus (HPV) status, disease burden and distribution in the neck, a patient’s overall health and well-being, potential treatment-related toxicity, and rehabilitation potential for functional recovery.
Preoperative Evaluation
- 1.1: Patients undergoing evaluation for a neck mass suspicious for squamous cell carcinoma should undergo a thorough history and physical examination including fiberoptic laryngoscopy that may be complemented with advanced visualization techniques such as narrow band imaging (NBI) to facilitate identification of the anatomic location of the primary tumor and to inform potential therapeutic management options. (Moderate recommendation; IC-B-L)
- 1.2: Fine-Needle aspiration or core biopsy of a clinically suspicious neck mass should be performed. (Strong recommendation; EB-B-I)
- 1.3: High-risk human papillomavirus (HR-HPV) testing should be done routinely on level II and III SCCUP nodes. Epstein-Barr virus (EBV) testing should be considered on HPV-negative metastases. (Moderate recommendation; EB-B-I)
Note: HR-HPV testing may be done non-routinely for squamous cell carcinoma metastases at other nodal levels when clinical suspicion is high. - 1.4: Contrast enhanced computed tomography (CECT) of the neck should be the initial test for work-up of metastatic cervical lymphadenopathy. (Strong recommendation; EB-B-I)
- 1.5: If a primary is not evident on clinical examination and CECT, positron emission tomography (PET)-CT should be the next diagnostic step. (Strong recommendation; EB-B-I)
Diagnostic And Therapeutic Surgical Procedures
- 2.1: Patients should undergo a complete operative upper aerodigestive tract evaluation of mucosal sites at-risk (oral cavity, nasopharynx, oropharynx, hypopharynx, and larynx) including directed biopsy of any suspicious areas. Random biopsies of non-suspicious areas have a low yield and should not be performed. Intraoperative advanced visualization techniques may be used to investigate potential primary sites for targeted biopsy. (Strong recommendation; EB-B-I)
- 2.2: For patients with unilateral lymphadenopathy, if a primary site is not confirmed on initial evaluation, the surgeon should perform ipsilateral palatine tonsillectomy. If palatine tonsillectomy fails to identify a primary, ipsilateral lingual tonsillectomy may be performed. Bilateral palatine tonsillectomy may be considered according to clinical suspicion, at the discretion of the surgeon. (Moderate recommendation; EB-B-I)
- 2.3: For patients with bilateral lymphadenopathy, if a primary site is not confirmed on endoscopic examination, the surgeon may perform unilateral lingual tonsillectomy on the side with the greater nodal burden and may perform contralateral lingual tonsillectomy if the ipsilateral procedure fails to identify a primary. Bilateral palatine tonsillectomy after bilateral lingual tonsillectomy should be avoided. (Moderate recommendation; EB-B-I)
- 2.4: For patients in whom the primary tumor is identified during operative upper aerodigestive tract evaluation and definitive surgical management is intended (including neck dissection), clinicians should make every effort to resect the identified primary using transoral techniques to a negative surgical margin. (Strong recommendation; EB-B-I)
- 2.5: Tissue specimens from suspected primary sites (biopsies, palatine and lingual tonsillectomies) should be entirely submitted for histologic examination. Resection specimens should be anatomically oriented by the surgeon, and margin evaluation should be performed. p16 immunohistochemistry may aid in evaluation of atypical or cauterized tissue for HPV-related squamous cell carcinoma. (Strong recommendation; EB-B-I)
- 2.6: Intraoperative frozen section of biopsies of suspicious primary sites may be performed to confirm the presence of tumor prior to resection. Intraoperative frozen section evaluation of palatine or lingual tonsillectomy specimens should be performed when the primary tumor remains clinically undetected. The tissue should be entirely submitted for frozen section examination. Resection specimens should be anatomically oriented by the surgeon, and margin evaluation should be performed intraoperatively. (Strong recommendation; EB-B-I)
