Diagnosis and Management of Squamous Cell Carcinoma of Unknown Primary in the Head and Neck

Publication Date: April 23, 2020
Last Updated: March 14, 2022


Recommendations 

Preoperative Evaluation 

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. ( IC , B , L , M )
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Fine-Needle aspiration or core biopsy of a clinically suspicious neck mass should be performed. ( EB , B , I , S )
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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. ( EB , B , I , M )

Note: HR-HPV testing may be done non-routinely for squamous cell carcinoma metastases at other nodal levels when clinical suspicion is high.

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Contrast enhanced computed tomography (CECT) of the neck should be the initial test for work-up of metastatic cervical lymphadenopathy. ( EB , B , I , S )
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If a primary is not evident on clinical examination and CECT, positron emission tomography (PET)-CT should be the next diagnostic step. ( EB , B , I , S )
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Diagnostic And Therapeutic Surgical Procedures 

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. ( EB , B , I , S )
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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. ( EB , B , I , M )
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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. ( EB , B , I , M )
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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. ( EB , B , I , S )
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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. ( EB , B , I , S )
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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. ( EB , B , I , S )
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Surgical Considerations 

For unilateral, small-volume neck disease, either definitive surgery or radiation therapy may be offered after multidisciplinary discussion. ( EB , B , I , M )
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For small-volume bilateral neck disease with no clinical evidence of extranodal extension, either definitive surgery (with or without adjuvant therapy) or radiation therapy (with or without concurrent chemotherapy) may be offered after multidisciplinary discussion. ( EB , B , I , M )
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Large-volume bilateral neck disease, and/or gross (macroscopic) extranodal extension (ENE) favor definitive chemoradiation therapy given the possible increased morbidity of extensive bilateral neck dissection and increased likelihood of trimodality therapy in such cases. ( EB , B , I , M )
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When primary surgery is planned, Levels IIA, III and IV should be routinely dissected in cases where an oropharyngeal primary is suspected or confirmed for SCCUP. Additional nodal basins should be considered for dissection depending on the extent of nodal burden. ( EB , B , I , S )
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Radiotherapy 

Patients receiving radiotherapy or concurrent chemoradiotherapy as primary management of CUP should receive treatment to gross nodal disease, neck regions at-risk of containing microscopic disease and the anatomic mucosal regions at-risk of harboring the occult primary. Specific volumes treated will depend on the clinicopathologic presentation of the patient after complete work-up. ( EB , B , I , S )
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Patients treated with primary radiotherapy for unilateral (American Joint Committee on Cancer [AJCC] 8th N1) HPV-related adenopathy and CUP should receive treatment to the gross node(s) and with consideration of coverage of putative primary sites in the ipsilateral tonsillar bed, ipsilateral soft palate, and the mucosa of the entire base of tongue, which may be modified based on prior surgical diagnostics at the discretion of the radiation oncologist. ( EB , B , I , M )
Note: Consideration may be given to including additional areas in the oropharynx in patients for whom a PET scan was not available or who did not undergo a contralateral tonsillectomy because of the low risk of an occult contralateral tonsillar primary. Patients presenting with bilateral (AJCC 8th N2) adenopathy and CUP require bilateral treatment of the oropharyngeal mucosa.
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Patients treated with primary radiotherapy for unilateral (AJCC 8th N1-N2b) HPV-negative nodal disease and SCCUP should receive treatment as above. Patients presenting with bilateral (AJCC 8th N2c) adenopathy and SCCUP should receive bilateral treatment of the oropharyngeal mucosa. (EB, B, I, M)
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In patients with a clinicopathologic presentation highly suggestive of an occult nasopharyngeal primary, the mucosal radiation treatment may be limited to the nasopharynx. Nodal volumes in this scenario should be typical for nasopharyngeal management and include bilateral levels II-V including retropharyngeal nodes. ( EB , B , I , M )
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Patients treated with primary radiotherapy for unilateral involvement of multiple nodes and no clinical and radiologic evidence of ENE should routinely receive bilateral treatment. ( EB , B , I , S )
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In addition to anatomic mucosal regions at risk, patients treated with primary radiotherapy for unilateral involvement of a single node and no clinical and radiologic evidence of ENE may consider treatment only to the unilateral involved neck (with the exception of those at risk of a nasopharyngeal primary. ( EB , B , I , M )
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Patients treated with primary radiotherapy for N3 and/or bilateral nodal involvement and/or clinical and/or radiologic evidence of ENE require bilateral neck treatment. ( EB , B , I , S )
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For patients treated with primary radiotherapy, a biologically equivalent dose of 70 Gy over 7 weeks should be delivered to gross nodal disease. The biologically equivalent dose of approximately 50 Gy in 2 Gy fractions or slightly higher should be delivered to mucosal regions at risk of harboring the occult primary site, and a biologically equivalent dose of 40-50 Gy in 2 Gy fractions electively to clinically and radiographically negative nodal regions at risk for microscopic spread of tumor. ( EB , B , I , M )
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Patients receiving radiotherapy or concurrent chemoradiotherapy adjuvant to surgical management of carcinoma of unknown primary (CUP) should receive treatment to regions of the neck and mucosa at-risk of containing microscopic disease. The need for treatment should be determined by the extent of the surgery performed and pathologic results of the surgery. ( EB , B , I , S )
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Patients for whom no primary site is pathologically identified at the time of surgery may benefit from treatment to the anatomic mucosal regions at-risk of harboring the occult primary site. Nodal volumes requiring treatment are similar to those covered above. ( EB , B , I , S )
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Adjuvant radiotherapy should not be administered to patients with a single pathologically positive node without ENE after high-quality neck dissection (definition in ASCO’s management of the neck practice guideline) and in whom after a thorough evaluation no primary tumor is identified. ( EB , B , I , S )
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Adjuvant radiotherapy should be administered to patients with multiple pathologically involved nodes and/or pathologic evidence of ENE. ( EB , B , I , S )
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Adjuvant radiation dose to the dissected regions of neck should be the equivalent of 60 Gy to the node levels that harbored gross resected disease and 50 Gy to regions beyond this thought to be at risk of microscopic residual disease. Nodal regions from which nodes were determined to have pathologic ENE may be considered for higher doses of adjuvant radiation, the equivalent of 60-66 Gy. ( EB , B , I , M )
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Concurrent administration of cisplatin with definitive radiation therapy should be offered to patients without contraindications to cisplatin chemotherapy and with an EBV encoded early RNA (EBER) positive Stage II-IVA (AJCC 8th N2-N3) carcinoma of unknown primary. ( EB , B , H , S )
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Systemic Therapy 

Concurrent administration of cisplatin with definitive radiation therapy should be offered to patients without contraindications to cisplatin chemotherapy and with a suspected mucosal primary HPV/p16-negative squamous cell carcinoma in the presence of unresected AJCC 8th N2-N3 nodal disease. ( EB , B , H , S )
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Concurrent administration of cisplatin with definitive radiation therapy should be offered to patients without contraindications to cisplatin chemotherapy and with a suspected mucosal primary HPV/p16-positive squamous cell carcinoma in the presence of unresected multiple ipsilateral, or bilateral lymph node involvement, or lymph nodes >3 cm in size. ( EB , B , H , S )
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Concurrent administration of cisplatin to adjuvant radiation should be offered to patients without contraindications to cisplatin chemotherapy and with a suspected mucosal primary squamous cell carcinoma and pathologic evidence of ENE. ( EB , B , H , S )
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Recommendation Grading

Overview

Title

Diagnosis and Management of Squamous Cell Carcinoma of Unknown Primary in the Head and Neck

Authoring Organization

American Society of Clinical Oncology

Publication Month/Year

April 23, 2020

Last Updated Month/Year

October 1, 2024

Document Type

Guideline

External Publication Status

Published

Country of Publication

US

Document Objectives

To provide evidence-based recommendations to practicing physicians and other health care providers on the diagnosis and management of squamous cell carcinoma of unknown primary in the head and neck (SCCUP).

Target Patient Population

Patients with SCCUP in the head and neck.

Target Provider Population

Medical oncologists, radiation oncologists, surgeons, radiologists, pathologists, nurses, speech pathologists, oncology pharmacists, and patients.

PICO Questions

  1. What is the appropriate preoperative evaluation for patients with a neck mass suspicious for malignancy?

  2. What are the appropriate surgical diagnostic and therapeutic procedures for squamous cell carcinoma of unknown primary (SCCUP)?

  3. What are the treatment considerations and appropriate techniques for surgical management of the neck?

  4. What are treatment considerations for radiotherapy and systemic therapy in SCCUP?

Inclusion Criteria

Male, Female, Adult, Older adult

Health Care Settings

Ambulatory, Hospital, Outpatient, Radiology services

Intended Users

Nurse, nurse practitioner, health systems pharmacist, physician, physician assistant, social worker, speech language pathologist

Scope

Diagnosis, Assessment and screening, Treatment, Management

Diseases/Conditions (MeSH)

D000077195 - Squamous Cell Carcinoma of Head and Neck

Keywords

head and neck squamous cell carcinoma (HNSCC), squamous cell carcinoma, positron emission tomography (PET), HNSCC, Cytology, cervical lymp nodes, oropharyngeal site, upper aerodigestive tract evalution, SCCUP

Supplemental Methodology Resources

Data Supplement

Methodology

Number of Source Documents
124
Literature Search Start Date
January 1, 1990
Literature Search End Date
December 31, 2017
Description of External Review Process
ASCO has a rigorous review process for guidelines. After the draft has been approved by the Expert Panel, the guideline is independently reviewed and approved by the Clinical Practice Guideline Oversight Committee (CPGC). Select members of the CPGC are asked to critically review the guideline prior to the next scheduled CPGC meeting. The CPGC members then present the results of their reviews to the full committee, discuss the review with the full committee, and the CPGC votes on whether to approve the guideline (with recusals from members who have relationships with affected companies). Approved ASCO Guidelines are then submitted to the Society’s journal for consideration of publication.
Description of Public Comment Process
ASCO Guidelines are available for open comment for a 2 to 3‐week period. Guideline recommendations available for open comment are posted on asco.org/open‐comment‐guidelines. Prospective reviewers must contact ASCO to request to review the draft guideline recommendations and are required to sign a non‐disclosure and confidentiality agreement before receiving the draft guideline recommendations. Reviewers must identify themselves by name and affiliation; anonymous comments will not be accepted. Guidelines staff review and summarize comments and bring relevant comments to the Expert Panel Co‐ chairs, and to the entire panel if necessary. Any changes made from the open comment process will be reviewed by the entire panel prior to CPGC approval. Comments are advisory only and ASCO is not bound to make any changes based on feedback from open comment. ASCO does not respond to reviewers or post responses to comments; however, major edits to the draft will be reflected in the open comment discussion.
Specialties Involved
Dermatology, Oncology, Otolaryngology, Pathology, Radiology, Surgery General, Dermatopathology, Medical Oncology, Surgical Oncology, Radiation Oncology, Pathology, Oncology, Oncology, Radiology
Description of Systematic Review
The Protocol specifies the purpose of the guideline product, target patient population, clinical outcomes of interest, key features of the systematic literature review, and a proposed timeline for completion. ASCO staff, the Expert Panel Co‐Chairs, and possibly other panel members selected by the Co‐Chairs (the Expert Panel Steering Committee), will typically draft the protocol for full panel review. A standard protocol worksheet is used for consistency. Once the Co‐Chairs have approved a first draft of the Protocol, the Protocol will be shared with the full Expert Panel. At the discretion of the Guidelines Director, the CPGC leadership and/or the CPGC Methodology Subcommittee may review the Protocol to make suggestions for revision intended to clarify aspects of the plan for developing the guideline. These suggestions are sent to the Expert Panel Co‐Chairs. Work on the systematic literature review can proceed upon the sign‐off of the Protocol by the Expert Panel.
List of Questions
Refer to full text
Description of Study Criteria
Refer to Supplement
Description of Search Strategy
Upon approval of the Protocol, a systematic review of the medical literature is conducted. ASCO staff use the information entered into the Protocol, including the clinical questions, inclusion/exclusion criteria for qualified studies, search terms/phrases, and range of study dates, to perform the systematic review. Literature searches of selected databases, including The Cochrane Library and Medline (via PubMed) are performed. Working with the Expert Panel, ASCO staff complete screening of the abstracts and full text articles to determine eligibility for inclusion in the systematic review of the evidence. Unpublished data from meeting abstracts are not generally used as part of normal ASCO guideline development (“Meeting Data”). However, abstract data from reputable scientific meetings and congresses may be included on a case‐by‐case basis after review by the CPGC leadership. Expert Panels should present a rationale to support integration of abstract data into a guideline. The CPGC leadership will consider the following inclusion criteria for the unpublished scientific meeting data: 1) whether the data were independently peer reviewed in connection with a reputable scientific meeting or congress; 2) the potential clinical impact of the unpublished data; 3) the methodological quality and validity of the associated study; 3) the potential harms of not including the data; and 4) the availability of other published data to inform the guideline recommendations.
Description of Study Selection
Literature search results were reviewed and deemed appropriate for full text review by two ASCO staff reviewers in consultation with the Expert Panel Co-Chairs. Data were extracted by two staff reviewers and subsequently checked for accuracy through an audit of the data by another ASCO staff member. Disagreements were resolved through discussion and consultation with the Co-Chairs if necessary. Evidence tables are provided in the manuscript and/or in Data Supplements 1.
Description of Evidence Analysis Methods
ASCO guideline recommendations are crafted, in part, using the GuideLines Into DEcision Support (GLIDES) methodology. ASCO adopted a five‐step approach to carry out quality appraisal, strength of evidence ratings and strength of recommendations ratings. The ASCO approach was primarily adapted from those developed by the AHRQ,, USPSTF, and GRADE, however with the validation of the GRADE methodology, the sole use of GRADE is being evaluated by the Clinical Practice Guidelines Committee.
Description of Evidence Grading
High: High confidence that the available evidence reflects the true magnitude and direction of the net effect (i.e., balance of benefits v harms) and that further research is very unlikely to change either the magnitude or direction of this net effect. Intermediate: Moderate confidence that the available evidence reflects the true magnitude and direction of the net effect. Further research is unlikely to alter the direction of the net effect; however, it might alter the magnitude of the net effect. Low: Low confidence that the available evidence reflects the true magnitude and direction of the net effect. Further research may change either the magnitude and/or direction this net effect. Insufficient: Evidence is insufficient to discern the true magnitude and direction of the net effect. Further research may better inform the topic. The use of the consensus opinion of experts is reasonable to inform outcomes related to the topic.
Description of Recommendation Grading
ASCO uses a formal consensus methodology based on the modified Delphi technique in clinically important areas where there is limited evidence or a lack of high‐quality evidence to inform clinical guidance recommendations. Evidence Based: There was sufficient evidence from published studies to inform a recommendation to guide clinical practice. Formal Consensus: The available evidence was deemed insufficient to inform a recommendation to guide clinical practice. Therefore, the Expert Panel used a formal consensus process to reach this recommendation, which is considered the best current guidance for practice. The Panel may choose to provide a rating for the strength of the recommendation (i.e., "strong," "moderate," or "weak"). The results of the formal consensus process are summarized in the guideline and reported in the Data Supplement (see the Supporting Documents" field). Informal Consensus: The available evidence was deemed insufficient to inform a recommendation to guide clinical practice. The recommendation is considered the best current guidance for practice, based on informal consensus of the Expert Panel. The Panel agreed that a formal consensus process was not necessary for reasons described in the literature review and discussion. The Panel may choose to provide a rating for the strength of the recommendation (i.e., "strong," "moderate," or "weak"). No recommendation: There is insufficient evidence, confidence, or agreement to provide a recommendation to guide clinical practice at this time. The Panel deemed the available evidence as insufficient and concluded it was unlikely that a formal consensus process would achieve the level of agreement needed for a recommendation.
Description of Funding Source
ASCO provides funding for Guideline Development.
Company/Author Disclosures
ASCO Conflict of Interest Policy complies with the CMSS Code for Interactions with Companies. ASCO requires disclosure by individuals involved in drafting, reviewing, and approving guideline recommendations.
Percentage of Authors Reporting COI
100