What is the preferred initial diagnostic approach, core biopsy or excisional biopsy, for a patient with recurrent or metastatic head and neck cancer and a neck node of unknown primary origin?

Neck Node Biopsy Approach in Head and Neck Cancer of Unknown Primary

For a patient with a neck node suspicious for metastatic head and neck cancer of unknown primary, core needle biopsy (preferably ultrasound-guided) should be the initial diagnostic approach, reserving excisional biopsy only for cases where core biopsy yields non-diagnostic results. 1

Initial Tissue Diagnosis Strategy

Core Needle Biopsy as First-Line

• Fine needle aspiration (FNA) is the traditional first-line biopsy method for neck masses, but core needle biopsy offers superior diagnostic yield, particularly for cystic or necrotic lymph nodes. 1

• Core needle biopsy, especially when combined with ultrasound guidance, increases diagnostic yield by sampling more solid components of metastatic lymph nodes, which is critical when nodes are cystic or highly necrotic. 1

• A subset of FNA biopsies will result in non-diagnostic yield, particularly in cystic or highly necrotic lymph nodes, making core biopsy a more reliable initial choice. 1

When to Proceed to Excisional Biopsy

• Excisional biopsy should be reserved as a secondary option only after core needle biopsy (or repeat image-guided core biopsy) has failed to provide adequate tissue for diagnosis. 2

• If the first core biopsy is non-diagnostic or shows atypical cells, repeat the biopsy with image guidance before proceeding to excisional biopsy. 2

Critical Pathological Testing Requirements

Essential Biomarker Assessment

Once tissue is obtained, specific testing must be performed to guide treatment:

• p16 immunohistochemistry must be performed on all squamous cell carcinoma specimens from neck nodes of unknown primary to identify HPV-positive oropharyngeal primaries. 1, 3

• Strong and diffuse nuclear and cytoplasmic p16 staining in at least 70% of tumor cells indicates HPV-positive oropharyngeal cancer. 1

• If p16 is positive in neck metastases of unknown origin, confirm with additional HPV-specific testing (DNA, RNA, or in situ hybridization) to definitively establish HPV status. 1, 3

• EBV status must be determined using EBER in situ hybridization to exclude nasopharyngeal cancer as the primary site. 1, 3

Rationale for Avoiding Excisional Biopsy as Initial Approach

Preservation of Surgical Options

• Excisional biopsy disrupts tissue planes and lymphatic drainage patterns, potentially complicating subsequent definitive neck dissection. 3

• Core needle biopsy provides adequate tissue for both histological diagnosis and comprehensive biomarker testing (p16, HPV-specific tests, EBV) without compromising future surgical management. 1

Diagnostic Adequacy

• Modern core needle biopsy techniques provide sufficient tissue architecture for accurate diagnosis and molecular testing, eliminating the historical justification for excisional biopsy. 1

Clinical Algorithm

1. Initial biopsy: Ultrasound-guided core needle biopsy of the neck node 1

2. If non-diagnostic: Repeat ultrasound-guided core needle biopsy targeting solid components 1, 2

3. If still non-diagnostic: Consider excisional biopsy 2

4. Mandatory testing on diagnostic specimen:

   • p16 immunohistochemistry 1, 3
   • If p16 positive: HPV-specific confirmatory testing 1, 3
   • EBER in situ hybridization for EBV 1, 3

Common Pitfalls to Avoid

• Do not proceed directly to excisional biopsy without attempting core needle biopsy first, as this unnecessarily disrupts surgical planes. 1, 2

• Do not rely on FNA alone in cystic or necrotic nodes, as diagnostic yield is significantly lower than core biopsy. 1

• Do not accept p16 positivity alone as definitive for HPV status in unknown primary cases—confirmatory HPV-specific testing is required. 1, 3

• Do not forget EBV testing, as nasopharyngeal primaries present differently and require distinct treatment approaches. 1, 3