What are the next steps for a patient with a cervical lesion (C7) and negative CK20 (cytokeratin 20) and p16 results?

Cervical Lesion with CK20 and p16 Negative: Diagnostic Approach

A cervical lesion that is both CK20-negative and p16-negative is highly unlikely to represent HPV-related cervical dysplasia or neuroendocrine carcinoma, and requires comprehensive immunohistochemical workup to establish the correct diagnosis and guide appropriate site-specific treatment.

Understanding the Immunohistochemical Profile

p16 Negativity in Cervical Context

• p16 is positive in 84-100% of HPV-related high-grade cervical lesions (HSIL/CIN2-3), making p16 negativity highly atypical for HPV-driven cervical dysplasia 1
• p16-negative HSIL/CIN2 lesions show 100% regression rates within 12 months, suggesting these may represent immature metaplasia rather than true dysplasia 1
• p16 negativity in a cervical lesion should prompt consideration of non-HPV etiologies including metastatic disease, primary non-HPV cervical carcinoma, or benign mimics 2

CK20 Negativity Excludes Specific Entities

• CK20 is typically negative in usual-type cervical adenocarcinomas (86% are CK20-negative), supporting a primary cervical origin if other features are consistent 3
• CK20 negativity effectively rules out Merkel cell carcinoma, which shows CK20 positivity in 97% of cases with a characteristic punctate pattern 4, 5
• CK20 negativity also argues against intestinal-type endocervical adenocarcinoma, where 84% show CK20 positivity 3
• Cervical neuroendocrine carcinomas may show CK20 positivity in 19% of cases, so negativity does not exclude this diagnosis 6

Recommended Diagnostic Algorithm

Immediate Next Steps

Perform expanded immunohistochemical panel including:

• CK7: Should be positive in primary cervical adenocarcinomas (100% positive) but also positive in 22% of colorectal metastases 3
• TTF-1: Positive in 71% of cervical neuroendocrine carcinomas; if positive, strongly consider neuroendocrine differentiation despite p16 negativity 6
• Chromogranin, synaptophysin, CD56: Essential for evaluating neuroendocrine differentiation, as cervical neuroendocrine carcinomas may be p16-negative in rare cases 6
• p63: Positive in 43% of cervical neuroendocrine carcinomas and helps distinguish squamous from glandular differentiation 6
• CK17: Positive in immature metaplasia; combined CK17+/p16- pattern confirms benign metaplasia rather than dysplasia 2

Differential Diagnosis Based on Immunoprofile

If CK7+/CK20-/p16-:

• Consider usual-type cervical adenocarcinoma (non-HPV associated)
• Consider endometrioid adenocarcinoma of cervix (50% are CDX-2 positive) 3
• Evaluate for metastatic breast or ovarian carcinoma if clinical context suggests 5

If neuroendocrine markers positive despite p16-:

• Diagnose as cervical neuroendocrine carcinoma (small cell or large cell type), as 29% may be p16-negative 6
• Note that TTF-1 positivity (71% of cases) does not exclude cervical origin and cannot distinguish from pulmonary primary 6
• Perform HPV-specific testing (PCR or ISH) as some cervical neuroendocrine carcinomas are HPV-negative 6

If CK17+/p16-:

• Reclassify as immature squamous metaplasia rather than dysplasia, which requires no treatment beyond routine screening 2
• This pattern has 100% specificity for benign metaplasia versus CIN III 2

Clinical Management Pathway

For metastatic squamous cell carcinoma in cervical lymph node (C7 region):

• Perform HPV-specific testing (not just p16) on all cervical lymph node metastases to identify occult oropharyngeal primary 5
• p16 alone is insufficient for unknown primary workup; additional HPV testing is mandatory for tumors outside levels II-III or with keratinizing morphology 5
• If HPV-negative, pursue comprehensive head and neck examination including nasopharyngoscopy and imaging (PET-CT) to identify primary site 5
• Consider non-oropharyngeal primaries including skin (especially if CK20+), salivary gland, or lung 5

For primary cervical lesion:

• If immunohistochemistry confirms benign metaplasia (CK17+/p16-), return to routine screening per USPSTF guidelines 5
• If malignancy confirmed but HPV-unrelated, treat according to histologic subtype with surgery and/or radiation 5
• For neuroendocrine carcinomas, treat with excisional therapy for early-stage or chemotherapy for advanced disease 5

Critical Pitfalls to Avoid

• Do not assume p16 negativity excludes all cervical neoplasia—29% of cervical neuroendocrine carcinomas are p16-negative 6
• Do not rely on TTF-1 to exclude cervical origin—71% of cervical neuroendocrine carcinomas are TTF-1 positive, identical to pulmonary primaries 6
• Do not use p16 alone for unknown primary workup in cervical lymph nodes—ASCO guidelines mandate HPV-specific testing for confirmation 5
• Do not overlook CK17 staining—this is the key marker to distinguish benign metaplasia from dysplasia when p16 is negative 2
• Ensure adequate tissue sampling and proper antigen retrieval techniques, as technical factors can cause false-negative results 4