Use of p16/Ki67 Dual Stain for Management of Individuals Testing Positive for Human Papillomavirus

Publication Date: March 6, 2024
Last Updated: March 8, 2024

Summary of Recommendations

Key Points

  1. These recommendations only apply to FDA-approved DS cytology assays. Currently, CINtec PLUS Cytology (Roche Diagnostics) is the only DS test with FDA approval. The performance of other, non–FDA-approved p16/Ki67 assays may not be similar, and the generalizability of these recommendations cannot be assumed.
  2. These recommendations apply only to results obtained in asymptomatic women; symptomatic women should undergo testing according to relevant protocols.
  3. Because of limited data availability for multiple rounds of testing or for specific clinical scenarios, estimates for downstream risks of CIN3+ are either not available or are insufficient to allow for the development of risk-based recommendations for all possible scenarios related to DS testing. For example, this includes a scenario of postcolposcopy management when the squamocolumnar junction was not fully visualized and no histologic CIN2+ was found on colposcopic biopsy/endocervical curettage. In these situations where recommendations are not available, clinical judgment and shared decision-making should consider the 2019 Guidelines1 and 2017 Colposcopy Standards, where applicable, and may also consider the increased risk that follows from DS-positive test results and the decreased risk that follows from DS-negative test results. Additional recommendations may be generated as more data become available allowing robust risk estimation.
DS is acceptable for triage of individuals testing HPV-positive when limited genotyping is not available. If using DS to triage HPV-positive test results without genotyping, colposcopy is recommended for individuals testing HPV-positive and DS-positive, and 1-year return is recommended for individuals testing HPV-positive and DS-negative. (A, II)
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A combination of DS and limited genotyping (provided by the screening HPV test) is acceptable for triage of individuals testing HPV-positive. If using DS to triage HPV-positive test results with limited genotyping, colposcopy is recommended for individuals testing positive for HPV16 or HPV18. For individuals testing positive for the pool of HR12, colposcopy is recommended when DS is positive and 1-year return is recommended when DS is negative. (A, II)
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In a cotesting setting, DS is acceptable for triage of individuals with HPV-positive test results and negative for intraepithelial lesion or malignancy (NILM), atypical squamous cell of undetermined significance (ASC-US), or low-grade squamous intraepithelial lesion (LSIL) cytology. If using DS to triage HPV-positive cotesting results without genotyping, colposcopy is recommended for individuals testing HPV-positive with NILM, ASC-US, or LSIL cytology, and positive for DS, and a 1-year return is recommended for individuals testing HPV-positive with NILM, ASC-US, or LSIL cytology, and negative for DS. (A, II)
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If using DS to triage HPV-positive cotesting results of NILM, ASC-US or LSIL with limited genotyping, colposcopy is recommended for individuals testing positive for HPV16 or HPV18. For individuals testing positive for the pool of HR12 with NILM, ASC-US, or LSIL cytology, colposcopy is recommended when DS is positive and 1-year return is recommended when DS is negative. (A, II)
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Use of DS in individuals with cytology results of atypical squamous cells, cannot rule out high-grade (ASC-H), atypical squamous cells, cannot rule out high-grade (AGC), or high-grade squamous intraepithelial lesion (HSIL) is not recommended, and if obtained, should not guide management. (D, III)
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When patients are being followed after (a) abnormal screening test results that did not require colposcopy, (b) colposcopy, or (c) treatment, it is acceptable to use DS according to the guidelines for management of an initial abnormal screening test result. (B, II)
For example, when using HPV-based testing (primary HPV or cotesting) colposcopy is recommended after an HPV-positive/DS-positive result, and 1-year follow-up is recommended after an HPV-positive, DS-negative result, except in the case of HPV16-positive, HPV18-positive, AGC, ASC-H, or HSIL, for which management according to the 2019 Guidelines is recommended (colposcopy or expedited treatment).
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For patients with 3 or more consecutive HPV-positive, DS-negative results, follow-up in 1 year or colposcopy is acceptable. (C, III)
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When a DS result is unsatisfactory due to sampling issues, repeating the sample as soon as convenient and no later than 4 months is acceptable (C-III). If other satisfactory results are available at the time of DS testing that can be used for management according to risk (e.g., HPV16- or HPV18-positive or cytology results), management based on those results is also acceptable. (C, III)
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Recommendation Grading

Disclaimer

The information in this patient summary should not be used as a substitute for professional medical care or advice. Contact a health care provider if you have questions about your health.

Overview

Title

Use of p16/Ki67 Dual Stain for Management of Individuals Testing Positive for Human Papillomavirus

Authoring Organization

Publication Month/Year

March 6, 2024

Last Updated Month/Year

March 13, 2024

Document Type

Guideline

Country of Publication

US

Document Objectives

The Enduring Consensus Cervical Cancer Screening and Management Guidelines Committee developed recommendations for dual stain (DS) testing with CINtec PLUS Cytology for use of DS to triage high-risk human papillomavirus (HPV)-positive results.

Inclusion Criteria

Male, Female, Adolescent, Adult, Older adult

Health Care Settings

Ambulatory, Laboratory services

Intended Users

Nurse, nurse practitioner, physician, physician assistant

Scope

Diagnosis, Assessment and screening, Management

Diseases/Conditions (MeSH)

D061809 - Human Papillomavirus DNA Tests, D000094302 - Human Papillomavirus Viruses

Keywords

human papillomavirus (HPV), HPV, Dual Stain, p16/Ki67

Source Citation

Clarke MA, Wentzensen N, Perkins RB, Garcia F, Arrindell D, Chelmow D, Cheung LC, Darragh TM, Egemen D, Guido R, Huh W, Locke A, Lorey TS, Nayar R, Risley C, Saslow D, Smith RA, Unger ER, Massad LS; Enduring Consensus Cervical Cancer Screening and Management Guidelines Committee. Recommendations for Use of p16/Ki67 Dual Stain for Management of Individuals Testing Positive for Human Papillomavirus. J Low Genit Tract Dis. 2024 Mar 6. doi: 10.1097/LGT.0000000000000802. Epub ahead of print. PMID: 38446575.

Supplemental Methodology Resources

Data Supplement