Review the latest recommendations with

Emma L. Grabinski, MD, FACOG

Dr Grabinski, a generalist OBGYN, is System Chief of OBGYN & Perinatology at Swedish Medical Center, and a clinical adjunct Professor at UW in Seattle WA

Dr. Grabinski would love to hear from her colleagues – check out the comments box at the end of this entry

Learning Objectives: Upon completion of this activity, participants should be better able to

• Apply current evidence regarding cytology and HPV detection when counseling patients about cervical cancer screening options
• Discuss the natural history of HPV infection and the impact of the virus in determining the risk of cervical dysplasia
• Describe the current screening recommendations for immunocompetent people

CONTENTS:

• Case
• Synopsis
• Professional Guidelines and Key Points for Shared Decision Making
• The Wrap-Up
• References

THE CASE:

• 36-year-old G1P1
• Presents for preventive exam | Otherwise well

Gyn History

• No significant gyn issues in past 10 years
• Pap smears (cervical cytology) every 3 years since age 21
• Monogamous | Received full HPV quadrivalent vaccine dose
• Previous cervical cancer screening results (3 yrs prior)
  • Negative for intraepithelial lesion or malignancy (NILM) | Negative for high risk HPV (hrHPV)
• Patient has read there are new guidelines for screening and would like to discuss options, including continued co-testing, cytology alone, or HPV testing alone

SYNOPSIS:

Cervical Cancer Overview  

• Cervix cancer is more common than vulva, vaginal, or penile cancer as HPV infects the transformation zone of the cervix, which is immature, metaplastic and hormonally responsive (McMurray et al. Int J Exp Pathol, 2001)
  • HPV’s ability to infect immature tissue is thought to contribute to the higher likelihood of premalignant, and malignant transformation
  • In contrast, the remainder of the genital tract is mature epithelium
• HPV Infectivity
  • Most people will be become infected with HPV soon after first intercourse
  • Most of these infections will clear
    • 67% clear within first 12 months (Rodríguez et al. J Natl Cancer Inst, 2008)
  • Long duration of infectivity predicts the risk of progression to pre-malignant and malignant transformation (Schiffman and Castle. NEJM 2005)
    • Takes time for mutations to accumulate and for the cells to become immortal
  • Mean age of diagnosis of cervical cancer (Wheeler et al. J Natl Cancer Inst, 2009)
    • HPV 16: 48.1 years
    • HPV 18: 45.9 years
    • Other high-risk HPV types: 52.3 years

Professional Guidelines Options and Shared Decision Making for Women (30 to 65 years)

ACOG, ASCCP and SGO have endorsed the USPSTF cervical cancer screening recommendations

Co-testing (cervical cytology and hrHPV testing) every 5 years

• Pros
  • Co-testing with cytology and hrHPV testing is more sensitive than cytology alone
  • Identifies people at higher risk of developing precancerous lesions
  • In women >30 years, liquid-based cytology/HPV cotesting improved screening for cervical cancer vs liquid-based cytology or HPV components alone (Kaufman et al. AJCP, 2020)
  • Although not designed for this purpose, abnormal glandular lesions may be detected, possibly representing endometrial pathology
  • Determines those who need shorter screening intervals
• Cons
  • More costly than hrHPV testing alone or cytology alone
  • Patient anxiety with prolonged screening intervals

Screening with cervical cytology alone every 3 years

• Pros
  • High specificity when abnormal (Kudva. AJCP, 2015)
  • Avoids detecting transient hrHPV infection
  • May reduce psychological harm associated with being labelled as having an STI
• Cons
  • Fewer cases of precancerous lesions detected
    • Cytology is less sensitive than HPV testing with regards to detecting precancerous lesions (Perkins et al. J Low Genit Tract Dis, 2020)
  • Cytology has a false negative rate of 10-20% | False positive rate of 10-20% (Kudva. AJCP, 2015)
  • Adenocarcinoma is not well identified on cytology

HrHPV testing alone as an alternative screening strategy (re-screen not more frequently than every 3 years)

• Pros
  • Fewer unnecessary diagnostic tests – as hrHPV testing has
    • Higher sensitivity than cytology alone, especially in vaccinated populations
• Cons
  • HPV testing has a false negative rate of up to 5%
    • An insufficient pap can clue the provider that the HPV result may be falsely negative
  • Has a lower specificity than co-testing (Kudva. AJCP, 2015)
    • HPV infection common
    • However, persistence less common
    • HPV alone may result in more diagnostic testing for lesions that would have regressed (Kaufman et al. AJCP, 2020)
  • Requires use of an FDA approved hrHPV testing platform
    • This is not available in all settings and requires the clinician to know what platform the lab uses
    • If not an appropriate platform, can result in inadequate screening for the patient
  • Management of positive hrHPV recommendations require reflex cytology on the same sample
    • Delay in obtaining results may increase anxiety for patient

American Cancer Society (ACS) 

Recommended for women 25 to 65 years of age

• HPV testing every 5 years
  • Aside from risks related to higher false negative rates based ‘HPV only’ strategy (see above), there are also other concerns regarding the ACS strategy of HPV only spaced 5 years apart
• Management and follow-up: ACS recommendations differ in that there is no reflex cytology if abnormal hrHPV
  • However, current recommended management is based on ASCCP risk-based guidelines
  • ASCCP guidelines assume cytology has been performed for optimal risk assessment and stratification

Other Issues With ACS Recommendations

• Race, ethnicity and socioeconomic factors (Curry et al. JAMA, 2018)
  • African American population: Receive screening at the same rate as white populations but 2x the rate of death from cervical cancer | Likely due to discrepancies in follow up and diagnosis
  • Native/Indigenous populations, Hispanic populations, and Asian populations: Have lower screening rates than white populations
  • White populations in poorer, rural areas are also disproportionally affected by cervical cancer
• Appropriate patient profile for ACS requires the following
  • Patient is average risk given history of normal screening
  • NO risk factors for immunocompromise
  • Has demonstrated compliance with screening and follow up
• HPV vaccination rates in the USA are not high enough currently to factor vaccination into screening guidelines

The ACOG Practice Advisory

• The ACOG Practice Advisory Update recommends individualizing care, providing counseling, and allowing patients to choose the option that best suits them

The specific strategy selected is less important than consistent adherence to routine screening guidelines. Inadequate cervical cancer screening remains a significant problem in the United States, with persistent health inequities across the entire spectrum of cervical cancer care

The Wrap-Up

Patients Are Individuals and Deserve Individualized Care

• Screening for asymptomatic individuals currently include the following options
  • Cytology with co-testing | Cytology alone | HPV with or without reflex cytology
• HPV 16/18 have the highest risk for development of CIN 3+ – do genotyping whenever possible!
• Cytology is not effective at detecting adenocarcinoma
  • The most effective way of preventing cervical adenocarcinoma is with HPV vaccination
• Cytology is important for individualizing the follow-up interval (see ASCCP risk-based guidelines in ‘References’ below)
  • Patient should be aware that even in the setting of HPV only strategy, an HPV positive report will default to ASCCP recommended follow up, which includes cytology
• New recommendations that favor HPV testing alone do not account for
  • US HPV vaccination rates
  • Lack of universal health care
  • Race and ethnicity related differences in cancer rates and access to care
• Educate your patients that
  • A preventive visit does NOT equal a pap smear
  • Not needing a pap smear does NOT mean you don’t need a preventive visit

REFERENCES:

Biology of human papillomaviruses (McMurray et al. Int J Exp Pathol, 2001)

Rapid clearance of human papillomavirus and implications for clinical focus on persistent infections (Rodríguez et al. J Natl Cancer Inst, 2008)

The Promise of Global Cervical-Cancer Prevention (Schiffman and Castle. NEJM 2005)

Human papillomavirus genotype distributions: implications for vaccination and cancer screening in the United States (Wheeler et al. J Natl Cancer Inst, 2009)

ACOG Practice Advisory: Updated Cervical Cancer Screening Guidelines

Screening for Cervical Cancer: US Preventive Services Task Force Recommendation Statement (Curry et al. JAMA, 2018)

The accuracy of Papanicolaou smear predictions: cytohistological correlation of 283 cases (Kudva. AJCP, 2015)

2019 ASCCP Risk-Based Management Consensus Guidelines for Abnormal Cervical Cancer Screening Tests and Cancer Precursors (Perkins et al. J Low Genit Tract Dis, 2020)

Contributions of Liquid-Based (Papanicolaou) Cytology and Human Papillomavirus Testing in Cotesting for Detection of Cervical Cancer and Precancer in the United States (Kaufman et al. AJCP, 2020)

Cervical cancer screening for individuals at average risk: 2020 guideline update from the American Cancer Society

Commercial Support

This educational activity is supported by Hologic

Faculty Disclosures

Dr. Grabinski reports that she has no relevant financial relationships to disclose

Related Curbside Consult Topics

The Evidence Behind the Three Testing Strategies for Cervical Cancer Screening – Implications for Your Practice

Related ObG Project Topics

Guidance Update: Professional Organizations Align on Cervical Cancer Screening