Why More is Not Always Better: New Pap Smear Guidelines

Case Report

A20-year-old woman presents for a routine annual physical examination. She has no significant past medical history. Sexually active since age 15, she has had a total of three sexual partners and is currently in a mutually monogamous relationship. She has not received the human papillomavirus (HPV) vaccine. Her menses are regular and she has no gynecological complaints or history of sexually transmitted infections. She would like to know if she should have cervical cancer screening performed today. The most appropriate next step is

Discussion

Cervical cancer is the third most common cancer in women worldwide. ¹ Statistical modeling estimates 12,340 new cases of invasive cervical cancer in the United States in 2013, with the number of deaths attributed to invasive cervical cancer estimated to be 4030. ² The cost to screen, diagnose, and treat cervical cancer in the United States has surpassed US$3 billion annually. ³ During the last several decades, there has been a remarkable decrease in the incidence of cervical cancer in the United States. ⁴ This has been attributed to cervical cancer screening with the Pap smear test, which allows for detection of precancerous lesions as well as detection of cancerous lesions at an earlier stage. ⁴

It is now well established that almost 100% of invasive cervical cancers are due to persistent infection with specific oncogenic or high-risk HPV genotypes. ^3,4 HPV infection is acquired through genital skin and sexual contact, and prevalence appears to peak several years after sexual debut. ⁴ In the United States, 92% of women have had their sexual debut by the age of 24. ⁵ Accordingly, the prevalence of high-risk HPV peaks at 43.4% in the 20–24 age group, and declines to 30.4% by age 30. ⁶ Persistent infection of the cervical epithelium with one of the high-risk HPV genotypes leads to the development of precancerous lesions and then rarely to invasive cervical cancer. ^7,8

There are over a dozen high-risk genotypes of HPV, but HPV16 and HPV18 account for more than 75% of invasive cervical cancer cases. ³ Infection with more than one genotype can occur, either sequentially or concurrently. ⁷ HPV infection is usually transient, with more than 90% of HPV infections resolving within 2 years. ^4,7,8 Infections that persist beyond 2 years do have a greater likelihood of progression to precancerous cervical lesions, with risk of eventual progression to invasive cervical cancer. ^4,8 Infection with HPV16 is particularly concerning. HPV16 infections are more likely to be associated with serious cytological abnormalities, and the time from persistent infection through progression to a precancerous cervical lesion is shorter for HPV16. ⁸

Fortunately most HPV infections resolve, through a cell-mediated immune response. ⁸ Though a variety of cytological abnormalities can be found on cervical cancer screening, the lesion of true concern is cervical intraepithelial neoplasia (CIN) grade 3 (CIN3), considered to be the immediate precancerous lesion before invasive cervical cancer. ⁴ Low-grade squamous intraepithelial lesions are thought to result from a mild proliferation of cervical basal cells with formation of perinuclear halos related to HPV infection and are considered to be benign reversible lesions. ⁹ Conversely, high-grade squamous intraepithelial lesions (HSILs) are thought to be part of the precancerous spectrum of lesions. ⁹ Pap smears with atypical squamous cells of undetermined significance cannot exclude HSILs and are associated with detecting a more serious lesion on colposcopy. ⁹ Cervical biopsy samples with CIN grade 1 (CIN1) are thought to be benign because the majority of these lesions regress. ⁹ CIN grade 2 (CIN2) lesions can be more difficult to predict because these lesions may include both precancerous lesions that will progress to CIN3 as well as lesions that may regress on their own. ^8,9 Accordingly, CIN2 is usually considered the threshold for treatment of a lesion, ⁸ with some pathologists grouping CIN2 and CIN3 as one diagnosis, labeling them CIN2/3. ⁹

The American Cancer Society, the American Society for Colposcopy and Cervical Pathology, and the American Society of Clinical Pathology convened in September 2012 to develop consolidated cervical cancer screening guidelines, ⁴ with an update published in 2013. ¹⁰ These agencies have unanimously agreed that screening for cervical cancer should not begin until age 21, irrespective of the age at which women start having vaginal intercourse. ^4,10 The rationale behind initiating screening at age 21 is that adolescents, despite having the highest incidence of HPV infection, are at minimal risk for developing invasive cervical cancer. ^11,12 The annual incidence of cervical cancer cases in women aged 15 to 19 is only 1 to 2 cases per 1,000,000. ¹³ Additionally, the rare cervical cancer cases that do happen are difficult to detect with regular Pap testing. They can go undetected by both cytological and colposcopic testing ^8,12 and tend to be more aggressive in nature and occur during the interval between screenings. ¹² Thus, it is thought that screening those under the age of 21 leads to the overtreatment of lesions that will either regress on their own or will take many years before they become an invasive cancer. ⁴

Screening women under the age of 21 for cervical cancer can cause adverse psychologic effects, ¹¹ which is unfortunate because the majority of abnormal lesions found in this age group will not require intervention. Overtreatment of lesions is not uncommon, subjecting young women to procedures that they may not need. Treatment of positive findings is not in and of itself benign. Evidence exists that cervical excisional procedures like the loop electrosurgical excision procedure are associated with preterm delivery and increased risk of premature rupture of membranes. ^11,14 Given the high prevalence of HPV infection in those under the age of 29 and the high likelihood of the infection clearing without any consequences, ⁶ testing for HPV status in patients with normal cytologic findings is not recommended until age 30. ^4,10 Overall, the new cervical cancer screening guidelines should reduce unnecessary overtreatment of patients less than 21 years of age, minimizing harm related to cervical cancer treatment.

Answer: D

The patient does not need a Pap smear or HPV testing. She will need to start cervical cancer screening at the age of 21. This is irrespective of the age at which she became sexually active, the presence of any high-risk sexual behavior, or her sexual orientation. Safe-sex counseling, contraception, and screening for sexually transmitted infections should also be discussed. At the age of 30, she should undergo HPV cotesting with her cervical cancer screening.

Another important aspect of routine counseling of young females should include education regarding HPV infection and vaccination. The Advisory Committee on Immunization Practices currently recommends routine vaccination for all young girls between the ages of 11 and 12 and catch-up vaccination up to age 26. Timely HPV vaccination can have a huge impact on the incidence of cervical cancer and should be offered to this patient. Clinicians should not be under the assumption that previous sexual activity, prior abnormal pap smears, or a documented HPV infection should preclude eligible patients from receiving the HPV vaccination. ³ The cost effectiveness and efficacy of the HPV vaccination in sexually active women is debatable. The guidelines for cervical cancer screening are the same for both vaccinated and unvaccinated women. ^4,10