Cervical Intraepithelial Neoplasia
Reinou S. Groen
Cornelia Liu Trimble
EPIDEMIOLOGY OF CERVICAL NEOPLASIA
In the United States, cervical cancer is diagnosed in approximately 12,000 women annually and fatal for approximately 4,000. It is the second leading cause of death in women aged 20 to 39 years. Approximately 50% of cervical cancer diagnoses can be attributed to inadequate screening.
Persistent infection with the oncogenic (high-risk) human papillomavirus (HPV) types 16, 18, 31, 33, 35, 39, 45, 52, 56, 58, 59, and 68 is required but not sufficient to develop cervical cancer and its precursor lesions. HPV 16 is the most common carcinogenic genotype, followed by HPV 18. Together, they are responsible for 70% of HPV-related cervical cancers. Although approximately 80% of women will be infected through sexual intercourse by an HPV type at some point in their lives, 90% of these infections are transient and will be cleared immunologically within
1 to 2 years. Risks for persistent infection include tobacco exposure and immune compromise, including coinfection with HIV. HPV infection in women older than 30 years is more likely to indicate a persistent infection than detectable HPV in younger women. Cervical cancer is thought to occur after a median of 20 to 25 years following the initiation of a persistent HPV infection.
The conventional cervical cytology smear or the liquid-based cytology (both referred to as Pap smear) is used as a screening test to identify the presence of visually abnormal cervical epithelial cells. Both techniques are equally sensitive and specific. Oncogenic HPV infection can be detected with the Digene hybrid capture test, which can be performed either on cytology specimens or using the Digene sampling brush.
Annually, 4.8 million women have an abnormal Pap smear in the United States. Cytologic abnormalities are categorized using the Bethesda system (see the following text).
Histologic abnormalities are classified in a two-tiered system of low-grade and high-grade squamous intraepithelial lesions. Low-grade squamous intraepithelial lesions (LSILs) include mild dysplasia and cervical intraepithelial neoplasia (CIN 1). High-grade squamous intraepithelial lesions (HSILs) include moderate and severe dysplasia, carcinoma in situ, and CIN 2/3.
CIN 1 is associated with a high rate of spontaneous regression, whereas untreated CIN 3 has a reported cumulative incidence of invasive cancer of 30.1% at 30 years.
PRIMARY PREVENTION
Smoking cessation: Women who smoke have an increased risk of developing cervical cancer compared to nonsmokers. This is thought to be related to the fact that smoking triples the likelihood of persistent HPV infection and doubles the risk of progression to CIN 3.
All women with abnormal Pap smears should be offered testing for HIV and other sexually transmitted infections.
A quadrivalent HPV vaccine directed against HPV types 6, 11, 16, and 18 (Gardasil, Merck, Whitehouse Station, NJ) was approved for use in 9- to 26-year-old females by the U.S. Food and Drug Administration (FDA) in 2006. The vaccine is very effective in HPV 16/18 naïve women, preventing essentially 100% of HSILs. However, the preventive vaccine does not have therapeutic effect against existing infection. Both the Advisory Committee on Immunization Practices (ACIP) and American College of Obstetricians and Gynecologists (ACOG) recommend administration of the vaccine to females aged 9 to 26 years.
The vaccine is administered in three doses at 0, 2, and 6 months. See Chapter 1. Currently, HPV vaccination does not change screening recommendations. However, looking forward, HPV vaccination is likely to influence positive and negative predictive values of the Pap smear by decreasing cervical abnormalities in the population.
SCREENING
Cytologic changes associated with HPV infection and neoplasia can be identified using Pap smears, which are the basis of cervical cancer screening programs. Abnormal Pap smears are followed by colposcopic evaluation of the cervix, as indicated in the flow diagrams later.
Screening guidelines are formulated by the American Society for Colposcopy and Cervical Pathology (ASCCP) and used in the 2013 ACOG practice bulletin. The guidelines were issued in 2001, 2006, and 2012, adapting new scientific insights and epidemiologic changes.
HPV vaccination may change the HPV genotype distribution as well as the positive and negative predictive value of Pap smears. Furthermore, vaccination may influence adherence to screening. Therefore, new guidelines will be needed to accommodate to those changes.
Based on the ASCCP guidelines from 2012:
Regular screening should begin at 21 years of age, regardless of the age of first sexual intercourse. Women aged 21 to 29 years should be screened every 3 years with cytology only. In this age cohort, HPV infections are likely to be transient.
In women aged 30 to 65 years, screening can be performed every 3 years with cytology alone. However, preferably, screening can be performed every 5 years with HPV cotesting (cytology and high-risk HPV testing).
Screening can be stopped at age 65 years if a woman does not have risk factors and has 10 years of negative screening that includes at least three negative test results. Screening should not be reinstituted, even in the case of a new sexual partner after the age of 65 years. Annual well-woman exams are still recommended for all adult women.
Women who have had a total hysterectomy for benign indications and who do not have a history of high-grade lesion do not require further screening.
Women with a history of CIN 2/3 should undergo screening every 3 years for at least 20 years after an initial adequate posttreatment surveillance period, regardless of their age. The same period of vaginal screening is advised for those who underwent a hysterectomy as part of treatment for recurrent CIN 2/3.
HIV-positive women should be screened at 6-month intervals for 1 year after the diagnosis of HIV and then may resume an annual screening schedule. Immunocompromised and women who were exposed to diethylstilbestrol (DES) in utero should also be screened annually.
Visual inspection with acetic acid and direct treatment with cryotherapy is currently the most effective cervical cancer prevention in low-resource settings where pathology laboratories and personnel are scarce and monetary and/or logistical constraints prohibit follow-up.
PAP SMEAR
Pap smear reports include specimen type, specimen adequacy, results, and any ancillary testing performed (i.e., high-risk HPV probe).
Specimen type indicates whether the test is a vaginal or cervical sample.
Adequacy is reported as satisfactory, unsatisfactory, or endocervical cells not present/lack of transformation zone.
Unsatisfactory Pap smears should be repeated in 2 to 4 months.
Pap smears that lack an endocervical component can be repeated in 1 year or postpartum unless any of the following risk factors are present, all of which necessitate repeat screening in 6 months:
History of atypical squamous cells of undetermined significance or greater abnormalities in the past, without three-interval normal Pap smears
High-risk HPV positivity in the previous 12 months
Previous glandular abnormality
Immunosuppression
Inability to visualize the endocervical canal
Patient noncompliance
The results section relays any cytologic abnormality.
DIAGNOSTIC CATEGORIES: CYTOLOGY
The 2001 revision of the Bethesda system is used to describe abnormal cervical cytology employing the following categories:
Atypical squamous cells (ASC)
Of undetermined significance (ASC-US)
Cannot exclude high grade (ASC-H)
Low-grade squamous intraepithelial lesion
High-grade squamous intraepithelial lesion
Atypical glandular cells (AGC) (endocervical or endometrial)
Not otherwise specified (AGC-NOS)
Favor neoplasia (AGC-favor neoplasia)
Adenocarcinoma in situ (AIS)
Atypical Squamous Cells
Approximately 2 million ASC Pap smears a year are recorded in the United States.
ASC-US is present in 4.7% of samples and is associated with a 7% to 12% prevalence of CIN 2/3.
ASC-H is present in 0.4% of samples and CIN 2/3 is present in 26% to 68% of women with this result.
The risk of invasive cancer associated with an ASC Pap is 0.1% to 0.2%.
Atypical Glandular Cells
AGC are found in 0.4% of Pap smears.
AGC are associated with significant neoplasia in 9% to 38% (CIN 2/3, AIS) and in 3% to 17% associated with cancer.
One study found that the malignancies of the women with AGC were found in women older than 35 years, are mainly of endometrial origin, and therefore suggested endometrial biopsy for every woman with AGC after the age of 35 years.
Stay updated, free articles. Join our Telegram channel
Full access? Get Clinical Tree
