18-19: Cervical Intraepithelial Neoplasia (CIN) (Dysplasia of the Cervix)

The squamocolumnar junction of the cervix is an area of active squamous cell proliferation. In childhood, this junction is located on the exposed vaginal portion of the cervix. At puberty, because of hormonal influence and possibly because of changes in the vaginal pH, the squamous margin begins to encroach on the single-layered, mucus-secreting epithelium, creating an area of metaplasia (transformation zone). Infection with HPV (see Prevention, below) may lead to cellular abnormalities, which over time may develop into squamous cell dysplasia or cancer. There are varying degrees of dysplasia (Table 18–5), defined by the degree of cellular atypia; all atypia must be observed and treated if persistent or worsening.

There are no specific symptoms or signs of CIN. The presumptive diagnosis is made by cytologic screening of an asymptomatic population with no grossly visible cervical changes. All visible abnormal cervical lesions should be biopsied (Figure 18–5).

A. Cytologic Examination (Papanicolaou Smear)

In immunocompetent women, cervical cancer screening should begin at age 21. The recommendation to start screening at age 21 years regardless of the age of onset of sexual intercourse is based on the very low incidence of cancer in younger women and the potential for adverse effects associated with treatment of young women with abnormal cytology screening results. In contrast to the high rate of infection with HPV in sexually active adolescents, invasive cervical cancer is very rare in women younger than age 21 years. The US Preventive Services Task Force (USPSTF) 2018 statement recommends screening for cervical cancer in women aged 21 to 65 years as follows: for women aged 21 to 29 years, screening with cytology (conventional [Papanicolaou smear] or liquid based) alone every 3 years; and for women aged 30 to 65 years, screening with cytology alone every 3 years, with high-risk HPV testing alone every 5 years, or with a combination of cytology and high-risk HPV testing (cotesting) every 5 years. These recommendations apply to women who have a cervix, regardless of their sexual history or HPV vaccination status. They do not apply to women who have previously been diagnosed with cervical cancer or a high-grade precancerous cervical lesion (ie, CIN grade II or III) or to women with immune compromise (eg, living with HIV) or with in utero exposure to diethylstilbestrol; such women may require more frequent screening.

The USPSTF recommends against screening for cervical cancer for women younger than age 21 years, for women older than age 65 years who have had adequate prior screening and are not otherwise at high risk for cervical cancer, and for women who have had a hysterectomy with removal of the cervix and who have no history of cervical cancer or a high-grade precancerous lesion.

The goal of screening is to identify high-grade precancerous cervical lesions to prevent their progression to cervical cancer. These high-grade cervical lesions may be treated with excisional and ablative therapies (see below). Early-stage cervical cancer may be treated with surgery (hysterectomy) or chemotherapy (see next section). Online guidelines are available for the management of abnormal screening test results at https://www.uspreventiveservicestaskforce.org/Page/Document/RecommendationStatementFinal/cervical-cancer-screening2 (August, 2018) and https://www.asccp.org/guidelines (April, 2019).

Cytology is performed by collecting exfoliated cells from the transformation zone of the cervix with a brush, broom, or spatula, and transferring the cells to a vial of liquid preservative that is processed in the laboratory to produce a slide for interpretation—the liquid-based technique—or to a slide and fixed using the conventional technique. Performance of conventional cervical cytology is now less commonly used because it requires avoidance of contaminating blood, discharge, and lubricant.

Cytologic reports from the laboratory may describe findings in one of several ways (see Table 18–5). The Bethesda System uses the terminology “atypical squamous cells of unknown significance” (ASC-US) and “squamous intraepithelial lesions,” either low-grade (LSIL) or high-grade (HSIL). HPV DNA testing can be used as an adjunct in cervical cancer screening as a triage test to stratify risk in women age 21 years and older with a cytologic diagnosis of ASC-US and in postmenopausal women with a cytologic diagnosis of ASC-US or LSIL.

B. Colposcopy

Women with ASC-US and a negative HPV screening may be followed up in 1 year for a repeat Papanicolaou smear and HPV co-testing. If the HPV screen is positive, colposcopy is indicated. If HPV screening is unavailable, repeat cytology may be done at 12 months. Women between ages 21–24 with LSIL should have repeat Papanicolaou smear in 1 year. Women age 25 and older with SIL or atypical glandular cells should undergo colposcopy. Viewing the cervix with 10–20 × magnification allows for assessment of the size and margins of an abnormal transformation zone and determination of extension into the endocervical canal. The application of 3–5% acetic acid (vinegar) dissolves mucus, and the acid’s desiccating action sharpens the contrast between normal and actively proliferating squamous epithelium. Abnormal changes include white patches and vascular atypia, which indicate areas of greatest cellular activity.

C. Biopsy

Colposcopically directed biopsy and endocervical curettage are office procedures. If colposcopy is not available, the normal-appearing cervix shedding atypical cells can be evaluated by endocervical curettage and multiple punch biopsies of nonstaining squamous epithelium or biopsies from each quadrant of the cervix. Data from both cervical biopsy and endocervical curettage are important in deciding on treatment.

Cervical infection with the HPV is associated with virtually all cervical dysplasias and cancers. There are over 100 recognized HPV subtypes. Types 6 and 11 tend to cause genital warts and mild dysplasia and rarely progress to cervical cancer; types 16, 18, 31, and others cause higher-grade dysplasia. The HPV 9-valent (Gardasil-9) recombinant vaccine (9vHPV) is indicated for the prevention of cervical, vaginal, and vulvar cancers (in women) and anal cancers (in women and men) caused by HPV types 16, 18, 31, 33, 45, 52, and 58; genital warts (in women and men) caused by HPV types 6 and 11; and precancerous/dysplastic lesions of cervix, vagina, vulva (in women), and anus (in women and men) caused by HPV types 6, 11, 16, 18, 31, 33, 45, 52, and 58. Gardasil-9 is recommended for vaccination of females and males ages 9-45 years old. The earlier HPV 4-valent vaccine known as Gardasil that was indicated for prevention of diseases related to HPV types 6, 11, 16, and 18 has been discontinued in the United States. The use of HPV vaccination in the United States continues to increase; however, the HPV vaccination continues to lag far behind other vaccines recommended for adolescents. In 2018, 51% of adolescents were up to date with the three-dose HPV vaccine series compared with 48% in 2017.

Because complete coverage of all carcinogenic HPV types is not provided by either vaccine, all women need to have regular cervical cancer screening as outlined above. In addition to vaccination, preventive measures include limiting the number of sexual partners and thus exposure to HPV, using a diaphragm or condom for coitus, and smoking cessation and avoiding exposure to secondhand smoke.

Treatment varies depending on the degree and extent of CIN. Biopsies should precede treatment, except in cases of HSIL where it may be appropriate to proceed directly to a LEEP.

A. Cryosurgery

The use of freezing (cryosurgery) is effective for noninvasive small lesions visible on the cervix without endocervical extension.

B. CO₂ Laser

This well-controlled method minimizes tissue destruction. It is colposcopically directed and requires special training. It may be used with large visible lesions. In current practice, it involves the vaporization of the transformation zone on the cervix and the distal 5–7 mm of endocervical canal.

C. Loop Excision

When the CIN is clearly visible in its entirety, a wire loop can be used for excisional biopsy. This office procedure, called LEEP (loop electrosurgical excision procedure), done with local anesthesia is quick and straightforward. Cutting and hemostasis are achieved with a low-voltage electrosurgical machine.

D. Conization of the Cervix

Conization is surgical removal of the entire transformation zone and endocervical canal. It is reserved for cases of severe dysplasia (CIN III) or carcinoma in situ, particularly those with endocervical extension. It can be performed with scalpel, CO₂ laser, needle electrode, or large-loop excision.

Because recurrence is possible—especially in the first 2 years after treatment—and because the false-negative rate of a single cervical cytologic test is 20%, close follow-up after colposcopy and biopsy is imperative. Following excisional or ablative procedure, co-testing (cytology and HPV DNA) should be repeated at 12-month intervals for 2 years. If CIN II or III is identified at the margins of an endocervical curettage procedure, however, repeat cytology with endocervical curettage is preferred at 4–6 months. If follow-up testing is normal, routine cytologic screening can be resumed. Colposcopy and endocervical sampling should be performed for any abnormality.

The American Society for Colposcopy and Cervical Pathology Guidelines for cervical cancer screening and management of abnormal Papanicolaou smears are available online (April, 2019, https://www.asccp.org/consensus-guidelines).

• Patients with CIN II/III should be referred to an experienced colposcopist.

• Patients requiring conization biopsy should be referred to a gynecologist.