Cervical Dysplasia and Cancer

Etiology and Epidemiology

There are 15 high-risk HPV types and types 16 and 18 are responsible for 70% of cervical cancers. Types 6 and 11 have been associated with cervical condylomas and low-grade cervical intraepithelial neoplasia (CIN).

The adolescent cervix is believed to be more susceptible to carcinogenic stimuli because of the active process of squamous metaplasia, which occurs within the transformation zone during periods of endocrine change. This squamous metaplasia is normally a physiologic process, but under the influence of the HPV, cellular alterations occur that result in an atypical transformation zone. These atypical changes initiate CIN, which is the preinvasive phase of cervical cancer.

Cervical cancer and its precursors have been associated with several epidemiologic variables ( Box 38-1 ). These risk factors basically increase the likelihood of exposure to a high-risk HPV type.

The disease is relatively rare before 25 years of age, and the mean age is about 47 years.

Primary Prevention

Two prophylactic vaccines are presently available. The quadrivalent vaccine Gardasil, which is manufactured by Merck and Co. and protects against HPV types 6, 11, 16, and 18, was approved by the U.S. Food and Drug Administration (FDA) in June 2006 for females aged 9 through 26 years. The bivalent vaccine Cervarix, which is manufactured by Glaxo Smith Kline and protects against HPV types 16 and 18, was approved by the FDA in October 2009, for use in females aged 10 through 25 years.

HPV vaccination is most effective if performed before the onset of sexual activity. Vaccination is still recommended after commencement of sexual activity, and even after prior abnormal cytology or CIN, but it is likely to be less effective after HPV exposure. In 2007, Australia was the first country in the world to introduce HPV vaccination into the National Immunization Program for all schoolgirls aged 12 years.

Screening of Asymptomatic Women

The American College of Obstetricians and Gynecologists (ACOG) has recommended that all women should undergo an annual physical examination, including a Papanicolaou (Pap) smear, within 3 years of sexual intercourse, or by age 21. The false-negative rate for conventional Pap smears for high-grade intraepithelial lesions is generally reported to be about 20%, but it is higher for glandular lesions and for invasive cancers.

New technologies have been developed to decrease the false negative rate. Thin Prep (Cytyc Corporation) and Surepath (TriPath Imaging) are automated liquid-based slide-preparation systems. With liquid-based cytology (LBC), the spatula or brush taking the smear is placed into a fixative solution, instead of smearing the cells directly onto a glass slide. Blood, mucus, and inflammatory cells are eliminated and a monolayer smear is then automatically prepared by a machine. Focal Point (Surepath) and ThinPrep Imager (Cytyc) are computerized image processors that select the most abnormal cells on a slide. They increase the sensitivity of slide reading, while decreasing the time needed by the cytotechnician to read each slide, thereby improving the cost effectiveness of screening.

The American Society for Colposcopy and Cervical Pathology (ASCCP) has recommended that screening with Liquid Based Cytology (LBC) should occur every 3 years from 21 to 30 years. Thereafter, they recommend continued screening every 3 to 5 years with LBC for HPV testing. Both the endocervical canal and the exocervix (or ectocervix) should be sampled when taking the Papanicolaou smear.

HPV deoxyribonucleic acid (DNA) testing is much more sensitive than cervical cytology, but less specific. It is presently being investigated as a primary screening test for women after the age of 25 to 30 in many developed countries. The negative predictive value of the HPV test is very high, so screening intervals could safely be extended to at least 5 years. If the HPV test is positive, reflex cervical cytology is performed to determine the need for referral for colposcopy.

Women should have regular cervical screening even if they have received the HPV vaccine, because the vaccine does not protect against all high-risk HPV viral types.

Cervical Topography

During early embryonic development, the cervix and upper vagina are covered with columnar epithelium. During intrauterine development, the columnar epithelium of the vagina is progressively replaced by squamous epithelium. At birth, the vagina is usually covered with squamous epithelium, and the columnar epithelium is limited to the endocervix and the central portion of the exocervix (or ectocervix). In about 4% of normal female infants, the columnar epithelium extends onto the vaginal fornices. Macroscopically, the columnar epithelium has a red appearance because it is only a single cell layer thick, allowing blood vessels in the underlying stroma to show through it.

The embryologic squamous and columnar epithelia are designated the original or native squamous and columnar epithelia, respectively. The junction between them on the exocervix (or ectocervix) is called the original squamocolumnar junction.

Throughout life, but particularly during adolescence and a woman's first pregnancy, metaplastic squamous epithelium covers the columnar epithelium so that a new squamocolumnar junction is formed more proximally. This junction moves progressively closer to the external os and then up the endocervical canal. The transformation zone is the area of metaplastic squamous epithelium located between the original squamocolumnar junction and the new squamocolumnar junction ( Figure 38-1 ).

Classification of an Abnormal Papanicolaou Smear

In 1988, a consensus meeting was convened by the Division of Cancer Control of the National Cancer Institute to review existing terminology and to recommend effective methods of cytologic reporting. As a result of this meeting, the Bethesda system was devised and requires (1) a statement regarding the adequacy of the specimen for diagnosis, (2) a diagnostic categorization (normal or other), and (3) a descriptive diagnosis. A revised Bethesda system was developed in 2001 and is shown in Box 38-2 .

Cervical Intraepithelial Neoplasia

CIN represents a spectrum of disease, ranging from LSIL, low-grade squamous intraepithelial lesion (formerly called CIN I or mild dysplasia) to HSIL, high-grade squamous intraepithelial lesion (formerly called CIN II and III, or moderate and severe dysplasia). At least 35% of patients with HSIL will develop invasive cancer within 10 years, whereas LSIL often spontaneously regresses. With CIN, there is abnormal epithelial proliferation and maturation above the basement membrane. Involvement of the inner one-third of the epithelium represents LSIL, while involvement of the outer two-thirds represents HSIL ( Figure 38-2 ). The disease is asymptomatic.