Prevalence of Abnormal Cytology
Several large studies have shown that approximately 3% to 14% of females younger than 19 years have abnormal cervical cytology (Bjorge et al., 1995; Mount and Papillo, 1999;Sadeghi et al., 1984). Fortunately, most of these abnormal cytologies are primarily low-grade squamous intraepithelial lesions (LSILs), which are considered as benign changes due to human papillomavirus (HPV) infection. These rates are consistent with the high rates of HPV infection reported in this age-group, which range from 20% to 57% (Moscicki et al., 1990,1999; Rosenfeld et al., 1989, Winer et al., 2003) with approximately 50% of adolescents acquiring an HPV infection within 5 years of starting sexual activity. Although rates of high-grade squamous intraepithelial lesions (HSILs), considered true pre-cancer lesions, are substantially lower than those of LSILs in adolescents, recent studies suggest that these rates are higher than previously reported. In 1981, Sadeghi et al. (1984) performed an analysis of more than 194,000 Papanicolaou (Pap) smears in adolescents aged 15 to 19 years. Using the World Health Organization's cytological classification, they found a combined rate for cervical intraepithelial neoplasia (CIN) grades 1 and 2 of 18/1,000 smears, and for carcinoma in situ, 1/1,000. In comparison, Mount et al. (1999) examined more than 10,000 Pap smears from young women and found that 14% of the smear results from females aged 15 to 19 years were considered abnormal, with 7% having LSIL and 0.7% having HSIL. Interestingly, the rate of HSIL in the 15- to 19-year-old group was similar to that reported in comparable smear tests from women aged 20 to 29 years (0.8%) and higher than that for women aged 30 to 39 years (0.5%). These rates reported for adolescents are likely underestimates because they only reflect women who enter the health care system. In a nationwide organized cervical screening program, Bjorge et al. (1995) reported a 0.2% incidence rate for HSIL among 20,000 smears of adolescents aged 15 to 19 years. However, the LSIL rate was highest for this age-group. Because of this disproportionate rate between LSIL and HSIL in adolescents, most adolescents with abnormal cytology are unnecessarily referred for colposcopy.
Vulnerability of the Cervix to Human Papillomavirus
The characteristic histological changes of the cervix associated with HPV infections generally occur within the transformation zone (T-zone). It is useful to review the formation of this zone and the natural history of HPV in understanding abnormal cervical changes.
During embryological development, the müllerian ducts give rise to the fallopian tubes, uterus, and vagina. These structures in the fetus are lined by immature cuboidal epithelium (which becomes columnar epithelium) from the uterus to the hymenal ring. The urogenital sinus epithelium grows up the vaginal vault and replaces the native epithelium up to the ectocervix with squamous epithelium. This replacement is usually incomplete, creating an abrupt squamocolumnar junction (SCJ) on the ectocervix. Squamous metaplasia is a process during which undifferentiated columnar cells transform themselves into squamous epithelium. However, the process is relatively quiescent until puberty, resulting in little changes to the SCJ during childhood. The area of columnar epithelium seen on the ectocervix is referred to as ectopy.
With puberty the pH level of the vagina drops. This is associated with glycogen production by squamous cells induced by rising levels of estrogen. The glycogen provides a source of carbohydrate for the vaginal flora. Vaginal bacteria proliferate, and the lactobacilli convert glycogen to lactic acids, resulting in a lowered pH level. This new acidic environment most likely contributes to the augmentation of the squamous metaplastic process, resulting in relatively rapid replacement of columnar epithelium by squamous epithelium.
Transformation Zone (T-zone)
With conversion of the columnar epithelium to squamous epithelium, a T-zone is created. The T-zone is a relatively fluid area of definition, because it represents the area between the original SCJ and the current SCJ. By a woman's late 20 s and early 30 s, most have had substantial replacement of their columnar epithelium, resulting in
little to no visible ectopy. Although squamous metaplasia continues, it is now found well inside the endocervical canal.
Native squamous epithelium appears as smooth, pink, and featureless epithelium. In general, it covers the vagina and a portion of ectocervix. Native columnar epithelium is a single-layer, mucus-producing, tall epithelium extending between the endometrium and into the T-zone. This area has an irregular surface with long papillae and deep clefts, often referred to as having a “grape-like” appearance. The physiological T-zone has a combination of columnar and squamous epithelium features, as well as several unique features, which are dependent on the stage of development. In early stages, the zone is predominantly covered with columnar epithelium and discrete patches where the fusion of the villi causes a loss of translucency and the villi assume a ground glass appearance. Later, successive villi are fused and the intervening spaces are filled. Eventually the papillary structures are lost, and the new surface takes on a less translucent, vascular, pearly tongue appearance. Because the conversion of columnar epithelium to squamous epithelium occurs in often disjointed or fragmented segments, the examiner can often see small glands that are predominantly lined with columnar or metaplastic epithelium. When these gland openings become completely closed by squamous epithelium, the mucus-secreting epithelium may continue to produce mucus. If that mucus becomes inspissated, the gland dilates and a nabothian cyst results. Nabothian cysts eventually self-destruct from the pressure of the inspissated mucus.
Vulnerability of the T-Zone
The T-zone is the area of the cervix most prone to the development of squamous intraepithelial lesions (SILs) and invasive squamous cell cancers. The vulnerability of the T-zone is most likely related to the process of squamous metaplasia and its vulnerability to HPV and SIL development (Moscicki et al., 1999). This association reflects the natural life cycle of HPV and its dependence on host cell proliferation and differentiation, both characteristics of squamous metaplasia. Initial HPV infections are thought to occur by invasion of cells of the basal epithelium. Disruption of the epithelium by inflammation or trauma may cause an increased risk for infection with HPV. Differentiation of these basal cells to well-differentiated squamous epithelial cells supports HPV replication by allowing expression of certain viral proteins at different layers of differentiation. The expression of the oncogenic proteins E6 and E7 in turn causes histological changes, which include abnormal cell proliferation, and the appearance of abnormal mitotic figures, both features of SIL. Features that are mild in nature and restricted to the basal and parabasal areas are referred to as LSIL. When these features become more extensive and extend into the upper half of the epithelium, the changes are referred to as HSIL. These changes coincide with increased expression of the oncogenes E6 and E7. Consequently, both LSIL and HSIL are pathological changes due to HPV infection.
Impact of Cofactors
HPV infection is clearly the causative factor for cervical SIL. However, because rates of HPV are 4 to 10 times more common than SIL, and 100 to 700 times more common than invasive cancers, it is assumed that HPV is necessary but not sufficient for the development of these lesions. In the case of cancer, numerous molecular events are most likely needed. Although HPV infection is clearly one of the first steps, most HPV infections are quickly eliminated by the host's immune response. Lack of an adequate immune response results in persistence of HPV infection, and in turn, HPV persistence is a strong risk for the development of HSIL (Ho et al., 1995; Moscicki et al., 1998, Ylitalo et al., 2000). HPV persistence is a common problem among persons with immunodeficiencies including human immunodeficiency virus (HIV) infection (Moscicki et al., 2004a; Sun et al., 1997). Other factors associated with HSIL and cancer development include tobacco exposure. Even when adjusted for numbers of sex partners, women who smoke have a higher risk of developing cervical SIL and invasive cancers than nonsmokers (Haverkos et al., 2003). This relationship appears to be dose related, because women who are heavier smokers for a longer time have the highest risk for developing SIL and cancers. Other risk factors implicated include herpes simplex virus (HSV) and Chlamydia Trachomatis infections, multiparity, and history of prolonged oral contraceptive use (Smith et al., 2003, 2004).
Cervical Screening Tests
Three U.S. organizations have established guidelines for the initiation and frequency of cervical cancer screening (Table 54.1). Current recommendations for Pap smear testing are that women should start having Pap smears within 3 years of becoming sexually active or at age 21 years (American College of Obstetricians and Gynecologists, 2004; Saslow et al., 2002). After a patient has had three consecutive annual tests whose results are read as normal, she may be screened at 1- to 3-year intervals, depending on risk behavior (i.e., multiple partners), older partners, and a high rate of sexually transmitted diseases (STDs) (ACOG, 2006; American Medical Association, 1997) . STD screening is generally performed at least annually for sexually active adolescents. The pelvic examination is generally included in this screening at least every 1 to 2 years starting 3 years after the initiation of sexual intercourse, and following the first three consecutive annual Pap smears. The recommendation to wait for Pap smears is recent because many groups recommended screening once sexual activity ensued. Waiting has raised anxiety among health care providers because the first Pap smear was considered an opportune time to discuss anatomy, birth control, and risk behaviors. The new guidelines continue to support this, but do not recommend starting a chain of events with triage and referral for abnormal cytology when most (93%) lesions in this age-group will regress (Moscicki et al., 2004).
Most cytologists in the United States have adopted the Bethesda reporting system and now provide more descriptive reports of their findings after screening of the specimen for adequacy and correct preparation. Smear tests that are considered inadequate or with missing endocervical cells should be repeated. A summary of the Bethesda system findings is found in Figure 54.1.
Sample preparation may contribute to the poor sensitivity of the Pap smears; that is, most Pap smears are difficult to read because of obscuring cells, drying artifact, and cell distortion. Liquid cytology has been devised, whereby exfoliated cells are placed immediately into a liquid fixative rather than smeared onto a slide. The fixative solution is transported to the laboratory, where monolayers are prepared using a company's processor. The cells are transferred from the filter onto a glass slide for routine Pap staining. An advantage is clearer images of the cells because the samples are depleted of blood and inflammatory cells that can obscure the readings. Because the agreement rate between conventional smears and liquid cytology is more than 90%, and the cost of liquid cytology smears is sometimes substantially more than that of conventional smears, the cost-effectiveness of using liquid cytology is in question. One advantage may be that the cells preserved in the liquid fixative can be used for ancillary studies such as reflex HPV testing (see subsequent text). Another advantage is that liquid cytology appears to pick up more abnormalities; hence screening intervals may be increased to every 2 years if liquid cytology is used (Saslow et al., 2002). The American Cancer Society has recommended biennial testing using this method (Table 54.1).
The follow-up evaluation required for benign Pap smear findings not associated with neoplastic changes is shown in Table 54.2. Current triage practices for abnormal Pap smear changes in adults followed by recommendations for adolescents are outlined in the following sections.
Recommendations for Adult Women
the detection of HSIL than repeat cytology (Manos et al., 1999). This triage works best in women aged 21 years and older. HPV testing in adolescents (see subsequent text) is not recommended. Currently, Hybrid Capture II HPV Test (Digene Diagnostics, Gaithersburg, MD) is the only U.S. Food and Drug Administration-approved commercially available test kit for clinical high-risk DNA detection in the United States. ASCUS with a positive result for high-risk HPV DNA test should be referred for colposcopy in the nonadolescent age-group.
The original intent of the developers of the Bethesda system was to permit more conservative management of patients with low-grade lesions. However, as many as 25% to 30% of patients with LSIL on Pap smears actually harbor more advanced disease, including HSIL and rarely invasive cancer. Currently, it is recommended that all LSIL in adult women be referred for colposcopy. HPV testing for triage in patients with LSIL is not recommended (Atypical Squamous Cells of Undetermined Significance/Low-Grade Squamous Intraepithelial Lesions Triage Study [ALTS] Group, 2000).
Triage on the basis of cytology results using this dual screening method in women older than 30 with ASCUS, LSIL, and HSIL is the same as the preceding recommendations 1 to 3. The major purpose of this dual screening is to allow a longer screening interval in those at low risk (negative cytology and HPV screening) and a more intense follow-up for those with HPV positive test despite negative cytology.
FIGURE 54.1 Summary of Bethesda system findings. (From Solomon D, Davey D, Kurman R, et al. The 2001 Bethesda system: terminology for reporting results of cervical cytology. JAMA 2002;287;(16):2114, with permission.)
Special Considerations for Triage of Cytology in Adolescents
The rate of invasive cancers among adolescents is extremely low, whereas a LSIL diagnosis is at its highest. The common nature of LSIL in adolescents is not surprising given the high rate of HPV infections in this group. Fortunately, LSIL and HPV are mostly transient in this age-group, with more than 90% of HPV infections and LSIL showing regression in adolescents and young women within 3 years (Moscicki et al., 2004a). For this reason, triage for ASCUS and LSIL differ for adolescents (defined as <21 years of age) than adult women. The following are recommendations by the author and other experts in adolescent health care, but are always subject to the latest consensus recommendations available at the American Society for Colposcopy and Cervical Pathology Web site: http://www.asccp.org/consensus.shtml. The major consensus recommendations have been based on consensus reports from 2001, ACOG committee opinion and expert opinion.
FIGURE 54.2 Algorithm for human papilloma virus (HPV) DNA testing and cytology as primary screening in women aged 30 years and older. ASCUS, atypical squamous cells of undetermined significance.
Therapy for Cervical Dysplasia
The colposcopically directed biopsy and the endocervical test results determine the extent of the lesion and direct the therapy. The principle in developing a treatment plan is that cervical dysplasia, specifically HSIL, is treated to prevent progression to cancer. If the lesions are confined to the ectocervix, a wide range of treatment options is available (Table54.3).
One practice to be avoided, particularly in adolescents, is to combine the diagnostic and treatment steps by performing colposcopic examination to rule out invasion and excising the T-zone by a loop electrocautery excision procedure (LEEP) without biopsy confirmation. This practice is inappropriate and expensive. Approximately 90% of such referred adolescents have no HSIL found on the specimen on undergoing an LEEP, and the cost exceeds the benefit for patients without dysplasia with regard to side effects (Sadler et al., 2004). As can be seen in Table 54.3, each of the major treatment modalities has minimal adverse impacts when used once. However, because recurrent lesions may develop and require further treatment, the cumulative effects of multiple treatments (particularly LEEP) must be considered. A recent meta-analysis showed that excisional therapy has a higher rate of premature labor and low birth weight (Kyrgiou et al., 2006). Hillard et al. (1991) reported another complication of treatment of cervical dysplasia related to cryotherapy in a group of 67 adolescents. Nine percent developed pelvic inflammatory disease (PID) within 1 month of treatment, and 2 teens developed cervical stenosis and hematometra. In general, screening for STDs before cryotherapy or LEEP is recommended to avoid the complications of PID. Because of the benign nature of histological CIN 1 in all ages, it is recommended that CIN 1 be observed and not treated. Observation of CIN 2 in compliant adolescents is also allowed. (www.asccp.org and American College of Obstetricians-Gynecologists ACOG Committee Opinion, 2006).
All women with dysplasia who smoke should be encouraged to stop smoking. Advise them that continued tobacco use increases susceptibility to cancer. Condom use has been shown to enhance LSIL regression, so condom use should be encouraged (Hogewoning et al., 2003).
After treatment, patients require repeat cytology or colposcopy and cytology at 4 to 6 months until three consecutive normal Pap smears are reported. The patient then can return to normal screening, including annual Pap smears for 3 years, then if all results remain normal, every 3 years. Follow-up with HPV testing at 6 months is also considered optional. The patient can return to normal screening after a single HPV negative test (www.asccp.org).
Conflicting information exists for associations between cervical cancer and HSV and C. Trachomatis infections, prolonged oral contraceptive use (>5–8 years), and multiparity (>6 children) (Smith et al., 2003, 2004, Lehtinen et al., 2002). It is currently not recommended to screen male partners of women with abnormal Pap smears for HPV infections
because few studies have demonstrated HPV disease in this group.
Recommendations for treatment of cervical lesions change over time and differ based on the patient's age and other risk factors. Clinicians involved in the treatment of cervical lesions should refer to the American Society for Colposcopy and Cervical Pathology Web site where consensus recommendations are updated as they become available: http://www.asccp.org/consensus.html.
The latest intervention for prevention of HPV infection is the HPV vaccine. One vaccine was approved in 2006 for types 6/11/16/18 and another vaccine is under approval process for types 16/18. These vaccines have the potential to significantly alter the prevalence of HPV infections in women (see Chapter 66).
For Teenagers and Parents
http://www.ashastd.org. American Social Health Association: Learn about STDs/HPV.
http://www.youngwomenshealth.org/abpap.html. Center for Young Women's Health information sheet for teens on abnormal Pap smears.
http://www.familydoctor.org/handouts/223.html. American Academy of Family Physicians handout.
http://www.nccc-online.org/. National Cervical Cancer Coalition site.
http://www.4woman.gov/faq/pap.htm. National Women's Health information center frequently asked questions sheet.
http://www.asccp.org. American Society for Colposcopy and Cervical Pathology: Patient Education.
For Health Professionals
http://www.asccp.org. American Society for Colposcopy and Cervical Pathology: Practice Recommendations.
http://www.asct.com/. American Society for Cytotechnologists.
http://www.ascp.org/general/pub_resources/papsmear/questions.asp. American Society of Clinical Pathologists.
http://www.bethesda2001.cancer.gov/terminology.html. Bethesda 2001 classifications.
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