Value of Cervical Cytology: Cervical Dysplasia & HPVWHEC Practice Bulletin and Clinical Management Guidelines for healthcare providers. Educational grant provided by Women's Health and Education Center (WHEC). Dysplasia or cervical intraepithelial neoplasia (CIN) means disordered growth and development of the epithelial lining of the cervix. Although cervical cancer was the leading cause of cancer death in USA in 1930s, both the incidence and mortality from cervical cancer have decreased by almost one half since the early 1970s, largely as a result of widespread screening with the Pap-test. New technology for performing cervical cytology is evolving rapidly, as are recommendations for classifying and interpreting the results. In USA cervical cancer is the third most common gynecologic malignancy and in countries where cytologic screening is not widely available, cervical cancer remains common. Cervical cytology screening programs have markedly reduced the cervical cancer incidence in the communities. The purpose of this document is to provide a review of the best available evidence on screening of cervical cancer. Value of Cervical Cytology Cervical cytology screening is, in many respects, the ideal screening test. Cervical cancer has a defined premalignant phase of many years, which allows repeated tests to significantly reduce the impact of individual false-negative test results. Cervical cytology is inexpensive and is readily accepted by women. Treatment is effective in reducing the chance of progression to invasive disease. Despite effective screening measures and treatment, it is estimated that 50% of the women who are diagnosed with cervical cancer have never had cervical cytology screening. Another 10% had not been screened within the 5 years before diagnosis. Thus, one approach to reducing the incidence and mortality of cervical cancer would be to increase screening rates among women who currently are not screened or undergo screening infrequently (1). In some cases cervical cancer is undetected despite a recent screening test because of errors in sampling, interpretation, or follow-up. Sampling errors occur when dysplastic cells on the cervix are not transferred to the slide; errors of interpretation are attributed to lack of recognition of abnormal cells in laboratory. These two sources of false-negative test results are associated with 30% of the new cases of cervical cancer each year (2). The problem of errors in interpretation is compounded by inconsistency among cytologists. Techniques on Cervical Cytology Sampling involves collecting exfoliated cells from the ectocervix and endocervical canal and transferring them to a glass microscope slide or into a liquid transport medium for review. Patient preparation and proper provider technique can help optimize the collection of cells (3): When performing cervical cytology by standard preparation, a single slide, combining both the endocervical and ectocervical samples, or two separate slides can be used. The most important consideration is rapid fixation. If liquid-based preparations are used, rapid immersion in liquid media is equally important. Screening Devices In 1980s new devices were developed for enhancing the collection of exfoliated cells from the cervix. These included nylon brushes for sampling the endocervix and "broom" sampling devices, which simultaneously sample both the ectocervix and endocervix. These devices have been shown to increase the amount of cells captured from the transformation zone and to increase the amount of dysplastic cells collected when compared with cotton-tipped applicators and wooden Ayre's spatulas. In 1996 the US Food and Drug Administration approved the first of two currently available liquid-based thin-layer cytology preparations for cervical screening. In addition, automated, computer-based technologies have been marketed that use digitally scanned images to facilitate primary screening. Cytologic Results The nomenclature for reporting cervical cytology results has undergone several changes. The Bethesda System of reporting is the most widely used system in the United States (4). In 2001 the revised terminology which is widely used in USA is as follows: Bethesda III System: Atypical Squamous Cells (ASC) Natural History of Cervical Neoplasia and Dysplasia Infection with HPV is a necessary factor in the development of cervical neoplasia and dysplasia; however, most HPV-infected women will not develop significant cervical abnormalities. The infection is easily transmitted during sexual intercourse. Cigarette smoking and compromised immune system appears to play a role in some women. The once widely held concept that low-grade lesions may progress to invasive cancer is doubtful. It is observed many women present with CIN 2 and CIN 3 without prior CIN 1 lesions. Foci of CIN 1 and CIN 3 with different HPV types have been reported in some cervical lesions. A few cases of invasive cancer of the cervix have been reported despite continuous and appropriate screening. A review of 30 years of the literature calculated pooled rates of progression from LSIL and HSIL to invasive caner to be 0.15% and 1.44%, respectively, over 24 months (6). In that analysis, 47% of LSIL and 35% of HSIL regressed to normal during the 2 year observation period. Cervical neoplasia and dysplasia develops in susceptible individuals in response to a sexually transmitted infection with a high-risk type of HPV. The cervix is especially vulnerable to this infection during adolescence when squamous metaplasia is most active. Human papillomavirus infections are commonly acquired by young women, but in most they are cleared by the immune system within 1-2 years without producing neoplastic changes. The risk of neoplastic transformation increases in those women whose infections persist. Most cervical squamous intraepithelial lesions do not progress to cervical cancer. It seems reasonable to begin cervical cancer screening approximately 3 years after initiation of sexual intercourse, but no later than age 21 years. Recognizing the time course in the progression of CIN and the unpredictable nature of follow-up in younger women, cytologic screening may be initiated earlier at the discretion of the healthcare providers. Optimal Frequency of Cervical Cytology Screening The optimal number of negative cervical cytology test results needed to reduce the false-negative rate to a minimum has not been demonstrated. Several practical considerations must be examined before biennial or triennial screening can be adopted as a national standard. American Cancer Society (ACS) and American College of Obstetricians and Gynecologists (ACOG) recommendations for Cervical Screening: Initiate Screening: Stop Screening: After Hysterectomy: Frequency of Screening: Additional Recommendations: Source: Saslow D et al (7) HPV's Role In Cervical Dysplasia and Cancer Human papillomavirus (HPV) is a sexually transmitted disease. The relationship between HPV infection and cervical cancer is known for decades. Over 100 types of HPV are known, and 13 to 15 of these are linked to cervical cancer. The subtype 16 (HPV-16) carries the highest risk for cervical cancer. Low-risk types that affect the genital tract usually manifest as genital warts. HPV is found in 99.7% of invasive cervical cancers and cancer/cervical intraepithelial neoplasia contains 1 of 13 oncogenic types. Millions of women in the United States and worldwide harbor HPV, but only a fraction develops cervical intraepithelial neoplasia or cancer. The prevalence of high-risk HPV infection is highest in women 20 to 24 years of age (24%) and decreases with age. When women older than 30 years of age have high-risk HPV infection, there is an increased risk for the development of high-grade lesions and cancer; women with persistent high-risk HPV infections are the population at greatest risk for developing cancer. Approximately 90% of HPV infections resolve within 2 years. Clinical progression to CIN 3 is mostly seen with high-risk HPV. DNA Testing and Clinical Utility in Triage: Several methods exist for DNA testing of HPV. Hybrid capture (Hybrid Capture 2, Digene Corp, Gaithersburg, MD) is the most common method in clinical use. It allows the separation of low- and high-risk subtypes. DNA testing was found to have greater sensitivity in detecting CIN 3 or more advanced lesions and showed specificity comparable to a single additional cytologic test indicating ASC-US or greater. DNA testing for HPV is an important tool in the management of women with an ASC-US cytologic diagnosis. Other issues that may impact the clinical utility of HPV testing include (8): In any sizable population, even among women with evidence of cytologic abnormalities, there will be a few cases of cervical pre-cancer that will test high-risk HPV negative for one or more reasons (10). HPV Vaccine Trials Vaccines for HPV can be separated into 2 different types: those aimed at prevention and those that focus on treatment. For prevention trials, the vaccine must be given before any viral exposure, and vaccination is performed with viral-like particles that allow the body to build immunity. To date, the only vaccines available protect against specific types of HPV rather than HPV infection in general (9). Summary The relationship between HPV infection with high-risk subtypes and cervical cancer is well-established. Results of clinical studies have demonstrated that reflex HPV testing has a role in triaging ASC-US patients identified with liquid-based cytology in clinical practice but has no role in LSIL or more advanced cases. The clinical utility of combining HPV/cytology testing as an alternative to Pap testing alone in women 30 years of age and older may serve to increase the necessary interval between Pap tests. Several HPV vaccination trials are under way and promise to provide more insight into the exciting possibility of eradicating HPV infections and thus cervical cancer. Healthcare providers should consider individualization in determining the time to begin screening, the interval between cervical cytology examinations, the age at which cervical cytology testing is no longer needed, and the testing methodology to be used. In addition to considering risk factors for cervical cancer, the provider ideally should be able to determine the patient's past screening history and reliability monitor the patient in the future. Yearly testing using cytology alone remains an acceptable screening plan. Regardless of the frequency of cervical cytology screening, women should be counseled that annual examinations, including pelvic examination, are still recommended. References: |