Commentary (Sedlis)-Human Papillomaviruses: Their Clinical Significance in the Management of Cervical Carcinoma

Cervical cancer, which has claimed over 4,500 deaths annually in the United States and hundreds of thousands of lives in other parts of the world, is a preventable disease. Most cervical cancers are preceded by a prolonged phase of cervical intraepithelial neoplasia (CIN) that may be detected by cytologic screening and successfully treated so that its progression to invasive cancer is halted. Consequently, for the past 3 to 4 decades, most women in North America and Western Europe have been periodically screened by Pap smears. During this period, the incidence of invasive cervical cancer in the United States fell by 75%, from 32.6 cases per 100,000 women in 1940 to 8.3 per 100,000 in 1984 [1]. Similar drops in cervical cancer rates were recorded in Canada and Western Europe.

Numerous epidemiologic studies have documented the role of cytologic examinations in reducing the frequency of cervical cancer by demonstrating that the decrease in cancer rates occurred specifically in the screened population. Conversely, rates of cervical cancer remained high in those countries in which cytologic screening was not practiced. For example, in India, the age-standardized incidence of cervical cancer is 46 cases per 100,000 women [2], compared with 2.6 per 100,000 in the United States for white women and 7.6 per 100,000 for black women [3].

Drawbacks of Current Screening Methods

Although the results achieved by cytologic screening and treatment of CIN are spectacular, the methods used in screening programs have many drawbacks and need to be improved. The main deficiency of cervical/vaginal cytology is its low sensitivity. The high incidence of false-negative results is responsible for numerous missed cancer diagnoses.

Another drawback of cytologic screening is the high cost of yearly medical visits, equipment , and supplies for taking smears, as well as the salaries of cytologic screeners. The high cost of screening is the main obstacle to the adoption of universal Pap smear programs in most countries, and also is the reason cited for recommendations to "ration" cytologic services in the United Kingdom and in this country.

The triaging system for women with abnormal Pap smears currently relies on colposcopy to determine whether a positive Pap test is due to cancer, CIN, or benign changes. Cervical intraepithelial neoplasia is treated by various ablative methods; increasingly, by means of the loop electrosurgical excision procedure. The routine use of colposcopy to evaluate women with abnormal smears and of ablative methods to treat CIN is considered by many critics as excessively aggressive, since most low-grade CINs may spontaneously regress.

The Bethesda terminology system for Pap smears has been blamed for the increased numbers of colposcopy referrals, by creating the category of atypia of squamous cells of undetermined significance and by including koilocytotic atypia into the category of low-grade squamous intraepithelial lesions. However, at present no methods are available that safely predict which of the low-grade cytologic abnormalities are of no consequence and which may progress to cancer. The cost of routine colposcopy is also high, estimated at over $6 billion per year. Therefore, a search for an alternative approach is being explored.

HPV and Cervical Cancer

Much evidence has accumulated during the last decade in support of the key role of human papillomavirus (HPV) in the etiology and pathogenesis of anogenital squamous carcinoma. The possibility that sexually transmitted infection plays a role in the etiology of cervical cancer was strongly suggested by numerous epidemiologic studies. In 1976 and 1977, attention was directed to HPV as the most likely infectious agent responsible for this cancer when a close association was observed between CIN and HPV infection, as demonstrated by cell morphology, immunocytochemistry, and electron microscopy.

The main support for HPV in cancer etiology came from the finding that DNA sequences of HPV were integrated into the cell genome of most cervical cancers. Subsequent developments in molecular biology techniques led to the elucidation of the steps of HPV carcinogenesis: (1) inactivation of the E2 region, with loss of repression and consequent overexpression of E6 and E7 oncoproteins; and (2) inactivation of p53 and pRb tumor-suppressor factors by these oncoproteins, which, in turn, promotes unrestricted cell proliferation.

The article by Hines, Jenson, and Barnes provides a comprehensive review of recent advances in the study of HPV and its role in the etiology and pathogenesis of cervical cancer. The authors point out, quite correctly, that identification of the heretofore elusive infectious agent of cervical cancer opened new avenues of approach to cancer prevention and treatment. For example, molecular tests for human papillomavirus DNA may become useful adjuncts to cervical smears for cancer detection. Preliminary reports show that testing for human papillomavirusDNA in cell washings, together with standard cytology, increases the sensitivity of detection of cervical neoplasms from 74% by Pap smear alone to 98.1% [4].

Today, improved DNA techniques, such as the polymerase chain reaction, offer lower cost and greater rapidity and dependability than the original hybridization tests, and make molecular tests increasingly attractive for clinical use. DNA testing for HPV types associated with a "high-risk" of cancer (eg, types 16 and 18) has been proposed as a method for triaging women with low-grade Pap smear abnormalities. Screening out women not infected with high-risk HPV types would reduce the number of colposcopy referrals, thus addressing concerns about the excessive cost of routine colposcopy for mildly abnormal Pap smears.

Prospects for a Vaccine

The most recent advances in HPV research, involving recombinant viral capsids with neutralizing conformational epitopes, may eventually lead to the development of serologic tests for HPV infection, and even to the manufacture of an anti-HPV vaccine for humans. Availability of serologic tests will greatly facilitate studies of the epidemiology of HPV infection, such as prevalence, trends, and infectivity. This important information is still lacking, due to the inability to propagate this virus in the laboratory.

The prospect for a vaccine against high-risk HPV types, described in the article by Hines et al, is exciting. Vaccination to prevent infection and neoplasia could become a valuable alternative to the laborious and costly cytologic screening, especially in countries that cannot afford Pap smear programs. Equally exciting is the potential for manipulating the immune system to improve the tumor-killing capacity of cytotoxic T lymphocytes and the use of antisense messenger RNAs to HPV types E6 and E7 to inhibit growth of established cancer cells bearing E6 and E7 viral sequences.

Considering the rapid path of current investigations into the cellular mechanisms of HPV and their role in oncogenesis, practical application of the newly found knowledge may be not far off. Some of the molecular techniques, eg, use of human papillomavirus DNA testing for following women with abnormal Pap smears, are about to enter the clinical trial phase.

Despite the rapid progress in the study of HPV molecular biology, no substantial impact of this line of research on cervical cancer mortality is expected in the near future. The exciting potential of an anticancer vaccine and molecular cancer therapy should not impede ongoing efforts to improve the efficiency of standard methods of cervical cancer detection and treatment.

References:

1. Devesa SS, Silverman DT, Young JL, et al: Cancer incidence and mortality trends among whites in the United States 1947-1984. J Natl Cancer Inst 79:701, 1987.

2. Luthra UK, Rengachari R: Organization of screening programs in developing countries with reference to screening for cancer of the uterine cervix in India, in Hakama M, Miller AB, Day NE (eds): Screening For Cancer of the Uterine Cervix, pp 279-292. Lyon, France, International Agency for Research on Cancer, 1986.

3. Black-white differences in cervical cancer mortality-United States, 1980-1987. Morbid Mortal Weekly Rep 39:245-248, 1990.

4. Ritter DB, Kadish AS, Stein HV, et al: Detecting of human papillomavirus deoxyribonucleic acid in exfoliated cervicovaginal cells as a predictor of cervical neoplasia in a high risk population. Am J Obstet Gynecol 59:1517-1525, 1989.