17: Cervical Dysplasia and Cancer

CHAPTER 17 Cervical Dysplasia and Cancer


The incidence of cervical cancer has declined dramatically in the United States since 1950, primarily as a result of early detection through the use of the Papanicolaou, or Pap, smear. Mortality from cervical cancer has also been reduced by early treatment of precancerous lesions. Between 1973 and 1995, the Surveillance, Epidemiology, and End Results Program (sponsored by the National Cancer Institute) documented a 43% decrease in incidence and a 46% decrease in mortality from cervical cancer. Cervical cancer has declined from the leading cause of cancer mortality in women in the United States in the 1950s; it is now 13th on the list. The American Cancer Society estimates that about 12,200 cases of invasive cervical cancer will be diagnosed in 2003. Early diagnosis and treatment remain critical; the 5-year survival rate is roughly 92% for localized cancer. However, access to health care is not equal in the United States, leading to higher mortality rates among minority women and poor women.1


When the global situation is considered with regard to cervical cancer, it is apparent that early screening and treatment programs must be improved for the number of deaths from cervical cancer to be reduced. The development and implementation of an effective vaccine for the prevention of human papillomavirus (HPV) infection would also help reduce cervical cancer, especially in those areas where access to care is limited. Cervical cancer is still the second leading cause of cancer deaths among women worldwide and remains the leading cause of cancer death among women in Central America, Southwest Asia, and sub-Saharan Africa. See Box 17-1 for cervical cancer risk factors.



Box 17-1 Risk factors for cervical cancer in all populations



image Early age at time of first intercourse (<18 years)

image Multiple male sexual partners

image Mother took diethylstilbestrol (DES) during pregnancy

image History of sexually transmitted diseases, including HPV and human immunodeficiency virus

image Cigarette smoking (the incidence of cervical cancer is two to three times greater in smokers*

image Immunocompromise


* From Lyon J, Gardner J, West D, et al: Smoking and carcinoma in situ of the uterine cervix, Am J Pub Health 73:558-562, 1983.



CAUSES OF CERVICAL CANCER



Human Papillomavirus


The HPVs comprise more than 100 different types of viruses; approximately 40 of these are transmitted sexually. In human beings, approximately 60 different types of papillomaviruses have been identified (Table 17-1).


Table 17-1 HPV
























VIRUS TYPE ASSOCIATED LESION
HPV-1 and 4 Plantar warts
HPV-2,7,27, and 29 Common warts
HPV-3,10,26, and 28 Flat warts
HPV-5 and 8 Skin cancer (in those with epidermodysplasia verruciformis)
HPV-6 and 11 Genital warts
HPV-16,18,31,33,45, and others Cervical cancers

For many years, researchers considered cervical cancer a sexually transmissible disease. It is extremely rare in nuns and is found most often in women with multiple male sexual partners. However, it was not until 1983 that the connection between HPV and cervical cancer was finally established, when HPV-16 was isolated from cervical cancer tissue. This same virus was found in tissue taken from cancers of the penis, vulva, and anal region. Fifty percent of these tumors contain HPV-16, 20% contain HPV-18, 10% contain HPV-33, and 10% contain various other HPV types. Clearly, 90% of all cervical cancers are linked to prior or current infection with HPV.2 The National Institutes of Health Consensus Conference on Cancer of the Cervix and the World Health Organization have concluded that a cause-and-effect relationship exists between HPV and cervical cancer.


As viral DNA from HPV integrates into the host cell genome, the expression of viral E6 and E7 proteins can lead to the development of cervical cancer. The E6 and E7 proteins inactivate host proteins that normally control cell growth.3 The latency period between the time of infection and cervical carcinogenesis is long (10 to 20 years),4 leading researchers to theorize that other risk factors must be present for cancer to develop. As one author notes, HPV is a necessary but not sufficient cause for cervical cancer.5 This situation opens the possibility that risk may be modified through various lifestyle and complementary modalities.



Chlamydia trachomatis


After HPV infection is taken into account, prior cervical infection with C. trachomatis is associated with an increased risk for the development of invasive cervical cancer. A large study was undertaken to determine the role of C. trachomatis infection as a cause of invasive cervical cancer among women with HPV infection. A total of 499 women with invasive cervical cancer and 539 control patients from São Paulo, Brazil, and Manila, the Philippines, were included. C. trachomatis infection was found to double the risk of cervical cancer among HPV-positive women from both countries. It seems possible that cancer risk increases with higher C. trachomatis antibody titers.6


A longitudinal Swedish study showed a relative risk of 17.1 for cervical cancer associated with past C. trachomatis infection.7 Other researchers have documented a causal relationship between HPV and C. trachomatis infections in the development of cervical neoplastic disease.8 CT infection may act as a cofactor to HPV in the development of cervical cancer by modulating the host’s immunity or by inciting chronic inflammation.9 C. trachomatis infection increases the expression of HPV-16, suggesting that C. trachomatis has the ability to modify HPV activity.10



Oral Contraceptive Use


The long-term use of oral contraceptives has been linked to an increased risk of cervical cancer. A review published in the Lancet showed that, compared with those of women who had never used oral contraceptives, the relative risk of cervical cancer increased with longer duration of use. For durations of less than 5 years, 5 to 9 years, and 10 or more years, respectively, the relative risks were 1.1 (95% confidence interval 1.1-1.2), 1.6 (1.4-1.7), and 2.2 (1.9-2.4) for all women; and 0.9 (0.7-1.2), 1.3 (1.0-1.9), and 2.5 (1.6-3.9) for HPV-positive women. The results were broadly similar for invasive and in situ cervical cancers and in studies adjusted for HPV infection status, number of sexual partners, cervical screening, smoking, and use of barrier contraceptives.11


An important question is whether a link exists between the use of oral contraceptives and persistent HPV infection. Preliminary research has shown that high-risk–type HPV-16 stimulates the development of vaginal and cervical squamous cell carcinomas in transgenic mice exposed to slow-release pellets of 17β-estradiol. An oncoprotein of HPV-16 has been shown to bind to a tumor suppressor gene and stimulate its degradation. Steroid hormones are believed to increase the expression of HPV-16 oncogenes, which in turn bind to and degrade the tumor suppressor gene product, leading to carcinogenesis.12


Although these findings suggest a mechanism by which oral contraceptives may enhance the carcinogenic potential of HPV, a recent systematic review of 19 epidemiologic studies of the risks of genital HPV infection and oral contraceptive use failed to reveal any evidence of a strong positive or negative association between HPV infection and the use of oral contraceptives.13 These data should be judged with some caution because of the heterogeneity of reports and confounders. Whether long duration of use increases the persistence of HPV infection remains uncertain.


The preceding information must be considered alongside the benefits of oral contraceptive use, which include an effective means of birth control and a reduction of ovarian cancer risk of up to 40% to 50%, especially when taken for at least 5 years. Unplanned pregnancies can be devastating, and ovarian cancer is the leading cause of death from all types of gynecologic cancer. Women should discuss the use of oral contraceptives with their health care provider, especially if they are at high risk (have a first-degree relative or genetic mutation) for ovarian cancer.



Vaccine for Human Papillomavirus


Intense research is currently under way to develop a reliable vaccine for the prevention of HPV and cervical cancer. A double-blind study randomly assigned 2392 women (ages 16 to 23 years) to receive three doses of placebo or HPV-16 virus-like–particle vaccine (40 μg per dose), given at day 0, month 2, and month 6. Genital samples to test for HPV-16 DNA were obtained at enrollment, 1 month after the third vaccination, and every 6 months thereafter. Women were referred for colposcopy according to a protocol. Biopsy tissue was evaluated for cervical intraepithelial neoplasia and analyzed for HPV-16 DNA with use of the polymerase chain reaction. The primary analysis was limited to women whose results were negative for HPV-16 DNA and HPV-16 antibodies at enrollment and HPV-16 DNA at month 7. Women were followed up for a median of 17.4 months after completing the vaccination regimen. The incidence of persistent HPV-16 infection was 3.8 per 100 woman-years at risk in the placebo group and 0 per 100 woman-years at risk in the vaccine group (100% efficacy; 95% confidence interval, 90-100; P <0.001). All nine cases of HPV-16–related cervical intraepithelial neoplasia occurred among the placebo recipients.13a


Several clinical trials investigating HPV vaccines are currently under way with the great hope that cervical cancer will soon go the way of smallpox and polio.



Genetic Factors


In light of the fact that cervical cancer never develops in a significant number of women with HPV infection, the role of genetics is being studied. Researchers have found an association between immune response genes and the risk of cervical cancer. Preliminary data suggest that the problem lies in a gene, or a cluster of genes, in the human leukocyte antigen region of chromosome 6, resulting in host immune responses to HPV infection that lead either to inherited susceptibility or resistance to the transforming properties of oncogenic papillomaviruses.14



SYMPTOMS OF CERVICAL CANCER


Early cervical cancer is usually asymptomatic. As the cancer advances, abnormal vaginal bleeding may occur, including spotting between menstrual periods, pink-tinged vaginal discharge, heavy menstrual periods, and bleeding after intercourse. Other symptoms include leg, back, or pelvic pain; swelling of the legs; and painful urination.



PREVENTION AND TREATMENT OF CERVICAL DYSPLASIA WITH NUTRITION AND DIETARY SUPPLEMENTS


This section focuses mainly on the evidence of safety and benefit for dietary supplements in the prevention and adjuvant treatment of cervical dysplasia. The appropriate guidelines for the current standard of care for the diagnosis, management, and treatment of abnormal Pap smear findings should be consulted.



Nutritional and Dietary Supplements


Nutritional deficiencies may be a cofactor in the development of cervical cancer. In general, research has demonstrated an inverse association between cervical cancer risk and dietary intake of dark green and yellow vegetables, vitamins C and E, and carotenoids. Researchers have examined the association of cervical cancer and diet for many years. Many of the early studies did not control for cigarette smoking, oral contraceptive use, or HPV infection. Oral contraceptives and cigarette smoking decrease serum levels of β-carotene, ascorbate, and folate, and these confounders must be adequately considered for a study to be valid. The following is a summary of the research available on nutrients that are thought valuable in the prevention of cervical cancer.



Carotenoids.


A great deal of information is available on the inverse relationships between β-carotene and other carotenoids and the risk of invasive cervical cancer. Low serum levels of retinol (vitamin A) have been associated with increased risk, whereas high intake of carotenoids15 and total vitamin A16 has been associated with a lower risk of precancerous and cancerous cervical lesions.17 Lycopene, a carotenoid found in tomatoes, pink grapefruit, watermelon, and other foods, may also offer protection against persistent HPV infection.15 Higher levels of vegetable consumption have been associated with a 54% decrease risk of HPV persistence. A 56% reduction in the risk of persistent HPV was observed in women with the highest plasma lycopene concentration compared with women with the lowest plasma lycopene concentration.18 Deficiency of β-carotene in cervical cells is believed to play a role in the development of cervical dysplasia,19 and low plasma levels of β-carotene have been noted in women with cervical cancer.20 A variety of mechanisms, including antioxidant protection, inhibition of viral gene expression, and modulation of immune response, have been proposed.21


In spite of the aforementioned research, clinical trials have not demonstrated a solid therapeutic role for β-carotene in the treatment of cervical dysplasia. A randomized, placebo-controlled, multicenter trial involving women with confirmed cervical intraepithelial neoplasia (CIN) was conducted in The Netherlands. Women received placebo (n = 141) or 10 mg/day β-carotene (n = 137) for 3 months. After 3 months, Pap smears, colposcopies, and, when necessary, biopsies were performed. Cervical cancer risk was comparable between the groups. Eighty-three percent of participants were available for evaluation at the end of the trial. Thirty-two percent of participants in both the control and treatment groups demonstrated regression to normal. No effect of β-carotene on the regression percentages was observed.22 Potential confounders include lack of dietary control (the placebo group had a slightly higher intake of β-carotene in their daily diet than the supplemented group), the dose of β-carotene may have been too low, duration of therapy too short, and HPV status of women was not determined.


In a 1997 double-blind, placebo-controlled study, 98 women with moderate cervical dysplasia were randomly assigned to receive 30 mg/day of β-carotene or placebo for 9 months. Patients were evaluated at 3, 6, and 9 months by questionnaire, plasma levels of micronutrients, and findings of cervicovaginal lavage for the detection of HPV. Colposcopy with biopsy was performed at the conclusion of the trial in 69 women. Seventy percent of women in the placebo group were found during the baseline examination to have a lesion, compared with just 36% of the women in the treatment group. The treatment group demonstrated serum β-carotene levels several times greater than those in the placebo group; however, 25% of the control group took multivitamins containing β-carotene. More than 60% of the women in the placebo group who had initial lesions demonstrated regression to a lower grade lesion, and 47% demonstrated regression to normal. Only 23% of women in the treatment group demonstrated regression to normal. Independent risk factors for persistent CIN at 9 months included type-specific persistent HPV infection and continual HPV infection with high viral loads at baseline and 9 months. After controlling for these factors, the researchers found that the β-carotene and placebo groups did not differ in their risk for CIN after 9 months. CIN regression was not related to the serum β-carotene level.23 Failure to control for dietary carotenoid intake and supplement use in this study is definitely a limitation.


A double-blind, placebo-controlled, randomized study involving dosages of 30 mg/day of β-carotene, 500 mg/day of vitamin C, or both, failed to show benefit over placebo in 141 women with CIN over a 2-year period.24 A more recent double-blind, placebo-controlled trial of 103 women with relatively advanced cervical dysplasia (CIN stage 2 or 3) who were given either placebo or 30 mg/day β-carotene revealed no difference between the groups at the end of the 2-year trial.25


Although preliminary research suggested benefit, the data from these four randomized, placebo-controlled trials are not supportive of the theory that β-carotene increases the rate of regression in cervical dysplasia. However, methodological shortcomings of the clinical trials have been mentioned and must be considered when considering the totality of evidence to date. β-Carotene in supplement form has been found ineffective against the risk of other cancers. It may be that combinations of carotenoids and other antioxidants typically found in fruits and vegetables would be more effective. It may also be that the real strength of carotenoids is a lifelong exposure to prevent cervical abnormalities and not once the abnormalities are already present.



Folate and vitamin B12.


Folic acid is a cofactor in many biochemical processes. It is essential to the formation of thymidilate, which is the rate-limiting step in DNA synthesis. Low folic acid intake is thought to be associated with an increased risk of cervical cancer.26 Some authors suggest that folic acid reduces the risk of cervical cancer by inhibiting the incorporation of HPV genes into chromosomal sites in affected cells.27 Low red blood cell folate levels may be a risk factor for abnormal cytologic smears in cervical dysplasia and more severe lesions.28


One study randomly assigned 235 women with CIN I or CIN II to receive 10 mg/day of folate or placebo for 6 months. Clinical status, HPV-16 infection, and blood folate levels were assessed at 2-month intervals, and a punch biopsy was performed at the end of the study. Prevalence of HPV-16 infection at baseline was 16% among subjects in the upper range of red blood cell folate, compared with 37% in those in the low range. Serum folate levels in the treatment group increased significantly, and 85% of participants completed the trial. At the end of the trial, no significant differences were detected between the treatment and placebo groups with regard to dysplasia status, biopsy results, or prevalence of HPV-16 infection. Half of the women in each group had normal Pap smears, and two thirds had normal findings on cervical biopsy. The authors concluded that “folate deficiency may be involved as a co-carcinogen during the initiation of cervical dysplasia, but folic acid supplements do not alter the course of established disease.”29


A 1995 double-blind, placebo-controlled study randomly assigned 331 women with biopsy-proven koilocytic atypia, mild CIN, or moderate CIN to receive oral folic acid (5 mg) or a similar-appearing placebo daily for 6 months. After a 1-month run-in period, cervical cytologic studies and colposcopy were repeated, and 45% of participants were found to be without detectable lesions; however, all of the participants continued the study. Pap smears, colposcopy, and assessment of serum vitamin levels (folate, retinol, alpha-tocopherol, β-carotene, and retinyl palmitate) were conducted at 3 and 6 months. No HPV analysis was performed. Median serum folate levels in the treatment arm at 3 and 6 months (29.0 and 20.0 μg/dL) were significantly higher than those in the placebo arm (7.8 and 7.1 μg/dL, respectively), and 79% of all participants finished the study. At the trial’s conclusion, 7% of the treatment group and 6% of the placebo group demonstrated regression to a milder dysplasia or complete resolution.30


Although most research has been focused on folate, the relationship between folate and vitamin B12 in the synthesis, repair, and methylation of DNA suggests that it might be better to study folate along with vitamins B6 and B12. Homocysteine, which is produced during methionine metabolism, is often used as a marker of low folate and B12 levels. Vitamin B12 is a cofactor for methionine synthase, an enzyme that catalyzes the conversion of homocysteine to methionine and controls cellular folate uptake.31


Even in the face of clinical trials that fail to show that these vitamins are effective in the treatment of CIN, the basic science suggests that they may play a role in the prevention of cervical abnormalities, thus making recommendation of a multivitamin with folate and B vitamins for women of all ages a wise one.


Multivariate logistic regression analysis was used to determine the adjusted odds ratios for persistent HPV infection associated with individual nutrients among 201 women with persistent or intermittent HPV infection. Circulating levels of vitamin B12 were inversely associated with HPV persistence after adjustment for age, age at time of first intercourse, marital status, cigarette-smoking status, race, and body mass index. In addition, women with circulating levels in the highest tertile of vitamin B12 were less likely to have a persistent infection.32 In a large, multiethnic community-based case-control study of invasive cervical cancer in five areas of the United States (183 cases, 540 controls), it was found that the risk of invasive cervical cancer was substantially and significantly greater in women in the upper three homocysteine quartiles.33 Other researchers have shown that serum homocysteine is significantly predictive of the risk of invasive cervical cancer, reflecting folate, B12, or B6 inadequacy or genetic polymorphisms.34


Even in the face of clinical trials that fail to show that these vitamins are effective in the treatment of CIN, the basic science suggests that they may play a role in the prevention of cervical abnormalities, thus making recommendation of a multivitamin with folate and B vitamins for women of all ages a wise one.

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  2. 6: Menopause
  3. 18: Urinary Tract Infection
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Nov 4, 2016 | Posted by in OBSTETRICS | Comments Off on 17: Cervical Dysplasia and Cancer

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