Cervical Dysplasia

Cervical Dysplasia and its Risk Factors

Cervical dysplasia refers to abnormal cells found on the surface of the cervix, that are considered to be premalignant and can progress to cancer.^[1] Cervical dysplasia is primarily caused by a sexually transmitted infection with different strains of the human papillomavirus (HPV). However, different strains can be involved in both benign and malignant lesions; therefore, the progression of the disease appears to depend on individual factors. Studies suggest that HPV exposure is the initiating event that can lead to the development of cervical dysplasia, often termed cervical intraepithelial neoplasia (CIN). HPV is the most common sexually transmitted infection in the U.S., with up to 80% of the adult population potentially being infected.^{[3, 4]} HPV is transmitted through skin-to-skin contact, and therefore condoms do not provide full protection; however, they can increase the likelihood of regression. The majority of genital HPV infections don’t cause symptoms, are often transient, and resolve spontaneously since the host’s immunity is able to defend against clinical disease.^[4] However, some cases do progress to cause abnormal cells, including cervical dysplasia and/or cervical cancer. Cervical dysplasia is treatable in its noninvasive state.^[3]

Even though HPV is the primary risk factor for cervical cancer and plays a role in cervical cancer development, other specific risk factors are associated with the development of cervical dysplasia. These include early sexual activity, multiple sexual partners, sexually transmitted diseases, oral contraceptive use, cigarette smoking, low socioeconomic status, immunosuppression, and poor diet Epidemiological and laboratory studies have suggested nutritional factors may play an important role in the development and progression of CIN and cervical cancer; therefore, primary prevention should focus on risk reduction. The most important way to reduce risk is to eliminate risky sexual behavior that increases exposure to HPV. Females are most susceptible to potential cancer development during adolescence and young adulthood due to the biological changes that occur in the cervix during puberty.^{[2, 5]} It is important to recognize that cervical dysplasia is not just a localized cervical tissue health issue, but actually involves the immune system health and the individual’s resistance to viral exposure.^[3] Oral contraceptives are known to potentiate the adverse effects of cigarette smoking and decrease several nutrients including vitamins C, vitamins B6 and B12, folic acid, riboflavin, and zinc.^[4]

Cervical Cancer

Squamous-cell cervical cancer is almost always preceded by cervical dysplasia.^[3] Cervical cancer is the second most common cancer in women between the ages of 20 and 39.^{[2, 6]} Cervical cancer is associated with long-term persistent HPV infection.^[4] There are over 50 strains of HPV, with the high-risk strains being 16, 18, and 31. These specific strains are associated with severe cervical dysplasia (CIN III) and cancer of the cervix, vulva, penis, and perineum.^[2] The time it takes from exposure to the appearance of a lesion or an abnormal Pap smear varies from a few weeks to decades.^[4] Symptoms of cervical cancer usually appear once the cancerous cells invade nearby tissue and include abnormal bleeding that occurs between regular menstrual periods, after sexual intercourse, douching, or a pelvic exam. Other symptoms may include bleeding after menopause, increased vaginal discharge, heavier and/or longer menstrual bleeding, and pain during intercourse.^[1]

Diet and Nutritional Supplementation

beta-Carotene and Vitamin A

Increased consumption of fruits and vegetables containing antioxidants is associated with lower risks for malignancies.^[2] Higher consumption of vegetables is associated with a 54% decrease in risk of HPV persistence.^[3] Fruits and vegetables are the primary dietary source of carotenoids, vitamin C, and folate, which may have synergistic effects in cancer prevention. Increased intake of foods rich in vitamin A, especially high-retinol foods such as carrots and spinach, may reduce the risk of developing early stage cancer while the high intake may inhibit progression to a more invasive form of this disease.^[2] Retinol intake and serum retinol levels have been found to be 4–5 times lower among women with cervical dysplasia who progress to in situ or invasive disease compared to women who experience disease regression.^{[2, 7]} Additionally, beta-carotene deficiency in the cervical cells has been linked to the development of cervical dysplasia; however, supplementation does not appear to have an effect.^{[3, 8]} It has been shown that 6% of patients with untreated cervical cancer have below-normal serum vitamin A levels.^[4] There is a three times greater risk of severe dysplasia when serum beta-carotene levels are low, and the severity of the dysplasia seems to correlate to the low level of beta-carotene.^{[4, 9, 10]} Carotenes and retinols improve the integrity and function of the epithelial tissues, act as antioxidants, and improve immune system function.^[4] Vitamin A and its analogues inhibit the proliferation of HPV infection via programmed cell death, also known as apoptosis, and inhibition of cell growth rates in laboratory studies.^[3]

Indole-3-Carbinol (I3C)
I3C is the phytochemical present in the members of the cruciferous vegetable family, which includes cabbage, broccoli, Brussels sprouts, cauliflower, and kale. I3C has been used to prevent and treat a number of cancers, especially those that are estrogen-related. I3C is converted to diindolylmethane (DIM) in the body and may be the predominant active agent. I3C can prevent transformation and/or tumor progression and can kill transformed cells selectively.^[2] I3C can act in several ways to prevent abnormal cell growth and prevent tumor progression.^[3] It has been demonstrated that women with moderate (CIN II) and severe (CIN III) dysplasia have lower 2-hydroxyestrone:16 alpha-hydroxyestrone ratios than women with no abnormal cervical pathology.^{[2, 11]} I3C and DIM are able to achieve apoptosis in the cervical tissue of mice, and therefore show promise for the treatment of cervical dysplasia.^{[2, 12]}

Folate/Folic Acid
Folate deficiency has been linked to cervical dysplasia.^[2] It is thought that folate deficiency allows the HPV to be more easily incorporated into a person’s DNA.^{[2, 13]} Deficiency impairs DNA synthesis, which is crucial to cell reproduction, growth, and differentiation. Tissues that are low in folate are at risk of developing weak areas of DNA, which increases attachment by carcinogens and viruses, increases potential for chromosomal damage and cancer-promoting gene expression, and inhibits DNA repair.^[2] Low levels of folic acid in the blood have been associated with a moderately increased risk of invasive cervical cancer.^[3] Folic acid deficiency is common and oral contraceptive use increases the risk of deficiency.^[4] Folate has been used in women with mild and moderate cervical dysplasia, and has been shown to improve or normalize cytologic smear in patients with cervical dysplasia.^{[3, 4]}

Green Tea
Two constituents of green tea, polyphenol E and epigallocatechin-3-gallate (EGCG), have been effective against HPV-infected cervical cells and lesions. These constituents have antitumor effects.^[3] The use of EGCG or high green tea consumption could reduce the incidence of cervical cancer or delay the progression of precancerous lesion.^[14]

Conventional Strategies

Pap smears play the most important role in the prevention of cervical cancer and in detecting milder grades of cervical dysplasia.^[3] Annual screening is recommended for women up to the age of 29, with the time between Pap smears increasing to 2 to 3 years after this age. Screening generally begins 3 years after the onset of vaginal intercourse and should occur no later than 21 years of age. Since regular PAP smears are currently part of our health-care model, cervical dysplasia is generally discovered before it becomes an invasive cervical cancer. If a Pap result comes back abnormal, patients are told to have a repeat Pap in six months to see if the lesion spontaneously remits.^[2] If another abnormal Pap smear is obtained, the next step is a referral to a gynecologist to have a colposcopy. Colposcopy involves the use of a scope in order to visualize the cervix while white vinegar is applied to the tissue to detect abnormal tissue. The table below summarizes the potential results of a Pap smear and their meaning, as well as recommended course of action.^[3]

If the biopsy shows dysplasia, ablation or destructive procedures may be considered. These include cryotherapy, carbon-dioxide laser, and electrocautery. Removal procedures are another option, and include cone biopsy and loop electrosurgical excision procedure (LEEP). All of these procedures remove the dysplastic cells and allow new cells to replace the old ones. They have a success rate of approximately 90% when used correctly. Despite these techniques being relatively safe and effective in preventing future cervical cancer, their effects on future fertility and pregnancy outcomes remain unclear.^[3] The HPV vaccine targets two of the main strains that are commonly associated with cervical cancer, and other strains associated with genital warts. HPV-16 vaccine has reduced the incidence of both HPV-16 infection and HPV-16–associated cervical dysplasia.^[3]

Conclusion

In conclusion, there are many risk factors associated with the development of cervical dysplasia and cervical cancer. Nutritional supplementation may be a worthwhile treatment approach in the noninvasive stages of this disease. It is absolutely critical to have an accurate diagnosis and sufficient evaluation in order to determine the best treatment course.^[3]