Cervical cancer and dysplasia

Abstract

Cervical cancer is the second-most common cancer in young women and is one of the most common causes of cancer deaths among women, particularly in minorities and in impoverished countries. Cervical dysplasia, a premalignant lesion that can progress to cervical cancer, is caused primarily by a sexually transmitted infection with an oncogenic strain of the human papillomavirus (HPV). Not all women with the virus develop cervical dysplasia or cervical cancer. It has been postulated there are multiple host factors that contribute to progression of disease. Many of these factors, such as nutrient deficiencies, can be reversed, which will result in regression of dysplastic lesions. Studies have shown dietary intervention and nutrient supplementation to be effective in preventing cervical cancer. Additionally, local escharotic treatment combined with systemic treatment shows significant potential in reducing dysplasia. Recent advances in vaccination technology demonstrate the effectiveness of an HPV vaccine. The vaccine, however, may have many social and cost-prohibiting limitations, as well as health side effects.

Introduction and Epidemiology

Cervical dysplasia is a premalignant lesion that can progress to cervical cancer, a common epithelial cancer that is the second-most common cancer in women age 20-39 years. (1) It disproportionately affects minority women and women living in underdeveloped countries. (2) Internationally, invasive cervical cancer accounts for 11.6 percent of all cancers. For every case of invasive cancer there are an estimated 50 cases of abnormal cervical smears that require monitoring and follow-up. (3) Current evidence suggests this lesion is primarily caused by a sexually transmitted infection with an oncogenic strain of the human papillomavirus (HPV). However, since this viral genome is found in healthy women as well as in healthy tissue adjacent to neoplastic lesions, factors unique to individual hosts appear to contribute to disease progression and dysplastic transformation.

Invasive cervical cancer develops from precursor lesions of the cervix called cervical intraepithelial neoplasia (CIN). Progression from normal tissue to invasive cervical cancer occurs through a series of increasing grades of cervical dysplasia (Figure 1). CIN I represents mild dysplasia and has a high rate of spontaneous remission (60%) and a low rate of progression to carcinoma. In contrast, approximately 38 percent of CIN II and III, moderate to severe dysplasia, will spontaneously regress, and 16-36 percent will progress to invasive cervical cancer. (4) Because reporting for CIN is not mandatory, the exact incidence is unknown. However, it is estimated that 2.5 million women are diagnosed with low-grade cervical abnormalities annually. (5)

[FIGURE 1 OMITTED]

Routine PAP smear screening is widely credited with reducing cervical carcinoma from the first to the eighth leading cause of cancer death in the United States, but the number of deaths attributable to the disease is still high (approximately 4,900 deaths). Additionally, the medical costs of providing PAP screening are considerable and a significant economic burden to health care systems. (6) Millions of ablative procedures (e.g. cryotherapy, electrocautery, cone biopsy) are performed each year as an approach to treatment. Screening is not available to all women, mainly due to lack of insurance or lack of insurance-wellness plans. In countries without screening, cervical cancer is the leading cause of cancer death in women.

Risk Factors

It is undisputed that infection with sexually acquired HPV is the primary risk factor for cervical cancer and plays a critical role in cervical carcinogenesis. (7,8) Several other cofactors have been implicated in the progression of low-grade to high-grade lesions and/or the development of cervical cancer, but these remain controversial in clinical trials. (9) These include early age at first intercourse, history of multiple sexual partners, oral contraceptive use, (10) high parity, low socioeconomic status, poor diet, cigarette smoking, (11) immunosuppression, (12) and promiscuous male sexual partners. (13) In one study, with respect to current use, the risk for cervical dysplasia increased for women who had been using oral contraceptives longer than 10 years. (14) A summary of risk factors is outlined in Table 1.

The correlation between cervical dysplasia and oral contraceptives is based on the premise that steroid hormones, such as estrogen and progesterone, are thought to play a role in the progression of disease. Progesterone has been reported to increase HPV-16 and HPV-18 gene expression at the levels of transcription and mRNA stability. (15,16) Most cases of cervical cancer are in the most estrogen-sensitive region of the cervix known as the transformation zone, (17) an area that displays a high level of conversion of estradiol to 16[alpha]-hydroxyestrone. When HPV-16 DNA immortalizes these cells, this activity increases eightfold. (18) Furthermore, the incidence of HPV DNA in exfoliated cervical cancer cells increases during pregnancy when estrogen levels are highest. (19)

The prevalence of HPV has steadily risen over the past few decades. In the United States, the Centers for Disease Control documented a 459-percent rise in the number of visits to private clinics for condyloma acuminata, a genital lesion caused by HPV, between 1966 and 1981. (20) That number continues to rise. Based on data from a cohort of 22-year-old Finnish women, an estimated 79 percent of Finnish women between the ages of 20 and 79 will contract at least one HPV infection. (21)

Certain HPV types are associated with certain types of disease, although a given HPV type can cause a range of diseases. HPV are double-stranded DNA viruses of approximately 8,000 base pairs. Over 60 types of HPV have been identified. HPV types 6 and 11 are considered low risk and are commonly associated with condyloma acuminata of the lower genital tract and flat cervical condyloma. The medium risk groups, HPV types 33, 35, 39, 40, 43, 45, 51-56, and 58, are associated with low-grade genital dysplasia and carcinomas. The high-risk group of HPV types 16, 18, and 31 are associated with CIN III and malignant neoplasia of the penis, cervix, vulva, and perineum (Table 2). (22)

Although risk for cervical cancer is significantly higher with the presence of HPV infection, HPV infection alone may be insufficient to cause cervical cancer. Approximately 28 percent of women with HPV go on to develop CIN. (23) Current studies indicate HPV exposure is the initiating event. However, for the lesion to be persistent or progress to cervical cancer, other risk factors must be present. Over the past two decades, numerous epidemiological and laboratory studies have suggested nutritional factors may play an important role in the development and progression of CIN and cervical cancer.

Primary Prevention

Because a number of important epidemiological risk factors have been identified as contributing to the development of CIN and cervical cancer, primary prevention should be geared toward risk reduction. Of utmost importance with regard to risk reduction is the elimination of risky sexual behavior that increases exposure to HPV. Such behaviors include early sexual experiences, number of sex partners, and male partner factors such as history of venereal disease and number of sex partners. (24-26) The target population is primarily adolescents and young adults. (27) Women are most susceptible to potential carcinogens such as HPV during this period. (28)

It has been proposed that adolescents are at a greater risk for cervical dysplasia than adult females because of biological changes occurring in the cervix during puberty. (29) A study conducted by Massad and Anoina reported that cervical dysplasia is prevalent in as many as 21 percent of adolescent females. (30) In this population, sexual behaviors are initiated and lifelong patterns are established. Among sexually active adolescents, interventions should include increased condom use, improved communication with partners and peers, and addressing risk behaviors. It is also important for women to understand they can be infected with different strains of HPV with a new partner. Existing infection often lowers host immunity and makes women more susceptible to additional strains of HPV as well as other sexually transmitted diseases. Additionally, risk factors such as smoking need to be addressed at this time. There appears to be a significant correlation between risk of dysplasia and cigarette consumption. One study demonstrates the risk for cervical dysplasia rises with increased number of sex partners, dependent on the number of cigarettes smoked. (31)

Nutritional Intervention