Epidemiology and Natural History

Almost all cervical cancer is associated with long-term persistent HPV infection, which is easily transmitted by genital-to-genital contact. The time from exposure to the appearance of a lesion or an abnormal Pap smear can range from a few weeks to decades. The incidence of medical visits for HPV disease has increased more than 500% in the past 30 years and HPV infection is considered epidemic by many. It is now so common that up to 80% of the adult population may be infected. HPV DNA tests have documented the presence of HPV DNA in at least 60% of young women; however, less than 10% develop cervical lesions. This suggests that the host immunity is able to defend against the development of clinical disease, and that HPV infections are often transient and result in minor manifestations such as ASC-US. For other individuals, especially women, HPV results in a clinical expression to which the host immune response has not been able to respond effectively. The result is clinical disease that can include flat or raised genital warts; cervical, vaginal, vulvar, or perianal dysplasias; or progression to invasive cancers of the same site. The first step in the development of dysplasias or invasive cancers is viral entry. A complex interaction of host immunity, viral load, viral type, and host susceptibility determines the natural course of the disease. HPV is implicated as the etiology of cervical cancer in virtually all (99.8%) of the 320,000 cases of cervical cancer that occur annually in women throughout the world. In addition, HPV is detected in approximately 50% to 80% of vaginal, 50% of vulvar, and nearly all penile and anal cancers.

Of nearly 120 HPV types, approximately 20% to 30% are unclassified types that have been only partially sequenced. About 30 HPV types primarily infect the squamous epithelium of the lower anogenital tracts of both men and women, resulting in both flat and raised warts or intraepithelial lesions of the vulva, vagina, cervix, and perianal regions. Disease caused by HPV types 6, 11, 42, 43, or 44 most commonly manifest as classic genital warts with a cauliflower appearance, but they may also manifest as flat lesions. Types 16, 18, 31, 33, 35, 45, 51, 52, and 56 are considered high-risk types because they have been found in cancers of the lower genital tract. They are also found in intraepithelial lesions. Lesions that are caused by low- and high-risk HPV types can regress to normal even without treatment, but currently it is not possible to predict which lesions will regress and which will persist or progress.

Approximately 80% of cervical cancers are associated with types 16, 18, 31, and 45; 15% are associated with types 31, 33, 35, 51, and 52. LGSILs can be caused by both low- and high-risk HPV types. In fact, high-risk types have been detected in 75% to 85% of low-grade lesions with mixed low- and high-risk types in approximately 15% and low-risk types exclusively in only 2% to 25%.

Histologic Considerations

The principal reservoir of HPV is the moist mucosa and the cutaneous epithelial tissue in adjacent areas. Ninety-five percent of cervical dysplasias and cancers originate in the squamocolumnar junction of the cervical os.¹ In adolescence, glandular epithelium covers much of the exocervix; but as adolescence progresses, the columnar epithelium is gradually replaced by squamous cells. This actively growing area seems to be more susceptible to multiple insults and the HPV, probably because of the metaplastic nature of the conversion process and the inflammatory process of metaplasia.

Development and Progression of the Disease

In heterosexual women, exposure to HPV is common in the teens and twenties, soon after unprotected intercourse. Detectable disease is uncommon, yet up to 60% in this age group test positive for HPV DNA by polymerase chain reaction (PCR) testing. As stated earlier, the nature of the HPV infection is transient and the immune system responds to HPV in most individuals. One of three things can happen following infection with HPV: (1) The infection remains permanently latent or produces only transient cytologic changes; (2) individuals develop HPV-associated cytologic changes diagnostic of HPV—infections in approximately 60% of women with atypia or LGSIL spontaneously regress and 20% to 30% persist; and (3) 10% develop HGSIL.

PCR testing has shown that up to 70% of women clear the virus within the first year of infection. Low-grade lesions can regress on their own, persist, or progress. Progression to high-grade lesions tends to peak between the ages of 25 and 29, an average of 4 to 7 years after peak incidence of mild cervical dysplasia. Most low-grade lesions, although the majority are due to high-risk HPV types, do not progress to invasive cancer even if allowed to follow the natural history of the disease with no treatment interventions. Even women infected with HPV type 16, the type detected in more than 60% of cervical cancers, tend to regress spontaneously over time. In the United States, the incidence of invasive cervical cancer reaches a plateau in white women approximately 15 years after the peak incidence of CIN III, usually between the ages of 40 and 45.

Sexual Transmission

Early age at first intercourse, multiple sexual contacts without use of condoms, or both are associated with an increased risk of cervical dysplasia/carcinoma.^1,2 From this and other evidence, it has been suggested that cervical cancer is a sexually transmitted disease in the sense that the implicated infectious agent, HPV, is easily transmitted by genital-to-genital contact. Because the time from exposure to the appearance of a lesion can range from weeks to decades, it is almost impossible to identify individuals who transmit the virus.

Table 156-1 Risk Factors in Cervical Dysplasia/Cancer^*

^* The actual values for the absolute risk of the various risk factors are as yet somewhat controversial. The numbers listed here represent the author’s summarization of the literature. These risks are not linearly additive because they are usually closely related; more extensive multivariant analysis will be necessary to determine the actual relative risk of each.

Genital-to-oral transmission is suggested to be possible owing to detection of HPV types 6, 11, and 16 in some oropharyngeal cancers, but oral HPV lesions are in fact rare. Nonsexual exposure to the virus may occur from examination tables, doorknobs, tanning beds, and other inanimate objects, but it is difficult to document and prove.

Other infectious agents such as herpes simplex, Chlamydia, and HIV may serve as cofactors for HPV. These agents may alter cervical immunity, contribute to inflammation, facilitate entry of HPV into the basal cells, accelerate replication of HPV in the host cell nucleus, and coexist with HPV infection.

Smoking

A significant risk factor for cervical cancer and cervical dysplasia is cigarette smoking: smokers have an approximately threefold increased incidence compared with nonsmokers (one study³ showed the increase to be as high as seventeenfold in women ages 20 to 29).^3–6 Several hypotheses have been proposed to explain this association:

Oral Contraceptives

Earlier studies suggested that the use of oral contraceptives (OCs) increased the risk of cervical neoplasia, both the invasive and precancerous types. More recent studies controlled for sexual history have not confirmed this association. Three large, well-controlled studies looked at invasive cervical cancer and OC use and did not find statistically significant associations compared with women who never used OCs.^8–10 There was no overall change in risk of invasive cervical cancer; however, one of the three studies⁸ found a modestly increased risk in long-term users of OCs. The other two studies failed to find a significantly increased risk of invasive cervical cancer even with long-term OC use. Two other studies assessed OC use and the risk of cervical dysplasia, and neither found any statistically significant associations.^11,12

A more disturbing aspect is that OC use has been associated with an increased incidence of adenocarcinoma, a rare cancer of the cervix. This is a less common variant of squamous cervical cancer. It appears that the incidence of this disease has increased over the past several decades, while the incidence of invasive squamous cervical cancer has decreased since the pill was introduced. Two studies found a modest but statistically significant increased risk of invasive cervical adenocarcinoma in women who had used OCs for more than 12 years.^13,14

OCs are known to potentiate the adverse effects of cigarette smoking and to decrease the levels of numerous nutrients, including vitamins C, B₆, and B₁₂ as well as folic acid, riboflavin, and zinc.¹⁵

Vitamin A and Beta-Carotene

A minor association appears to exist between dietary retinoids and the risk of cervical cancer or dysplasia as well as a strong inverse correlation between beta-carotene intake and the risk of cervical cancer or dysplasia.^21–23 Although only 6% of patients with untreated cervical cancer have below-normal serum vitamin A levels, 38% have stage-related abnormal levels of beta-carotene.¹⁷ Low serum beta-carotene levels are associated with a threefold greater risk for severe dysplasia,²³ and serum vitamin A and beta-carotene levels were found to be significantly lower in patients with cervical dysplasia than in a control group (54 vs 104 mg/dL for vitamin A and 21.3 vs. 13.9 mcg/dL for beta-carotene).^24,25

Unfortunately response rates to intervention with carotenoids have been inconsistent. In a double-blind randomized placebo-controlled trial comprised of over 100 women who used either 30 mg/day of beta-carotene or placebo,^25a cervical biopsies were performed before treatment and after 6 and 24 months. Persistence of CIN 3 resulted in the patient’s removal from the study. Of the 124 women included, 21 were not randomized because they moved, became pregnant, or voluntarily withdrew or the pathologic review of their initial cervical biopsies did not confirm CIN 2 or 3. Of the remaining 103 women, 33 experienced lesion regression, 45 had persistent or progressive disease, and 25 women did not complete the study and were considered nonresponders.

The overall regression rate (32%) was similar between beta-carotene and placebo arms and when stratified for CIN grade. HPV typing of 99 women showed that 77% were HPV-positive and 23% HPV-negative at enrollment. HPV-positive lesions were subdivided into indeterminate, low-, and high-risk categories. The response rate was highest for women with no HPV detected (61%), lower for those ranked at indeterminate or low risk (30%), and lowest for those classified at high risk (18%). In conclusion, beta-carotene did not enhance the regression of high-grade CIN, especially in HPV-positive subjects.²⁶

Other intervention studies also faired poorly for beta-carotene:

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