Chapter 156 Cervical Dysplasia
• Abnormal Pap smears (atypical cells of undetermined significance [ASC-US]; low-grade squamous intraepithelial lesions [LGSILs]; high-grade squamous intraepithelial lesions [HGSILs])
• Human papillomavirus (HPV) testing for the presence of high-risk strains
Since the Bethesda System of reporting was first established in 1988, it has been revised several times. The current U.S. cervical disease management guidelines were last updated in 2009 and include algorithms for managing high-risk HPV strains, ASC-US, atypical cells for which high-grade lesions cannot be ruled out (ASC-H), LGSILs, and HGSILs have changed and continue to evolve. Recommendations for HPV testing and cytology testing and the combination of the two, colposcopy and biopsies, follow-up cytology testing, and colposcopy based on abnormal results are complex and often change. Guidelines differ depending on the patient’s age, history of previous abnormal cytology testing, pregnancy status, previous exposure to diethylstilbestrol, immunosupression status (ex/kidney transplants), human immunodeficiency virus (HIV) status, and hysterectomy for benign indications and prior history of cervical intraepithelial neoplasia (CIN). We recommend that the clinician consult the latest available guidelines for screening and evaluation with colposcopy, biopsy, and follow-up testing from the American College of Obstetricians and Gynecologists, the American Cancer Society, and/or the U.S. Preventive Services Task Force.
Cervical dysplasia is generally regarded as a precancerous lesion with risk factors similar to those of cervical cancer.1 Therefore, this discussion focuses on the following lifestyle and nutritional factors that appear to be cofactors in the development and progression of cervical dysplasias and ultimately cervical cancer:
• Early age of first intercourse
• Multiple sex partners (in heterosexual women without barrier contraception)
• Other infectious agents (Chlamydia, herpesvirus)
• Immunosuppression (HIV, transplant patient)
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%.
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.
Risk Factors (Table 156-1)
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.
|Risk Factor||Relative Risk|
|Smoking (10+ cigarettes/day)||3.06|
|Multiple sex partners (2-5)||3.46|
|First intercourse before age 18||2.76|
|Deficient dietary β-carotene (<5000 IU/day)||2.813|
|Deficient dietary vitamin C (<30 mg/day)||6.716|
* 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.
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:
• Smoking may depress immune function, allowing a sexually transmitted agent to promote abnormal cellular development, leading to the onset of cervical dysplasia.
• Smoking induces vitamin C deficiency, since vitamin C levels are significantly depressed in smokers.7
• Cervical cells may concentrate nicotine.
• There may be unrecognized associations between smoking and sexual behavior.3–6
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
A follow-up Pap test is used to determine what course of action is needed. Many cases of mild cervical dysplasia (ASC-US, LSILs) will go away spontaneously. The median time required for progression from cervical dysplasia to carcinoma in situ ranges from 86 months for LSIL to 12 months for HSIL. In LSIL, the natural approaches provided in this chapter can be followed with a follow-up Pap smear and colposcopy at 3 months. If colposcopy finds abnormal tissue, endocervical curettage may be appropriate. Prescribing a patient diagnosed with HSIL a colposcopy with endocervical curettage is recommended.
Numerous nutritional factors have been implicated as cofactors in the development of cervical dysplasia. Although many single nutrients may play a significant role (particularly beta-carotene and retinoids, folic acid, pyridoxine, and vitamin C), it is important to recognize that a large proportion (67%) of patients with cervical cancer have multiple nutrient deficiencies or abnormal anthropometric measurements. Significant abnormalities have been found in height-to-weight ratios, triceps skin fold thickness, midarm muscle circumference, serum albumin levels, total iron-binding capacity, hemoglobin levels, creatinine height index, prothrombin time, and lymphocyte count. Many other patients have marginal but “normal” nutritional status as determined by these cursory evaluations,16 suggesting that multiple nutrient deficiencies are probably the rule rather than the exception.
Vitamin assessment by biochemical evaluation (plasma and red cell folate; serum beta-carotene; vitamins A, B12, and C; erythrocyte transketolase for thiamine determination; erythrocyte glutathione reductase for riboflavin determination; and erythrocyte aspartate transaminase for pyridoxine determination) in patients with untreated cervical cancer shows that at least one abnormal vitamin level was present in 67% of patients, whereas 38% displayed multiple abnormal parameters.17
General dietary factors are also important. A high fat intake has been associated with an increased risk for cervical cancer, whereas a diet rich in fruits and vegetables is believed to offer significant protection against carcinogenesis, probably owing to the higher intake of fiber, beta-carotenes, and vitamin C.5 Total serum carotene and tocopherol levels and their association with dietary intakes and the risk of newly diagnosed CIN and invasive cervical cancer were evaluated in a case-control study in Brazil.18 Increasing concentrations of serum lycopene were negatively associated with CIN 1, CIN 3, and cervical cancer. Increasing concentrations of serum alpha and gamma tocopherols and higher dietary intakes of dark green and deep yellow vegetables/fruits were associated with nearly 50% decreased risk of CIN 3. In another case-control study, 239 women with squamous cell carcinoma of the cervix from the tumor registry in Buffalo, New York, completed a questionnaire, whereby researchers investigated the relationships between intakes of selected dietary nutrients and food groups and risk of cervical cancer.19 Significant reductions in risk of cervical cancer of approximately 40% to 60% were observed for women in the highest versus the lowest tertiles of dietary fiber, vitamin C, vitamin E, vitamin A, α-carotene, beta-carotene, lutein, and folate.
Nutritional Botanical Supplements
Several key individual supplements are discussed later, but a combination of products may work best. One study showed multiple vitamins and mineral formulas, vitamins A and E, and calcium were significantly associated with a lower risk of cervical cancer and a lower HPV viral load.20 The study enrolled 1096 women between the ages of 18 and 65 and included 328-HPV positive women, 166 controls, 90 women with CIN I, and 72 women with CIN 2 or 3. Multiple vitamins and minerals, vitamins A and E, and calcium were significantly associated with a lower risk of CIN 2 or 3. The patients who took the multiple vitamins and minerals had a lower HPV viral load and a significantly decreased frequency of CIN 1.
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:
• No difference in regression of CIN 1 lesions after 12 months with 30 mg of beta-carotene daily versus placebo27
• No regression of CIN lesions with 10 mg/day of beta-carotene versus placebo28
• After 9 months, lower regression rates of CIN 1 to 3 with 30 mg/day beta-carotene versus placebo29
• Slightly increased progression of ASCUS and CIN 1 with 30 mg/day of beta-carotene versus no treatment30