Chapter 156 Cervical Dysplasia
Diagnostic Summary
General Considerations
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)
Human Papillomavirus
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.
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.
Risk Factors (Table 156-1)
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.
| 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.
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:
• 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
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
Therapeutic Considerations
Dietary Factors
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
That said, mixed natural carotenoids have been a mainstay of comprehensive naturopathic treatment plans. Carotenoids and retinols offer several types of protection. They improve the integrity and function of the epithelial tissues, provide antioxidant properties, and enhance immune system function (see Chapter 56). As with other diseases, it appears that supplementation with beta-carotene is more advantageous than that with retinoids, possibly owing to their greater antioxidant properties, immune-enhancing effects, and tendency to be concentrated in epithelial tissues.
Topical vitamin A was used in a study of 301 women who received either four consecutive 24-hour applications (using a collagen sponge in a cervical cap) of retinoid or placebo followed by two more applications at 3 and 6 months. Retinoic acid increased the complete regression rate of moderate dysplasia from 27% in the placebo group to 43% in the treatment group. The women with severe cervical dysplasia did not improve.31 In a University of Arizona study, vitamin A was delivered to 20 women via a cervical cap. In 10 of 20 women, cervical dysplasia completely disappeared. Of the 10 patients with a complete response, 5 had mild dysplasia and 5 had moderate dysplasia.32 There were too few patients with severe dysplasia to be evaluated.
Vitamin A suppositories have also been used as part of a multifactorial treatment plan using oral folic acid, vitamin C, and carotenes with topical vitamin A suppositories and herbal vitamin suppositories. Other patients with more severe disease were treated with a topical “escharotic treatment.” This study of atypia, mild, moderate, and severe dysplasia and carcinoma in situ comprised 43 women.33,34 Of these, 38 returned to a normal disease-free state, 3 had partial improvements, 2 stayed the same, and none progressed to a more severe state of dysplasia during the course of the natural treatment protocol.
Vitamin C
A significant decrease in vitamin C intake and plasma levels occurs in patients with cervical dysplasia, and it has been documented that inadequate vitamin C intake is an independent risk factor for the development of premalignant cervical disease and carcinoma in situ.35,36 Vitamin C is known to do the following15:
Folic Acid
Low folic acid levels are implicated in many cases of cervical dysplasia, although this link is less now with widespread folic acid fortification of the food supply. When cervical cells lack folic acid, they become “macrocytic” in the same way as red blood cells (RBCs). Cervical cytologic abnormalities related to folic acid deficiency precede hematologic abnormalities by many weeks.37,38 Prior to fortification of the food supply with folic acid it was the most common vitamin deficiency in the world and was especially common in women who were pregnant or taking oral contraceptives (OCs).38,39 it is possible that many abnormal cytologic smears in the past reflected folate deficiency rather than “true” dysplasia.38,30,31
Even with food fortification, folic acid is still a factor in many cases of cervical dysplasia. This observation is particularly applicable to patients taking OCs. It has been hypothesized that OCs induce a localized interference with folate metabolism and, although serum levels may be increased, tissue levels at end-organ targets, such as the cervix, may be deficient.40,41 This is consistent with the observation that tissue status as measured by erythrocyte folate is typically decreased (especially in those with cervical dysplasia), whereas serum levels may be normal or even increased.42 OCs are believed to induce the synthesis of a macromolecule that inhibits folate uptake by cells. In controlled clinical studies in women with cervical dysplasia taking OCs, folic acid supplementation (10 mg/day) has resulted in the improvement or normalization of Pap smears.40,43,44 Regression rates for patients with untreated cervical dysplasia are typically 1.3% for mild and 0% for moderate dysplasia. When patients were treated with folic acid, the regression-to-normal rate, as determined by colposcopy/biopsy examination, was observed to be 20% in one study,44 63.7% in another,43 and 100% in another.40 Furthermore, the progression rate of cervical dysplasia in untreated patients is typically 16% at 4 months, a figure matched in the placebo group in one study, while the folate-supplemented group had a 0% progression rate.41 These figures were achieved despite the fact that the women remained on OCs.
Lower folic acid status has been shown to enhance the effect of the other risk factors for cervical dysplasia. For example, low RBC folate appears to be a major risk factor for HPV infection of the cervix.43–45 In particular, higher circulating concentrations of folate are independently associated with a lower likelihood of becoming positive for high-risk human papillomaviruses (HR-HPVs) and of having a persistent HR-HPV infection and a greater risk for HSIL.
Vitamin B12 supplementation should always accompany folate supplementation to rule out the possibility that the latter may be masking an underlying vitamin B12 deficiency. In addition, women with higher concentrations of plasma folate who also had sufficient plasma vitamin B12 had 70% lower odds of being diagnosed with cervical dysplasia.46
Pyridoxine
Vitamin B6 status, as determined by erythrocyte transaminase, is decreased in one third of patients with cervical cancer.47 Decreased pyridoxine status would have a significant effect on the metabolism of estrogens and tryptophan while also impairing the immune response.
Selenium
Low selenium levels in the diet and blood have been reported to be significantly lower in patients with cervical dysplasia. In one study, significantly lower selenium and zinc levels were found in both HSIL and cervical cancer patients compared with the control group. The activity of the selenium containing antioxidant enzyme glutathione peroxidase was significantly lower in the patients with HSIL or cancer than with the control group, and total antioxidant ability decreased from the control group to those with CIN to those with cancer. Increased glutathione peroxidase activity resulting from increased selenium intake is believed to be the factor responsible for selenium’s anticarcinogenic effect, although other factors may be of equal significance.48
Copper:Zinc Ratio, Zinc, and Retinol
An increase in the serum copper:zinc ratio is a nonspecific reaction to inflammation or malignancy. In a study involving gynecologic cancer, it was suggested that the serum copper:zinc ratio “is clinically of utmost importance, since it constitutes a tool with which to establish the extent of the cancer.”49 A ratio above 1.95 indicated malignancy in 90% of the patients in that study. Elevated ratios are also seen in various conditions, including the following:
Therefore, the serum copper:zinc ratio should not be used to predict malignancy in patients with these conditions. A decrease in available zinc may explain why retinol-binding protein was either absent or undetectable in 80% of dysplastic tissue samples as compared with 23.5% in normal tissue. A large study of 206 women found an inverse relationship between serum levels of both retinol and zinc and the incidence of cervical dysplasia.50
Indole-3-Carbinol/Diindolymethane
Indole-3-carbinol (I3C) is a phytochemical found in cabbage family vegetables. It is converted in the stomach to several compounds including diindolymethane (DIM). I3C and DIM are antioxidants and potent stimulators of natural detoxifying enzymes in the body. Studies have shown that increasing the intake of cabbage family vegetables or taking I3C or DIM as a dietary supplement significantly increases the conversion of estrogen from cancer-producing forms to non-toxic breakdown products.51,52 The body breaks down estrogen in several ways. It can be converted into a substance called 16-α-hydroxyestrone, a compound that promotes estrogen-dependent cancer. Another method of breakdown produces 2-hydroxyestrone, which does not stimulate cancer cells. Women with HSIL have altered estrogen metabolism with a higher level of 16-α hydroxyestrone and fewer 2-hydroxyestrogen metabolites than normal.53
Given the ability of I3C or DIM to improve estrogen metabolism and possibly exert anti-HPV activity, these agents are very good candidates in the treatment of cervical dysplasia.52 Preliminary studies are very encouraging. In one double-blind placebo-controlled study of 30 women with HSIL (biopsy-proved CIN 2 or 3), the women were given either 200 or 400 mg of I3C or a placebo for 12 weeks.53 In 4 of 8 patients in the group who took 200 mg per day of I3C and 4 of 9 in the 400-mg group there was complete regression of their severe dysplasia, compared with none of the placebo group. HPV was detected in 7 of 10 placebo patients, in 7 of 8 in the 200 mg/day group, and in 8 of 9 in the 400 mg/day group.
DIM was used in another study of 64 patients with HSIL (biopsy-proved CIN 2 or 3) who were scheduled for loop electrosurgical excision procedure (LEEP). The patients were randomized 2:1 to receive DIM at approximately 2 mg/kg/day for 12 weeks or placebo. Although there was no statistically significant difference in any outcome between the DIM and placebo group overall the results with DIM showed an improved Pap smear in 49% (22 out of 45) with either a less severe abnormality or normal result. Colposcopy also improved in twenty-five subjects in the DIM group (56%).54
Green Tea
Constituents of green tea, namely polyphenol E and epigallocatechin-3-gallate (EGCG), have been effective against HPV-infected cervical cells and lesions in both laboratory and clinical studies. Green tea appears to induce apoptosis of HPV-infected cervical cells and also to arrest cell cycles, modify gene expression, and inhibit tumor formation.55,56
A clinical study confirmed these findings in patients through the use of either topical application via a green tea polyphenol ointment and/or oral ingestion of a green tea polyphenol capsule or an EGCG capsule. All treatment groups improved more than the placebo group (50% to 75% vs. 10%), but those given the topical treatment improved most significantly.56
Miscellaneous Considerations
Vaginal Depletion Pack
The vaginal depletion pack (or “vag pack”) has a long history of effective use by naturopathic and eclectic physicians in the treatment of cervical dysplasia. Although its mechanism of action has not yet been elucidated, it is thought to work by promoting the sloughing of the superficial cervical cells, particularly those that are abnormal. It is effective as part of a multifactorial nutritional and topical treatment approach.33,34 (See Appendix 12 for a complete description of this technique.)
Escharotic Treatment
The escharotic treatment is a topical herbal cryotherapy treatment of the cervix used to remove abnormal cells. It involves the use of zinc chloride mixed with Sanguinaria canadensis, a botanical. A full description of this protocol is given in Appendix 2. The escharotic treatment is especially indicated for CIN 2 and CIN 3, both HGSIL, but only when a satisfactory colposcopy has been performed by a clinician. In addition, the use of the escharotic treatment, rather than a LEEP or conization, must fall within the guidelines outlined under “Therapeutic Approach.” The escharotic treatment is best implemented twice a week with 2 full days between treatments. The zinc chloride solution must be made by a compounding pharmacy as a prescription item.
Therapeutic Approach
Treatment of cervical dysplasia requires proper monitoring and coordination of care if one practitioner is doing the workup with colposcopy/biopsies and another is proceeding with natural or integrated treatment approaches. The basic approach is to eliminate all factors known to be associated with cervical dysplasia and to optimize the patient’s nutritional status. In particular, smoking and OC use are eliminated and the patient follows the supplementation program listed here.
The guidelines provide further insight on what is appropriate medical care of cervical dysplasia.
A. Criteria for Naturopathic Protocol
B. Referrals for Colposcopy with Biopsies
C. Referrals for Conization or Loop Electrosurgical Excision Procedure (LEEP)
D. At the Discretion of the Practitioner and Patient
Nutritional Supplements
• High potency multiple vitamin and mineral formula
• Folic acid: 10 mg/day for 3 months, then 2.5 mg/day for one year
• Vitamin B12 (methylcobalamin): 1 mg/day
• Beta-carotene: 150,000 IU/day for 3 months, then decrease to 25,000 IU/day for one year
• Vitamin C: 1 to 3 g/day for 3 to 12 months
• Vitamin E: 200 IU/day for 3 to 12 months
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