The Encyclopedia of Natural Medicine, 3rd Ed.

Cervical Dysplasia

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• A Pap smear of the cervix showing abnormal (but not cancerous) cells

The cervix is a small, cylindrical organ that comprises the lower part and neck of the uterus. The cervix contains a central canal (the endocervical canal) for passage of sperm and menstrual blood, and for childbirth. Both the canal and the outer surface of the cervix are lined with two types of cells: mucus-producing (glandular) cells and protective (squamous) cells.

The term dysplasia refers to abnormal cells that are not cancerous but have the potential to become cancer. So cervical dysplasia is a precancerous lesion of the cervix. Cervical dysplasia is diagnosed by a Pap smear—a sampling of cells from the surface of the cervix. Before any cancer appears, abnormal changes occur in cells on the surface of the cervix. Cancer of the cervix is one of the most common cancers affecting women. Fortunately, cervical cancer is one of the few cancers with well-defined precancerous stages, so when detected early it usually can be treated quite successfully. Women routinely receive Pap smears on a yearly basis.

Understanding a Pap Smear

A Pap smear examines the cells that cover the cervix. Most laboratories in the United States use a standard set of terms, called the Bethesda System, to report Pap test results. The Bethesda System considers abnormalities of squamous cells (the thin, flat cells that form the surface of the cervix) and glandular cells (mucus-producing cells found in the endocervical canal or in the lining of the uterus) separately. Glandular cell abnormalities are much less common than squamous cell abnormalities. Samples with cell abnormalities are divided into the following categories, ranging from the mildest to the most severe.

Squamous Cell Abnormalities

• ASC (atypical squamous cells). This is the most common abnormal finding in Pap tests. The Bethesda System divides this category into two groups:

  images ASC-US (atypical squamous cells of undetermined significance).

  images ASC-H (atypical squamous cells, cannot exclude a high-grade squamous intraepithelial lesion). The cells do not appear normal, but doctors are uncertain about what the cell changes mean. ASC-H lesions may be at higher risk of being precancerous compared with ASC-US lesions.

• LSIL (low-grade squamous intraepithelial lesion). Low-grade means that there are early changes in the size and shape of cells. Intraepithelial refers to the layer of cells that forms the surface of the cervix. LSILs are considered mild abnormalities caused by human papillomavirus (HPV) infection. LSILs are sometimes referred to as mild dysplasia. They may also be referred to as cervical intraepithelial neoplasia (CIN 1). Neoplasia means an abnormal growth of cells, and the number describes how much of the thickness of the lining of the cervix contains abnormal cells—only the top layer, in this case.

• HSIL (high-grade squamous intraepithelial lesion). High-grade means that there are more evident changes in the size and shape of the abnormal (precancerous) cells and that the cells look very different from normal cells. HSILs are more severe abnormalities that have a higher likelihood of progressing to cancer. HSILs include lesions with moderate or severe dysplasia or carcinoma in situ. (With carcinoma in situ, abnormal cells are present only on the surface of the cervix. Although they are not cancer, these abnormal cells may become cancer and spread into nearby healthy tissue.) HSIL lesions are sometimes referred to as CIN 2, CIN 3, or CIN 2/3, indicating that the abnormal cells occupy most of the layers of the lining of the cervix.

• Squamous cell carcinoma. Cervical cancer occurs when abnormal cervical squamous cells invade deeper into the cervix or to other tissues or organs. In a well-screened population, such as that in the United States, a finding of cancer on a Pap test is extremely rare.

Glandular Cell Abnormalities

• AGC (atypical glandular cells). The glandular cells do not appear normal, but doctors are uncertain about what the cell changes mean.

• AIS (endocervical adenocarcinoma in situ). Precancerous cells are found in the glandular tissue.

Causes

Since cervical dysplasia is a precancerous lesion, the risk factors for cervical dysplasia are identical to those for cervical cancer. These risk factors include exposure to human papillomavirus (HPV), early age of first intercourse, multiple sexual partners, low income, smoking, oral contraceptive use, and many nutritional factors.1

Terms Used to Describe Pap Smear and Biopsy Results

BETHESDA SYSTEM

DYSPLASIA

CIN

Negative

Benign

Benign

ASC-US

Benign with inflammation

Benign with inflammation

Low-grade SIL

Mild dysplasia

CIN 1

High-grade SIL

Moderate dysplasia

CIN 2

High-grade SIL

Severe dysplasia

CIN 3

High-grade SIL

Carcinoma in situ

CIN 3

Carcinoma

Carcinoma

Invasive cancer

CIN = cervical intraepithelial neoplasia; SIL = squamous epithelial lesion; carcinoma = squamous cell carcinoma.

Of these factors, the most significant is HPV, as it is implicated 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.

HPV, which is easily transmitted by genital-to-genital contact, can cause genital warts. The time from exposure to the appearance of a genital wart or an abnormal Pap smear can range from a few weeks to decades. The number of medical visits for HPV disease has increased more than 500% in the past 30 years, and HPV infection is often considered epidemic. At least 60% of young women have evidence of HPV in their cervix; however, less than 10% develop any signs of an infection or cervical change. This suggests that the immune system is able to defend against the development of clinical infection, cervical dysplasia, and cancer.

A complex interaction of defense mechanisms, including immunity, viral load, viral type, and host susceptibility, determines the natural course of the disease. One of three things can happen following infection with HPV: (1) the infection remains permanently latent (silent) or produces only temporary cellular changes in the cervix; (2) women develop low-grade HPV-associated cervical dysplasia or cellular changes; and (3) women develop the more serious high-grade squamous intraepithelial lesion (HSIL). The other risk factors given above are largely what determines which of these possibilities will occur. For example, smoking is a significant risk factor for cervical cancer and cervical dysplasia: smokers have an approximately threefold increased incidence compared with nonsmokers, with one study showing the increase to be as high as 17-fold in women ages 20 to 29.26 Possible explanations offered for this association are:

• Smoking may depress immune function, allowing a sexually transmitted agent to promote abnormal cellular development.

• Smoking induces vitamin C deficiency, since vitamin C levels are significantly depressed in smokers.

• Cervical cells may be especially sensitive to the harmful free radicals from cigarette smoke.

• There may be unrecognized associations between smoking and sexual behavior.

Therapeutic Considerations

A follow-up Pap test is always indicated to determine what course of action is needed. Many cases of mild cervical dysplasia (LSIL) will go away. 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, there is time to try the natural approaches provided in this chapter, with a follow-up Pap smear and colposcopy at three months. A colposcopy is a procedure in which a colposcope—an instrument much like a microscope—is used to examine the vagina and the cervix. During a colposcopy, the doctor inserts a speculum to widen the vagina and may apply a dilute vinegar solution to the cervix; this solution causes abnormal areas to turn white. The doctor then uses the colposcope (which remains outside the body) to observe the cervix. If colposcopy finds abnormal tissue, the doctor may perform endocervical curettage—a type of biopsy that involves scraping cells from inside the endocervical canal with a small spoon-shaped tool called a curette.

If testing shows carcinoma in situ or HSIL, conventional medical treatment is recommended. Current treatment options include the following:

• LEEP (loop electrosurgical excision procedure) uses an electrical current that is passed through a thin wire loop to act like a knife to remove tissue.

• Cryotherapy destroys abnormal tissue by freezing it.

• Laser therapy uses a narrow beam of intense light to destroy or remove abnormal cells.

• Conization removes a cone-shaped piece of tissue using a knife, a laser, or the LEEP technique.

In the event that these methods are not indicated for or desired by the patient who has HSIL, the natural approach can be tried, with the same follow-up recommended above—Pap smear and colposcopy at three-month intervals. However, the patient who has CIN 3 should definitely be treated with one of the conventional options above if there is no regression after three months.

Diet

Numerous nutritional factors have been implicated as cofactors for cervical dysplasia. A large proportion (67%) of patients with cervical cancer are deficient in at least one nutrient (particularly beta-carotene and vitamin A, folic acid, vitamin B6, and vitamin C), while 38% show more than one deficiency.7 In addition, many patients have a marginal nutritional status, on the lower end of normal.8

General dietary factors are important as well. A high fat intake has been associated with an increased risk for cervical cancer, while a diet rich in fruits and vegetables is believed to offer significant protection against carcinogenesis, probably owing to the higher intake of fiber, beta-carotene, and vitamin C.5 Increasing concentrations of serum lycopene and higher dietary intakes of dark green and deep yellow vegetables and fruits decrease the risk of cervical dysplasia and cervical cancer.9 Significant reductions (approximately 40% to 60%) in risk of cervical cancer were observed for women who had the highest intakes of dietary fiber, vitamin C, vitamin E, vitamin A, alpha-carotene, beta-carotene, lutein, and folate.10

Nutritional Supplements

Several key individual supplements are discussed below, but a combination of products may work best. One study showed that multiple vitamin and mineral formulas, vitamins A and E, and calcium were significantly associated with a lower risk of cervical cancer and a lower HPV load.11

Vitamin A and Beta-Carotene

There is a strong inverse relationship between dietary beta-carotene intake and the risk of cervical cancer or dysplasia.8,1216 Unfortunately, the response to intervention with supplemental beta-carotene has been inconsistent. In a double-blind, randomized, placebo-controlled trial with more than 100 women who used either 30 mg per day of beta-carotene or a placebo, beta-carotene did not appear to promote the regression of carcinoma in situ, especially in HPV-positive subjects.17 Although one study found higher regression rates of mild to severe dysplasia with 30 mg per day beta-carotene vs. a placebo,18 for the most part other studies failed to show much, if any, benefit:

• No difference in regression of mild dysplasia after 12 months with 30 mg beta-carotene per day vs. placebo19

• No regression of cervical dysplasia with 10 mg per day of beta-carotene vs. placebo20

• Slightly increased progression of mild dysplasia with 30 mg per day of beta-carotene vs. no treatment21

One of the shortcomings of these studies may be the use of isolated, synthetic beta-carotene. Mixed natural carotenoids are preferred by naturopathic physicians.

Several studies have shown that topical vitamin A therapy produces rather impressive results. In one study, 301 women received either four consecutive two-hour applications (using a collagen sponge in a cervical cap) of vitamin A or a placebo followed by two more applications at three and six months. Vitamin A (retinoic acid) increased the complete regression rate of moderate dysplasia from 27% in the placebo group to 43% in the treatment group. However, the women with severe dysplasia did not improve.22 In another 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 had mild dysplasia and 5 had had moderate dysplasia.23 There were too few patients with severe dysplasia to be evaluated.

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 cervical dysplasia and carcinoma in situ.24,25 Vitamin C is known to do the following:

• Act as an antioxidant

• Strengthen and maintain normal epithelial integrity

• Improve wound healing

• Enhance immune function

Selenium

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 controls. The activity of the selenium-containing antioxidant enzyme glutathione peroxidase was significantly lower in patients with HSIL or cancer as well, and total antioxidant ability decreased from controls to CIN to 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.26

Folic Acid

Low folic acid levels have been implicated in many cases of cervical dysplasia, though this may change now that there is widespread folic acid fortification of the food supply. When cells lack folic acid, they display abnormal shapes or size. For example, folic acid deficiency in red blood cells causes the cells to become macrocytic, or larger than normal. Interestingly, abnormal cell structure due to folic acid insufficiency is visible in the cervix before it is visible in the red blood cells.27,28 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.28,29It is probable that many abnormal Pap smears in the past reflected folate deficiency rather than true dysplasia.28,30,31

Even with food fortification, folic acid is still a factor in many cases of cervical dysplasia. This observation is particularly applicable to patients taking oral contraceptives. It has been hypothesized that the hormones induce a localized interference with folate metabolism, so although serum levels may be increased, tissue levels at end-organ targets such as the cervix may be inadequate.30,31 This is consistent with the observation that tissue status (as measured by erythrocyte folate) is typically decreased, especially in those with cervical dysplasia, while serum levels may be normal or even increased.32 In controlled clinical studies of women with cervical dysplasia taking oral contraceptives, a very high dosage of folic acid (10 mg per day) resulted in the improvement or normalization of Pap smears.30,33,34 Regression rates for patients with untreated cervical dysplasia are typically 1.3% for mild dysplasia 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,34 63.7% in another,33 and 100% in yet another.30 Furthermore, the progression rate of cervical dysplasia in untreated patients is typically 16% at four months, a figure matched in the placebo group in one study, while the folate-supplemented group had a 0% progression rate.31 These figures were achieved despite the fact that the women remained on oral contraceptives.

Lower folic acid status has been shown to enhance the effect of other risk factors for cervical dysplasia. For example, low red blood cell folate appears to be a major risk factor for HPV infection of the cervix.3335 In particular, higher circulating concentrations of folate are independently associated with a lower likelihood of becoming positive for high-risk human papillomaviruses (HRHPVs) 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 a 70% lower risk of being diagnosed with cervical dysplasia.36

Indole-3-Carbinol/Diindolylmethane

Indole-3-carbinol (I3C) is a phytochemical found in vegetables in the brassica (cabbage) family. It is converted in the stomach to several compounds including diindolylmethane (DIM). I3C and DIM are antioxidants and potent stimulators of natural detoxifying enzymes in the liver. Studies have shown that increasing the intake of brassica vegetables or taking I3C or DIM as a dietary supplement significantly increases the conversion of estrogen from cancer-producing forms to nontoxic breakdown products.37,38 The body breaks down estrogen in several ways. It can be converted into a substance called 16-alpha-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-alpha hydroxyestrone and fewer 2-hydroxyestrogen metabolites than normal.39

Given the ability of I3C or DIM to improve estrogen metabolism and possibly exert anti-HPV activity, these agents would seem to be very good candidates for the treatment of cervical dysplasia.37,38Preliminary studies are very encouraging. In one double-blind, placebo-controlled study of 30 women with HSIL (biopsy-proven CIN 2 or 3), the women were given either 200 or 400 mg I3C or a placebo for 12 weeks.39 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 group, and in 8 of 9 in the 400-mg group.

DIM was used in another study of 64 patients with HSIL (biopsy-proven CIN 2 or 3) who were scheduled for LEEP. The patients were randomized to receive either a daily dose of DIM (approximately 2 mg/kg) or a placebo for 12 weeks. Though there was no statistically significant difference in any outcome between the DIM and placebo groups overall, the results with DIM showed an improved Pap smear in 49%, with either a less severe abnormality or a normal result. Colposcopy also improved in 56% of subjects in the DIM group.40

Botanical Medicines

Constituents of green tea (Camellia sinensis), 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.41

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. Twenty out of 27 patients (74%) under green tea topical therapy showed a response. Six out of 8 patients using the green tea ointment plus EGCG capsule therapy (75%) showed a response, and 6 out of 10 patients (60%) taking the EGCG capsule showed a response. Overall, a 69% response rate was noted for treatment with green tea extracts, as compared with a 10% response rate in untreated controls.41

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QUICK REVIEW

• Cervical dysplasia reflects the presence of abnormal cells on the cervix and is usually a precancerous condition.

• Severe surgical dysplasia (stage IV Pap smear) requires cone biopsy or a similar procedure.

• Risk factors for cervical dysplasia include early age of first intercourse, multiple sexual partners, exposure to viruses, low income, smoking, oral contraceptive use, and many nutritional factors.

• Women who have low vitamin C levels are 6.7 times more likely to develop cervical cancer than women with sufficient vitamin C levels.

• The higher the intake of dietary sources of beta-carotene, the lower the rate of cervical dysplasia.

• Many abnormal Pap smears reflect folic acid deficiency rather than true dysplasia.

• Folic acid supplementation (10 mg per day) has resulted in improvement or normalization of Pap smears in patients with cervical dysplasia.

• Selenium levels are significantly lower in patients with cervical dysplasia.

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TREATMENT SUMMARY

Proper medical evaluation and monitoring are required. The basic strategy is to eliminate all factors known to be associated with cervical dysplasia and to optimize the patient’s nutritional status regardless of current staging. In patients with HSIL a colposcopy with endocervical curettage is recommended.

Diet

Follow the guidelines in the chapter “A Health-Promoting Diet.” Try to achieve the recommended intake of fruits and vegetables, especially those green, yellow, and orange in color. Eat vegetables from the brassica family on a regular basis.

Nutritional Supplements

• A high-potency multiple vitamin and mineral formula as described in the chapter “Supplementary Measures”

• Key individual nutrients:

  images Beta-carotene (mixed carotenes preferred): 50,000 to 150,000 IU per day

  images Vitamin B6: 25 to 50 mg per day

  images Folic acid: 800 to 2,000 mcg per day

  images Vitamin B12 (methylcobalamin): 1,000 mcg per day

  images Vitamin C: 500 to 1,000 mg per day

  images Vitamin E (mixed tocopherols): 100 to 200 IU per day multiple vitamin and mineral formula

  images Selenium: 100 to 200 mcg per day

  images Zinc: 30 to 45 mg per day

  images Vitamin D3: 2,000 to 4,000 IU per day (ideally, measure blood levels and adjust dosage accordingly)

• Fish oils: 1,000 mg EPA + DHA per day

• One of the following:

  images Grape seed extract (>95% procyanidolic oligomers): 100 to 300 mg per day

  images Pine bark extract (>95% procyanidolic oligomers): 100 to 300 mg per day

  images Some other flavonoid-rich extract with a similar flavonoid content, super greens formula, or another plant-based antioxidant that can provide an oxygen radical absorption capacity (ORAC) of 3,000 to 6,000 units or more per day

• One of the following:

  images I3C: 200 to 400 mg per day

  images DIM: 2.2 mg/kg per day

Botanical Medicines

• Green tea extract (>90% total polyphenol content): 150 to 300 mg per day