Cervical dysplasia (CD) is a precancerous lesion; risk factors similar to cervical cancer; lifestyle and nutritional factors in aetiology of cervical carcinoma; early age of first intercourse, multiple sexual partners, herpes simplex type II and papilloma viruses, lower socioeconomic class, smoking, oral contraceptive use, and many nutritional factors; all risk factors are closely related.

Abnormal Papanicolaou smear (stages II-IV); positive Schiller test.

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Classification systems for Papanicolaou smears
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Numerical  Dysplasia   CIN   Bethesda
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I     Benign   Benign   Normal
II    Benign with   Benign with  Normal  inflammation
III   Mild dysplasia  CIN I   Low-grade SIL
III   Moderate dysplasia CIN II   Low-grade SIL
III   Severe dysplasia CIN III   High-grade SIL
IV   Carcinoma in situ CIN III   High-grade SIL
V    Invasive cancer Invasive cancer Invasive cancer

(CIN (cervical intraepithelial neoplasia); SIL (squamous epithelial lesion))

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• Epidemiology: Cervical cancer is the second most common malignancy in women aged 15-34 (can occur at any age); peak incidence of invasive lesions is age 45; in situ lesions peak age 30; invasive carcinoma rate is falling; incidence of carcinoma in situ increasing – increase in risk factors (early age at first intercourse, multiple sexual partners, oral contraceptive use, cigarette smoking).

• Histology: 95% of cervical cancers originate in squamocolumnar junction of cervical os; in adolescence, glandular epithelium covers much of exocervix; as adolescence progresses columnar epithelium replaced by squamous cells; activity growing area susceptible to multiple insults and carcinogenic substances – metaplastic nature of conversion process.

Risk factors

• Sexual activity: early age at first intercourse and/or multiple sexual partners – suggests sexually transmissible agent; arginine-rich histone or protamine released by sperm during degradation could be oncogenic agent.

• Viruses:
           - Herpes simplex type II (HSV-II): 23% of women with herpes have CD or cancer, but 2.6% of those without infection; HSV-II antibody titers are much higher in women with CD or cancer than in controls; women with herpetic cervicitis have four to 16-fold increased risk of cervical cancer/dysplasia.
           - Human papillomavirus (HPV): agent in condyloma acuminate (venereal warts); detected in cervical tissue of the majority of patients with CD.

• Smoking: smokers have two to three times increased incidence compared with non-smokers (17 times in women aged 20-29) – depressed immunity, allowing sexually transmitted agent to promote abnormal cellular development; induces vitamin C deficiency; vaginal or endometrial cells may concentrate and secrete smoke carcinogens; unrecognized links between smoking and sexual behaviour.

• Oral contraceptives (OCs): long-term use linked to increased risk of thromboembolism, gall bladder disease, MI, mental illness, hyperthyroidism, hypertension, and cervical cancer; OCs potentiate adverse effects of smoking and diminish numerous nutrient levels – vitamin C, B6, and B12, folate, riboflavin, and zinc.  

Therapeutic considerations

Nutrition

Large proportion (67%) of patients with cervical cancer have abnormal anthropometric or biochemical parameters – height-to-weight ratios, triceps skin fold thickness, mid-arm muscle circumference, serum albumin levels, total iron-binding capacity, haemoglobin levels, creatinine height index, prothrombin time, and lymphocyte count; other patients marginal but ‘normal’ nutritional status; multiple nutrient deficiencies are the typical situation; at least one abnormal vitamin level in 67% in patients, 38% have multiple abnormal parameters; nutrition plays major role in onset of CD/carcinoma; high-fat intake linked to increased risk; diet rich in fruits and vegetables protects against carcinogenesis – fiber, beta-carotenes, and vitamin C.

• Vitamin A and beta-carotene: minor association between dietary retinoids and CD risk; strong inverse correlation between beta-carotene intake and CD risk: only 6% of patients with untreated cervical cancer have < normal serum vitamin A; 38% have stage-related abnormal beta-carotene; low serum beta-carotene linked to three times increased risk for severe dysplasia; serum vitamin A and beta-carotene are much lower in CD patients than in controls; carotenes and retinols improve integrity and function of epithelial tissues, provide antioxidant properties, and enhance immune function; beta-carotene is more advantageous than retinoids – greater antioxidant properties, immune-enhancing effects and tendency to be concentrated in epithelial tissues.

• Vitamin C: diminished vitamin C intake and plasma levels in CD patients; inadequate vitamin C intake is an independent risk factor for premalignant cervical disease and carcinoma in situ; acts as an antioxidant, maintains normal epithelial integrity, improves wound healing, enhances immunity, and normal carcinogen formation.

• Folic acid: cervical cytological abnormalities related to folate deficiency precede haematological abnormalities; most common vitamin deficiency in the world, especially women who are pregnant or taking OCs; folate deficiency is the probable cause of many abnormal cytological smears rather than ‘true’ dysplasia; OCs induce localized interference with folate metabolism – tissue levels at end-organ targets (cervix) are deficient; RBC folate decreased (especially with CD), while serum levels are normal or increased; OCs induce synthesis of macromolecule that inhibits folate uptake by cells; low RBC folate enhances effect of other CD risk factors – HPV infection; low RBC folate is a risk factor for cervical HPV infection; folate supplements improve/normalise cytological smears in CD patients; regression rates for untreated CD = 1.3% for mild and 0% for moderate; folate regression-to-normal rate reported 20%, 63.7%, and 100%; progression rate of untreated cd="16%" at 4 months; folate-supplemented rate= 0% (women remained on OCs); use vitamin B12 with folate to avoid folate masking underlying B12 deficiency.

• Pyridoxine: vitamin B6 (RBC transaminase test) decreased in one-third of CD patients; decreased B6 status affects metabolism of estrogens and tryptophan, and impairs immunity.

• Selenium: serum, dietary, and soil selenium inversely correlated with all epithelial cancers and much lower in CD patients; one anti-carcinogenic effect is increased glutathione peroxidase activity; toxic elements (lead, cadmium, mercury, gold) have selenium-antagonistic properties.

• Copper:zinc ratio, zinc, retinol: increased serum copper:zinc ratio is a non-specific reaction to inflammation or malignancy; serum copper:zinc ratio may be tool to establish extent of cancer; ratio > 1.95 indicated malignancy in 90% of patients studied; elevated ratios also seen in OC use, pregnancy, acute and chronic infections, chronic liver disease, and inflammatory conditions; serum Cu:Zn ratio should not be used to predict malignancy in these patients; decreased available zinc may cause retinol binding protein to be absent or undetectable in 80% of dysplastic tissue vs. 23.5% or normal tissue – inverse relationship between serum retinol/zinc and incidence of CD.

Miscellaneous considerations

• Vaginal depletion packs (vag pack): long history of efficacy for CD; mechanism of action not yet elucidated; may promote sloughing superficial abnormal cervical cells; effective in most cases of CD.

Therapeutic approach

• Pap class: class IV Pap – ascertain carcinoma in situ by gynaecologist; class III Pap – biopsy if patient has had recurrent abnormal Paps, has significant risk factors, or has been unresponsive to therapy; carcinoma in situ or class V Pap – conization.
• Eliminate all factors linked to CD (smoking and OCs); optimize patient’s nutritional status – supplement folic acid, beta-carotenes, and vitamin C; vag pack will usually accelerate the rate of normalisation of cervix; treat patients who undergo conization for underlying causes of CD; repeat Pap smears every 1-3 months, according to severity.
• Diet: decrease animal products – animal fats and exogenous estrogens increase high-fiber foods.
• Supplements :    
- folic acid
- pyridoxine
- vitamin B12
- beta-carotene
- vitamin C
- vitamin E
- selenium
- zinc
• Vaginal depletion pack: weekly until Pap normalizes (unless patient has had conization).