The relations between cervical cancer and serological markers of nutritional status.

We evaluated whether differences in serological nutrient indicators between cases and controls were likely to be due to different usual levels for cases or to altered metabolism due to disease. Blood samples obtained as part of a case-control study of invasive cervical cancer conducted in Latin America were evaluated for case-control differences and for trends with stage of disease. Serum alpha- and beta-carotene, cryptoxanthin, and alpha- and gamma-tocopherol showed no trend with extent of disease, although Stage IV cases had lower alpha- and beta-carotene values than did other cases. A slight trend of decreasing values with stage was observed for serum retinol, lycopene, and lutein. For cholesterol and triglyceride concentrations, an inverse trend was observed with stage of disease, which suggested a clinical effect of the disease on blood lipids. Adjustment for smoking, alcohol intake, or oral contraceptive use did not alter observed relations, nor was there evidence that the altered blood nutrient levels differed by histological type. These data suggest that serum values for some carotenoids from Stage I, II, and III cervical cancer are suitable for etiological studies, but spurious results may be obtained if late-stage cases are included. Evidence of trends with severity of disease for cholesterol and triglycerides, and possibly for retinol, lycopene, and lutein, suggest that special attention be given to disease effects of these nutrients in studies of cervical cancer.

Risk factors for cervical cancer by histology.

A case-control study in four Latin American countries enabled assessment of risk factors for different histologic types of invasive cervical cancers, with the main analyses focusing on 667 patients with squamous cell cancers and 43 with adenocarcinomas. The epidemiology of the squamous cell tumors resembled that found in other studies, namely a high risk associated with multiple sexual partners (RR = 1.5 for > or = 2 vs 1), early ages at first intercourse (RR = 2.3 for < 16 vs > or = 20), history of a sexually transmitted disease (RR = 1.8), multiple births (RR = 2.2 for > or = 7 vs 1-3), absence of prior Pap smear screening (RR = 3.0 vs Pap within 24 months), detection of HPV DNA (RR = 3.6), and limited years of schooling (RR = 1.9 for < 4 vs > or = 7). The adenocarcinomas appeared less affected by sexual, reproductive, or socioeconomic factors. There was no relationship with age at first intercourse, history of a sexually transmitted disease or education, and only marginal associations with number of sexual partners or parity. Absence of prior Pap smear screening as well as detection of HPV DNA, however, were associated with relationships equally strong as those for the squamous cell tumors. Oral contraceptive use distinctly affected risk of the adenocarcinomas, increasing risk by approximately two-fold. Analyses of the 18 subjects with adenosquamous cancer suggested some resemblance to the squamous cell tumors, especially with respect to the role of sexual and sociodemographic variables. These findings support the need for detailed studies of etiologic differences between the different histologic types of cervical cancers, with an emphasis on careful pathologic review and precise measurement of HPV.

[Human papilloma virus infections in adult women in Panama]. / Infección por el virus del papiloma humano en la mujer adulta de Panamá.

This study shows that 10% of Panamanian women are infected with VPH. This incidence of premalign and malign infection is one of the highest in the world. It is necessary that panamanian women be educated to participate in the program of the early detection of the disease to control the incidence of cancer in the uterine cervix.

Infección por el virus del papiloma humano en la mujer adulta de Panamá / Human papilloma virus infections in adult women in Panama

This study shows that 10% of Panamanian women are infected with VPH. This incidence of premalign and malign infection is one of the highest in the world. It is necessary that panamanian women be educated to participate in the program of the early detection of the disease to control the incidence of cancer in the uterine cervix

Screening for cervical cancer in Latin America: a case-control study.

The beneficial effect of cervical cytology in reducing the incidence of invasive cervical cancer is well accepted, but many issues regarding specific patterns of screening remain to be resolved, and preventive programmes need to be adapted to regional characteristics. In a case-control study conducted in Latin America, we investigated cytological screening histories of 759 cases of invasive cervical cancer and 1430 controls, with participation rates of 99% and 96%, respectively. Fifty per cent of the cases and 29% of the controls reported never having been screened. Screening was less common among older, less educated and less parous women; non-users of oral contraceptives and women without histories of venereal diseases. There was also evidence that older women and those with multiple partners had longer intervals between examinations. The relative risk (RR) associated with no prior screening was approximately 3 and was not modified by other risk factors. Women reporting a Pap smear within 24-47 months before interview had the same RR as those examined within 12-23 months. Women tested longer ago had higher risks, but still much lower than women never examined. There was evidence that one examination is associated with less reduction in risk than two, regardless of the interval since last Pap smear. Screening appeared to reduce risk of both squamous cell carcinomas and adenocarcinomas. As expected, cases presenting at advanced stages were less likely to have been screened and reported longer intervals since their last examination. These results support the need to concentrate limited resources in the groups that need screening most, mainly older and less educated women who have never been screened.

A case-control study of nutrient status and invasive cervical cancer. I. Dietary indicators.

A study of 748 cases and 1,411 hospital and community controls in four Latin American countries evaluated the association between certain elements of diet and invasive cervical cancer. Subjects were interviewed about their adult consumption of 58 food items, including the major sources of putative protective agents (vitamin A, carotenoids, vitamin C, and folacin) as well as other behavioral and medical characteristics related to cervical cancer. Participation rates were above 95% for both cases and controls. After adjustment for age, study site, sexual and reproductive behavior, socioeconomic status, screening practices, and detection of human papillomavirus 16/18 by filter in situ hybridization, a slightly lower risk was observed for the highest quartiles of consumption of fruit and fruit juices, while no reductions in risk were associated with vegetables, foods of animal origin, complex carbohydrates, legumes, or folacin-rich foods. When nutrient indices were derived, significant trends of decreasing risk were observed for vitamin C (adjusted odds ratio (OR) = 0.69 for the highest vs. the lowest quartile; p for trend = 0.003), beta-carotene (OR = 0.68; p = 0.02), and other carotenoids (OR = 0.61; p = 0.003). Inclusion of vitamin C and beta-carotene in the same model attenuated the association with beta-carotene, while the association with vitamin C remained unchanged. The results are consistent with those of other investigations and provide support for a protective effect of vitamin C, carotenoids, and other substances found in the same fruits and vegetables against the development of invasive cervical cancer. However, the fact that the associations were driven by relation in two of the study sites and among women of higher socioeconomic status leaves open the possibility of selection bias or effects of unidentified aspects of dietary patterns.

A case-control study of nutrient status and invasive cervical cancer. II. Serologic indicators.

A study of 387 cases and 670 controls from four Latin American countries evaluated the hypothesis that lower serum levels of eight micronutrients were associated with a higher risk of invasive cervical cancer. The serologic analyses were restricted to a sample of subjects with stage I and II disease to minimize effects of the disease on the serologic markers. Ninety-four percent of eligible subjects donated blood samples, which were analyzed for carotenoids, retinol, and tocopherols by high-pressure liquid chromatography. Cases did not differ significantly from controls in mean serum levels of retinol, cryptoxanthin, lycopene, alpha-carotene, lutein, or alpha-tocopherol. The mean level of beta-carotene was lower and the mean level of gamma-tocopherol was higher among cases as compared with controls. After adjustment for age, study site, sexual and reproductive behavior, socioeconomic status, screening practices, detection of human papillomavirus types 16/18, cholesterol, and triglycerides, a trend of decreasing risk was associated with higher levels of beta-carotene (p for trend = 0.05), with the adjusted odds ratio decreasing to 0.72 for the highest versus the lowest quartile. beta-Carotene results were similar by stage of disease, which argues against an effect of disease progression on nutrient values. Unexpectedly, increasing risks were observed as the level of gamma-tocopherol increased (odds ratio = 2.09; p for trend = 0.03); however, levels were higher among stage II cases as compared with stage I cases, suggesting a metabolic alteration resulting from the disease process. The concordance in the strength and direction of the blood and dietary results, presented in the accompanying report (Herrero R, Potischman N, Brinton LA, et al., American Journal of Epidemiology 1991;134:1335-46), supports a role for beta-carotene or foods rich in beta-carotene in the etiology of cervical cancer. This study also indicates that simultaneous analysis using serologic and dietary nutrient indicators allows better discrimination of the association.

A case-control study of serum folate levels and invasive cervical cancer.

Although small intervention trials have suggested that folate supplementation reduces cervical dysplasia, the association of blood folate concentrations with invasive cervical cancer risk has not been investigated in well-controlled epidemiological studies. A study was conducted with newly diagnosed Stage I and II invasive cervical cancer cases and controls in 4 Latin American countries. Ninety-five% of subjects donated blood samples, resulting in 330 case and 565 control serum samples analyzed for folate concentrations by radioassay. Cases did not differ significantly from controls in mean levels of folate (5.00 and 4.90 ng/ml, respectively). No associations were observed between quartiles of serum folate and risk of cervical cancer after adjustment for other risk factors, and no interactions with established risk factors were observed. Folate levels were also unrelated to risk among women who might have compromised folate status because of recent or extended oral contraceptive usage or multiple pregnancies. Further, mean levels of folate were similar by stage of disease, arguing against an effect of disease progression on serum values. These results do not support a role for serum folate in the etiology of invasive cervical cancer.

[The risk factors of invasive carcinoma of the cervix uteri in Latin America]. / Factores de riesgo de carcinoma invasor del cuello uterino en América Latina.

A study of 759 patients with invasive cervical cancer, 1,430 controls, and 689 sexual partners of the participants who declared that they were monogamous was conducted in Colombia, Costa Rica, Mexico, and Panama from January 1986 to June 1987, to evaluate the risk factors associated with this neoplasm. The principal risk factors identified were: initiation of sexual relations by the woman at an early age, number of stable sexual partners (relationships of more than three months' duration), number of liveborn children, presence of DNA from human papilloma virus (HPV) types 16 or 18, history of venereal disease, lack of exposure to early detection programs, deprived socioeconomic conditions, and number of sexual partners of the partners of the monogamous women. Smoking increased the risk in those women who were shown to have DNA from HPV types 16 or 18. Fifty percent of the patients and 29% of the controls said they had never had a cytological examination (Papanicolaou test). No association was observed between the presence of HPV and sexual behavior. The study showed the need for further research on the possible mechanisms involved in carcinogenesis and infection. The common denominators of the risk factors mentioned are underdevelopment and poverty, which affect broad sectors of these populations. Mass detection programs targeting high-risk groups can reduce the high incidence of cervical cancer in Latin America.

Injectable contraceptives and risk of invasive cervical cancer: evidence of an association.

In a case-control study conducted in Latin America, the relationship of injectable contraceptive (IC) use to risk of invasive cervical cancer was analyzed while controlling for a variety of other risk factors, including female and spouse sexual behavior and infection with human papillomaviruses (HPV). Thirty-two cases and 82 controls reported ever having used IC. Women reporting use of IC for less than 5 years had an adjusted RR of 0.5 (95% Cl = 0.3-0.9), but users for 5 or more years had an RR of 2.4 (95% Cl = 1.0-5.7). The effect of prolonged IC use was stronger for women reporting first use 10 or more years before interview (adjusted RR = 3.4, 95% Cl = 1.1-24.9) and more than 5 years since last use (adjusted RR = 5.3, 95% Cl = 1.1-10.0). Cervical cancer risk associated with prolonged IC use was particularly high among women who reported never having had a Pap smear or having had one 2 or more years before interview (adjusted RR = 6.3, 95% Cl = 2.1-18.7). The reduced cervical cancer risk associated with short-term use of IC may reflect intensive Pap smear screening as the method is initiated. Although hampered by small numbers, these results suggest an adverse effect of prolonged IC use on cervical cancer risk, particularly among women who cease participation in screening programs after terminating usage, and indicate that long-term IC users should be monitored for cervical disease until more conclusive results are available.

Oral contraceptive use and risk of invasive cervical cancer.

A case-control study of 759 invasive cervical cancer patients and 1430 controls in Panama, Costa Rica, Colombia and Mexico enabled an evaluation of risk in relation to oral contraceptive use. Overall use was associated with a 21% nonsignificant elevation in risk, with some further increases in risk for more extensive durations of use. Although risks were similar for recent and non-recent users (RRs = 1.3 versus 1.2), recent long-term users were at highest risk (RR for 5+ years use = 1.7, 95% Cl 1.1-2.6). Relationships were similar for women with and without a recent Pap smear, arguing against detection bias. There was little evidence that other risk factors, including smoking and detection of human papillomaviruses (HPV), altered the effects of oral contraceptives. The risk associated with oral contraceptives was significantly increased for adenocarcinomas (RR = 2.2), whereas for squamous cell tumours the effect was minimal (RR = 1.1). These results provide some support for an adverse effect of oral contraceptives on cervical cancer risk, although possibly limited only to a subpopulation of cases.

Sexual behavior, venereal diseases, hygiene practices, and invasive cervical cancer in a high-risk population.

A case-control study of 759 women with invasive cervical cancer and 1430 controls in four Latin American countries evaluated risk in relation to sexual behavior, histories of specific venereal diseases, and hygiene practices. Early age at first sexual intercourse and increasing number of sexual partners were associated with significantly increased risks even after adjustment for their mutual effects. Risk increased to a twofold excess among women reporting first intercourse at 14 to 15 years of age compared with 20+ years. The number of steady sexual partners was a more important predictor of risk than the number of nonsteady partners, particularly before age 30, possibly reflecting the need for prolonged or repeated exposures to a transmissible agent, or different methods of protection against sexually transmitted diseases or pregnancy. Reported frequency of intercourse was not generally associated with risk, except among women reporting increased frequencies before 20 years of age. Histories of gonorrhea or crab lice were associated with increased risk, but histories of other venereal diseases were not significant predictors. No consistently increased risks were detected for women reporting specific hygiene or douching habits, except the practice of washing the genitalia infrequently during menstruation. These results provide support for a period of increased susceptibility to carcinogens during adolescence, and suggest that this may be an important determinant of the high incidence of cervical cancer in Latin America.

Risk factors for invasive carcinoma of the uterine cervix in Latin America.

A study of 759 cervical cancer patients, 1,430 controls, and 689 sex partners in four Latin American countries has made it possible to assess the influence of multiple factors upon the risk of invasive cervical cancer. The principal risk factors identified were the woman's age at first coitus, the number of her steady sex partners, her number of live births, the presence of DNA from human papillomavirus (HPV) types 16 or 18, a history of venereal disease, nonparticipation in early detection programs, and low socioeconomic status. There is good reason to believe that extensive detection programs directed mainly at high-risk groups in the Americas can reduce the high incidence of cervical cancer in this Region.

PIP: Risk factors for invasive carcinoma of the cervix were analyzed in 759 cancer patients from Mexico City, Costa Rica, Panama and Bogota, Colombia, in comparison with 1430 controls and 689 male partners, by interview and analysis for human papilloma virus (HPV) types 16 and 18. Community and hospital controls were combined for the analysis, since they did not differ significantly. Average age is 1st coitus was 17.4 years for patients and 18.8 for controls. A relative risk of 1.8 resulted for women with coitus at age 14-15 compared to age 20 or more. Those with 6 or more sex partners had a risk of 1.7 compared to monogamous women, with a significant trend (p0.0001). Anal sex conferred a risk of 1.5-1.9 depending on frequency. There was a significant trend toward increasing risk for number of pregnancies up to 5.1 for 14 or more pregnancies, and especially for number of live births, with a risk of 3.7 for 12 of more. No relationship was found between risk and stillbirths, or spontaneous or induced abortions. Cesarean sections and prenatal care reduced risks. DNA from HPV types 16 or 18 was found in 62% of patients and 32% of controls. A relative risk of 1.7 was found in women who had HPV and who smoked. Risks decreased with rising educational level, and with increasing socioeconomic status. Neither oral contraception nor condoms affected risks. Factors associated with male partners related to increased risk were his number of sex partners (25 vs 5 of less) and lower education. Not having Pap smears increased risk to 2.5. Providing cervical cytology to women at risk is an obvious intervention needed to reduce the several-fold higher incidence of cervical cancer in Latin American compared to that in developed countries.

Parity as a risk factor for cervical cancer.

In a case-control study of 759 invasive cervical cancer patients and 1,430 controls in Colombia, Costa Rica, Mexico, and Panama conducted during 1986-1987, an association with number of pregnancies persisted after adjustment for sexual and socioeconomic variables. Risks rose steadily to 5.1 (95% confidence interval 2.7-9.7) for those with 14 or more pregnancies and a relation of risk to multiparity was observed in all four study countries. Pregnancy associations appeared to relate to the number of live births rather than to miscarriages or abortions, with multiparity relations most pronounced among premenopausal women and oral contraceptive users. Human papillomaviruses types 16 and 18, as measured by filter in situ hybridization, were not significantly associated with number of births and did not explain the strong relation of parity to risk. Our results indicate the need for further consideration of reproductive factors on cervical cancer risk, with attention given to possible mechanisms of action, including hormonal factors and cervical trauma.

The male factor in the etiology of cervical cancer among sexually monogamous women.

To address the hypothesis that male sexual behavior may affect the etiology of invasive cervical cancer, a case-control study was undertaken in Panama, Costa Rica, Colombia and Mexico. The study enrolled husbands of those women with invasive cervical cancer and of those age-matched controls who reported only one lifetime sexual partner. A total of 204 case and 485 control husbands (78% and 72%, respectively, of identified husbands) were interviewed, clinically examined, and had penile swabs taken for papillomavirus assays. Risk increased significantly (p = 0.005) with the number of sexual partners reported by the husband (RR = 2.0 for 26+ vs. less than 6 partners). Low educational status of the husband was also an important predictor of risk, possibly indicating the role of unmeasured aspects of sexual behavior. Visits to prostitutes, circumcision status and sexually transmitted disease histories were not important predictors of risk, but evidence from clinical examination indicated that poor genital hygiene may be involved. Human papillomavirus (HPV) expression as defined by filter in situ hybridization was detected in 20-23% of subjects and, except in the small group with both HPV types 6/11 and 16/18, was not related to risk. This may reflect sampling problems in the male or the importance of host factors which enhance viral carcinogenicity in the female.

Human papillomavirus infection and cervical cancer in Latin America.

To evaluate a possible association between infection with human papillomavirus (HPV) and cervical cancer, we performed a multicenter case-control study in Latin America of 759 cases of invasive cervical cancer and 1467 randomly selected age-matched controls. Demographic, sexual, behavioral, and other clinical data were obtained by interview, and HPV DNA was assayed in cervical-swab specimens with use of filter in situ hybridization. Cervical infection with HPV 16 or 18 or both was strongly associated with cervical cancer. HPV DNA was detected in 62 percent of the cases but only 32 percent of the controls, and the relative risk of cancer increased from 2.1 (95 percent confidence interval, 1.6 to 2.8) to 9.1 (6.1 to 13.6) with hybridization reactions of increasing strength. Although the number of sexual partners, age at first intercourse, number of live births, and Pap-smear history were also significant risk factors, the strong associations between infection with HPV 16 or 18 or both and cervical cancer persisted after we adjusted for these variables. These observations are consistent with the hypothesis that genital infection with HPV 16 or 18 may have a role in the pathogenesis of cervical cancer. Other well-known risk factors were also identified in the study, but they did not affect the association between HPV and cervical cancer.

Invasive cervical cancer and smoking in Latin America.

A case-control study of 667 patients with invasive squamous cell carcinoma of the cervix and 1,430 controls from four Latin American countries showed an age-adjusted relative risk (RR) of 1.2 [95% confidence interval (CI) = 1.0-1.4] for women who had ever smoked, with risk rising to 1.7 (95% CI, 0.8-3.6) for women who smoked greater than or equal to 30 cigarettes per day. The associations were practically eliminated after adjustment for the number of sexual partners and alcohol consumption, probably a surrogate for an unidentified life-style risk factor. Some excess risk persisted among women who smoked for extended periods (RR = 1.5 for greater than or equal to 40 yr), as well as those who began smoking at older ages (RR = 1.7 for greater than 30 yr), which suggests a late-stage effect. In addition, among women who tested positive for human papillomavirus (HPV) type 16 or 18 by filter in situ hybridization, there was an increased risk for women who had ever smoked and a dose-response relationship with the number of cigarettes smoked (adjusted RRs compared with HPV-negative nonsmokers = 5.0 for HPV-positive nonsmokers, 5.5 for less than 10 cigarettes/day, and 8.4 for greater than or equal to 10 cigarettes/day). In contrast, HPV-negative women had no increased risk associated with smoking. These results, from a high-incidence area where intensive smoking among women is still relatively rare, suggest that smoking has a limited effect on cervical cancer risk, possibly only among women with specific types of HPV.

Case-control study of human papillomaviruses and cervical cancer in Latin America.

Human papillomavirus (HPV) types 16 and 18 have been implicated as risk factors for cervical dysplasia and neoplasia. However, most studies have been observational, uncontrolled and conducted in populations at low risk for invasive cancer. We report a pilot case-control study of incident invasive cervical cancer in Panama, Costa Rica and Bogota, Colombia. Between July and September 1985 we enrolled 46 consecutive newly diagnosed invasive cervical cancer cases and 51 age-matched control women. Subjects were interviewed and samples collected for HPV DNA assays. HPV infection was defined by a filter in situ DNA hybridization technique under non-stringent and stringent conditions against HPV-6/11, 16 and 18 DNA probes. More cases (91%) than controls (63%) had HPV DNA detected (non-stringent) and more cases than controls had HPV-16 or 18 DNA (67% vs. 43%, p = 0.02). Age at first intercourse was the most significant risk factor for HPV 16/18 infection in all subjects. Smoking was significantly associated with cervical cancer (52% of cases vs. 27% controls) but was not associated with HPV infection.

Case control study of cervical cancer in Herrera Province, Republic of Panama.

A previous survey found the average annual age-adjusted incidence of cervical cancer in Herrera Province, Panama, to be 79/100,000, exceeding any other reported world rate. In an effort to clarify the reasons for this excessive occurrence, a case-control study was conducted among patients diagnosed between 1974-1980. Sixty-six percent of cervical cancer patients from Herrera Province were alive and were contacted by the study team; of these 91% were successfully interviewed and provided serum specimens. The total study encompassed 156/169 surviving patients and 309 age-neighborhood matched controls. Sexual promiscuity was uncommon, but it exerted a major effect, with those reporting 4 or more life-time sex partners being at a 4-fold excess risk compared to those reporting only one partner. First intercourse at a young age was common (21% began sexual activity prior to age 16) but it failed to alter risk once number of partners was taken into account. Oral contraceptive use was associated with a 2-fold excess risk and this was not substantially affected by controlling for sexual parameters. Thirty-three percent of the study subjects had anti-herpes-simplex type-2 antibody as measured by both neutralization and radioimmunoassays. Although results of the neutralization test were not predictive of risk, women with a radioimmunoassay indicative of HSV-2 infection were at a 40% excess risk for cervical cancer after adjustment for sexual characteristics.

Herpes simplex virus type 2 and human papillomavirus type 16 in cervicitis, dysplasia and invasive cervical carcinoma.

Sera and biopsies of cervical lesions from 55 women with benign or malignant disease were analyzed for evidence of infection with herpes simplex virus type 2 (HSV-2) or human papillomavirus (HPV). In addition, information regarding known risk factors for cervical cancer was obtained by interview. The sera were tested for HSV-2 antibodies and the biopsies were tested for HPV or HSV DNA sequences by Southern blot hybridization. HSV-2 sequences were detected in 2/13 (15%) invasive neoplasms and in 1/12 (7%) benign lesions. Under non-stringent conditions of hybridization, reactions with HPV DNA were detected in biopsies of 2/17 (12%) inflammatory lesions, 6/12 (50%) intraepithelial neoplasms and 13/20 (65%) invasive neoplasms. All but one of the positive biopsies of invasive cancer, but only 4/11 biopsies of non-invasive lesions, contained HPV-16 DNA as determined by stringent hybridization conditions. Women with cervical cancer possessed the risk factors associated with the disease. Cigarette smoking and the presence of HPV-16 DNA were the most prominent risk factors. No evidence of an interaction between HSV-2 and HPV-16 was found among the cases of invasive cervical cancer.