Elevated serum homocysteine levels and increased risk of invasive cervical cancer in US women.

OBJECTIVES: To explore the relationship between serum homocysteine, a sensitive biomarker for folate inadequacy and problems in one-carbon metabolism, and invasive cervical cancer. METHODS: A large case-control study was conducted in five US areas with up to two community controls, obtained by random-digit dialing, individually matched to each case. Cervical cancer risk factors were assessed through at-home interview. Blood was drawn at least 6 months after completion of cancer treatment from 51% and 68% of interviewed cases and controls. Serum homocysteine was measured by high-performance liquid chromatography, and exposure to human papillomavirus (HPV) type 16, the most prevalent oncogenic type, was assessed using an enzyme-linked immunosorbent assay. Cases with advanced cancer and/or receiving chemotherapy were excluded, leaving 183 cases and 540 controls. RESULTS: Invasive cervical cancer risk was substantially elevated for women in the upper three homocysteine quartiles (> 6.31 micromol/L); multivariate-adjusted odds ratios ranged from 2.4 to 3.2 (all 95% CIs excluded 1.0). A trend was apparent and significant (p = 0.01). When cases were compared with HPV-16 seropositive controls only, odds ratios were comparable. CONCLUSIONS: Serum homocysteine was strongly and significantly predictive of invasive cervical cancer risk. This association could reflect folate, B12 and/or B6 inadequacy, or genetic polymorphisms affecting one-carbon metabolism.

Low serum and red blood cell folate are moderately, but nonsignificantly associated with increased risk of invasive cervical cancer in U.S. women.

Previous observational epidemiologic studies of folate and cervical cancer, as well as folate supplementation trials for cervical dysplasia, have produced mixed results. We examined the relationship between serum and RBC folate and incident invasive cervical cancer in a large, multicenter, community-based case-control study. Detailed in-person interviews were conducted, and blood was drawn at least 6 mo after completion of cancer treatment from 51% of cases and 68% of controls who were interviewed. Blood folate was measured with both microbiologic and radiobinding assays. Included in the final analyses were 183 cases and 540 controls. Logistic regression was used to control for all accepted risk factors, including age, sexual behavior, smoking, oral contraceptive use, Papanicolaou smear history and human papillomavirus (HPV)-16 serology. For all four folate measures, the geometric mean in cases was lower than in controls (e.g., 11.6 vs. 13.0 nmol/L, P < 0.01 for the serum radiobinding assay). Folate measures using microbiologic and radiobinding assays were correlated (serum: r = 0.90; RBC: r = 0.77). For serum folate, multivariate-adjusted odds ratios (OR) in the lowest vs. highest quartile were 1.3 [95% confidence interval (CI) = 0.8--2.9] and 1.6 (0.9--2.9), using the microbiologic and radiobinding assays, respectively. For RBC folate, comparable OR were 1.2 (0.6--2.2) and 1.5 (0.8--2.7). Similar risks were obtained when restricting analyses to subjects with a history of HPV infection. Thus, low serum and RBC folate were each moderately, but nonsignificantly, associated with increased invasive cervical cancer risk. These findings support a role for one-carbon metabolism in the etiology of cervical cancer.

A nested case-control study of bladder cancer incidence in a steel manufacturing plant.

BACKGROUND: A surveillance study of bladder cancer incidence in northwestern Illinois detected a number of cases who had worked in a large steel manufacturing plant. To investigate these cancers further, a nested case-control study of bladder cancer was conducted at this plant. METHODS: Cases from the surveillance study were matched to company personnel files. Four controls per case were selected from company files and frequency matched on age (cases and controls were all white males). Employment histories were abstracted from company records and odds ratios calculated according to job titles and departments worked. Cases and controls who held only white collar jobs were excluded from the analysis. RESULTS: Results for 16 cases and 75 controls showed elevated odds ratios for heaters (OR = 21.1, 95% cCI = 2.2-205.8) based on three cases. Heaters monitored electric reheat furnaces and may have been exposed to polycyclic aromatic hydrocarbons. Previous studies have shown moderate risks for bladder cancer among furnace operators, but most of these studies were also based on a small number of cases. CONCLUSIONS: Additional studies of furnace operators' exposures and cancer risks are needed to investigate these results further.

Agreement between patient self-reports and medical records for Pap smear histories.

As part of a larger cervical cancer study, we tried to verify the Pap smear histories for 125 black women with cervical cancer. For 105 of the patients, we identified all possible providers for the five-year period before the calendar year of diagnosis. Agreement between the medical records and the patient reports was poor to fair (kappa = 0.34) for whether the patient had a Pap smear in the three-year period before diagnosis. Patients tended to report far more Pap smears than medical records confirmed. Important determinants of agreement were the number of Pap smears reported during the five-year period and the age of the patient. The older the patient and the more Pap smears reported, the larger the discrepancy between the medical record and her self-report. The medical records did not contain enough data for us to complete an investigation of the possible reasons for this disagreement. Our results suggest these implications: (1) clinicians should strongly consider performing Pap smears if they doubt a patient's screening history, and (2) Pap smear registries are required for reliable and efficient evaluations of cervical cancer control programs because neither the patient report nor medical records are adequate.

Diet and the risk of vulvar cancer.

In this case-control study, 201 case patients with vulvar cancer and 342 community control subjects responded to a 61-item food frequency questionnaire. Risk was unrelated to intake of dark green vegetables, citrus fruits, legumes, and vitamins A and C and folate. Risk increased modestly with decreased intake of dark yellow-orange vegetables; the relative risk for the lowest versus the highest quartile was 1.6. Analyses using preliminary determinations of the major carotenoids in common fruits and vegetables suggested that alpha carotene might be the protective constituent in dark yellow-orange vegetables. Intake of beta carotene and provitamin A carotenoids was unrelated to risk. Multivitamin users were at lower risk, compared to nonusers, but no trend was observed with increasing years of use, suggesting that this association was due to unmeasured differences in life-style factors. Risk increased irregularly with the number of cups of coffee consumed per week whereas consumption of alcohol was unrelated to risk.

Diet and the risk of in situ cervical cancer among white women in the United States.

A case-control study of women with incident in situ and invasive cervical cancer was conducted during 1982-83 in five US areas reporting to the Comprehensive Cancer Patient Data System: Birmingham, AL; Chicago, IL; Denver, CO; Miami, FL; and Philadelphia, PA. Controls were selected by random-digit dialing and matched to invasive cases on age, race, and telephone exchange. Of the white non-Hispanic in situ cases and controls identified, 229 (78 percent) and 502 (74 percent) were successfully interviewed. Diet was assessed by asking about the usual adult frequency of consumption of 75 food items and the use of vitamin supplements. Included were the major sources of the four micronutrients postulated to reduce the risk of cervical cancer: carotenoids, vitamin A, vitamin C, and folate. Weak inverse associations between risk of in situ disease and intake of carotenoids, vitamin C, folate, fruit, and vegetables/fruits were noted but, with further analysis, these seemed attributable to residual confounding by the multiple lifestyle-related risk factors for this disease and possibly to selection bias. Vitamin A and vegetable intake were unrelated to risk. Dark yellow-orange vegetable consumption and duration of multivitamin use were each strongly related to reduced risk of in situ disease (P for trend = 0.02 and 0.002, respectively) and need to be evaluated in other studies. The absence of persuasive protective effects for the four micronutrients and the similar findings from our analysis of invasive cervical cancer do not concur with other epidemiologic studies and suggest that the role of diet and nutrition in the etiology of cervical cancer is not yet resolved.

Diet and the risk of invasive cervical cancer among white women in the United States.

A case-control study of incident invasive cervical cancer was conducted in Birmingham, Alabama; Chicago, Illinois; Denver, Colorado; Miami, Florida; and Philadelphia, Pennsylvania, during 1982-1983. Controls were selected by random-digit dialing and were matched to cases by age, race, and telephone exchange. Of the white, non-Hispanic cases and controls identified, 271 (73%) and 502 (74%), respectively, were successfully interviewed. Diet was assessed by asking about the usual adult frequency of consumption of 75 food items and the use of vitamin supplements. Included were the major sources of the four micronutrients believed to reduce the risk of cervical cancer: carotenoids, vitamin A, vitamin C, and folate. Women in the highest quartiles of intake of each of these micronutrients had adjusted relative risks of invasive squamous cell cervical cancer comparable to those of women in the lowest quartiles, although their micronutrient intake was estimated to be 3-4 times as high. Risk was not affected by increased consumption of vegetables, dark green vegetables, dark yellow-orange vegetables, fruits, or legumes, or by high intake of the basic food groups. These generally negative findings stand in contrast to findings in previous epidemiologic studies, and the discrepancy is not readily explained by bias, uncontrolled confounding, or inadequate power. The question of the role of diet and nutrition in the etiology of cervical cancer is not yet resolved.

Investigation of a bladder cancer cluster in northwestern Illinois.

Cancer maps from 1950 through 1979 revealed areas of high mortality from bladder cancer for both males and females in several northwestern Illinois counties. In order to further explore this excess, a bladder cancer incidence study was conducted in the eight counties comprising this region. Eligible cases were those first diagnosed with bladder cancer between 1978 and 1985. Age adjusted standardized incidence ratios were calculated for each county and for 97 zip codes within these counties. County results revealed no excesses. Zip code results indicated elevated risks in a few areas, but only two zip codes had significantly elevated results. One of these zip codes had a significant excess in males (standardized incidence ratio = 1.5) and females (standardized incidence ratio = 1.9). This excess was primarily confined to one town in this zip code, in which standardized incidence ratios were significantly elevated in males (1.7) and females (2.6). Further investigation revealed that one of four public drinking water wells in this town had been closed due to contamination; two wells were within a half mile (0.8 km) of a landfill site that had ceased operating in 1972. Tests of these two wells revealed traces of trichloroethylene, tetrachloroethylene, and other solvents. Further investigation of this cluster is discussed.

Case-control study of in situ and invasive carcinoma of the vagina.

A case-control study of 41 patients with carcinoma in situ (CIS) or invasive cancer of the vagina and 97 community controls was undertaken to identify potential risk factors. Although vaginal and cervical cancers often occur as multiple primaries, only a few common risk factors prevailed. Similar to cervical cancer, low education and family income were risk factors for vaginal CIS and invasive cancer. In addition, history of genital warts was strongly related (RR = 2.9), although other sexual factors were not. Previous genital abnormalities related to subsequent cancer risk, with significant associations seen for vaginal discharge or irritation (RR = 6.1), a previous abnormal Pap smear (RR = 3.8), or an early hysterectomy (RR = 6.7). In addition, there was some evidence that vaginal trauma might be involved, with nonsignificant and independent associations relating to regular douching with preparations other than water or vinegar (RR = 2.7) and frequent washing of the genital area (RR = 2.7). Further studies are needed to determine whether our findings persist among a larger series of cases.

Barrier and spermicidal contraceptive methods and risk of invasive cervical cancer.

The effects of barrier and spermicidal methods of contraception on cervical cancer risk were examined by studying 479 cases of histologically confirmed invasive cervical cancer cases and 788 random digit dialing controls. In addition to a detailed history of contraceptive practices, information was available on numerous potential confounders, including demographic characteristics, sexual behavior, reproductive factors, Pap smear screening history, and smoking. After adjustment for relevant confounders, diaphragm and condom use were found not to be significantly associated with risk of cervical cancer. Although there was a small reduction in risk (OR = 0.8) associated with long-term use (5+ years) of the diaphragm, the effect appeared to relate to concomitant spermicide use, since there was evidence of further decreases in risk for women using spermicides alone for extended periods (OR = 0.7 for 5+ years). Effects were only seen among subjects of higher income and education levels, suggesting that patterns of usage may be important. The potential ability of spermicides to reduce cervical cancer risk by neutralizing viral agents warrants further attention.

PIP: A case-control study of cervical cancer and confounding factors barrier and spermicidal contraceptives, smoking, socio-economic status, and screening found that barrier methods confer no protection against cervical cancer, but spermicides may offer some protection. 479 cases diagnosed with invasive cervical cancer at 5 centers (Birmingham, Chicago, Denver, Miami and Philadelphia) and 788 community controls selected by random dialing were interviewed at home. Questions covered contraception, sociodemographics, pregnancies, menstruation, hygiene, sexual behavior, medical history, smoking, diet, marriage, and family history of cancer. 7 contraceptive methods, spermicides, diaphragm, condom, pill, IUD, female and male sterilization were analyzed. In unconditional logistic regression, at first barrier methods appeared to lower cancer risk. After controlling for age, race, education, income, last Pap smear, number of sex partners, barrier methods were not significant (odds ratio 1.2), with no significance in trend. Neither did duration of oral contraception or smoking alter the results. A slight insignificant decrease in risk was seen over time with diaphragm use. The odds ratio for vaginal spermicides was 1.0 with no trend for duration of use. For the small number of women reporting use of vaginal spermicides solely (11 cases and 29 controls) for 5 or more years, however, the odds ratio was 0.7 indicating protection against cervical cancer. The test for trend was not significant. Long-term users of spermicides were also less likely to develop cancer when ever-pill users were excluded from analysis. Analyzing only high socioeconomic groups, spermicide use gave an odds ratio of 0.5 for long-term use, and a significant trend for duration of use. Some explanations of these results were the possible protection of the whole vagina with spermicides compared to diaphragm or condom, and the potential use of larger quantities, or more consistent use of spermicides, by high socioeconomic groups of women. It is known that human papilloma virus may infects the penile shaft and that it can spread from the vagina to the cervix.

Risk factors for in situ cervical cancer: results from a case-control study.

A case-control study of 293 patients with in situ cervical cancer and 801 community controls was conducted between 1982 and 1984 in five geographic areas in the United States. Relative risk (RR) was elevated among women reporting multiple sexual partners (RR for greater than or equal to 5 partners = 5.0), a history of an abnormal Papanicolaou smear (RR = 5.0), interval since last Papanicolaou smear (RR for greater than or equal to 10-year interval versus 0- to 2-year interval = 4.1), use of oral contraceptives (RR for greater than or equal to 10 years use = 1.4), a history of nonspecific genital infection (RR = 2.6), and smoking (RR for current smokers = 1.9). Risk was low among diaphragm users (RR for greater than 2 years use = 0.5). Neither age at first coitus nor number of births was predictive of risk of in situ disease. Comparisons between this analysis and risk factors previously identified for invasive cervical cancer in this same study indicate that the risk factors were quite similar.

Case-control study of cancer of the vulva.

A case-control study of 209 vulvar cancer patients and 348 community controls allowed assessment of risk factors for this rare tumor. As with cervical cancer, risk increased with the number of reported lifetime sexual partners, with five or more partners associated with two- to threefold increases in risk compared with zero to one partner. This factor largely explained the associations of risk with early age at first intercourse and low socioeconomic status. An independent association, however, was noted between vulvar cancer and a history of genital warts (relative risk 15.2; 95% confidence interval 5.5-42.1). Women who reported a previous abnormal Papanicolaou smear were at excess risk (relative risk 1.8), as were current smokers (relative risk 2.0). A significant interaction was noted between smoking and genital warts, with women reporting both having 35 times the risk of those with neither factor. Menstrual, reproductive, and hygiene factors were generally unrelated to risk. The relationships with sexual factors and genital warts support a common etiology for cervical and vulvar cancers. Future studies should focus on the etiologic agents for genital warts--the human papillomaviruses--and their enhancement by other factors, especially smoking and/or immune deficiencies.

Occupational cancer mortality in Illinois white and black males, 1979-1984, for seven cancer sites.

A death certificate mortality odds ratio study of seven cancer sites was conducted by using 1979-1984 data on Illinois deaths in white and black males. Cancer sites selected include stomach, pancreas, lung, prostate, bladder, brain, and non-Hodgkin's lymphomas. This surveillance study was undertaken to detect occupational associations that might suggest further avenues of research. Some of the occupations and industries found to have elevated cancer risks and that are consistent with previous studies include: brickmasons and stonemasons (stomach); metal workers (pancreas, lung); photoengravers and lithographers (pancreas); butchers (lung); locomotive operators and truck drivers (lung); farmers (prostate, brain, non-Hodgkin's lymphoma); mechanics and repairers, especially auto mechanics (prostate); physicians (brain); glass products manufacturing workers (brain); and communications industry (brain) and chemical plant workers (non-Hodgkin's lymphomas). It was also noted that for black males, the death certificate occupational data are of limited usefulness due to the high percentage of missing or inexact information. The Division of Vital Records in the State of Illinois should make an effort to improve the reporting of this data through additional training of the funeral directors and hospital clerks who collect this information and by follow-up of incomplete or missing data.

Cancer mortality in Illinois Mexican and Puerto Rican immigrants, 1979-1984.

The site-specific cancer mortality in Illinois immigrant Hispanics for 1979-1984 was compared to that of US-born, non-Hispanic whites (Anglos). Using indirect methods of standardization, 22 site-specific cancer SMRs (Standard Mortality Ratios) were calculated for Mexican and Puerto Rican immigrants, using standard rates for Illinois Anglos. SMRs were also calculated for Puerto Rican immigrants using 1979-1982 mortality rates from Puerto Rico. Cancer mortality for all sites was lower in both immigrant groups than in Anglos. Colon cancer mortality risk was lower in immigrants, but had increased from home country rates in Puerto Rican male immigrants. In addition, immigrants retained their lower home country risks for cancer of the lung, prostate and female breast. Significantly higher risks were found in immigrant females only, for cancer of the stomach, cervix and gall-bladder (Mexican females). The cancer rates for immigrant Puerto Rican males were closer to those of Anglos than the rates for females and Mexicans, suggesting differences in the rates of transition to the Anglo cancer experience.

Substance data bases and right to know laws: application to occupational epidemiology.

The Illinois Right to Know (RTK) law included requirements for substance lists to be submitted by companies to the Illinois Department of Labor (IDOL). This provided an opportunity to test the feasibility of identifying workplaces utilizing common chemicals for future epidemiologic investigations. A sample of IDOL files (n = 115) was obtained, and relevant data elements were coded. A second sample of substance names within these files (n = 1,015) was selected, and searches in three standard references were conducted to identify chemical descriptions. Equal proportions of employers and manufacturer/suppliers were in general compliance with RTK law reporting requirements (58%). Forty-five percent of substances sampled from employers (chemical users) and 71% of substances sampled from manufacturer/suppliers (chemical producers and distributors) could be identified. The ability to identify substances reported using chemical names was approximately equal across companies (90%), while the ability to identify substances with nonchemical names was greater in manufacturer (59%) than in employer (32%) files. This study suggests that the ability to identify potential occupationally exposed groups using this resource may be greater among manufacturers than among employers. Recognition of substances used in the workplace could be improved if companies were required to report chemical names.

Sexual and reproductive risk factors for invasive squamous cell cervical cancer.

A case-control study of 418 women with invasive squamous cell cervical cancer and 704 population controls enabled evaluation of risk factors for this relatively rare cancer. Consistent with an infectious etiology was a pronounced effect of multiple sexual partners, with those reporting 10 or more partners being at a significant threefold excess risk. Early first intercourse also was associated with some residual effect on risk, although the relationship was not linear, nor the explanation readily apparent. Those with multiple births were at significantly elevated risks, even after adjustment for sexual parameters. Menstrual and hygiene factors, including use of tampons, vaginal deodorants, and douching products, were not consistently related to risk. Histories of specific infections involving the genital tract were poor predictors of risk, since few women provided positive responses, but those with nonspecific diseases were at a significant twofold excess risk.

Epidemiology of cervical cancer by cell type.

A multicenter case-control study of 481 invasive cervical cancer patients and 801 population controls enabled comparison of risk factors for squamous cell tumors (n = 418), adenosquamous cancers (n = 23), and adenocarcinomas (n = 40). The epidemiology of the squamous cell tumors resembled that found in other studies, with the major risk factors being absence of Pap smear screening (relative risk = 3.6 to 4.8 for those not screened within 5 yr), multiple sexual partners (relative risk = 2.9 for over ten partners), and history of genital infections or sores (relative risk = 2.3). Although based on small numbers, adenosquamous tumors appeared to share some of these risk factors, notably number of sexual partners, years since last Pap smear, and level of education. Adenocarcinomas were not similarly affected, although sexual practices were marginally predictive. Obesity increased the risk of adenocarcinoma, but no other similarities to endometrial adenocarcinoma were observed. Smoking was a significant predictor of squamous cell tumors but did not affect adenocarcinomas. Extended use of oral contraceptives was a risk factor for all tumor types, especially adenocarcinoma, and a familial tendency to cervical cancer was also observed for all cell types.

Long-term use of oral contraceptives and risk of invasive cervical cancer.

To evaluate the relationship between use of oral contraceptives and risk of invasive cervical cancer, a case-control study involving 479 patients and 789 population controls was undertaken in 5 geographic regions of the US. Initially, the relationship was obscured by confounding variables, particularly the interval since last Pap smear. Control for this variable as well as for sexual and sociodemographic factors revealed an RR of 1.5 overall, with long-term users (5 or more years) being at a 2-fold higher risk than non-users. Pill associations prevailed for both adenocarcinomas and squamous-cell tumors, and risks were highest for those using pills containing high estrogen potencies. In addition, there was some evidence that pill associations were most pronounced among women who had never used barrier methods of contraception or who had histories of genital infections, suggesting that oral contraceptives may act as co-carcinogens with transmissible agents. Our findings provide further evidence that long-term use of oral contraceptives may have a carcinogenic effect on cervical epithelium, but emphasize the need for careful evaluation of confounding influences.

A proportional mortality ratio study of workers in a construction equipment and diesel engine manufacturing plant.

The mortality of 461 workers who were employed 10 or more years in a Midwest engine and construction equipment plant was examined, using the method of proportional mortality ratios. Both state and national deaths were used as the standard population. Major exposures in this plant included solvents, cutting oils, and metal fumes and dusts. However, precise exposure data were not available. Among white males, no significant deviations from expected deaths were found. Among black males, significant excess deaths were found for all malignant neoplasms combined, for cancer of the pancreas, and for non-Hodgkin's lymphomas. Proportional cancer mortality ratios produced similar results, although the excess of pancreatic cancer in blacks was only significant among those with 20 or more years of service. Although complete occupational histories were not available, these results may provide hypotheses for future studies of workers in heavy machinery production.

The fall of zinc protoporphyrin levels in workers treated for chronic lead intoxication.

A temporal fall of zinc protoporphyrin (ZPP) levels in whole blood was observed in 51 patients with occupational chronic lead intoxication who were removed from exposure, treated with intravenous calcium disodium edetate (EDTA), and followed for periods up to 2,273 days. ZPP levels fell, with a mean half-life of 68 days, to a mean baseline level of 36 micrograms/dl of whole blood. The baseline ZPP level was positively associated with the length of exposure (p less than .01) and the blood lead half-life (p less than .001). The amount of EDTA received had no apparent effect on ZPP levels. These data suggest that the fall of ZPP levels is largely a function of red blood cell turnover. The baseline ZPP level appears to be a useful biologic index of the biologically active pool of lead for at least two years after removal from exposure.