Materials and Methods

Prorok et al have described the design and methods of the PLCO, which is the setting and source population for this observational cohort analysis. Briefly, the PLCO is a prospective evaluation of whether screening with a posteroanterior chest x-ray, flexible sigmoidoscopy, and cancer antigen-125 (CA-125) plus transvaginal ultrasound (TVU) can reduce mortality rates for lung, colon, and ovarian cancers, respectively, in women. Comparable questions are being investigated for lung, colon, and prostate cancer among men. Women were eligible if they were between 55–74 years old and had no previous lung, colon, or ovarian cancer diagnosis. Women who were receiving cancer treatment or were participating in another screening or prevention trial were not eligible. Women who had undergone oophorectomy previously were excluded from ovarian cancer screening in the trial.

Recruitment occurred from November 1993–July 2001. Women were assigned randomly to either the intervention or the control arm after stratification by age, sex, and screening center ( Appendix ). Participants responded to a self-administered general risk factor questionnaire at entry. Ovarian cancer screening in the PLCO included a CA-125 blood test and TVU at baseline, an annual TVU for 3 additional years, and annual CA-125 tests for 5 years beyond baseline. For TVU screening, qualified sonographers used a 5–7.5 MHz transvaginal probe to measure each ovary and describe any observed abnormalities. The examiner spent at least 5 minutes searching for each ovary, although the examiner could end the search if the iliac vessels were visualized and the ovaries were not observable. Ovaries were measured along major and minor axes of both transverse and longitudinal planes, and the prolate ellipsoid formula (width × height × thickness × 0.523) was used to calculate the volume of each ovary and/or cyst. Quality-assurance procedures on a sample of participants included either repeating the screening examination, independent observation of the examination, or independent review of TVU films at a later time.

In the trial, the TVU screening examination was considered positive (abnormal and suspicious for ovarian cancer) when findings included (1) ovarian volume >10 cubic cm, (2) cyst volume >10 cubic cm, (3) any solid area or papillary projection that extended into the cavity of a cystic ovarian tumor of any size, or (4) any mixed (solid/cystic) component within a cystic ovarian tumor. As part of the trial protocol, women with positive screening examination results were referred to regular medical care for follow-up investigation. Ovarian cysts with volume <10 cubic cm and no solid areas, septae, or papillary projections that were noted in the cyst cavity were not considered to be a positive screening examination in the trial. These simple cysts are, however, the subject of this cohort analysis. Ovarian cancers were ascertained in the PLCO through a review of medical records and pathology reports after a positive screen or a report of cancer on annual study surveys.

This analysis is based on the subset of women in the intervention arm with both ovaries visualized ≥1 times during TVU screenings. As in a previous PLCO report, women were classified by the most serious abnormality that was present. Prevalence was the proportion of women for whom a simple cyst was discovered at the screening in which both ovaries were visualized for the first time (prevalent cyst). Most of these were discovered during the baseline screen; however, for some women, the first informative screen was in a later round. A 1-year incidence rate was the proportion of women who experienced the development of a new simple cyst in their second screen with visualized ovaries, after no cysts had been discovered 1 year before in their first screen with visualized ovaries (incident cyst).

Descriptive evaluation of the natural history of simple cysts was performed by an examination of the status of all ovaries that were visualized in 2 consecutive study years (baseline to year 1, years 1–2, or years 2–3). For this particular analysis, each ovary was counted as a separate unit of evaluation. A 1-year change in CA-125 levels was compared, in an analysis of variance, between women with simple cysts who had more extensive findings (increased number or complexity) 1 year later and those who did not. χ ² or Fisher’s exact test and multivariable logistic regression were used to evaluate the potential association between the detection of simple cysts and subsequent discovery of invasive ovarian cancer through year 7 after baseline.

χ ² analysis evaluated possible correlates of simple ovarian cyst occurrence, by comparing women with prevalent or incident simple cysts with women without detected cysts at the corresponding screen. The primary objective of this analysis was to evaluate whether known or potential ovarian cancer risk factors correlate with simple cyst occurrence, based on the approach of Hartge et al. Potential predictors in this analysis included age, education, smoking status, number of sisters, first-degree family history of ovarian cancer and breast cancer, number of pregnancies, parity, number of miscarriages, use and duration of oral contraceptives, age at first pregnancy, use of hormone replacement, regular use of nonsteroidal antiinflammatory drugs or aspirin, age at menarche, age at menopause, previous gynecologic surgery, body mass index, history of benign ovarian tumors or cysts, and history of infertility. Multivariable logistic regression models contained factors with probability values ≤ .2 from the χ ² analyses. All multivariable models were adjusted for race and screening center. For dichotomous variables, the “no” category served as the referent; for categoric variables, the referent was the most common category. Probability values < .05 were considered statistically significant. The study was approved by the Marshfield Clinic Research Foundation Institutional Review Board.

Results

The trial enrolled 78,237 women and randomly assigned 39,115 women to the screening arm ( Table 1 ). Of 4895 women in the screening arm who were not eligible for TVU, 4892 women had previous oophorectomy; 2 women had died; and 1 woman had ovarian cancer before the baseline screen. Of 34,220 eligible women, 30,389 women (89%) received at least 1 examination. A total of 15,735 women had both ovaries visualized ≥1 times during the study. Approximately two-thirds of these women were enrolled between the ages of 55–64; 89% of the women reported their race as white; and 94% of the women indicated that they had received at least a high school diploma ( Table 2 ).

Prevalence and incidence of simple cysts

Among the 15,735 women, 2217 women (14.1%) had ≥1 simple cysts detected at their first fully visualized TVU screening ( Table 3 ). In a stratified analysis, prevalence varied by age ( P = .001), with simple cyst detection slightly more common for women who were 55–59 years old (16%) than for women in older age groups (13%). Among women without a cyst of any kind on their first fully visualized screen, the rate of having a new simple cyst at the second screen 1 year later was 8.3% ( Table 4 ). The incidence rate of new cyst development did not vary systematically with age and ranged across age groups from 7–9% ( P = .20). When we calculated a simple cyst incidence rate for each individual screening year of the trial, the results were 8.4% at year 1 after baseline, 7.4% from years 1–2, and 7.3% from years 2–3.

TABLE 3

Simple ovarian cyst prevalence

	Prevalent simple cysts		Adjusted association a
Characteristic	Women, n	Rate, %	Odds ratio	95% CI
Overall	2217	14.1
Age
55–59	884	15.6	ref
60–64	658	13.2	0.83	(0.73–0.94)
65–69	434	13.3	0.97	(0.84–1.12)
70–74	241	13.4	1.01	(0.84–1.22)
Education
<12 y	94	11.8	0.85	(0.66–1.09)
12 y/completed high school	842	13.6	ref
Some college	515	14.6	1.11	(0.97–1.26)
College graduate	411	15.8	1.32	(1.14–1.53)
Postgraduate	338	13.6	1.19	(1.02–1.40)
Missing	17	14.8	NA
Cigarette use
Never smoked	1248	14.1	ref
Current smoker	155	11.5	0.75	(0.61–0.91)
Former smoker	797	14.7	1.04	(0.93–1.15)
Missing	17	16.2	NA
First-degree family history of breast cancer
No	1739	13.8	ref
Yes	342	15.3	1.12	(0.98–1.28)
Unknown	81	15.0	NA
Missing	55	16.0	NA
Total years of oral contraceptive use
0	946	13.2	ref
<1	337	15.2	1.02	(0.88–1.18)
2–3	254	14.7	0.95	(0.80–1.13)
4–5	179	15.2	0.94	(0.77–1.14)
6–9	212	14.9	0.94	(0.78–1.13)
10+	266	14.1	0.97	(0.83–1.15)
Missing	23	17.8	NA
Age at first pregnancy
Never pregnant	135	12.2	0.82	(0.60–1.12)
<20	516	15.6	1.04	(0.91–1.19)
20–24	1078	14.7	ref
25–29	366	12.4	0.85	(0.74–0.98)
30+	102	11.2	0.71	(0.55–0.91)
Missing	20	13.9	NA
Number of pregnancies
Never pregnant	135	12.2	NA
1	120	13.5	1.25	(0.99–1.58)
2	359	12.8	0.97	(0.84–1.12)
3–4	938	14.5	ref
5–9	612	15.1	0.97	(0.86–1.09)
10+	34	12.2	0.72	(0.49–1.06)
Missing	19	14.2	NA
Hormone replacement
No	682	12.5	ref
Yes	1512	14.9	1.09	(0.98–1.22)
Don’t know	6	11.5	NA
Missing	17	14.8	NA
Age at menopause
<40	390	24.7	2.09	(1.77–2.46)
40–44	272	15.7	1.26	(1.07–1.49)
45–49	410	11.6	0.93	(0.82–1.07)
50–54	786	11.9	ref
55+	313	15.1	1.24	(1.07–1.44)
Missing	46	19.0	NA
Previous gynecologic surgery
No	1070	11.4	ref
Yes	1124	18.2	1.48	(1.33–1.66)
Don’t know	1	3.1	NA
Missing	22	15.9	NA
History of benign ovarian tumors or cysts
No	1934	13.7	ref
Yes	220	17.8	1.29	(1.09–1.52)
Missing	63	15.8	NA
Use of NSAIDs or aspirin
No	920	13.5	ref
Yes	1268	14.5	1.00	(0.91–1.10)
Missing	29	17.3	NA
History of infertility
No	1862	13.9	ref
Yes	335	15.1	0.95	(0.69–1.30)
Missing	20	14.0	NA

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