Materials and Methods
Kaiser Permanente Northern California is a closed integrated health care delivery system, providing care through 19 medical centers to approximately 35% of the population in the geographic areas served by the health plan. All formal ultrasound studies, laboratory tests, pathology reports, and diagnoses are captured in electronic databases and are linked to electronic medical records.
The study population was defined as women older than 50 years of age who had a pelvic ultrasound from 2007 through 2011 in which a mass described as complex and 1–6 cm in size was reported. Ultrasound reports were derived from all 19 medical centers within the system, representing 408 radiologists. Women with a history of ovarian cancer, a diagnosis of metastatic cancer of any kind, or with evidence of metastatic disease on imaging or an abnormal CA125 blood test (>35 U/mL) drawn within a month of the ultrasound were excluded.
We chose these selection criteria as those that typically define women for whom ovarian cancer is a significant concern but for whom observation would be potentially considered. Women were also excluded if they did not maintain active membership in the health plan for at least 24 months after the initial detection of the mass for any reason other than death.
The study was designed to have a sample size that could provide reasonable precision around an estimated 1% risk of subsequent diagnosis of ovarian cancer, which was based on the known incidence of ovarian cancer in the population and the volume of gynecological pelvic ultrasound done for an adnexal abnormality annually within the system. With a sample size of 900, the 95% confidence interval around an observed incidence of 1% is 0.3-1.7%. The study period of 2007-2011 was determined based on preliminary data that indicated that 5 years of data would be needed to ensure a sample size of at least 1000 cases.
Following approval from the Kaiser Permanente Northern California Institutional Review Board for Health Services, women meeting the selection criteria were identified using an electronic database that houses all radiology reports done within the health care system. The reports from these studies were searched to identify text strings that included the word complex and any of the following: ovary, ovarian, adnexa, adnexal, cyst, neoplasm, or mass. Chart review of the electronic medical record was then done to review the entirety of the ultrasound report to identify those cases in which a complex adnexal mass was found whose greatest dimension was 1-6 cm and to screen for exclusion criteria.
Any additional pelvic ultrasounds done prior to or following the identified ultrasound were reviewed to identify the study when the complex mass was first described. The mass was considered to be the same from one ultrasound to the next if the laterality of the mass was the same and there was no intervening radiological evidence of resolution. Repeat ultrasound studies done for follow-up of the mass were categorized as showing the mass to be increased, decreased, resolved, or stable.
Given the inherently variable nature of ultrasound measurements secondary to differences in technique and equipment and to capture changes in complexity as well as size, change was assessed by the following rules: if the radiologist’s stated impression was that the mass was unequivocally increased in size and/or there were new solid features not previously seen, the mass was considered increased, regardless of measurements given. If the radiologist’s stated impression was that the mass was unequivocally decreased in size or if the mass was judged to be simple rather than complex on a follow-up study, it was considered decreased. If the mass was no longer seen, it was considered resolved. If the radiologist reported the mass as only slightly or minimally changed or if the radiologist equivocated on whether there was any change, it was considered stable, regardless of measurements given. If there was no comment on the report comparing the mass to the previous studies, the mass was considered changed if the greatest dimension of the measurement differed by more than 25% from the prior study.
Age at the time of the initial ultrasound and self-reported race/ethnicity were determined from health plan databases. All surgical pathology records were reviewed to determine whether the mass was removed and the histological findings. Diagnoses of cancer made in the 24 months following the initial ultrasound were identified by chart review and tumor registry data. We defined malignancy to include epithelial ovarian cancer and fallopian tube and primary peritoneal cancers as well as stromal tumors with low malignant potential and borderline ovarian tumors.
The exact confidence intervals around the incidence of malignancy were calculated using binomial proportions. We also compared age, race/ethnicity, and mass size at index ultrasound by subsequent management. We divided the cohort into 4 groups: (A) repeat ultrasound and eventual removal (n = 218), (B) surgery only (n = 204), (C) no repeat ultrasound or surgery (n = 165), and (D) repeat ultrasound only (n = 776).
We used a χ 2 test for categorical variables and an analysis of variance and a Wilcoxon rank-sum test for continuous variables. The Tukey-Kramer method was used for adjusting P values in multiple comparisons. All analyses were performed using SAS version 9.3 (SAS Institute Inc, Cary, NC).
Results
We identified 1363 women who met the inclusion criteria, 18 of whom (1.3%; 95% confidence interval, 0.8–2.1%) were subsequently found to harbor either an ovarian cancer or borderline tumor. In all cases the diagnosis was made at the surgical removal of the mass.
Two hundred four women (15%) underwent surgical removal without repeat ultrasound. Of these, 6 (2.9%) were malignant (2 epithelial ovarian cancers and 4 borderline tumors). The majority of women, 994 of 1363 (73%) were followed up with 1 or more ultrasounds (mean, 2.2; range, 1–9). Of these women, 218 of 994 (22%) ultimately underwent surgery, with 6 borderline tumors and 6 cancers identified, including 5 epithelial cancers (4 of 5 high grade) and 1 granulosa cell tumor. There were 169 women who had neither formal repeat ultrasound nor surgical removal (12%). However, they were followed up clinically for at least 24 months as active health plan members with no diagnoses of ovarian, fallopian tube, or peritoneal cancer during that time.
For 261 women (19%), the initial ultrasound was done to follow up an incidental finding on computed tomography (n = 240), magnetic resonance imaging (n = 15), PET scan (n = 3), renal ultrasound (n = 2) or plain film (n = 1). Age, demographic comparison, and mass size for women with and without repeat ultrasound and/or subsequent surgical removal are shown in Table 1 .
| Variable | Total (n =1363) | Group A: At least 1 repeat sonogram, eventual removal (n = 218) | Group B: Surgical removal, no repeat sonogram (n = 204) | Group C: No repeat sonogram, no surgical removal (n = 165) | Group D: Repeat sonogram, no surgical removal (n = 776) |
|---|---|---|---|---|---|
| Age, y | |||||
| Mean (SD) | 61.2 (10.1) | 59.5 (8.1) | 60.8 (7.8) | 61.5 (11.9) | 61.8 (10.7) |
| 50-59 | 750 (55.0) | 129 (59.2) | 101 (49.3) | 98 (59.4) | 422 (54.4) |
| 60-69 | 319 (23.4) | 56 (25.7) | 72 (35.1) | 29 (17.6) | 162 (20.9) |
| 70-79 | 203 (14.9) | 31 (14.2) | 30 (14.6) | 18 (10.9) | 124 (16.0) |
| 80+ | 92 (6.7) | 2 (0.9) | 2 (1.0) | 20 (12.1) | 68 (8.8) |
| Race/ethnicity, n, % | |||||
| White | 874 (64.1) | 135 (61.9) | 133 (64.9) | 108 (65.5) | 498 (64.2) |
| Black | 76 (5.6) | 8 (3.7) | 13 (6.3) | 12 (7.3) | 43 (5.5) |
| Hispanic | 184 (13.5) | 36 (16.5) | 31 (15.6) | 14 (8.5) | 102 (13.1) |
| Asian | 133 (9.8) | 26 (11.9) | 12 (5.9) | 17 (10.3) | 78 (10.1) |
| Other | 97 (7.1) | 13 (6.0) | 15 (7.3) | 14 (8.5) | 55 (7.1) |
| Mass size, mean/median (SD), cm | 3.6/3.6 (1.4) | 4.1/4.2 (1.3) | 4.2/4.4 (1.3) | 3.2/3.0 (1.3) | 3.4/3.3 (1.3) |
| 1-1.9 | 157 | 12 (7.6) | 15 (9.6) | 26 (16.6) | 104 (66.2) |
| 2-2.9 | 303 | 36 (11.9) | 23 (7.6) | 46 (15.2) | 198 (65.4) |
| 3-3.9 | 311 | 44 (14.2) | 39 (12.5) | 44 (14.2) | 184 (59.2) |
| 4-4.9 | 295 | 56 (19) | 49 (16.6) | 29 (9.8) | 161 (54.6) |
| 5-5.9 | 217 | 51 (23.5) | 61 (28.1) | 12 (5.5) | 93 (42.9) |
| 6 | 80 | 19 (23.7) | 17 (21.2) | 8 (10) | 36 (45) |
Of the 994 masses that were followed up with repeat ultrasound, 155 (15.6%) were found to regress, and 160 (16.1%) were found to resolve. When outcomes were examined based on size, although the vast majority of masses in each size category were initially observed, surgical removal generally correlated with increasing mass size, with 45% of 6 cm masses removed compared with 17% of masses of 1–1.9 cm.
For the 12 women who elected initial observation and whose masses were later found to be malignant or borderline, the time interval to the first repeat ultrasound varied from 2 to 7 months. For the 6 masses later diagnosed as borderline tumors, 3 demonstrated growth on their initial ultrasound done at 2, 6, and 7 months, whereas 3 were observed to be initially stable at 2 months. One mass that was stable on a 2 month ultrasound was removed at that point, whereas 2 demonstrated growth on follow-up ultrasounds done at 3 months and 6 months from the initial ultrasound.
For the 5 masses later diagnosed as an epithelial ovarian cancer, in all cases, the mass demonstrated growth on the initial repeat ultrasound at 2-7 months. Only 1 mass that was categorized as malignant remained stable for more than 7 months and was subsequently removed at 13 months, revealing an adult granulosa cell tumor. The clinical characteristics and management for malignant and borderline cases are detailed in Table 2 .
| Characteristic | Age | Mass size a | Initial CA125, U/mL | Management | Surgical pathology |
|---|---|---|---|---|---|
| Epithelial cancer | |||||
| 1 | 66 | 4.6 | 16 | Immediate removal | 1a high grade serous (FS) |
| 2 | 54 | 5.4 | 28 | Immediate removal | 1c high grade (FS) |
| 3 | 53 | 2.6 | none | 6 mo, increased, removed | 1a mucinous (FS), concurrent 1a endometrial cancer |
| 4 | 60 | 5 | 8 initial, 10 at 2 mo | 2 mo, increased, removed | 1c high grade (FS) |
| 5 | 79 | 4.5 | No initial, 59 at 7 mo | 7 mo, increased, removed | 3c high grade serous (FS) |
| 6 | 51 | 3.1 | No initial, 8 at 7 months | 7 mo, increased, removed | 1a clear cell (FS) |
| 7 | 53 | 2.1 | No initial, 10 at 5 mo, 10 at 9 mo | 5 mo, increased; 9 mo increased, removed | 1a clear cell in endometrioma (CS) |
| Borderline | |||||
| 1 | 62 | 5.2 | 16 | Immediate removal | 1a serous (FS) |
| 2 | 54 | 5 | 11 | Immediate removal | 1a serous (CS) |
| 3 | 71 | 4 | 27 | Immediate removal | 1a mucinous and serous (CS) |
| 4 | 60 | 5 | 29 | Immediate removal | 3c serous (FS) |
| 5 | 51 | 4.3 | 16 | 2 mo, stable; 6 mo, increased, removed | 1a serous (CS) |
| 6 | 84 | 4.4 | 5 | 2 mo, stable, removed | 1a mucinous (CS) |
| 7 | 66 | 2.3 | 19 initial, 25 at 6 mo | 6 mo increased, removed | 3c serous (FS) |
| 8 | 63 | 4.1 | 2 | 2 mo, increased, removed | 1a mucinous (CS) |
| 9 | 64 | 4.1 | 8 | 2 mo, stable; 3 mo increased, removed | 1a serous (CS) |
| 10 | 78 | 3.9 | 9 initial; 7 at 17 mo | 6 mo, increased; 17 mo increased; 24 mo stable, removed | 1a serous (CS) |
| Stromal tumor | |||||
| 1 | 57 | 2 | None | Stable at 5 mo; 8 mo, 13 mo, removed | 1a adult granulosa cell (CS) |
Four of the 10 borderline tumors had staging procedures done at the time of surgical removal that included the evaluation of retroperitoneal nodes and omentum, and the remainder were unstaged but were clinically stage 1 based on gross surgical findings. Six of the 7 epithelial ovarian cancers were fully staged, with one case determined to be stage 3c and the remainder stage 1. No staging was done for the granulosa cell tumor, but it was presumed to be stage 1a.
Overall, 422 of the 1363 women (31%) ultimately underwent surgical removal, with 404 (96%) demonstrating benign adnexal pathology, most commonly cystadenofibroma, serous cystadenoma, and nonneoplastic cyst ( Table 3 ). Among the women who did not have surgical removal, there were no additional clinical diagnoses of ovarian cancer within 24 months follow-up. A flow diagram illustrating the distribution of the groups and outcomes is shown in the Figure .
| Pathology finding | Surgical removal, no repeat sonogram (n = 204) | Surgical removal after at least 1 follow-up sonogram (n = 218) | ||
|---|---|---|---|---|
| Borderline | 4 | 2.0% | 6 | 2.8% |
| Epithelial cancer | 2 | 1.0% | 5 | 2.3% |
| Granulosa cell tumor | 0 | 0 | 1 | 0.5% |
| Brenner | 6 | 2.9% | 5 | 2.3% |
| Cystadenofibroma/adenofibroma/fibroma | 39 | 19.1% | 29 | 13.3% |
| Endometrioma | 4 | 2.0% | 14 | 6.4% |
| Fibrothecoma | 1 | 0.5% | 0 | 0 |
| Leiomyoma | 1 | 0.5% | 0 | 0 |
| Mucinous cystadenoma | 10 | 4.9% | 14 | 6.4% |
| Nonneoplastic cyst a | 32 | 15.7% | 39 | 17.9% |
| Nonspecific (no specific pathological abnormality) | 39 | 19.1% | 28 | 12.8% |
| Nongynecological | 4 | 2.0% | 3 | 1.4% |
| Other | 3 | 1.5% | 8 | 3.7% |
| Paratubal cyst | 6 | 2.9% | 1 | 0.5% |
| Serous cystadenoma | 38 | 18.6% | 44 | 20.2% |
| Mixed serous/mucinous cystadenoma | 0 | 0 | 2 | 0.9% |
| Struma ovary II | 1 | 0.5% | 1 | 0.5% |
| Mature teratoma | 13 | 6.4% | 18 | 8.3% |
| Tuboovarian abscess | 1 | 0.5% | 0 | 0 |
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