We divided the screening data into three time periods based on the evolution of the ovarian cancer screening program algorithm (Table 5). Period A (December 14, 1987, to December 31, 1999) represents an era when serial transvaginal ultrasonography was not used. Period B (January 1, 2000, to December 31, 2007) incorporated serial monitoring of simple, unilocular cysts with the understanding that they were at low risk for malignancy.14,15 Period C (January 1, 2008, to May 15, 2012) expanded serial observation to also include septate cysts after published data confirmed this group to be at low risk for malignancy.16
There have been 85 true-positive malignancies identified through the ovarian cancer screening program and 472 nonmalignancies for a calculated positive predictive value (PPV) of 15.3% (Table 5). Notably, before serial transvaginal ultrasonography was used, the PPV was only 8.1%; however, as serial ultrasonography was introduced, the PPV progressively improved to 24.7% (Table 5), representing an improvement of 304% compared with the first study period. Each woman who had a serial transvaginal ultrasonography true-positive averaged 2.9 abnormal ultrasonograms and 7.5 total ultrasonograms (normal+abnormal). Finally, 463.8 women needed to receive ultrasonography to detect one malignancy, whereas 92.5 women with an abnormal transvaginal ultrasonogram were needed to detect one malignancy.
The distribution of findings for women with persisting abnormal transvaginal ultrasonograms who underwent surgery is shown in Table 6. Fifty-three invasive epithelial cancers were detected: stage I, 24 (45%); stage II, 12 (23%); stage III, 17 (32%); and stage IV, 0 (0%). Using a two-tier classification system in which grades 2 and 3 are combined, 83.3% (30 of 36) of early-stage epithelial cancers detected by screening were aggressive type II ovarian malignancies.25–28 Of the benign tumors surgically removed, serous cystadenomas were the most frequent (46.6%), whereas endometriomas, mucinous cystadenomas, leiomyomas, and cystic teratomas each accounted for 5–7% of the benign findings (Table 6).
It has been reported previously that unilocular ovarian cysts and uncomplicated septate cysts have a very low probability of malignancy and can be monitored with serial ultrasonography.14–16 Many of these low-risk cystic tumors spontaneously resolve without surgical intervention, even in postmenopausal women. Here we report additional findings showing that complex ovarian abnormalities formally considered high risk may resolve when monitored. As a result of serial ultrasonographic observation, we have shown that the number of operations performed for benign ovarian tumors can be reduced, effectively decreasing false-positive results and increasing the PPV of recent screening efforts to 24.7%.
Our data would suggest that monitoring an ovarian cyst over time is a novel and valuable clinical variable. Serial transvaginal ultrasonography permits a functional evaluation of a tumor, identifying nonmalignant tumors that decrease in size and complexity and malignant tumors that often increase in both volume and morphologic complexity. Thus, a sequential observation of tumors over time can help segregate benign from malignant tumors. Because the duration of ovarian abnormalities may vary considerably, in the absence of persistent growth or worsening tumor complexity, short-term surveillance is a reasonable alternative to surgery. The ultrasonographic interval can be lengthened once evidence of improvement is documented. Complex tumors that increase in size and complexity should be surgically removed.
This longitudinal approach has translated into a significant improvement in ultrasonographic screening (PPV=24.7%), where serial transvaginal ultrasonography now has a level of performance comparable to mammography,31–33 especially with regard to the PPV.34–36 Moreover, transvaginal ultrasonography with serial morphology evaluation seems to perform favorably to published outcomes of diagnostic ovarian algorithms (PPV=29.5% overall; 17.9% premenopausal, 39.1% postmenopausal).37 This is particularly compelling because the cancer prevalence in a diagnostic population, where there is a known ovarian tumor, far exceeds that of a screening population.
The exact time interval recommended for serial observation is difficult to define. Our data suggest that the ultrasonographic interval depends on both the initial tumor morphology and the change in volume and complexity over time. In general, for unilocular or septate cysts, a 6-month surveillance ultrasonogram is suggested. Although more complex tumors may resolve, they should be cautiously followed at 6-week to 3-month intervals. The result of each subsequent ultrasonogram determines the recommended course of action, which could include continued monitoring or surgery. Although many cysts resolved in fewer than 6–12 months, some took considerably longer and, when documented to be stable, were followed on an annual basis.
One of the strengths of this investigation is that it presents data from a large, 25-year prospective population-based study with carefully defined ultrasonographic metrics. All ultrasonography is monitored for quality control and each abnormal result is individually reviewed by the principal investigator. Some have questioned the inclusion of borderline ovarian tumors as a true-positive result. The ovarian cancer screening program has maintained this classification since the inaugural ultrasonogram, which seems justified given the potential for having micropapillary projections and the association with peritoneal implants that correlate with increased risk. Moreover, both serous and mucinous ovarian borderline tumors can be lethal.38,39 The study was performed at a single institution (although multiple, statewide screening sites are used) and thus is susceptible to the biases associated with such an investigation. The screening algorithm has been cautiously modified over time to reflect the evolving knowledge of ovarian ultrasonography.
In current practice, many clinicians are faced with a small ovarian abnormality having some complexity that continues to persist over a long time. When it is clear that there are no increases in size or complexity, surveillance at a longer 6- to 12-month interval would seem appropriate. The data presented here indicate that some of these ovarian abnormalities can have a lengthy persistence. However, we have published ultrasonographic images of a variety of complex ovarian structure as the last view before resolution40 so that complexity alone does not indicate against resolution. Serial ultrasonography has established that many ovarian abnormalities resolve, even if they are complex, solid, or bilateral. With serial observation, more than 60% of ovarian abnormalities discovered on the initial transvaginal ultrasonogram returned to normal on subsequent visits. The strategy of serial ultrasonographic monitoring reduced the false-positive results over time, raising the PPV from 8.1% to 24.7%. Thus, it is advantageous to avoid a single abnormality as a trigger for surgery and to take a measured serial approach to improve the performance transvaginal ultrasonographic screening for ovarian cancer.
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