Risk of Malignancy in Unilocular Ovarian Cystic Tumors Less Than 10 Centimeters in Diameter

Risk of Malignancy in Unilocular Ovarian Cystic Tumors Less Than 10 Centimeters in Diameter Susan C. Modesitt, MD, Edward J. Pavlik, PhD, Frederick R. Ueland, MD, Paul D. DePriest, MD, R. J. Kryscio, PhD, and J. R. van Nagell, Jr, MD OBJECTIVE: To determine the natural history and to estimate the risk of malignancy of unilocular ovarian cystic tumors less than 10 cm in diameter followed conservatively by transvaginal ultrasound. METHODS: From 1987 to 2002, 15,106 asymptomatic women at least 50 years old entered the University of Kentucky s Ovarian Cancer Screening Program and underwent initial transvaginal ultrasonography. If the screen revealed nothing abnormal, women were asked to repeat transvaginal ultrasonography yearly. If the screen revealed abnormalities, transvaginal ultrasonography was repeated in 4 to 6 weeks, along with Doppler flow ultrasonography and CA 125 testing. RESULTS: Of the 15,106 women at least 50 years old, 2763 women (18%) were diagnosed with 3259 unilocular ovarian cysts. A total of 2261 (69.4%) of these cysts resolved spontaneously, 537 (16.5%) developed a septum, 189 (5.8%) developed a solid area, and 220 (6.8%) persisted as a unilocular lesion. During this time, 27 women received a diagnosis of ovarian cancer, and ten had been previously diagnosed with simple ovarian cysts. All ten of these women, however, developed another morphologic abnormality, experienced resolution of the cyst before developing cancer, or developed cancer in the contralateral ovary. No woman with an isolated unilocular cystic ovarian tumor has developed ovarian cancer in this population. CONCLUSION: The risk of malignancy in unilocular ovarian cystic tumors less than 10 cm in diameter in women 50 years old or older is extremely low. The majority will resolve spontaneously and can be followed conservatively with serial transvaginal ultrasonography. (Obstet Gynecol 2003;102:594 9. 2003 by The American College of Obstetricians and Gynecologists.) Ovarian cancer is the second most common gynecologic malignancy in the United States and is the fifth leading From the Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, and Department of Statistics, University of Kentucky Markey Cancer Center, Lexington, Kentucky. Supported in part by a grant from the Abercrombie Foundation and the R. L. Telford Foundation. cause of cancer death among US women. 1 Most women are diagnosed with advanced-stage cancer and undergo extensive surgical debulking, followed by combination chemotherapy. Initial complete response to therapy can be achieved in most women; however, relapse is the rule, and once ovarian cancer recurs, it is almost universally fatal. The dismal outcomes associated with the diagnosis of ovarian cancer in advanced stages has prompted the investigation of potential screening methods in an effort to detect the cancer at an earlier stage and to decrease mortality. The use of transvaginal ultrasonography for ovarian cancer screening has been increasing in recent years. Sonography is also routinely performed in patients whose clinical examinations reveal ovarian enlargement. Transvaginal ultrasonography is a sensitive procedure that tests for ovarian abnormalities. It has limited interobserver variability but low positive predictive value. 2 4 As a result of the increasing use of sonography, the diagnosis of unilocular ovarian cysts in postmenopausal women has been increasing. Women with cystic ovarian tumors had been treated surgically until it was recognized that the malignant potential of a simple cyst was extremely low. 5,6 The purpose of this study was to determine this disease s natural history and to estimate the risk of malignancy of unilocular cystic ovarian tumors 10 cm or less in diameter in women at least 50 years old followed conservatively by transvaginal sonography. MATERIALS AND METHODS From 1987 to 2002, a total of 18,464 women were enrolled onto the University of Kentucky s Ovarian Cancer Screening Program, and 15,106 of these women were at least 50 years old. Eligibility criteria for the screening program included the following: all women at least 50 years old, or women at least 25 years old with a documented family history of ovarian cancer in at least one primary or secondary relative. All study participants completed a questionnaire regarding medical history 594 VOL. 102, NO. 3, SEPTEMBER 2003 0029-7844/03/$30.00 2003 by The American College of Obstetricians and Gynecologists. Published by Elsevier. doi:10.1016/s0029-7844(03)00670-7

and family history of cancer. Any woman with a known ovarian tumor, previous diagnosis of ovarian cancer, or symptoms consistent with a pelvic mass was excluded from this investigation. After informed consent was obtained, as monitored by the Institutional Review Board, patients underwent transvaginal ultrasonography with Aloka 620, Aloka 680 (years 1987 to 2001), GE Logic 200, or GE Logic 400 (2001 to present) ultrasound units with a 5.0-MHz vaginal probe. Ultrasonographers and clinicians were not blinded to the results of previous screens. All images were reviewed by at least one of the authors. At each screen, both ovaries were measured in three dimensions. Screens on which ovaries were not visualized were treated as normal. Ovarian volume was calculated by the prolate ellipsoid formula (length width height 0.523). All screening information was entered into a Medlog database on a local network. Criteria for abnormality included a volume of more than 20 cm 3 for premenopausal women and 10 cm 3 for postmenopausal women. These values were defined by being more than two standard deviations above the mean normal ovarian volume for premenopausal and postmenopausal women. 7 In addition, any cystic ovarian tumor with a solid or papillary projection into its lumen was considered abnormal. A unilocular tumor was defined as a fluid-filled cyst without internal septa, papillary projections, or solid components (Figure 1). If the initial screen revealed nothing abnormal, women were scheduled to undergo transvaginal ultrasonography every year (Figure 2). If the results revealed an abnormality, transvaginal ultrasound was repeated in 4 to 6 weeks, along with Doppler flow sonogram, CA 125 testing, and tumor morphology indexing. A modified version of our previously published 2 tumor morphology index was used, as follows. 1) Tumor volume was scored as 0 to 5 by use of the following scale 0, less than 10 cm 3 ;1,10to50cm 3 ; 2, more than 50 to 100 cm 3 ; 3, more than 100 to 200 cm 3 ; 4, more than 200 to 500 cm 3 ; and 5, more than 500 cm 3. 2) Tumor structure was scored from 0 to 5 by use of the following scale: 0, simple cyst; 1, blood-filled cyst; 2, cysts with one or more septae and/or some wall thickening; 3, cyst with papillary projection; 4, cyst with a significant solid component or a complex mass; and 5, the presence of ascites accompanying the previous structural descriptors. Each cyst would have a score ranging from 0 to 10 when this index is used. If a wall abnormality or solid area developed within a cystic ovarian tumor during serial ultrasound, the patient was advised to undergo surgical exploration. An isolated septum was not considered an indication for surgery. Figure 1. Sonogram of unilocular cystic ovarian tumor. No evidence exists of wall abnormality or solid component. Modesitt. Uniocular Ovarian Tumors. Obstet Gynecol 2003. Statistical analysis to compare frequencies of ovarian cysts among groups with regard to age, hormone use, and cyst volume and presence of solid components was performed by 2 tests on the Medlog database. P.05 was considered statistically significant. RESULTS Of the 15,106 women at least 50 years old who participated in this program, 2763 women (18%) were diagnosed with 3259 unilocular cysts during their participation in the screening program. In 496 women, more than one cyst was found during their screening evaluations. The frequencies of ovarian cysts vary significantly (P.001) with age (Table 1). The mean follow-up for each woman with a documented ovarian cyst was 6.3 years (range, 4 days to 14 years). The frequency of ovarian cysts is related to hormone replacement therapy in women at least 50 years old (Table 2) (P.001). A total of 2746 women reported that they were receiving estrogen therapy at the time of screening, 4200 reported receiving estrogen and progesterone, and 440 patients were unsure whether they had VOL. 102, NO. 3, SEPTEMBER 2003 Modesitt et al Unilocular Ovarian Tumors 595

Figure 2. Ovarian cancer screening algorithm used at the University of Kentucky since 1998. Modesitt. Uniocular Ovarian Tumors. Obstet Gynecol 2003. received some form of hormone replacement before screening. The frequency of unilocular ovarian cystic tumors over the duration of screening was 21% in patients receiving estrogen alone, 18.5% in patients receiving estrogen and progesterone, and 17.5% in patients receiving no hormones. The mean initial diameter of these unilocular cystic tumors was 2.7 cm. A total of 2245 cysts (68.9%) had a maximum diameter less than 3 cm; 973 (29.9%) had a maximum diameter of 3 to 6 cm; and 40 (1.2%) had a maximum diameter of more than 6 to 10 cm at the time of initial diagnosis. With regard to ovarian volume, the mean volume was 9.4 cm 3 ; 538 (47%) had a volume less than 5 cm 3, 924 (28%) had a volume of 5 to 9.99 cm 3, 386 (12%) had a volume of 10 to 14.99 cm 3, 150 (5%) had a volume of 15 to 19.99 cm 3, and 261 (8%) had a volume Table 1. Unilocular Ovarian Cystic Tumors Related to Age in Screened Patients Age (y) Patients (n) Ovarian tumor, n (%) 50 54 5229 1315 (25.1) 55 59 3278 481 (14.7) 60 64 2694 373 (13.8) 65 69 2008 271 (13.5) 70 1897 323 (17.0) Statistically significant (P.001). Table 2. Unilocular Ovarian Cysts Related to Exogenous Hormones Hormone replacement Unilocular cystic ovarian tumor, n (%) Patients (n) None 7720 1349 (17.5) Estrogen 2746 579 (21) Estrogen and 4200 778 (18.5) progesterone Statistically significant (P.001). 596 Modesitt et al Unilocular Ovarian Tumors OBSTETRICS & GYNECOLOGY

Figure 3. Resolution of unilocular ovarian cystic tumors with time. Open triangles indicate less than 5 cm 3 (n 1540); open diamonds, 5 to 9.99 cm 3 (n 924); open squares, 10 to 14.99 cm 3 (n 386); open circles, 15 to 19.99 cm 3 (n 150); and solid circles, more than 20 cm 3 (n 259). Modesitt. Uniocular Ovarian Tumors. Obstet Gynecol 2003. more than 20 cm 3. A total of 2261 (69.4%) of these cysts resolved spontaneously. Total cyst resolution occurred within 3 months in 66% of cases and within 12 months in 70% of cases and was similar regardless of cyst volume (Figure 3). A total of 537 cysts (16.5%) developed a septum, 189 (5.8%) developed a solid area, and 220 (6.8%) persisted as a unilocular lesion (Table 3). The percentage of unilocular cystic tumors that subsequently developed a solid component was significantly related to size, with the larger cysts having a larger proportion developing a solid component (Table 4, P.001). Table 3. Ovarian Cyst Evolution (N 3259) Cyst evolution Value, n (%) Spontaneous resolution 2261 (69.4) Cyst septum 537 (16.5) Persistent cyst 220 (6.8) Cyst solid area 168 (5.2) Solid mass 21 (0.6) Nonvisualization of ovary 12 (0.3) Removed during unrelated surgery 40 (1.2) One hundred thirty-three patients with unilocular ovarian cysts underwent surgery. Seventy-nine of these patients underwent surgery because of the persistence or progression of an ovarian cyst; an additional 54 patients with a history of unilocular ovarian cysts had their ovaries removed during another indicated procedure (eg, hysterectomy for uterine leiomyomata or pelvic prolapse). Twenty-seven of 54 patients still had a unilocular cyst at the time of surgery, whereas the other 27 had surgery after their ovarian cyst had resolved and had no histologic evidence of an ovarian abnormality. Table 4. Development of Solid Components Related to Original Cyst Volume Original volume (cm 3 ) Total (n) Cyst solid, n (%) Solid, n (%) 5 1538 25 (1.6) 0 (0) 5 9.99 924 45 (4.9) 1 (0.1) 10 14.99 386 36 (9.3) 6 (1.6) 15 19.99 150 20 (13.3) 3 (2) 20 261 42 (16) 11 (4.2) Statistically significant (P.001). VOL. 102, NO. 3, SEPTEMBER 2003 Modesitt et al Unilocular Ovarian Tumors 597

Table 5. Pathologic Diagnoses of Removed Cystic Ovarian Tumors (N 117) Tumor Value, n (%) Serous cystadenoma 61 (52) Serous cystadenofibroma 14 (12) Mucinous cystadenoma 9 (8) Paraovarian or paratubal cyst 9 (8) Fibrothecoma 7 (6) Endometrioma 5 (4) Cystic teratoma 3 (3) Mucinous cystadenofibroma 1 (0.9) Benign other* 8 (7) * Includes hydrosalpinx, mesothelial cyst, lipoma, and inclusion cyst. Most women chose local doctors as their surgeons, and the pathology report was available for review from 106 patients with 117 cystic masses (11 patients had bilateral cystic masses). Ovarian histology in the remaining 117 cases is illustrated in Table 5. The most common pathologic diagnoses were serous cystadenoma (52%), serous cystadenofibroma (12%), and mucinous cystadenoma (8%). There were no cases of ovarian carcinoma or ovarian tumors of low malignant potential. During the same time, 27 women in the University of Kentucky Ovarian Cancer Screening Program were diagnosed with ovarian cancer (stage I, n 17; stage II, n 4; stage III, n 6). Of these 27 women, ten had been diagnosed with simple ovarian cysts at one time during their screening. Seven of these ten patients had an additional morphologic abnormality, such as a solid or papillary area in the ovary; two experienced resolution of the unilocular cyst before developing cancer; and one developed a cancer in the contralateral ovary. No woman with an isolated unilocular cystic ovarian tumor who was assessed by sonography developed ovarian cancer in this population; the risk of malignancy was less than 0.1% with a 95% exact confidence interval. DISCUSSION Eighteen percent of 15,106 women at least 50 years old in the Kentucky Ovarian Screening Program were diagnosed with unilocular cystic ovarian tumors during their participation in the screening program. This frequency is higher than values that have been reported previously in the literature (range, 3 15%). 5,8 Part of this increase is because most women in this study had screening ultrasounds many times over a long time period. In contrast, other studies reported the frequency of these lesions at only one point in time. In addition, increased detection may be the result of improved technology used in this trial and to the vigilance of sonographic follow-up mandated by the screening algorithm. Although our observation period was long, the study technology and personnel have remained essentially unchanged, and thus limited variation exists from year to year. Finally, there could be selection bias: We cannot be certain that women participating in our ovarian cancer screening program are representative of the population as a whole. Regardless, cystic ovarian tumors remain a common diagnostic entity in this population of women, and appropriate treatment guidelines should be developed on the basis of the natural history of these cysts. The rate of spontaneous resolution of cystic ovarian tumors in our series was 69%, and most tumors resolved within 3 months. This confirms the work of other clinicians reporting much smaller patient populations, where the rate of resolution of unilocular ovarian cysts ranged from 8% to 73%. 9 12 The low rate of malignancy and the high rate of spontaneous resolution of cystic ovarian tumors less than 10 cm in diameter indicates that these lesions can be treated conservatively even in postmenopausal women. Our study found that larger unilocular cystic tumors are more likely to develop solid areas; however, the overall percentage remains relatively low. Obviously, the development of any wall abnormalities or solid areas merits further evaluation and treatment. Previous authors have confirmed that immediate surgical intervention is unwarranted in asymptomatic women with unilocular cystic ovarian tumors because of the tumors low rate of malignancy. 5,6,11,13,14 Bailey et al, 5 for example, reported that no invasive malignancies or borderline tumors were noted in 45 women undergoing operative removal of unilocular ovarian tumors less than 10 cm in diameter. Likewise, Roman, 6 in a summary of the literature published through 1998, noted a 0.7% rate of malignancy in 569 unilocular cystic ovarian tumors. Our data support this low rate of malignancy because none of the women with unilocular ovarian cysts who did not undergo surgery have been diagnosed with ovarian cancer in more than 70,000 patient-years of follow-up. The findings of the present investigation provide longterm follow-up data on the natural history of more than 3000 unilocular cystic ovarian tumors followed by periodic transvaginal sonography. More than two thirds of these tumors resolved spontaneously, and no ovarian malignancies have been detected. These findings support the conclusion that unilocular cystic ovarian tumors are associated with an extremely low risk of malignancy (less than 0.1% with 95% confidence interval) and can be followed even in postmenopausal women with serial ultrasound examinations without immediate operative intervention. 598 Modesitt et al Unilocular Ovarian Tumors OBSTETRICS & GYNECOLOGY

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