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Prevalence and histologic diagnosis of adnexal cysts in postmenopausal women: An autopsy study
American Journal of Obstetrics and Gynecology (2005) 192, 48–54
www.ajog.org
Prevalence and histologic diagnosis of adnexal cysts in postmenopausal women: An autopsy study Anne Dørum, MD, PhD,a,* Gustav P. Blom, MD,b Erling Ekerhovd, MD, PhD,c Seth Granberg, MD, PhDd Department of Gynecological Oncology, The Norwegian Radium Hospital, Oslo, Norway,a Department of Pathology, Akershus University Hospital, Oslo, Norway,b Department of Obstetrics and Gynecology, Sahlgrenska University Hospital, Go¨teborg, Sweden,c and Department of Obstetrics and Gynecology, Ultrasound Unit, Karolinska Hospital, Stockholm, Swedend Received for publication March 16, 2004; revised July 15, 2004; accepted July 20, 2004
KEY WORDS Cyst Diagnosis Ovary
Objective: The purpose of this autopsy study was to examine the prevalence and histologic condition of adnexal cysts in postmenopausal women. Study design: Adnexa of 234 postmenopausal women who had died from nongynecologic diseases were examined by the team pathologist. Results: Ovarian cysts were found in 36 of the women (15.4%). Nine women (3.8%) had ovarian cysts with a diameter between 20 and %50 mm; 4 women (1.7%) had cysts that were O50 mm in diameter. Four women had bilateral ovarian cysts. Paraovarian cysts were found in 11 women (4.7%). All cysts were benign, except for 1 woman, who had bilateral serous cystadenoma of borderline type. Macroscopically, the borderline cysts were multilocular with mean diameters of 60 mm and 15 mm, respectively. Conclusion: Because of the high prevalence of benign adnexal cysts, the identification of small unilocular cysts in postmenopausal women should be regarded as a normal finding Ó 2005 Elsevier Inc. All rights reserved.
The life risk of ovarian cancer for women who live in western industrial countries is approximately 1.4% (ie, 1 woman in 70) will have the disease. Ovarian cancer is the leading cause of death that is related to gynecologic malignancies and the second most common gynecologic malignancy in the United States and western Europe.1,2 The incidence of ovarian cancer increases dramatically around menopause and onwards, with an incidence of * Reprint requests: Anne Dørum, Department of Gynecological Oncology, The Norwegian Radium Hospital, University of Oslo, N-0310 Oslo, Norway. E-mail: [email protected] 0002-9378/$ - see front matter Ó 2005 Elsevier Inc. All rights reserved. doi:10.1016/j.ajog.2004.07.038
about 70 cases/100,000 women at age 60 years.3,4 This figure should be compared with 0.4 to 8.9 cases per 100,000 women who are !40 years old and 12 cases per 100,000 women who are aged between 35 and 39 years. The overall 5-year survival rate is almost 40%. However, this rate varies according to the histologic features of the malignancy and the stage at the time of diagnosis and treatment.5 Unlike most other types of gynecologic cancer, early ovarian cancer is not associated with symptoms and signs, and more than two thirds of all ovarian cancers are diagnosed at stage III or IV.6 Evidence has shown that the overall survival rate might be approximately 90% if primary ovarian tumors were
Dørum et al identified and removed when the cancer was confined within the ovaries (ie, at stage I).7 By contrast, the survival rate in women with ovarian cancer stage III and IV is only 23%. Consequently, various strategies have been used to identify early ovarian cancer in asymptomatic women. Whichever method is chosen, transvaginal ultrasonography has proved to be the most important diagnostic tool for the detection and characterization of ovarian tumors. The use of high-resolution transvaginal ultrasonography as a part of the routine gynecologic examination has led to the detection of an increasing number of adnexal cystic structures. Initially, the standard treatment of all adnexal cysts that are visualized in postmenopausal women was surgical removal because of fear of ovarian cancer. It then became clear that the postmenopausal ovary is not a static organ whose cyst-generating capacity is lost after menopause, but far more active than what was presumed previously.8 A prevalence of 14% to 18% of adnexal cysts, especially simple cysts (unilocular, anechoic cysts with smooth walls) has been visualized by transvaginal ultrasonography in asymptomatic postmenopausal women.8,9 The clinical dilemma is the conflict between identification of ovarian malignancy as early as possible and the avoidance of unnecessary operations. Although transvaginal ultrasonography is the most commonly used tool to identify adnexal cysts, its positive predictive value is low.10,11 It is generally accepted that multilocular ovarian cysts in postmenopausal women should be removed surgically because of a high malignancy risk.12 Although several studies have shown that the risk of malignancy in unilocular adnexal cysts in this group of women is low, others have come to the opposite conclusion.13 Appropriate treatment guidelines of simple cysts have to be developed on the basis of the natural history of these cysts. If unilocular adnexal cysts in postmenopausal women represent a low risk of malignancy, conservative treatment (ie, serial transvaginal ultrasonography) should be the method of choice.14-17 On the other hand, if a high frequency of adnexal cysts proves to be malignant, operative removal should be performed. The real prevalence of adnexal cysts in postmenopausal women is not known, because all cysts presumably are not visualized by ultrasonography. In addition, there is still uncertainty about the likely histologic diagnosis of painless cysts that are frequently identified in postmenopausal women. We therefore conducted the present autopsy study to determine the real prevalence and histologic condition of adnexal cysts in postmenopausal women.
Material and methods The study was undertaken between August 1995 and November 2000 at Akershus University Hospital, Norway. This hospital has patients from Oslo, the capital of Norway, and from the suburban and rural districts
49 around Oslo, the capital of Norway. Included in the study were consecutive women who were O45 years of age, who underwent autopsy at the university hospital. On the basis of the medical records, all women included were postmenopausal, and none of the women had undergone operations because of gynecologic disease. Excluded from the study were women with previous or known gynecologic cancer, breast cancer, any kind of metastatic intraperitoneal cancer, and previous pelvic radiotherapy or tamoxifen treatment. Women with blood-borne infectious diseases (such as hepatitis, human immunodeficiency virus, and tuberculosis) were also excluded from the study. The cause of death was determined on the basis of the results of the autopsy. A total number of 468 adnexa from 234 women were included in the study. The adnexa were removed from the body, fixed in 4% formaldehyde solution, and examined by the team pathologist. Macroscopic appearance of the adnexa was assessed according to standard routine procedures; the left and right side was secured, and the presence and number of both ovarian and extraovarian cysts and solid tumors was registered. The cysts were classified as either unilocular, unilocular solid, multilocular, multilocular solid, or solid, in accordance with the macroscopic characterization previously used by Granberg et al.12 All available material was embedded in paraffin and stained with hematoxylin-eosin and Masson’s trichrome stain. The ovaries and extraovarian cysts were cut in several slices, and cystic lesions of O4 mm in diameter were examined. At least 2 sections of each ovary were examined under contact reticules (Periplan 5x/ 18 MP; Leitz, Stuttgart, Germany). Histologic diagnosis of each lesion was based on criteria that were set before the study. Simple cysts lined by serous epithelium without septa or papillary projections were characterized as unilocular cysts in accordance with the presumable sonographic appearance if transvaginal ultrasonography had been performed. In addition, the cysts were described as serous or mucinous according to standard criteria that were used normally. Serous and mucinous cysts with papillary formations were diagnosed as serous cystadenomas and mucinous cystadenomas, respectively. These cysts are described normally as unilocular with papillary projections or as unilocular-solid when visualized by transvaginal ultrasonography. Serous and mucinous cysts with R2 cystic structures were characterized as multilocular cystadenomas. After macroscopic examination, all cysts were described histologically and given a diagnosis. For ethical reasons, no ultrasound scan was performed before the removal of the adnexa.
Results The mean and median age of the women was 73 years and 75 years, respectively, and the range was 45 to 96
50
Dørum et al
Table I
Description of 40 ovarian cysts from 36 women, as related to histologic diagnosis Women (n)
Age (y)*
Cyst size (mm)*
Cyst chamber
Bilateral (n)
70
37.5 (15-60)
1 Multilocular
1
1
1
11 4
75.1 (46-86) 79.3 (73-85)
15.2 (5-45) 35.4 (10-60)
2 1
5 1
8 4
Mucinous cysts Mucinous cystadenomas Fibroma Other cysts
1z 1 1 17
62 52 74 68.2 (45-87)
10 40 18 23.1
0 0 0 0
1 1 10
1 7
Mesothelial
10
13 Unilocular 1 Unilocular, 4 multilocular 1 Unilocular 1 Multilocular 1 Solid 16 Unilocular, 1 multilocular 9 Unilocular, 1 multilocular 2 Unilocular 2 Unilocular 2 Unilocular 1 Unilocular
71.1 (45-87)
18.4 (5-75)
4
19
21
Type Serous borderline cancery Benign Serous cysts Serous cystadenomas
1
Follicle Corpus luteum Corpus albicans Endometrioma Total
2 2 2 1 36
(10) (40) (18) (5-75)
Left side (n)
Right side (n)
* Data are mean (range). y Serous cystadenoma with atypia. z One woman had an ovarian and a paraovarian cyst.
Table II Description of the 11 paraovarian cysts found in 11 women, as related to histologic diagnosis; all cysts were unilocular, and none of the cysts were bilateral Type
Women (n)
Age (y)*
Cyst size (mm)*
Left side (n)
Right side (n)
Serous cyst Mesothelial cyst TOTAL
5 6y 11
74.4 (68-79) 74.5 (62-85) 74.5 (62-85)
29.2 (20-40) 23.7 (8-40) 26.2 (8-40)
3 4 7
2 2 4
* Data are given as mean (range). y One woman had both an ovarian and a paraovarian cyst.
years. The causes of death were mostly cardiac, vascular, and pulmonary diseases or extra-genital malignancy. Adnexal cysts with a mean diameter O4 mm were found in 19.7% of the women (46/234), of which 15.4% women (36/234) had ovarian cysts (Table I); 4.7% women (11/234) had paraovarian cysts (Table II). One woman had both a unilocular ovarian cyst (Figure 1) and a unilocular paraovarian cyst that were located to the same adnexal side. Three women had bilateral unilocular ovarian cysts. None of the paraovarian cysts were bilateral. Eight women had multilocular ovarian cysts, and 1 of these women had bilateral multilocular cysts. Histopathologic diagnosis of the bilateral cysts showed serous ovarian cystadenoma of borderline type. In addition, 1 woman had solid ovarian cyst. Histologic examination of this lesion showed a fibroma with a mean diameter of 18 mm. All cysts were benign, except for the 2 borderline cysts described earlier. Of all ovarian cysts that were examined, 52.5% cysts (21/40) were right sided, and 47.5% cysts (19/40) left sided.
Of the adnexal cysts, 62.7% (32/51) measured from 5 to 20 mm; 29.4% (15/51) measured from 21 to 50 mm, and 7.8% (4/51) had a diameter of O50 mm. All paraovarian cysts measured !50 mm; however, 54.5% paraovarian cysts (6/11) had a diameter of O20 mm. The borderline cysts had a diameter of 60 mm and 15 mm, respectively. The histologic diagnosis of the cysts is shown in Tables I and II. Serous ovarian cysts were diagnosed in 4.7% of the women (11/234); 2 women had bilateral serous cysts. Four women had serous cystadenomas (Figure 2); 1 woman had bilateral serous cystadenomas. As already mentioned, 1 woman had bilateral serous cystadenomas of borderline type; 1 woman had a unilocular mucinous cyst, and 1 woman had a multilocular mucinous cystadenoma. Of special interest is the fact that 4.3% of the ovarian cysts (10/234) proved to be multipotent mesothelial cysts. Nine of these cysts were unilocular; 1 cyst was multilocular. The other cysts were functional cysts. One endometrioma was diagnosed (Table I).
Dørum et al
51
Figure 2 A serous cystadenoma, described as unilocular solid, with a mean diameter of 22 mm at autopsy. On the inside of the cyst wall papillary formations can be seen. The cyst was diagnosed after death in a 65-year-old woman. Figure 1 A serous cyst, described as unilocular, with a mean diameter of 12 mm. The cyst was diagnosed after death in a 80-year-old woman.
Comment The present autopsy study shows that the real prevalence of adnexal cysts in postmenopausal women is high. In 46 of the 234 women (19.7%) who were examined, adnexal cysts were found. However, most of the cysts were small: 62.7% of the cysts (32/51) had a mean diameter !20 mm, and 29.4% of the cysts (15/51) had a diameter between 20 and 50 mm. Only 7.8% cysts (4/ 51) were O50 mm. These results are in accordance with several previous studies that have examined the prevalence of adnexal cysts that were visualized by ultrasonography in postmenopausal women. In a study by Wolf et al,8 unilocular adnexal cysts that ranged from 4 to 47 mm in diameter were found in 22 of 149 unselected asymptomatic postmenopausal women (14.8%) who were examined by transvaginal and transabdominal ultrasonography. Statistic calculations that were based on the results of the study showed that the relative frequency of unilocular adnexal cysts in postmenopausal women was 14.8% G 5.7%. Conway et al18 performed transvaginal sonography on 1769 asymptomatic postmenopausal women and found that 116 women (6.6%) had simple ovarian cysts with a diameter between 15 and 50 mm. The frequency of unilocular adnexal cysts in the study by Conway et al is in agreement with our finding that 6.4% of the adnexal cysts that were diagnosed measured O20 mm but !50 mm. Almost the same figures were found by Andolf and Jo¨rgensen14 and Aubert et al.19 In the study by Andolf and Jo¨rgensen the frequency of cysts between 20 and 80 mm was 5.6% (30/534), although Aubert et al described a frequency of 5.7% (36/622) of cysts between 10 and 50 mm. Levine
et al9 performed serial transabdominal and transvaginal ultrasonography on 184 asymptomatic postmenopausal women. Thirty-two simple cysts (17.4%) were identified at the initial examination. Because most studies that are performed to assess the frequency of adnexal cysts that are visualized by ultrasonography are similar to the prevalence that is found in the present autopsy study, it seems clear that ultrasonography is an excellent procedure to identify adnexal cysts. Only very small cysts may be missed by transvaginal ultrasonography. This fact was demonstrated clearly in a recent study by Valentin et al,20 which was conducted between January 2000 and March 2001. In that study, the frequency of adnexal cysts that were visualized by ultrasonography was compared with the prevalence of cysts that were found by histologic examination in an autopsy material of 52 postmenopausal women. Unilocular adnexal cysts between 2 and 65 mm were seen in 28 women (54%) when they were examined by ultrasonography. In addition to these cysts, histopathologic examination of the adnexa revealed 87 unilocular cysts with the largest diameter between 1 and 8 mm. Thus, the number of cysts that were found by the pathologist was significantly higher than what was identified by ultrasonography. However, the vast majority of the cysts that were not identified by ultrasonography had a diameter !5 mm. None of the cysts proved to be malignant. The women who were included in the present study are likely to represent a selected group with very healthy adnexa, because none of them had undergone operation previously for gynecologic disease. Despite this fact, adnexal lesions were found frequently. None of the cysts proved to be malignant. This finding is in agreement with several studies in which unilocular cysts have been removed operatively after identification by ultrasonograhy.17,18,20,21 Most studies have found that the risk of malignancy is !1% in asymptomatic postmenopausal
52 women who have a unilocular cyst with a mean diameter !50 mm.17,21 Thus, based on these studies and the present study, it seems clear that the malignancy risk is low. It is well known that not all ovaries in postmenopausal women can be identified by transvaginal ultrasonography. In a study by Granberg and Wikland,22 87% of the ovaries were visualized. Ovarian size declines with increasing age and time since menopause. Hysterectomy is another factor that appears to limit ovarian visualization.8 This problem may be that normal anatomic landmarks are not present in women who have undergone hysterectomy. In addition, transvaginal ultrasonography may not enable the visualization of adnexal cysts that are located high in the pelvis beyond the limited field of view of the transducer. Other intraabdominal factors (such as intestinal contents or peristalsis) may also limit ovarian visualization. Finally, the experience of the ultrasound examiner and the quality the ultrasound equipment that is used is of importance. On the other hand, ovarian cysts make the ovary more readily visible, and failure to visualize the ovary is often interpreted as an indication of absence of cystic structures within the ovary. Thus, ultrasonography can only indicate the relative frequency of adnexal cysts, as opposite to the present autopsy study, where the real prevalence of cysts is described. In addition, it is extremely important that transvaginal ultrasonography is conducted under optimal conditions. After all, the focal range of the transducers is normally not O6 cm from the transducer tip. Thus, all women who are examined should have voided bladders and be in the lithotomy position with a slight reverse Trendelenburg tilt. The abdominal hand of the examiner should be used, when necessary, to push the adnexa to the pelvic floor, thereby the transducer tip is located as close as possible or even in contact with the adnexa through the vaginal wall. Recent screening trials for ovarian cancer have demonstrated that transvaginal ultrasonography is unable to identify precursor lesions of ovarian malignancy and that even complex ovarian cysts in postmenopausal women are not associated with ovarian cancer risk factors.21,23 These findings may explain the reason that ovarian cancer often is diagnosed in late stages, despite the common use of transvaginal ultrasonography. The resolution of cysts before the development of ovarian cancer and cancer development in a sonographically normal ovary were described in the recent report of the University of Kentucky’s Ovarian Cancer Screening Program.21 Likewise, ovarian cancers that were detected microscopically after normal preoperative, perioperative, and gross pathologic examinations have proved actually to be stage III disease.24 These studies show that the orderly progression of ovarian cancer through stages I and II to reach stages III and IV does not always
Dørum et al occur. In fact, no description of a stepwise progression of ovarian cancer that is comparable with the progression found in cancer of the uterine cervix or colorectal cancer has been published. On the other hand, circumstantial evidence of the existence of premalignant ovarian abnormalities has been collated.25 The clinical problem is, however, that premalignant ovarian changes normally are not identified by ultrasonography. In the present autopsy study, no ovarian cancer was diagnosed. On the other hand, 1 of the women had bilateral serous cystadenomas of borderline type. Both of the borderline cysts were multilocular when examined macroscopically by the pathologist. It seems clear that transvaginal ultrasonography of the adnexa would have demonstrated bilateral multilocular cysts. In several papers, the diagnosis of a borderline cyst after the visualization of the cyst by ultrasonography has been looked on as an identification of a malignancy. In our opinion, this is not always correct because ovarian borderline tumors, in the same way as ovarian cancers, represent a heterogenous category. There is evidence that serous borderline tumors, as diagnosed in the present study, represent a separate category with its own pathogenesis, which has very little potential for malignant transformation.24 The present study shows that the real prevalence of ovarian cysts with a mean diameter of O4 mm in postmenopausal women is similar to the frequency of cysts that are visualized by ultrasonography in this group of women. This indicates that transvaginal ultrasonography is an excellent method for the identification of ovarian cysts. In addition, the study verifies the results of several previous ultrasound studies that the frequency of ovarian malignancy is extremely low when unilocular cysts with a mean diameter of !50 mm are identified. Based on the results of the present study, the real prevalence of adnexal cysts is approximately 20,000 cases per 100,000 postmenopausal women. Because the prevalence of ovarian cancer is 70 cases per 100,000 women at age 60 years, adnexal cysts seems to occur O200 times as frequently as ovarian cancer. However, although the risk of malignancy is low even in unilocular cysts with a mean diameter !10 mm,21 the risk of malignancy increases with the size of the cyst; and because of the limits in focal range of the transducers, the risk of not visualizing solid parts or septa is increased.17 Because transvaginal ultrasonography as a screening procedure does not identify precursor lesions of ovarian cancer or ovarian cancer as early as once expected, additional measures are being assessed extensively. At present there is consensus that routine screening for ovarian cancer should not be undertaken until the effectiveness of a screening procedure has been demonstrated. However, screening in breast cancer susceptibility
Dørum et al gene 1, breast cancer susceptibility gene 2 carriers, and breast cancer susceptibility gene–like families are recommended as an alternative or until prophylactic surgery; the use of strict ultrasound criteria for surgical intervention is helpful.12,26 The result of the present study supports these guidelines (Table I). Various strategies for the diagnosis of ovarian cancer as early as possible have been reviewed recently.27 The effects of screening strategies for ovarian cancer are being evaluated in ongoing controlled clinical trials that are using mortality and morbidity rates as the main end points. So far, it seems clear that a raised serum level of the tumor antigen CA 125 is a powerful risk factor for ovarian cancer in postmenopausal studies.28 Very little is known about the genetic and biochemical changes that are associated with the transformation of benign ovarian cells into cancer. Whether some benign ovarian cysts can develop into cancer is not known.24 Recent data have indicated that tubal ligation of women with a long-standing history of ovarian endometriosis is protective for endometrioid and clear-cell carcinoma.24,29 If these results are confirmed in other studies, prophylactic tubal ligation should be used more extensively in this group of patients. In our opinion, until more effective procedures for early detection of ovarian cancer are described than the present ones, the criteria that are described already for the conservative treatment or operative removal of adnexal cysts should be used.17 The fact that we found benign ovarian and paraovarian cysts in 19.7% of the women, in our opinion, should cause the gynecologists to reconsider the need for surgical intervention in favor of follow-up procedures. After all, almost one half of all simple cysts that are visualized by transvaginal ultrasonography in postmenopausal women resolve spontaneously, and most of those cysts that persist remain unchanged.30 According to recent studies, the carcinogenesis of sporadic epithelial ovarian cancer and inherited ovarian cancer have in common that they seem to start within the inclusion cysts and are more frequent with increasing age. We also found that time since menopause influenced the frequency of tumors (Table I). We found no data that support surgery of a persisting unilocular cysts that are !50 mm in diameter, unless the cyst increases in size or develops papillary formations/solid areas, which increases the risk of malignancy. However, the decision of which approach to be used in each case must be taken in accordance with the opinion of the affected woman after a thorough presentation of the malignancy risk.
References 1. Annual report of the results of treatment in gynecological cancer: statements of results obtained in patients treated in 1982 to 1986, inclusive 3 and 5-year survival up to 1990. Int J Obstet Gynecol 1991;36(suppl):1-315.
53 2. Greenlee RT, Hill-Harmon MB, Murray T, Thun M. Cancer statistics, 2001. CA Cancer J Clin 2001;51:15-36. 3. Cancer incidence in Sweden: annual report 1996. Stockholm: Swedish Cancer Registry, Center for Epidemiology, National Board of Health and Welfare; 1996. 4. Cancer facts and figures: 1996. Atlanta: American Cancer Society; 1996. 5. Petterson F. Annual FIGO Report on the results of treatment in gynecological cancer, volume 22. Stockholm, Sweden: Repro Print; 1995. p. 83-102. 6. Goldstein SR. Postmenopausal adnexal cysts: how clinical management has evolved. Am J Obstet Gynecol 1996;175:1498-501. 7. Parker SL, Tong T, Bolden S, Wingo PA. Cancer statistics, 1996. Cancer J Clin 1996;65:5-27. 8. Wolf SI, Gosink BB, Feldesman MR, Lin MC, Stuenkel CA, Braly PS, et al. Prevalence of simple adnexal cysts in postmenopausal women. Radiology 1991;180:65-71. 9. Levine D, Gosink BB, Wolf SI, Feldesman MR, Pretorius DH. Simple adnexal cysts: the natural history in postmenopausal women. Radiology 1992;184:653-9. 10. DePriest PD, van Nagell JR, Gallion HH, Shenson D, Hunter JE, Andrews SJ, et al. Ovarian cancer screening in asymptomatic postmenopausal women. Gynecol Oncol 1993;51:205-9. 11. van Nagell JR, DePriest PD, Reedy MB, Gallion HH, Ueland FR, Pavlik EJ, et al. The efficacy of transvaginal sonographic screening in asymptomatic women at risk for ovarian cancer. Gynecol Oncol 2000;77:350-6. 12. Granberg S, Wikland M, Jansson I. Macroscopic characterization of ovarian tumors and the relation to histological diagnosis: criteria to be used for ultrasound evaluation. Gynecol Oncol 1989;35:139-44. 13. Osmers R, Osmers M, von Maydell B, Wagner B, Kuhn W. Evaluation of ovarian tumors in postmenopausal women. Eur J Obstet Gynecol Reprod Biol 1998;77:81-8. 14. Andolf E, Jo¨rgensen C. Simple adnexal cysts diagnosed by ultrasound in postmenopausal women. J Clin Ultrasound 1988; 16:301-3. 15. Goldstein S, Subramanyam B, Snyder JR, Beller U, Raghavendra BN, Beckman EM. The postmenopausal cystic adnexal mass: the potential role of ultrasound in conservative management. Obstet Gynecol 1989;73:8-10. 16. Bailey CL, Ueland FR, Land GL, DePriest PD, Gallion HH, Kryscio RJ, et al. The malignant potential of small cystic ovarian tumors in women over 50 years of age. Gynecol Oncol 1998;69:3-7. 17. Ekerhovd E, Weinerroith H, Staudach A, Granberg S. Preoperative assessment of unilocular adnexal cysts by transvaginal ultrasonography: a comparison between ultrasonographic morphologic imaging and histopathologic diagnosis. Am J Obstet Gynecol 2001;184:48-54. 18. Conway C, Zalud I, Dilena M, Maulik D, Schulman H, Haley J, et al. Simple cyst in the post- menopausal patient: detection and management. J Ultrasound Med 1998;17:369-72. 19. Aubert JM, Rombaut C, Argacha P, Romero F, Leira J, GomezBolea F. Simple adnexal cysts in postmenopausal women: conservative management. Maturitas 1998;30:51-4. 20. Valentin L, Skoog L, Epstein E. Frequency and type of adnexal lesions in autopsy material form postmenopausal women: ultrasound study with histological correlation. Ultrasound Obstet Gynecol 2003;22:284-9. 21. Modesitt SC, Pavlik EJ, Ueland FR, DePriest PD, Kryscio RJ, van Nagell JR. Risk of malignancy in unilocular ovarian cystic tumors less than 10 cm in diameter. Obstet Gynecol 2003;102:594-9. 22. Granberg S, Wikland M. A comparison between ultrasound and gynaecologic examination for detection of enlarged ovaries in a group of women at risk of ovarian carcinoma. J Ultrasound Med 1988;7:59-64.
54 23. Hartge P, Hayes R, Reding D, Sherman ME, Sherman ME, Prorok P, et al. Complex ovarian cysts in postmenopausal women are not associated with ovarian cancer risk factors. Am J Obstet Gynecol 2000;183:1232-7. 24. Feeley KM, Wells M. Precursor lesions of ovarian epithelial malignancy. Histopathology 2001;38:87-95. 25. Scully RE, Bell D, Abu-Jawdeh G. Update on early ovarian cancer and cancer developing in benign ovarian tumors. In: Sharp F, Mason P, Blackett T, Berek J, editors. Ovarian cancer. London: Chapman & Hall; 1995. p.139-44. 26. Dørum A, Kristensen GB, Abeler VM, Trope´ CG, Møller P. Early detection of familial ovarian cancer. Eur J Cancer 1996;32:1645-51.
Dørum et al 27. Collins WP, Bourne TH, Campbell S. Screening strategies for ovarian cancer. Curr Opin Obstet Gynecol 1998;10:33-9. 28. Jacobs IJ, Skates S, Prys Davies A, Woolas RP, Jeyerajah A, Weidemann P, et al. Risk of diagnosis of ovarian cancer after raised serum CA 125 concentration: a prospective cohort study. BMJ 1996;313:1355-8. 29. Rosenblatt KA, Thomas D. Reduced risk of ovarian cancer in women with a tubal-ligation or hysterectomy. Cancer Epidemiol Biomarkers Prev 1996;5:933-5. 30. Castillo G, Alca´zar JL, Jurado M. Natural history of sonographically detected simple unilocular adnexal cysts in asymptomatic postmenopausal women. Gynecol Oncol 2004;92:965-9.
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Prevalence and histologic diagnosis of adnexal cysts in postmenopausal women: An autopsy study Anne Dørum, MD, PhD,a,* Gustav P. Blom, MD,b Erling Ekerhovd, MD, PhD,c Seth Granberg, MD, PhDd Department of Gynecological Oncology, The Norwegian Radium Hospital, Oslo, Norway,a Department of Pathology, Akershus University Hospital, Oslo, Norway,b Department of Obstetrics and Gynecology, Sahlgrenska University Hospital, Go¨teborg, Sweden,c and Department of Obstetrics and Gynecology, Ultrasound Unit, Karolinska Hospital, Stockholm, Swedend Received for publication March 16, 2004; revised July 15, 2004; accepted July 20, 2004
KEY WORDS Cyst Diagnosis Ovary
Objective: The purpose of this autopsy study was to examine the prevalence and histologic condition of adnexal cysts in postmenopausal women. Study design: Adnexa of 234 postmenopausal women who had died from nongynecologic diseases were examined by the team pathologist. Results: Ovarian cysts were found in 36 of the women (15.4%). Nine women (3.8%) had ovarian cysts with a diameter between 20 and %50 mm; 4 women (1.7%) had cysts that were O50 mm in diameter. Four women had bilateral ovarian cysts. Paraovarian cysts were found in 11 women (4.7%). All cysts were benign, except for 1 woman, who had bilateral serous cystadenoma of borderline type. Macroscopically, the borderline cysts were multilocular with mean diameters of 60 mm and 15 mm, respectively. Conclusion: Because of the high prevalence of benign adnexal cysts, the identification of small unilocular cysts in postmenopausal women should be regarded as a normal finding Ó 2005 Elsevier Inc. All rights reserved.
The life risk of ovarian cancer for women who live in western industrial countries is approximately 1.4% (ie, 1 woman in 70) will have the disease. Ovarian cancer is the leading cause of death that is related to gynecologic malignancies and the second most common gynecologic malignancy in the United States and western Europe.1,2 The incidence of ovarian cancer increases dramatically around menopause and onwards, with an incidence of * Reprint requests: Anne Dørum, Department of Gynecological Oncology, The Norwegian Radium Hospital, University of Oslo, N-0310 Oslo, Norway. E-mail: [email protected] 0002-9378/$ - see front matter Ó 2005 Elsevier Inc. All rights reserved. doi:10.1016/j.ajog.2004.07.038
about 70 cases/100,000 women at age 60 years.3,4 This figure should be compared with 0.4 to 8.9 cases per 100,000 women who are !40 years old and 12 cases per 100,000 women who are aged between 35 and 39 years. The overall 5-year survival rate is almost 40%. However, this rate varies according to the histologic features of the malignancy and the stage at the time of diagnosis and treatment.5 Unlike most other types of gynecologic cancer, early ovarian cancer is not associated with symptoms and signs, and more than two thirds of all ovarian cancers are diagnosed at stage III or IV.6 Evidence has shown that the overall survival rate might be approximately 90% if primary ovarian tumors were
Dørum et al identified and removed when the cancer was confined within the ovaries (ie, at stage I).7 By contrast, the survival rate in women with ovarian cancer stage III and IV is only 23%. Consequently, various strategies have been used to identify early ovarian cancer in asymptomatic women. Whichever method is chosen, transvaginal ultrasonography has proved to be the most important diagnostic tool for the detection and characterization of ovarian tumors. The use of high-resolution transvaginal ultrasonography as a part of the routine gynecologic examination has led to the detection of an increasing number of adnexal cystic structures. Initially, the standard treatment of all adnexal cysts that are visualized in postmenopausal women was surgical removal because of fear of ovarian cancer. It then became clear that the postmenopausal ovary is not a static organ whose cyst-generating capacity is lost after menopause, but far more active than what was presumed previously.8 A prevalence of 14% to 18% of adnexal cysts, especially simple cysts (unilocular, anechoic cysts with smooth walls) has been visualized by transvaginal ultrasonography in asymptomatic postmenopausal women.8,9 The clinical dilemma is the conflict between identification of ovarian malignancy as early as possible and the avoidance of unnecessary operations. Although transvaginal ultrasonography is the most commonly used tool to identify adnexal cysts, its positive predictive value is low.10,11 It is generally accepted that multilocular ovarian cysts in postmenopausal women should be removed surgically because of a high malignancy risk.12 Although several studies have shown that the risk of malignancy in unilocular adnexal cysts in this group of women is low, others have come to the opposite conclusion.13 Appropriate treatment guidelines of simple cysts have to be developed on the basis of the natural history of these cysts. If unilocular adnexal cysts in postmenopausal women represent a low risk of malignancy, conservative treatment (ie, serial transvaginal ultrasonography) should be the method of choice.14-17 On the other hand, if a high frequency of adnexal cysts proves to be malignant, operative removal should be performed. The real prevalence of adnexal cysts in postmenopausal women is not known, because all cysts presumably are not visualized by ultrasonography. In addition, there is still uncertainty about the likely histologic diagnosis of painless cysts that are frequently identified in postmenopausal women. We therefore conducted the present autopsy study to determine the real prevalence and histologic condition of adnexal cysts in postmenopausal women.
Material and methods The study was undertaken between August 1995 and November 2000 at Akershus University Hospital, Norway. This hospital has patients from Oslo, the capital of Norway, and from the suburban and rural districts
49 around Oslo, the capital of Norway. Included in the study were consecutive women who were O45 years of age, who underwent autopsy at the university hospital. On the basis of the medical records, all women included were postmenopausal, and none of the women had undergone operations because of gynecologic disease. Excluded from the study were women with previous or known gynecologic cancer, breast cancer, any kind of metastatic intraperitoneal cancer, and previous pelvic radiotherapy or tamoxifen treatment. Women with blood-borne infectious diseases (such as hepatitis, human immunodeficiency virus, and tuberculosis) were also excluded from the study. The cause of death was determined on the basis of the results of the autopsy. A total number of 468 adnexa from 234 women were included in the study. The adnexa were removed from the body, fixed in 4% formaldehyde solution, and examined by the team pathologist. Macroscopic appearance of the adnexa was assessed according to standard routine procedures; the left and right side was secured, and the presence and number of both ovarian and extraovarian cysts and solid tumors was registered. The cysts were classified as either unilocular, unilocular solid, multilocular, multilocular solid, or solid, in accordance with the macroscopic characterization previously used by Granberg et al.12 All available material was embedded in paraffin and stained with hematoxylin-eosin and Masson’s trichrome stain. The ovaries and extraovarian cysts were cut in several slices, and cystic lesions of O4 mm in diameter were examined. At least 2 sections of each ovary were examined under contact reticules (Periplan 5x/ 18 MP; Leitz, Stuttgart, Germany). Histologic diagnosis of each lesion was based on criteria that were set before the study. Simple cysts lined by serous epithelium without septa or papillary projections were characterized as unilocular cysts in accordance with the presumable sonographic appearance if transvaginal ultrasonography had been performed. In addition, the cysts were described as serous or mucinous according to standard criteria that were used normally. Serous and mucinous cysts with papillary formations were diagnosed as serous cystadenomas and mucinous cystadenomas, respectively. These cysts are described normally as unilocular with papillary projections or as unilocular-solid when visualized by transvaginal ultrasonography. Serous and mucinous cysts with R2 cystic structures were characterized as multilocular cystadenomas. After macroscopic examination, all cysts were described histologically and given a diagnosis. For ethical reasons, no ultrasound scan was performed before the removal of the adnexa.
Results The mean and median age of the women was 73 years and 75 years, respectively, and the range was 45 to 96
50
Dørum et al
Table I
Description of 40 ovarian cysts from 36 women, as related to histologic diagnosis Women (n)
Age (y)*
Cyst size (mm)*
Cyst chamber
Bilateral (n)
70
37.5 (15-60)
1 Multilocular
1
1
1
11 4
75.1 (46-86) 79.3 (73-85)
15.2 (5-45) 35.4 (10-60)
2 1
5 1
8 4
Mucinous cysts Mucinous cystadenomas Fibroma Other cysts
1z 1 1 17
62 52 74 68.2 (45-87)
10 40 18 23.1
0 0 0 0
1 1 10
1 7
Mesothelial
10
13 Unilocular 1 Unilocular, 4 multilocular 1 Unilocular 1 Multilocular 1 Solid 16 Unilocular, 1 multilocular 9 Unilocular, 1 multilocular 2 Unilocular 2 Unilocular 2 Unilocular 1 Unilocular
71.1 (45-87)
18.4 (5-75)
4
19
21
Type Serous borderline cancery Benign Serous cysts Serous cystadenomas
1
Follicle Corpus luteum Corpus albicans Endometrioma Total
2 2 2 1 36
(10) (40) (18) (5-75)
Left side (n)
Right side (n)
* Data are mean (range). y Serous cystadenoma with atypia. z One woman had an ovarian and a paraovarian cyst.
Table II Description of the 11 paraovarian cysts found in 11 women, as related to histologic diagnosis; all cysts were unilocular, and none of the cysts were bilateral Type
Women (n)
Age (y)*
Cyst size (mm)*
Left side (n)
Right side (n)
Serous cyst Mesothelial cyst TOTAL
5 6y 11
74.4 (68-79) 74.5 (62-85) 74.5 (62-85)
29.2 (20-40) 23.7 (8-40) 26.2 (8-40)
3 4 7
2 2 4
* Data are given as mean (range). y One woman had both an ovarian and a paraovarian cyst.
years. The causes of death were mostly cardiac, vascular, and pulmonary diseases or extra-genital malignancy. Adnexal cysts with a mean diameter O4 mm were found in 19.7% of the women (46/234), of which 15.4% women (36/234) had ovarian cysts (Table I); 4.7% women (11/234) had paraovarian cysts (Table II). One woman had both a unilocular ovarian cyst (Figure 1) and a unilocular paraovarian cyst that were located to the same adnexal side. Three women had bilateral unilocular ovarian cysts. None of the paraovarian cysts were bilateral. Eight women had multilocular ovarian cysts, and 1 of these women had bilateral multilocular cysts. Histopathologic diagnosis of the bilateral cysts showed serous ovarian cystadenoma of borderline type. In addition, 1 woman had solid ovarian cyst. Histologic examination of this lesion showed a fibroma with a mean diameter of 18 mm. All cysts were benign, except for the 2 borderline cysts described earlier. Of all ovarian cysts that were examined, 52.5% cysts (21/40) were right sided, and 47.5% cysts (19/40) left sided.
Of the adnexal cysts, 62.7% (32/51) measured from 5 to 20 mm; 29.4% (15/51) measured from 21 to 50 mm, and 7.8% (4/51) had a diameter of O50 mm. All paraovarian cysts measured !50 mm; however, 54.5% paraovarian cysts (6/11) had a diameter of O20 mm. The borderline cysts had a diameter of 60 mm and 15 mm, respectively. The histologic diagnosis of the cysts is shown in Tables I and II. Serous ovarian cysts were diagnosed in 4.7% of the women (11/234); 2 women had bilateral serous cysts. Four women had serous cystadenomas (Figure 2); 1 woman had bilateral serous cystadenomas. As already mentioned, 1 woman had bilateral serous cystadenomas of borderline type; 1 woman had a unilocular mucinous cyst, and 1 woman had a multilocular mucinous cystadenoma. Of special interest is the fact that 4.3% of the ovarian cysts (10/234) proved to be multipotent mesothelial cysts. Nine of these cysts were unilocular; 1 cyst was multilocular. The other cysts were functional cysts. One endometrioma was diagnosed (Table I).
Dørum et al
51
Figure 2 A serous cystadenoma, described as unilocular solid, with a mean diameter of 22 mm at autopsy. On the inside of the cyst wall papillary formations can be seen. The cyst was diagnosed after death in a 65-year-old woman. Figure 1 A serous cyst, described as unilocular, with a mean diameter of 12 mm. The cyst was diagnosed after death in a 80-year-old woman.
Comment The present autopsy study shows that the real prevalence of adnexal cysts in postmenopausal women is high. In 46 of the 234 women (19.7%) who were examined, adnexal cysts were found. However, most of the cysts were small: 62.7% of the cysts (32/51) had a mean diameter !20 mm, and 29.4% of the cysts (15/51) had a diameter between 20 and 50 mm. Only 7.8% cysts (4/ 51) were O50 mm. These results are in accordance with several previous studies that have examined the prevalence of adnexal cysts that were visualized by ultrasonography in postmenopausal women. In a study by Wolf et al,8 unilocular adnexal cysts that ranged from 4 to 47 mm in diameter were found in 22 of 149 unselected asymptomatic postmenopausal women (14.8%) who were examined by transvaginal and transabdominal ultrasonography. Statistic calculations that were based on the results of the study showed that the relative frequency of unilocular adnexal cysts in postmenopausal women was 14.8% G 5.7%. Conway et al18 performed transvaginal sonography on 1769 asymptomatic postmenopausal women and found that 116 women (6.6%) had simple ovarian cysts with a diameter between 15 and 50 mm. The frequency of unilocular adnexal cysts in the study by Conway et al is in agreement with our finding that 6.4% of the adnexal cysts that were diagnosed measured O20 mm but !50 mm. Almost the same figures were found by Andolf and Jo¨rgensen14 and Aubert et al.19 In the study by Andolf and Jo¨rgensen the frequency of cysts between 20 and 80 mm was 5.6% (30/534), although Aubert et al described a frequency of 5.7% (36/622) of cysts between 10 and 50 mm. Levine
et al9 performed serial transabdominal and transvaginal ultrasonography on 184 asymptomatic postmenopausal women. Thirty-two simple cysts (17.4%) were identified at the initial examination. Because most studies that are performed to assess the frequency of adnexal cysts that are visualized by ultrasonography are similar to the prevalence that is found in the present autopsy study, it seems clear that ultrasonography is an excellent procedure to identify adnexal cysts. Only very small cysts may be missed by transvaginal ultrasonography. This fact was demonstrated clearly in a recent study by Valentin et al,20 which was conducted between January 2000 and March 2001. In that study, the frequency of adnexal cysts that were visualized by ultrasonography was compared with the prevalence of cysts that were found by histologic examination in an autopsy material of 52 postmenopausal women. Unilocular adnexal cysts between 2 and 65 mm were seen in 28 women (54%) when they were examined by ultrasonography. In addition to these cysts, histopathologic examination of the adnexa revealed 87 unilocular cysts with the largest diameter between 1 and 8 mm. Thus, the number of cysts that were found by the pathologist was significantly higher than what was identified by ultrasonography. However, the vast majority of the cysts that were not identified by ultrasonography had a diameter !5 mm. None of the cysts proved to be malignant. The women who were included in the present study are likely to represent a selected group with very healthy adnexa, because none of them had undergone operation previously for gynecologic disease. Despite this fact, adnexal lesions were found frequently. None of the cysts proved to be malignant. This finding is in agreement with several studies in which unilocular cysts have been removed operatively after identification by ultrasonograhy.17,18,20,21 Most studies have found that the risk of malignancy is !1% in asymptomatic postmenopausal
52 women who have a unilocular cyst with a mean diameter !50 mm.17,21 Thus, based on these studies and the present study, it seems clear that the malignancy risk is low. It is well known that not all ovaries in postmenopausal women can be identified by transvaginal ultrasonography. In a study by Granberg and Wikland,22 87% of the ovaries were visualized. Ovarian size declines with increasing age and time since menopause. Hysterectomy is another factor that appears to limit ovarian visualization.8 This problem may be that normal anatomic landmarks are not present in women who have undergone hysterectomy. In addition, transvaginal ultrasonography may not enable the visualization of adnexal cysts that are located high in the pelvis beyond the limited field of view of the transducer. Other intraabdominal factors (such as intestinal contents or peristalsis) may also limit ovarian visualization. Finally, the experience of the ultrasound examiner and the quality the ultrasound equipment that is used is of importance. On the other hand, ovarian cysts make the ovary more readily visible, and failure to visualize the ovary is often interpreted as an indication of absence of cystic structures within the ovary. Thus, ultrasonography can only indicate the relative frequency of adnexal cysts, as opposite to the present autopsy study, where the real prevalence of cysts is described. In addition, it is extremely important that transvaginal ultrasonography is conducted under optimal conditions. After all, the focal range of the transducers is normally not O6 cm from the transducer tip. Thus, all women who are examined should have voided bladders and be in the lithotomy position with a slight reverse Trendelenburg tilt. The abdominal hand of the examiner should be used, when necessary, to push the adnexa to the pelvic floor, thereby the transducer tip is located as close as possible or even in contact with the adnexa through the vaginal wall. Recent screening trials for ovarian cancer have demonstrated that transvaginal ultrasonography is unable to identify precursor lesions of ovarian malignancy and that even complex ovarian cysts in postmenopausal women are not associated with ovarian cancer risk factors.21,23 These findings may explain the reason that ovarian cancer often is diagnosed in late stages, despite the common use of transvaginal ultrasonography. The resolution of cysts before the development of ovarian cancer and cancer development in a sonographically normal ovary were described in the recent report of the University of Kentucky’s Ovarian Cancer Screening Program.21 Likewise, ovarian cancers that were detected microscopically after normal preoperative, perioperative, and gross pathologic examinations have proved actually to be stage III disease.24 These studies show that the orderly progression of ovarian cancer through stages I and II to reach stages III and IV does not always
Dørum et al occur. In fact, no description of a stepwise progression of ovarian cancer that is comparable with the progression found in cancer of the uterine cervix or colorectal cancer has been published. On the other hand, circumstantial evidence of the existence of premalignant ovarian abnormalities has been collated.25 The clinical problem is, however, that premalignant ovarian changes normally are not identified by ultrasonography. In the present autopsy study, no ovarian cancer was diagnosed. On the other hand, 1 of the women had bilateral serous cystadenomas of borderline type. Both of the borderline cysts were multilocular when examined macroscopically by the pathologist. It seems clear that transvaginal ultrasonography of the adnexa would have demonstrated bilateral multilocular cysts. In several papers, the diagnosis of a borderline cyst after the visualization of the cyst by ultrasonography has been looked on as an identification of a malignancy. In our opinion, this is not always correct because ovarian borderline tumors, in the same way as ovarian cancers, represent a heterogenous category. There is evidence that serous borderline tumors, as diagnosed in the present study, represent a separate category with its own pathogenesis, which has very little potential for malignant transformation.24 The present study shows that the real prevalence of ovarian cysts with a mean diameter of O4 mm in postmenopausal women is similar to the frequency of cysts that are visualized by ultrasonography in this group of women. This indicates that transvaginal ultrasonography is an excellent method for the identification of ovarian cysts. In addition, the study verifies the results of several previous ultrasound studies that the frequency of ovarian malignancy is extremely low when unilocular cysts with a mean diameter of !50 mm are identified. Based on the results of the present study, the real prevalence of adnexal cysts is approximately 20,000 cases per 100,000 postmenopausal women. Because the prevalence of ovarian cancer is 70 cases per 100,000 women at age 60 years, adnexal cysts seems to occur O200 times as frequently as ovarian cancer. However, although the risk of malignancy is low even in unilocular cysts with a mean diameter !10 mm,21 the risk of malignancy increases with the size of the cyst; and because of the limits in focal range of the transducers, the risk of not visualizing solid parts or septa is increased.17 Because transvaginal ultrasonography as a screening procedure does not identify precursor lesions of ovarian cancer or ovarian cancer as early as once expected, additional measures are being assessed extensively. At present there is consensus that routine screening for ovarian cancer should not be undertaken until the effectiveness of a screening procedure has been demonstrated. However, screening in breast cancer susceptibility
Dørum et al gene 1, breast cancer susceptibility gene 2 carriers, and breast cancer susceptibility gene–like families are recommended as an alternative or until prophylactic surgery; the use of strict ultrasound criteria for surgical intervention is helpful.12,26 The result of the present study supports these guidelines (Table I). Various strategies for the diagnosis of ovarian cancer as early as possible have been reviewed recently.27 The effects of screening strategies for ovarian cancer are being evaluated in ongoing controlled clinical trials that are using mortality and morbidity rates as the main end points. So far, it seems clear that a raised serum level of the tumor antigen CA 125 is a powerful risk factor for ovarian cancer in postmenopausal studies.28 Very little is known about the genetic and biochemical changes that are associated with the transformation of benign ovarian cells into cancer. Whether some benign ovarian cysts can develop into cancer is not known.24 Recent data have indicated that tubal ligation of women with a long-standing history of ovarian endometriosis is protective for endometrioid and clear-cell carcinoma.24,29 If these results are confirmed in other studies, prophylactic tubal ligation should be used more extensively in this group of patients. In our opinion, until more effective procedures for early detection of ovarian cancer are described than the present ones, the criteria that are described already for the conservative treatment or operative removal of adnexal cysts should be used.17 The fact that we found benign ovarian and paraovarian cysts in 19.7% of the women, in our opinion, should cause the gynecologists to reconsider the need for surgical intervention in favor of follow-up procedures. After all, almost one half of all simple cysts that are visualized by transvaginal ultrasonography in postmenopausal women resolve spontaneously, and most of those cysts that persist remain unchanged.30 According to recent studies, the carcinogenesis of sporadic epithelial ovarian cancer and inherited ovarian cancer have in common that they seem to start within the inclusion cysts and are more frequent with increasing age. We also found that time since menopause influenced the frequency of tumors (Table I). We found no data that support surgery of a persisting unilocular cysts that are !50 mm in diameter, unless the cyst increases in size or develops papillary formations/solid areas, which increases the risk of malignancy. However, the decision of which approach to be used in each case must be taken in accordance with the opinion of the affected woman after a thorough presentation of the malignancy risk.
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54 23. Hartge P, Hayes R, Reding D, Sherman ME, Sherman ME, Prorok P, et al. Complex ovarian cysts in postmenopausal women are not associated with ovarian cancer risk factors. Am J Obstet Gynecol 2000;183:1232-7. 24. Feeley KM, Wells M. Precursor lesions of ovarian epithelial malignancy. Histopathology 2001;38:87-95. 25. Scully RE, Bell D, Abu-Jawdeh G. Update on early ovarian cancer and cancer developing in benign ovarian tumors. In: Sharp F, Mason P, Blackett T, Berek J, editors. Ovarian cancer. London: Chapman & Hall; 1995. p.139-44. 26. Dørum A, Kristensen GB, Abeler VM, Trope´ CG, Møller P. Early detection of familial ovarian cancer. Eur J Cancer 1996;32:1645-51.
Dørum et al 27. Collins WP, Bourne TH, Campbell S. Screening strategies for ovarian cancer. Curr Opin Obstet Gynecol 1998;10:33-9. 28. Jacobs IJ, Skates S, Prys Davies A, Woolas RP, Jeyerajah A, Weidemann P, et al. Risk of diagnosis of ovarian cancer after raised serum CA 125 concentration: a prospective cohort study. BMJ 1996;313:1355-8. 29. Rosenblatt KA, Thomas D. Reduced risk of ovarian cancer in women with a tubal-ligation or hysterectomy. Cancer Epidemiol Biomarkers Prev 1996;5:933-5. 30. Castillo G, Alca´zar JL, Jurado M. Natural history of sonographically detected simple unilocular adnexal cysts in asymptomatic postmenopausal women. Gynecol Oncol 2004;92:965-9.