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Obstetrics & Gynecology:
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Epithelial Ovarian Tumors of Low Malignant Potential: The Role of Microinvasion

Buttin, Barbara M. MD; Herzog, Thomas J. MD; Powell, Matthew A. MD; Rader, Janet S. MD; Mutch, David G. MD

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Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Washington University School of Medicine, St. Louis, Missouri.

Address reprint requests to: David G. Mutch, MD, Washington University School of Medicine, Department of Obstetrics and Gynecology, 4911 Barnes Hospital Plaza, Box 8064, St. Louis, MO 63110; E‐mail: mutchd@msnotes.wustl.edu.

Received May 21, 2001. Received in revised form September 24, 2001. Accepted October 2, 2001.

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Abstract

OBJECTIVE: To identify prognostic factors that may be used to predict an aggressive disease course and poor outcome in patients with epithelial ovarian tumors of low malignant potential (borderline tumors).

METHODS: Data on 126 patients with ovarian borderline tumors were analyzed with regard to demographic characteristics, staging, presence of microinvasion, duration of follow‐up, recurrence rate, rate of recurrence as invasive disease, mortality rate, preoperative and postoperative CA‐125, and treatment. Chi‐square and Fisher exact tests were used to evaluate proportions for statistical significance. Disease‐free and overall survival was calculated by using the Kaplan–Meier method and log‐rank test.

RESULTS: Patients were followed for a median of 39.0 months (mean 47.8 months). Seven patients (5.6%) had recurrent disease. Advanced stage disease and microinvasion were associated with significantly higher recurrence and mortality rates than were stage I/II disease and borderline tumors without microinvasion, respectively. Two of 13 (15%, 95% CI 8.7, 21.3) patients with microinvasion died of recurrent invasive cancer, whereas only 1 out of 113 patients without microinvasion died of recurrent borderline tumor (OR 20.4, 95% CI 1.2, 239). All 3 patients with an aggressive disease course and poor outcome had increasing CA 125 levels at the time of recurrence.

CONCLUSION: Certain patients with microinvasion may be at higher risk for recurrence as invasive disease and may require different treatment strategies. CA 125 monitoring may have a role in early detection of recurrence in patients with aggressive disease.

Epithelial ovarian tumors of low malignant potential were first described by Taylor1 in 1929 as a group of tumors with histologic features and biological behavior between benign and frankly malignant epithelial ovarian neoplasms. In 1971, the International Federation of Gynecology and Obstetrics (FIGO) included these tumors as a separate entity in its classification and staging system of gynecologic malignancies.2 Since then, consensus has been reached about the excellent prognosis of ovarian low malignant potential (borderline) tumors compared with invasive epithelial ovarian tumors. A large, retrospective study by Kaern et al3 of 370 patients followed for a median duration of 127 months showed a total mortality rate of 7.8% and total recurrence rate of 7.3% for all stages. In contrast, 5‐year survival rates for invasive epithelial ovarian cancer range from 20% to 70% depending on age and stage at presentation.4 A prospective study of 406 patients by the Gynecologic Oncology Group5 is currently in progress to confirm these results.

Nonetheless, several controversies exist with regard to biological behavior, prognostic factors, and treatment of these tumors, which account for 5% to 20% of all ovarian cancers.6 A small but significant number of patients have been reported by multiple investigators to have a poor prognosis, with mortality rates of 20% to 50%, high recurrence rates, and poor response to chemotherapy.3,6–13 Factors most commonly associated with a poor outcome are advanced stage at presentation, presence of surgical residual, and presence of invasive peritoneal implants.3,6–11 Some investigators have also proposed micropapillary architecture in serous borderline tumors,7,10,14 aneuploidy and histologic type,3,9 degree of cytologic atypia and mitotic index,6 presence of endosalpingiosis,11,12,14 and p53 overexpression15 as predictors of poor outcome. Stromal microinvasion and retroperitoneal lymph node involvement have not been consistently shown to alter prognosis, although these two factors have been studied less extensively.3,6,7,9,16–23 Recurrences can be seen as late as 10 to 39 years after initial diagnosis,12 and 0.6% to 19% of patients have recurrence as invasive carcinoma.7,10,12,13,16

To date, we cannot accurately predict which patients are prone to such an aggressive course of their disease. To further address this issue, we summarized our experience with 126 ovarian borderline tumors and compared it with findings in the most recent literature. Special emphasis was placed on stromal microinvasion as a predictor of recurrence and survival. Other prognostic factors, such as stage, histologic subtype, and lymph node involvement, were examined along with usefulness of CA 125 monitoring in ovarian borderline tumors.

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MATERIALS AND METHODS

One hundred sixty patients with a diagnosis of ovarian borderline tumor who were seen and treated at the Washington University School of Medicine Department of Gynecologic Oncology between September 1989 and February 2000 were identified from a computerized database. For 126 of these patients, adequate follow‐up information was available for retrospective review, consisting of complete charts, follow‐up visits, treatment and operative reports, information on patients' death, and available pathology slides. Patients with incomplete charts or final pathology not consistent with borderline ovarian tumors were excluded. All pathology was reviewed by one of the gynecologic pathologists in our department, even if the patient's primary surgery was done at an outside institution. The pathologist assigned histologic classification according to World Health Organization criteria from 1973,24 and retrospective staging was performed by one of the authors according to FIGO classification2 after review of operative and pathology reports.

Tumors were classified as borderline tumors with microinvasion if the primary tumor had all features of a typical borderline tumor except for small invasive foci, each measuring less than 3 mm in diameter for a total area of less than 5% of the tumor. A microinvasive focus could consist of single cells, glands, or small clusters of cells within the stroma. Stromal reaction, degree of cellular atypia, and total number of foci were not part of the diagnostic criteria.14,18,19 A peritoneal implant was considered invasive on the basis of the number of cells in the stroma and cellular characteristics. CA 125 levels were obtained by our laboratory using an OC 125 hybridization assay (Abbott Axsym Systems, Abbott Park, IL). The upper limit of normal was 34 U/mL. A tumor was presumed to be adequately sampled if at least one section per centimeter of tumor diameter was available for review.7

Patient information was analyzed with regard to age at diagnosis, premenopausal as opposed to postmenopausal status, race, stage, staging procedure, and presence of microinvasion. Follow‐up information included duration of follow‐up, recurrence rate, rate of recurrence as invasive cancer, mortality rate, preoperative and postoperative CA 125 level (when available), and treatment.

Chi‐square and Fisher exact tests were used as appropriate to evaluate proportions for statistical significance. Disease‐free and overall survival was calculated from the date of surgery to the time of recurrence, last follow‐up, or death. Disease‐free and overall survival curves for patients with and without microinvasion were generated by using the Kaplan–Meier method, and significance of observed differences was determined by using the log‐rank test.25

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RESULTS

For the 126 patients analyzed, the mean age at the time of diagnosis was 49.2 years (range 16–85 years). Seventy‐one patients (56.3%) were premenopausal and 55 (43.7%) were postmenopausal. One hundred four (82.5%) were white and 22 (17.5%) were black. The median follow‐up was 39.0 months (mean 47.8 months, range 2–277 months). Stage and histology at presentation is summarized in Table 1.

Table 1
Table 1
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One hundred fifteen patients (91%) underwent complete staging procedures. This includes 87 patients with bilateral salpingo‐oophorectomy with or without total abdominal hysterectomy, omentectomy, multiple biopsies, and retroperitoneal lymph node sampling; 12 patients with total abdominal hysterectomy, bilateral salpingo‐oophorectomy, omentectomy, and multiple biopsies; 15 patients with unilateral salpingo‐oophorectomy, omentectomy, multiple biopsies, and lymph node sampling. Eleven of 126 patients (8.7%) had incomplete staging procedures performed, including 7 with total abdominal hysterectomy and bilateral salpingo‐oophorectomy only, 1 with cystectomy only, and 3 with unilateral salpingo‐oophorectomy.

Preoperative CA 125 levels were available in 97 of the 126 patients (77%) and were elevated in 54 of 97 (55.7%). In serous tumors only, elevated preoperative CA 125 level was more likely to be associated with advanced stage (48.7% with stage I and II disease vs 88.2% with stage III disease, P = .007).

Seven patients (5.6%) had recurrent disease during the study (Table 2). Stage III disease was associated with a higher recurrence rate than was stage I and II disease (21% [5/24 patients] vs 2.2% [2/9 patients], P = .004). This difference was also significant when analyzed by using the Kaplan–Meier method for disease‐free survival (P = .009), but overall survival was not significant (P = .15). The difference in recurrence rates between stage III tumors with and without retroperitoneal lymph node involvement was not significant (10% [1/10 patients] vs 29% [4/14 patients], P < .358). Tumors with serous compared with nonserous histology did not significantly differ in recurrence rates (7% [5/73 patients] vs 4% [2/55 patients], P <. 726). Microinvasive borderline tumors were found to have a significantly higher recurrence rate than borderline tumors, without microinvasion (23% [3/13 patients] vs 3.5% [4/113 patients], P = .023). Two of 13 patients with tumors (15%, 95% CI 8.7, 21.3) with microinvasive foci according to the above definition had recurrence as invasive carcinoma resembling the microscopic focus in the primary tumor. Both of these patients (5 and 6, Table 2) died of disease, whereas only 1 of 113 patients without microinvasion died of recurrent borderline tumor. This difference in mortality rates was significant (15% [2/13 patients] vs 0.88% [1/113 patients], P = .022), with an odds ratio of 20.4 (95% CI 1.2, 239). Survival analysis for patients with and without microinvasion also demonstrated a significant difference in disease‐free and overall survival (P = .002, P = .008, respectively) (Figures 1 and 2).

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Figure 1
Figure 1
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Figure 2
Figure 2
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Table 2
Table 2
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Patient 5 had been treated with seven cycles of carboplatin and paclitaxel after optimal debulking for a stage IIIC mixed borderline tumor with microinvasion. Her tumor recurred as a new pelvic mass 6 months after completing chemotherapy, and she subsequently underwent suboptimal debulking of her recurrent disease. She died 1 month later. Patient 6 was treated conservatively after initial staging and optimal debulking of a stage III, predominantly mucinous borderline tumor with pseudomyxoma peritonei as well as pseudomyxoma ovarii. Her appendix contained a mucinous adenoma without atypia, and her ovarian tumor was unilateral. The primary ovarian tumor contained microinvasive foci (2 mm in diameter) with clear cell features; disease recurred 17 months later as invasive clear cell carcinoma. The patient died 6 months after her recurrence was diagnosed. Patient 2 had a recurrence of an optimally debulked stage IIIA serous borderline tumor without microinvasion 15 years after initial diagnosis. Her cause of death was inferior vena caval and right atrial tumor thrombosis. Although her recurrent tumor was aggressive, no invasive or microinvasive foci were present. All three of these patients with recurrence as either invasive cancer or as a very aggressive borderline tumor had elevated CA‐125 levels at the time of recurrence (124, 200, and 322 U/mL), whereas the other four patients with recurrent tumors did not.

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DISCUSSION

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Our study represents the largest contemporary series of ovarian borderline tumors of all histologic types. We also present a larger proportion of completely staged borderline tumors with microinvasion than any previously published series. Overall, the low recurrence and mortality rates of 5.6% and 2.4%, respectively, are consistent with those reported in the literature (Table 3). Our demographic data also confirm those in previous reports on ovarian borderline tumors. They tend to occur in a younger age group than do invasive ovarian tumors; more than half of patients are premenopausal.6,9 These patients often desire conservative, fertility‐sparing surgery, which has been shown to be safe and successful without compromising long‐term outcome.21

Table 3
Table 3
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Staging is of paramount importance, even in young patients with apparent stage I disease, because stage has consistently been shown to be a significant prognostic indicator.3,6,8,9 Several investigators have demonstrated that 18% to 20% of apparent stage I tumors were of higher stage on final pathologic examination.9,17 Leake et al reported a higher incidence of recurrence in stage III tumors with localized intraperitoneal disease plus retroperitoneal lymph node involvement and stage III tumors with distant intraperitoneal disease, whereas overall survival was not affected.17 We and others6,7,9,16 found no significant difference in recurrence or mortality rates between stage III tumors with and without lymph node involvement. These data suggest that retroperitoneal lymph node dissection may be avoided in ovarian borderline tumors if distant intraperitoneal disease is present. However, it must be performed if disease seems to be confined to the ovaries or the pelvis.

Up to 90% of ovarian borderline tumors (67.5% in our study) present as stage I disease. These patients have a 5‐year disease‐free survival of almost 100% and an excellent overall prognosis.5 The approximate incidence of stage III disease has been reported to be 15% to 20% in most studies, including ours.6 Stage III is more common than stage II disease,6 and stage IV disease is rarely encountered. Many investigators have reported as much as a 10‐fold increase in recurrence and mortality rates when comparing stage I and stage III or IV disease.8 As expected, patients with an aggressive disease course and poor outcome usually present with stage III disease. However, the exact mechanism of extraovarian disease spread and the significance of metastatic disease is controversial.

Several investigators endorse the concept of noninvasive peritoneal implants.6,7,11,13,15 Several authors cite a four times increased rate of recurrence and mortality with invasive peritoneal implants.11,15 Other investigators question the concept of invasive peritoneal implants in the absence of any invasive areas in the primary tumor,16 noting that this finding is often associated with inadequately sampled primary tumors. Alternatively, it has been theorized that most peritoneal implants represent separate primary tumors arising in the peritoneum.9 A study using X‐chromosome inactivation techniques demonstrated that some bilateral and advanced‐stage serous ovarian borderline tumors may be multifocal in origin.22 We did not detect any stage III tumors with invasive peritoneal implants in the absence of microinvasion in the primary tumor. This may be related to the lack of uniform diagnostic criteria for what constitutes an invasive implant.

Similarly, microinvasion is a controversial subject. No consensus exists on size criteria for microinvasive lesions or the inclusion of other factors, such as stromal reaction or degree of cellular atypia. Microinvasive foci can easily be missed, even in tumors that are by definition adequately sampled. Microinvasion has been studied separately in mucinous and in serous tumors. Most investigators believe that microinvasion, regardless of the histologic subtype of the tumor, does not change the patient's overall prognosis, although only relatively few cases have been studied.14,19,20,23,24,26,27 Some authors have suggested a possible association of microinvasion and endosalpingiosis with higher recurrence rates and worse prognosis.11,12,14 The combination of microinvasion and advanced stage has also been proposed as an adverse prognostic factor.14 Very few cases of advanced stage borderline tumors with microinvasion are found in the literature to date (Table 3). Most of the data on microinvasion are derived from stage I and unstaged tumors.

Because the exact size of a microinvasive area that is significant for prognosis remains unknown, other factors, such as stromal reaction, degree of cellular atypia, and growth pattern, have more meaning in terms of future malignant potential. For serous tumors, a distinction between “borderline tumors with microinvasion and borderline tumors with microinvasive carcinoma” was proposed on the basis of cell morphology, growth pattern, and stromal response.14 Similarly, “intraepithelial carcinoma” has been defined for mucinous tumors21; the term implies a difference in prognosis even in the absence of stromal invasion. If a future consensus is reached on a more extended classification of ovarian borderline tumors of all histologic types, patients 5 and 6 in our series may be reclassified as having microinvasive carcinoma. We included patient 6 in our series despite the presence of pseudomyxoma peritonei because her disease course was clearly independent of this entity and her recurrence was of ovarian origin.

We believe that certain patients with ovarian borderline tumors with microinvasion are at high risk for invasive cancer. The difference in mortality and recurrence rates between these patients and patients without microinvasion was apparent in our study despite the relatively short median duration of follow‐up and the relatively small sample. We strongly believe that this patient group merits further investigation, particularly with regard to the possible benefits of adjuvant chemotherapy.

Finally, the exact role of CA 125 monitoring in ovarian borderline tumors has not been established. We agree with Rice et al that preoperative CA 125 levels correlate with stage in serous borderline tumors only28 and therefore should be obtained in patients with these tumors. However, only scant and conflicting data are available regarding CA 125 levels at the time of recurrence in borderline tumors.29–31 In our series, all three patients with aggressive recurrent tumors and adverse outcome had increasing CA 125 levels with recurrent disease. Although further study is necessary, it appears that CA 125 monitoring may have a role in the detection of recurrence in patients with aggressive borderline tumors.

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© 2002 by The American College of Obstetricians and Gynecologists.

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