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ORIGINAL RESEARCH |
From the *Department of Obstetrics and Gynecology, University of Texas Southwestern Medical Center, Dallas, Texas; Department of Obstetrics and Gynecology, University of North Carolina at Chapel Hill Medical School, Chapel Hill, North Carolina; and Department of Obstetrics, Gynecology and Reproductive Biology, Massachusetts General Hospital, Boston, Massachusetts.
Address reprint requests to: John O. Schorge, MD, Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, J7.124, Dallas, TX; e-mail: john.schorge{at}utsouthwestern.edu.
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ABSTRACT |
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METHODS: Between 1984 and 2003, all women with ovarian low malignant potential tumors were identified at 3 institutions. Data were extracted from clinical records.
RESULTS: One hundred eighty-three (74%) of 248 women were surgically staged. Forty of 183 staged patients had clinically obvious extraovarian disease. Forty (28%) of the remaining 143 women with disease apparently confined to the ovary were upstaged. Cytologic washings were positive in 28 cases, 10 had microscopic implants detected by peritoneal or omental biopsy, and 2 were upstaged to stage IIIC solely on the basis of nodal metastases. One hundred eighteen women underwent pelvic node dissection (median: 5 nodes), and 86 underwent para-aortic node dissection (median: 2 nodes). Overall, 9 (1%) metastases were detected in 832 submitted pelvic nodes. All 314 para-aortic nodes were negative. Intraoperative blood loss (P < .001) and length of hospital stay (P < .001) were increased in women without gross disease who were surgically staged. Eight (3%) of 248 patients received adjuvant platinum-based chemotherapy, but neither of the women upstaged to IIIC based on the results of their nodal dissection were treated. Fifteen (6%) recurrences developed and 1 (0.4%) death occurred after a median follow-up of 28 (range, 1–208) months.
CONCLUSION: Routine pelvic and para-aortic lymph node dissection is not necessary in the majority of women with ovarian low malignant potential tumors.
LEVEL OF EVIDENCE: III
Surgical staging for low malignant potential tumors apparently confined to the ovary involves cytologic washings, random peritoneal biopsies, omentectomy or generous omental biopsy, and retroperitoneal lymph node sampling.5 Appendectomy is also commonly performed, especially for mucinous tumors. Staging biopsies will upstage 24–47% of women, and 4–27% will have retroperitoneal lymph node metastases.6–8 Advanced stage seems to be a prognostic factor for decreased survival.4,9 However, few upstaged patients will receive adjuvant therapy, because it has not been shown to improve clinical outcome.10,11
In a previous report of 93 women with ovarian low malignant potential tumors, survival and recurrence rates were not significantly different between those who were staged and those who were unstaged.3 However, a recent survey of gynecologic oncologists revealed that 97% advocate surgical staging.5 The purpose of this multicenter study was to compare the outcome of surgically staged patients with low malignant potential tumors with those who were not staged.
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MATERIALS AND METHODS |
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Medical records were reviewed for data extraction. Patient age, race, gravidity, parity, preoperative CA 125, histology, tumor size, stage, presence of microinvasion, staging procedures performed, location and number of resected lymph nodes, length of postoperative hospital stay, estimated blood loss, location of metastases, type of adjuvant therapy, duration of follow-up, and development of disease recurrence or death were recorded. Surgically staged women were compared with those who were unstaged. Secondarily, a separate analysis was performed by excluding women with gross disease at the time of surgery.
Categorical variable comparisons were conducted by 2-tailed 
2 and Fisher exact tests. Continuous variables were evaluated for normality by the Shapiro-Wilk (W test) statistic. If normality was assured, parametric comparisons were compared by analysis of variance and Student t test. Nonnormally distributed continuous variables were compared with the Mann-Whitney U statistic and Kruskal-Wallis test. Evaluation of independent factors predicting disease-specific recurrence was conducted by nominal logistic regression analysis. Survival estimates were calculated using the Kaplan-Meier product limit method.12 Comparisons between survival curves were made using the log-rank test.13 Two-tailed P values are reported, with the 
for all tests set at 0.05.
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RESULTS |
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.001). International Federation of Gynecology and Obstetrics (FIGO) stage I disease was assigned in 131 (72%) surgically staged patients and 64 (98%) unstaged patients (P < .001). However, rates of disease recurrence and duration of follow-up were similar (Table 1). None of the 57 patients with mucinous low malignant potential tumors had metastases.
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The type of surgical staging procedures varied widely (Table 2). Forty of 183 staged patients had clinically obvious extraovarian disease. Forty (28%) of the remaining 143 patients with disease apparently confined to the ovary were upstaged. Cytologic washings were positive in 28 (20%) cases, 10 (7%) had microscopic implants detected by peritoneal or omental biopsy, and 2 (1%) were upstaged to FIGO stage IIIC solely on the basis of nodal metastases. One hundred eighteen patients underwent pelvic lymph node dissection with a median of 5 (inner quartile range, 3–10) nodes resected. Seven (6%) patients had positive pelvic lymph nodes. Overall, 9 (1%) of 832 pelvic nodes were positive. Eighty-six women underwent para-aortic lymph node dissection with a median of 2 (inner quartile range, 0–6) nodes submitted. All 314 para-aortic nodes were negative.
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Eight (3%) of 248 patients received adjuvant platinum-based chemotherapy. All had surgical stage III disease, with 6 (75%) having gross disease. Three women were clinically disease-free after a median of 43 (range, 19–141) months of follow-up. Five (62.5%) experienced a disease recurrence with a median progression-free survival of 35 (range, 3–75) months: 2 were in clinical remission after salvage therapy and 2 were alive with measurable disease at the time of the report and 1 stage IIIA patient died of disease 37 months after diagnosis. Neither of the patients upstaged to FIGO stage IIIC based on the results of their nodal dissection received adjuvant therapy.
Fifteen (6%) women developed recurrent disease. Thirteen were originally surgically staged and 2 were unstaged (P = .21). Table 3 presents the relationship by univariate and multivariate analysis of suspected risk factors for recurrence. In this analysis, 2 independent prognostic factors for recurrence were identified: gravidity (P = .043) and stage category (P .001). Six recurrences in the contralateral ovary were salvaged with surgery alone. Five patients had recurrences after receiving adjuvant therapy. None of the recurrences were isolated pelvic or para-aortic nodal metastases. Only 1 mucinous tumor recurred; there was a tendency, although not statistically significant, for mucinous tumors to recur less frequently (P = .12).
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Twenty-seven (15%) of 183 surgically staged patients had low malignant potential tumors with microinvasion, compared with none of the 65 that were unstaged (P < .001). Thirteen (48%) of 27 had extraovarian disease, including 1 with a pelvic lymph node metastasis. Fourteen were stage I, 1 was stage II, and 12 were stage III. Three (11%) women received adjuvant treatment. Overall, 2 (7%) patients had recurrences. One died of disease 35 months after diagnosis despite reinitiation of platinum-based chemotherapy. The other received salvage chemotherapy and was clinically free of disease 67 months later.
Median estimated blood loss was increased (300 mL compared with 200 mL; P < .001), and median length of hospital stay was prolonged (5 days compared with 3 days; P < .001) in women who underwent surgical staging. The exclusion of 40 staged patients with gross disease did not alter these observations.
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DISCUSSION |
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Surgically staged ovarian low malignant potential patients do not seem to benefit from adjuvant therapy. Platinum-based chemotherapy effectively achieves surgically documented responses in patients with residual disease after primary surgery, but the survival benefit in an adjuvant setting remains unproven.10,11,16,17 The Gynecologic Oncology Group (GOG) conducted a prospective observation trial of 146 patients with surgical stage I serous low malignant potential tumors not receiving adjuvant therapy. After a median follow-up of 42 months, there were no disease recurrences.18 A prospective trial of platinum-based adjuvant chemotherapy conducted by the GOG for 32 women with stage III low malignant potential tumors concluded that the need for adjunctive therapy was speculative.10 In a Surveillance, Epidemiology, and End Results database study, 2,818 women with ovarian low malignant potential tumors were analyzed. The 10-year survival rate of women with stage III disease was 96%, and adjuvant chemotherapy was given to approximately 30% of women with stage III-intravenously disease. The authors concluded that there were insufficient data to support a role for adjuvant chemotherapy for women with advanced disease.4 The indolent nature of ovarian low malignant potential tumors is characterized by slow growth and late recurrences. As a result, most patients would not be expected to benefit from adjuvant chemotherapy.
Women with mucinous low malignant potential tumors are especially unlikely to benefit from aggressive surgical staging. None of the 57 staged mucinous low malignant potential patients in this study had metastatic disease. Rodriguez et al19 described the outcome of 41 women who had borderline mucinous tumors. All had stage I disease, which behaved in a clinically benign fashion. In addition, other studies have not identified nodal metastases in these patients.8,14 Mucinous low malignant potential tumors are relatively infrequent, and surgical staging is of limited value, but this histologic type seems to be more prone to misinterpretation at frozen section.20
Only 2 independent prognostic factors for recurrence were identified: gravidity and assigned stage category. Women with fewer pregnancies and advanced stage were significantly more likely to have recurrences. Fewer pregnancies most likely predisposes to recurrence because many of these women underwent fertility-sparing surgery. Previous studies have shown a high (33–53%) rate of recurrence with this procedure, although death from disease is extremely rare.21,22 Advanced disease stage is a well-known risk factor for recurrence.23,24
The inability to reliably exclude stromal invasion at the time of intraoperative frozen section is a recognized limitation in developing a consistent strategy for staging ovarian low malignant potential tumors.20 Menzin et al25 compared the accuracy of frozen section diagnosis with the final pathologic interpretation in 48 patients. Thirteen (27%) were found to have focal, well-differentiated invasive cancer in a background of low malignant potential neoplasia. The frozen section qualifying diagnosis of "at least" low malignant potential was more likely (41% compared with 19%) to portend stromal invasion than low malignant potential tumor or "rule out" low malignant potential tumor. In addition, the level of experience of the pathologist responsible for the frozen section did not influence the accuracy. In another retrospective review of 94 frozen section diagnoses of low malignant potential tumors, 6% were subsequently changed to invasive carcinoma.20 The accuracy of intraoperative frozen section undoubtedly varies among pathologists and institutions. Buttin et al24 observed a higher rate of recurrence in microinvasive low malignant potential tumors (23% compared with 3.5%; P = .023), but this association was not identified in our study (7% compared with 5%). Complete surgical staging, including lymph node dissection, may be indicated when frankly invasive disease is suspected.
Surgical staging provides more accurate prognostic information at the cost of increased blood loss and prolongation of the postoperative hospital stay. We speculate that some staging procedures, most notably para-aortic node dissection, may result in longer operative time, greater morbidity, and extended recovery time. A recent survey of gynecologic oncologists revealed that 97% advocate surgical staging of low malignant potential tumors.5 However, only 12% of patients undergo complete surgical staging in current practice.7 Stage III ovarian low malignant potential tumors have the same rate of recurrence whether they have peritoneal disease or lymph node metastases or neither.24,26 Camatte et al14 noted that in their experience, all patients with lymph node metastases also had peritoneal implants. We advocate cytologic washings, exploration, random peritoneal biopsies, and partial omentectomy in the absence of enlarged nodes or a frozen section suggestive of frankly invasive disease. A frozen section diagnosis of mucinous tumor is another reason to consider retroperitoneal lymph node dissection, because many invasive mucinous tumors are often underdiagnosed.20 These procedures can be easily performed by laparoscopy or laparotomy without extending the incision or appreciably prolonging the operation. In addition, it is hard to justify routine surgical restaging for patients with a final pathologic diagnosis of low malignant potential ovarian tumor confined to a single ovary.27
The findings of this study are limited by the retrospective data acquisition, relatively short follow-up, and lack of central pathology review. However, another prospective study of adjuvant therapy in surgically staged patients is unlikely to be performed in the near future given the infrequency of this diagnosis and the previous GOG experience.10,18 Longer follow-up would be expected to identify additional disease recurrences in both groups, but we believe our conclusions would not be altered. Winters et al3 observed no clinical difference in staged and unstaged patients after an average duration of 6.5 years. Central pathology review might have reinterpreted some low malignant potential tumors as benign or frankly invasive ovarian carcinoma. We believe that including cases from 3 geographically separated institutions should dilute this effect and make our findings broadly applicable to clinical practice.
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Footnotes |
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Presented at the 35th Annual Meeting of the Society of Gynecologic Oncologists, February 2004, San Diego, California.
10.1097/01.AOG.0000133484.92629.88
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REFERENCES |
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