Intraoperative frozen section analysis was performed in 83 of 93 patients with a diagnosis of ovarian tumor of low malignant potential on final pathology. Of these 83 frozen sections, 21 (25%) were reported as benign cystadenomas, eight (10%) as invasive carcinomas, and 54 (65%) as ovarian low malignant potential tumors. Therefore, the sensitivity of the frozen section analysis for low malignant potential tumors was 65% (95% confidence interval 55%, 75%).
During the time of this study, eight additional patients who had a low malignant potential tumor on frozen section analysis but a diagnosis of invasive carcinoma on final pathology were identified through pathology records. This translated to an 8% incidence of upgrading to invasive carcinoma from a low malignant potential frozen section diagnosis during the period of collection. Complete follow-up data were available for only five of the eight patients. Four cancer patients were surgically staged, three of whom had stage I cancers (two serous and one mucinous) and one of whom had a stage IIIC mucinous adenocarcinoma. Two of the staged patients received chemotherapy, whereas the other two patients (both stage IA) were observed. Only the patient with stage IIIC mucinous adenocarcinoma had cancer recurrence and died of causes secondary to the tumor. Only one patient with cancer on final pathology was unstaged. She had an apparent stage IC clear cell carcinoma of the ovary and received adjuvant chemotherapy, but the tumor recurred 35 months after her original diagnosis and she died of the disease. The inclusion of these five occult cancers on final pathology in the staged (n = 4) and unstaged (n = 1) groups did not change our results and conclusions regarding the minimal effects of staging on outcome. There was one additional recurrence and death from disease in both the staged and unstaged cohorts, with inclusion of the outcome data from these occult cancer patients.
There is still considerable debate about the surgical treatment of ovarian tumors of low malignant potential. The current practice in many institutions is surgical debulking, rather than complete staging, followed by observation. However, many surgeons still advocate formal surgical staging of patients with low malignant potential ovarian tumors. Investigators have reported that patients with localized intraperitoneal disease can be upstaged in 22–27% of cases based on retroperitoneal involvement found at staging procedures in patients with presumed stage I and II tumors.12,21 In contrast, we found that 17% of patients were upstaged on the basis of surgical staging, with only 6% of these cases (three of 48 staged patients) upstaged because of retroperitoneal involvement. Although the total number of patients in our report is small (n = 48), this series of staged patients is larger than that of either series previously reported.12,21 Because of the low risk of retroperitoneal involvement suggested by our data, we question the utility of lymph node sampling for low malignant potential tumors of the ovary even though morbidity is apparently limited when the procedure is performed by a gynecologic oncologist.22 Our data on intraoperative assessment of disease also indicated that early-stage disease was significantly more common in patients who did not have complete surgical staging. The high percentage of apparent early-stage disease in this group might not only reflect unrecognized extraovarian disease but also might result from selection bias by the surgeon, who chose to defer surgical staging in patients with tumors that had more grossly reassuring features.
Because of the indolent nature of borderline ovarian tumors, adjuvant therapy has a limited role in the primary treatment of patients, even patients with advanced low malignant potential ovarian tumors on final pathology.5,23 Chemotherapeutic treatment of patients with low malignant potential tumors reportedly has led to more treatment-related deaths than the number of patients who have progressed from low malignant potential disease to invasive carcinoma.14 Typically, secondary debulking is performed for recurrence of low malignant potential tumors, and salvage chemotherapy is reserved for recurrences that are suboptimally debulked or have histologic features consistent with invasive cancer. Each of the six patients who had histologic confirmation of low malignant potential recurrence received salvage chemotherapy after secondary debulking.
Although many investigators have acknowledged the lack of data showing a survival benefit associated with surgical staging for patients with low malignant potential ovarian tumors, this diagnostic procedure has been advocated in order to provide the patient and family with more accurate prognostic information regarding recurrence. In a previous analysis of 255 patients with tumors of low malignant potential from MD Anderson Cancer Center, Lin et al15 found that only 27 (12%) patients had staging, defined by the investigators as sampling of the omentum, pelvic and abdominal peritoneum, and retroperitoneal lymph nodes (cytologic washings not included). The authors advocated surgical staging for patients with low malignant potential tumors even though they did not report an increased risk of recurrence in the 88% of patients with tumors that were not staged. Based on the data from our series, the ability of surgical staging to identify microscopic extraovarian low malignant potential disease did not appear to affect recurrence or survival in patients with low malignant potential tumors of the ovary.
Proponents of surgical staging argue that the diagnosis of low malignant potential on frozen section analysis of the tumor can be upgraded to invasive cancer by final pathologic analysis in approximately 6–27% of cases.15,16 To address this issue, we identified eight additional patients with low malignant potential tumors on frozen section, who had invasive cancer on final pathology during the study period. We obtained outcome data on five of the eight cases. The inclusion of these occult cancers and subsequent recurrences in the staged (n = 1) and unstaged (n = 1) groups did not change our statistical results and conclusions regarding the minimal effects of staging on outcome.
In our series, only one case of low malignant potential tumor with invasive implants was observed among the 93 low malignant potential cases. Our conclusions regarding surgical staging might not be applicable to cases involving low malignant potential tumors with invasive implants. This form of low malignant potential disease is associated with an increased likelihood of recurrence, prompting some surgeons to consider surgical staging, adjuvant therapy, or both. Retrospective series by Gershenson et al9,10 have found a median time from diagnosis to progression of 24 months for patients with invasive implants and 7.1 years for those with noninvasive implants. In contrast, the largest reported prospective series of low malignant potential tumors (n = 339) showed that the disease-free interval might be better than that previously reported.3 Although recurrence occurred in five of 16 patients with invasive implants, all of the patients were without evidence of disease 21, 25, 30, 35, and 81 months after salvage therapy. Persistence of tumor was noted in four of 16 (25%) patients who were not given postoperative chemotherapy compared with five of 12 recurrences in patients who received platinum-based treatment, illustrating that adjuvant therapy has limited value in the treatment of low malignant potential tumors with invasive implants.3 In institutions where adjuvant therapy is prescribed for patients with invasive implants, formal surgical staging could be considered until data in which the outcomes of staged and unstaged patients are available. Our understanding of the efficacy of adjuvant therapy on outcome in patients with low malignant potential tumors with invasive implants remains poorly understood.
Conservative surgery has been described in several case series of patients with ovarian low malignant potential tumors. Unilateral salpingo-oophorectomy or cystectomy has been advocated as part of fertility-sparing surgery for women with low malignant potential ovarian tumors. Retrospective data have revealed recurrence rates of 12–58% for cystectomy18,19 to 23% for unilateral oophorectomy.19 The prospective series reported by Zanetta et al3 likewise showed that, although the risk of recurrence is higher after fertility-sparing surgery (35 of 189 cases) than after radical surgery (seven of 150 cases), all but one woman with recurrence of low malignant potential after conservative treatment were salvaged. Because future recurrence can be treated effectively in most cases, young women can have surgery designed to conservatively debulk the tumor allowing for future conception. Morris et al19 reported delivery of 16 viable infants among 12 of 24 patients who had conservative surgery for low malignant potential tumors. No fetal abnormalities in the offspring of these women were noted.
We acknowledge that the low incidence of recurrence of low malignant potential tumors makes the evaluation of recurrence and survival among patients with this disease suboptimal. However, because the proportion of patients with recurrence was almost identical in the staged and unstaged groups, the likelihood of a type II error is unlikely. To detect a 20% difference in recurrence rates between the staged and unstaged groups using the log rank test, a sample size of 2020 patients per group would be required to achieve 80% power, assuming a recurrence rate of 10% for early-stage low malignant potential ovarian tumors. If the study were to analyze only advanced-stage low malignant potential tumors, approximately 748 patients in each group would be required to detect a 20% difference in the recurrence rate (assumed to be 30% in unstaged patients). These sample sizes make the likelihood of a prospective trial with adequate power unlikely. However, our results suggest that the effects of surgical staging on outcome in patients with low malignant potential tumors are not clinically that staggering.
Physicians should consider the concordance of frozen section analysis and final pathology, at their respective institution, before determining whether a diagnosis based on frozen section analysis of a low malignant potential tumor should prompt surgical staging. In health care settings where frozen section analysis and final pathology are relatively consistent, surgery aimed at optimal debulking or complete excision of the tumor without formal surgical staging is an acceptable option. Alternatively, surgeons may chose to surgically stage patients in institutions where the frozen section false-negative rate for low malignant potential tumors is unacceptably high or in practice settings where adjuvant therapy is prescribed for low malignant potential tumors based on the presence of invasive implants or advanced-stage disease.
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