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Abstract
Objective Mucinous ovarian carcinoma is a rare subtype of epithelial ovarian cancer with scarce literature guiding its management. We aimed to investigate the optimal surgical management of clinical stage I mucinous ovarian carcinoma by examining the prognostic significance of lymphadenectomy and intra-operative rupture on patient survival.
Methods We conducted a retrospective cohort study of all pathology-reviewed invasive mucinous ovarian carcinomas diagnosed between 1999 and 2019 at two tertiary care cancer centers. Baseline demographics, surgical management details, and outcomes were collected. Five-year overall survival, recurrence-free survival, and the association of lymphadenectomy and intra-operative rupture on survival were examined.
Results Of 170 women with mucinous ovarian carcinoma, 149 (88%) had clinical stage I disease. Forty-eight (32%; n=149) patients had a pelvic and/or para-aortic lymphadenectomy, but only 1 patient with grade 2 disease was upstaged due to positive pelvic lymph nodes. Intra-operative tumor rupture was documented in 52 cases (35%). On multivariable analysis, after adjusting for age, final stage, and use of adjuvant chemotherapy, there was no significant association between intra-operative rupture with overall survival (HR 2.2 (0.6–8.0); p=0.3) or recurrence-free survival (HR 1.3 (0.5–3.3); p=0.6), or lymphadenectomy with overall survival (HR 0.9 (0.3–2.8); p=0.9) or recurrence-free survival (HR 1.2 (0.5–3.0); p=0.7). Advanced stage was the only factor that was significantly associated with survival.
Conclusions In clinical stage I mucinous ovarian carcinoma, systematic lymphadenectomy has low utility, as very few patients are upstaged and recurrence typically occurs in the peritoneum. Furthermore, intra-operative rupture does not appear to independently confer a worse survival, and therefore these women may not benefit from adjuvant treatment based on rupture alone.
- Cystadenocarcinoma, Mucinous
- Lymph Nodes
Data availability statement
All data relevant to the study are included in the article or uploaded as supplementary information.
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WHAT IS ALREADY KNOWN ON THIS TOPIC
Mucinous ovarian cancer is a rare subtype with scarce literature guiding the surgical management of these tumors.
WHAT THIS STUDY ADDS
Our findings show that in clinical stage I mucinous ovarian cancers, systematic lymphadenectomy has low utility, as few patients are upstaged. Furthermore, intra-operative rupture does not confer a worse survival, so these patients do not benefit from adjuvant treatment based on rupture alone.
HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE OR POLICY
Based on our findings, systematic lymphadenectomy can be omitted from surgical staging in cases of stage I mucinous ovarian cancers.
Introduction
Primary mucinous ovarian cancers account for 3% of all epithelial ovarian cancers and have distinct epidemiologic, clinical, and pathological differences compared with other epithelial ovarian cancers.1 They often present in younger patients in early stage with large primary tumors that are limited to the ovary.2 The overall prognosis in such early-stage disease tends to be excellent, with 5- year survival as high as 90%. Conversely, advanced-stage disease is associated with worse prognosis likely due to lower response to platinum-based chemotherapy.3
Due to the rarity of mucinous ovarian cancers, there are scarce data guiding the optimal management of these tumors. They are often mixed in with other epithelial ovarian cancers in large clinical trials, and represent a very small subset of patient population in these studies. In retrospective studies with larger cohorts, and the lack of central pathology review, patient population tends to be heterogeneous with borderline tumors or ovarian metastases from other sites.
Given the paucity of literature, surgical management of these tumors can present a number of conundrums. For one, comprehensive surgical staging in epithelial ovarian cancers usually includes lymph node sampling/dissection, but the utility and the prognostic significance of systematic lymphadenectomy in early-stage invasive mucinous ovarian cancers remain unclear. Furthermore, the rate of peri-operative tumor rupture and its influence on patient outcomes also remain to be elucidated. It is unclear whether adjuvant therapy should be prescribed solely based on intra-operative tumor rupture. To further explore these issues in this rare subtype of ovarian cancer we performed a retrospective cohort study in order to investigate the prognostic significance of lymphadenectomy and intra-operative rupture on patient survival.
Methods
Participants
This was a retrospective cohort study of all invasive mucinous ovarian cancer cases diagnosed between 1999 and 2019 at two large volume tertiary care cancer centers in Ontario, Canada. Institutional review board approvals and data transfer agreements were obtained. Cases of ovarian metastasis from gastrointestinal tract or borderline tumors were excluded through central pathology review. For grading, the Silverberg grading system was used. Cases with incomplete follow-up information were also excluded. Patient charts were reviewed for baseline demographics, disease characteristics, surgical treatment details, recurrence information, and survival outcomes. Overall survival was defined as time from surgery to death from any cause, and recurrence-free survival was defined as time from surgery to first recurrence confirmed by imaging and/or pathology. Those patients that did not experience a recurrence or death were censored at date of their last follow-up visit.
Statistical Analysis
Analysis was restricted to those with apparent stage I disease at presentation. All categorical variables were reported as frequencies and percentages, and continuous variables were described with medians (interquartile ranges). For comparison of patient characteristics between various groups (lymphadenectomy vs no lymphadenectomy, intra-operative tumor rupture vs no rupture), Wilcoxon rank-sum test or Fisher exact tests were performed. Five-year overall survival and recurrence-free survival were calculated from Kaplan–Meier curves and comparisons made using log-rank test. Cox proportional hazards models were used to determine the association of lymphadenectomy and intra-operative rupture on overall survival and recurrence-free survival. Clinically important variables were chosen a priori for inclusion in Cox proportional hazards models. P values <0.05 were considered statistically significant. Statistical Analysis System (SAS) version 9.4 was used.
Results
Of 170 patients that were identified and met the inclusion criteria, 149 (88%) had apparent stage I disease at the time of diagnosis, with 51 (34%) that received care at Sunnybrook Cancer Center and 98 (66%) that received care at Princess Margaret Cancer Center. Thirty-five (23%) patients had their initial surgery by a general gynecologist before referral to one of these two centers for further management, while 114 (77%) patients had their initial surgery by a gynecologic oncologist. The median age for this cohort was 49 years (IQR 33–58). Most presented with a large (21 cm; IQR 16–28) unilateral (99%) ovarian mass with median pre-operative CA-125 of 44 (18–99) (Table 1).
Clinicopathologic characteristics of patients with apparent stage I disease
Of 149 patients with apparent stage I disease, 43 (29%) had fertility-sparing surgery in the form of unilateral salpingo-oophorectomy while 106 (71%) had hysterectomy and bilateral salpingo-oophorectomy. Complete peritoneal staging with cytology, random peritoneal biopsies, and omentectomy was done in 34 (23%) patients. Omentectomy was done in 128 (86%) patients, and 2 patients with grade 2 disease were upstaged due to microscopic omental deposit (1.6%). Washings were done in 80 (54%) patients, and 11 were positive (7%). Peritoneal biopsies of suspicious areas were done in 40 (27%) cases and returned positive for disease in 3 (8%). There was one patient that had positive omental biopsy, positive washing, and positive peritoneal biopsy, and another patient that had positive washing and positive omentum only. Frozen section was requested in 114 (77%), with ‘benign’ reported in 7 (5%), ‘mucinous borderline’ in 52 (35%), ‘mucinous adenocarcinoma’ in 44 (30%), and ‘non-mucinous’ in 11 (7%). At final pathology, 137 had stage I (92%), 5 stage II (3%), 6 stage III (4%), and 1 stage IV (1%) disease; 106 were Silverberg grade 1 (71%), 35 Silverberg grade 2 (23%), and 8 Silverberg grade 3 (5%). Lymphovascular space invasion was documented in 4 cases (3%). At the conclusion of the procedure, 146 had no gross residual disease (98%), 2 had 1–10 mm residual disease (1%), and 1 without documentation in the operative report (Table 1).
In Apparent Stage I Disease, is Systematic Lymphadenectomy Required?
Pelvic and/or para-aortic lymphadenectomy was done as part of staging surgery in 48 (32%) patients. Of 45 (30%) patients that underwent pelvic lymph node dissection, 24 (53%) had bilateral, and 21 (47%) had unilateral dissections. The median number of pelvic lymph nodes dissected was 8 (IQR 4–14). There was only 1 patient with grade 2 disease that was upstaged due to positive pelvic lymph nodes. Of 26 (17%) patients that underwent para-aortic lymph node dissection, 14 had (54%) had bilateral and 12 (46%) had unilateral dissections, with median 7 (IQR 5–13) lymph nodes obtained. None of the para-aortic lymph nodes were involved with disease. Of the 35 patients that had their initial surgery by a general gynecologist, 5 (14%) had reoperation for completion of lymphadenectomy, and none of these 5 patients had positive pelvic and/or para-aortic lymph nodes. There was no difference in overall survival (5-year overall survival 86% vs 91%; p=1.0) or recurrence-free survival (5-year recurrence-free survival 82% vs 83%; p=0.9) between those patients that underwent lymphadenectomy and those that did not (Figure 1). In Cox proportional hazards model, after adjusting for age, final stage, and use of adjuvant chemotherapy, there was no significant association between lymphadenectomy with overall survival (HR 0.9; 95% CI 0.3 to 2.8; p=0.9) or recurrence-free survival (HR 1.2; 95% CI 0.5 to 3.0; p=0.7) (Table 2).
Kaplan–Meier overall survival (left) and recurrence-free survival curves (right) for patients with apparent stage I disease comparing patients with or without lymphadenectomy.
Cox proportional hazards model of overall and recurrence-free survival on lymphadenectomy and intra-operative rupture
In Apparent Stage I Disease, Does Intra-operative Tumor Rupture Lead to Worse Outcomes?
Intra-operative tumor rupture was documented in 52 cases (35%) and these cases were more likely to have initial surgery performed by a non-gynecologic oncologist (48% vs 11%; p<0.001). There was no difference in the rate of adjuvant therapy use between those that had intra-operative tumor rupture compared with those that did not (13% vs 8%; p=0.4). There was also no difference in the rate of recurrence (13% vs 13%; p=1.0), distribution of recurrence (single site 43% vs 31%; p=0.7), and the location of recurrence (peritoneal; 75% vs 89%; p=0.5). Finally, there was no difference in overall survival (5-year overall survival 95% vs 85%; p=0.3) or recurrence-free survival (5-year recurrence-free survival 81% vs 83%; p=0.9) between those patients that had intra-operative tumor rupture and those that did not (Figure 2). In Cox proportional hazards model, after adjusting for age, final stage, and use of adjuvant chemotherapy, there was no significant association between intra-operative rupture with overall survival (HR 2.2; 95% CI 0.6 to 8.0; p=0.3) or recurrence-free survival (HR 1.3; 95% CI 0.5 to 3.3; p=0.6) (Table 2).
Kaplan–Meier overall survival (left) and recurrence-free survival curves (right) for patients with apparent stage I disease with or without intra-operative tumor rupture.
In Apparent Stage I Disease, What is the Overall Clinical Course?
Median follow-up for the entire cohort was 3.9 years (IQR 2.1–5.6) with 5-year overall survival 88.9% (82.9–95.3%) and recurrence-free survival 82.7% (75.7–90.3%). Fifteen patients (10%) received adjuvant chemotherapy, with 13 (87%) that received chemotherapy only and 2 (13%) that received chemotherapy and radiation. Thirteen (87%) received a platinum-based regimen while 2 (13%) received a gastrointestinal cancer-based regimen.
There were 20 recurrences in the overall cohort (13%; 9 grade 1, 6 grade 2, 5 grade 3), with the vast majority being peritoneal (95%). There were 7 (35%) with single-site recurrence and 13 (65%) with multifocal recurrences. For treatment of recurrences, 9 (45%) had further chemotherapy (4 with platinum-based, 5 with gastrointestinal regimen), 5 had surgery (25%), 1 had radiation (5%), and 5 were observed (25%). Bevacizumab was added in 3 of the 9 patients (33%) for treatment of their recurrences. Twelve patients (8%) ultimately died due to their disease. In Cox proportional hazards model, use of adjuvant chemotherapy was not associated with improvement in recurrence-free survival (Table 2). Advanced stage was the only factor that remained significantly associated with survival.
Discussion
Summary of Main Results
Our findings show that systematic lymphadenectomy in clinically stage I mucinous ovarian carcinoma has low utility, as rate of upstaging based on lymph node status is low, and recurrences tend to occur in the peritoneum rather than lymph nodes. Therefore, when patients present after a unilateral salpingo-oophorectomy in the community, it is not necessary to take them back to the operating room for the sole purpose of sampling the lymph nodes. Furthermore, intra-operative rupture does not confer a worse risk, and should not be the deciding factor in recommending adjuvant treatment. However, omental biopsy and sampling of suspicious areas should be strongly considered at the time of initial staging, as it does upstage the patient and may lead to adjuvant treatment that may be helpful.
Results in the Context of Published Literature
There exists a number of population-based studies examining the role of lymphadenectomy in mucinous ovarian cancers; however, the majority of these studies have not performed central pathology review to exclude borderline tumors or metastasis from other sites. Nasioudis et al has examined 2855 apparent stage I mucinous carcinomas through the National Cancer Institute’s Surveillance, Epidemiology, and End Results database in which 56% underwent lymphadenectomy; a total of 27 women (1.7%) had positive lymph nodes for metastasis.4 The 5-year cancer-specific survival was better in the lymphadenectomy group for women with stage IC disease (89% vs 81%; p=0.006) but not for those with stage IA or IB disease. However, after controlling for year of diagnosis, stage, race, grade and age, lymphadenectomy was not associated with significantly lower cancer-specific mortality. Similarly, in a meta-analysis of 16 studies including 278 women with mucinous ovarian cancers, the rate of lymph node metastasis in those with stage I-II disease was reported as 0.8%; given that nodal metastasis was rare, the authors concluded that complete surgical lymph node assessment has no significant impact on staging.5
The prognostic significance of intra-operative tumor rupture has also been a topic of debate in the literature, with some studies showing lower survival due to intra-operative capsule rupture, and some studies showing no difference.6–8 Furthermore, the role of adjuvant therapy for intra-operative tumor rupture has not been well elucidated in mucinous ovarian cancers. National Comprehensive Cancer Network (NCCN) guidelines recommend either observation alone or chemotherapy (with consideration of gastrointestinal regimen such as capecitabine/oxaliplatin) for patients with stage IC disease,9 but there is no recommendation to treat solely for intra-operative capsule rupture. A population-based study from Japan reported the rate of intra-operative tumor rupture in mucinous ovarian cancer to be around 32%, similar to the rate of 35% reported in our study.10 Similar to our findings, after controlling for confounders (age, year of diagnosis, registry area, performance of lymphadenectomy and hysterectomy, and post-operative chemotherapy use), intra-operative capsule rupture had no significant effect on cause-specific survival with a HR of 1.28 (95% CI 0.79 to 2.09). Again, similar to our findings, use of post-operative chemotherapy did not affect cause-specific survival in cases with intra-operative tumor rupture.
Strengths and Weaknesses
A major strength of our study is the central pathology review to ensure that only ovarian primary cases were being examined and that any borderline tumors were excluded. This was conducted on all consecutive cases at two large tertiary cancer centers. The study is limited by its retrospective nature, as well as the limited sample size. Furthermore, given that these early mucinous ovarian cancers are usually associated with excellent survival outcomes, it is hard to ascertain whether the lack of survival difference in the groups (lymphadenectomy vs no lymphadenectomy and intra-operative tumor rupture vs no rupture) is due to sample size or short follow-up. Also, our study is limited by lack of classification according to growth pattern (expansile vs infiltrative) since this was not routinely reported during the time period of our cohort; it is unclear whether the role of lymphadenectomy or intra-operative tumor rupture would remain small in the more aggressive infiltrative subtype, which has been associated with rate of lymph node metastasis as high as 17–30%.1 Subclassification according to growth pattern may ultimately change surgical management.
Implications for Practice and Future Research
Based on our study findings, systematic lymphadenectomy can be omitted at time of surgical staging of early-stage mucinous ovarian cancers. Future studies should examine the value of lymphadenectomy in expansile versus infiltrative mucinous ovarian cancers based on the subtype.
Conclusions
In summary, the findings of our study show that in women with apparent stage I mucinous carcinomas of the ovary, systematic lymphadenectomy has limited value; the rate of upstaging based on lymphadenectomy was only 2%. The majority of recurrences were multifocal and peritoneal, which implies that lymphadenectomy at the time of initial surgical staging is unlikely to influence the site of recurrence. Intra-operative tumor rupture also did not lead to worse survival, and indicates that intra-operative rupture alone may not dictate whether adjuvant therapy should be prescribed in patients with apparent stage I disease.
Data availability statement
All data relevant to the study are included in the article or uploaded as supplementary information.
Ethics statements
Patient consent for publication
Footnotes
Twitter @AinhoaMada, @stephanielheur5
Contributors SRK: data curation, formal analysis, project administration, visualization, writing—original draft, writing—review and editing. AM: data curation, investigation, methodology, writing—review and editing. LH: conceptualization, investigation, writing—review and editing. DV: investigation, writing—review and editing. AC: investigation, writing—review and editing. CP-H: data curation, investigation, writing—review and editing. SL: conceptualization, investigation, writing—review and editing. LTG: guarantor, conceptualization, formal analysis, funding acquisition, project administration, investigation, methodology, supervision, writing—review and editing.
Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests None declared.
Provenance and peer review Not commissioned; externally peer reviewed.