Canadian high risk endometrial cancer (CHREC) consortium: Analyzing the clinical behavior of high risk endometrial cancers

    Canadian high risk endometrial cancer (CHREC) consortium: Analyzing the clinical behaviour of high risk endometrial cancers Alon D. Altman, Sarah E. Ferguson, Eshetu G. Atenafu, Martin K¨obel, Jessica N. McAlpine, Tony Panzarella, Susie Lau, Lilian T. Gien, Blake Gilks, Blaise Clarke, Anna Cameron, Gregg Nelson, Guangming Han, Vanessa Samou¨elian, T.C. Ho, Kim Louie, Marcus Q. Bernardini PII: DOI: Reference:

S0090-8258(15)30119-0 doi: 10.1016/j.ygyno.2015.09.001 YGYNO 976040

To appear in:

Gynecologic Oncology

Received date: Revised date: Accepted date:

31 July 2015 1 September 2015 3 September 2015

Please cite this article as: Alon D. Altman, Sarah E. Ferguson, Eshetu G. Atenafu, Martin K¨ obel, Jessica N. McAlpine, Tony Panzarella, Susie Lau, Lilian T. Gien, Blake Gilks, Blaise Clarke, Anna Cameron, Gregg Nelson, Guangming Han, Vanessa Samou¨elian, T.C. Ho, Kim Louie, Marcus Q. Bernardini, Canadian high risk endometrial cancer (CHREC) consortium: Analyzing the clinical behaviour of high risk endometrial cancers, Gynecologic Oncology (2015), doi: 10.1016/j.ygyno.2015.09.001

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ACCEPTED MANUSCRIPT Canadian High Risk Endometrial Cancer (CHREC) Consortium:

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Analyzing the Clinical Behaviour of High Risk Endometrial Cancers

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Alon D. Altman MD, FRCSC1 Sarah E. Ferguson MD, FRCSC3 Eshetu G. Atenafu MSc PStat13,14 Martin Köbel MD8 Jessica N. McAlpine MD, FRCSC7 Tony Panzarella MSc PStat13, 14 Susie Lau MD, FRCSC4 Lilian T. Gien MD, MSc. FRCSC3 Blake Gilks MD, FRCPC6 Blaise Clarke MD, FRCPC2 Anna Cameron MD, FRCSC1 Gregg Nelson MD, PhD, FRCSC9 Guangming Han MD MSc FRCPC10 Vanessa Samouëlian, MD PhD11 TC Ho 3 Kim Louie MD12 * Marcus Q. Bernardini MD, MSc, FRCSC3

Division of Gynecologic Oncology, University of Manitoba, 2Department of Pathology and Laboratory Medicine,

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University of Toronto, 3Division of Gynecologic Oncology, University of Toronto, 4Division of Gynecologic Oncology, McGill University, 5Department of Molecular Medicine, Laval University, 6Division of Anatomic Pathology, University of British Columbia, 7Division of Gynecologic Oncology, University of British Columbia, 8

Department of Pathology and Laboratory Medicine, University of Calgary, 9 Division of Gynecologic Oncology,

University of Calgary, 10Department of Pathology and Laboratory Medicine, University of Toronto, 11Division of Gynecologic Oncology, CHUM - Hôpital Notre-Dame, 12Division of Obstetrics and Gynecology, University of British Columbia, 13 Biostatistics Department, Princess Margaret Cancer Centre,14Division of Biostatistics, Dalla Lana School of Public Health, University of Toronto

*Corresponding Author: Marcus Q. Bernardini MD, MSc, FRCSC University of Toronto Princess Margaret Hospital M700 610 University Ave Toronto, Ontario M5G 2M9 (416) 946-4501 ext 2668 [email protected]

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ACCEPTED MANUSCRIPT Abstract:

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Objectives: The objective of this study is to analyze the clinical behaviour of endometrial carcinomas by high

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risk(HR) histotype, including stage, overall survival, recurrence free survival and patterns of failure.

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Methods:

This is a retrospective multi-institutional cohort study performed at 7 tertiary care centers

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across Canada between 2000 and 2012 and included: grade 3 endometrioid (EC3), endometrial serous cancer (ESC), clear cell carcinomas (CCC) and carcinosarcoma (CS). Clinicopathological and outcome

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Results:

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data was collected.

1260 women with endometrial carcinoma with 1013 having staging procedures were identified; 398 EC3, 449 ESC, 236 CS and 91 CCC. 51.8% had lymphovascular space invasion (LVSI) and 18.5% had omental involvement with a statistically significant difference between tumour types (p=0.0005 and 0.0047 respectively); ESC had a significantly greater rate of omental involvement compared EC3 (22% to 9%, p =0.0005). Within the entire cohort 49.3% were stage 1, 10.6% were stage 2, 27.4% were stage 3 and 12.7% were stage 4. Overall and recurrence free survival was significantly different between histotypes (p< 0.0001) with CS having the worst outcome. Overall 31.5% of patients recurred. CS and ESC had a higher distant recurrence rate compared to EC3 (29.6%, 31.0% compared to 16.4%, p = 0.0002 and p < 0.001).

Conclusion:

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ACCEPTED MANUSCRIPT This study is one of the largest clinical cohorts of HR endometrial cancers. We have further clarified the impact of histotype and stage on recurrence and survival, and the high likelihood of distant

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recurrence. However, the differences are modest and risk prediction models will require additional

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molecular markers.

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Introduction:

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Endometrial cancer is the most common gynecologic malignancy in North America. In 1983,

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Bokhman first described a two tier classification system into: type 1 endometrioid carcinoma, which was

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estrogen stimulated, and type 2 non-endometrioid carcinoma, comprised of high risk histologies and associated with worse prognosis (1-5). Type 2 cancers include: endometrial serous cancer (ESC), clear

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cell (CCC), grade 3 endometrioid (EC3), carcinosarcomas (CS) and others (2,3,6). Although traditionally

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only type 1 cancers have been associated with obesity, there is increased evidence that all endometrial cancers are associated with obesity (3,6,7); molecular alterations within EC3 adenocarcinomas (e.g.

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TP53 mutations) seem to resemble other type 2 tumors (5), creating a less clear division of this

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dichotomous classification. While this provides a framework of the pathogenesis, the WHO classification

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by histotype remains the gold standard for subclassification of endometrial carcinomas (8).

High risk endometrial carcinoma behave differently, having a higher likelihood of metastatic disease, poorer prognosis and increased recurrences compared to low risk histologies (6,9). High risk histotypes may also be associated with an increased age at diagnosis and are more likely to be AfricanAmerican (2,4,6,9-11). Several studies have shown that lymphovascular space invasion (LVSI), myometrial invasion, lower uterine segment involvement and tumor size are independent prognostic factors for these cancers (2,9,11-16). Some studies have shown worse overall survival for ESC compared to EC3 (9,10,12,17,18), while others have not shown any difference in survival between histotypes (5,11,13,19-22), with higher rates of extrauterine spread for EC3 when compared to ESC and CCC (19), completely contradicting each other’s findings (4).

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ACCEPTED MANUSCRIPT Endometrial serous carcinoma (ESC) is an uncommon malignancy, making up only 5-10% of endometrial cancers, but accounts for approximately 40% of endometrial cancer deaths (2,3,10). This

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entity was first described by Hendrickson in 1982, who noted a histology similarity to tubo-ovarian highgrade serous carcinoma, with a higher propensity for peritoneal spread and recurrent disease (6,23,24).

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These tumors are also found to have high prevalence of TP53 mutations and Her2/neu amplification

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(2,6,25). CCC was first described by de Bonneville in 1911 and only accounts for 2-4% of uterine

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malignancies (2,9), but also has a high rate of recurrence and poor overall outcome accounting for 8% of

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uterine cancer deaths (9,25,26).

Although initially believed to be sarcomas, uterine CS are now thought to be metaplastic

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carcinomas. Historically, they were often excluded from endometrial carcinoma studies (10,20,27,28),

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but rather included in sarcomas studies and incompletely staged (20). Recurrence rates and overall

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survival range from 0-66% and 33-100% respectively, with some studies showing no difference between CS compared to other histologies (20) and others showing worse outcomes for CS (27,28).

Although high risk endometrial histotypes clearly behave worse than low risk endometrial carcinomas, the overall survival and recurrence rates differ widely between studies with 5 year survival rates varying between 33-79% (9,10,12,13,17-19,21,22,29), and the role of chemotherapy and radiation remains questionable (2,6,9,11,14,16,19,24,25,30). Since high risk endometrial cancers comprise a relatively smaller proportion of patients in prospective randomized studies, it is difficult to compare outcomes and come to conclusions because of small numbers. In this collaboration, we have the opportunity to analyze a large cohort of patients with high risk histology.

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ACCEPTED MANUSCRIPT The purpose of this study is to analyze the clinical behaviour of high risk endometrial cancers in a large nationwide cohort of patients including stage distribution, overall survival, recurrence free

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survival and patterns of failure. We believe that this study will be critical for providing clinicians with a

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central reference for discussions with their patients about prognosis and disease course.

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Materials and Methods:

This retrospective multi-institutional cohort study was performed at 7 centers (Princess

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Margaret Cancer Centre/University Health Network, Vancouver General Hospital, Tom Baker Cancer Center, Jewish General Hospital, CancerCare Manitoba, Centre Hospitalier de l'Université de Montréal,

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and Odette Cancer Centre), in 5 cities (Vancouver BC, Calgary AB, Winnipeg MB, Toronto ON, Montreal

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QC) across Canada between 2000 and 2012. Charts were reviewed from each cancer centre’s electronic

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medical records. Inclusion criteria included any women with high risk endometrial cancer, including EC3, ESC, CCC and CS of any stage. Charts were excluded if they had a diagnosis of grade 1 or 2 endometrioid adenocarcinoma, or if the primary site of disease was unknown. Data on mixed tumour histotypes was collected but were excluded from the analysis.

All data was collected and reviewed by two individuals from every center, and all pathology was reviewed by a subspecialty gynaecologic pathologist prior to inclusion in the study. A standardized data collection sheet was created and tested on an initial subset of cancer patients. The database was then formatted to ensure standardized information from all participating centers.

The primary objective was to determine the clinical behavior of high risk endometrial cancers, including: stage distribution, overall survival (rates and durations), recurrence free survival (rates and 6

ACCEPTED MANUSCRIPT durations), and patterns of failure/locations of recurrence. The secondary objective of this study was to establish a pan-Canadian, multi-centered, repository of “high risk” endometrial cancers, and create one

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of the largest collections of high risk endometrial cancers to date.

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Overall survival was defined as the interval from the date of initial diagnosis to the date of death

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or, if alive, censored at the date of last known contact. Recurrence free survival was defined as the

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interval from the date of initial diagnosis to the date of first recurrence or date of death, whichever occurs first. Patients who were alive and recurrence free were censored on the date of last known

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contact. No distinction was made between cancer-related and non-cancer related deaths. Data was also collected on patient characteristics, clinical presentation and primary treatment, including surgery,

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chemotherapy and radiation. Complete staging was defined as surgery with pelvic lymphadenectomy

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+/- paraaortic lymphadenectomy +/-omentectomy.

Each site attained individual Research Ethics Board approval according to local protocol. This study is a retrospective review based on acquired data. The study did not interfere with the care that the women received during the course of their cancer care, and subjects were not contacted directly.

Statistical Analysis Summary statistics were used to describe patient and treatment-related characteristics and outcomes. Categorical variables such as stage, histology, extent of surgical staging, LVSI, omental involvement, and recurrence was expressed as count and proportions, whereas continuous variables such as age and follow-up were expressed as mean and standard deviation and/or median and range as appropriate. Chi-square/Fisher’s exact test, as appropriate, was used to assess any association of the categorical variables of interest with histotypes or among histotypes. Analysis of variance (ANOVA) was 7

ACCEPTED MANUSCRIPT also used to compare mean age of patients among histotypes and further pair-wise analysis, when there was significant association, was done using Tukey-Kramer adjustment for multiple comparison. Overall

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Survival (OS) rates were calculated using the Kaplan-Meier product-limit method. The log-rank test was used to assess any difference among histology to the outcome OS. Gray’s test for competing risk was

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used to assess any difference among histology to the outcome of cumulative incidence of relapse

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considering death as competing risk. All P-values were 2-sided and for the statistical analyses, P < 0.05

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was considered to indicate a statistically significant result. Statistical analysis was performed using version 9.4 of the SAS system for Windows, Copyright © 2002-2012 SAS Institute, Inc., Cary, NC, and the

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open source statistical software R version 3.0 (The R Foundation for Statistical Computing, Vienna,

Results:

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Austria, 2013).

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A total of 1260 charts were reviewed, with 398 EC3, 449 ESC, 91 CCC, 236 CS, 83 other types and 3 missing data. Overall 81.4% of submitted cases underwent surgical staging with at least a pelvic lymphadenectomy in the absence of extra-uterine disease, for a total of 1013 patients, with 319 EC3, 366 ESC, 68 CCC, 177 CS, 72 other types and 11 missing data comprising the main cohort for analysis in our study.

The mean overall age of the patients was 67.3 years (STD 10.9) with a statistically significant difference between groups (p < 0.0001); Using multiple comparison testing, women with EC3 were significantly younger than women with CS (p =0.0002), CCC (p = 0.0036) and ESC (p < 0.0001). Of all patients included within the study, 51.8% had LVSI and 18.5% had omental involvement, with a statistically significant difference between histotypes (Table 1). Based on all available data, 51.5% of the

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ACCEPTED MANUSCRIPT patients received adjuvant radiation therapy and 54.8% received adjuvant chemotherapy; 74.5% of

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patients had received at least one treatment modality.

Using pairwise analysis, we identified that omental involvement was statistically greater in ESC

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and CS compared to EC3 (Table 1). Pairwise comparison identified that the presence of LVSI in women

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with CS and CCC were statistically different to the other groups, but there was no statistical significance

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in the remaining pairings of LVSI. As an example of the importance of LVSI we can compare stage 1A EC3 and ESC; when LVSI was positive, the rate of recurrences were not significantly different between

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groups. On the other hand, when LVSI was negative, ESC had a significantly higher rate of recurrence

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(21.3% vs 4.5%. p = 0.0001).

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In patients who underwent surgical staging (Table 2) 50.4% were stage 1 or 2 and 49.6% of

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patients were stage 3 or 4. Stage distribution differed among the histotypes. 54.6% of women with EC3 were stage 1 compared to 34.7%, 36.8% and 32.8% for ESC, CCC and CS respectively.

The median follow up for the study was 34 months. Thirty eight percent of study patients died. OS was statistically different between histotypes (p< 0.0001)(Figure 1A and 1B). In a subgroup analysis, including the comparative removal of the EC3 and other histotypes, there remained a statistically significant difference in survival between ESC, CCC and CS (p=0.0018), with CS having the worst outcome. OS was significantly different between final stages (p<0.0001). Median OS for all histologic subtypes were 118 months for stage 1A disease, 95 months for stage 1B, 82 months for stage 2, 42 months for stages 3A and 3B, 39 months for stage 3C and 20 months for stage 4. The RFS for this same cohort was: not reached within the follow-up time for stage 1A, 95 months for stage 1B, 54 months for stage 2, 22 months for stages 3A and 3B, 21 months for stage 3C and 13 months for stage 4 (p<0.0001).

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Table 3 identifies the statistical differences in 5 year OS rates between the histotypes for stages 3A/B and Stage 4. The 5 year OS for stage 1A EC3 was 91% compared to 87%,95% and 80% for ESC, CCC

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and CS respectively. Eighty two percent of women with stage 1B EC3 were alive at 5 years compared to

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63% with ESC, 50% CCC and 72% CS. These differences were not significantly different in the staged

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cohort alone, however in the entire cohort did reach statistical significance (p = 0.0485). Sixty eight percent of women with stage 3A/B EC3 were alive at 5 years compared to 49%, 20% and 12% for ESC,

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CCC and CS respectively (p<0.0001). Fifty percent of women with Stage 3C EC3 were alive at 5 years compared to 35%, 31% and 27% for ESC, CCC and CS, which was not significantly different. For stage 4

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CS respectively (p = 0.0014).

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disease 33% of women with EC3 were alive at 5 years compared to 12%, 11% and 13% for ESC, CCC and

The RFS was also statistically different based on histologic type (p<0.0001) (Figure 2A and 2B). Overall in our entire population, 31.5% of patients had a recurrence; when subdivided by histologic group, 19.4% of EC3, 37.9% of ESC, 37.4% of CCC, 41.5% of CS recurred. Among all patients: 16.8% of stage 1, 32.1% of stage 2, 46.5% of stage 3 and 56.3% of stage 4 recurred (Table 4). Recurrence in stage 1 disease was varied among the histotypes. There was a 8.1% and 14.8% recurrence rate for women with EC3 stage 1A and 1B respectively compared to 19.5% and 34.2% in women with ESC stage 1A and 1B respectively. High recurrence rates were also identified for CCC and CS stage 1B (20% and 30.3% respectively).

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ACCEPTED MANUSCRIPT Variations in the location of recurrences were also identified. Vault recurrences were documented in 9% of the entire patient population, and pelvic recurrence were noted in 15.4% of the

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entire population (Appendix 2). Distant recurrences were the most common at 26.1% of the population, and were the most common site of recurrence in all subtypes: 16.4% EC3, 31% ESC, 35.2% CCC, 29.6%

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CS. CS and SC had a higher distant recurrence rates compared toEC3 (29.6% and 35.2% compared to to

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16.4%, p = 0.0002, p = 0.0003).

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Discussion:

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There are approximately 50,000 new cases of endometrial cancer diagnosed per year in North

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America, making it the most common gynecologic malignancy. High risk endometrial cancers including ESC, CCC, EC3 and others, have a greater likelihood of metastatic disease, poorer prognosis and distant

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recurrences, causing the majority of deaths in endometrial cancer patients (6,9).

The mean overall age of patients in our study was 67.2 years with a significant difference between histologic types; this is in agreement to other previously published studies (10,30). Our study ages are also very similar to previously published results, supporting the currently available literature (2,10,12,14,24,26,30).

The current literature is mixed in reporting outcome differences for various histotypes of endometrial cancer, however the results of the current study generally complement the outcomes reported by Hamilton et al., the largest database cohort of patients reported to date. The previous study used the SEER database to perform a large retrospective review of women with EC3, CCC and ESC whereas the current study collected data directly from the patients’ charts and had pathology confirmed 11

ACCEPTED MANUSCRIPT by gynecologic pathologists using a more recent cohort of patients. Despite minor difference in stage distribution within ESC and CCC, multiple parallels can be drawn between these two studies, with similar

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ages of onset and overall outcomes by high risk endometrial cancer histotypes, with a better prognosis

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for EC3 reported in both studies(10).

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This multicenter collaborative study provides confirmation of differences in clinical behaviour

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between the major high risk histotypes of endometrial carcinomas with women diagnosed with EC3 having a better prognosis than the other histotypes. OS was statistically different between the various

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high risk histotypes. Women with CS had the worst OS compared to CCC and ESC after excluding EC3 from the analysis. Our study reports similar 5-year OS rate as previously reported in the literature for

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high risk endometrial cancer(2,6,29).

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One of the reported explanations for improved outcomes in women with EC3 is due to stage distribution, with the majority of women with EC presenting with stage 1 disease compared to other hisotypes. The current dataset confirms that women with EC3 are more likely to present with stage 1 disease compared to ESC, CCC and CS (Table 2). When examining survival however, statistical differences were observed among the histotypes for stages 3A/B and 4 (Table 3).

Multiple studies have shown that LVSI, myometrial invasion, lower uterine segment involvement and tumour size are independent poor prognostic factors for high risk endometrial cancers (2,9,11-16). There was a significant rate of LVSI (>50%) and omental disease (18%) in this population. As expected, omental involvement was greater in CS, CCC and ESC, and lower in EC3. These significant rates of omental involvement further support the current practice of omentectomy for all high risk histotypes. An unusual finding within our data, was the different rate of LVSI between subtypes with CCC having a

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ACCEPTED MANUSCRIPT significantly lower rate and CS having a significantly higher rate. EC3 had a surprisingly high rate of LVSI at 50 percent which was similar to ESC. We observed, that LVSI negative patients had a significantly

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better outcome for EC3 at stage IA compared to LVSI positive patients, but that difference was not seen

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with ESC patients.

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In the comprehensively staged group of women, 50.4% presented as early stage disease (stage 1-2)

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and 49.6% as late stage disease (stage 3-4). Previously studies have given wide ranges for stage distribution based on histologic type. For ESC the ranges for stage 1 are 36-54%, stage 2 are 8-12%,

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stage 3 are 18-27% and stage 4 are 8-36% (6,10,11,17,19). For CCC the ranges for stage 1 are 32-73%, stage 2 are 14-26%. stage 3 are 15-34% and stage 4 are 8-18% (10,11,19,26). Finally, for EC3 the ranges

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for stage 1 are 42-78%, stage 2 are 7-15%, stage 3 are 15-28% and stage 4 are 4-22% (5,10-12,18,19,26).

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Our results are generally comparable to the literature, with several notations. In this cohort we found

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lower rates of early stage ESC and CCC compared to stage 3, and was likely related to stage migration with the identification of occult stage 3 disease.

Hamilton et. al. (2006) also reviewed survival of ESC, CCC and EC3 patients with better survival for both early and late stage disease compared to our study. Creasman et. al. (2004) examined stage 1 disease high risk cancers and showed a worse prognosis for stage 1C ESC (FIGC stage 1B 2009) and similar 5 year survival rates compared with our results; contrary to the Creasman study, we had slightly lower rates of stage 1 disease. Finally, our results show a worse survival for CS which supports currently published literature (27,28). Previous large studies have excluded CS due to their poor prognosis and high recurrence rates.

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ACCEPTED MANUSCRIPT The recurrence rate was high with over one third of women developing a distant or local recurrence However, distant recurrence was the most common site, occurring within 22.5% of women. Though

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distant recurrence was least common in women with EC it was still the most common site in this population. In addition, EC3 patients also had the lowest rates of vault and pelvic recurrences at 4.3%

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and 7.4% respectively. This contradicts the common misconception that EC3 is more likely to recur in

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the pelvis and “other” high grade tumours are more likely to recur in distant sites. Our study also reports

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the high rate of recurrence in women with stage 1 with over 20 percent of women with ESC and CS

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recurring, highlighting the need for effective adjuvant treatments for these cancer types.

Our data support high risk histotypes differ in their clinical behaviour. But it is noteworthy that

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although all pathology was required to be reviewed by a subspecialty gynecologic pathologist, even

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expert pathologists show only a modest inter-observer agreement for assigning histotype (31,32). These

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data show the limitation of current prognostic models. With the expanding knowledge on the molecular basis of these tumors, molecular prognostic markers such as POLE mutation status may be incorporated into current classification schemas to improve risk prediction (33,34).

One of the limitations of this study is the inherent problems with accurate collection of data in a retrospective study. Though data collection was standardized, in an attempt to minimize this problem, reporting bias likely still occurred. There was also no clear indications for adjuvant treatment available in the charts and there were limited data on patient co-morbidities that may have impacted OS. The study population is also heterogeneous and the ethnicity of study participants was not determined or recorded. The ethnic diversity within Canada however, should be noted, in order to better determine the generalizability of the study results. According to Statistics Canada, in the 2011 National Household Survey, 19.1% of the population is a visible minority with a composition of: 4.8% South Asian, 4.0%

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ACCEPTED MANUSCRIPT Chinese, 2.9% Black, 1.9% Filipino, 1.2% Latin American, 1.2% Arab and 2.3% Asian other origin (Southeast Asian, West Asian, Korean, Japanese). The majority of the population identifies themselves

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as Christian (67.3%), with other religions forming small minorities: Buddist 1.1%, Hindu 1.5%, Jewish

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1.0%, Muslim 3.2% and Sikh 1.4% (35).

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Our study is the largest recent retrospective collection of high risk endometrial cancers directly from

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hospital and patient charts, with collaboration between 7 of 18 tertiary care centres across Canada. This study also established a pan-Canadian, multi-centered, repository of “high risk” endometrial cancers,

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and hopes to create one of the largest collections of high risk endometrial cancers to date. The data confirms the poorer outcome in ESC, CCC and CS compared to EC3, and the impact of LVSI and omental

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involvement. It also highlights that not all histotypes behave in the same manner, and caution should be

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taken when grouping them together in therapeutic trials for this patient population. Finally, this is the

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first study to have done an in depth analysis of clinical behavior, creating clinical reference tables for physicians for distribution, overall survival and recurrence rate divided by stage.

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Conflict of interest:

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The authors have no conflict of interest to disclose

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(20) Vandenput I, Trovik J, Vergote I, Moerman P, Leunen K, Berteloot P, et al. The role of adjuvant

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chemotherapy in surgical stages I-II serous and clear cell carcinomas and carcinosarcoma of the endometrium: a collaborative study. Int J Gynecol Cancer 2011 Feb;21(2):332-336.

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(21) Halperin R, Zehavi S, Langer R, Hadas E, Bukovsky I, Schneider D. Uterine papillary serous carcinoma (pure and mixed type) compared with moderately and poorly differentiated endometrioid carcinoma. A

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clinicopathologic study. Eur J Gynaecol Oncol 2002;23(4):300-304.

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(22) Soslow RA, Bissonnette JP, Wilton A, Ferguson SE, Alektiar KM, Duska LR, et al. Clinicopathologic

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analysis of 187 high-grade endometrial carcinomas of different histologic subtypes: similar outcomes belie distinctive biologic differences. Am J Surg Pathol 2007 Jul;31(7):979-987. (23) Hendrickson M, Ross J, Eifel P, Martinez A, Kempson R. Uterine papillary serous carcinoma: a highly malignant form of endometrial adenocarcinoma. Am J Surg Pathol 1982 Mar;6(2):93-108. (24) Kwon JS, Abrams J, Sugimoto A, Carey MS. Is adjuvant therapy necessary for stage IA and IB uterine papillary serous carcinoma and clear cell carcinoma after surgical staging? Int J Gynecol Cancer 2008 JulAug;18(4):820-824. (25) McMeekin DS, Filiaci VL, Thigpen JT, Gallion HH, Fleming GF, Rodgers WH, et al. The relationship between histology and outcome in advanced and recurrent endometrial cancer patients participating in first-line chemotherapy trials: a Gynecologic Oncology Group study. Gynecol Oncol 2007 Jul;106(1):1622.

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Radiat Oncol Biol Phys 2003 Apr 1;55(5):1272-1276. (27) Desai NB, Kollmeier MA, Makker V, Levine DA, Abu-Rustum NR, Alektiar KM. Comparison of

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outcomes in early stage uterine carcinosarcoma and uterine serous carcinoma. Gynecol Oncol 2014 Jul

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(28) Amant F, Cadron I, Fuso L, Berteloot P, de Jonge E, Jacomen G, et al. Endometrial carcinosarcomas have a different prognosis and pattern of spread compared to high-risk epithelial endometrial cancer.

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Gynecol Oncol 2005 Aug;98(2):274-280.

(29) Scarfone G, Secomandi R, Parazzini F, Vigano R, Mangili G, Frigerio L, et al. Clear cell and papillary

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Feb;287(2):351-356.

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serous endometrial carcinomas: survival in a series of 128 cases. Arch Gynecol Obstet 2013

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(30) Foerster R, Kluck R, Rief H, Rieken S, Debus J, Lindel K. Survival of women with clear cell and papillary serous endometrial cancer after adjuvant radiotherapy. Radiat Oncol 2014 Jun 18;9(1):141. (31) Hoang LN, McConechy MK, Kobel M, Han G, Rouzbahman M, Davidson B, et al. Histotype-genotype correlation in 36 high-grade endometrial carcinomas. Am J Surg Pathol 2013 Sep;37(9):1421-1432. (32) Han G, Sidhu D, Duggan MA, Arseneau J, Cesari M, Clement PB, et al. Reproducibility of histological cell type in high-grade endometrial carcinoma. Mod Pathol 2013 Dec;26(12):1594-1604. (33) Meng B, Hoang LN, McIntyre JB, Duggan MA, Nelson GS, Lee CH, et al. POLE exonuclease domain mutation predicts long progression-free survival in grade 3 endometrioid carcinoma of the endometrium. Gynecol Oncol 2014 Jul;134(1):15-19. (34) Church DN, Stelloo E, Nout RA, Valtcheva N, Depreeuw J, ter Haar N, et al. Prognostic significance of POLE proofreading mutations in endometrial cancer. J Natl Cancer Inst 2014 Dec 12;107(1):402.

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Government of Canada; Statistics Canada; 2011 National Household Survey report. 2011

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Table 1: Risk of Lymphovascular space invasion (LVSI), omental involvement and age distribution, based on histologic histotype (Grade 3 endometrioid adenocarcinoma-EC3; Endometrial serous carcinoma-ESC;

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Clear cell carcinoma-CCC; Carcinosarcoma-CS)

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Table 2: Stage distribution of staged patients within the study (N=1002) using FIGO 2009 classification.

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Grade 3 Endometrioid adenocarcinoma (EC3), Endometrial serous carcinoma (ESC), Clear cell carcinoma (CCC) and Carcinosarcoma (CS). Missing data on 11 cases.

Table 3: 5 year overall survival rates in all completely staged patients. Grade 3 Endometrioid adenocarcinoma (EC3), Endometrial serous carcinoma (ESC), Clear cell carcinoma (CCC) and Carcinosarcoma (CS); results reported as percentage with 95% CI

Table 4: Number and proportion of patient recurrences at a particular stage, divided by histologic type. Each cell represents the number of recurrences in reference to the total number of patients for theat

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carcinoma (CCC) and Carcinosarcoma (CS)

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Figure 1A: Overall survival stratified by final histotype (Complete data)

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Figure 1B: Overall survival stratified by final histotype (for appropriately staged only)

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Figure 2A: Incidence of recurrence stratified by final histotype (Complete data)

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Figure 2B: Incidence of recurrence stratified by final histotype (appropriately staged patients only)

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Figure 2A

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CS 140 (62%) 30 (22.2%) 68.4 (11)

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CCC 32 (36.8%) 8 (19.1%) 68.9 (10.5)

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ESC 220 (50.2%) 72 (22.2%) 68.7 (9.6)

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LVI (%) Omentum (%) Age mean (STD)

EC3 197 (50.5%) 14 (9.1%) 64.7 (11.8)

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Table 1: Risk of Lymphovascular space invasion (LVSI), omental involvement and age distribution, based on histologic histotype (Grade 3 endometrioid adenocarcinoma-EC3; Endometrial serous carcinoma-ESC; Clear cell carcinoma-CCC; Carcinosarcoma-CS)

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P-value 0.0005 0.0047 <0.0001

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All

EC3

ESC

CCC

All

1002

319

366

68

1

420 (41.8%)

174 (54.6%)

127 (34.7%)

25 (36.8%)

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288 (28.7%) 132 (13.2%)

111 (34.8%) 63 (19.8%)

98 (26.8%) 29 (7.9%)

19 (27.9%) 6 (8.8%)

40 (22.6%) 18 (10.2%)

86 (8.6%) 340 (33.9%)

28 (8.8%) 93 (29.2%)

33 (9.0%) 123 (33.6%)

7 (10.3%) 24 (35.3%)

12 (6.8%) 72 (40.7%)

156 (15.6%) 184 (18.3%)

39 (12.2%) 54 (16.9%)

57 (15.6%) 66 (18.0%)

10 (14.7%) 14 (20.6%)

36 (20.3%) 36 (20.3%)

158 (15.7%)

24 (7.5%)

83 (22.7%)

12 (17.7%)

35 (19.8%)

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Table 2: Stage distribution of staged patients within the study (N=1002) using FIGO 2009 classification. Grade 3 Endometrioid adenocarcinoma (EC3), Endometrial serous carcinoma (ESC), Clear cell carcinoma (CCC) and Carcinosarcoma (CS). Missing data on 11 cases.

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3C 4

87.3% (75.8-93.5) 62.7% (38.4-79.6) 59.4% (36.8-76.2) 49.0% (32.9-63.3) 35.1% (20.5-50.0) 12.1% (5.1-22.2)

94.7% (68.1-99.2) 50.0% (0.6-91.0) 62.5% (14.2-89.3) 20.0% (1.4-54.7) 31.2% (9.7-55.9) 11.4% (0.7-38.9)

79.6% (59.1-90.5) 71.6% (39.8-88.6) 54.6% (22.9-78.0) 11.9% (3.3-26.5) 27.0% (9.7-47.9) 13.3% (4.1-27.7)

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90.6% (80.6-95.6) 82.4% (68.4-90.6) 67.7% (42.8-83.5) 68.3% (48.8-81.7) 50.0% (34.2-63.9) 32.6% (14.6-52.0)

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0.1120 0.5742

<0.0001 0.5581 0.0014

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EC3

ESC

CCC

CS

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103 (16.8%)

25 (10.6 %)

43 (22.6%)

7 (17.1%)

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63 (14.9%) 40 (21.2%)

12 (8.1%) 13 (14.8%)

29 (19.5%) 14 (34.2%)

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24 (24.5%)

5 (16.1%) 2 (20.0%)

14 (21.5%) 10 (30.3%)

42 (32.1%) 158 (46.5%)

9 (22.5%) 31 (33.3%)

19 (39.6%) 59 (48.0%)

5 (38.5%) 13 (54.2%)

8 (34.8%) 43 (59.7%)

69 (44.2%) 89 (48.4%)

9 (23.1%) 22 (40.7%)

28 (49.1%) 31 (47.0%)

8 (80.0%) 5 (35.7%)

21 (58.3%) 22 (61.1%)

89 (56.3%)

12 (50.0%)

49 (59.0%)

9 (75.0%)

18 (51.4%)

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Table 4: Number and proportion of patient recurrences at a particular stage, divided by histologic type. Each cell represents the number of recurrences in reference to the total number of patients for theat stage. Grade 3 Endometrioid adenocarcinoma (EC3), Endometrial serous carcinoma (ESC), Clear cell carcinoma (CCC) and Carcinosarcoma (CS)

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Lymphovascular invasion and omental involvement varies by histotype

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Location of recurrence and stage distribution varies by histotype

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