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The amount of preoperative endometrial tissue surface in relation to final endometrial cancer classification

Open AccessPublished:September 09, 2022DOI:https://doi.org/10.1016/j.ygyno.2022.08.016

      Highlights

      • Obtaining higher amount of preoperative endometrial tissue does not increase correct final EC classification.
      • No significant difference was found between the diagnostic sampling methods and the correct final EC classification.
      • Patients with concordant low-grade EC had a significant superior DSS compared to patients that were downgraded.
      • Patients with concordant high-grade EC had a significant impaired DSS compared to patients that were upgraded.

      Abstract

      Objective

      To evaluate whether the amount of preoperative endometrial tissue surface is related to the degree of concordance with final low- and high-grade endometrial cancer (EC). In addition, to determine whether discordance is influenced by sampling method and impacts outcome.

      Methods

      A retrospective cohort study within the European Network for Individualized Treatment of Endometrial Cancer (ENITEC). Surface of preoperative endometrial tissue samples was digitally calculated using ImageJ. Tumor samples were classified into low-grade (grade 1–2 endometrioid EC (EEC)) and high-grade (grade 3 EEC + non-endometroid EC).

      Results

      The study cohort included 573 tumor samples. Overall concordance between pre- and postoperative diagnosis was 60.0%, and 88.8% when classified into low- and high-grade EC. Upgrading (preoperative low-grade, postoperative high-grade EC) was found in 7.8% and downgrading (preoperative high-grade, postoperative low-grade EC) in 26.7%. The median endometrial tissue surface was significantly lower in concordant diagnoses when compared to discordant diagnoses, respectively 18.7 mm2 and 23.5 mm2 (P = 0.022). Sampling method did not influence the concordance in tumor classification. Patients with preoperative high-grade and postoperative low-grade showed significant lower DSS compared to patients with concordant low-grade EC (P = 0.039).

      Conclusion

      The amount of preoperative endometrial tissue surface was inversely related to the degree of concordance with final tumor low- and high-grade. Obtaining higher amount of preoperative endometrial tissue surface does not increase the concordance between pre- and postoperative low- and high-grade diagnosis in EC. Awareness of clinically relevant down- and upgrading is crucial to reduce subsequent over- or undertreatment with impact on outcome.

      Keywords

      1. Introduction

      Endometrial cancer (EC) is the most common gynecological malignancy in industrialized developed countries with an increasing incidence [
      • Siegel R.L.
      • Miller K.D.
      • Jemal A.
      Cancer statistics, 2018.
      ,
      • Ferlay J.
      • Colombet M.
      • Soerjomataram I.
      • Dyba T.
      • Randi G.
      • Bettio M.
      • et al.
      Cancer incidence and mortality patterns in Europe: estimates for 40 countries and 25 major cancers in 2018.
      ,
      • Morice P.
      • Leary A.
      • Creutzberg C.
      • Abu-Rustum N.
      • Darai E.
      Endometrial cancer.
      ]. These carcinomas are histopathological classified as either endometrioid endometrial cancer (EEC) or non-endometrioid endometrial cancer (NEEC) [
      • Matias-Guiu X.
      • Prat J.
      Molecular pathology of endometrial carcinoma.
      ]. Primary surgical treatment for EC consist of hysterectomy and bilateral salpingo-oophorectomy [
      • Bokhman J.V.
      Two pathogenetic types of endometrial carcinoma.
      ,
      • Colombo N.
      • Creutzberg C.
      • Amant F.
      • Bosse T.
      • Gonzalez-Martin A.
      • Ledermann J.
      • et al.
      ESMO-ESGO-ESTRO consensus conference on endometrial Cancer: diagnosis, treatment and follow-up.
      ]. Additional lymph node surgery, i.e. sentinel lymph node mapping, lymph node dissection or algorithm-based approach for staging, is recommended in patients with increased risk of lymph node metastasis (LNM) [
      • Creasman W.T.
      • Ali S.
      • Mutch D.G.
      • Zaino R.J.
      • Powell M.A.
      • Mannel R.S.
      • et al.
      Surgical-pathological findings in type 1 and 2 endometrial cancer: an NRG oncology/gynecologic oncology group study on GOG-210 protocol.
      ,
      • Hamilton C.A.
      • Pothuri B.
      • Arend R.C.
      • Backes F.J.
      • Gehrig P.A.
      • Soliman P.T.
      • et al.
      Endometrial cancer: a society of gynecologic oncology evidence-based review and recommendations.
      ]. The recent ESGO-ESTRO-ESP guideline recommended a modified binary FIGO grading considering both grade 1 and 2 EC together as low-grade EC and grade 3 EC and NEEC as high-grade EC [
      • Concin N.
      • Matias-Guiu X.
      • Vergote I.
      • Cibula D.
      • Mirza M.R.
      • Marnitz S.
      • et al.
      ESGO/ESTRO/ESP guidelines for the management of patients with endometrial carcinoma.
      ]. Most patients are diagnosed with low-grade EC, and generally have a favorable prognosis with a 5-year survival rate of 85.6% [
      • Bokhman J.V.
      Two pathogenetic types of endometrial carcinoma.
      ]. About 20.0% of the patients are diagnosed with high-grade EC, have an overall poor prognosis with a 5-year survival rate of 58.8% and are associated with increased risk of regional or distant metastases [
      • Bokhman J.V.
      Two pathogenetic types of endometrial carcinoma.
      ,
      • Morice P.
      • Leary A.
      • Creutzberg C.
      • Abu-Rustum N.
      • Darai E.
      Endometrial cancer.
      ].
      A meta-analysis has shown only moderate concordance of 67.0% between pre- and postoperative tumor grading [
      • Visser N.C.M.
      • Reijnen C.
      • Massuger L.
      • Nagtegaal I.D.
      • Bulten J.
      • Pijnenborg J.M.A.
      Accuracy of endometrial sampling in endometrial carcinoma: a systematic review and Meta-analysis.
      ]. The lowest concordance was found for grade 2 EC (61.0%), and as these are generally classified as low-grade, disagreement in grading might impact treatment and outcome since performance of lymph node surgery is generally performed in high-grade EC only [
      • Concin N.
      • Matias-Guiu X.
      • Vergote I.
      • Cibula D.
      • Mirza M.R.
      • Marnitz S.
      • et al.
      ESGO/ESTRO/ESP guidelines for the management of patients with endometrial carcinoma.
      ,
      • Eggink F.A.
      • Mom C.H.
      • Bouwman K.
      • Boll D.
      • Becker J.H.
      • Creutzberg C.L.
      • et al.
      Less-favourable prognosis for low-risk endometrial cancer patients with a discordant pre- versus post-operative risk stratification.
      ,
      • Werner H.M.
      • Trovik J.
      • Marcickiewicz J.
      • Tingulstad S.
      • Staff A.C.
      • Engh M.E.
      • et al.
      A discordant histological risk classification in preoperative and operative biopsy in endometrial cancer is reflected in metastatic risk and prognosis.
      ]. Explanations for discordance on grade include 1) sampling errors leading to missed tumor components, 2) interobserver disagreement due to subjective interpretation of the defined criteria and 3) limited amount of tissue obtained by preoperative endometrial sampling, that might impair assessment of tumor characteristics. In 13–30% of the pipelle endometrial samples, insufficient material requires repeated biopsy for a reliable diagnosis, as in 7.3% of the failed samples women are subsequently diagnosed with EC [
      • Reijnen C.
      • Visser N.C.M.
      • Bulten J.
      • Massuger L.
      • van der Putten L.J.M.
      • Pijnenborg J.M.A.
      Diagnostic accuracy of endometrial biopsy in relation to the amount of tissue.
      ,
      • van der Putten L.J.
      • Visser N.C.
      • van de Vijver K.
      • Santacana M.
      • Bronsert P.
      • Bulten J.
      • et al.
      L1CAM expression in endometrial carcinomas: an ENITEC collaboration study.
      ,
      • Lax S.F.
      Pathology of endometrial carcinoma.
      ,
      • Murali R.
      • Davidson B.
      • Fadare O.
      • Carlson J.A.
      • Crum C.P.
      • Gilks C.B.
      • et al.
      High-grade endometrial carcinomas: morphologic and Immunohistochemical features, diagnostic challenges and recommendations.
      ]. Interestingly, Visser et al. showed that hysteroscopic biopsies had a higher concordance (89%) compared to samples obtained by dilatation and curettage (D&C) (70%), questioning whether in addition to the amount of tissue, the sampling method may also be relevant [
      • Visser N.C.M.
      • Reijnen C.
      • Massuger L.
      • Nagtegaal I.D.
      • Bulten J.
      • Pijnenborg J.M.A.
      Accuracy of endometrial sampling in endometrial carcinoma: a systematic review and Meta-analysis.
      ].
      In a previous study of our research group, we showed that the amount of endometrial tissue surface to classify an endometrial sample as conclusive with high diagnostic accuracy as malignant or non-malignant, was defined by a minimum cut-off level of 35 mm2 [
      • Visser N.C.M.
      • Reijnen C.
      • Massuger L.
      • Nagtegaal I.D.
      • Bulten J.
      • Pijnenborg J.M.A.
      Accuracy of endometrial sampling in endometrial carcinoma: a systematic review and Meta-analysis.
      ,
      • Reijnen C.
      • Visser N.C.M.
      • Bulten J.
      • Massuger L.
      • van der Putten L.J.M.
      • Pijnenborg J.M.A.
      Diagnostic accuracy of endometrial biopsy in relation to the amount of tissue.
      ]. However, this study was not designed to further specify the diagnosis on tumor grade and/or histological subtype. Therefore, in the present study, we aim to evaluate the amount of preoperative endometrial tissue surface in relation to the degree of concordance with final low- and high-grade EC. Furthermore, we investigate whether discordancy in pre- and postoperative grading is influenced by the sampling method and whether discordancy impacts outcome.

      2. Methods

      2.1 Patients

      The samples of patients were retrospectively collected within the European Network for Individualized Treatment of Endometrial Cancer (ENITEC) from a previous study including 1199 EC patients [
      • van der Putten L.J.
      • Visser N.C.
      • van de Vijver K.
      • Santacana M.
      • Bronsert P.
      • Bulten J.
      • et al.
      L1CAM expression in endometrial carcinomas: an ENITEC collaboration study.
      ]. Patients were only included when they were diagnosed by an expert gynecological pathologist of the participating hospitals, with complete data on treatment and histopathology. Clinical and pathological data were recorded from the patient files into a database; including patient age, date of diagnosis, preoperative sampling method, surgical treatment, original pre- and postoperative tumor grade and histological subtype, myometrial invasion (MI), cervical invasion (CI), lymphovascular space invasion (LVSI), FIGO (International Federation of Gynaecology and Obstetrics) stage, adjuvant treatment, recurrent disease and death [
      • van der Putten L.J.
      • Visser N.C.
      • van de Vijver K.
      • Santacana M.
      • Bronsert P.
      • Bulten J.
      • et al.
      L1CAM expression in endometrial carcinomas: an ENITEC collaboration study.
      ]. The sole additional inclusion criterion used for this study was the availability of preoperative EC tissue samples, resulting in 644 patients.

      2.2 Tumor classification

      In addition to the FIGO three-tiered tumor grade, EC tissue samples were classified into low- and high-grade EC as recommended by the recent ESGO-ESTRO-ESP guideline and the World health organization (WHO) classification of tumors [
      • Concin N.
      • Matias-Guiu X.
      • Vergote I.
      • Cibula D.
      • Mirza M.R.
      • Marnitz S.
      • et al.
      ESGO/ESTRO/ESP guidelines for the management of patients with endometrial carcinoma.
      ,
      ]. Low-grade EC was defined as grade 1 and 2 EEC, and included samples with mucinous histology as well since prognosis and molecular characterization are similar to low-grade EECs [
      • van der Putten L.J.
      • Visser N.C.
      • van de Vijver K.
      • Santacana M.
      • Bronsert P.
      • Bulten J.
      • et al.
      L1CAM expression in endometrial carcinomas: an ENITEC collaboration study.
      ]. High-grade EC included grade 3 EEC and NEEC, i.e. serous, clear cell carcinoma, carcinosarcoma and mixed carcinomas [
      • Concin N.
      • Matias-Guiu X.
      • Vergote I.
      • Cibula D.
      • Mirza M.R.
      • Marnitz S.
      • et al.
      ESGO/ESTRO/ESP guidelines for the management of patients with endometrial carcinoma.
      ,
      ]. Endometrial tissue samples were defined as upgraded if the preoperative sample was low-grade and postoperative high-grade EC. Downgraded was defined as preoperative high-grade and postoperative low-grade EC. Biopsies initially diagnosed as premalignant, but EC on final hysterectomy specimen were included in this study.

      2.3 Scoring

      All the preoperative endometrial sampling slides were digitalized using Pannoramic Scanner 250 Flash III (3DHISTECH, Budapest, Hungary). As described previously by Reijnen et al., images were saved as a JPEG-compressed file and the area of endometrial tissue was digitally calculated using ImageJ software, selecting only benign, premalignant and malignant endometrial epithelium (Supplementary Fig. S1) [
      ]. Thresholds 24-bit RGB images based on Hue Saturation and Brightness (HSB) were used to select the endometrial tissue surface, by adjusting the different threshold values to segment the image into the area of interest and the background. The Pannoramic Viewer software was used to examine the original-size digital slide in order to ensure ImageJ correctly selected the proper tissue. Subsequently, analysis was performed on the area selection to count and measure pixels in the threshold images and calculate the total area of endometrial tissue. A set of 50 slides were scored independently by two investigators (AH, CR) to assess the degree of inter-rater variability and intraclass correlation coefficient (ICC). A set of 90 slides were double-checked by a third investigator (SV) to ensure ImageJ selected the proper tissue.

      2.4 Statistical analysis

      All statistical analyses were performed using IBM Statistical Package for the Social Sciences (SPSS) statistics for Windows, version 25.0 (released 2017, Armonk, NY, United States) and P < 0.05 was considered statistically significant. For observing within the low- and high-grade classification, the pre- and postoperative tumor diagnosis was specified in individual FIGO tumor grade and histological subtype. These included the original diagnosis (including premalignant tissue); grade 1, grade 2, grade 3 EEC or NEEC. For continuous data that were not normally distributed, the Mann-Whitney U and Kruskal Wallis test were used to compare the differences in median endometrial tissue surface and patient characteristics. Clinicopathological characteristics between dichotomous subgroups were compared using the χ2 or Fisher's exact test for categorical data. Survival analyses were performed using the Kaplan Meier curves (first 10 years after diagnosis). Disease-specific survival (DSS) was defined as time from date of diagnosis to date of death from EC, all censored by date of last contact.

      2.5 Ethics approval

      Ethical approval was obtained from the Institutional Review Board (IRB) CMO Radboudumc (number: 2018–4955).

      3. Results

      3.1 Patients

      From the original cohort of 1199 patients, 644 preoperative biopsies were available, of those 46 patients were excluded because absence of tumor tissue due to insufficient amount of tissue and benign endometrium and 25 because of an unspecified grade on preoperative biopsy, resulting in a total of 573 patients included in this study with a median follow-up of 5.7 years (Supplementary Fig. S2). Excluded patients did not significantly differ from included patients with respect to tumor histology (data not shown). Baseline characteristics for all included patients, classified into postoperative low- and high-grade, are summarized in Table 1. Among these 573 patients, 462 patients (80.6%) were postoperative low-grade and 111 (19.4%) high-grade EC. The mean age at diagnosis was 64.8 years, most patients were preoperative diagnosed with grade 1 EEC (53.8%) and postoperative FIGO stage I (82.9%). The most used preoperative sampling method was the pipelle (45.2%). Patients diagnosed with postoperative high-grade EC were significantly older, had lower Body Mass Index (BMI), more often LNM, subsequently resulting in more applied adjuvant chemotherapy and chemoradiotherapy compared to patients with low-grade EC.
      In Supplementary Table S1 detailed baseline information about patients diagnosed with postoperative NEEC (n = 34) is shown. Most patients with NEEC had serous histology (n = 14, 41.2%).

      3.2 Concordance pre- and postoperative tumor grade and histology

      Fig. 1 shows the number and percentages of the pre- vs. postoperative individual tumor grade and histological subtype. Dark green shows the exact concordance between grading and histology, light green the concordance for the clinically relevant low- and high-grade classification and in red the clinically relevant discordancy. Overall, of the 573 EC tissue samples, 60.0% (n = 345) showed concordant pre- and postoperative tumor grade and histological subtype (dark green). The lowest concordance was found for preoperative grade 3 EC (51.4%).
      Table 1Baseline characteristics.
      Total (n = 573)Postoperative Low-grade (n = 462)Postoperative High-grade (n = 111)P
      Age (years)64.8 ± 9.864.1 ± 9.666.6 ± 10.00.014*
      BMI (kg/m2)30.2 ± 6.730.4 ± 6.528.7 ± 5.50.013*
      Preoperative grade
       Premalignant
      Including simple or complex hyperplasia, with or without atypia.
      8 (1.4)8 (1.7)0 (0.0)<0.001*
       1 EEC308 (53.8)295 (63.9)13 (11.7)
       2 EEC156 (27.2)132 (28.6)24 (21.6)
       3 EEC74 (12.9)22 (4.8)52 (46.8)
       NEEC27 (4.7)5 (1.1)22 (19.8)
      Preoperative sampling method
       Pipelle259 (45.2)199 (43.1)60 (54.1)0.002*
       D&C77 (13.4)63 (13.6)14 (12.6)
       Hysteroscopic biopsy213 (37.2)189 (40.9)24 (21.6)
       Not specified24 (4.2)11 (2.4)13 (11.7)
      FIGO stage
       I475 (82.9)413 (89.4)62 (55.9)<0.001*
       II36 (6.3)24 (5.2)12 (10.8)
       III45 (7.9)22 (4.8)23 (20.7)
       IV17 (2.9)3 (0.6)14 (12.6)
      Positive nodes
       No299 (52.2)240 (52.0)59 (53.2)<0.001*
       Pelvic17 (3.0)7 (1.5)10 (9.0)
       Para-aortic11 (1.9)2 (0.4)9 (8.1)
       Both5 (0.9)1 (0.2)4 (3.6)
       Not specified241 (42.0)212 (45.9)29 (26.1)
      Adjuvant treatment
       No267 (46.7)238 (51.5)29 (26.1)<0.001*
       Radiotherapy263 (46.0)204 (44.2)59 (53.2)
       Chemotherapy17 (3.0)5 (1.1)12 (10.8)
       Chemoradiotherapy25 (4.4)14 (3.0)11 (9.9)
       Missing1 (0.2)1 (0.2)
      Data is presented in number (%), mean ± standard deviation (SD).
      Abbreviations: EEC, endometrioid endometrial cancer; NEEC, non-endometroid endometrial cancer; BMI, Body Mass Index; FIGO, International Federation of Gynaecology and Obstetrics
      * P < 0.05.
      Including simple or complex hyperplasia, with or without atypia.
      Fig. 1
      Fig. 1Number and percentages (n (%)) of the pre- vs. postoperative individual tumor grade and histological subtype.
      Abbreviations: EEC, endometroid endometrial cancer; NEEC, non-endometroid endometrial cancer.
      Concordance between pre-and postoperative low- and high-grade EC was found in 88.8% (n = 509) patients (light green + dark green). Patients with preoperative low-grade EC showed concordant diagnoses in 92.2% (n = 435) and were upgraded to high-grade EC in 7.8% (n = 37). Patients with preoperative high-grade EC showed concordant diagnoses in 73.3% (n = 74) and were downgraded in 26.7% (n = 27).

      3.3 Median endometrial tissue surface and degree of concordance

      An overview of the median endometrial tissue surface related to pre- vs. postoperative tumor grade and histological subtype is shown in Table 2. There was no significant difference between the median endometrial tissue surface of the individual tumor grade and histological subtype preoperatively, nor postoperatively, (P = 0.063 and P = 0.888, respectively).
      Table 2Overview of pre- vs. postoperative tumor grade and histological subtype. Median endometrial tissue surface (mm2) of endometrial cancer patients are shown. Displayed in dark green are the concordant diagnoses. Dark green shows the exact concordance between grading and histology, light green the concordance for the clinically relevant low- and high-grade classification and in red the clinically relevant discordancy.
      Table thumbnail fx1
      Data is presented in median (range).
      Abbreviations: EEC, endometroid endometrial cancer; NEEC, non-endometroid endometrial cancer.
      P = 0.888 between the total median postoperative endometrial tissue surface.
      ⁎⁎P = 0.063 between the total median preoperative endometrial tissue surface.
      The median endometrial tissue surface between concordant (dark green) and discordant (light green + red) individual tumor grade and histological subtype showed no significant difference (19.6 mm2 vs. 18.6mm2, respectively, P = 0.468). For the clinically relevant low- and high-grade classification, the median endometrial tissue surface for concordant diagnoses (dark green + light green) was significant lower compared to the discordant diagnoses (red) (18.7 mm2 vs. 23.5 mm2, respectively, P = 0.022) (Table 2). In Supplementary Table S2 the correlation between median endometrial tissue and concordant and discordant diagnoses is shown per included center.
      Patients with concordant pre- and postoperative low-grade EC showed lower median endometrial tissue surface compared to preoperative low-grade and postoperative high-grade EC (upgraded), but not significantly (18.4 vs 20.1 mm2, P = 0.335). Patients with concordant pre- and postoperative high-grade EC had significant lower endometrial tissue surface compared to patients with preoperative high-grade and postoperative low-grade EC (downgraded) (20.3 vs 38.6 mm2, P = 0.044) (Fig. 2).
      Fig. 2
      Fig. 2A-B: A. Patients with preoperative low-grade endometrial cancer (EC) and the median endometrial tissue surface for postoperative discordant or concordant diagnoses. B. Patients with preoperative high-grade EC and the median endometrial tissue surface for postoperative discordant or concordant diagnoses.

      3.4 Sampling method

      For 549 (95.8%) patients preoperative sampling method was available. Pipelle endometrial sampling was performed in 47.2%, D&C in 14.0% and hysteroscopic biopsy in 38.8% of the patients with available sampling method (Supplementary Table S3). No significant difference was found between the diagnostic sampling methods and the concordance between pre- and postoperative low- and high-grade EC (P = 0.364), nor for the individual tumor grade and histological subtype (P = 0.097).
      Median endometrial tissue surface for the preoperative sampling method pipelle was 18.6 mm2, D&C 67.8 mm2 and hysteroscopic biopsy 15.4 mm2 (P < 0.001). All preoperative sampling methods (pipelle, D&C, hysteroscopic biopsy) showed higher median endometrial tissue surface in discordant low-and high-grade diagnoses, compared to concordant low- and high-grade diagnoses. Similar was shown for individual tumor grade and histological subtype diagnoses (Supplementary Fig. S3).

      3.5 Concordance, discordance and survival outcome

      The DSS of the concordant and discordant diagnoses are shown in Fig. 3A-C . Fig. 3A showed the DSS of the patients with concordant high-grade EC, concordant low-grade EC, and clinically relevant downgraded and upgraded diagnoses (P < 0.001). Patients with concordant low-grade EC had a significant superior DSS compared to patients that were downgraded (96.5% and 88.9% respectively, P = 0.039) (Fig. 3B). Patients with concordant high-grade EC had a significant impaired DSS compared to patients that were upgraded (71.4% and 88.6% respectively, P = 0.046) (Fig. 3C).
      Fig. 3
      Fig. 3A-C: Kaplan-Meier survival curves of disease-specific survival A. Disease-specific survival of concodant low-grade endometrial cancer (EC), concordant high-grade EC, downgraded and upgraded patients. B. Disease-specific survival of concordant low-grade EC and downgraded patients. C. Disease-specific survival of concordant high-grade EC and upgraded patients.

      4. Discussion

      This study assessed whether the amount of preoperative endometrial tissue surface is related to the degree of concordance with final classification of low- and high-grade EC, and whether discordance is influenced by the diagnostic sampling method and impacts outcome. Overall, 60% showed concordant pre- and postoperative tumor grade and histological subtype and there was 88.8% concordance in pre- and postoperative classification into low- and high-grade EC, with 92.2% concordant low-grade, and 73.3% concordant high-grade EC. The median endometrial tissue surface between concordant and discordant individual tumor grade and histological subtype showed no significant difference. Interestingly, concordant diagnoses revealed a significant lower median endometrial tissue surface compared to discordant diagnoses. Furthermore, the sampling method did not influence the degree of concordance. Finally, patients with preoperative low-grade and postoperative high-grade EC had significant improved DSS compared to patients with concordant high-grade EC.
      Numerous studies stated that preoperative endometrial sampling is poorly correlated with final tumor grade and histological subtype [
      • Eltabbakh G.H.
      • Shamonki J.
      • Mount S.L.
      Surgical stage, final grade, and survival of women with endometrial carcinoma whose preoperative endometrial biopsy shows well-differentiated tumors.
      ,
      • Frumovitz M.
      • Singh D.K.
      • Meyer L.
      • Smith D.H.
      • Wertheim I.
      • Resnik E.
      • et al.
      Predictors of final histology in patients with endometrial cancer.
      ,
      • Thomas S.
      • Hussein Y.
      • Bandyopadhyay S.
      • Cote M.
      • Hassan O.
      • Abdulfatah E.
      • et al.
      Interobserver variability in the diagnosis of uterine high-grade Endometrioid carcinoma.
      ]. On the contrary, Sany et al. mentioned good agreement between preoperative and final pathology with sensitivities of 96.5% for EECs and 86.5% for NEECs [
      • Sany O.
      • Singh K.
      • Jha S.
      Correlation between preoperative endometrial sampling and final endometrial cancer histology.
      ]. Our study findings are in line with Visser et al. who reported an overall moderate concordance of 67% on tumor grade [
      • Visser N.C.M.
      • Reijnen C.
      • Massuger L.
      • Nagtegaal I.D.
      • Bulten J.
      • Pijnenborg J.M.A.
      Accuracy of endometrial sampling in endometrial carcinoma: a systematic review and Meta-analysis.
      ]. Clinically relevant downgrading was reported in 26% of the included patient samples and upgrading in 8% [
      • Visser N.C.M.
      • Reijnen C.
      • Massuger L.
      • Nagtegaal I.D.
      • Bulten J.
      • Pijnenborg J.M.A.
      Accuracy of endometrial sampling in endometrial carcinoma: a systematic review and Meta-analysis.
      ]. Our results show similar clinically relevant downgrading of 26.7% and upgrading in 7.8%. Several studies note that the diagnostic consensuses of tumor grade and histological subtype based on morphology alone are overall moderate. Performing immunohistochemical (IHC) markers on preoperative tissue could help to improve the degree of concordance between pre- and postoperative diagnosis, especially for preoperative grade 2 and grade 3 EC with the lowest concordance [
      • Visser N.C.M.
      • Reijnen C.
      • Massuger L.
      • Nagtegaal I.D.
      • Bulten J.
      • Pijnenborg J.M.A.
      Accuracy of endometrial sampling in endometrial carcinoma: a systematic review and Meta-analysis.
      ,
      • Gilks C.B.
      • Oliva E.
      • Soslow R.A.
      Poor interobserver reproducibility in the diagnosis of high-grade endometrial carcinoma.
      ,
      • Han G.
      • Sidhu D.
      • Duggan M.A.
      • Arseneau J.
      • Cesari M.
      • Clement P.B.
      • et al.
      Reproducibility of histological cell type in high-grade endometrial carcinoma.
      ,
      • Nielsen A.L.
      • Thomsen H.K.
      • Nyholm H.C.
      Evaluation of the reproducibility of the revised 1988 International Federation of Gynecology and Obstetrics grading system of endometrial cancers with special emphasis on nuclear grading.
      ,
      • Visser N.C.M.
      • van der Wurff A.A.M.
      • IntHout J.
      • Reijnen C.
      • Dabir P.D.
      • Soltani G.G.
      • et al.
      Improving preoperative diagnosis in endometrial cancer using systematic morphological assessment and a small immunohistochemical panel.
      ]. For preoperative grade 2, a panel of progesterone (PR) and p53 biomarkers has been recommended, and, for grade 3/high-grade EC additional PR, IMP3 and L1CAM [
      • Visser N.C.M.
      • van der Wurff A.A.M.
      • IntHout J.
      • Reijnen C.
      • Dabir P.D.
      • Soltani G.G.
      • et al.
      Improving preoperative diagnosis in endometrial cancer using systematic morphological assessment and a small immunohistochemical panel.
      ]. Whether combined pathologic and molecular classification might further improve preoperative classification for high-grade EC needs to be determined [
      • Piulats J.M.
      • Guerra E.
      • Gil-Martín M.
      • Roman-Canal B.
      • Gatius S.
      • Sanz-Pamplona R.
      • et al.
      Molecular approaches for classifying endometrial carcinoma.
      ].
      Our study design is comparable to Reijnen et al. in which the diagnostic accuracy of pipelle endometrial sampling and the amount of endometrial tissue surface for benign, premalignant and malignant tissue was quantified [
      • Reijnen C.
      • Visser N.C.M.
      • Bulten J.
      • Massuger L.
      • van der Putten L.J.M.
      • Pijnenborg J.M.A.
      Diagnostic accuracy of endometrial biopsy in relation to the amount of tissue.
      ]. Reijnen et al. found a positive correlation between the amount of endometrial tissue surface and concordance of diagnosis for premalignant and malignant tissue, furthermore he defined a minimum cut-off of 35 mm2 to classify an endometrial sample as conclusive. Interestingly, whereas the amount of tissue seems to be important for classifying tissue as premalignant or malignant, in our study, no positive correlation was found when malignant tissue was classified into tumor grade and histology and we did not found a minimum cut-off for concordant grading (data not shown). An explanation for this contra-intuitive finding could be interobserver agreement, yet, both studies show a high intraclass correlation coefficient (ICC) (0.98 vs. 0.92 in our study) [
      • Reijnen C.
      • Visser N.C.M.
      • Bulten J.
      • Massuger L.
      • van der Putten L.J.M.
      • Pijnenborg J.M.A.
      Diagnostic accuracy of endometrial biopsy in relation to the amount of tissue.
      ]. Another explanation could be sampling bias or a missed tumor component by the pathologist. In our study, three experienced expert gynecological pathologists (JB, HK, KV) performed an explorative analysis in 30 (46.9%) cases with low- vs. high-grade discrepancy. Sampling bias based on heterogeneous and mixed tumors, or only superficial tumor tissue sampling was present in a third of the cases. In two third of the cases the discrepancy was caused by the pathologist, by miscalculation of the percentage solid growth or missed tumor component (data not shown). So, incorrect classification by the pathologist seems to be present, and will remain in the current diagnostic context. This might partially be resolved by molecular profiling in high-grade EEC as demonstrated by Bosse et al., but will not solve the sampling bias [
      • Bosse T.
      • Nout R.A.
      • McAlpine J.N.
      • McConechy M.K.
      • Britton H.
      • Hussein Y.R.
      • et al.
      Molecular classification of grade 3 Endometrioid endometrial cancers identifies distinct prognostic subgroups.
      ].
      The concordance between pre- and postoperative low- and high-grade EC did not significantly differ between the three sampling methods, which is quite comparable to other studies [
      • Visser N.C.M.
      • Reijnen C.
      • Massuger L.
      • Nagtegaal I.D.
      • Bulten J.
      • Pijnenborg J.M.A.
      Accuracy of endometrial sampling in endometrial carcinoma: a systematic review and Meta-analysis.
      ,
      • Demirkiran F.
      • Yavuz E.
      • Erenel H.
      • Bese T.
      • Arvas M.
      • Sanioglu C.
      Which is the best technique for endometrial sampling? Aspiration (pipelle) versus dilatation and curettage (D&C).
      ]. Illustrating, that more tissue provided with D&C or accurate sampling by hysteroscopic biopsy will not automatically result in more concordant diagnoses.
      Accurate preoperative classification of tumor grade and histological subtype is crucial in EC, as this may be directive to the extent of the surgical approach. Consequently, postoperative upgrading will lead to omitted lymph node surgery and/or staging procedure and altered adjuvant therapy, whereas downgrading may result in unnecessarily surgical related complications both impacting clinical outcome [
      • Visser N.C.M.
      • Reijnen C.
      • Massuger L.
      • Nagtegaal I.D.
      • Bulten J.
      • Pijnenborg J.M.A.
      Accuracy of endometrial sampling in endometrial carcinoma: a systematic review and Meta-analysis.
      ]. A significant increase of DSS has been found in patients that were postoperatively upgraded, compared to patients with concordant high-grade EC. Furthermore, patients that were downgraded had significant decreased DSS compared to concordant low-grade EC. Both of our findings are in line with Werner et al. [
      • Werner H.M.
      • Trovik J.
      • Marcickiewicz J.
      • Tingulstad S.
      • Staff A.C.
      • Engh M.E.
      • et al.
      A discordant histological risk classification in preoperative and operative biopsy in endometrial cancer is reflected in metastatic risk and prognosis.
      ], and may be explained by the presence of tumor heterogeneity and/or minor mixed morphologic characteristics [
      • Quddus M.R.
      • Sung C.J.
      • Zhang C.
      • Lawrence W.D.
      Minor serous and clear cell components adversely affect prognosis in “mixed-type” endometrial carcinomas: a clinicopathologic study of 36 stage-I cases.
      ,
      • Octeau D.
      • Abitbol J.
      • Amajoud Z.
      • Laskov I.
      • Ferenczy A.
      • Pelmus M.
      • et al.
      Targeted sequencing of histologically defined serous endometrial cancer reflects prognosis and correlates with preoperative biopsy.
      ].
      To our knowledge, this is the first study that quantified the amount of endometrial tissue surface by computerized measurement, and related this to the degree of concordance with final tumor grade and histological subtype in EC. The computerized assessment of the endometrial tissue surface was performed in a structured and reproducible fashion with a good interobserver agreement (ICC 0.92, 95% CI 0.80–0.97).
      As this was a retrospective study, one limitation could be that there has been no study protocol for the assessment of endometrial tissue. In addition, there might be a selection bias as the original diagnosis and classification of both pre- and postoperative histology was used without centralized pathology review. However, slides were from large referral hospitals and diagnoses were made by expert gynecological-pathologists. The results of this study are therefore applicable to daily practice and, as agreement is in line with previous findings, bias may be therefore considered to be limited. Finally, the small number of patients with serous EC (n = 14, 2.4%) could limit the generalizability for this type of EC. Yet, serous carcinoma represents <10% of all ECs [
      • Gatius S.
      • Matias-Guiu X.
      Practical issues in the diagnosis of serous carcinoma of the endometrium.
      ]. Also, it is known that there is poor interobserver agreement in differentiating serous EC from high-grade EEC based on preoperative histology [
      • Gilks C.B.
      • Oliva E.
      • Soslow R.A.
      Poor interobserver reproducibility in the diagnosis of high-grade endometrial carcinoma.
      ,
      • Han G.
      • Sidhu D.
      • Duggan M.A.
      • Arseneau J.
      • Cesari M.
      • Clement P.B.
      • et al.
      Reproducibility of histological cell type in high-grade endometrial carcinoma.
      ,
      • Goksedef B.P.
      • Akbayir O.
      • Corbacioglu A.
      • Guraslan H.
      • Sencan F.
      • Erol O.
      • et al.
      Comparison of preoperative endometrial biopsy grade and final pathologic diagnosis in patients with endometrioid endometrial cancer.
      ,
      • Hu S.
      • Hinson J.L.
      • Matnani R.
      • Cibull M.L.
      • Karabakhtsian R.G.
      Are the uterine serous carcinomas underdiagnosed? Histomorphologic and immunohistochemical correlates and clinical follow up in high-grade endometrial carcinomas initially diagnosed as high-grade endometrioid carcinoma.
      ,
      • Garg K.
      • Soslow R.A.
      Strategies for distinguishing low-grade endometrioid and serous carcinomas of endometrium.
      ,
      • Darvishian F.
      • Hummer A.J.
      • Thaler H.T.
      • Bhargava R.
      • Linkov I.
      • Asher M.
      • et al.
      Serous endometrial cancers that mimic endometrioid adenocarcinomas: a clinicopathologic and immunohistochemical study of a group of problematic cases.
      ].
      Although several studies support the use of a binary grading system (low- vs. high-grade) over the FIGO grading system with respect to reproducibility, awareness of clinically relevant down- and upgrading remains crucial [
      • Concin N.
      • Matias-Guiu X.
      • Vergote I.
      • Cibula D.
      • Mirza M.R.
      • Marnitz S.
      • et al.
      ESGO/ESTRO/ESP guidelines for the management of patients with endometrial carcinoma.
      ,
      ,
      • Garg K.
      • Soslow R.A.
      Strategies for distinguishing low-grade endometrioid and serous carcinomas of endometrium.
      ,
      • Lax S.F.
      • Kurman R.J.
      • Pizer E.S.
      • Wu L.
      • Ronnett B.M.
      A binary architectural grading system for uterine endometrial endometrioid carcinoma has superior reproducibility compared with FIGO grading and identifies subsets of advance-stage tumors with favorable and unfavorable prognosis.
      ,
      • Taylor R.R.
      • Zeller J.
      • Lieberman R.W.
      • O'Connor D.M.
      An analysis of two versus three grades for endometrial carcinoma.
      ]. Instead of providing more endometrial tissue, the use of a simple and relatively cheap set of IHC markers, such as p53 (reflecting the most aggressive molecular subgroup of the TCGA), ER/PR and L1CAM, could improve the concordance between pre- and postoperative low- and high-grade EC, and pre- and postoperative individual tumor grade and histological subtype [
      • Visser N.C.M.
      • van der Wurff A.A.M.
      • IntHout J.
      • Reijnen C.
      • Dabir P.D.
      • Soltani G.G.
      • et al.
      Improving preoperative diagnosis in endometrial cancer using systematic morphological assessment and a small immunohistochemical panel.
      ,
      • Vrede S.W.
      • van Weelden W.J.
      • Visser N.C.M.
      • Bulten J.
      • van der Putten L.J.M.
      • van de Vijver K.
      • et al.
      Immunohistochemical biomarkers are prognostic relevant in addition to the ESMO-ESGO-ESTRO risk classification in endometrial cancer.
      ]. According to the recent recommendations of the Society of Gynecologic Oncology (SGO), current clinicopathological prognostic parameters (e.g. histology and grade) should guide initial clinical management in EC. Molecular classification, especially TP53 mutations, may help guide future treatment decisions [
      • Hamilton C.A.
      • Pothuri B.
      • Arend R.C.
      • Backes F.J.
      • Gehrig P.A.
      • Soliman P.T.
      • et al.
      Endometrial cancer: a society of gynecologic oncology evidence-based review and recommendations.
      ].
      In conclusion, obtaining a higher amount of preoperative endometrial tissue surface does not increase the concordance between pre- and postoperative low- and high-grade classification in EC. Awareness of clinically relevant down- and upgrading is crucial to reduce subsequent over- or undertreatment with impact on outcome.
      The following are the supplementary data related to this article.
      • Supplementary Fig. S3

        A-D: A. Median endometrial tissue surface (mm2) by preoperative sampling method. B. Median endometrial tissue surface (mm2) for concordant and discordant low- and high-grade diagnosis distributed by sampling method. C. Median endometrial tissue surface (mm2) for concordant and discordant individual tumor grade and histological subtype distributed by sampling method. D. Median endometrial tissue surface (mm2) for preoperative individual tumor grade and histological subtype distributed by sampling method.

      • Supplementary Table S1

        Baseline characteristics of patients diagnosed with postoperative non-endometrioid endometrial cancer (NEEC) histology and divided by the NEEC subgroups.

        Data is presented in number (%) and median (range).

        Abbreviations: NEEC, non-endometroid endometrial cancer; BMI, body mass index; FIGO, International Federation of Gynaecology and Obstetrics. †including simple or complex hyperplasia, with or without atypia

      • Supplementary Table S2

        Median endometrial tissue surface (mm2) for concordant and discordant tumor grade and histological subtype, and low- and high-grade classification per included center.

        Data is presented in median (range).

        Abbreviation: EC, endometrial cancer.

      • Supplementary Table S3

        Patient characteristics versus the preoperative sampling method.

        Data is presented in number (%).

        Abbreviations: EC, endometrial cancer; EEC, endometroid endometrial cancer; NEEC, non-endometroid endometrial cancer; D&C, dilatation & curettage.

        *p < 0.05, †including simple or complex hyperplasia, with or without atypia, †† n = 24 missing sampling method.

      Funding

      This work was not funded.

      CRediT author statement

      S.W. Vrede: Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Visualization, Writing – original draft. A.M.C. Hulsman: Conceptualization, Resources, Formal analysis, Investigation, Visualization, Writing – review & editing. C. Reijnen: Conceptualization, Methodology, Resources, Writing – review & editing. K. Van de Vijver: Conceptualization, Methodology, Resources, Writing – review & editing. E. Colas: Resources. G. Mancebo: Resources. C.P. Moiola: Resources. A. Gil-Moreno: Resources. J. Huvila: Resources. M. Koskas: Resources. V. Weinberger: Resources. L. Minar: Resources. E. Jandakova: Resources. M. Santacana: Resources. X. Matias-Guiu: Resources. F. Amant: Resources, Writing – review & editing. M.P.L.M. Snijders: Resources, Supervision, Writing – review & editing. H.V.N. Küsters-Vandevelde: Conceptualization, Methodology, Resources, Writing – review & editing. J. Bulten: Conceptualization, Methodology, Resources, Supervision, Writing – review & editing. J.M.A. Pijnenborg: Conceptualization, Methodology, Project administration, Resources, Supervision, Writing – review & editing.

      Declaration of Competing Interest

      The authors report no conflict of interest.

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