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Original research
Molecular classification of endometrial carcinoma on endometrial biopsy: an early prognostic value to guide personalized treatment
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  1. Stefano Restaino1,2,
  2. Alice Poli1,3,
  3. Martina Arcieri1,
  4. Laura Mariuzzi3,4,
  5. Maria Orsaria4,
  6. Angelica Tulisso4,
  7. Giulia Pellecchia1,3,
  8. Federico Paparcura1,3,
  9. Marco Petrillo5,
  10. Giorgio Bogani6,
  11. Stefano Cianci7,
  12. Vito Andrea Capozzi8,
  13. Anna Biasioli1,
  14. Alessandro Buda9,
  15. Jessica Mauro9,
  16. Francesco Fanfani10,11,
  17. Anna Fagotti10,11,
  18. Lorenza Driul1,3,
  19. Giovanni Scambia10,11 and
  20. Giuseppe Vizzielli1,3
    1. 1 Clinic of Obstetrics and Gynecology, ‘Santa Maria della Misericordia’ University Hospital, Azienda Sanitaria Universitaria Friuli Centrale, Udine, Italy
    2. 2 School in Biomedical Sciences, Gender Medicine, Child and Women Health, University of Sassari, Sassari, Italy
    3. 3 Department of Medicine, University of Udine, Udine, Italy
    4. 4 Institute of Pathological Anatomy, ‘Santa Maria della Misericordia’ University Hospital, Azienda Sanitaria Universitaria Friuli Centrale, Udine, Italy
    5. 5 Department of Medicine, Surgery and Pharmacy, University of Sassari, Sassari, Italy
    6. 6 Department of Maternal and Child Health and Urological Sciences, Sapienza University of Rome, Policlinico Umberto I, Rome, Italy
    7. 7 Unit of Gynecology and Obstetrics, Department of Human Pathology of Adult and Childhood ‘G. Barresi’, University of Messina, Messina, Italy
    8. 8 Department of Obstetrics and Gynecology, University of Parma, Parma, Italy
    9. 9 Division of Gynecologic Oncology, Michele e Pietro Ferrero Hospital, Verduno, Italy
    10. 10 Dipartimento Scienze della Salute della Donna e del Bambino, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy
    11. 11 Dipartimento Scienze della Vita e Sanità Pubblica, Università Cattolica del Sacro Cuore Facoltà di Medicina e Chirurgia, Rome, Italy
    1. Correspondence to Dr Martina Arcieri, Clinic of Obstetrics and Gynecology, 'Santa Maria della Misericordia' University Hospital, Azienda Sanitaria Universitaria Friuli Centrale, Udine, Italy; martina.arcieri{at}asufc.sanita.fvg.it

    Abstract

    Objective Molecular features are essential for estimating the risk of recurrence and impacting overall survival in patients with endometrial cancer. Additionally, the surgical procedure itself could be personalized based on the molecular characteristics of the tumor. This study aims to assess the feasibility of obtaining reliable molecular classification status from biopsy specimens collected during hysteroscopy to better modulate the appropriate surgical treatment.

    Methods This monocentric, retrospective, observational study was conducted on 106 patients who underwent a biopsy procedure followed by radical surgery for endometrial cancer, with concurrent molecular investigation. The molecular classification was determined through immunohistochemical staining for p53 and mismatch repair proteins, along with gene sequencing for POLE.

    Results Overall, 106 patients underwent molecular investigation, which was finally achieved on 99 patients (93.4%). Among these, the molecular analysis was conducted in 71 patients (67%) on the pre-operative endometrial biopsy and on the final uterine specimen in 28 patients (26.4%). Most of the endometrial biopsies were performed using Bettocchi hysteroscopy (66%). Molecular analysis was not possible in seven patients (6.6%), with six cases due to sample inadequacy and one case attributed to intra-mucosal carcinoma. The molecular results showed that the copy number low sub-group was the most common, and five cases of ‘multiple classifiers’ were observed in the low-risk category.

    Conclusion Our experience in obtaining molecular information from biopsy samples underscores the feasibility and efficacy of this technique, even in small tissue samples. This capability helps define the prognostic group of patients, facilitates timely decision-making, and develops a personalized strategy for each patient.

    • Endometrial Neoplasms
    • Gynecologic Surgical Procedures
    • Gynecology
    • Surgical Oncology
    • Hysteroscopes

    Data availability statement

    Data are available upon reasonable request. Following the journal’s guidelines, we will provide our data for independent analysis by a selected team by the Editorial Team for the purposes of additional data analysis or for the reproducibility of this study in other centers if such is requested.

    https://doi.org/10.1136/ijgc-2024-005478

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      WHAT IS ALREADY KNOWN ON THIS TOPIC

      • Current knowledge on endometrial cancer treatment and prognosis highlights the significance of molecular features in determining the risk of recurrence and influencing overall survival among patients with endometrial cancer.

      WHAT THIS STUDY ADDS

      • The possibility of obtaining molecular classification from biopsy specimens collected during hysteroscopy is feasible and allows clinicians to make treatment decisions earlier in the patient’s care pathway.

      HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE OR POLICY

      • The ability to develop personalized strategies for each patient based on their molecular profile can lead to more tailored and effective treatment approaches, potentially improving patient outcomes and quality of life. Having access to molecular data earlier in the diagnostic process prior to surgery enables clinicians to identify prognostic factors which, in turn, facilitates timely decision-making regarding treatment options and interventions.

      Introduction

      Endometrial cancer is the most common gynecological malignancy in high income countries with increasing incidence and mortality rates.1 Overall survival for patients with endometrial cancer is generally favorable; however, approximately 10–15% of low-risk patients with endometrial cancer experience recurrence.2 3 It is also relevant that about 50% of high-risk patients do not recur.2 3 One of the biggest challenges in endometrial cancer treatment has been the risk stratification; indeed, an early evaluation of the risk of metastases and recurrence along with post-operative pathological findings are necessary to ensure the best oncological treatment, to improve prognosis, and reduce side effects of unnecessary adjuvant treatment.1 3 4

      Until recently, the risk stratification of endometrial cancer and indications for adjuvant treatment has been based on clinical and histopathological features such as age, tumor grade, histological type, depth of myometrial invasion, presence of lymphovascular space invasion, and cervical and adnexal involvement.1 5 In 2013 the Cancer Genome Atlas integrated molecular characterization of endometrial cancer showed that it could be sub-divided into four prognostic groups.6 7 The four molecular groups are: POLE ultramutated; mismatch repair deficient (MMRd)/hypermutated; non-specific molecular profile or copy number low (NSMP/p53wt/CNL); and copy number high/TP53 mutated (p53abn).1 These molecular sub-groups have demonstrated a stronger prognostic impact than traditional histopathological tumor characteristics.1 8

      For this reason, the European guidelines for endometrial cancer management (European Society of Gynecological Oncology-European Society for Radiotherapy and Oncology-European Society of Pathology) have introduced molecular risk stratification.6 9 Recently, the International Federation of Gynecology and Obstetrics (FIGO) staging system for endometrial cancer in 2023 includes a significant amount of new information that better defines endometrial cancer pathology and molecular findings.10 Molecular findings brought an amendment of endometrial cancer guidelines, declaring a new era of molecular classification-based diagnostics and treatment approaches and highlighting the potential of molecular classification to refine and further individualize patients’ risk stratification.11–13

      Molecular features are valuable indicators for estimating the risk of recurrence and influencing overall survival in patients with endometrial cancer.8 12 Several groups have shown that molecular sub-types of endometrial cancer have a substantial impact on prognosis, recurrence, and survival outcomes in various cohorts of patients.14 15 Depending on the molecular profile of the tumor, adjuvant treatment strategies can be tailored to either de-escalate or intensify treatments after surgery, and the surgical procedure itself can be personalized.16 This study evaluates the feasibility of obtaining molecular classification results from biopsy specimens during hysteroscopy. The goal is to obtain molecular results from biopsy specimens; this timely information is significant for promptly initiating the most appropriate treatment and developing a personalized strategy for each patient.

      Methods

      This monocentric, retrospective, observational study was conducted at the Clinic of Gynecology and Obstetrics of the ‘Santa Maria della Misericordia’ University Hospital-Azienda Sanitaria Universitaria Friuli Centrale in Udine, Italy from April 2021 to October 2023. We included 106 women with endometrial cancer and a biopsy with molecular investigation on the specimen was performed on all patients in an outpatient hysteroscopy service or operating room. Inclusion criteria were: patients aged >18 years; confirmation of endometrial carcinoma on biopsy sample and final hysterectomy; all FIGO stages and grading; total hysterectomy + bilateral salpingo-oophorectomy + sentinel lymph node (SLN) mapping or pelvic lymphadenectomy. Exclusion criteria were: atypical hyperplasia on biopsy sample; any surgery that was not a total hysterectomy + bilateral salpingo-oophorectomy + SLN mapping; or pelvic lymphadenectomy. Patients with incomplete demographic or clinical data were excluded from the study.

      Demographic and medical history data were collected anonymously and included age, body mass index, FIGO staging, tumor grading, and type of lymphovascular space invasion at final pathology.17 Surgical and treatment information included biopsy technique, type of surgery, type of lymph node removal technique, and type of adjuvant treatment. Molecular results and molecular analysis data were also collected. Molecular classification was obtained by immunohistochemical staining for p53 and mismatch repair proteins (MSH6, PMS2, MSH2 and MLH1 proteins) and by gene sequencing for POLE. p53 was also assessed by gene sequencing as it was present in the gene panel used. Microsatellite instability sequencing was obtained in case of doubt on the immunohistochemical evaluation of mismatch repair proteins.

      Data Collection

      All data were collected and stored in a database. Collected variables included baseline demographic characteristics, pre-operative and intra-operative data, and final pathology report.

      Statistical Analysis

      The statistical analysis was carried out using Statistical Package for Social Science (SPSS) version 19.0 (IBM, Armonk, New York, USA). Quantitative variables were described using mean values and qualitative variables were summarized with absolute and percentage frequency tables. A p value <0.050 was considered statistically significant (two-tailed test).

      Results

      All patients included in the study had a diagnosis of endometrial cancer through biopsy. All endometrial biopsy specimens underwent molecular profiling, which was achieved in 99 patients (93.4%). Molecular analysis was performed on the biopsy in 71 patients (67%) and on the uterus after hysterectomy in 28 (26.4%). The analysis was not available in seven patients (6.6%) and, consequently, the molecular classification was unknown. In six patients the analysis was not performed due to inadequate samples (sample size or storage) and, in one case, due to the finding of an intra-mucosal carcinoma on both the biopsy and the uterus sample (the limited material quantity in intra-mucosal carcinoma samples precludes molecular analysis) (Table 1 and Figure 1).

      Figure 1
      Figure 1

      Molecular analysis summary.

      View this table:
      Table 1

      Biopsy and molecular analysis

      In all 71 cases where molecular analysis was conducted on biopsy samples, the molecular results were available within 15–20 days (median 17 days), preceding the scheduling of surgery (total hysterectomy + bilateral salpingo-oophorectomy + SLN mapping or pelvic lymphadenectomy). Table 2 summarizes the molecular results with copy number low identified as the most common sub-group; five cases of endometrial cancer were categorized as ‘multiple classifiers’, all of which were observed within the low-risk group (Table 3). The molecular study for microsatellite instability was conducted in 31 patients who exhibited the loss of expression of one or more mismatch repair proteins detected through immunohistochemistry. Molecular analysis confirmed microsatellite instability in 27 patients, while four patients demonstrated stable microsatellites.

      View this table:
      Table 2

      Molecular results

      View this table:
      Table 3

      Multiple classifiers

      As shown in Table 1 and Figure 2, the biopsy technique was heterogeneous. Most biopsy techniques were performed through diagnostic hysteroscopic ‘Bettocchi’ procedures (66%), resectoscopic hysteroscopy was the second most common biopsy technique (27.4%), and mini-resectoscopic surgeries constituted a smaller percentage (6.6%). Table 1 and Figure 1 show that 55.7% of procedures were performed at the study center whereas 44.3% of women underwent external procedures. However, all external biopsy samples were re-evaluated by the dedicated pathologist of the study center to ensure accurate results.

      Figure 2
      Figure 2

      Molecular analysis and endometrial biopsy method.

      The demographic and surgical data, histology results, and adjuvant treatment information are summarized in online supplemental material 1. The median age of the patients in the study was 68 years (range 41–88) and the most frequent pathological FIGO stages were IA and IB with negative lymphovascular space invasion (54.7% and 24.6%, respectively). Following the clinical stage, most patients (80.2%) underwent SLN excision. No residual tumor was observed in any of the cases. When required, according to international guidelines, adjuvant treatment was performed; most patients had endometrial cancer FIGO stage IA–IB on final pathology and were categorized as low risk, therefore only 3.8% of patients underwent adjuvant chemotherapy or combined treatment chemotherapy + radiotherapy (6.6%). Instead, most patients required no adjuvant treatment (49%) or, at most, adjuvant radiotherapy on the pelvis and lymphatic drainage (40.6%).

      Supplemental material

      Discussion

      Summary of Main Results

      All endometrial biopsy specimens underwent molecular profiling, which was successfully completed for 99 patients (93.4%). Molecular data were obtained from endometrial biopsies in 67% of cases, with a median processing time of 17 days. In 26.4% of cases, molecular analysis was performed directly on the uterus. Molecular analysis was not available for seven patients (6.6%). Most patients had FIGO stage IA–IB endometrial cancer on final pathology and were categorized as having low-risk disease. Consequently, only 3.8% of patients underwent adjuvant chemotherapy and 6.6% received combined chemotherapy and radiotherapy.

      Results in the Context of Published Literature

      In 2019, Abdulfatah et al published a study that focused on evaluating the concordance between biopsy and hysterectomy specimens for mismatch repair proteins, p53, and POLE in 50 patients with endometrial cancer; thus, the authors showed the possibility of obtaining molecular information from biopsy samples.18 Timely molecular data can expedite treatment decisions in patients with a mutational pattern of p53 who may require starting adjuvant treatment or avoiding adjuvant therapy in intermediate-risk cancers with a POLEmut pattern which downstages the risk group.10 Moreover, knowing the molecular characteristics before surgery can influence intra-operative decisions.

      Currently, the precise risk of extra-uterine metastasis and the appropriate type of surgical staging for each of the four molecular sub-groups remains unknown. The ongoing prospective multicentric EUGENIE trial aims to investigate whether each molecular sub-group of endometrial cancer has a specific pattern of spread that could guide the extent of surgical staging.19 This research will enable gynecologic oncologists to tailor the treatment of patients with endometrial cancer accordingly. The performance of complete molecular classification (POLEmut, MMRd, NSMP, p53abn) is encouraged in all cases of endometrial carcinoma for prognostic risk group stratification and as potential influencing factors for adjuvant or systemic treatment decisions.

      In June 2023 the updated FIGO staging of endometrial cancer was released, which incorporates various histological types, tumor patterns, and molecular classification to reflect the improved understanding of the complex nature of endometrial carcinoma and its biologic behavior. The changes incorporated in the 2023 staging system should provide a more evidence-based context for treatment recommendations and the more refined future collection of outcome and survival data.10 20 Leon-Castillo et al20 21 investigated the prognostic relevance of the molecular classification using tissue samples donated by participants in the PORTEC-3 clinical trial. The study showed the prognostic information the endometrial cancer molecular classification carries and its potential to guide adjuvant treatment. It confirmed the importance of implementing the molecular classification in clinical diagnostics and decision making.21 22 The average time required for molecular analyses was investigated by the PORTEC-4a trial, which established the feasibility of completing the molecular assessment within a 2-week timeframe.23 Indeed, the study showed an average duration between randomization of patients and determination of the molecular-integrated risk profile of 10.2 days (range 1–23).24

      Strengths and Weaknesses

      The study has a number of limitations as not all biopsies were performed at the same center and the study involved retrospective data collection. It is essential to consider that, in our institution, molecular tests are always available. Indeed, most patients underwent this analysis (except for seven cases of sample inadequacy). Nevertheless, we recognize the challenges associated with the procedure’s cost and equipment, which may limit the widespread availability of molecular tests in many centers.

      The strength of this study lies in the fact that this is the first assessment of the feasibility of molecular classification on endometrial biopsies with a large sample size. Additionally, despite the biopsy samples being collected from different hospitals, our pathologist re-evaluated all external biopsy samples to ensure the accuracy of the results.

      Implications for Practice and Future Research

      FIGO staging of endometrial cancer 2023 affirms that molecular sub-type assignment can be conducted on a biopsy specimen in which appropriate handling and control of fixation conditions may allow for better immunohistochemical and molecular techniques performance than on the final hysterectomy specimen.10 Moreover, obtaining a molecular classification from biopsy specimens may provide guidance for tailored surgery, such as a guide for fertility-sparing options in young women. The literature confirms that the progress in molecular biology, coupled with the refined clinical and prognostic classification of endometrial cancer, enables the identification of patients eligible for fertility-sparing treatments.25 When feasible, the molecular analysis on endometrial biopsy samples is recommended. However, there are some cases in which it is not possible, such as when the sample is inadequate or if there is intra-mucosal carcinoma on the biopsy specimen.

      Conclusions

      The molecular characterization of endometrial cancer and its clinical relevance is rapidly evolving, and this implies ongoing changes and advancements based on discoveries. Molecular findings are guiding treatment decisions for patients with endometrial cancer and are paving the way for molecular-integrated adjuvant therapy. Obtaining molecular results from the biopsy allows for the earliest classification of patients into different risk groups, thereby potentially ensuring the most suitable personalized surgery. Our study demonstrates the feasibility of molecular analysis on endometrial biopsy specimens. Further prospective studies should assess its role in shortening the time required for treatment decisions.

      Data availability statement

      Data are available upon reasonable request. Following the journal’s guidelines, we will provide our data for independent analysis by a selected team by the Editorial Team for the purposes of additional data analysis or for the reproducibility of this study in other centers if such is requested.

      Ethics statements

      Patient consent for publication

      Ethics approval

      This study involves human participants and was approved by Udine’s Institutional Review Board (Protocol ID: 208/2023). Participants gave informed consent to participate in the study before taking part.

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      Supplementary materials

      • Supplementary Data

        This web only file has been produced by the BMJ Publishing Group from an electronic file supplied by the author(s) and has not been edited for content.

      Footnotes

      • X @jess393, @annafagottimd

      • Collaborators Udine Hospital Gynecological-Oncological Tumor Board Group.

      • Contributors SR and GV conceptualized the study and conducted the statistical analyses. AP and MA drafted the initial version of the manuscript. LM, MO, AT, GP, FP and AB assisted with database searches. MP, GB, SC, VAC, AB, JM and FF reviewed the manuscript. GS and LD provided supervision during the writing process. SR is the guarantor.

      • 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.

      • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.