Premature Use of Evolving and Controversial Variables

Another disadvantage of the new FIGO system is the premature incorporation of variables for which definitions are still evolving, as well as variables that are subject to considerable interobserver variability in their assessment. Many cancer care guidelines and reporting resources model on FIGO. Two major examples are the College of American Pathologists (CAP) reporting tools and the AJCC staging. Controversial and poorly reproducible variables introduced in the 2023 update will be translated to those guidelines, greatly impacting patient care. One illustrative example is the requirement to distinguish between a superficially myoinvasive tumor and one confined to the endometrium. This distinction is problematic, particularly in the setting of non-aggressive (low-grade endometrioid) cancers, as it is known to suffer from poor interobserver agreement due to various factors such as the often irregular endometrial/myometrial interface and the presence of adenomyosis, which when involved by tumor can be difficult to separate from true myoinvasive disease.12 13

Another potentially controversial variable introduced by the 2023 FIGO is tumor involvement of ‘uterine subserosa’, mentioned in the publication as a criterion for stage IIIA2 but not defined in a way that can be reproducibly evaluated by the pathologist. The International Society of Gynecological Pathologists (ISGyP) recommendations already include the submesothelial fibroconnective tissue as part of the definition of serosal involvement.12 The concept of uterine subserosal (different from serosal) invasion is not included in any current staging system, scientific guideline or reporting resource document, and will cause interpretation issues.

A histologic variable still in evolution and without concrete reproducible agreement is quantification of LVSI, and several different definitions are in use. FIGO 2023 uses involvement of five or more lymphovascular spaces to define substantial (extensive) LVSI, as does the 2020 WHO Classification of Female Genital Tumors14 and the ESGO/ESTRO/ESP management guidelines.9 Other resources use different definitions for substantial LVSI—for example, four or more spaces in at least one hematoxylin and eosin (H&E) slide in the National Comprehensive Cancer Network (NCCN) guidelines,15 and three or more spaces in the 2022 International Collaboration on Cancer Reporting (ICCR),16 the 2019 ISGyP Endometrial Cancer Project recommendations,12 and the 2023 CAP cancer reporting protocol.17 Most resources, including the 2023 FIGO update, do not clarify whether the extent of LVSI is based on the maximum involvement in a single tissue section or on the cumulative extent across all tissue sections. In light of these multiple definitions and overall lack of clarity, the reproducibility of LVSI quantification remains to be fully documented. This may lead to potential difficulties in comparability between practices and regions. For example, if one center has a very rigorous approach and a high threshold for diagnosis of substantial LVSI, a stage drift compared with other centers will develop. This will result in differing outcomes between centers, stage by stage, not due to real differences in patient outcome, but to systematic differences in stage assignment (the so-called ‘stage migration effect’).18

The existence of a subset of patients with low-grade endometrioid carcinoma confined to the uterine corpus and ovary who have a favorable outcome is recognized by several reporting systems. Thus, the incorporation of a separate category for these patients in the 2023 FIGO (new stage IA3) is, in principle, well-received. However, the criteria to define this subset are not uniformly established in the literature. For instance, bilateral ovarian involvement by tumor is a criterion of unfavorable outcome in the 2023 FIGO, ICCR, and ISGyP Endometrial Cancer Project recommendations,1 12 16 but not in the 2020 WHO classification.14 Similarly, LVSI qualifiers (focal vs substantial) are used by 2023 FIGO and WHO but not by ICCR and ISGyP recommendations. Precursors to endometrioid carcinoma in the endometrium (atypical hyperplasia) and in the ovary (endometriosis, adenofibroma) are among the criteria for classification of favorable outcome by ICCR and ISGyP recommendations, but not WHO or 2023 FIGO. The 2023 FIGO update fails to provide evidence in favor of their approach rather than the approach used in other recommendations.

Regarding the incorporation of molecular results in FIGO 2023 staging, we offer several points for consideration. First, the incorporation of molecular parameters essentially precludes staging as proposed in resource-poor settings. Second, the methodology for determining the molecular group is not specified in the 2023 FIGO update, which carries potential deleterious implications because of variation in testing for TP53 and MMR abnormalities and POLE mutations. A combination of immunohistochemistry and standalone POLE sequencing appears to be the preferred approach based on the current evidence.19 20 However, these ancillary tools have great variability in terms of access, workflow, interpretation, and reporting. DNA sequencing assays suffer from long turnaround times, and the pathologist may find the workflow related to ancillary testing and optimal incorporation into the pathology report challenging. Lastly, as POLE testing has become more widespread, assays have expanded from limited/‘hot spot’ sequencing of POLE to full exonic sequencing within targeted next generation sequencing panels. This has created great opportunities to learn more about the effects of specific POLE mutations, but has also led to the identification of variants of unknown significance. Given the significant changes in stage and clinical management imparted by POLE status alone, clear direction as to which pathogenic POLE mutations are appropriate to classify an endometrial cancer as ‘POLEmut’ is essential.

Unnecessary Duplication of Risk Stratification Models

The 2023 FIGO staging system resembles the approach taken by 2021 ESGO/ESTRO/ESP guidelines in defining risk categories based on multiple pathological features beyond anatomic spread.9 In fact, the authors of the FIGO 2023 system state that the ESGO/ESTRO/ESP guidelines were used as a template.1 Whether the stage should be an element of patient risk stratification models or become the risk model itself by incorporating other factors beyond anatomic tumor extent is still debatable. However, we argue that ‘refining’ stage as the overarching and all-inclusive cancer stratifier has important drawbacks. Staging as traditionally conceived is a concept familiar to all cancer care providers; it is practical and applicable in under-resourced settings where the capacity to perform ancillary studies may not exist and the FIGO staging update is difficult to apply on a global scale.

Less Applicability and Adoption by Stakeholders

Another significant drawback is related to the considerable variability worldwide in terms of access to diagnostic and therapeutic modalities. There have been considerable advances in endometrial carcinoma classification, transitioning from an era of poor reproducibility in histologic typing and grading to a more objective and reproducible molecular classification, although with the caveats regarding POLE, TP53, and MMR testing discussed earlier.19–21 Patients are increasingly knowledgeable about the concept of personalized medicine, and that their care may differ from other patients based on molecular features, ranging from de-escalation of therapy to targeted treatments. Clinical trials that have stratified treatment assignment by molecular features have high patient acceptance rates.22

For treating clinicians, international multidisciplinary efforts for undertaking molecular testing by the WHO, ESGO/ESTRO/ESP, ICCR, and other bodies have, in our opinion, successfully driven change globally. However, a wide variability in implementation exists. Some of this variation is driven by the resources available, and some by knowledge translation and education. Allowing clinicians to maintain their traditional practice of assigning stage based on anatomic spread of disease, but allowing them to include molecular features and other non-anatomic parameters for clinical context and decision making, has been successful in generating impactful change in endometrial carcinoma management; there are concerns that a one-time set of changes across the entire staging system as proposed by FIGO may impede this progress.

There is significant concern that the new FIGO staging system will confuse both patients and clinicians. It will potentially frustrate those who are only recently coming to terms with the value added by molecular subtyping. It may pose even greater challenges to those who lack the tools (molecular testing, immunohistochemistry) to implement the staging system as proposed; to them, the most critical piece of the puzzle in their cancer care will be missing. The system also creates an extra step of memorizing a new non-anatomic staging system that is non-intuitive. In discussing a historical clinical trial with a patient, extensive explanation of stage differences will be required, and it is unlikely that interpretation of treatment efficacy will be possible. For new or currently active clinical trials, it is unclear how enrolment criteria could be adapted to fit the new FIGO system. It is also possible that disparities in clinical trial enrolment between institutions could be exacerbated.

Further, we anticipate confusion with the assigned stage potentially changing at different points during the patient’s cancer journey. For example, a hysterectomy specimen deemed to have a grade 2 endometrioid carcinoma with invasion into the outer half of the myometrium (stage IB), is reviewed at a local cancer center where the tumor is considered grade 3, and therefore assigned FIGO stage IIC; finally, when molecular classification results become available and a pathogenic POLE mutation is identified, the same patient has the stage changed to stage IAm_POLEmut.

Lack of Supporting Evidence

Added to the lack of a detailed description regarding evidence appraisal methodology, of concern is the fact that many of the changes and recommendations are provided without any citations. Throughout the text, the 2023 FIGO update lacks references to original, peer-reviewed literature in support of many of the proposed changes. For instance, the publication does not provide recent evidence supporting the re-introduction of evaluating superficial myometrial invasion versus no myoinvasion, or the grouping of FIGO grade 3 endometrioid carcinoma, a molecularly and clinically heterogeneous group, with other histologic subtypes as ‘aggressive’ histologic carcinoma types.23 24 Where there is discordance in definitions with other cancer reporting resources and recommendations, the 2023 FIGO does not point out that controversy exists, nor does it explain how it decided to follow the diagnostic criteria endorsed by one reporting recommendation over another. It is also worth pointing out that prospective studies regarding the incorporation of molecular data into management algorithms are lacking, although these are ongoing.

Lack of Consultation with the Pathology Community

Regular updates to the FIGO staging have far-reaching consequences influencing patient management, research, and communication among medical professionals. As such, a rigorous and formalized process of consultation with appropriate disciplines prior to formal publication should be expected. In the case of the FIGO 2023 endometrial carcinoma update, consultation with the pathology community and the societies that represent it is particularly critical, as the staging parameters are largely pathologic in nature (meaning they are determined and reported by the pathologist). To this end, pathology representation in the committee that developed the 2023 FIGO update appears largely insufficient; only a single pathologist was part of the committee. Likewise, the absence of a meaningful contribution by pathology societies in the staging update development, discussion, and publication is a major oversight. These issues are likely to hinder efforts to implement the 2023 system into practice.

We express concern that the recent FIGO staging update lacked the rigorous process that is expected for the magnitude of its recommendations. The authors of the FIGO update state that they have performed a literature review but do not provide any further details on the process. The methodology section does not mention any feedback rounds, external review, or opportunities for input by relevant gynecology, pathology, gynecologic oncology, medical oncology, and radiation oncology societies. There is also no mention of a public consultation period, in which the proposed changes are subjected to the review of the medical and scientific community at large. Given the scope and significance of the changes, we are of the opinion that substantial input by the ISGyP and other relevant societies should have been sought prior to publication of the update. An open comment period would have also been greatly beneficial and likely to increase adoption.

Importantly, the limited pathology input in the FIGO 2023 endometrial carcinoma update follows an unsettling trend by FIGO of limiting and/or omitting pathologist’s input in their staging recommendations, as evidenced by the most recent updates for carcinomas of the uterine cervix and vulva.25 26 In fact, FIGO did not include a single gynecological pathologist in either of these publications. Expectedly, this has resulted in issues that have caused major confusion in the field, increasing heterogeneity among practices, and likely leading to disparities in patient care. If FIGO intends to retain the confidence of pathologists and other clinicians, the issues highlighted herein need to be rectified.

In 2021, the ISGyP carried out a survey among pathologists and treating clinicians to identify and rank perceived controversies in endometrial carcinoma staging as well as areas lacking solid evidence, with the overarching aim of defining topics for future outcome-based research to inform subsequent changes in the staging system. The survey was circulated via email to members of the ISGyP and the International Gynecologic Cancer Society and drew responses from 172 pathologists and 135 treating clinicians.27 We acknowledge that the 2023 FIGO update addresses many of the relevant points covered in the survey. Notably, however, very few questions elicited a consensus response, defined as at least 75% agreement among either pathologists or treating clinicians. Those that approached or reached consensus have in fact been addressed in the 2023 FIGO update: substaging of nodal involvement based on the size of metastasis, defining criteria to separate cases of simultaneous uterine corpus and ovarian carcinoma into favorable versus unfavorable prognostic categories, and agreement that LVSI represents an independent prognostic variable.

Conversely, additional changes in the 2023 FIGO update did not achieve consensus agreement among pathologists or treating clinicians. A slim majority of pathologists (52%) and a higher proportion of treating clinicians (65%) supported the incorporation of histological tumor type into staging. Likewise, 48% of pathologists and 61% of treating clinicians agreed that LVSI should be incorporated into staging. Regarding LVSI, defining the cut-off between focal and substantial LVSI was identified as the leading research priority. Finally, 48% of pathologists and 63% of treating clinicians felt that molecular classification should be incorporated into staging.