Abstract
Histopathological evaluation including subtyping and grading is the current cornerstone for endometrial cancer (EC) classification. This provides clinicians with prognostic information and input for further treatment recommendations. Nonetheless, patients with histologically similar ECs may have very different outcomes, notably in patients with high‐grade endometrial carcinomas. For endometrial cancer, four molecular subgroups have undergone extensive studies in recent years: POLE ultramutated (POLEmut), mismatch repair‐deficient (MMRd), p53 mutant (p53abn) and those EC lacking any of these alterations, referred to as NSMP (non‐specific molecular profile). Several large studies confirm the prognostic relevance of these molecular subgroups. However, this ‘histomolecular’ approach has so far not been implemented in clinical routine. The ongoing PORTEC4a trial is the first clinical setting in which the added value of integrating molecular parameters in adjuvant treatment decisions will be determined. For diagnostics, the incorporation of the molecular parameters in EC classification will add a level of objectivity which will yield biologically more homogeneous subclasses. Here we illustrate how the management of individual EC patients may be impacted when applying the molecular EC classification. We describe our current approach to the integrated diagnoses of EC with a focus on scenarios with conflicting morphological and molecular findings. We also address several pitfalls accompanying the diagnostic implementation of molecular EC classification and give practical suggestions for diagnostic scenarios.
Highlights
In the 4th edition of the World Health Organisation (WHO) classification of tumours of female reproductive organs,[1] the definition for endometrial cancer (EC) entities were mainly based on histological characteristics supplemented with immunohistochemical markers
These four subgroups include: (i) ultra-mutated ECs characterised by pathogenic variants in the exonuclease domain of DNA polymerase-epsilon (POLE); (ii) hyper-mutated ECs characterised by microsatellite instability (MSI); (iii) a copy-number low subgroup with a low mutational burden; and (iv) a copy-number high group with frequent TP53 mutations.[4]
Available survival data demonstrated that POLE ultramutated (POLEmut)-p53abn EC show clinical outcomes comparable to POLEmut EC without abnormal p53 expression. These findings show that TP53 mutations in these ‘multiple-classifiers’ are probably passenger mutations not affecting the clinical behaviour, indicating that these cases should be classified and treated as POLEmut EC
Summary
In the 4th edition of the World Health Organisation (WHO) classification of tumours of female reproductive organs,[1] the definition for endometrial cancer (EC) entities were mainly based on histological characteristics supplemented with immunohistochemical markers. As there are distinct prognostic differences between the four molecular subgroups, the question arises as to which biological behaviour these multiple classifiers follow POLEmut and MMRd EC, due to their high mutational burden, obtain high levels of neoantigens and TILs, making them attractive candidates for immunotherapy such as anti-PD1 immune checkpoint blockade.[32,33,51–57] Despite this theoretical argument, the excellent clinical outcomes for patients with POLEmut EC under current treatment regimens (independent of stage), argues against the rationale to the use of immunotherapy for this subpopulation. The gold standard for testing the homologous recombination status of tumours, including EC, should be defined
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