Abstract
IntroductionIndividual prediction of tumour behaviour based on molecular markers may refine adjuvant treatment strategies in endometrial cancer (EC). As these molecular alterations are determined in a small tumour fraction, high intratumour heterogeneity may interfere with correct risk prediction. This study aimed to investigate to which extent intratumour heterogeneity exists for molecular markers and whether it affects the molecular risk assignment in EC.MethodsForty-nine ECs (three tumour blocks/case) were selected with alterations in POLE (n=10), CTNNB1 (n=8), p53 (n=10), mismatch repair (n=11), L1CAM (n=10), and ECs without any of these markers (n=9). Nine ECs carried more than one molecular marker. All 147 blocks were analysed for POLE exonuclease domain and CTNNB1 exon 3 mutations, and for p53, mismatch repair and L1CAM protein expression. All blocks were assigned to a favourable, intermediate or unfavourable risk group, based on a molecular risk assignment.RESULTSConcordance between the three tumour blocks for POLE and CTNNB1 mutational status, and p53, mismatch repair and L1CAM protein expression was found in 100% (48/48), 95.9% (47/49), 93.9% (46/49), 98.0% (48/49), and 91.8% (45/49) of tumours, respectively. These discordances were found in a total of nine cases (18.4%). The intratumour heterogeneity impacted the risk assignment in five cases (10.2%).ConclusionIntratumour heterogeneity of prognostic molecular markers in EC without morphologic heterogeneity is uncommon among three tumour fractions, affecting the molecular risk allocation in a limited number of cases. This low intratumour heterogeneity facilitates the implementation of the molecular risk assignment, advocating its use in clinical decision making.
Highlights
Individual prediction of tumour behaviour based on molecular markers may refine adjuvant treatment strategies in endometrial cancer (EC)
In this study we aimed to investigate to which extent intratumour heterogeneity exists for the promising prognostic molecular markers and whether it affects the molecular risk assignment in EC
The selected cases were representative of the endometrial cancer population with regard to age, FIGO stage (87.8% stage I+II) and tumour type (85.7% endometrioid), with a slight overrepresentation of grade 3 tumours (28.6%) [32]
Summary
Individual prediction of tumour behaviour based on molecular markers may refine adjuvant treatment strategies in endometrial cancer (EC). As these molecular alterations are determined in a small tumour fraction, high intratumour heterogeneity may interfere with correct risk prediction. As a result, based on an extensive integrated analysis of these molecular markers, two molecular integrated risk assignments, combining clinicopathological and molecular risk factors, have been proposed [6, 7] In one of these assignments, to the other, p53-mutant-like, L1CAM-positive, and substantial lymphovascular space invasion (LVSI) tumours were designated to have an unfavourable risk. MMR-deficient and CTNNB1-mutant were considered at intermediate risk, while POLE-mutant tumours and tumours with no specific molecular profile are designated favourable [5,6,7]
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