Molecular classification of endometrial carcinoma on diagnostic specimens is highly concordant with final hysterectomy: Earlier prognostic information to guide treatment

Abstract

Objective Categorization and risk stratification of endometrial carcinomas is inadequate; histomorphologic assessment shows considerable interobserver variability, and risk of metastases and recurrence can only be derived after surgical staging. We have developed a Proactive Molecular Risk classification tool for Endometrial cancers (ProMisE) that identifies four distinct prognostic subgroups. Our objective was to assess whether molecular classification could be performed on diagnostic endometrial specimens obtained prior to surgical staging and its concordance with molecular classification performed on the subsequent hysterectomy specimen. Methods Sequencing of tumors for exonuclease domain mutations (EDMs) in POLE and immunohistochemistry for mismatch repair (MMR) proteins and p53 were applied to both pre- and post-staging archival specimens from 60 individuals to identify four molecular subgroups: MMR-D, POLE EDM, p53 wild type, p53 abn(abnormal). Three gynecologic subspecialty pathologists assigned histotype and grade to a subset of samples. Concordance of molecular and clinicopathologic subgroup assignments were determined, comparing biopsy/curetting to hysterectomy specimens. Results Complete molecular and pathologic categorization was achieved in 57 cases. Concordance metrics for pre- vs. post-staging endometrial samples categorized by ProMisE were highly favorable; average per ProMisE class sensitivity(0.9), specificity(0.96), PPV(0.9), NPV(0.96) and kappa statistic 0.86(95%CI, 0.72-0.93), indicating excellent agreement. We observed the highest level of concordance for ‘p53 abn’ tumors, the group associated with the worst prognosis. In contrast, grade and histotype assignment from original pathology reports pre- vs. post-staging showed only moderate levels of agreement (kappa=0.55 and 0.44 respectively); even with subspecialty pathology review only moderate levels of agreement were observed. Conclusion Molecular classification can be achieved on diagnostic endometrial samples and accurately predicts the molecular features in the final hysterectomy specimens, demonstrating concordance superior to grade and histotype . This biologically relevant information, available at initial diagnosis, has the potential to inform management (surgery, adjuvant therapy) from the earliest time point in cancer care.

Limited impact of intratumour heterogeneity on molecular risk assignment in endometrial cancer

“…This series of 49 cases showed, depending on the marker analysed, no or low intratumour heterogeneity among three tumour blocks for POLE and CTNNB1 mutations, and p53, MMR and L1CAM expression (range of concordance rate: 92-100%). Similarly, previous studies showed that the molecular analysis on endometrial cancer preoperative specimens are concordant with final hysterectomy specimens obtained at definitive surgical staging [10, 29–31]. The intratumour heterogeneity in our study affected the integrated molecular risk assignment in only five cases.…”

Tumor Grade Correlation Between Preoperative Biopsy and Final Surgical Specimen in Endometrial Cancer: The Use of Different Diagnostic Methods and Analysis of Associated Factors

“…26,27 We should note that endometrial carcinomas are uniform, with respect to genetic events that occur early during oncogenesis, such as MMR loss, POLE mutation, or TP53 mutation. 26,28 Thus, endometrial biopsy or curettings can predict genomic subtypes of endometrial cancer more accurately than grade. Genetic analysis may figure out the tumor heterogeneity and overcome the lack of correlation between biopsy sample and final specimen.…”

New classification of endometrial cancers: the development and potential applications of genomic-based classification in research and clinical care

“…Biologically relevant information about an individual’s tumor could guide surgical urgency and aggressiveness, fertility or hormonal function sparing management options, adjuvant therapy, and/or surveillance schedules. We have demonstrated high concordance between ProMisE molecular classification in diagnostic vs. final hysterectomy samples, far superseding concordance of grade, or histotype as assigned on original pathology reports or within or between reviews by expert gynecologic cancer pathologists [80]. The Leiden team has also shown high concordance of molecular tumor alterations between pre-operative curettage specimens and final hysterectomy specimens (13 gene panel and MSI assay) [81] and a multicenter, prospective trial in Holland is in process to see if surgical management can be improved [82].…”

“…However, in the cases examined, although single nucleotide variations and copy number analysis revealed some diversity between anatomic sites within an individual (at time of diagnosis) the ProMisE molecular subgroup categorization was concordant across all tumor sites (6–14 anatomic sites examined per individual) [114]. We have reported on a case of discordant ProMisE categorization between a diagnostic endometrial biopsy and final hysterectomy specimen in an individual with a dedifferentiated endometrial carcinoma [80]. This was secondary to concurrent low grade and high grade areas within the endometrium and myometrium where mismatch repair profiles differed.…”