Serial genomic analysis of endometrium supports the existence of histologically indistinct endometrial cancer precursors

Abstract

The endometrium is unique as an accessible anatomic location that can be repeatedly biopsied and where diagnostic biopsies do not extirpate neoplastic lesions. We exploited these features to retrospectively characterize serial genomic alterations along the precancer/cancer continuum in individual women. Cases were selected based on (1) endometrial cancer diagnosis/hysterectomy and (2) preceding serial endometrial biopsies including for some patients an early biopsy before a precancer histologic diagnosis. A comprehensive panel was designed for endometrial cancer genes. Formalin‐fixed, paraffin‐embedded specimens for each cancer, preceding biopsies, and matched germline samples were subjected to barcoded high‐throughput sequencing to identify mutations and track their origin and allelic frequency progression. In total, 92 samples from 21 patients were analyzed, providing an opportunity for new insights into early endometrial cancer progression. Definitive invasive endometrial cancers exhibited expected mutational spectra, and canonical driver mutations were detectable in preceding biopsies. Notably, ≥1 cancer mutations were detected prior to the histopathologic diagnosis of an endometrial precancer in the majority of patients. In 18/21 cases, ≥1 mutations were confirmed by abnormal protein levels or subcellular localization by immunohistochemistry, confirming genomic data and providing unique views of histologic correlates. In 19 control endometria, mutation counts were lower, with a lack of canonical endometrial cancer hotspot mutations. Our study documents the existence of endometrial lesions that are histologically indistinct but are bona fide endometrial cancer precursors. © 2021 The Authors. The Journal of Pathology published by John Wiley & Sons, Ltd. on behalf of The Pathological Society of Great Britain and Ireland.

Reliable Identification of Endometrial Precancers Through Combined Pax2, β-Catenin, and Pten Immunohistochemistry

“…This number is comparable to a recent serial genomic analysis of endometrial cancer progression, where next generation sequencing-directed immunohistochemistry found that 86% of endometrial cancers were aberrant for at least 1 of the 5 non-Pax2 markers, with persistence of AH/EIN marker patterns in samples from each patient. 37 Conversely, since 7.2% of bona fide AH/EIN were not aberrant for any of these markers, lack of aberrancy of all 3 should not dissuade from a diagnosis of AH/EIN when definitive histologic features are present.…”

“… 14 This likely reflects a sequential acquisition of mutations that characterize clonal outgrowth in early endometrial neoplasia. 19 , 37 …”

“… 53 β-Catenin patterns are also likely to be recapitulated following treatment. 37 Thus, in addition to facilitating the initial diagnosis of AH/EIN, establishment of baseline expression patterns should be useful diagnostically in follow-up biopsies in the setting of progestin treatment. Although this study provides critical information regarding patterns of marker aberrance and panel performance in definitive AH/EIN, additional investigations will be needed to determine the incidence and patterns of marker aberrance in mimics of AH/EIN, including endometrial polyps, disordered proliferative endometrium, or non-AH.…”

Diagnostic value of endometrial cytology and related technology

“…In endometrial hyperplasia, PTEN and KRAS have been reported to have mutations frequently. [8][9][10][11][12][13] In addition, recent studies using next generation sequencer revealed many driver gene mutations in atypical hyperplasia and even in normal endometrial glands. [13][14][15][16] Li et al analyzed formalin-fixed paraffin embedded tissue with a diagnosis of atypical endometrial hyperplasia and found frequent mutations in driver genes, including PTEN, ARID1A, CTNNB1, KRAS, and PIK3CA.…”

New Trends in the Detection of Gynecological Precancerous Lesions and Early-Stage Cancers

“…It is important to note that these mutations were confirmed in the invasive cancer. This research provided unique insights into precancer initiation and progression and clearly demonstrated the existence of endometrial premalignant lesions with definitive mutations not readily identifiable by histology [ 100 ]. These findings are also supported by a case report in which tumor-specific mutations were identified in an asymptomatic individual without clinical or pathologic evidence of cancer nearly one year before symptoms developed, i.e., postmenopausal bleeding and a single microscopic focus of EC diagnosed at the time of hysteroscopy [ 101 ].…”