A Selective Biomarker Panel Increases the Reproducibility and the Accuracy in Endometrial Biopsy Diagnosis

Abstract

Grading and histologic typing of endometrial cancer in biopsy material has a direct impact on the decision to perform lymphadenectomy and/or omentectomy in many cancer centers. Endometrial biopsies are among the most common general surgical pathology specimens. Multiple studies have shown that biopsy diagnosis suffers from a lack of reproducibility. Although many biomarkers have been proposed, none have been demonstrated to improve the diagnosis in the biopsy setting. In this study, 70 biopsies with endometrial carcinoma were supplemented with a biomarker panel consisting of ER, PR, P53, and DNA ploidy. A representative H&E slide was scanned digitally and made available to 12 gynecologic pathologists in 4 Nordic countries: Finland, Denmark, Sweden, and Norway. Reviewers diagnosed the cases both before and after being provided with the biomarker results. The interobserver percent agreement and Cohen κ improved from 75.8% (κ=0.52, moderate) to 84% (κ=0.68, substantial) with inclusion of the biomarker panel. Agreement with the subsequent hysterectomy diagnosis also improved from 83.6% (κ=0.67) to 88.7% (κ=0.77). There was no statistical improvement between a reflex (84% agreement) and a reflective testing algorithm (82.9% agreement), suggesting that the selective use of biomarkers is appropriate. Difficult cases were almost exclusively high-grade tumors. Finally, a statistical model indicated that only P53 and DNA ploidy, in conjunction with an H&E review, had an impact on the decision to upgrade or downgrade cases.

Interpretation of P53 Immunohistochemistry in Endometrial Carcinomas: Toward Increased Reproducibility

“…However, one point worth mentioning is that a small percentage of low grade endometrioid adenocarcinomas contain TP53 mutations and exhibit mutation-type immunoreactivity. However, that being said, mutation-type p53 staining may be helpful in avoiding underdiagnosis of a serous carcinoma with intermediate grade nuclear features as grade 1 or 2 endometrioid carcinoma (3,20). Abnormal p53 staining alone is not sufficient for the differential diagnosis of endometrioid from serous carcinomas as a significant minority of grade 3 endometrioid carcinomas show mutation-type p53 immunoreactivity (21).…”

Interobserver diagnostic reproducibility in advanced-stage endometrial carcinoma

“…When defining endometrioid features such as squamous or mucinous differentiation on a background of endometrial hyperplasia present, a diagnosis of endometrioid carcinoma can be rendered. The use of a panel of IHC stains can help to establish a confirmatory diagnosis when histomorphological findings are unclear or overlapping [6,9,15]. Biomarkers commonly used to distinguish between endometrioid and serous carcinomas are immunostaining for p53, p16, ER, PR, PTEN, and DNA mismatch repair proteins [6,9,12,16,17].…”

“…Han et al [8] demonstrated that a seven-marker immunostaining panel (consisting of estrogen receptor [ER], progesterone receptor [PR], p16, p53, vimentin, PTEN, and IGF2BP3) could differentiate high-grade endometrioid carcinoma and serous carcinoma with 100% concordance. Nastic et al [9] reported an increase in interobserver agreement rates after application of ER, PR, and p53 immunostaining and DNA ploidy studies. Molecular profiling can also aid in the differential diagnosis of endometrial carcinoma.…”

The prognostic role of LRIG proteins in endometrial cancer

“…The high-risk group includes women with type II EC, FIGO grade 3, and deep myometrial invasion/cervical stroma invasion according to ultrasound and/or magnetic resonance imaging [7]. All surgical treatment is performed based on the results of a diagnostic endometrial biopsy and radiological examinations, but the subjective nature of histology means that biopsy diagnoses often have poor reproducibility [8]. Moreover, histological features do not show the molecular properties of tumors, like abnormal genetic factors, epigenetic alterations, or environmental factors.…”

“…Moreover, histological features do not show the molecular properties of tumors, like abnormal genetic factors, epigenetic alterations, or environmental factors. However, the heterogenic nature of many primary tumors makes proper molecular diagnosis difficult [8], which may explain why 20% of EC that develop into aggressive and metastatic cancer are first classified as nonaggressive [9]. The molecular characteristics of tumors need to be further investigated in order to address the limitations of the histopathological diagnosis of EC.…”