Biomarker-Based Ovarian Carcinoma Typing: A Histologic Investigation in the Ovarian Tumor Tissue Analysis Consortium

Abstract

Background Ovarian carcinoma is composed of five major histological types which associate with outcome and predict therapeutic response. Our aim was to evaluate histological type assessments across centres participating in the Ovarian Tumor Tissue Analysis (OTTA) consortium using an immunohistochemical (IHC) prediction model. Methods Tissue microarrays (TMAs) and clinical data were available for 524 pathologically confirmed ovarian carcinomas. Centralized IHC was performed for ARID1A, CDKN2A, DKK1, HNF1B, MDM2, PGR, TP53, TFF3, VIM, and WT1, and three histological type assessments were compared: the original pathologic type, an IHC-based calculated type (termed TB_COSPv2), and a WT1-assisted TMA core review. Results The concordance between TB_COSPv2 type and original type was 73%. Applying WT1-assisted core review, the remaining 27% discordant cases subdivided into unclassifiable (6%), TB_COSPv2 error (6%), and original type error (15%). The largest discordant subgroup was classified as endometrioid carcinoma (EC) by original type and as high-grade serous carcinoma (HGSC) by TB_COSPv2. When TB_COSPv2 classification was used, the difference in overall survival of EC compared to HGSC became significant (RR 0.60, 95% CI 0.37–0.93, p=0.021), consistent with previous reports. In addition, 71 cases with unclear original type could be histologically classified by TB_COSPv2. Conclusions Research cohorts, particularly those across different centres within consortia, show significant variability in original histological type diagnosis. Our IHC-based reclassification produced more homogeneous types with respect to outcome than original type. Impact Biomarker-based classification of ovarian carcinomas is feasible, improves comparability of results across research studies, and can reclassify cases which lack reliable original pathology.

Time to diagnosis of Type I or II invasive epithelial ovarian cancers: a multicentre observational study using patient questionnaire and primary care records

“…Central pathological review was not undertaken before this analysis. Although there is evidence of discordance in histological subtyping between local and expert review, this relates to reclassification of high‐grade endometrioid, high‐grade mixed and undifferentiated into high‐grade serous 32. This was anticipated when we undertook our classification into Type I and Type II disease and therefore does not affect our analysis.…”

Trefoil factor 3 expression in epithelial ovarian cancer exerts a minor effect on clinicopathological parameters

“…Ovarian carcinomas of different histological types originate from different precursor cells; thus, they retain specific gene and biomarker expression profiles (2). Ovarian cancer subtyping remains one of the major challenges in order to establish prognostic and predictive markers.…”

“…However, histological subtypes other than serous EOC were underrepresented. Under the assumption that TFF3 is part of the subtype markers for different histopathological entities of ovarian cancer, larger studies are required in order to clearly differentiate between the different histological subtypes (2). In particular, the subgroup of mucinous EOC should be further investigated due to its similarities to gastrointestinal tumors.…”

“…Histological subtyping is a reasonable first stratification; however, the identification of prognostic and predictive biomarkers remains a major challenge in order to establish targeted therapies. The five major histological/morphological types of ovarian carcinoma are as follows: High-grade serous carcinoma (68%), clear cell (12%), endometrioid (11%), mucinous (3%) and low-grade serous carcinoma (3%) (2).…”

“…Furthermore, TFF3 has been found to be involved in gastric cancer progression (5). TFF3 is part of the marker panel that was selected for the calculator for ovarian carcinoma subtype prediction, introduced by Kölbel et al in 2011, as being most predictive of ovarian carcinoma subtype in both the archival and the tumor bank cohorts (2). The selection of TFF3 was based on comprehensive gene expression profiling data (2,6).…”