A Limited Panel of Immunomarkers Can Reliably Distinguish Between Clear Cell and High-grade Serous Carcinoma of the Ovary

Abstract

The distinction of ovarian clear cell carcinomas (CCCs) from high-grade serous carcinomas (HG-SCs) is sometimes a diagnostic challenge. With the recognition that CCCs respond poorly to conventional chemotherapy there are efforts to initiate clinical trials for CCC, making accurate diagnosis critical. The purpose of this study was to test and validate a set of antibodies that could aid in the diagnosis of CCC, using a series of cases from different centers in North America. Using a test set of 133 CCCs, we identified the following markers: Cyclin E, estrogen receptor, hepatocyte nuclear factor (HNF)-1beta, Ki-67, p21, p53, and Wilms tumor (WT)1 that show significant discrimination from 200 HG-SCs. For validation, these markers were characterized on an independent set of 104 CCCs from 3 other centers. There were no significant differences in expression of these 7 markers between the independent test and validation sets of CCC. Combining all CCC cases (N=237), HNF-1beta showed the highest sensitivity (82.5%) and specificity (95.2%) for CCC, and WT1 for HG-SC (sensitivity: 79.9%, specificity: 97.4%). A diagnostic panel consisting of WT1, ER, and HNF-1beta demonstrated nearly identical performance as a panel using all 7 markers in distinguishing CCCs from HG-SCs, correctly classifying 84% of cases. Three percent of cases were misclassified and 13% carried an uninformative triple negative immunophenotype. CCCs show a distinct, reproducible immunophenotype, compared with HG-SCs, and a panel of 3 immunomarkers can serve as a diagnostic aid in problematic cases.

The Utility of Immunohistochemistry in the Differential Diagnosis of Gynecologic Disorders

“…[47][48][49][50][51][52] On the other hand, a useful panel of HNF-1b and ER was suggested in a recent study differentiating pure classic clear cell carcinoma of the endometrium from endometrioid and serous carcinomas. 52 Positive staining of more than 70% of tumor cells with HNF-1b and negative staining with ER characterized most clear cell carcinomas but not endometrioid or serous carcinomas.…”

“…[112][113][114] Serous borderline tumors are negative for p53, whereas strong expression of this marker is observed in up to 50% of serous carcinomas. 51,115 High-grade serous carcinomas usually show diffuse and strong p53 expression with a high Ki-67 proliferative index, in contrast to the low-grade serous tumors.…”

“…A prototype of clear cell carcinoma is HNF-1b (þ), WT1 (À), ER (À), PR (À), and p53 (À or þ). 51,118 On the other hand a prototype of HGSC is HNF-1b (À), WT1 (þ), ER (þ), PR (þ), and p53 (þ). Additional findings include deficient ARID1A expression in up to 57% of ovarian clear cell carcinoma but not in HGSC.…”

Calculator for ovarian carcinoma subtype prediction

“…3,7 Carcinomas with a Figure 1 Experimental design for the study detailing independent discovery of the immunohistochemical marker panel from two unrelated cohorts, prediction accuracy represented by the k statistic (k), and internal validation. 8,13,14 and added eight markers reported as differentially expressed in the literature: cyclin-dependent kinase inhibitor 2A (p16) (CDKN2A), mouse double minute 2 (MDM2), catenin (cadherin-associated protein), beta 1, 88 kDa (CTNNB1), phosphatase and tensin homolog (PTEN), mucin 5AC, oligomeric mucus/gel-forming (MUC5AC), paired box 2 (PAX2), secretoglobin, family 1A, member 1 (SCGB1A), CD44 molecule, splice variant 6 (CD44v6). [15][16][17][18][19][20][21] Three additional markers: growth differentiation factor 15 (GDF15), trefoil factor 3 (intestinal) (TFF3), dickkopf homolog 1 (DKK1) were derived from comprehensive gene expression profiling data generated using Human Exonic Evidence Based Oligonucleotide microarray (Stanford, CA, USA) or whole transcriptome sequencing, as recently described.…”

Recommendations for biomarker testing in epithelial ovarian cancer: a National Consensus Statement by the Spanish Society of Pathology and the Spanish Society of Medical Oncology

“…Immunohistochemically, CCC is characterised by PAX8 expression and no expression of WT1 (Wilms' tumour 1), ERs or PRs. Both the napsin A protein (NAPSA) and HNF-1b (hepatocyte nuclear factor 1 beta) have shown high sensitivity and specificity as CCC markers and are very useful in differential diagnosis from HGSOC [9,10].…”