Histotype classification of ovarian carcinoma: A comparison of approaches

Abstract

Objective: Major changes in the classification of ovarian carcinoma histotypes occurred over the last two decades, resulting in the current 2014 World Health Organization (WHO) diagnostic criteria that recognize five principal histotypes: high-grade serous, low-grade serous, endometrioid, clear cell, and mucinous carcinoma. We assessed the impact of these guidelines and use of immunohistochemical (IHC) markers on classification of ovarian carcinomas in existing population-based studies.

Methods: We evaluated histotype classification for 2361 ovarian carcinomas diagnosed between 1999 and 2009 from two case-control studies using three approaches: 1. pre-2014 WHO ("historic") histotype; 2. Standardized review of pathology slides using the 2014 WHO criteria alone; and 3. An integrated IHC assessment along with the 2014 WHO criteria. We used Kappa statistics to assess agreement between approaches, and Kaplan-Meier survival curves and Cox proportional hazards models to evaluate mortality.

Results: Compared to the standardized pathologic review histotype, agreement across approaches was high (kappa = 0.892 for historic, and 0.849 for IHC integrated histotype), but the IHC integrated histotype identified more low-grade serous carcinomas and a subset of endometrioid carcinomas that were assigned as high-grade serous (n = 25). No substantial differences in histotype-specific mortality were observed across approaches.

Conclusions: Our findings suggest that histotype assignment is fairly consistent regardless of classification approach, but that progressive improvements in classification accuracy for some less common histotypes are achieved with pathologic review using the 2014 WHO criteria and with IHC integration. We additionally recommend a classification scheme to fit historic data into the 2014 WHO categories to answer histotype-specific research questions.

Keywords: Histotype; Ovarian carcinoma; Stage; Survival.

Figure 1.

Sankey diagrams of histotype assignment across the different classification approaches. Panel A: Comparison of histotype assignment for Historic Histotype (Column 1) and Standardized Pathologic Review (Column 2) for all DOVE and NCOCS cases (N=2,361). ‘Other Histology’ refers to tumors that were designated as an invasive epithelial histology other than the five principal histotypes (e.g., carcinoma NOS, adenocarcinoma NOS, mixed carcinoma). ‘Excluded After Review’ refers to tumors that were reviewed by expert pathologists at UBC but excluded due to various reasons, including insufficient tissue for histotyping, tissue in block received was not ovarian primary, etc., and ‘Unavailable Tissue’ refers to tumors that could not be obtained and were unable to be reviewed by the second approach, standardized pathologic review. Panel B: Because NCOCS cases were not evaluated for IHC Integrated Histotype, the comparison of histotype assignment for Historic Histotype (Column 1), Standardized Pathologic Review (Column 2), and IHC Integrated Histotype (Column 3) was restricted to DOVE cases assigned one of the five principal histotypes by Standardized Pathologic Review (N=1,106). ‘Insufficient Tissue/Assay Failure’ refers to tumors that either did not have enough tissue for IHC staining or had an IHC assay failure. HGSC: high-grade serous carcinoma; LGSC: low-grade serous carcinoma; EC: endometrioid carcinoma; MC: mucinous carcinoma; CCC: clear cell carcinoma; DOVE: Diseases of the Ovary and their Evaluation; NCOCS: North Carolina Ovarian Cancer Study; NOS: not otherwise specified; IHC: immunohistochemistry.

Figure 2.

Kaplan-Meier survival curves for the association between histotype and ovarian carcinoma survival by stage and histotype assignment approach. (A-C) Localized and regional stage disease. (A) Historic histotype. (B) Standardized pathologic review approach. (C) IHC integrated histotype. (D-F) Distant stage disease. (D) Historic histotype. (E) Standardized pathologic review approach. (F) IHC integrated histotype. HGSC: high-grade serous carcinoma; LGSC: low-grade serous carcinoma; EC: endometrioid carcinoma; MC: mucinous carcinoma; CCC: clear cell carcinoma; IHC: immunohistochemistry.