Establishment of a Novel Histopathological Classification of High-Grade Serous Ovarian Carcinoma Correlated with Prognostically Distinct Gene Expression Subtypes.

Recently, The Cancer Genome Atlas data revealed four molecular subtypes of high-grade serous ovarian cancer (HGSOC) that exhibited distinct prognoses on the basis of a transcriptome analysis. We developed a novel histopathological classification dividing HGSOC into four subtypes: mesenchymal transition, defined by remarkable desmoplastic reaction, immune reactive by lymphocytes surrounding and infiltrating tumor, solid and proliferative by a solid growth pattern, and papilloglandular by a papillary architecture. Unsupervised hierarchical clustering revealed four clusters correlated with histopathological subtypes in both Kyoto and Niigata HGSOC gene expression microarray data sets (P < 0.001). Gene set enrichment analysis revealed pathways enriched in our histopathological classification significantly overlapped with the four Cancer Genome Atlas molecular subtypes: mesenchymal, immunoreactive, proliferative, and differentiated (P < 0.0001, respectively). In 132 HGSOC cases, progression-free survival and overall survival were best in immune reactive, whereas overall survival was worst in mesenchymal transition (P < 0.001, respectively), findings reproduced in 89 validation cases (P < 0.05, respectively). The MES_UP single-sample gene set enrichment analysis scores representing the mesenchymal molecular subtype were higher in paclitaxel responders than nonresponders (P = 0.002) in the GSE15622 data set. Taxane-containing regimens improved survival of cases with high MES_UP scores compared with nontaxane regimens (P < 0.001) in the GSE9891 data set. Our novel histopathological classification of HGSOC correlates with distinct prognostic gene expression subtypes. Mesenchymal or mesenchymal transition subtype may be particularly sensitive to taxane.