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

Abstract

Recently, The Cancer Genome Atlas data revealed four molecular subtypes of high-grade serous ovarian carcinoma (HGSOC) exhibiting distinct prognoses. We developed four novel HGSOC histopathological subtypes by focusing on tumor microenvironment: mesenchymal transition, defined by a remarkable desmoplastic reaction; immune reactive by lymphocytes infiltrating the 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 transcriptome data sets (P < 0.001). Gene set enrichment analysis revealed pathways enriched in our histopathological classification significantly overlapped with the four molecular subtypes: mesenchymal, immunoreactive, proliferative, and differentiated (P < 0.0001, respectively). In 132 HGSOC cases, progression-free survival and overall survival were best in the immune reactive, whereas overall survival was worst in the mesenchymal transition (P < 0.001, respectively), findings reproduced in 89 validation cases (P < 0.05, respectively). The CLOVAR_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 transcriptome subtypes. The mesenchymal transition subtype might be particularly sensitive to taxane.

Distinct preoperative clinical features predict four histopathological subtypes of high-grade serous carcinoma of the ovary, fallopian tube, and peritoneum

“…Our previous study revealed that these pathological subtypes are statistically correlated with the previously defined TCGA gene expression subtypes, and that the MT subtype is a poor prognostic factor, while the IR subtype is a favorable prognostic factor [10]. Although, in general, high-grade serous ovarian, fallopian tube, and peritoneal cancer are considered a single clinical entity because of their shared clinical behavior and treatment, some studies have found a significantly poorer survival or a non-significant trend of poorer survival for primary peritoneal tumors compared with ovarian tumors [5].…”

“…1) [10]. At least four blinded pathologists and gynecologists determined the pathological subtypes of HGSC cases.…”

“…These sub-classifications display distinct prognoses and sensitivities to chemotherapy [7–9]. We recently established four histopathological classifications of HGSC that correlate with the TCGA gene expression subtypes and prognoses: immune reactive (IR), which is defined by lymphocytes surrounding and infiltrating the malignant tissue; papillo-glandular (PG), which is defined by a papillary architecture; solid and proliferative (SP), which is defined by a solid growth pattern; and mesenchymal transition (MT), which is defined by a remarkable desmoplastic reaction [10]. Of these histopathological sub-classifications, the MT subtype has the worst prognosis, and the IR subtype has the most favorable prognosis.…”

Subtypes of Ovarian Cancer and Ovarian Cancer Screening

“…Our group reported that the progression-free and overall survival were best in the immunoreactive group, whereas the overall survival was worst in the mesenchymal transition group ( p < 0.001 for each) [38]. Expression of vascular endothelial growth factor (VEGF) inhibits tumor immunity through the accumulation of myeloid-derived suppressor cells, and contributes to poor prognosis [39].…”

Challenges and Opportunities in Studying the Epidemiology of Ovarian Cancer Subtypes

“…Mesenchymal tumors are associated with a strong stromal reaction and increased desmoplasia while immunoreactive tumors have high levels of infiltrating T-cells [6]. Recently, a pathology-based scoring system recapitulated the TCGA-defined subtypes [86]. The authors propose a scoring scheme for proliferative as tumors with “proliferative and solid growth architecture,” and differentiated as tumors with “papillary growth and glandular architecture.” This classification scheme was highly reproducible, with a reported overall average consistency of 74% across scores from six pathologists.…”