Clinicopathologic Analysis of Low-stage Sporadic Ovarian Carcinomas A Reappraisal

Current histologic criteria endorsed by World Health Organization for surface epithelial ovarian tumors suffer from less than optimal reproducibility and correlation with clinical outcomes. A modified approach for histologic subclassification of ovarian carcinomas (OCs), proposed by the group of Gilks and colleagues, has been shown to be reproducible and clinically meaningful. We hypothesized that this approach could be validated using a well-annotated, external cohort of OCs with detailed immunophenotypic, genotypic, and clinical data. The cohort comprised 91 patients with low-stage (FIGO stage I/II) OC who underwent primary surgical management at our institution from 1980 to 2000. The clinical and histologic features of this cohort were reported in 2004. In this study we rereviewed the hematoxylin and eosin slides and reassigned histologic type using the criteria proposed by Gilks and colleagues. p53 and Wilms tumor 1 (WT1) expressions were evaluated using standard immunohistochemical techniques on a tissue microarray. Absence of (null) or strong and diffuse p53 staining in >75% of tumor cells (overexpression) was interpreted as aberrant p53 expression, in contrast to the 2004 study in which the "null" result had been interpreted as negative. Direct TP53 gene sequencing of the entire coding region had been performed on all cases with available tissue. Relationships between survival and the following parameters were studied: tumor cell type, histologic grade, stage, p53 and WT1 expression, TP53 mutation, and presence of associated endometriosis. Results were compared with those of the 2004 study, at which time only TP53 mutation was shown to correlate with adverse survival; notably, TP53 mutation did not correlate with p53 expression by immunohistochemical analysis. After review, presence of TP53 mutations, WT1 positivity, and aberrant p53 expression were strongly associated with high-grade serous histology (P=0.0001). Modification of p53 staining assessment revealed strong correlations with TP53 mutation status, which was superior to the positive versus negative approach used previously (P=0.0005). Redefined histologic criteria revealed a stronger association between the high-grade serous type and WT1 positivity (P=0.02). Prolonged 10-year disease-specific and progression-free survival were associated with endometrioid histology (P<0.02; 94%+/- 4% vs. 53%+/- 7% and 96%+/- 4% vs. 50%+/- 7%, respectively). Inferior 10-year disease-specific survival and progression-free survival were associated with high histologic grade (vs. low and intermediate; P<0.01; 54%+/- 7% vs. 89%+/- 6% and 56%+/- 7% vs. 89%+/- 6%, respectively), presence of TP53 mutation (P<0.04; 54%+12% vs. 64%+10% and 34%+12% vs. 70%+/- 6%, respectively), aberrant p53 expression (P<0.02; 35%+/- 12% vs. 75%+/- 7% and 36%+/- 12% vs. 73%+/- 7%, respectively), and absence of associated endometriosis (P=0.01; 48%+/- 9% vs. 80%+/- 6% and 51%+/- 9% vs. 80%+/- 6%, respectively). In addition, inferior 10-year PFS was associated with WT1 positivity (P=0.01; 42%+/- 7% vs. 72%+/- 7%) and high substage (IA-IB vs. IC-IIC; P=0.04; 53%+/- 7% vs. 81%+/- 8%). These results validate updated approaches to scoring p53 expression as well as the revised criteria proposed by the group of Gilks and colleagues.