Abstract
Granulosa cell tumors (GCTs) carry a risk of recurrence also at an early stage, but reliable prognostic factors are lacking. We assessed clinicopathological prognostic factors and the prognostic roles of the human epidermal growth factor receptors (HER 2–4) and the transcription factor GATA4 in GCTs. We conducted a long-term follow-up study of 80 GCT patients with a mean follow-up time of 16.8 years. A tumor-tissue microarray was immunohistochemically stained for HER2–4 and GATA4. Expression of HER2–4 mRNA was studied by means of real time polymerase chain reaction and HER2 gene amplification was analyzed by means of silver in situ hybridization. The results were correlated to clinical data on recurrences and survival. We found that GCTs have an indolent prognosis, with 5-year disease-specific survival (DSS) being 97.5%. Tumor recurrence was detected in 24% of the patients at a median of 7.0 years (range 2.6–18 years) after diagnosis. Tumor stage was not prognostic of disease-free survival (DFS). Of the molecular prognostic factors, high-level expression of HER2, and GATA4, and high nuclear atypia were prognostic of shorter DFS. In multivariate analyses, high-level coexpression of HER2 and GATA4 independently predicted DFS (hazard ratio [HR] 8.75, 95% CI 2.20–39.48, P = 0.002). High-level expression of GATA4 also predicted shorter DSS (HR 3.96, 95% CI 1.45–12.57, P = 0.006). In multivariate analyses, however, tumor stage (II–III) and nuclear atypia were independent prognostic factors of DSS. In conclusion HER2 and GATA4 are new molecular prognostic markers of GCT recurrence, which could be utilized to optimize the management and follow-up of patients with early-stage GCTs.
Highlights
Granulosa cell tumor (GCT) is a rare subtype of ovarian cancer, representing 3–5% of all ovarian malignancies
Expression of HER2–4 mRNA was studied by means of real time polymerase chain reaction and HER2 gene amplification was analyzed by means of silver in situ hybridization
We found that GCTs have an indolent prognosis, with 5-year disease-specific survival (DSS) being 97.5%
Summary
Granulosa cell tumor (GCT) is a rare subtype of ovarian cancer, representing 3–5% of all ovarian malignancies. GCT presents with the juvenile and the more common adult subtype with mean age at diagnosis between 50 and 54 years [1]. Adult GCTs are characterized by an indolent, albeit unpredictable, course of disease with a recurrence risk of 20–30% even with earlystage disease [2, 3]. Adult GCTs were shown to have a distinct molecular background since a single somatic mutation (402C->G) in the gene encoding for Forkhead Box L2 (FOXL2) was found in 90–97% of GCTs [4,5,6,7]. The functional role of the FOXL2 mutation in GCTs remains unresolved.
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