High GATA-4 expression associates with aggressive behavior, whereas low anti-Mullerian hormone expression associates with growth potential of ovarian granulosa cell tumors

Context: Granulosa cell tumors (GCTs) are ovarian malignancies that produce estrogens, inhibins, and anti-Mullerian hormone (AMH). The molecular pathogenesis of GCTs is likely to involve defects in the genes regulating normal granulosa cell proliferation during folliculogenesis. Objective: The objective of this study was to test the role of factors regulating the normal granulosa cell function, i.e. AMH, inhibin-alpha, SF-1 (steroidogenic factor-1), and GATA transcription factors in the pathobiology and clinical behavior of GCTs. Design: We selected randomly a cohort of 80 GCT patients treated at our university hospital during 1971-2003, analyzed protein expression in the tumor samples embedded on a tissue microarray by immunohistochemistry, and correlated the data to clinical and histopathological parameters. Results: We found no significant differences in the immunoreactivity levels of inhibin-alpha, GATA- 6, FOG-2 (friend of GATA-2), or SF-1 in GCTs compared with normal granulosa cells. AMH expression was, however, low (i.e. reduced) in 69% of GCTs and correlated inversely with tumor size (P = 0.0025). In contrast, GATA- 4 expression was high (i.e. resembled normal granulosa cells) in 44% of GCTs and correlated positively with clinical stage and recurrence (P = 0.0232 and P = 0.0038, respectively). Fifty of the 80 patients had a follow-up for at least 10 yr, and 13 of them had recurrence(s). In multivariate analysis of recurrence, the high GATA- 4 expression remained the only independent factor ( risk ratio, 9.2; 95% confidence interval, 2.0-43.3; P = 0.0048). Conclusions: The more aggressive GCTs retain a high GATA- 4 expression, whereas the larger tumors lose the proliferation-suppressing-AMH-expression. The high GATA- 4 expression in GCTs may serve as a marker of poor prognosis.