Ovarian granulosa cell tumorigenesis in SWR-derived F1 hybrid mice: preneoplastic follicular abnormality and malignant disease progression.

A high incidence (27.5%; 174 of 633) of spontaneous, malignant ovarian granulosa cell tumors develop in (SWR x SWXJ-9)F1 hybrid females between 3 and 6 weeks. Granulosa cell tumors developed in predictable stages, starting as preneoplastic lesions appearing as hyperemic follicles on the ovarian surface. These follicles were characterized by hypertrophied theca, degenerating oocytes, and large fluid- or erythrocyte-filled antra lined by irregular masses of granulosa cells. Rapidly proliferating granulosa cells filled the antra and the theca/interstitial cells became more dysplastic as granulosa cell tumors developed. Thus the morphology of the preneoplastic lesion suggests that disturbed mechanisms for normal follicular development underlie granulosa cell tumor initiation. Estradiol treatment before but not after preneoplastic lesions appeared inhibited granulosa cell tumor formation. By 6 to 9 months 42% of these mice show metastases in major abdominal and thoracic organs. Thus this model can be experimentally analyzed both for mechanisms of granulosa cell tumor initiation and subsequent malignant progression.