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Virilisation and juvenile granulosa cell tumor of the ovary: pathophysiology and prognostic consequences

N. Kalfa 1,2, G. Méduri 3, P. Philibert 1, C. Patte 4, B. Boizet-Bonhouré 5, M. Fellous 6, E. Thibaud 7, C. Pienkowski 8, F. Jaubert 9, M. Misrahi 3, RB. Galifer 2, Ch. Sultan 1,10.

1: Endocrinology Department of Development and Reproduction, Lapeyronie Hospital, CHU Montpellier

2: Department of Pediatric Surgery, Lapeyronie Hospital, CHU Montpellier

3: Laboratory of Molecular Genetics, Pharmacogenetics and Endocrinology, CHU Bicêtre, Paris

4: Oncology Department, Gustave Roussy Institute, Villejuif

5: Institute of Human Genetics, CNRS UPR1142, Montpellier

6: Human Genetics, Inserm 709, University of Paris 7, Cochin Hospital, Paris

7: Department of Pediatric Endocrinology, Necker- Enfants Malades Hospital, Paris

8: Department of Pediatric Endocrinology, Children Hospital, CHU Toulouse

9: Department of Anatomopathology, Necker-Enfants Malades Hospital, Paris

10: Unit of Pediatric Endocrinology-Gynaecology, Arnaud de Villeneuve Hospital, CHU Montpellier, France

 

ABSTRACT

Introduction: During a previous national multicenter study, we found that most of 30 juvenile granulose cell tumours of the ovary (JGTO) were revealed by a peripheral precocious pseudopuberty. However, unusual signs of hyperandrogenism were present in 6 cases.

Aim: To determine the physiopathology of these symptoms (abnormal expression of a gene for testicular determination (SOX9), decreased expression of a gene for the ovary determination (FOXL2), decreased expression of aromatase and the prognostic value of the hyperandrogenism in these tumours.

Material and methods: A precocious menarche, pilosis and/or increasing in size of the clitoris were present. The average plasma testosterone level was 1,1 ng/dl vs <0,2 ng/dl for the control group. An immunofluorescence (SOX9, FOXL2) and immunohistochemistry (aromatase, P450 Scc, P450C17a) marking of the tumour was performed. The FIGO stage was assigned retrospectively in accordance with the surgical and histological data. The results are compared to patients without hyperandrogenemia. results: Physiopathology: SOX9 is expressed aberrant in only 2/6 cases and FOXL2 is absent in 3/6 case, without significant difference from tumors without hyperandrogenism. The tumoral expression of aromatase is absent (n=5) or much diminished (n=1) in all cases, while 15/24 patients without virilisation presented aromatase expression in the tumor. This intratumoral aromatase deficiency appears to be responsible for signs of virilization by default conversion of testosterone to estrogen. Prognostic value: The mitotic activity is elevated in 50% of the tumors with hyperandrogenism (vs. 35% without hyperandrogenism) with extraovarian extension in one case.

Conclusion: An unusual virilization in girls having JGTO is explained by a deficiency of intratumoral aromatase. This result, combined with mitotic activity often higher and the possibility of extraovarian extension could be related to a defect in cellular differentiation characteristic of these tumors with hyperandrogenism.

 

Key words: juvenile granulose cell tumours of the ovary, hyperandrogenism, SOX9, FOXL2, aromatase