Because of the rarity of Sex Cord-Stromal Tumors, only a few studies investigated their biological characteristics in children. The vast majority of data comes from previous experiences in adults, in whom, however, these tumors are characterized by different clinical behaviour and histology.
In children, the completeness of resection, favoured by an early diagnosis, and histology are important prognostic factors. In our series, all patients who underwent an initial complete excision were cured, independently from tumor size 
. Our previous study confirmed a favourable clinical course in the majority of SCST, and a more aggressive behaviour of Sertoli-Leydig cell tumors.
The diagnosis of SCST relies essentially upon morphology, while immunohistochemistry plays a minor role. As previously reported, Inhibin is expressed in the vast majority of cases, except in fibroma-thecoma, where it may be negative 
; GATA-4 has been recently found to be expressed in adult ovarian GCT and in testis SLCT 
and to be associated with an aggressive behaviour in adult Granulosa Cell Tumors 
In the present series, the immunohistochemical pattern of GATA-4 and FOG-2 expression differed among the various histotypes. Intriguingly, juvenile granulosa cell tumors, the more indolent subtype, were mostly negative for GATA-4, but showed a strong expression of FOG-2. This is in contrast with adult GCTs, which have been reported to co-express FOG-2 and GATA-4 in most cases 
. This apparent contrast may be explained by a different histogenesis of these tumors, reproducing the JGCT the phenotype of primordial follicle during fetal life, and the adult granulosa cell tumors the normal primary follicle 
It might be speculated that the overall good prognosis of JGCT can be related to a different genetic pathway with repression of GATA-4, as confirmed by the high levels of FOG-2. To further support this hypothesis, we observed that the only tumor presenting a weak positivity for GATA-4 (case 4) showed a mitotic activity superior to 21 mitoses/10 HPF, although none of JGCTs of our series could be considered clinically malignant and considering that mitotic rate is not prognostically relevant in low stage JGCT 
. The good outcome of low stage JGCT, although showing a high mitotic rate (), may be probably explained not only by the inhibiting activity of FOG-2, abundantly expressed in most JGCTs of this series, but also by an early diagnosis and prompt excision.
Bar charts showing Mitotic Rate for each Sex Cord-Stromal Tumor subgroup (A, High MI tumors and Low MI tumors for each histological subtype; B, MI for each case grouped by histology).
The phenotypic overlap between embryonic gonad and tumors was observed also in Sertoli-Leydig cell tumors: GATA-4 and FOG-2 pattern of expression replicates the phenotype of Sertoli cells during embryogenesis in the normal testis in which FOG-2 is weakly expressed and GATA-4 more frequently positive 
. In the human testis GATA-4 is expressed from early gonadal development to adulthood: in Sertoli cells it is evident through fetal and postnatal development, whilst in Leydig cells it is expressed during fetal period and after puberty, coinciding with the phases of active androgen synthesis in the testis. FOG-2 expression has been demonstrated to decrease with the progression of gonadal development 
High GATA-4 expression in tumoral cells was reported in a pediatric series of 1 testicular Sertoli cell tumor and 5 testicular Leydig cell tumors: this expression was higher in neoplastic cells than in normal adjacent Sertoli cells and Leydig cells of the same patients 
This increased expression of GATA-4 in Sertoli-Leydig cell tumors in comparison to juvenile granulosa cell tumors did not seem to be related to a more aggressive behaviour as expected: there was no apparent correlation between high mitotic rate and GATA-4 expression, whereas detection of a high FOG-2 expression could be linked to a lower tumor stage at diagnosis. These data suggest that FOG-2 might maintain its role as GATA-4 downregulator even in tumoral cells. This has already been suggested by Mannisto and colleagues who observed that in a series of yolk sac tumors the aggressive clinical behaviour was related to the higher activity of GATA-4 in the absence of FOG-2 
In the thecoma/fibroma group the expression of both FOG-2 and GATA-4 might be useful in differential diagnosis from other spindle cell tumors: 2/3 (cases 13 and 14) showed high expression of both GATA-4 and FOG-2, and the sclerosing stromal tumor (case 15) showed an intermediate positivity for GATA-4. Although the scarcity of cases in this group prevents to draw assured conclusions, some hints can be underlined. GATA-4 and FOG-2 are expressed in normal embryonal stroma: in adult tissues of mesenchymal origin, GATA-4 is less expressed and FOG-2 is lacking 
. On the contrary, their concomitant strong expression might indicate an abnormal activation of the GATA pathway of cellular proliferation and immortalization: GATA-4 may be co-responsible of the progression of these neoplasms, though they are indolent and clinically benign. On the other hand, the high expression of FOG-2 might indicate once again an inhibiting action on GATA-4-mediated proliferation and antiapoptotic activity, thus partially explaining the low mitotic rate of this subgroup.
In conclusion, our study on Sex Cord Stromal Tumors in childhood showed a possible switch to embryonal gonadal phenotype: respectively, juvenile granulosa cell tumors appeared to express a FOG-2/GATA-4 pattern in keeping with primordial ovarian follicles and Sertoli-Leydig cell tumors with embryonal testis.
The overall good prognosis of juvenile granulosa cell tumors is consistent with their low expression of GATA-4: this factor is probably involved in cell proliferation and its absence may be linked to the better outcome of JGCT. Sertoli-Leydig cell tumors, which represent the more aggressive histotype, showed a higher expression of GATA-4, conversely to what detected in JGCTs. Nevertheless, this data did not seem to have a prognostic value by itself. FOG-2 might have a more relevant prognostic value: its absent expression in advanced stage tumors, and also its higher expression in low stage and low grade tumors, may reveal a hypothetical role in inhibiting GATA-4 cell proliferation pathway.