Sertoli-Leydig Cell Tumors: Just Variants of Granulosa Cell Tumors? – FOXL2, SOX9 and SRY Distinguish the Lineage of the Sex Cord Derivatives.
Rebecca Buell-Gutbrod, Marina Ivanovic, Oluwole Fadare, Jamie Steinmetz, Anthony Montag, Ernst Lengyel, Katja Gwin. University of Chicago, IL; Vanderbilt, Nashville
Background: Sertoli-Leydig cell tumors (SLCTs) of the ovary are composed of sex-cord derivatives resembling those of the testis and a stromal component containing variable amounts of Leydig cells. Based on morphology the sex-cord derivatives have traditionally been regarded as Sertoli cells. However, the pathogenesis has yet to be elucidated and it is unclear if these cells are true Sertoli cells. FOXL2 is a member of the forkhead-winged-helix family of transcription factors and one of the first genes expressed in the development of the female gonad. It is required for proper differentiation of granulosa cells during folliculogenesis. The transcription factor SOX9 is an intermediate downstream target of SRY and is required for testis development by formation and maintenance of (pre-) Sertoli cells. The aim of our study was to further characterize the differentiation of the sex-cord derivatives by evaluating the expression of these two counteracting transcription factors and SRY.
Design: Paraffin embedded material of 10 SLCTs, one Sertoli cell (SC) hamartoma arising in a background of testicular feminization, and a TMA containing 38 granulosa cell tumors (GCTs) were examined by IHC for the expression and localization of FOXL2, SOX9 and SRY.
Results: The sex cord-stromal derivatives revealed strong nuclear staining for FOXL2 in 10/10 cases and were negative for SOX9 expression. Leydig cells were devoid of FOXL2 and SOX9 expression. The SC hamartoma exhibited strong positivity for SOX9 and did not express FOXL2. All GCTs revealed nuclear staining for FOXL2 and SOX9 negativity. SRY was not expressed in any component of the SLCTs, the SC hamartoma or the GCTs.
Conclusions: FOXL2 actively suppresses SOX9 throughout adult life via an upstream regulatory element, leading to mutually exclusive expression of these two transcription factors. Based on consistent FOXL2 expression in all SLCTs and GCTs, our findings support that the sex-cord derivatives of SLCTs are of granulosa cell lineage. SOX9 expression in the SC hamartoma is consistent with a true Sertoli cell component in this tumor. The encountered SRY negativity in the SCST is in concordance with previous studies. Of interest, SRY was not expressed in the SC harmatoma, however SRY activates SOX9 and might not be co-expressed. Our study suggests that the sex-cord derivatives of SLCTs are of granulosa cell and not of Sertoli cell lineage and may represent a morphologic variant of GCTs.
Category: Gynecologic & Obstetrics
Monday, February 28, 2011 9:30 AM
Poster Session I Stowell-Orbison/Surgical Pathology/Autopsy Awards Poster Session # 144, Monday Morning