FOXL2 Mutations in Granulosa Cell Tumors Occurring in Males

Lima, Joema Felipe; Jin, Long; Araujo, Ana Rose C. de; Erikson-Johnson, Michele R.; Oliveira, André M.; Sebo, Thomas J.; Keeney, Gary L.; Medeiros, Fabíola

doi:10.5858/arpa.2011-0355-oa

Cited by 52 publications

(41 citation statements)

References 12 publications

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“…14F). Our FOXL2 staining result is in accordance with the reported consistent immunohistochemical expression of FOXL2 in JGCTs 18,19 ; however, our experience has been that other testicular sex cord stromal tumors may also express FOXL2, including Sertoli cell tumor, fibrothecoma, and myoid gonadal stromal tumor, so FOXL2 positivity should not be considered specific.…”

Section: Discussionsupporting

confidence: 91%

Juvenile Granulosa Cell Tumors of the Testis

Kao

Cornejo

Ulbright

et al. 2015

American Journal of Surgical Pathology

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All authors have no conflict of interest to declare. Abstract 2The clinical and pathologic features of 70 juvenile granulosa cell tumors of the testis are presented. The patients were from 30-weeks gestational age to 10 years old; 60 of 67 (90%) whose age is known to us were < 6 months old. Sixty-two underwent gonadectomy, 6 wedge excision, and 2 only biopsy. Twenty-six tumors were left-sided, and 22 right-sided. Six occurred in an undescended testis and 2 in dysgenetic gonads. The most common presentation was a testicular mass (65%) followed by an "enlarging testis" (25%). Six of 14 patients in whom it was measured had "elevated" serum AFP, likely physiologically, and 1 had gynecomastia. The tumors measured 0.5 to 5 cm (mean, 1.7; median, 1.5) and were most commonly wellcircumscribed and typically yellow-tan; approximately 2/3 had a cystic component, while 1/3 were entirely solid. Microscopic examination typically showed a lobular growth, punctuated in 67 cases by variably-sized and shaped follicles containing material that was basophilic (21%), eosinophilic (44%), or of both characters (35%); 3 lacked follicles. In non-follicular areas, the tumor cells typically grew diffusely, but occasionally had a corded arrangement (26%) or reticular appearance (29%). The stroma was either fibrous or fibromyxoid; hemorrhage associated with hemosiderin-laiden macrophages was focally seen in 16%. The tumor cells were mostly small to medium sized with round to oval nuclei containing inconspicuous nucleoli and moderate to abundant, but occasionally scant, pale to lightly eosinophilic, sometimes vacuolated, cytoplasm; nuclear grooves were infrequent (6%). Focal columnar morphology was seen in 27% of the tumors. Mitoses were plentiful in 37% and apoptosis was prominent in 46%. Intratubular tumor was seen in 43% and entrapped seminiferous tubules in 70%. Lymphovascular invasion was present in 2 cases, rete testis involvement in 4, and necrosis in 1. Rare features/patterns included: regressed tumor with hyalinization and prominent blood vessels (13%), papillary (4%), basaloid (1%), spindle cell predominant (1%), microcystic (1%), adult granulosa cell-like (1%) 3 patterns, and hyaline globules (1%). Inhibin (16/18), calretinin (8/9), WT1 (6/7), FOXL2 (12/12), SF-1 (12/12), and SOX9 (6/11) were positive, while SALL4 and glypican-3 were consistently negative in the neoplastic granulosa cells. Only one tumor was focally positive for AFP. Juvenile granulosa cell tumor is a rare neoplasm with a wide morphologic spectrum that also occurs rarely in undescended testes and dysgenetic gonads. The solid and reticular patterns may pose diagnostic challenges but the lobular appearance and follicular differentiation are characteristic. Immunohistochemical stains may aid in its distinction from other tumors of young males, particularly yolk sac tumor, a neoplasm that peaks at a somewhat later age. Twenty-four patients with follow-up, including 4 of 6 patients treated with wedge resection /biopsy, had no evidence of disease (2-348 months; mean, 83...

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Section: Discussionsupporting

confidence: 91%

Juvenile Granulosa Cell Tumors of the Testis

Kao

Cornejo

Ulbright

et al. 2015

American Journal of Surgical Pathology

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“…Foxl2 is a particularly interesting target due to its involvement in many types of diseases, including blepharophimosis syndrome ( Jiang et al, 2013) and ovarian granulosa cell tumors (Benayoun et al, 2012). Foxl2 is also mutated in granulosa cell tumors in males (Lima et al, 2012). In addition, we provided evidence that miR-133a reduced Foxl2 expression in C2C12 cells.…”

Section: Discussionsupporting

confidence: 53%

microRNA133a TargetsFoxl2and Promotes Differentiation of C2C12 into Myogenic Progenitor Cells

Luo

Ling

et al. 2015

DNA and Cell Biology

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microRNAs are endogenous noncoding RNA molecules of *22 nucleotides that regulate gene function by modification of target mRNAs. Due to tissue specific of miR-133a and miR-1/206 for skeletal muscles, we investigated the role of miR-133a and miR-1/206 in promoting the differentiation of the C2C12 cells. The results show that directly transfecting mature miR-133a, miR-1/206, or combinations (miR-1 and miR-206, miR-1 and miR-133a, and miR-133a and miR-206) into C2C12 cells, respectively, for 5 days induces formation of myogenic progenitor cells. Overexpression of miR-133a and miR-206 in C2C12 cells greatly improved multinucleated myotube formation. microRNA-133a (miR-133a) is highly expressed during human muscle development. Using bioinformatics, we identified one putative miR-133a binding site within the 3¢-untranslated region of the mouse Foxl2 mRNA. The expression of Foxl2 was shown to be downregulated by subsequent western blot analysis.

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“…Another study looked for FOXL2 mutations in microscopic stromal proliferations resembling small foci of AGCT in association with ovarian epithelial lesions and found these to be negative (36). A small number of testicular AGCTs have been evaluated for FOXL2 mutation (37,38). In 1 study, all 4 cases were mutation negative (37), whereas in another a FOXL2 mutation was identified in 2 of 5 (40%) cases but not in the small number of testicular juvenile granulosa cell tumors, Leydig cell tumors and Sertoli-Leydig cell tumors tested (38).…”

Section: Discussionmentioning

confidence: 99%

“…A small number of testicular AGCTs have been evaluated for FOXL2 mutation (37,38). In 1 study, all 4 cases were mutation negative (37), whereas in another a FOXL2 mutation was identified in 2 of 5 (40%) cases but not in the small number of testicular juvenile granulosa cell tumors, Leydig cell tumors and Sertoli-Leydig cell tumors tested (38). Taken together, the results of the various studies indicate that FOXL2 mutation is highly sensitive and quite specific for AGCT and may be useful in the categorization of problematic ovarian sex cordstromal tumors which can sometimes be extremely difficult due to overlapping morphology between the various tumor types and between sex cord-stromal and nonsex cord-stromal tumors.…”

Section: Discussionmentioning

confidence: 99%

Uterine Tumor Resembling Ovarian Sex Cord Tumor (UTROSCT) Commonly Exhibits Positivity With Sex Cord Markers FOXL2 and SF-1 but Lacks FOXL2 and DICER1 Mutations

Croce

Kock

Boshari

et al. 2016

International Journal of Gynecological Pathology

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Uterine tumor resembling ovarian sex cord tumor (UTROSCT) is a rare neoplasm which morphologically and immunohistochemically exhibits overlap with an ovarian sex cord tumor. Although many of these neoplasms are positive with markers of ovarian sex cord-stromal tumors, staining is often limited and the pathogenesis of UTROSCT is unknown. To further explore the sex cord lineage of UTROSCT, we studied 19 of these neoplasms and examined the expression of 2 recently described markers of ovarian sex cord-stromal tumors, FOXL2, and steroidogenic factor-1. We also undertook FOXL2 and DICER1 mutation analysis in these cases; a somatic missense mutation in codon C134W (402C→G) of FOXL2 gene has been demonstrated in the vast majority (>95%) of ovarian adult granulosa cell tumors and somatic DICER1 mutations are found in approximately 60% of ovarian Sertoli-Leydig cell tumors. Ten of 19 cases (53%) exhibited nuclear immunoreactivity with FOXL2 and 11 of 19 (58%) exhibited nuclear staining with steroidogenic factor-1. Neither FOXL2 nor DICER1 mutations were identified in any case where there was sufficient tumor tissue for analysis (18 and 9 cases, respectively). Despite exhibiting an immunophenotype characteristic of a sex cord-stromal tumor, mutations in FOXL2 and DICER1, the 2 most common mutations hitherto reported in ovarian sex cord-stromal tumors, are not a feature of UTROSCT.

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FOXL2 Mutations in Granulosa Cell Tumors Occurring in Males

Abstract: The FOXL2 402C→G (C134W) mutation is also present in adult-type granulosa cell tumors occurring in men, although in a smaller proportion when compared with the rates reported in women. FOXL2 mutational analysis can be a helpful in the diagnosis of granulosa cell tumors of the testis.

Cited by 52 publications

References 12 publications

Juvenile Granulosa Cell Tumors of the Testis

Juvenile Granulosa Cell Tumors of the Testis

microRNA133a TargetsFoxl2and Promotes Differentiation of C2C12 into Myogenic Progenitor Cells

Uterine Tumor Resembling Ovarian Sex Cord Tumor (UTROSCT) Commonly Exhibits Positivity With Sex Cord Markers FOXL2 and SF-1 but Lacks FOXL2 and DICER1 Mutations

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