The role of FOXL2, SOX9, and β-catenin expression and DICER1 mutation in differentiating sex cord tumor with annular tubules from other sex cord tumors of the ovary


Sex cord tumor with annular tubules (SCTAT) is a highly rare type of ovarian sex cord-stromal tumor (SCST), the diagnosis of which remains to be challenging. The aim of this study was to scrutinize the utility of three immunohistochemical markers including Forkhead box protein 2 (FOXL2), SOX9, and β-catenin and DICER1 mutation status in distinguishing SCTATs from other ovarian SCSTs. Nine cases of SCTAT, 10 Sertoli-Leydig cell tumor (SCLT), 10 adult-type granulosa cell tumor (AGCT), and 8 juvenile-type granulosa cell tumor (JGCT) were included in the study. SCTATs were characterized by diffuse and strong expression of SOX9, focal and weak expression of FOXL2, and the absence of DICER1 mutation. However, AGCTs and JGCTs displayed strong and diffuse expression of FOXL2, focal/no immunoreaction for SOX9. SLCTs generally showed moderate intensity of FOXL2 and SOX9 expression. Nuclear β-catenin expression was observed in none of SLCT, 1/9 of SCTAT, 6/8 JGCT, and 4/10 AGCT cases, respectively. DICER1 hotspot mutation was detected in only 3 cases of SLCT and 2 cases of JGCT. We conclude that in addition to strong and diffuse SOX9 expression, weak/absent expression of FOXL2 is suggestive for the diagnosis of SCTAT. Hence, we suggest that inclusion of these two markers, SOX-9 and FOXL2, to the immunohistochemical panel helps in differentiation of SCTAT from other SCSTs in addition to morphologic findings. We also conclude that SCTATs of the ovary do not harbor DICER1 hotspot mutation.

This is a preview of subscription content, access via your institution.

Fig. 1
Fig. 2
Fig. 3

Data availability


Code availability

Not applicable.


  1. 1.

    Young RH (2018) Ovarian sex cord-stromal tumors: reflections on a 40-year experience with a fascinating group of tumors, including comments on the seminal observations of Robert E. Scully, MD. Arch Pathol Lab Med 142(12):1459–1484

    CAS  Article  Google Scholar 

  2. 2.

    Young RH (2018) Ovarian sex cord-stromal tumours and their mimics. Pathology 50(1):11

    Article  Google Scholar 

  3. 3.

    Lim D, Oliva E (2018) Ovarian sex cord-stromal tumours: an update in recent molecular advances. Pathology 50(2):178–189

    CAS  Article  Google Scholar 

  4. 4.

    Hanley KZ, Mosunjac MB (2019) Practical review of ovarian sex cord-stromal tumors. Surg Pathol Clin 12(2):587–620

    Article  Google Scholar 

  5. 5.

    Han Y, Li S, Wu L, Zhang X, Cao D (2016) Non-Peutz-Jeghers syndrome-associated ovarian sex cord tumor with annular tubules: report of a malignant case. J Obstet Gynaecol Res 42(2):224–227

    Article  Google Scholar 

  6. 6.

    Jaegle WT, Keyser EA, Messersmith L, Brady RO, Miller C (2018) Extraovarian sex cord tumor with annular tubules discovered arising from a leiomyoma. Gynecol Oncol Rep 26:17–20

    Article  Google Scholar 

  7. 7.

    Kim J, Field A, Schultz KAP, Hill DA, Stewart DR (2017) The prevalence of DICER1 pathogenic variation in population databases. Int J Cancer 141(10):2030–2036

    CAS  Article  Google Scholar 

  8. 8.

    Goulvent T, Ray-Coquard I, Borel S, Haddad V, Devouassoux-Shisheboran M, Vacher-Lavenu MC, Pujade-Laurraine E, Savina A, Maillet D, Gillet G, Treilleux I, Rimokh R (2016) DICER1 and FOXL2 mutations in ovarian sex cord-stromal tumours: a GINECO Group study. Histopathology 68(2):279–285

    Article  Google Scholar 

  9. 9.

    Rosario R, Cohen PA, Shelling AN (2014) The role of FOXL2 in the pathogenesis of adult ovarian granulosa cell tumours. Gynecol Oncol 133(2):382–387

    CAS  Article  Google Scholar 

  10. 10.

    Leung DTH, Fuller P, Chu S (2016) Impact of FOXL2 mutations on signaling in ovarian granulosa cell tumors. Int J Biochem Cell Biol 72:4

    Article  Google Scholar 

  11. 11.

    Al-Agha OM, Huwait H, Chow C, Yang W, Senz J, Kalloger SE, Huntsman DG, Young RH, Gilks CB (2011) FOXL2 is a sensitive and specific marker for sex cord-stromal tumors of the ovary. Am J Surg Pathol 35:11

    Article  Google Scholar 

  12. 12.

    Bremmer F, Behnes CL, Schildhaus HU, Gaisa NT, Reis H, Jarry H, Radzun HJ, Stroebel P, Schweyer S (2017) The role of beta-catenin mutation and SOX9 expression in sex cord-stromal tumours of the testis. Virchows Arch 470(4):421–428

    CAS  Article  Google Scholar 

  13. 13.

    Nicol B, Yao HH (2015) Gonadal identity in the absence of pro-testis factor SOX9 and pro-ovary factor beta-catenin in mice. Biol Reprod 93(2):35

    Article  Google Scholar 

  14. 14.

    Kato N, Fukase M, Motoyama T (2004) Expression of a transcription factor, SOX9, in Sertoli-stromal cell tumors of the ovary. Int J Gynecol Pathol 23(2):180–181

    Article  Google Scholar 

  15. 15.

    Barrionuevo FJ, Hurtado A, Kim GJ, Real FM, Bakkali M, Kopp JL, Sander M, Scherer G, Burgos M, Jiménez R (2016) Sox9 and Sox8 protect the adult testis from male-to-female genetic reprogramming and complete degeneration. Elife 5:e15635

  16. 16.

    Kanai Y, Hiramatsu R, Matoba S, Kidokoro T (2005) From SRY to SOX9: mammalian testis differentiation. J Biochem 138(1):13–19

    CAS  Article  Google Scholar 

  17. 17.

    Hersmus R, Kalfa N, de Leeuw B, Stoop H, Oosterhuis JW, de Krijger R, Wolffenbuttel KP, Drop SLS, Veitia RA, Fellous M, Jaubert F, Looijenga LHJ (2008) FOXL2 and SOX9 as parameters of female and male gonadal differentiation in patients with various forms of disorders of sex development (DSD). J Pathol 215(1):31–38

    CAS  Article  Google Scholar 

  18. 18.

    Buell-Gutbrod R, Ivanovic M, Montag A, Lengyel E, Fadare O, Gwin K (2011) FOXL2 and SOX9 distinguish the lineage of the sex cord-stromal cells in gonadoblastomas. Pediatr Dev Pathol 14(5):391–395

    Article  Google Scholar 

  19. 19.

    Zhao C, Bratthauer G, Barner R, Vang R (2006) Immunohistochemical analysis of SOX9 in ovarian sertoli cell tumors and other tumors in the differential diagnosis. Int J Gynecol Pathol 26:9

    Google Scholar 

  20. 20.

    Shang S, Hua F, Hu ZW (2017) The regulation of beta-catenin activity and function in cancer: therapeutic opportunities. Oncotarget 8(20):33972–33989

    Article  Google Scholar 

  21. 21.

    Chang H, Gao F, Guillou F, Taketo MM, Huff V, Behringer RR (2008) Wt1 negatively regulates beta-catenin signaling during testis development. Development 135(10):1875–1885

    CAS  Article  Google Scholar 

  22. 22.

    Kommoss S, Anglesio MS, Mackenzie R, Yang W, Senz J, Ho J, Bell L, Lee S, Lorette J, Huntsman DG, Blake Gilks C (2013) FOXL2 molecular testing in ovarian neoplasms: diagnostic approach and procedural guidelines. Mod Pathol 26(6):860–867

    CAS  Article  Google Scholar 

  23. 23.

    Kao CS, Cornejo KM, Ulbright TM, Young RH (2015) Juvenile granulosa cell tumors of the testis: a clinicopathologic study of 70 cases with emphasis on its wide morphologic spectrum. Am J Surg Pathol 39(9):1159–1169

    Article  Google Scholar 

  24. 24.

    Papanastasopoulos P, Repanti M, Damaskou V, Bravou V, Papadaki H (2008) Investigating differentiation mechanisms of the constituent cells of sex cord-stromal tumours of the ovary. Virchows Arch 453(5):465–471

    CAS  Article  Google Scholar 

  25. 25.

    Stavrinou S, Clark A, Irving J, Lee CH, Oliva E, Young R, Sriraksa R, Magdy N, van Noorden S, McCluggage WG, el-Bahrawy M (2016) Differential expression of E-cadherin and catenins in ovarian sex cord stromal tumours. Histopathology 69(2):298–306

    Article  Google Scholar 

  26. 26.

    Stewart CJ et al (2013) beta-Catenin and E-cadherin expression in stage I adult-type granulosa cell tumour of the ovary: correlation with tumour morphology and clinical outcome. Histopathology 62(2):257–266

    Article  Google Scholar 

  27. 27.

    Gullo I, Batista R, Rodrigues-Pereira P, Soares P, Barroca H, do Bom-Sucesso M, Sobrinho-Simões M (2018) Multinodular goiter progression toward malignancy in a case of DICER1 syndrome: histologic and molecular alterations. Am J Clin Pathol 149(5):379–386

    Article  Google Scholar 

  28. 28.

    Heravi-Moussavi A, Anglesio MS, Cheng SWG, Senz J, Yang W, Prentice L, Fejes AP, Chow C, Tone A, Kalloger SE, Hamel N, Roth A, Ha G, Wan ANC, Maines-Bandiera S, Salamanca C, Pasini B, Clarke BA, Lee AF, Lee CH, Zhao C, Young RH, Aparicio SA, Sorensen PHB, Woo MMM, Boyd N, Jones SJM, Hirst M, Marra MA, Gilks B, Shah SP, Foulkes WD, Morin GB, Huntsman DG (2012) Recurrent somatic DICER1 mutations in nonepithelial ovarian cancers. N Engl J Med 366(3):234–242

    CAS  Article  Google Scholar 

  29. 29.

    Kato N, Kusumi T, Kamataki A, Tsunoda R, Fukase M, Kurose A (2017) DICER1 hotspot mutations in ovarian Sertoli-Leydig cell tumors: a potential association with androgenic effects. Hum Pathol 59:41–47

    CAS  Article  Google Scholar 

Download references

Author information




SO: Designed the study, performed research, collected and analyzed data, and wrote the paper.

OH: Performed research, collected and analyzed data, and wrote the paper.

AB: Performed research and collected data.

IY: Performed research and collected data.

HS: Performed research and collected data.

EY: Designed the study, performed research, collected and analyzed data, and wrote the paper.

Corresponding author

Correspondence to Ozge Hurdogan.

Ethics declarations

Ethics approval

Permission was obtained from the Academic Committee at Istanbul Faculty of Medicine and the study was performed in compliance with ethical standards.

Consent to participate

Not applicable.

Consent for publication


Conflict of interest

The authors declare no conflicts of interest.

Additional information

To be used for non-life science journals: Not applicable.

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Onder, S., Hurdogan, O., Bayram, A. et al. The role of FOXL2, SOX9, and β-catenin expression and DICER1 mutation in differentiating sex cord tumor with annular tubules from other sex cord tumors of the ovary. Virchows Arch (2021).

Download citation


  • Sex cord tumor
  • Ovary
  • Immunohistochemistry
  • Sex cord tumor with annular tubules
  • DICER1