Multimodality imaging and genomics of granulosa cell tumors

  • Sherif Elsherif
  • Matthew BourneEmail author
  • Erik Soule
  • Chandana Lall
  • Priya Bhosale
Special Section : Ovarian Cancer



The purpose of this article is to review the imaging findings and genomics of granulosa cell tumors (GCTs) in order to aid in diagnosis and management of GCTs. GCTs are the most common type of sex cord-stromal tumors of the ovary. They are usually diagnosed initially with ultrasound and are subsequently further characterized with CT and MRI. PET/CT is often ordered as well to measure the extent of disease and for follow-up, but its usefulness is in question as some GCTs lack FDG avidity. There is significant variability in imaging phenotypes of GCTs, ranging from mostly cystic to almost solid. More resources have recently been dedicated to understanding the genetics and molecular mechanisms of GCT development. Current research shows that the main cause of GCT carcinogenesis is the FOXL2 mutation, but there are several other noteworthy mutations that contribute to the pathogenesis of this disease. Certain mutations, like GATA4, are known to be associated with more aggressive disease and higher rates of recurrence.


Using this information, imaging protocols can be altered depending on the genotype of the tumor. Further understanding of the genetic alterations that underpin the development of GCTs is indicated as genotypic knowledge could be used to guide optimal imaging and management strategies.


Ovary Ovarian neoplasms Sex cord-gonadal stromal tumors Granulosa cell tumor 


Compliance with ethical standards

Conflict of interest

The authors declare that they have no disclosure or conflict of interests.


  1. 1.
    Young RH (2005) Sex cord-stromal tumors of the ovary and testis: their similarities and differences with consideration of selected problems. Modern Pathology: An Official Journal of the United States and Canadian Academy of Pathology, Inc 18(Suppl 2):81. CrossRefGoogle Scholar
  2. 2.
    Lack EE, Perez-Atayde AR, Murthy AS, Goldstein DP, Crigler JF, Vawter GF (1981) Granulosa theca cell tumors in premenarchal girls: a clinical and pathologic study of ten cases. Cancer 48 (8):1846–1854CrossRefGoogle Scholar
  3. 3.
    Zhang H, Zhang H, Gu S, Zhang Y, Liu X, Zhang G (2018) MR findings of primary ovarian granulosa cell tumor with focus on the differentiation with other ovarian sex cord-stromal tumors. J Ovarian Res 11 (1):46. CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Li J, Bao R, Peng S, Zhang C (2018) The molecular mechanism of ovarian granulosa cell tumors. Journal of Ovarian Research 11 (13)Google Scholar
  5. 5.
    Thomakos N, Biliatis I, Koutroumpa I, Sotiropoulou M, Bamias A, Liontos M, Vlachos G, Rodolakis A (2016) Prognostic factors for recurrence in early stage adult granulosa cell tumor of the ovary. Arch Gynecol Obstet 294 (5):1031–1036. CrossRefPubMedGoogle Scholar
  6. 6.
    Inada Y, Nakai G, Yamamoto K, Yamada T, Hirose Y, Terai Y, Ohmichi M, Narumi Y (2018) Rapidly growing juvenile granulosa cell tumor of the ovary arising in adult: a case report and review of the literature. J Ovarian Res 11 (1):100. CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Elbachiri M, Taleb A, Derrabi N, Bouchbika Z, Benchakroun N, Jouhadi H, Tawfiq N, Sahraoui S, Benider A (2017) Adult-type granulosa cell tumor of the testis: report of a case and review of literature. Pan Afr Med J 26:198. CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Boyce EA, Costaggini I, Vitonis A, Feltmate C, Muto M, Berkowitz R, Cramer D, Horowitz NS (2009) The epidemiology of ovarian granulosa cell tumors: a case-control study. Gynecol Oncol 115 (2):221–225. CrossRefPubMedGoogle Scholar
  9. 9.
    Skinner MK, Schmidt M, Savenkova MI, Sadler-Riggleman I, Nilsson EE (2008) Regulation of granulosa and theca cell transcriptomes during ovarian antral follicle development. Mol Reprod Dev 75 (9):1457-1472. CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Stein M, Koenigsberg M, Han M (1996) US case of the day. Adult-type granulosa cell tumor. Radiographics 16 (1):200-203. CrossRefPubMedGoogle Scholar
  11. 11.
    Ko SF, Wan YL, Ng SH, Lee TY, Lin JW, Chen WJ, Kung FT, Tsai CC (1999) Adult ovarian granulosa cell tumors: spectrum of sonographic and CT findings with pathologic correlation. AJR Am J Roentgenol 172 (5):1227–1233. CrossRefPubMedGoogle Scholar
  12. 12.
    Kim JH, Yoon S, Park M, Park HO, Ko JJ, Lee K, Bae J (2011) Differential apoptotic activities of wild-type FOXL2 and the adult-type granulosa cell tumor-associated mutant FOXL2 (C134 W). Oncogene 30 (14):1653–1663. CrossRefPubMedGoogle Scholar
  13. 13.
    Suh D-S, Oh HK, Kim J-H, Park S, Shin E, Lee K, Kim Y-H, Bae J (2015) Identification and Validation of Differential Phosphorylation Sites of the Nuclear FOXL2 Protein as Potential Novel Biomarkers for Adult-Type Granulosa Cell Tumors. J Proteome Res 14 (6):2446–2456. CrossRefPubMedGoogle Scholar
  14. 14.
    Leung DTH, Fuller PJ, Chu S (2016) Impact of FOXL2 mutations on signaling in ovarian granulosa cell tumors. Int J Biochem Cell Biol 72:51-54. CrossRefPubMedGoogle Scholar
  15. 15.
    Jamieson S, Fuller PJ (2012) Molecular pathogenesis of granulosa cell tumors of the ovary. Endocr Rev 33 (1):109–144. CrossRefPubMedGoogle Scholar
  16. 16.
    Fuller PJ, Leung D, Chu S (2017) Genetics and genomics of ovarian sex cord-stromal tumors. Clin Genet 91 (2):285–291. CrossRefPubMedGoogle Scholar
  17. 17.
    Farkkila A, Haltia UM, Tapper J, McConechy MK, Huntsman DG, Heikinheimo M (2017) Pathogenesis and treatment of adult-type granulosa cell tumor of the ovary. Ann Med 49 (5):435–447. CrossRefPubMedGoogle Scholar
  18. 18.
    Anttonen M, Unkila-Kallio L, Leminen A, Butzow R, Heikinheimo M (2005) High GATA-4 expression associates with aggressive behavior, whereas low anti-Müllerian hormone expression associates with growth potential of ovarian granulosa cell tumors. The Journal of Clinical Endocrinology and Metabolism 90 (12):6529–6535. CrossRefPubMedGoogle Scholar
  19. 19.
    Färkkilä A, Pihlajoki M, Tauriala H, Bützow R, Leminen A, Unkila-Kallio L, Heikinheimo M, Anttonen M (2011) Serum vascular endothelial growth factor A (VEGF) is elevated in patients with ovarian granulosa cell tumor (GCT), and VEGF inhibition by bevacizumab induces apoptosis in GCT in vitro. The Journal of Clinical Endocrinology and Metabolism 96 (12):1973. CrossRefGoogle Scholar
  20. 20.
    Chang HL, Pahlavan N, Halpern EF, MacLaughlin DT (2009) Serum Müllerian Inhibiting Substance/anti-Müllerian hormone levels in patients with adult granulosa cell tumors directly correlate with aggregate tumor mass as determined by pathology or radiology. Gynecol Oncol 114 (1):57–60. CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Kalfa N, Veitia RA, Benayoun BA, Boizet-Bonhoure B, Sultan C (2009) The new molecular biology of granulosa cell tumors of the ovary. Genome Med 1 (8):81. CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Tsoi M, Laguë M-N, Boyer A, Paquet M, Nadeau M-È, Boerboom D (2013) Anti-VEGFA Therapy Reduces Tumor Growth and Extends Survival in a Murine Model of Ovarian Granulosa Cell Tumor. Transl Oncol 6 (3):226–233CrossRefGoogle Scholar
  23. 23.
    Dridi M, Chraiet N, Batti R, Ayadi M, Mokrani A, Meddeb K, Yahiaoui Y, Raies H, Mezlini A (2018) Granulosa Cell Tumor of the Ovary: A Retrospective Study of 31 Cases and a Review of the Literature. Int J Surg Oncol 2018:4547892. CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Khosla D, Dimri K, Pandey AK, Mahajan R, Trehan R (2014) Ovarian Granulosa Cell Tumor: Clinical Features, Treatment, Outcome, and Prognostic Factors. N Am J Med Sci 6 (3):133–138. CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Evans AT, Gaffey TA, Malkasian GD, Annegers JF (1980) Clinicopathologic review of 118 granulosa and 82 theca cell tumors. Obstet Gynecol 55 (2):231–238PubMedGoogle Scholar
  26. 26.
    Lappöhn RE, Burger HG, Bouma J, Bangah M, Krans M, de Bruijn HW (1989) Inhibin as a marker for granulosa-cell tumors. The New England Journal of Medicine 321 (12):790–793. CrossRefPubMedGoogle Scholar
  27. 27.
    Mom CH, Engelen MJA, Willemse PHB, Gietema JA, ten Hoor KA, de Vries EGE, van der Zee AGJ (2007) Granulosa cell tumors of the ovary: the clinical value of serum inhibin A and B levels in a large single center cohort. Gynecol Oncol 105 (2):365–372. CrossRefPubMedGoogle Scholar
  28. 28.
    Kottarathil VD, Antony MA, Nair IR, Pavithran K (2013) Recent advances in granulosa cell tumor ovary: a review. Indian journal of surgical oncology 4 (1):37–47. CrossRefPubMedGoogle Scholar
  29. 29.
    Färkkilä A, Koskela S, Bryk S, Alfthan H, Bützow R, Leminen A, Puistola U, Tapanainen JS, Heikinheimo M, Anttonen M, Unkila-Kallio L (2015) The clinical utility of serum anti-Müllerian hormone in the follow-up of ovarian adult-type granulosa cell tumors–A comparative study with inhibin B. Int J Cancer 137 (7):1661–1671. CrossRefPubMedGoogle Scholar
  30. 30.
    Levin G, Zigron R, Haj-Yahya R, Matan LS, Rottenstreich A (2018) Granulosa cell tumor of ovary: A systematic review of recent evidence. Eur J Obstet Gynecol Reprod Biol 225:57–61. CrossRefPubMedGoogle Scholar
  31. 31.
    Seung Eun J, Jae Mun L, Sung Eun R, Jae Young B, Jung Im J, Seong Tai H (2002) CT and MR Imaging of Ovarian Tumors with Emphasis on Differential Diagnosis1. Radiographics 22 (6):1305. CrossRefGoogle Scholar
  32. 32.
    Jung SE, Rha SE, Lee JM, Park SY, Oh SN, Cho KS, Lee EJ, Byun JY, Hahn ST (2005) CT and MRI Findings of Sex Cord-Stromal Tumor of the Ovary. AJR Am J Roentgenol 185 (1):207-215. CrossRefPubMedGoogle Scholar
  33. 33.
    Kim SH, Kim SH (2002) Granulosa cell tumor of the ovary: common findings and unusual appearances on CT and MR. J Comput Assist Tomogr 26 (5):756–761CrossRefGoogle Scholar
  34. 34.
    Iyer VR, Lee SI (2010) MRI, CT, and PET/CT for Ovarian Cancer Detection and Adnexal Lesion Characterization. AJR Am J Roentgenol 194 (2):311–321. CrossRefPubMedGoogle Scholar
  35. 35.
    Mansour GM, El-Lamie IK, El-Sayed HM, Ibrahim AM, Laban M, Abou-Louz SK, Abd Allah MY, El-Mahallawi MN, El-Lamie KI, Gad-Allah M (2009) Adnexal mass vascularity assessed by 3-dimensional power Doppler: does it add to the risk of malignancy index in prediction of ovarian malignancy?: four hundred-case study. Int J Gynecol Cancer 19 (5):867–872. CrossRefPubMedGoogle Scholar
  36. 36.
    Kinkel K, Lu Y, Mehdizade A, Pelte M-F, Hricak H (2005) Indeterminate Ovarian Mass at US: Incremental Value of Second Imaging Test for Characterization—Meta-Analysis and Bayesian Analysis. Radiology 236 (1):85–94. CrossRefPubMedGoogle Scholar
  37. 37.
    Adusumilli S, Hussain HK, Caoili EM, Weadock WJ, Murray JP, Johnson TD, Chen Q, Desjardins B (2006) MRI of Sonographically Indeterminate Adnexal Masses. AJR Am J Roentgenol 187 (3):732–740. CrossRefPubMedGoogle Scholar
  38. 38.
    Inoue C, Fujii S, Nosaka K, Mukuda N, Fukunaga T, Ogawa T (2018) A Small Granulosa Cell Tumor of the Ovary Incidentally Detected on Diffusion-weighted Images. Magn Reson Med Sci.
  39. 39.
    Morikawa K, Hatabu H, Togashi K, Kataoka ML, Mori T, Konishi J (1997) Granulosa cell tumor of the ovary: MR findings. J Comput Assist Tomogr 21 (6):1001–1004CrossRefGoogle Scholar
  40. 40.
    Thomassin-Naggara I, Aubert E, Rockall A, Jalaguier-Coudray A, Rouzier R, Darai E, Bazot M (2013) Adnexal masses: development and preliminary validation of an MR imaging scoring system. Radiology 267 (2):432–443. CrossRefPubMedGoogle Scholar
  41. 41.
    Pereira PN, Sarian LO, Yoshida A, Araújo KG, Barros RH, Baião AC, Parente DB, Derchain S (2018) Accuracy of the ADNEX MR scoring system based on a simplified MRI protocol for the assessment of adnexal masses. Diagn Interv Radiol 24 (2):63PubMedPubMedCentralGoogle Scholar
  42. 42.
    Gunyeli I, Bozkurt KK, Yalcin Y, Tatar B, Cerci SS, Erdemoglu E (2014) Granulosa cell tumor and concurrent endometrial cancer with (18)F-FDG uptake. Hell J Nucl Med 17 (2):153-155PubMedGoogle Scholar
  43. 43.
    Horny HP, Marx L, Krober S, Luttges J, Kaiserling E, Dietl J (1999) Granulosa cell tumor of the ovary. Immunohistochemical evidence of low proliferative activity and virtual absence of mutation of the p53 tumor-suppressor gene. Gynecol Obstet Invest 47 (2):133–138.
  44. 44.
    Caoduro C, Ungureanu CM, Singeorzan CM, Angoue O, Blagosklonov O, Boulahdour H (2013) Granulosa cell tumor of the ovary with high FDG uptake. Clin Nucl Med 38 (7):553–556. CrossRefPubMedGoogle Scholar
  45. 45.
    Tanizaki Y, Kobayashi A, Shiro M, Ota N, Takano R, Mabuchi Y, Yagi S, Minami S, Terada M, Ino K (2014) Diagnostic value of preoperative SUVmax on FDG-PET/CT for the detection of ovarian cancer. Int J Gynecol Cancer 24 (3):454–460. CrossRefPubMedGoogle Scholar
  46. 46.
    Miller BE, Barron BA, Wan JY, Delmore JE, Silva EG, Gershenson DM (1997) Prognostic factors in adult granulosa cell tumor of the ovary. Cancer 79 (10):1951–1955CrossRefGoogle Scholar
  47. 47.
    Mutch DG, Prat J (2014) 2014 FIGO staging for ovarian, fallopian tube and peritoneal cancer. Gynecol Oncol 133 (3):401–404. CrossRefPubMedGoogle Scholar
  48. 48.
    Berek JS, Kehoe ST, Kumar L, Friedlander M (2018) Cancer of the ovary, fallopian tube, and peritoneum. Int J Gynaecol Obstet 143 Suppl 2:59–78. CrossRefPubMedGoogle Scholar
  49. 49.
    Pankratz E, Boyes DA, White GW, Galliford BW, Fairey RN, Benedet JL (1978) Granulosa cell tumors. A clinical review of 61 cases. Obstet Gynecol 52 (6):718–723PubMedGoogle Scholar
  50. 50.
    Schumer ST, Cannistra SA (2003) Granulosa cell tumor of the ovary. J Clin Oncol 21 (6):1180-1189. CrossRefPubMedGoogle Scholar
  51. 51.
    Chan JK, Zhang M, Kaleb V, Loizzi V, Benjamin J, Vasilev S, Osann K, Disaia PJ (2005) Prognostic factors responsible for survival in sex cord stromal tumors of the ovary–a multivariate analysis. Gynecol Oncol 96 (1):204-209. CrossRefPubMedGoogle Scholar
  52. 52.
    Zhang M, Cheung MK, Shin JY, Kapp DS, Husain A, Teng NN, Berek JS, Osann K, Chan JK (2007) Prognostic factors responsible for survival in sex cord stromal tumors of the ovary–an analysis of 376 women. Gynecol Oncol 104 (2):396–400. CrossRefPubMedGoogle Scholar
  53. 53.
    Seagle BL, Ann P, Butler S, Shahabi S (2017) Ovarian granulosa cell tumor: A National Cancer Database study. Gynecol Oncol 146 (2):285-291. CrossRefPubMedGoogle Scholar
  54. 54.
    Zhao SH, Li HM, Qiang JW, Wang DB, Fan H (2018) The value of MRI for differentiating benign from malignant sex cord-stromal tumors of the ovary: emphasis on diffusion-weighted MR imaging. J Ovarian Res 11 (1):73. CrossRefPubMedPubMedCentralGoogle Scholar
  55. 55.
    Shinagare AB, Meylaerts LJ, Laury AR, Mortele KJ (2012) MRI features of ovarian fibroma and fibrothecoma with histopathologic correlation. AJR Am J Roentgenol 198 (3):W296–W303. CrossRefPubMedGoogle Scholar
  56. 56.
    Kobayashi E, Yokoyama T, Nakagawa S, Matsuzaki S, Kimura T, Ueda YJGO (2013) Pedunculated sub-serous leiomyosarcoma mimicking ovarian cancer: case report and review of literature. 3 (157):2161–0932.1000157Google Scholar
  57. 57.
    Lee JH, Jeong YK, Park JK, Hwang JC (2003) “Ovarian vascular pedicle” sign revealing organ of origin of a pelvic mass lesion on helical CT. AJR Am J Roentgenol 181 (1):131–137CrossRefGoogle Scholar
  58. 58.
    Gershenson DM (1994) Management of early ovarian cancer: germ cell and sex cord-stromal tumors. Gynecol Oncol 55 (3 Pt 2):62Google Scholar
  59. 59.
    van Meurs HS, Bleeker MC, van der Velden J, Overbeek LI, Kenter GG, Buist MR (2013) The incidence of endometrial hyperplasia and cancer in 1031 patients with a granulosa cell tumor of the ovary: long-term follow-up in a population-based cohort study. Int J Gynecol Cancer 23 (8):1417–1422. CrossRefPubMedGoogle Scholar
  60. 60.
    Iavazzo C, Gkegkes ID, Vrachnis N (2015) Fertility sparing management and pregnancy in patients with granulosa cell tumour of the ovaries. J Obstet Gynaecol 35 (4):331–335. CrossRefPubMedGoogle Scholar
  61. 61.
    Uygun K, Aydiner A, Saip P, Kocak Z, Basaran M, Dincer M, Topuz E (2003) Clinical parameters and treatment results in recurrent granulosa cell tumor of the ovary. Gynecol Oncol 88 (3):400-403CrossRefGoogle Scholar
  62. 62.
    Zanagnolo V, Pasinetti B, Sartori E (2004) Clinical review of 63 cases of sex cord stromal tumors. Eur J Gynaecol Oncol 25 (4):431–438PubMedGoogle Scholar
  63. 63.
    Sonoyama A, Kanda M, Ojima Y, Kizaki T, Ohara N (2016) Aggressive Granulosa Cell Tumor of the Ovary with Rapid Recurrence: a Case Report and Review of the Literature. Kobe J Med Sci 61 (4):E109–114Google Scholar
  64. 64.
    Hauspy J, Beiner ME, Harley I, Rosen B, Murphy J, Chapman W, Le LW, Fyles A, Levin W (2011) Role of adjuvant radiotherapy in granulosa cell tumors of the ovary. Int J Radiat Oncol Biol Phys 79 (3):770–774. CrossRefPubMedGoogle Scholar
  65. 65.
    Mangili G, Ottolina J, Gadducci A, Giorda G, Breda E, Savarese A, Candiani M, Frigerio L, Scarfone G, Pignata S, Rossi R, Marinaccio M, Lorusso D (2013) Long-term follow-up is crucial after treatment for granulosa cell tumours of the ovary. Br J Cancer 109 (1):29–34. CrossRefPubMedPubMedCentralGoogle Scholar
  66. 66.
    Stuart GC, Dawson LM (2003) Update on granulosa cell tumours of the ovary. Curr Opin Obstet Gynecol 15 (1):33–37. CrossRefPubMedGoogle Scholar
  67. 67.
    Salani R, Khanna N, Frimer M, Bristow RE, Chen LM (2017) An update on post-treatment surveillance and diagnosis of recurrence in women with gynecologic malignancies: Society of Gynecologic Oncology (SGO) recommendations. Gynecol Oncol 146 (1):3–10. CrossRefGoogle Scholar
  68. 68.
    Doubeni CA, Doubeni AR, Myers AE (2016) Diagnosis and Management of Ovarian Cancer. Am Fam Physician 93 (11):937–944PubMedGoogle Scholar
  69. 69.
    Ray-Coquard I, Brown J, Harter P, Provencher DM, Fong PC, Maenpaa J, Ledermann JA, Emons G, Rigaud DB, Glasspool RM, Mezzanzanica D, Colombo N (2014) Gynecologic Cancer InterGroup (GCIG) consensus review for ovarian sex cord stromal tumors. Int J Gynecol Cancer 24 (9 Suppl 3):S42–47. CrossRefPubMedGoogle Scholar
  70. 70.
    Thrall MM, DeLoia JA, Gallion H, Avril N (2007) Clinical use of combined positron emission tomography and computed tomography (FDG-PET/CT) in recurrent ovarian cancer. Gynecol Oncol 105 (1):17–22. CrossRefPubMedGoogle Scholar
  71. 71.
    Raj G, Proietto A, Jaaback K (2009) Positron emission tomography and granulosa cell tumor recurrence: a report of 2 cases. Int J Gynecol Cancer 19 (9):1542–1544. CrossRefPubMedGoogle Scholar
  72. 72.
    Huang YT, Lee JC, Kumar ASR (2009) Variable F-18 fluorodeoxyglucose avidity of metastatic recurrent adult granulosa cell tumor. Clin Nucl Med 34 (10):710-712. CrossRefPubMedGoogle Scholar
  73. 73.
    Manganaro L, Gigli S, Antonelli A, Saldari M, Tomao F, Marchetti C, Anastasi E, Laghi A (2018) Imaging strategy in recurrent ovarian cancer: a practical review. Abdom Radiol (NY).
  74. 74.
    Sohaib SAA, Reznek RH (2007) MR imaging in ovarian cancer. Cancer imaging: the official publication of the International Cancer Imaging Society 7 Spec No A (Special issue A):S119–S129.
  75. 75.
    Low RN, Barone RM, Lucero J (2015) Comparison of MRI and CT for predicting the Peritoneal Cancer Index (PCI) preoperatively in patients being considered for cytoreductive surgical procedures. Ann Surg Oncol 22 (5):1708-1715CrossRefGoogle Scholar

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Authors and Affiliations

  1. 1.Department of RadiologyUniversity of Florida College of Medicine-JacksonvilleJacksonvilleUSA
  2. 2.Department of RadiologyMedStar Health/Georgetown University Hospital ProgramWashingtonUSA
  3. 3.Department of Diagnostic RadiologyThe University of Texas MD Anderson Cancer CenterHoustonUSA

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