Complex immunohistochemical and molecular study on 5 cases of ovarian juvenile granulosa cell tumors reveals a consistent alteration in the PI3K/AKT/mTOR signaling pathway
Jazyk angličtina Země Velká Británie, Anglie Médium electronic
Typ dokumentu časopisecké články
PubMed
39773640
PubMed Central
PMC11707838
DOI
10.1186/s13000-025-01599-1
PII: 10.1186/s13000-025-01599-1
Knihovny.cz E-zdroje
- Klíčová slova
- Immunohistochemistry, Juvenile granulosa cell tumor, NGS, Ovary, Sex cord-stromal tumors,
- MeSH
- dítě MeSH
- fosfatidylinositol-3-kinasy genetika metabolismus MeSH
- fosfohydroláza PTEN genetika metabolismus MeSH
- imunohistochemie * MeSH
- lidé MeSH
- metylace DNA MeSH
- mladiství MeSH
- nádor z folikulárních buněk * patologie genetika metabolismus MeSH
- nádorové biomarkery * genetika analýza metabolismus MeSH
- nádory vaječníků * patologie genetika metabolismus MeSH
- protoonkogenní proteiny c-akt * metabolismus genetika MeSH
- signální transdukce * MeSH
- TOR serin-threoninkinasy * metabolismus MeSH
- Check Tag
- dítě MeSH
- lidé MeSH
- mladiství MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- fosfatidylinositol-3-kinasy MeSH
- fosfohydroláza PTEN MeSH
- MTOR protein, human MeSH Prohlížeč
- nádorové biomarkery * MeSH
- protoonkogenní proteiny c-akt * MeSH
- PTEN protein, human MeSH Prohlížeč
- TOR serin-threoninkinasy * MeSH
BACKGROUND: Juvenile granulosa cell tumor (JGCT) of the ovary is a rare tumor with distinct clinicopathological and hormonal features primarily affecting young women and children. We conducted a complex clinicopathological, immunohistochemical, and molecular analysis of five cases of JGCT. METHODS: The immunohistochemical examination was performed with 32 markers, including markers that have not been previously investigated. Moreover, DNA next-generation sequencing (NGS) and PTEN methylation analysis was performed. RESULT: We found the expression of calretinin, inhibin A, SF1, FOXL2, CD99, CKAE1/3, ER, PR, AR in all cases. WT1 was expressed in one case. Conversely, the expression of p16, OCT3/4, SALL4, GATA3, Napsin A, SATB2, MUC4, TTF1, and CAIX was completely negative. All tumors showed the wild-type pattern of p53 expression. Regarding predictive markers, all tumors were HER2 negative and did not express PD-L1. Mismatch repair proteins (MMR) showed no loss or restriction of expression, similarly to ARID1A, DPC4, BRG1, and INI1. The molecular analysis revealed AKT1 internal tandem duplication in two tumors. Two other cases exhibited mutations in TERT and EP400 and both developed recurrence. All AKT1-wild type tumors exhibited immunohistochemical loss of PTEN expression. However, no mutations, deletions (as assessed by CNV analysis), or promoter hypermethylation in the PTEN gene were detected. CONCLUSION: The results of our study further support the hypothesis that the pathogenesis of JGCT may be driven by activation of the PIK3/AKT/mTOR pathway. These findings could potentially have future therapeutic implications, as treatment strategies targeting the PTEN/mTOR pathways are currently under investigation.
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Schweppe KW, Beller FK. Clinical data of granulosa cell tumors. J Cancer Res Clin Oncol. 1982;104(1–2):161–9. PubMed
Babarović E, Franin I, Klarić M, et al. Adult granulosa cell tumors of the ovary: a retrospective study of 36 FIGO stage I cases with emphasis on prognostic pathohistological features. Anal Cell Pathol (Amst). 2018;2018:9148124. PubMed PMC
Young RH, Dickersin GR, Scully RE. Juvenile granulosa cell tumor of the ovary. A clinicopathological analysis of 125 cases. Am J Surg Pathol. 1984;8(8):575–96. PubMed
Bouffet E, Basset T, Chetail N, et al. Juvenile granulosa cell tumor of the ovary in infants: a clinicopathologic study of three cases and review of the literature. J Pediatr Surg. 1997;32(5):762–5. PubMed
Kalfa N, Méduri G, Philibert P, et al. Unusual virilization in girls with juvenile granulosa cell tumors of the ovary is related to intratumoral aromatase deficiency. Horm Res Paediatr. 2010;74(2):83–91. PubMed
Rod J, Renard C, Lacreuse I, Ravasse P, Becmeur F. Hypercalcemia in a child with juvenile granulosa cell tumor of ovary: report of an unusual paraneoplastic syndrome and review of the literature. Gynecol Oncol Case Rep. 2013;5:10–2. PubMed PMC
Iqbal A, Novodvorsky P, Lubina-Solomon A, Kew FM, Webster J. Juvenile granulosa cell tumour of the ovary presenting with hyperprolactinaemic amenorrhoea and galactorrhoea. Endocrinol Diabetes Metab Case Rep. 2016;2016:160006. PubMed PMC
Calaminus G, Wessalowski R, Harms D, Göbel U. Juvenile granulosa cell tumors of the ovary in children and adolescents: results from 33 patients registered in a prospective cooperative study. Gynecol Oncol. 1997;65(3):447–52. PubMed
Ndhlovu E, Liu L, Dai J, Dong X, Zhang W, Chen B. Retrospective analysis of clinicopathological characteristics of 19 ovarian juvenile granulosa cell tumor cases. J Obstet Gynaecol Res. 2021;47(7):2492–9. PubMed
Powell JL, Connor GP, Henderson GS. Management of recurrent juvenile granulosa cell tumor of the ovary. Gynecol Oncol. 2001;81(1):113–6. PubMed
Bessière L, Todeschini AL, Auguste A, et al. A hot-spot of In-frame duplications activates the oncoprotein AKT1 in Juvenile granulosa cell tumors. EBioMedicine. 2015;2(5):421–31. PubMed PMC
Heravi-Moussavi A, Anglesio MS, Cheng SW, et al. Recurrent somatic DICER1 mutations in nonepithelial ovarian cancers. N Engl J Med. 2012;366(3):234–42. PubMed
Shah SP, Köbel M, Senz J, et al. Mutation of FOXL2 in granulosa-cell tumors of the ovary. N Engl J Med. 2009;360(26):2719–29. PubMed
Goulvent T, Ray-Coquard I, Borel S, et al. DICER1 and FOXL2 mutations in ovarian sex cord-stromal tumours: a GINECO Group study. Histopathology. 2016;68(2):279–85. PubMed
Kalfa N, Ecochard A, Patte C, et al. Activating mutations of the stimulatory g protein in juvenile ovarian granulosa cell tumors: a new prognostic factor? J Clin Endocrinol Metab. 2006;91(5):1842–7. PubMed
Tanaka Y, Sasaki Y, Nishihira H, Izawa T, Nishi T. Ovarian juvenile granulosa cell tumor associated with Maffucci’s syndrome. Am J Clin Pathol. 1992;97(4):523–7. PubMed
Burgetova A, Matejovsky Z, Zikan M, et al. The association of enchondromatosis with malignant transformed chondrosarcoma and ovarian juvenile granulosa cell tumor (Ollier disease). Taiwan J Obstet Gynecol. 2017;56(2):253–7. PubMed
Guo H, Keefe KA, Kohler MF, Chan JK. Juvenile granulosa cell tumor of the ovary associated with tuberous sclerosis. Gynecol Oncol. 2006;102(1):118–20. PubMed
Schultz KA, Pacheco MC, Yang J, et al. Ovarian sex cord-stromal tumors, pleuropulmonary blastoma and DICER1 mutations: a report from the International Pleuropulmonary Blastoma Registry. Gynecol Oncol. 2011;122(2):246–50. PubMed PMC
Plon SE, Pirics ML, Nuchtern J, et al. Multiple tumors in a child with germ-line mutations in TP53 and PTEN. N Engl J Med. 2008;359(5):537–9. PubMed
Němejcová K, Šafanda A, Kendall Bártů M, et al. An extensive immunohistochemical analysis of 290 ovarian adult granulosa cell tumors with 29 markers. Virchows Arch. 2024;485(3):427–37. PubMed
McCluggage WG, Soslow RA, Gilks CB. Patterns of p53 immunoreactivity in endometrial carcinomas: ‘all or nothing’ staining is of importance. Histopathology. 2011;59(4):786–8. PubMed
Wolff AC, Hammond MEH, Allison KH, et al. Human epidermal growth factor receptor 2 testing in breast cancer: American Society of Clinical Oncology/College of American Pathologists Clinical Practice Guideline Focused Update. J Clin Oncol. 2018;36(20):2105–22. PubMed
Dundr P, Bártů M, Bosse T, et al. Primary mucinous tumors of the ovary: an interobserver reproducibility and detailed molecular study reveals significant overlap between diagnostic categories. Mod Pathol. 2023;36(1):100040. PubMed
García JM, Silva J, Peña C, et al. Promoter methylation of the PTEN gene is a common molecular change in breast cancer. Genes Chromosomes Cancer. 2004;41(2):117–24. PubMed
Zhang R, Zhao R, Shen Q. Giant juvenile granulosa cell tumor torsion: a case report. Am J Transl Res. 2022;14(9):6823–7. PubMed PMC
Ye Y, Lv C, Xu S, et al. Juvenile granulosa cell tumors of the ovary. Am J Clin Pathol. 2020;154(5):635–44. PubMed
Schneider DT, Jänig U, Calaminus G, Göbel U, Harms D. Ovarian sex cord-stromal tumors–a clinicopathological study of 72 cases from the Kiel Pediatric Tumor Registry. Virchows Arch. 2003;443(4):549–60. PubMed
Wang Y, Wang W, Xu C, et al. Childhood ovarian juvenile granulosa cell tumor: a retrospective study with 3 cases including clinical features, pathologic results, and therapies. J Pediatr Hematol Oncol. 2011;33(3):241–5. PubMed
Kondi-Pafiti A, Grapsa D, Kairi-Vassilatou E, et al. Granulosa cell tumors of the ovary: a clinicopathologic and immunohistochemical study of 21 cases. Eur J Gynaecol Oncol. 2010;31(1):94–8. PubMed
Rishi M, Howard LN, Bratthauer GL, Tavassoli FA. Use of monoclonal antibody against human inhibin as a marker for sex cord-stromal tumors of the ovary. Am J Surg Pathol. 1997;21(5):583–9. PubMed
Movahedi-Lankarani S, Kurman RJ. Calretinin, a more sensitive but less specific marker than alpha-inhibin for ovarian sex cord-stromal neoplasms: an immunohistochemical study of 215 cases. Am J Surg Pathol. 2002;26(11):1477–83. PubMed
Deavers MT, Malpica A, Liu J, Broaddus R, Silva EG. Ovarian sex cord-stromal tumors: an immunohistochemical study including a comparison of calretinin and inhibin. Mod Pathol. 2003;16(6):584–90. PubMed
Costa MJ, Ames PF, Walls J, Roth LM. Inhibin immunohistochemistry applied to ovarian neoplasms: a novel, effective, diagnostic tool. Hum Pathol. 1997;28(11):1247–54. PubMed
Kommoss F, Oliva E, Bhan AK, Young RH, Scully RE. Inhibin expression in ovarian tumors and tumor-like lesions: an immunohistochemical study. Mod Pathol. 1998;11(7):656–64. PubMed
McCluggage WG, Maxwell P. Immunohistochemical staining for calretinin is useful in the diagnosis of ovarian sex cord-stromal tumours. Histopathology. 2001;38(5):403–8. PubMed
Bai S, Wei S, Ziober A, Yao Y, Bing Z. SALL4 and SF-1 are sensitive and specific markers for distinguishing granulosa cell tumors from yolk sac tumors. Int J Surg Pathol. 2013;21(2):121–5. PubMed
D’Angelo E, Mozos A, Nakayama D, et al. Prognostic significance of FOXL2 mutation and mRNA expression in adult and juvenile granulosa cell tumors of the ovary. Mod Pathol. 2011;24(10):1360–7. PubMed
Kalfa N, Philibert P, Patte C, et al. Extinction of FOXL2 expression in aggressive ovarian granulosa cell tumors in children. Fertil Steril. 2007;87(4):896–901. PubMed
Onder S, Hurdogan O, Bayram A, Yilmaz I, Sozen H, Yavuz E. 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;479(2):317–24. PubMed
Vougiouklakis T, Zhu K, Vasudevaraja V, et al. Integrated analysis of ovarian juvenile granulosa cell tumors reveals distinct epigenetic signatures and recurrent TERT rearrangements. Clin Cancer Res. 2022;28(8):1724–33. PubMed
Gordon MD, Corless C, Renshaw AA, Beckstead J. CD99, keratin, and vimentin staining of sex cord-stromal tumors, normal ovary, and testis. Mod Pathol. 1998;11(8):769–73. PubMed
Jarboe EA, Hirschowitz SL, Geiersbach KB, Wallander ML, Tripp SR, Layfield LJ. Juvenile granulosa cell tumors: immunoreactivity for CD99 and Fli-1 and EWSR1 translocation status: a study of 11 cases. Int J Gynecol Pathol. 2014;33(1):11–5. PubMed
Costa MJ, DeRose PB, Roth LM, Brescia RJ, Zaloudek CJ, Cohen C. Immunohistochemical phenotype of ovarian granulosa cell tumors: absence of epithelial membrane antigen has diagnostic value. Hum Pathol. 1994;25(1):60–6. PubMed
Mayr D, Kaltz-Wittmer C, Arbogast S, Amann G, Aust DE, Diebold J. Characteristic pattern of genetic aberrations in ovarian granulosa cell tumors. Mod Pathol. 2002;15(9):951–7. PubMed
Staibano S, Franco R, Mezza E, et al. Loss of oestrogen receptor beta, high PCNA and p53 expression and aneuploidy as markers of worse prognosis in ovarian granulosa cell tumours. Histopathology. 2003;43(3):254–62. PubMed
Dowsett M, Nielsen TO, A’Hern R, et al. Assessment of Ki67 in breast cancer: recommendations from the International Ki67 in Breast Cancer working group. J Natl Cancer Inst. 2011;103(22):1656–64. PubMed PMC
Nakatsuka S, Oji Y, Horiuchi T, et al. Immunohistochemical detection of WT1 protein in a variety of cancer cells. Mod Pathol. 2006;19(6):804–14. PubMed
Wens FSPL, Hulsker CCC, Fiocco M, et al. Small Cell Carcinoma of the Ovary, Hypercalcemic Type (SCCOHT): patient characteristics, treatment, and outcome-a systematic review. Cancers (Basel). 2023;15(15):3794. PubMed PMC
Ramos P, Karnezis AN, Craig DW, et al. Small cell carcinoma of the ovary, hypercalcemic type, displays frequent inactivating germline and somatic mutations in SMARCA4. Nat Genet. 2014;46(5):427–9. PubMed PMC
Jelinic P, Mueller JJ, Olvera N, et al. Recurrent SMARCA4 mutations in small cell carcinoma of the ovary. Nat Genet. 2014;46(5):424–6. PubMed PMC
Kupryjańczyk J, Dansonka-Mieszkowska A, Moes-Sosnowska J, et al. Ovarian small cell carcinoma of hypercalcemic type - evidence of germline origin and SMARCA4 gene inactivation. A pilot study. Pol J Pathol. 2013;64(4):238–46. PubMed
Witkowski L, Carrot-Zhang J, Albrecht S, et al. Germline and somatic SMARCA4 mutations characterize small cell carcinoma of the ovary, hypercalcemic type. Nat Genet. 2014;46(5):438–43. PubMed
Sakr S, Abdulfatah E, Thomas S, et al. Granulosa cell tumors: novel predictors of recurrence in early-stage patients. Int J Gynecol Pathol. 2017;36(3):240–52. PubMed PMC
Leibl S, Bodo K, Gogg-Kammerer M, et al. Ovarian granulosa cell tumors frequently express EGFR (Her-1), Her-3, and Her-4: an immunohistochemical study. Gynecol Oncol. 2006;101(1):18–23. PubMed
Liu Z, Ren YA, Pangas SA, et al. FOXO1/3 and PTEN Depletion in granulosa cells promotes ovarian granulosa cell tumor development. Mol Endocrinol. 2015;29(7):1006–24. PubMed PMC
Álvarez-Garcia V, Tawil Y, Wise HM, Leslie NR. Mechanisms of PTEN loss in cancer: it’s all about diversity. Semin Cancer Biol. 2019;59:66–79. PubMed
Laguë MN, Paquet M, Fan HY, et al. Synergistic effects of Pten loss and WNT/CTNNB1 signaling pathway activation in ovarian granulosa cell tumor development and progression. Carcinogenesis. 2008;29(11):2062–72. PubMed PMC