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Keimstrang-Stromatumoren des Ovars

Aktuelle Aspekte, insbesondere zu Granulosazelltumoren, Sertoli-Leydig-Zell-Tumoren und Gynandroblastomen

Sex cord-stromal tumors of the ovary

Current aspects with a focus on granulosa cell tumors, Sertoli-Leydig cell tumors, and gynandroblastomas

  • Schwerpunkt: Gynäkopathologie
  • Published:
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Zusammenfassung

Die ovariellen Keimstrang-Stromatumoren (OKST) umfassen eine faszinierende, heterogene Gruppe von Neoplasien mit einem breiten Spektrum klinischer und pathologischer Merkmale. Hierzu gehören neben gutartigen Tumoren auch solche mit malignem Potenzial.

Klinische Besonderheit erlangen diese Tumoren durch spezifische hyperöstrogene oder -androgene Symptomatik als Folge intratumoraler Produktion von Steroidhormonen. Die rein histologische Diagnosestellung ist aufgrund gelegentlich komplexer oder überlappender Merkmale anspruchsvoll und gelegentlich frustran. Zur Abgrenzung der OKST von keimstrangartigen anderen Ovarialtumoren hat sich die Verwendung eines Panels immunhistochemischer Keimstrangmarker (z. B. Inhibin-α, Calretinin) bewährt. In jüngerer Zeit sind molekulare Besonderheiten dieser Tumorgruppe erforscht worden, insbesondere wurden Mutationen von FOXL2 und DICER1 in bestimmten OKST beschrieben. Entsprechende Mutationsanalysen können bereits heute in besonderen Fällen diagnostisch hilfreich sein, auch werden sie womöglich einen Impuls für die zukünftige Klassifikation von OKST geben und sollten auf ihr Potenzial als Prognosefaktoren sowie im Rahmen neuer Therapieansätze überprüft werden.

In der vorliegenden Übersichtsarbeit werden die klinischen und histopathologischen Merkmale der adulten und juvenilen Granulosazelltumoren (AGCT und JGCT) sowie der Sertoli-Leydig-Zell-Tumoren (SLCT) als klinisch wichtigster, potenziell maligner Vertreter der OKST dargestellt und im Rahmen der aktuellen molekularen Forschungsergebnisse diskutiert. Ergänzend wird über aktuelle, möglicherweise ebenfalls für die zukünftige Klassifikation von OKST bedeutsame Ergebnisse zu den seltenen Gynandroblastomen (GAB) berichtet.

Abstract

Sex cord-stromal tumors of the ovary (SCSTO) comprise a heterogeneous and fascinating group of neoplasms with diverse clinicopathological features, including benign lesions as well as tumors with malignant potential. Clinically, SCSTO may be associated with hyperestrogenic or androgenic function as a result of steroid hormone production by the tumor cells.

Histological diagnosis may be challenging due to complex and sometimes overlapping morphological features of the various tumor types. A panel of immunohistochemical sex cord markers (e. g. inhibin-α, calretinin) has proven to be helpful in confirming the cellular lineage of SCSTO and differentiating them from other sex cord-like ovarian lesions. Recently, molecular analysis of SCSTO has led to the discovery of specific molecular events such as FOXL2 and DICER1 mutations. In selected diagnostically challenging cases, mutation analysis of FOXL2 and DICER1 may be helpful in the differential diagnosis. Molecular analysis is also expected to help advance the classification of SCSTO, and it may hold prognostic potential and form the basis for future type-specific therapies.

This review focuses on the clinicopathological as well as the molecular features of adult and juvenile granulosa cell tumors (AGCTs and JGCTs) as well as Sertoli-Leydig cell tumors (SLCTs), these being the most relevant lesions with malignant potential in the SCSTO category. In addition, recently published molecular findings among rare ovarian gynandroblastomas (GABs) are described, which may also impact the future classification of SCSTO.

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Literatur

  1. Aguirre P, Scully RE, DeLellis RA (1986) Ovarian heterologous Sertoli-Leydig cell tumors with gastrointestinal-type epithelium. An immunohistochemical analysis. Arch Pathol Lab Med 110:528–533

    CAS  PubMed  Google Scholar 

  2. Akman L, Ertas IE, Gokcu M et al (2016) Ovarian sertoli-leydig cell tumors: A multicenter long-term clinicopathological analysis of 27 patients. J Cancer Res Ther 12:290–294

    Article  CAS  Google Scholar 

  3. Al-Agha OM, Huwait HF, Chow C et al (2011) FOXL2 is a sensitive and specific marker for sex cord-stromal tumors of the ovary. Am J Surg Pathol 35:484–494

    Article  Google Scholar 

  4. Anglesio MS, Wang Y, Yang W et al (2013) Cancer-associated somatic DICER1 hotspot mutations cause defective miRNA processing and reverse-strand expression bias to predominantly mature 3p strands through loss of 5p strand cleavage. J Pathol 229:400–409

    Article  CAS  Google Scholar 

  5. Auguste A, Bessière L, Todeschini AL (2015) Molecular analyses of juvenile granulosa cell tumors bearing AKT1 mutations provide insights into tumor biology and therapeutic leads. Hum Mol Genet 2015(24):6687–6698

    Article  Google Scholar 

  6. Bessière L, Todeschini AL, Auguste A et al (2015) A Hot-spot of In-frame Duplications Activates the Oncoprotein AKT1. Juv Granulosa Cell Tumors Ebiomedicine 2:421–431

    Google Scholar 

  7. Brown J, Brady WE, Schink J et al (2014) Efficacy and safety of bevacizumab in recurrent sex cord-stromal ovarian tumors: results of a phase 2 trial of the Gynecologic Oncology Group. Cancer 120:344–351

    Article  CAS  Google Scholar 

  8. Caburet S, Anttonen M, Todeschini AL et al (2015) Combined comparative genomic hybridization and transcriptomic analyses of ovarian granulosa cell tumors point to novel candidate driver genes. BMC Cancer 15:251

    Article  Google Scholar 

  9. Chivukula M, Hunt J, Carter G et al (2007) Recurrent gynandroblastoma of ovary – A case report: a molecular and immunohistochemical analysis. Int J Gynecol Pathol 26:30–33

    Article  Google Scholar 

  10. Cocquet J, Pailhoux E, Jaubert F et al (2002) Evolution and expression of FOXL2. J Med Genet 39:916–921

    Article  CAS  Google Scholar 

  11. Conlon N, Schultheis AM, Piscuoglio S et al (2015) A survey of DICER1 hotspot mutations in ovarian and testicular sex cord-stromal tumors. Mod Pathol 28:1603–1612

    Article  CAS  Google Scholar 

  12. Crisponi L, Deiana M, Loi A et al (2001) The putative forkhead transcription factor FOXL2 is mutated in blepharophimosis/ptosis/epicanthus inversus syndrome. Nat Genet 27:159–166

    Article  CAS  Google Scholar 

  13. D’Angelo E, Mozos A, Nakayama D et al (2011) Prognostic significance of FOXL2 mutation and mRNA expression in adult and juvenile granulosa cell tumors of the ovary. Mod Pathol 24:1360–1367

    Article  Google Scholar 

  14. Deavers MT, Malpica A, Liu J et al (2003) Ovarian sex cord-stromal tumors: an immunohistochemical study including a comparison of calretinin and inhibin. Mod Pathol 16:584–590

    Article  Google Scholar 

  15. Erdreich-Epstein A, Monforte HL, Lavey RS et al (2002) Successful multimodality therapy of recurrent multifocal juvenile granulosa cell tumor of the ovary. J Pediatr Hematol Oncol 24:229–233

    Article  Google Scholar 

  16. Espinosa I, Gallardo A, D’Angelo E et al (2015) Simultaneous carcinomas of the breast and ovary: utility of Pax-8, WT-1, and GATA3 for distinguishing independent primary tumors from metastases. Int J Gynecol Pathol 34:257–265

    Article  CAS  Google Scholar 

  17. Foulkes WD, Priest JR, Duchaine TF (2014) DICER1: mutations, microRNAs and mechanisms. Nat Rev Cancer 14:662–672

    Article  CAS  Google Scholar 

  18. Goulvent T, Ray-Coquard I, Borel S et al (2016) DICER1 and FOXL2 mutations in ovarian sex cord-stromal tumours: a GINECO Group study. Histopathology 68:279–285

    Article  Google Scholar 

  19. Heravi-Moussavi A, Anglesio MS, Cheng SW (2012) Recurrent somatic DICER1 mutations in nonepithelial ovarian cancers. N Engl J Med 366:234–242

    Article  CAS  Google Scholar 

  20. Kalfa N, Ecochard A, Patte C et al (2006) Activating mutations of the stimulatory g protein in juvenile ovarian granulosa cell tumors: a new prognostic factor? J Clin Endocrinol Metab 91:1842–1847

    Article  CAS  Google Scholar 

  21. Karnezis AN, Wang Y, Keul J et al (2019) DICER1 and FOXL2 mutation status correlates with clinicopathologic features in ovarian Sertoli-Leydig cell tumors. Am J Surg Pathol, accepted for publication

    Google Scholar 

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

    Article  CAS  Google Scholar 

  23. Kim MS, Hur SY, Yoo NJ, Lee SH (2010) Mutational analysis of FOXL2 codon 134 in granulosa cell tumour of ovary and other human cancers. J Pathol 221:147–152

    Article  CAS  Google Scholar 

  24. Kim MS, Lee SH, Yoo NJ et al (2013) DICER1 exons 25 and 26 mutations are rare in common human tumours besides Sertoli-Leydig cell tumour. Histopathology 63:436–438

    Article  Google Scholar 

  25. de Kock L, Terzic T, McCluggage WG et al (2017) DICER1 Mutations Are Consistently Present in Moderately and Poorly Differentiated Sertoli-Leydig Cell Tumors. Am J Surg Pathol 41:1178–1187

    Article  Google Scholar 

  26. Kommoss F, Oliva E, Bhan AK, Young RH, Scully RE (1998) Inhibin expression in ovarian tumors and tumor-like lesions: an immunohistochemical study. Mod Pathol 11:656–664

    CAS  PubMed  Google Scholar 

  27. Kommoss F, Schmidt D (2007) Immunohistochemical sex cord markers. Description and use in the differential diagnosis of ovarian tumors. Pathologe 28:187–194

    Article  CAS  Google Scholar 

  28. Kommoss S, Anglesio MS, Mackenzie R et al (2013) FOXL2 molecular testing in ovarian neoplasms: diagnostic approach and procedural guidelines. Mod Pathol 26:860–867

    Article  CAS  Google Scholar 

  29. Kommoss S, Gilks CB, Penzel R et al (2014) A current perspective on the pathological assessment of FOXL2 in adult-type granulosa cell tumours of the ovary. Histopathology 64:380–388

    Article  Google Scholar 

  30. Kurman RJ, Carcangiu ML, Herrington CS, Young RH (Hrsg) (2014) WHO Classification of Tumours of Female Reproductive Organs. International Agency for Research on Cancer, Lyon

    Google Scholar 

  31. Leitlinienprogramm Onkologie (Deutsche Krebsgesellschaft, Deutsche Krebshilfe, AWMF) Therapie und Nachsorge maligner Ovarialtumoren, Langversion 1.0, AWMF Registrierungsnummer: 032-035OL. http://leitlinienprogramm-onkologie.de/Leitlinien.7.0.html

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

    Article  CAS  Google Scholar 

  33. Lin YS, Eng HL, Jan YJ et al (2005) Molecular cytogenetics of ovarian granulosa cell tumors by comparative genomic hybridization. Gynecol Oncol 97:68–73

    Article  CAS  Google Scholar 

  34. Mayr D, Kaltz-Wittmer C, Arbogast S et al (2002) Characteristic pattern of genetic aberrations in ovarian granulosa cell tumors. Mod Pathol 15:951–957

    Article  CAS  Google Scholar 

  35. McConechy MK, Färkkilä A, Horlings HM et al (2016) Molecularly Defined Adult Granulosa Cell Tumor of the Ovary: The Clinical Phenotype. J Natl Cancer Inst 108(11):13

    Article  Google Scholar 

  36. McCluggage WG, Young RH (2005) Immunohistochemistry as a diagnostic aid in the evaluation of ovarian tumors. Semin Diagn Pathol 22:3–32

    Article  Google Scholar 

  37. van Meurs HS, van Lonkhuijzen LR et al (2014) Hormone therapy in ovarian granulosa cell tumors: a systematic review. Gynecol Oncol 134:196–205

    Article  Google Scholar 

  38. Moh M, Krings G, Ates D et al (2016) SATB2 Expression Distinguishes Ovarian Metastases of Colorectal and Appendiceal Origin From Primary Ovarian Tumors of Mucinous or Endometrioid Type. Am J Surg Pathol 40:419–432

    Article  Google Scholar 

  39. Movahedi-Lankarani S, Kurman RJ (2002) 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 26:1477–1483

    Article  Google Scholar 

  40. Nolan A, Joseph NM, Sangoi AR et al (2017) FOXL2 Mutation Status in Granulosa Theca Cell Tumors of the Ovary. Int J Gynecol Pathol 36:568–574

    Article  CAS  Google Scholar 

  41. Oost EE, Charles A, Choong CS et al (2015) Ovarian sex cord-stromal tumors in patients with probable or confirmed germline DICER1 mutations. Int J Gynecol Pathol 34:266–274

    Article  CAS  Google Scholar 

  42. Oparka R, Cassidy A, Reilly S et al (2012) The C134W (402 C〉G) FOXL2 mutation is absent in ovarian gynandroblastoma: insights into the genesis of an unusual tumour. Histopathology 60:838–842

    Article  Google Scholar 

  43. Park M, Shin E, Won M et al (2010) FOXL2 interacts with steroidogenic factor-1 (SF-1) and represses SF-1-induced CYP17 transcription in granulosa cells. Mol Endocrinol 24:1024–1036

    Article  CAS  Google Scholar 

  44. Prat J, Young RH, Scully RE (1982) Ovarian Sertoli-Leydig cell tumors with heterologous elements. II. Cartilage and skeletal muscle: a clinicopathologic analysis of twelve cases. Cancer 50:2465–2475

    Article  CAS  Google Scholar 

  45. Rabban JT, Zaloudek CJ (2013) A practical approach to immunohistochemical diagnosis of ovarian germ cell tumours and sex cord-stromal tumours. Histopathology 62:71–88

    Article  Google Scholar 

  46. Rosario R, Wilson M, Cheng WT et al (2013) Adult granulosa cell tumours (GCT): clinicopathological outcomes including FOXL2 mutational status and expression. Gynecol Oncol 131:325–329

    Article  CAS  Google Scholar 

  47. Roth LM, Slayton RE, Brady LW et al (1985) Retiform differentiation in ovarian Sertoli-Leydig cell tumors. A clinicopathologic study of six cases from a Gynecologic Oncology Group study. Cancer 55:1093–1098

    Article  CAS  Google Scholar 

  48. Schmidt D, Ovitt CE, Anlag K et al (2004) The murine winged-helix transcription factor Foxl2 is required for granulosa cell differentiation and ovary maintenance. Development 131:933–942

    Article  CAS  Google Scholar 

  49. Schultz KA, Pacheco MC, Yang J et al (2011) Ovarian sex cord-stromal tumors, pleuropulmonary blastoma and DICER1 mutations: a report from the International Pleuropulmonary Blastoma Registry. Gynecol Oncol 122:246–250

    Article  CAS  Google Scholar 

  50. Schultz KAP, Harris AK, Finch M et al (2017) DICER1-related Sertoli-Leydig cell tumor and gynandroblastoma: Clinical and genetic findings from the International Ovarian and Testicular Stromal Tumor Registry. Gynecol Oncol 147:521–527

    Article  CAS  Google Scholar 

  51. Shah SP, Köbel M, Senz J et al (2009) Mutation of FOXL2 in granulosa-cell tumors of the ovary. N Engl J Med 360:2719–2729

    Article  CAS  Google Scholar 

  52. Sigismondi C, Gadducci A, Lorusso D et al (2012) Ovarian Sertoli-Leydig cell tumors. A retrospective MITO study. Gynecol Oncol 125:673–676

    Article  Google Scholar 

  53. Slade I, Bacchelli C, Davies H et al (2011) DICER1 syndrome: clarifying the diagnosis, clinical features and management implications of a pleiotropic tumour predisposition syndrome. J Med Genet 48:273–278

    Article  CAS  Google Scholar 

  54. Staebler A, Kommoss F (2013) Ovarialtumoren IV. LS195 T 300 20100515. Int Akademie Für Pathol, 115–156

  55. Takeda A, Watanabe K, Hayashi S et al (2017) Gynandroblastoma with a Juvenile Granulosa Cell Component in an Adolescent: Case Report and Literature Review. J Pediatr Adolesc Gynecol 30:251–255

    Article  Google Scholar 

  56. Talerman A (1987) Ovarian Sertoli-Leydig cell tumor (androblastoma) with retiform pattern. A clinicopathologic study. Cancer 60:3056–3064

    Article  CAS  Google Scholar 

  57. Tanaka Y, Sasaki Y, Nishihira H, Izawa T, Nishi T (1992) Ovarian juvenile granulosa cell tumor associated with Maffucci’s syndrome. Am J Clin Pathol 97:523–527

    Article  CAS  Google Scholar 

  58. Vassal G, Flamant F, Caillaud JM et al (1988) Juvenile granulosa cell tumor of the ovary in children: a clinical study of 15 cases. J Clin Oncol 6:990–995

    Article  CAS  Google Scholar 

  59. Vaz RM, Turner C (1986) Ollier disease (enchondromatosis) associated with ovarian juvenile granulosa cell tumor and precocious pseudopuberty. J Pediatr 108:945–947

    Article  CAS  Google Scholar 

  60. Wang Y, Karnezis AN, Magrill J et al (2018) DICER1 hot-spot mutations in ovarian gynandroblastoma. Histopathology 73:306–313

    Article  Google Scholar 

  61. Witkowski L, Mattina J, Schönberger S et al (2013) DICER1 hotspot mutations in non-epithelial gonadal tumours. Br J Cancer 109:2744–2750

    Article  CAS  Google Scholar 

  62. Young RH, Prat J, Scully RE (1982) Ovarian Sertoli-Leydig cell tumors with heterologous elements. I. Gastrointestinal epithelium and carcinoid: a clinicopathologic analysis of thirty-six cases. Cancer 50:2448–2456

    Article  CAS  Google Scholar 

  63. Young RH, Scully RE (1983) Ovarian Sertoli-Leydig cell tumors with a retiform pattern: a problem in histopathologic diagnosis. A report of 25 cases. Am J Surg Pathol 7:755–771

    Article  CAS  Google Scholar 

  64. Young RH, Dickersin GR, Scully RE (1984) Juvenile granulosa cell tumor of the ovary. A clinicopathological analysis of 125 cases. Am J Surg Pathol 8:575–596

    Article  CAS  Google Scholar 

  65. Young RH, Perez-Atayde AR, Scully RE (1984) Ovarian Sertoli-Leydig cell tumor with retiform and heterologous components. Report of a case with hepatocytic differentiation and elevated serum alpha-fetoprotein. Am J Surg Pathol 8:709–718

    Article  CAS  Google Scholar 

  66. Young RH, Scully RE (1985) Ovarian Sertoli-Leydig cell tumors. A clinicopathological analysis of 207 cases. Am J Surg Pathol 9:543–569

    Article  CAS  Google Scholar 

  67. Zaloudek C, Norris HJ (1982) Granulosa tumors of the ovary in children: a clinical and pathologic study of 32 cases. Am J Surg Pathol 6:503–512

    Article  CAS  Google Scholar 

  68. Zaloudek C, Norris HJ (1984) Sertoli-Leydig tumors of the ovary. A clinicopathologic study of 64 intermediate and poorly differentiated neoplasms. Am J Surg Pathol 8:405–418

    Article  CAS  Google Scholar 

  69. Zhao C, Vinh TN, McManus K et al (2009) Identification of the most sensitive and robust immunohistochemical markers in different categories of ovarian sex cord-stromal tumors. Am J Surg Pathol 33:354–366

    Article  Google Scholar 

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  1. Institut für Pathologie, Medizin Campus Bodensee, Röntgenstr. 2, 88048, Friedrichshafen, Deutschland

    F. Kommoss & H.-A. Lehr

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Correspondence to F. Kommoss.

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S. F. Lax, Graz

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Kommoss, F., Lehr, HA. Keimstrang-Stromatumoren des Ovars. Pathologe 40, 61–72 (2019). https://doi.org/10.1007/s00292-018-0562-3

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