Management of malignant dysgerminoma of the ovary

The evolution of treatment for malignant ovarian germ cell tumors has been one of the most successful in the history of gynecologic oncology, with dysgerminoma as the most common type of malignant ovarian germ cell tumors. Since the introduction of platinum-based chemotherapy in the 1980s, 5-year survival rates for early-stage dysgerminomas have been close to 100%, and as high as 98% for advanced stages. Despite this remarkable achievement, many questions remain in routine treatment. By performing a literature review, we aim to highlight both the current treatment of malignant dysgerminoma and unanswered questions in the modern management of this disease. These issues relate firstly to surgical therapy, such as the role of routine omentectomy and lymphadenectomy, the value of complete surgical resection, and the possibility of fertility-sparing surgery. Second, chemotherapy and the question of the possibility of de-escalation in early stages and the potential of neoadjuvant chemotherapy in advanced stages will be addressed. Finally, a brief overview of the current developments of new drug treatment regimens will be given.

non epithelial ovarian cancer; ovarian germ cell tumor; dysgerminoma; surgery; chemotherapy; targeted therapies.

[1] Boussios S, Karathanasi A, Zakynthinakis-Kyriakou N, Tsiouris AK, Chatziantoniou AA, Kanellos FS, et al. Ovarian carcinosarcoma: Current developments and future perspectives. Critical Reviews in Oncology/Hematology. 2019; 134: 46–55.

[2] Sessa C, Schneider DT, Planchamp F, Baust K, Braicu EI, Concin N, et al. ESGO-SIOPE guidelines for the management of adolescents and young adults with non-epithelial ovarian cancers. The Lancet Oncology. 2020; 21: e360–e368.

[3] Ray-Coquard I, Morice P, Lorusso D, Prat J, Oaknin A, Pautier P, et al. Non-epithelial ovarian cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Annals of Oncology. 2018; 29: iv1–iv18.

[4] Torre LA, Trabert B, DeSantis CE, Miller KD, Samimi G, Runowicz CD, et al. Ovarian cancer statistics, 2018. CA: A Cancer Journal for Clinicians. 2018; 68: 284–296.

[5] Ledermann JA, Raja FA, Fotopoulou C, Gonzalez-Martin A, Colombo N, Sessa C. Newly diagnosed and relapsed epithelial ovarian carcinoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Annals of Oncology. 2013; 24: vi24–vi32.

[6] Smith HO, Berwick M, Verschraegen CF, Wiggins C, Lansing L, Muller CY, et al. Incidence and Survival Rates for female Malignant Germ Cell Tumors. Obstetrics & Gynecology. 2006; 107: 1075–1085.

[7] Young RH. Ovarian sex cord-stromal tumours and their mimics. Pathology. 2018; 50: 5–15.

[8] Hanley KZ, Mosunjac MB. Practical Review of Ovarian Sex Cord-Stromal Tumors. Surgical Pathology Clinics. 2019; 12: 587–620.

[9] Palmer RD, Murray MJ, Saini HK, van Dongen S, Abreu-Goodger C, Muralidhar B, et al. Malignant germ cell tumors display common microRNA profiles resulting in global changes in expression of messenger RNA targets. Cancer Research. 2010; 70: 2911–2923.

[10] Patterson DM, Murugaesu N, Holden L, Seckl MJ, Rustin GJS. A review of the close surveillance policy for stage i female germ cell tumors of the ovary and other sites. International Journal of Gynecological Cancer. 2008; 18: 43–50.

[11] Vicus D, Beiner ME, Klachook S, Le LW, Laframboise S, Mackay H. Pure dysgerminoma of the ovary 35 years on: a single institutional experience. Gynecologic Oncology. 2010; 117: 23–26.

[12] AL Husaini H, Soudy H, Darwish AED, Ahmed M, Eltigani A, AL Mubarak M, et al. Pure dysgerminoma of the ovary: a single institutional experience of 65 patients. Medical Oncology. 2012; 29: 2944–2948.

[13] Kraggerud SM, Hoei-Hansen CE, Alagaratnam S, Skotheim RI, Abeler VM, Rajpert-De Meyts E, et al. Molecular characteristics of malignant ovarian germ cell tumors and comparison with testicular counterparts: implications for pathogenesis. Endocrine Reviews. 2013; 34: 339–376.

[14] Weinberg LE, Lurain JR, Singh DK, Schink JC. Survival and reproductive outcomes in women treated for malignant ovarian germ cell tumors. Gynecologic Oncology. 2011; 121: 285–289.

[15] Mangili G, Sigismondi C, Lorusso D, Pignata S. Surveillance Policy for Stage IA Malignant Ovarian Germ Cell Tumors in Children and Young Adults. Journal of Clinical Oncology. 2014; 32: 2814–2815.

[16] Billmire D, Vinocur C, Rescorla F, Cushing B, London W, Schlatter M, et al. Outcome and staging evaluation in malignant germ cell tumors of the ovary in children and adolescents: an intergroup study. Journal of Pediatric Surgery. 2004; 39: 424–429.

[17] Low JJ, Perrin LC, Crandon AJ, Hacker NF. Conservative surgery to preserve ovarian function in patients with malignant ovarian germ cell tumors. a review of 74 cases. Cancer. 2000; 89: 391–398.

[18] Mangili G, Sigismondi C, Gadducci A, Cormio G, Scollo P, Tateo S, et al. Outcome and risk factors for recurrence in malignant ovarian germ cell tumors: a MITO-9 retrospective study. International Journal of Gynecological Cancer. 2011; 21: 1414–1421.

[19] Zanetta G, Bonazzi C, Cantù M, Binidagger S, Locatelli A, Bratina G, et al. Survival and reproductive function after treatment of malignant germ cell ovarian tumors. Journal of Clinical Oncology. 2001; 19: 1015–1020.

[20] Gershenson DM, Frazier AL. Conundrums in the management of malignant ovarian germ cell tumors: toward lessening acute morbidity and late effects of treatment. Gynecologic Oncology. 2016; 143: 428–432.

[21] Stoneham SJ, Hale JP, Rodriguez-Galindo C, Dang H, Olson T, Murray M, et al. Adolescents and Young Adults with a “Rare” Cancer: Getting Past Semantics to Optimal Care for Patients with Germ Cell Tumors. The Oncologist. 2014; 19: 689–692.

[22] Veneris JT, Mahajan P, Frazier AL. Contemporary management of ovarian germ cell tumors and remaining controversies. Gynecologic Oncology. 2020; 158: 467–475.

[23] Fonseca A, Frazier AL, Shaikh F. Germ Cell Tumors in Adolescents and Young Adults. Journal of Oncology Practice. 2019; 15: 433–441.

[24] Bremer GL, Land JA, Tiebosch A, van der Putten HW. Five different histological subtypes of germ cell malignancies in an XY female. Gynecologic Oncology. 1993; 50: 247–248.

[25] Bleyer A. Magic still Needed for Germ Cell Tumor Research, Especially in Adolescents and Young Adults. Journal of Oncology Practice. 2019; 15: 445–446.

[26] De Giorgi U, Casadei C, Bergamini A, Attademo L, Cormio G, Lorusso D, et al. Therapeutic Challenges for Cisplatin-Resistant Ovarian Germ Cell Tumors. Cancers. 2019; 11: 1584.

[27] Mueller CW, Topkins P, Lapp WA. Dysgerminoma of the ovary; an analysis of 427 cases. American Journal of Obstetrics and Gynecology. 1950; 60: 153–159.

[28] Vale-Fernandes E, Rodrigues F, Monteiro C, Serrano P. Pelvic mass in a young woman with a background of ovarian dysger-minoma: differential diagnosis. BMJ Case Reports. 2015; 2015: bcr2015212550.

[29] Björkholm E, Lundell M, Gyftodimos A, Silfverswärd C. Dys-germinoma. The Radiumhemmet series 1927–1984. Cancer. 1990; 65: 38–44.

[30] Mangili G, Sigismondi C, Lorusso D, Cormio G, Scollo P, Viganò R, et al. Is surgical restaging indicated in apparent stage IA pure ovarian dysgerminoma? The MITO group retrospective experience. Gynecologic Oncology. 2011; 121: 280–284.

[31] Pectasides D, Pectasides E, Kassanos D. Germ cell tumors of the ovary. Cancer Treatment Reviews. 2008; 34: 427–441.

[32] Patterson DM, Rustin GJS. Controversies in the management of germ cell tumours of the ovary. Current Opinion in Oncology. 2006; 18: 500–506.

[33] Gershenson DM. Management of ovarian germ cell tumors. Journal of Clinical Oncology. 2007; 25: 2938–2943.

[34] Zogbi L, Gonçalves CV, Tejada VF, Martins D, Karam F, Machado Dos Santos S, et al. Treatment of bilateral ovarian dysgerminoma with 11-year follow-up: a case report. Annals of Medicine and Surgery. 2018; 33: 50–52.

[35] Buskirk SJ, Schray MF, Podratz KC, Lee RA, Stanhope CR, Gaffey TA, et al. Ovarian dysgerminoma: a retrospective analysis of results of treatment, sites of treatment failure, and radiosensitivity. Mayo Clinic Proceedings. 1987; 62: 1149–1157.

[36] Valdespino VE, Montenegro YB, Hernandjez MR, et al. Two cases dysgerminoma with micrometastasis in lymph nodes. Obstetrics & Gynecology International Journal. 2019; 10: 31‒34.

[37] Kumar S, Shah JP, Bryant CS, Imudia AN, Cote ML, Ali-Fehmi R, et al. The prevalence and prognostic impact of lymph node metastasis in malignant germ cell tumors of the ovary. Gynecologic Oncology. 2008; 110: 125–132.

[38] Robert E. Scully, Robert H. Young and Philip B. Clement tumors of the ovary, maldeveloped gonads, fallopian tube and broad ligament. Atlas of Tumor Pathology. Third Series, Fascicle 23. Armed Forces Institute of Pathology: Washington, DC. 1998.

[39] Low JJH, Ilancheran A, Ng JS. Malignant ovarian germ-cell tumours. Best Practice & Research. Clinical Obstetrics & Gynaecology. 2012; 26: 347–355.

[40] Guerriero S, Testa AC, Timmerman D, Van Holsbeke C, Ajossa S, Fischerova D, et al. Imaging of gynecological disease (6): clinical and ultrasound characteristics of ovarian dysgerminoma. Ultrasound in Obstetrics & Gynecology. 2011; 37: 596–602.

[41] Brown J, Friedlander M, Backes FJ, Harter P, O’Connor DM, de la Motte Rouge T, et al. Gynecologic Cancer Intergroup (GCIG) consensus review for ovarian germ cell tumors. International Journal of Gynecological Cancer. 2014; 24: S48–S54.

[42] Kawai M, Kano T, Kikkawa F, Morikawa Y, Oguchi H, Nakashima N, et al. Seven tumor markers in benign and malignant germ cell tumors of the ovary. Gynecologic Oncology. 1992; 45: 248–253.

[43] Obata NH, Nakashima N, Kawai M, Kikkawa F, Mamba S, Tomoda Y. Gonadoblastoma with dysgerminoma in one ovary and gonadoblastoma with dysgerminoma and yolk sac tumor in the contralateral ovary in a girl with 46XX karyotype. Gynecologic Oncology. 1995; 58: 124–128.

[44] Kemp B, Hauptmann S, Schröder W, Amo-Takyi B, Leeners B, Rath W. Dysgerminoma of the ovary in a patient with triple-X syndrome. International Journal of Gynaecology and Obstetrics. 1995; 50: 51–53.

[45] Meisel JL, Woo KM, Sudarsan N, Eng J, Patil S, Jacobsen EP, et al. Development of a risk stratification system to guide treatment for female germ cell tumors. Gynecologic Oncology. 2015; 138: 566–572.

[46] Göbel U, Schneider DT, Calaminus G, Haas RJ, Schmidt P, Harms D. Germ-cell tumors in childhood and adolescence. Annals of Oncology. 2000; 11: 263–272.

[47] Sigismondi C, Scollo P, Ferrandina G, Candiani M, Angioli R, Viganò R, et al. Management of bilateral malignant ovarian germ cell tumors: a MITO-9 retrospective study. International Journal of Gynecological Cancer. 2015; 25: 203–207.

[48] Ray-Coquard I, Pujade Lauraine E, Le Cesne A, Pautier P, Vacher Lavenue MC, Trama A, et al. Improving treatment results with reference centres for rare cancers: where do we stand?European Journal of Cancer. 2017; 77: 90–98.

[49] Poynter JN, Radzom AH, Spector LG, Puumala S, Robison LL, Chen Z, et al. Family history of cancer and malignant germ cell tumors in children: a report from the Children’s Oncology Group. Cancer Causes & Control. 2010; 21: 181–189.

[50] Calaminus G, Schneider DT, von Schweinitz D, et al. Age-dependent presentation and clinical course of 1465 patients aged 0 to less than 18 years with ovarian or testicular germ cell tumors; data of the MAKEI 96 protocol revisited in the light of prenatal germ cell biology. Cancers. 2020; 12: 611.

[51] Newton C, Murali K, Ahmad A, Hockings H, Graham R, Liberale V, et al. A multicentre retrospective cohort study of ovarian germ cell tumours: Evidence for chemotherapy deescalation and alignment of paediatric and adult practice. European Journal of Cancer. 2019; 113: 19–27.

[52] Li J, Wu X. Current Strategy for the Treatment of Ovarian Germ Cell Tumors: Role of Extensive Surgery. Current Treatment Options in Oncology. 2016; 17: 44.

[53] Agarwal R, Rajanbabu A, Keechilattu P, Nair IR, Vijaykumar DK, Unnikrishnan UG. A retrospective analysis of the pattern of care and survival in patients with malignant ovarian germ cell tumors. South Asian Journal of Cancer. 2020; 8: 35–40.

[54] Garcia-Soto AE, Boren T, Wingo SN, Heffernen T, Miller DS. Is comprehensive surgical staging needed for thorough evaluation of early-stage ovarian carcinoma? American Journal of Obstetrics and Gynecology. 2012; 206: 242.e1–242.e5.

[55] Billmire DF. Germ Cell Tumors. Surgical Clinics of North America. 2006; 86: 489–503.

[56] Royal College of Obstetricians and Gynaecologists. Management of Female Malignant Ovarian Germ Cell Tumours. 2016. Available at: https://www.rcog.org.uk/globalassets/documents /guidelines/scientific-impact-papers/sip_52.pdf (Accessed: 29 July 2020)

[57] Nasioudis D, Mastroyannis SA, Latif NA, Ko EM. Trends in the surgical management of malignant ovarian germcell tumors. Gynecologic Oncology. 2020; 157: 89–93.

[58] Xu W, Li Y. Is Omentectomy Mandatory among Early Stage (i, II) Malignant Ovarian Germ Cell Tumor Patients? A Retrospective Study of 223 Cases. International Journal of Gynecological Cancer. 2017; 27: 1373–1378.

[59] Morgan, R. J., Alvarez, R. D., Armstrong, D. K., Boston, B., Burger, R. A., Chen, L. M., et al. Epithelial Ovarian Cancer. Journal of the National Comprehensive Cancer Network. 2011; 9: 82–113.

[60] Mahdi H, Swensen RE, Hanna R, Kumar S, Ali-Fehmi R, Semaan A, et al. Prognostic impact of lymphadenectomy in clinically early stage malignant germ cell tumour of the ovary. British Journal of Cancer. 2011; 105: 493–497.

[61] Chan JK, Tewari KS, Waller S, Cheung MK, Shin JY, Osann K, et al. The influence of conservative surgical practices for malignant ovarian germ cell tumors. Journal of Surgical Oncology. 2008; 98: 111–116.

[62] Johansen G, Dahm-Kähler P, Staf C, Flöter Rådestad A, Rodriguez-Wallberg KA. Fertility-sparing surgery for treatment of non-epithelial ovarian cancer: Oncological and reproductive outcomes in a prospective nationwide population-based cohort study. Gynecologic Oncology. 2019; 155: 287–293.

[63] Ghalleb M, Bouzaiene H, Slim S, Hadiji A, Hechiche M, Ben Hassouna J, et al. Fertility-sparing surgery in advanced stage malignant ovarian germ cell tumor: a case report. Journal of Medical Case Reports. 2017; 11: 350.

[64] Ertas IE, Taskin S, Goklu R, Bilgin M, Goc G, Yildirim Y, et al. Long-term oncological and reproductive outcomes of fertility-sparing cytoreductive surgery in females aged 25 years and younger with malignant ovarian germ cell tumors. The Journal of Obstetrics and Gynaecology Research. 2014; 40: 797–805.

[65] Yang Z, Liu Z, Wei R, Li L. An Analysis of Prognostic Factors in Patients with Ovarian Malignant Germ Cell Tumors who are Treated with Fertility-Preserving Surgery. Gynecologic and Obstetric Investigation. 2016; 81: 1–9.

[66] Gershenson DM. Management of early ovarian cancer: germ cell and sex cord-stromal tumors. Gynecologic Oncology. 1994; 55: S62–S72.

[67] Buttram VC, Vaquero C. Post-Ovarian Wedge Resection Adhesive Disease. Fertility and Sterility. 1975; 26: 874–876.

[68] Gershenson DM. Update on malignant ovarian germ cell tumors. Cancer. 1993; 71: 1581–1590.

[69] Gershenson DM. Fertility-sparing surgery for malignancies in women. Journal of the National Cancer Institute. Monographs. 2005; 43–47.

[70] Gershenson DM, Morris M, Cangir A, Kavanagh JJ, Stringer CA, Edwards CL, et al. Treatment of malignant germ cell tumors of the ovary with bleomycin, etoposide, and cisplatin. Journal of Clinical Oncology. 1990; 8: 715–720.

[71] Dimopoulos MA, Papadopoulou M, Andreopoulou E, Papadimitriou C, Pavlidis N, Aravantinos G, et al. Favorable outcome of ovarian germ cell malignancies treated with cisplatin or carboplatin-based chemotherapy: a Hellenic Cooperative Oncology Group study. Gynecologic Oncology. 1998; 70: 70–74.

[72] Dark GG, Bower M, Newlands ES, Paradinas F, Rustin GJ. Surveillance policy for stage i ovarian germ cell tumors. Journal of Clinical Oncology. 1997; 15: 620–624.

[73] Williams SD, Birch R, Einhorn LH, Irwin L, Greco FA, Loehrer PJ. Treatment of disseminated germ-cell tumors with cisplatin, bleomycin, and either vinblastine or etoposide. The New England Journal of Medicine. 1987; 316: 1435–1440.

[74] Segelov E, Campbell J, Ng M, Tattersall M, Rome R, Free K, et al. Cisplatin-based chemotherapy for ovarian germ cell malignancies: the Australian experience. Journal of Clinical Oncology. 1994; 12: 378–384.

[75] Bajorin DF, Sarosdy MF, Pfister DG, Mazumdar M, Motzer RJ, Scher HI, et al. Randomized trial of etoposide and cisplatin versus etoposide and carboplatin in patients with good-risk germ cell tumors: a multiinstitutional study. Journal of Clinical Oncology. 1993; 11: 598–606.

[76] Boussios S, Zarkavelis G, Seraj E, Zerdes I, Tatsi K, Penther-oudakis G. Non-epithelial Ovarian Cancer: Elucidating Uncommon Gynaecological Malignancies. Anticancer Research. 2016; 36: 5031–5042.

[77] Satoh T, Aoki Y, Kasamatsu T, Ochiai K, Takano M, Watanabe Y, et al. Administration of standard-dose BEP regimen (bleomycin+etoposide+cisplatin) is essential for treatment of ovarian yolk sac tumour. European Journal of Cancer. 2015; 51: 340–351.

[78] Dimopoulos MA, Papadimitriou C, Hamilos G, Efstathiou E, Vlahos G, Rodolakis A, et al. Treatment of ovarian germ cell tumors with a 3-day bleomycin, etoposide, and cisplatin regimen: a prospective multicenter study. Gynecologic Oncology. 2004; 95: 695–700.

[79] Howard R, Gilbert E, Lynch CF, Hall P, Storm H, Holowaty E, et al. Risk of leukemia among survivors of testicular cancer: a population-based study of 42,722 patients. Annals of Epidemiology. 2008; 18: 416–421.

[80] Mann JR, Raafat F, Robinson K, Imeson J, Gornall P, Sokal M, et al. The United Kingdom Children’s Cancer Study Group’s second germ cell tumor study: carboplatin, etoposide, and bleomycin are effective treatment for children with malignant extracranial germ cell tumors, with acceptable toxicity. Journal of Clinical Oncology. 2000; 18: 3809–3818.

[81] Shah R, Xia C, Krailo M, Amatruda JF, Arul SG, Billmire DF, et al. Is carboplatin-based chemotherapy as effective as cisplatin-based chemotherapy in the treatment of advanced-stage dysger-minoma in children, adolescents and young adults? Gynecologic Oncology. 2018; 150: 253–260.

[82] Williams SD, Kauderer J, Burnett AF, Lentz SS, Aghajanian C, Armstrong DK. Adjuvant therapy of completely resected dys-germinoma with carboplatin and etoposide: a trial of the Gy-necologic Oncology Group. Gynecologic Oncology. 2004; 95: 496–499.

[83] Talukdar S, Kumar S, Bhatla N, Mathur S, Thulkar S, Kumar L. Neo-adjuvant chemotherapy in the treatment of advanced malignant germ cell tumors of ovary. Gynecologic Oncology. 2014; 132: 28–32.

[84] Eurich KE, Swisher E, Toukatly M, Koch L, Wu ES. A case of metastatic dysgerminoma treated with two cycles neoadjuvant chemotherapy followed by fertility-sparing minimally invasive surgery. Gynecologic Oncology Reports. 2019; 28: 124–127.

[85] Lakshmanan M, Gupta S, Kumar V, Akhtar N, Chaturvedi A, Misra S, et al. Germ Cell Tumor Ovary: an Institutional Experience of Treatment and Survival Outcomes. Indian Journal of Surgical Oncology. 2019; 9: 215–219.

[86] Reddy Ammakkanavar N, Matei D, Abonour R, Einhorn LH. High-dose chemotherapy for recurrent ovarian germ cell tumors. Journal of Clinical Oncology. 2015; 33: 226–227.

[87] Zhao Q, Yang J, Cao D, Han J, Xu K, Liu Y, et al. Tailored therapy and long-term surveillance of malignant germ cell tumors in the female genital system: 10-year experience. Journal of Gynecologic Oncology. 2016; 27: e26.

[88] Chi EA, Schweizer MT. Durable Response to Immune Checkpoint Blockade in a Platinum-Refractory Patient with Nonseminomatous Germ Cell Tumor. Clinical Genitourinary Cancer. 2017; 15: e855–e857.

[89] Boussios S, Moschetta M, Tatsi K, Tsiouris AK, Pavlidis N. A review on pregnancy complicated by ovarian epithelial and non-epithelial malignant tumors: Diagnostic and therapeutic perspectives. Journal of Advanced Research. 2018; 12: 1–9.

[90] Fauvet R, Brzakowski M, Morice P, Resch B, Marret H, Graesslin O, et al. Borderline ovarian tumors diagnosed during pregnancy exhibit a high incidence of aggressive features: results of a French multicenter study. Annals of Oncology. 2012; 23: 1481–1487.

[91] Zhao XY, Huang HF, Lian LJ, Lang JH. Ovarian cancer in pregnancy: a clinicopathologic analysis of 22 cases and review of the literature. International Journal of Gynecological Cancer. 2006; 16: 8–15.

[92] Kodama M, Grubbs BH, Blake EA, Cahoon SS, Murakami R, Kimura T, et al. Fetomaternal outcomes of pregnancy complicated by ovarian malignant germ cell tumor: a systematic review of literature. European Journal of Obstetrics, Gynecology, and Reproductive Biology. 2014; 181: 145–156.

[93] Buller RE, Darrow V, Manetta A, Porto M, DiSaia PJ. Conservative surgical management of dysgerminoma concomitant with pregnancy. Obstetrics and Gynecology. 1992; 79: 887–890.

[94] Han J, Nava-Ocampo AA, Kim T, Shim J, Park C. Pregnancy outcome after prenatal exposure to bleomycin, etoposide and cisplatin for malignant ovarian germ cell tumors: report of 2 cases. Reproductive Toxicology. 2005; 19: 557–561.

[95] Cheng L, Roth LM, Zhang S, Wang M, Morton MJ, Zheng W, et al. KIT gene mutation and amplification in dysgerminoma of the ovary. Cancer. 2011; 117: 2096–2103.

[96] Van Nieuwenhuysen E, Busschaert P, Neven P, Han SN, Moerman P, Liontos M, et al. The genetic landscape of 87 ovarian germ cell tumors. Gynecologic Oncology. 2018; 151: 61–68.

[97] Adra N, Einhorn LH, Althouse SK, Ammakkanavar NR, Musapatika D, Albany C, et al. Phase II trial of pembrolizumab in patients with platinum refractory germ-cell tumors: a Hoosier Cancer Research Network Study GU14-206. Annals of Oncology. 2018; 29: 209–214.

[98] ClinicalTrials.gov. Evaluating Immune Therapy, Duravalumab (MEDI4736) With Tremelimumab for Relapsed/Refractory Germ Cell Tumors. 2017. Available at: https://clinicaltrials.gov /ct2/show/NCT03158064(Accessed: 26 August 2020).

[99] Cheung A, Shah S, Parker J, Soor P, Limbu A, Sheriff M, et al. Non-Epithelial Ovarian Cancers: How Much Do We Really Know? International Journal of Environmental Research and Public Health. 2022; 19: 1106.

[100] Nappi L, Thi M, Lum A, Huntsman D, Eigl BJ, Martin C, et al. Developing a highly specific biomarker for germ cell malignancies: Plasma MiR371 expression across the germ cell malignancy spectrum. Journal of clinical oncology. 2019; 37: 3090–3098.