Clinicopathologic predictors of outcomes in children with stage I testicular germ cell tumors: A pooled post hoc analysis of trials from the Children's Oncology Group



      Patients with clinical stage I (CS I: cN0M0) testicular germ cell tumors (TGCT) exhibit favorable oncologic outcomes. While prognostic features can help inform treatment in adults with CS I TGCT, we lack reliable means to predict relapse among pediatric and adolescent patients.


      We sought to identify predictors of relapse in children with CS I TGCT.

      Study design

      We performed a pooled post hoc analysis on pediatric and adolescent AJCC CS I TGCT patients enrolled in 3 prospective trials: INT-0097 (phase II), INT-0106 (phase III), and AGCT0132 (phase III). Pathology was centrally reviewed. Patient demographics, pT stage, serum tumor markers, margin status, histology, relapse, and survival were compiled. Cox regression analyses were used to identify predictors of events, defined as relapse, secondary malignant neoplasm, or death.


      106 patients were identified with outcomes data available. Most patients were pT1-2 stage. Among patients with evaluable histopathology, yolk sac tumor elements were present in all patients and lymphovascular invasion in 51% of patients. Over a median follow-up of 56 months, no patients died, and 25 patients (24%) experienced an event (median event-free survival not reached). Independent predictors of events on multivariable analysis included age ≥12 years at diagnosis (HR 8.87, p < 0.001) and higher pT stage (pT2 HR 7.31, p = 0.0017; pT3 HR 13.5, p = 0.0043).


      Although our study population reflects the largest pooled prospective cohort of CS I pediatric and adolescent TGCT to our knowledge, the relatively low event rate limits our multivariable analysis, and longer follow-up duration would help further characterize the natural history of these patients. Centralized pathologic review was also unable to be performed for several patients.


      Summary Figure
      Graphical AbstractEvent free survival by age at diagnosis (A) and pathologic T stage (B).


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        • Siegel R.L.
        • Miller K.D.
        • Jemal A.
        Cancer statistics, 2020.
        CA Cancer J Clin. 2020; 70: 7-30
        • Walsh T.J.
        • Grady R.W.
        • Porter M.P.
        • Lin D.W.
        • Weiss N.S.
        Incidence of testicular germ cell cancers in U.S. children: SEER program experience 1973 to 2000.
        Urology. 2006; 68 (discussion 405): 402-405
        • Gobel U.
        • Schneider D.T.
        • Calaminus G.
        • Haas R.J.
        • Schmidt P.
        • Harms D.
        Germ-cell tumors in childhood and adolescence. GPOH MAKEI and the MAHO study groups.
        Ann Oncol. 2000; 11: 263-271
        • Bagrodia A.
        • Pierorazio P.
        • Singla N.
        • Albers P.
        The complex and nuanced Care for early-stage testicular cancer: lessons from the European association of urology and American urological association testis cancer guidelines.
        Eur Urol. 2020; 77: 139-141
        • Blok J.M.
        • Pluim I.
        • Daugaard G.
        • et al.
        Lymphovascular invasion and presence of embryonal carcinoma as risk factors for occult metastatic disease in clinical stage I nonseminomatous germ cell tumour: a systematic review and meta-analysis.
        BJU Int. 2020; 125: 355-368
        • Brimo F.
        • Srigley J.
        • Ryan C.
        in: Amin M.B. Edge S.B. Greene F.L. AJCC cancer staging manual. 8th ed. Springer, New York, NY2017: 727-735
        • Schlatter M.
        • Rescorla F.
        • Giller R.
        • et al.
        Excellent outcome in patients with stage I germ cell tumors of the testes: a study of the Children's Cancer Group/Pediatric Oncology Group.
        J Pediatr Surg. 2003; 38 (discussion 319-324): 319-324
        • Rescorla F.J.
        • Ross J.H.
        • Billmire D.F.
        • et al.
        Surveillance after initial surgery for Stage I pediatric and adolescent boys with malignant testicular germ cell tumors: report from the Children's Oncology Group.
        J Pediatr Surg. 2015; 50: 1000-1003
        • Cushing B.
        • Giller R.
        • Cullen J.W.
        • et al.
        Randomized comparison of combination chemotherapy with etoposide, bleomycin, and either high-dose or standard-dose cisplatin in children and adolescents with high-risk malignant germ cell tumors: a pediatric intergroup study--Pediatric Oncology Group 9049 and Children's Cancer Group 8882.
        J Clin Oncol. 2004; 22: 2691-2700
        • Rogers P.C.
        • Olson T.A.
        • Cullen J.W.
        • et al.
        Treatment of children and adolescents with stage II testicular and stages I and II ovarian malignant germ cell tumors: a Pediatric Intergroup Study--Pediatric Oncology Group 9048 and Children's Cancer Group 8891.
        J Clin Oncol. 2004; 22: 3563-3569
        • Billmire D.F.
        • Cullen J.W.
        • Rescorla F.J.
        • et al.
        Surveillance after initial surgery for pediatric and adolescent girls with stage I ovarian germ cell tumors: report from the Children's Oncology Group.
        J Clin Oncol. 2014; 32: 465-470
        • Stephenson A.
        • Eggener S.E.
        • Bass E.B.
        • et al.
        Diagnosis and treatment of early stage testicular cancer: AUA guideline.
        J Urol. 2019; 202: 272-281
        • Nayan M.
        • Jewett M.A.
        • Hosni A.
        • et al.
        Conditional risk of relapse in surveillance for clinical stage I testicular cancer.
        Eur Urol. 2017; 71: 120-127
        • Huddart R.A.
        • Reid A.M.
        Adjuvant therapy for stage IB germ cell tumors: one versus two cycles of BEP.
        Adv Urol. 2018; 2018: 8781698
        • Gilligan T.
        • Lin D.W.
        • Aggarwal R.
        • et al.
        Testicular cancer, version 2.2020, NCCN clinical practice guidelines in Oncology.
        J Natl Compr Canc Netw. 2019; 17: 1529-1554
        • Shaikh F.
        • Stark D.
        • Fonseca A.
        • et al.
        Outcomes of adolescent males with extracranial metastatic germ cell tumors: a report from the Malignant Germ Cell Tumor International Consortium.
        Cancer. 2021 Jan 15; 127: 193-202
        • Murray M.J.
        • Halsall D.J.
        • Hook C.E.
        • Williams D.M.
        • Nicholson J.C.
        • Coleman N.
        Identification of microRNAs from the miR-371∼373 and miR-302 clusters as potential serum biomarkers of malignant germ cell tumors.
        Am J Clin Pathol. 2011; 135: 119-125
        • Belge G.
        • Dieckmann K.P.
        • Spiekermann M.
        • Balks T.
        • Bullerdiek J.
        Serum levels of microRNAs miR-371-3: a novel class of serum biomarkers for testicular germ cell tumors?.
        Eur Urol. 2012; 61: 1068-1069
        • Syring I.
        • Bartels J.
        • Holdenrieder S.
        • Kristiansen G.
        • Muller S.C.
        • Ellinger J.
        Circulating serum miRNA (miR-367-3p, miR-371a-3p, miR-372-3p and miR-373-3p) as biomarkers in patients with testicular germ cell cancer.
        J Urol. 2015; 193: 331-337
        • van Agthoven T.
        • Looijenga L.H.J.
        Accurate primary germ cell cancer diagnosis using serum based microRNA detection (ampTSmiR test).
        Oncotarget. 2017; 8: 58037-58049
        • Bezan A.
        • Gerger A.
        • Pichler M.
        MicroRNAs in testicular cancer: implications for pathogenesis, diagnosis, prognosis and therapy.
        Anticancer Res. 2014; 34: 2709-2713
        • van Agthoven T.
        • Eijkenboom W.M.H.
        • Looijenga L.H.J.
        microRNA-371a-3p as informative biomarker for the follow-up of testicular germ cell cancer patients.
        Cell Oncol (Dordr). 2017; 40: 379-388
        • Radtke A.
        • Hennig F.
        • Ikogho R.
        • et al.
        The novel biomarker of germ cell tumours, Micro-RNA-371a-3p, has a very rapid decay in patients with clinical stage 1.
        Urol Int. 2018; 100: 470-475
        • Dieckmann K.P.
        • Radtke A.
        • Geczi L.
        • et al.
        Serum levels of MicroRNA-371a-3p (M371 test) as a new biomarker of testicular germ cell tumors: results of a prospective multicentric study.
        J Clin Oncol. 2019; : JCO1801480
        • Singla N.
        • Lafin J.T.
        • Bagrodia A.
        MicroRNAs: turning the tide in testicular cancer.
        Eur Urol. 2019; 76: 541-542
        • Lafin J.T.
        • Singla N.
        • Woldu S.L.
        • et al.
        Serum MicroRNA-371a-3p levels predict viable germ cell tumor in chemotherapy-naive patients undergoing retroperitoneal lymph node dissection.
        Eur Urol. 2020; 77: 290-292
        • Badia R.R.
        • Abe D.
        • Wong D.
        • et al.
        Real-world application of pre-orchiectomy miR-371a-3p test in testicular germ cell tumor management.
        J Urol. 2020; 101097JU0000000000001337