Update on pediatric testicular germ cell tumors

https://doi.org/10.1016/j.jpedsurg.2021.04.001Get rights and content

Abstract

Background

Testicular germ cell tumors are uncommon tumors that are encountered by pediatric surgeons and urologists and require a knowledge of appropriate contemporary evaluation and surgical and medical management.

Method

A review of the recommended diagnostic evaluation and current surgical and medical management of children and adolescents with testicular germ cell tumors based upon recently completed clinical trials was performed and summarized in this article.

Results

In this summary of childhood and adolescent testicular germ cell tumors, we review the initial clinical evaluation, surgical and medical management, risk stratification, results from recent prospective cooperative group studies, and clinical outcomes. A summary of recently completed clinical trials by pediatric oncology cooperative groups is provided, and best surgical practices are discussed.

Conclusions

Testicular germ cell tumors in children are rare tumors. International collaborations, data-sharing, and enrollment of patients at all stages and risk classifications into active clinical trials will enhance our knowledge of these rare tumors and most importantly improve outcomes of patients with testicular germ cell tumors.

Level of evidence

This is a review article of previously published and referenced level 1 and 2 studies, but also includes expert opinion level 5, represented by the American Pediatric Surgical Association Cancer Committee.

Introduction

Testicular germ cell tumors (GCT) in children are uncommon, comprising approximately 3% of all pediatric solid malignant tumors, but up to 15% of malignancies diagnosed during adolescence [1,2]. In this summary of childhood and adolescent testicular GCTs, we review the initial clinical evaluation, surgical and medical management, risk stratification, results from recent prospective cooperative group studies, and clinical outcomes.

Section snippets

Differential diagnosis of a testicular mass

Testicular masses are rare in prepubertal boys (age <11 years) and when present in this age group are typically benign lesions such as teratoma (40%), epidermoid cysts, or Leydig cell hyperplasia [3]. The most common primary testicular malignancy in children and adolescents is GCT.[2] GCTs can occur at any age and demonstrate a bimodal age distribution with a small peak before age 5 years and a larger peak after age 15 years [1,4].

In prepubertal boys, testicular GCTs are typically either benign

History and physical examination

The most common presentation of a testicular GCT is a painless testicular mass (90%), with trauma and persistent swelling, hydrocele, hernia, or bruising less common findings [6]. A physical examination often reveals a firm and usually nontender testicular mass. Alternate etiologies, including testicular torsion, hernia, hydrocele, epididymitis, or paratesticular masses, should be excluded [7]. Evaluation of all nodal basins should be performed, and the abdomen should be carefully palpated for

Staging

Given the presentation patterns in both adults and children, multiple staging systems have been developed for testicular GCTs which have resulted in some inconsistencies in the literature. Adult testicular GCTs are most frequently staged using the American Joint Committee on Cancer (AJCC) system. This is a complex scheme that makes use of tumor characteristics, nodal disease, distant metastases, and serum markers in a TNMS system (Table 1). Patients are then grouped or staged I to IIIC (Table 2

Risk classification

Similar concerns exist with respect to risk assignment in adult GCTs, which prompted the creation of an International Germ Cell Consensus Classification (IGCCC) in the 1990s [27]. Multiple previous clinical trials, which included over 5000 patients, were pooled together to create a robust system of risk assignments. This system incorporates histology, tumor site, presence and location of metastases, and tumor markers to assign a “good,” “intermediate,” or “poor” risk classification. However,

Inguinal approach

The standard of care for the initial management of testicular GCTs is a radical orchiectomy via inguinal incision with high ligation of the cord structures at the internal ring [2,[30], [31], [32], [33]]. (Fig. 2) Additionally, surgical guidelines recommend vascular control of the testicle prior to mobilization, achieving a spermatic cord proximal margin of 5 cm, and avoidance of trans-scrotal resection, needle biopsy or aspiration [32]. The inguinal approach facilitates important oncologic

Systemic therapy

The evolution of current systemic therapy for GCT began with studies in adult men with testicular tumors in the late 1970′s, when cisplatin was first utilized for disseminated testicular GCTs [75]. Cisplatin has remained the cornerstone of chemotherapy for GCTs. In the mid-1980s, a randomized clinical trial in men with disseminated GCTs was performed comparing the substitution of vinblastine to etoposide in the GCT regimen and found less toxicity with improved efficacy in the

Outcomes

Prior to the development of platinum-based therapy, metastatic testicular cancer was associated with a high mortality, up to 90% within a year of diagnosis. However, outcomes have significantly improved since the introduction of BEP in the late 1970s [75,76]. Subsequently, the Children's Cancer Group and Pediatric Intergroup Germ Cell combined studies demonstrated excellent 6-year Event Free Survival (EFS) and overall survival (OS), with stage 1 EFS of 78.5% and OS 100%, Stage 2 of 100% and

Summary of completed COG clinical trials that include testicular GCT

Over the past 25 years, the Intergroup trial of testes cancer (POG/CCG9048/8891), as well as the COG (AGCT 0131, AGCT 0132, AGTC 01P1, AGCT 0521 and AGCT1531) have performed several clinical GCT trials, including testicular GCTs in pediatric patients. Furthermore, a broader international consortium with close collaboration between the COG, European countries, Brazil, China, India, Japan and Australia (https://magicconsortium.com) was launched in 2009 and has been working towards a better

Future directions and challenges

Similar to other pediatric cancers, correlations between biology, risk stratification, and outcomes have recently been investigated for GCTs including testicular GCTs. Through the COG with Project Every Child (APEC14B1), and through the MaGIC collaboration, centralized biospecimen repositories and patient data are now available to study biomarkers at diagnosis and at relapse, providing the ability to study these longitudinally with patient outcome data. Several biomarkers within the tumors and

Conclusion

Testicular GCTs in children are rare tumors. International collaborations, data-sharing, and enrollment of patients at all stages and risk classifications into active clinical trials will enhance our knowledge of these rare tumors and most importantly improve outcomes of patients with testicular GCTs.

References (101)

  • S.N. Huddart et al.

    The UK Children's Cancer Study Group: testicular malignant germ cell tumors 1979–1988

    J Pediatr Surg

    (1990)
  • N.G. Cost et al.

    Risk stratification of pubertal children and postpubertal adolescents with clinical stage I testicular nonseminomatous germ cell tumors

    J Urol

    (2014)
  • R. Mano et al.

    Current controversies on the role of retroperitoneal lymphadenectomy for testicular cancer

    Urol Oncol

    (2019)
  • M.A. Jewett et al.

    Nerve-sparing retroperitoneal lymphadenectomy

    Urol Clin North Am.

    (2007)
  • M.A. Jewett

    Nerve-sparing technique for retroperitoneal lymphadenectomy in testis cancer

    Urol Clin North Am

    (1990)
  • A.P. Glaser et al.

    Robot-assisted retroperitoneal lymph node dissection (RA-RPLND) in the adolescent population

    J Pediatr Urol

    (2017)
  • S.A. Mansfield et al.

    Alternative approaches to retroperitoneal lymph node dissection for paratesticule rhabdomyosarcoma

    J Ped Surg

    (2020)
  • H. Steiner et al.

    Postchemotherapy laparoscopic retroperitoneal lymph node dissection for low-volume, stage II, nonseminomatous germ cell tumor: first 100 patients

    Eur Urol

    (2013)
  • S.M. Pearce et al.

    Safety and early oncologic effectiveness of primary robotic retroperitoneal lymph node dissection for nonseminomatous germ cell testicular cancer

    Eur Urol

    (2017)
  • J.J. Rassweiler et al.

    Laparoscopic retroperitoneal lymph node dissection for nonseminomatous germ cell tumors: indications and limitations

    J Urol

    (1996)
  • S. Stepanian et al.

    Robot-assisted laparoscopic retroperitoneal lymph node dissection for testicular cancer: evolution of the technique

    Eur Urol

    (2016)
  • H. Steiner et al.

    Long-term results of laparoscopic retroperitoneal lymph node dissection: a single-center 10-year experience

    Urology

    (2004)
  • J.K. Giguere et al.

    The clinical significance of unconventional orchiectomy approaches in testicular cancer: a report from the testicular cancer intergroup study

    J Urol

    (1988)
  • I. Leibovitch et al.

    The clinical implications of procedural deviations during orchiectomy for nonseminomatous testis cancer

    J Urol

    (1995)
  • N.G. Cost et al.

    Adolescent urologic oncology: current issues and future directions

    Urol Oncol

    (2014)
  • C. Bokemeyer et al.

    A randomized trial of cisplatin, etoposide and bleomycin (PEB) versus carboplatin, etoposide and bleomycin (CEB) for patients with 'good-risk' metastatic non-seminomatous germ cell tumors

    Ann Oncol

    (1996)
  • S.A. Tjulandin et al.

    Cisplatin-etoposide and carboplatin-etoposide induction chemotherapy for good-risk patients with germ cell tumors

    Ann Oncol.

    (1993)
  • A.L. Frazier et al.

    Comparison of carboplatin versus cisplatin in the treatment of paediatric extracranial malignant germ cell tumours: a report of the malignant germ cell international consortium

    Eur J Cancer

    (2018)
  • G. Daugaard et al.

    A randomized phase III study comparing standard dose BEP with sequential high-dose cisplatin, etoposide, and ifosfamide (VIP) plus stem-cell support in males with poor-prognosis germ-cell cancer. An intergroup study of EORTC, GTCSG, and Grupo Germinal (EORTC 30974)

    Ann Oncol

    (2011)
  • M. Pfreundschuh et al.

    Two-weekly or 3-weekly CHOP chemotherapy with or without etoposide for the treatment of young patients with good-prognosis (normal LDH) aggressive lymphomas: results of the NHL-B1 trial of the DSHNHL

    Blood

    (2004)
  • M. Chovanec et al.

    Long-term toxicity of cisplatin in germ-cell tumor survivors

    Ann Oncol

    (2017)
  • Y. Li et al.

    Predicting cisplatin ototoxicity in children: the influence of age and the cumulative dose

    Eur J Cancer

    (2004)
  • C. Nord et al.

    Gonadal hormones in long-term survivors 10 years after treatment for unilateral testicular cancer

    Eur Urol

    (2003)
  • R.A. Costabile

    The effects of cancer and cancer therapy on male reproductive function

    J Urol

    (1993)
  • K.A. Ostrowski et al.

    Infertility with testicular cancer

    Urol Clin North Am

    (2015)
  • H. Shen et al.

    Integrated molecular characterization of testicular germ cell tumors

    Cell Rep

    (2018)
  • J.L. Pierce et al.

    Pediatric germ cell tumors: a developmental perspective

    Adv Urol

    (2018)
  • F.J. Rescorla

    Pediatric germ cell tumors

    Semin Surg Oncol

    (1999)
  • A.F. Saltzman et al.

    Adolescent and Young Adult Testicular Germ Cell Tumors: special Considerations

    Adv Urol

    (2018)
  • P.D. Metcalfe et al.

    Pediatric testicular tumors: contemporary incidence and efficacy of testicular preserving surgery

    J Urol

    (2003)
  • A. Fonseca et al.

    Detection of relapse by tumor markers versus imaging in children and adolescents with nongerminomatous malignant germ cell tumors: a report from the children's oncology group

    J Clin Oncol

    (2019)
  • T. van Agthoven et al.

    Accurate primary germ cell cancer diagnosis using serum based microRNA detection (ampTSmiR test)

    Oncotarget

    (2017)
  • K.P. Dieckmann 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)
  • X. Rosas Plaza et al.

    miR-371a-3p, miR-373-3p and miR-367-3p as serum biomarkers in metastatic testicular germ cell cancers before, during and after chemotherapy

    Cells

    (2019)
  • P.M. Pierorazio et al.

    Comparative effectiveness of surveillance, primary chemotherapy, radiotherapy and retroperitoneal lymph node dissection for the management of early stage testicular germ cell tumors: a systematic review

    J Urol

    (2021)
  • G. Tallen et al.

    High reliability of scrotal ultrasonography in the management of childhood primary testicular neoplasms

    Klin Padiatr

    (2011)
  • E.I. Kreydin et al.

    Testicular cancer: what the radiologist needs to know

    AJR Am J Roentgenol

    (2013)
  • P.M. Pierorazio et al.

    Performance characteristics of clinical staging modalities for early stage testicular germ cell tumors: a systematic review

    J Urol

    (2020)
  • S. Hilton et al.

    CT detection of retroperitoneal lymph node metastases in patients with clinical stage I testicular nonseminomatous germ cell cancer: assessment of size and distribution criteria

    AJR Am J Roentgenol

    (1997)
  • L. Leibovitch et al.

    Improved accuracy of computerized tomography based clinical staging in low stage nonseminomatous germ cell cancer using size criteria of retroperitoneal lymph nodes

    J Urol

    (1995)

    • Cited by (2)

    • Treatment Outcome of Response-Based Radiation Therapy in Children and Adolescents With Central Nervous System Nongerminomatous Germ Cell Tumors: Results of a Prospective Study

      2024, International Journal of Radiation Oncology Biology Physics

    • Imaging of pediatric testicular tumors: A COG Diagnostic Imaging Committee/SPR Oncology Committee White Paper

      2023, Pediatric Blood and Cancer
    View full text
    © 2021 Elsevier Inc. All rights reserved.