Childhood Extracranial Germ Cell Tumors

Summary Type: Treatment
Summary Audience: Health professionals
Summary Language: English
Summary Description: Expert-reviewed information summary about the treatment of childhood extracranial germ cell tumors.

Childhood Extracranial Germ Cell Tumors

General Information

This cancer treatment information summary provides an overview of the prognosis, histologic classification, staging, and treatment of childhood (pediatric) extracranial germ cell tumors. (Refer to the PDQ summary on Childhood Brain Tumors Treatment for more information regarding the management of patients with intracranial germ cell tumors.)

The National Cancer Institute provides the PDQ pediatric cancer treatment information summaries as a public service to increase the availability of evidence-based cancer information to health professionals, patients, and the public. These summaries are updated regularly according to the latest published research findings by an Editorial Board of pediatric oncology specialists.

Cancer in children and adolescents is rare. Children and adolescents with cancer should be referred to medical centers that have a multidisciplinary team of cancer specialists with experience treating the cancers that occur during childhood and adolescence. This multidisciplinary team incorporates the skills of the primary care physician, pediatric surgical subspecialists, radiation therapists, pediatric oncologists/hematologists, rehabilitation specialists, pediatric nurse specialists, social workers, and others to ensure that children receive treatment, supportive care, and rehabilitation that will achieve optimal survival and quality of life. Specific information about supportive care for children and adolescents with cancer can be found in the PDQ Supportive Care summaries.

Guidelines for pediatric cancer centers and their role in the treatment of pediatric patients with cancer have been outlined by the American Academy of Pediatrics.¹ At these pediatric cancer centers, clinical trials are available for most of the types of cancer that occur in children and adolescents, and the opportunity to participate in these trials is offered to most patients/families. Clinical trials for children and adolescents with cancer are generally designed to compare potentially better therapy with therapy that is currently accepted as standard. The majority of the progress made in identifying curative therapies for childhood cancers has been achieved through clinical trials. Information about ongoing clinical trials is available from the NCI Web site.

In recent decades, dramatic improvements in survival have been achieved for children and adolescents with cancer. Childhood and adolescent cancer survivors require close follow-up since cancer therapy side effects may persist or develop months or years after treatment. Refer to the PDQ summary on Late Effects of Treatment for Childhood Cancer for specific information about the incidence, type, and monitoring of late effects in childhood and adolescent cancer survivors.

Childhood extracranial germ cell tumors are rare in children younger than 15 years, accounting for approximately 3% of cancer cases in this age group.^2,3 Extracranial germ cell tumors (particularly testicular germ cell tumors) are much more common among adolescents aged 15 to 19 years, representing approximately 14% of cancer diagnoses in this age group. The distribution of extracranial germ cell tumors by 5-year age group and by gender is shown in Table 1 below.

Table 1: Extracranial Germ Cell Tumors by Age Group and Gender

0-4 years5-9 years10-14 years 15-19 years*Rates are per million children for 1986 to 1995 for the 9 SEER regions plus Los Angeles. Males7* 0.3 1.4 31 Females5.8 2.4 7.8 25.3

Germ cell tumors develop from primordial germ cells, which migrate during embryogenesis from the yolk sac through the mesentery to the gonads.⁴ Childhood extracranial germ cell tumors most commonly arise in midline extragonadal sites (i.e., sacrococcygeal, mediastinal, retroperitoneal), and the midline location may represent aberrant embryonic migration of the primordial germ cells.

The genetic and histologic properties of these tumors are heterogeneous and vary by primary tumor site and the sex and age of the patient.^5,6 The germ cell tumors that arise in younger children have different biological characteristics from those that arise in adolescents and young adults. The following paragraphs describe the biologically distinct subtypes of germ cell tumors found in children and adolescents. Treatment approaches for each tumor category are provided later in this document.

Testicular Germ Cell Tumors

• Fetal/neonatal: Both benign and malignant congenital teratomas present in the fetal/neonatal period. The majority of these teratomas are benign, extragonadal tumors occurring at midline locations, including the sacrococcygeal, retroperitoneal, mediastinal, and cervical regions. Despite the small percentage of malignant teratomas, the perinatal tumors have a high morbidity due to hydrops fetalis and premature delivery.^7,8,
• Children: These germ cell tumors typically present during early childhood. The tumors commonly present with yolk sac tumor (endodermal sinus tumor) histology, are generally diploid or tetraploid, and lack the isochromosome of the short arm of chromosome 12 that characterizes testicular cancer in young adults.^9,10,11,12 Deletions of chromosomes 1p, 4q, and 6q and gains of chromosomes 1q, 3, and 20q are reported as recurring chromosomal abnormalities for this group of tumors.^11,12,13,
• Adolescents and young adults: These tumors typically possess an isochromosome of the short arm of chromosome 12 ^14,15,16,17 and are aneuploid.^9,17 Testicular cancer is broadly divided into seminomatous and nonseminomatous tumors, which is an important distinction for treatment planning because seminomas are more sensitive to radiation therapy. Although adolescent testicular germ cell patients may be best treated at pediatric oncology centers, the treatment regimens for adolescents older than 14 years follow regimens used in adults. (Refer to the PDQ summary on Testicular Cancer Treatment for more information.)

Ovarian Germ Cell Tumors

Ovarian germ cell tumors occur primarily in adolescent and young adult females. While the majority of ovarian germ cell tumors are benign mature teratomas, a heterogeneous group of malignant germ cell tumors occur in females, including immature teratomas, dysgerminomas, yolk sac tumors, and mixed germ cell tumors. The malignant ovarian germ cell tumors commonly show increased copies of the short arm of chromosome 12.¹⁸ (Refer to the PDQ summary on Ovarian Germ Cell Tumor Treatment for more information.)

Extragonadal, Extracranial Germ Cell Tumors

• Children: These tumors typically present at birth or during early childhood. The majority of these tumors are benign teratomas occurring in the sacrococcygeal region, and hence SEER areas do not report them.^19,20 Malignant yolk sac tumor histology occurs in a minority of these tumors, however, with cytogenetic abnormalities similar to those observed for tumors occurring in the testes of young males.^10,11,12,13,
• Older children, adolescents, and young adults: The mediastinum is the most common primary site for extragonadal germ cell tumors in older children and adolescents.²¹ Mediastinal germ cell tumors in children younger than 8 years share the same genetic gains and losses as sacrococcygeal and testicular tumors in young children.^22,23,24 The gain in chromosome 12p has been reported in mediastinal tumors in children aged 8 years and older.²⁴

Very little is known about the potential genetic or environmental factors associated with childhood extracranial germ cell tumors. Patients with Klinefelter’s syndrome ^25,26,27 appear to be at increased risk for mediastinal germ cell tumors, while patients with Swyer syndrome ^28,29 appear to be at increased risk for gonadoblastomas and germinomas.

¹ Guidelines for the pediatric cancer center and role of such centers in diagnosis and treatment. American Academy of Pediatrics Section Statement Section on Hematology/Oncology. Pediatrics 99 (1): 139-41, 1997.

² Miller RW, Young JL Jr, Novakovic B: Childhood cancer. Cancer 75 (1 Suppl): 395-405, 1995.

³ Ries LA, Smith MA, Gurney JG, et al., eds.: Cancer incidence and survival among children and adolescents: United States SEER Program 1975-1995. Bethesda, Md: National Cancer Institute, SEER Program, 1999. NIH Pub.No. 99-4649. Also available online. Last accessed April 19, 2007.

⁴ Dehner LP: Gonadal and extragonadal germ cell neoplasia of childhood. Hum Pathol 14 (6): 493-511, 1983.

⁵ Hawkins EP: Germ cell tumors. Am J Clin Pathol 109 (4 Suppl 1): S82-8, 1998.

⁶ Schneider DT, Calaminus G, Koch S, et al.: Epidemiologic analysis of 1,442 children and adolescents registered in the German germ cell tumor protocols. Pediatr Blood Cancer 42 (2): 169-75, 2004.

⁷ Isaacs H Jr: Perinatal (fetal and neonatal) germ cell tumors. J Pediatr Surg 39 (7): 1003-13, 2004.

⁸ Heerema-McKenney A, Harrison MR, Bratton B, et al.: Congenital teratoma: a clinicopathologic study of 22 fetal and neonatal tumors. Am J Surg Pathol 29 (1): 29-38, 2005.

⁹ Oosterhuis JW, Castedo SM, de Jong B, et al.: Ploidy of primary germ cell tumors of the testis. Pathogenetic and clinical relevance. Lab Invest 60 (1): 14-21, 1989.

¹⁰ Silver SA, Wiley JM, Perlman EJ: DNA ploidy analysis of pediatric germ cell tumors. Mod Pathol 7 (9): 951-6, 1994.

¹¹ Perlman EJ, Cushing B, Hawkins E, et al.: Cytogenetic analysis of childhood endodermal sinus tumors: a Pediatric Oncology Group study. Pediatr Pathol 14 (4): 695-708, 1994 Jul-Aug.

¹² Schneider DT, Schuster AE, Fritsch MK, et al.: Genetic analysis of childhood germ cell tumors with comparative genomic hybridization. Klin Padiatr 213 (4): 204-11, 2001 Jul-Aug.

¹³ Perlman EJ, Valentine MB, Griffin CA, et al.: Deletion of 1p36 in childhood endodermal sinus tumors by two-color fluorescence in situ hybridization: a pediatric oncology group study. Genes Chromosomes Cancer 16 (1): 15-20, 1996.

¹⁴ Rodriguez E, Houldsworth J, Reuter VE, et al.: Molecular cytogenetic analysis of i(12p)-negative human male germ cell tumors. Genes Chromosomes Cancer 8 (4): 230-6, 1993.

¹⁵ Bosl GJ, Ilson DH, Rodriguez E, et al.: Clinical relevance of the i(12p) marker chromosome in germ cell tumors. J Natl Cancer Inst 86 (5): 349-55, 1994.

¹⁶ Mostert MC, Verkerk AJ, van de Pol M, et al.: Identification of the critical region of 12p over-representation in testicular germ cell tumors of adolescents and adults. Oncogene 16 (20): 2617-27, 1998.

¹⁷ van Echten J, Oosterhuis JW, Looijenga LH, et al.: No recurrent structural abnormalities apart from i(12p) in primary germ cell tumors of the adult testis. Genes Chromosomes Cancer 14 (2): 133-44, 1995.

¹⁸ Riopel MA, Spellerberg A, Griffin CA, et al.: Genetic analysis of ovarian germ cell tumors by comparative genomic hybridization. Cancer Res 58 (14): 3105-10, 1998.

¹⁹ Malogolowkin MH, Mahour GH, Krailo M, et al.: Germ cell tumors in infancy and childhood: a 45-year experience. Pediatr Pathol 10 (1-2): 231-41, 1990.

²⁰ Marsden HB, Birch JM, Swindell R: Germ cell tumours of childhood: a review of 137 cases. J Clin Pathol 34 (8): 879-83, 1981.

²¹ Rescorla FJ: Pediatric germ cell tumors. Semin Surg Oncol 16 (2): 144-58, 1999.

²² Dal Cin P, Drochmans A, Moerman P, et al.: Isochromosome 12p in mediastinal germ cell tumor. Cancer Genet Cytogenet 42 (2): 243-51, 1989.

²³ Aly MS, Dal Cin P, Jiskoot P, et al.: Competitive in situ hybridization in a mediastinal germ cell tumor. Cancer Genet Cytogenet 73 (1): 53-6, 1994.

²⁴ Schneider DT, Schuster AE, Fritsch MK, et al.: Genetic analysis of mediastinal nonseminomatous germ cell tumors in children and adolescents. Genes Chromosomes Cancer 34 (1): 115-25, 2002.

²⁵ Dexeus FH, Logothetis CJ, Chong C, et al.: Genetic abnormalities in men with germ cell tumors. J Urol 140 (1): 80-4, 1988.

²⁶ Nichols CR, Heerema NA, Palmer C, et al.: Klinefelter's syndrome associated with mediastinal germ cell neoplasms. J Clin Oncol 5 (8): 1290-4, 1987.

²⁷ Lachman MF, Kim K, Koo BC: Mediastinal teratoma associated with Klinefelter's syndrome. Arch Pathol Lab Med 110 (11): 1067-71, 1986.

²⁸ Coutin AS, Hamy A, Fondevilla M, et al.: [Pure 46XY gonadal dysgenesis] J Gynecol Obstet Biol Reprod (Paris) 25 (8): 792-6, 1996.

²⁹ Amice V, Amice J, Bercovici JP, et al.: Gonadal tumor and H-Y antigen in 46,XY pure gonadal dysgenesis. Cancer 57 (7): 1313-7, 1986.

Histologic Classification

The childhood extracranial germ cell tumors comprise a variety of histologic diagnoses and can be broadly classified into mature or immature teratomas and malignant germ cell tumors.

Mature Teratomas

Mature teratomas generally occur in the ovary or at extragonadal locations and are the most common histological subtype of childhood germ cell tumor.^1,2 These teratomas usually contain well-differentiated tissues from the ectodermal, mesodermal, and endodermal germ cell layers, and any tissue type may be found among the tumor. Mature teratomas are benign, though some mature and immature teratomas may secrete enzymes or hormones, including insulin, growth hormone, androgens, prolactin, and vasopressin.^3,4,5,

Immature Teratomas

Immature teratomas also contain tissues from all 3 germ cell layers, but immature tissues, primarily neuroepithelial, are present. Immature teratomas can be graded from 0 to 3 based on the amount of immature tissue found in the tumor specimen.⁶ Tumors of higher grade are more likely to have foci of yolk sac tumor.⁷ Immature teratomas occur primarily in young children at extragonadal sites and in the ovaries of girls near the age of puberty, but there is no correlation between tumor grade and patient age.^7,8,

Malignant Germ Cell Tumors

Malignant germ cell tumors usually contain frankly malignant tissues of germ cell origin (i.e., yolk sac tumors, germinomas, embryonal carcinomas, or choriocarcinomas) or rarely, tissues of somatic origin. Isolated malignant elements may constitute a small fraction of a predominantly immature teratoma.⁸ Yolk sac tumors produce alpha-fetoprotein (AFP), while germinomas, and especially choriocarcinomas, produce beta human chorionic gonadotropin, resulting in the elevated serum levels of these substances.

Most children with malignant germ cell tumors will have a component of yolk sac tumor and have elevations of AFP,^9,10 which is serially monitored during treatment to help assess response to therapy.^8,9 The germ cell tumors of adolescents and young adults consist of seminomatous tumors (i.e., germinomas, testicular or mediastinal seminomas, or ovarian dysgerminomas) and nonseminomatous tumors (i.e., embryonal carcinomas, teratomas, yolk sac tumors, or choriocarcinomas). Seminomatous tumors are more sensitive to radiation therapy, and thus the distinction is important. Tumors found to have both seminomatous and nonseminomatous elements or seminomatous histology associated with elevated serum AFP levels, however, are usually treated as nonseminomas. Patients with nonseminomatous germ cell tumors currently receive the same therapy, regardless of their histologic diagnosis.

¹ Göbel U, Calaminus G, Engert J, et al.: Teratomas in infancy and childhood. Med Pediatr Oncol 31 (1): 8-15, 1998.

² Rescorla FJ: Pediatric germ cell tumors. Semin Surg Oncol 16 (2): 144-58, 1999.

³ Tomlinson MW, Alaverdian AA, Alaverdian V: Testosterone-producing benign cystic teratoma with virilism. A case report. J Reprod Med 41 (12): 924-6, 1996.

⁴ Lam SK, Cheung LP: Inappropriate ADH secretion due to immature ovarian teratoma. Aust N Z J Obstet Gynaecol 36 (1): 104-5, 1996.

⁵ Kallis P, Treasure T, Holmes SJ, et al.: Exocrine pancreatic function in mediastinal teratomata: an aid to preoperative diagnosis? Ann Thorac Surg 54 (4): 741-3, 1992.

⁶ Norris HJ, Zirkin HJ, Benson WL: Immature (malignant) teratoma of the ovary: a clinical and pathologic study of 58 cases. Cancer 37 (5): 2359-72, 1976.

⁷ Heifetz SA, Cushing B, Giller R, et al.: Immature teratomas in children: pathologic considerations: a report from the combined Pediatric Oncology Group/Children's Cancer Group. Am J Surg Pathol 22 (9): 1115-24, 1998.

⁸ Marina NM, Cushing B, Giller R, et al.: Complete surgical excision is effective treatment for children with immature teratomas with or without malignant elements: A Pediatric Oncology Group/Children's Cancer Group Intergroup Study. J Clin Oncol 17 (7): 2137-43, 1999.

⁹ Mann JR, Raafat F, Robinson K, 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. J Clin Oncol 18 (22): 3809-18, 2000.

¹⁰ Marina N, Fontanesi J, Kun L, et al.: Treatment of childhood germ cell tumors. Review of the St. Jude experience from 1979 to 1988. Cancer 70 (10): 2568-75, 1992.

Stage Information

As with other childhood solid tumors, stage directly impacts the outcome of patients with malignant germ cell tumors.^1,2,3 The most commonly used staging system is described below.^4,

• Stage I: localized disease, completely resected without microscopic disease in the resected margins or in regional lymph nodes.
• Stage II: microscopic residual disease, capsular invasion, or microscopic lymph node involvement.
• Stage III: gross residual disease, gross lymph node involvement (>2 cm), or cytologic evidence of tumor cells in ascites or pleural fluid.
• Stage IV: disseminated disease involving lungs, liver, brain, bone, distant nodes, or other sites.

Another staging system used most frequently by gynecologic oncologists is the International Federation of Gynecologic Oncologists (FIGO) staging system, which is based on an adequate staging operation at the time of diagnosis.⁵ This system has also been used by some pediatric centers,² and is as follows:

Stage I: tumor limited to the ovaries
• IA: one ovary, no ascites, intact capsule.
• IB: both ovaries, no ascites, intact capsule.
• IC: ruptured capsule, capsular involvement, positive peritoneal washings, or malignant ascites.

Stage II: ovarian tumor with pelvic extension
• IIA: pelvic extension to uterus or tubes.
• IIB: pelvic extension to other pelvic organs (bladder, rectum, or vagina).
• IIC: pelvic extension, plus findings indicated for stage IC.

Stage III: tumor outside the pelvis, or positive nodes
• IIIA: microscopic seeding outside the true pelvis.
• IIIB: gross deposits less than 2 cm.
• IIIC: gross deposits greater than 2 cm or positive nodes.

Stage IV: distant organ involvement, including liver parenchyma or pleural space

¹ Ablin AR, Krailo MD, Ramsay NK, et al.: Results of treatment of malignant germ cell tumors in 93 children: a report from the Childrens Cancer Study Group. J Clin Oncol 9 (10): 1782-92, 1991.

² Mann JR, Pearson D, Barrett A, et al.: Results of the United Kingdom Children's Cancer Study Group's malignant germ cell tumor studies. Cancer 63 (9): 1657-67, 1989.

³ Marina N, Fontanesi J, Kun L, et al.: Treatment of childhood germ cell tumors. Review of the St. Jude experience from 1979 to 1988. Cancer 70 (10): 2568-75, 1992.

⁴ Brodeur GM, Howarth CB, Pratt CB, et al.: Malignant germ cell tumors in 57 children and adolescents. Cancer 48 (8): 1890-8, 1981.

⁵ Cannistra SA: Cancer of the ovary. N Engl J Med 329 (21): 1550-9, 1993.

Treatment Option Overview

Prior to effective chemotherapy, children with extracranial malignant germ cell tumors had 3-year survival rates of 15% to 20% with surgery and radiation therapy,^1,2,3 though boys with localized testicular tumors did well with surgical resection.^4,5 Cisplatin-based chemotherapy has dramatically improved the outcome for these children, with 5-year survival rates increasing to 75% and more than 90%.^6,7,8,9 The standard chemotherapy regimen for both adults and children with malignant nonseminomatous germ cell tumors includes cisplatin, etoposide, and bleomycin (PEB), though children receive fewer doses of bleomycin than adults.^6,7,10,11,12 The combination of carboplatin, etoposide, and bleomycin (JEB) has undergone clinical investigation in the United Kingdom in children younger than 16 years and is reported to have a similar event-free survival (EFS) by site and stage as PEB.^8,13 The use of JEB appears to be associated with less ototoxicity and nephrotoxicity than PEB.⁸ Adult studies have substituted standard-dose carboplatin for cisplatin in combination with etoposide alone and in combination with etoposide and low-dose bleomycin,¹⁴ but the carboplatin regimens demonstrated inferior EFS and overall survival compared with cisplatin-containing therapy among patients with malignant germ cell tumors. No randomized comparison of PEB versus JEB has been conducted in children. See Table 2 for comparison of pediatric versus adult PEB and JEB chemotherapy dosing schedules.

Table 2: Comparison of Pediatric Versus Adult PEB and JEB Chemotherapy Dosing Schedules

RegimenBleomycinEtoposideCisplatinCarboplatinReferencesPediatric PEB (every 21 days)15 units/m², day 1100 mg/m², days 1-520 mg/m², days 1-5^6,7,Pediatric JEB (every 21-28 days)15 mg/m², day 1120 mg/m², days 1-3600 mg/m² or 6 mg/mL/min., day 2^8,Adult PEB (every 21 days)30 units, days 1, 8, 15100 mg/m², days 1-520 mg/m², days 1-5^10,Adult JEB (every 21 days)30 units, day 2120 mg/m², days 1-35 mg/mL/min.^14,

The outcome for most children and adolescents with extracranial germ cell tumors is now favorable when appropriate treatment is provided.¹⁵ Prognosis and appropriate treatment depend upon factors such as histology (e.g., seminomatous vs. nonseminomatous), age (young children vs. adolescents), stage of disease, and primary site.^16,17 To maximize the likelihood of long-term survival while minimizing the likelihood of treatment-related long-term sequelae (e.g., secondary leukemias, infertility, hearing loss, renal dysfunction), it is important that children with extracranial malignant germ cell tumors be cared for at pediatric cancer centers with experience treating these rare tumors. Based on clinical factors, appropriate treatment may involve: surgical resection followed by careful monitoring for disease recurrence; diagnostic tumor biopsy and preoperative platinum-based chemotherapy followed by definitive tumor resection; or initial surgical resection followed by a platinum-based chemotherapy.¹⁸ The current approach to the management of extracranial germ cell tumors has been informed by the results of 2 recent intergroup studies conducted by the Children's Cancer Group (CCG) and the Pediatric Oncology Group (POG).^6,7,19 These studies explored the use of PEB for the treatment of localized gonadal germ cell tumors⁶ and the benefit of increasing the dose of cisplatin (HD-PEB: 200 mg/m2 vs. PEB: 100 mg/m2 of cisplatin) in a randomized manner in patients with extragonadal and advanced gonadal germ cell tumors.⁷ Amifostine was not effective in preventing hearing loss in patients who received HD-PEB.²⁰

For patients with completely resected immature teratomas at any location (even those with malignant elements) or patients with completely resected (stage 1) gonadal tumors, additional therapy may not be necessary; however, close follow-up is important.¹⁹ The watch and wait approach requires scheduled serial physical examination, tumor marker determination, and primary tumor imaging to ensure that a recurrent tumor is detected without delay. For patients with stage II gonadal tumors, treatment with PEB results in survival rates greater than 94%. The survival rates for patients with advanced gonadal tumors (stages III and IV) were also greater than 90% using standard PEB, and higher doses of platinum (HD-PEB) did not add any significant benefit. The subgroup of patients older than 15 years with metastatic testicular tumors, however, had a worse outcome (survival <85%). For patients with extragonadal tumors, locoregional disease (stage I and stage II) was associated with very good outcome with standard PEB (survival of 93%), whereas patients with stages III and IV had survival rates of approximately 80%. For patients with advanced extragonadal tumors, the intensification of cisplatin in the HD-PEB provided some improvement in EFS; however, the use of the HD-PEB regimen was associated with a significantly higher incidence and severity of ototoxicity and nephrotoxicity.

The discussion of treatment options below focuses on the extracranial germ cell tumors of children. (Refer to the PDQ summaries on Ovarian Germ Cell Tumor Treatment and Testicular Cancer Treatment for more information.) Specific details of treatment by primary site and clinical condition are given below. Table 3 provides an overview of standard treatment options.

Table 3: Standard Treatment Approaches for Infants and Children Younger Than 15 Years With Germ Cell Tumors by Histology, Stage, and Primary Site

Histology Primary site Stage Treatment*Patients ≥15 years with stage IV testicular tumors and all patients with stages III and IV extragonadal tumors treated with PEB have suboptimal outcome and should be considered for more intensive therapies.**The role for surgery at diagnosis for extragonadal tumors is age- and site-dependent and must be individualized. Depending on the clinical setting, the appropriate surgical approach may range from no surgery (e.g., mediastinal primary tumor in a patient with a compromised airway and elevated tumor markers), to biopsy, to primary resection. In some cases, an appropriate strategy is biopsy at diagnosis followed by subsequent surgery in selected patients who have residual masses following chemotherapy.Mature teratomaAll sitesLocalized Surgery + Observation Immature teratoma All sitesLocalized Surgery + Observation Malignant germ cell tumors Testicular Stage I Surgery + Observation Stage II-IV* Surgery + PEBOvarianStage I Surgery + Observation Stage II-IV Surgery + PEB Extragonadal Stage I-IISurgery** + PEB Stage III-IV* Surgery** + PEB

¹ Kurman RJ, Norris HJ: Endodermal sinus tumor of the ovary: a clinical and pathologic analysis of 71 cases. Cancer 38 (6): 2404-19, 1976.

² Chretien PB, Milam JD, Foote FW, et al.: Embryonal adenocarcinomas (a type of malignant teratoma) of the sacrococcygeal region. Clinical and pathologic aspects of 21 cases. Cancer 26 (3): 522-35, 1970.

³ Billmire DF, Grosfeld JL: Teratomas in childhood: analysis of 142 cases. J Pediatr Surg 21 (6): 548-51, 1986.

⁴ Hawkins EP, Finegold MJ, Hawkins HK, et al.: Nongerminomatous malignant germ cell tumors in children. A review of 89 cases from the Pediatric Oncology Group, 1971-1984. Cancer 58 (12): 2579-84, 1986.

⁵ Marina N, Fontanesi J, Kun L, et al.: Treatment of childhood germ cell tumors. Review of the St. Jude experience from 1979 to 1988. Cancer 70 (10): 2568-75, 1992.

⁶ Rogers PC, Olson TA, Cullen JW, 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 22 (17): 3563-9, 2004.

⁷ Cushing B, Giller R, Cullen JW, 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 22 (13): 2691-700, 2004.

⁸ Mann JR, Raafat F, Robinson K, 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. J Clin Oncol 18 (22): 3809-18, 2000.

⁹ Göbel U, Schneider DT, Calaminus G, et al.: Multimodal treatment of malignant sacrococcygeal germ cell tumors: a prospective analysis of 66 patients of the German cooperative protocols MAKEI 83/86 and 89. J Clin Oncol 19 (7): 1943-50, 2001.

¹⁰ Einhorn LH, Williams SD, Loehrer PJ, et al.: Evaluation of optimal duration of chemotherapy in favorable-prognosis disseminated germ cell tumors: a Southeastern Cancer Study Group protocol. J Clin Oncol 7 (3): 387-91, 1989.

¹¹ de Wit R, Roberts JT, Wilkinson PM, et al.: Equivalence of three or four cycles of bleomycin, etoposide, and cisplatin chemotherapy and of a 3- or 5-day schedule in good-prognosis germ cell cancer: a randomized study of the European Organization for Research and Treatment of Cancer Genitourinary Tract Cancer Cooperative Group and the Medical Research Council. J Clin Oncol 19 (6): 1629-40, 2001.

¹² Gershenson DM, Morris M, Cangir A, et al.: Treatment of malignant germ cell tumors of the ovary with bleomycin, etoposide, and cisplatin. J Clin Oncol 8 (4): 715-20, 1990.

¹³ Stern JW, Bunin N: Prospective study of carboplatin-based chemotherapy for pediatric germ cell tumors. Med Pediatr Oncol 39 (3): 163-7, 2002.

¹⁴ Horwich A, Sleijfer DT, Fosså SD, et al.: Randomized trial of bleomycin, etoposide, and cisplatin compared with bleomycin, etoposide, and carboplatin in good-prognosis metastatic nonseminomatous germ cell cancer: a Multiinstitutional Medical Research Council/European Organization for Research and Treatment of Cancer Trial. J Clin Oncol 15 (5): 1844-52, 1997.

¹⁵ Toner GC: Early identification of therapeutic failure in nonseminomatous germ cell tumors by assessing serum tumor marker decline during chemotherapy: still not ready for routine clinical use. J Clin Oncol 22 (19): 3842-5, 2004.

¹⁶ Baranzelli MC, Kramar A, Bouffet E, et al.: Prognostic factors in children with localized malignant nonseminomatous germ cell tumors. J Clin Oncol 17 (4): 1212, 1999.

¹⁷ Marina N, London WB, Frazier AL, et al.: Prognostic factors in children with extragonadal malignant germ cell tumors: a pediatric intergroup study. J Clin Oncol 24 (16): 2544-8, 2006.

¹⁸ Rescorla FJ: Pediatric germ cell tumors. Semin Surg Oncol 16 (2): 144-58, 1999.

¹⁹ Marina NM, Cushing B, Giller R, et al.: Complete surgical excision is effective treatment for children with immature teratomas with or without malignant elements: A Pediatric Oncology Group/Children's Cancer Group Intergroup Study. J Clin Oncol 17 (7): 2137-43, 1999.

²⁰ Marina N, Chang KW, Malogolowkin M, et al.: Amifostine does not protect against the ototoxicity of high-dose cisplatin combined with etoposide and bleomycin in pediatric germ-cell tumors: a Children's Oncology Group study. Cancer 104 (4): 841-7, 2005.

Current Treatment Strategies for Children with Malignant Extracranial Germ Cell Tumors

The Pediatric Oncology Group (POG) and Children’s Cancer Group (CCG) studies discussed in the Treatment Option Overview section of this summary, as well as other contemporary European studies,^1,2 suggest that a more refined risk-adapted therapy, based on stage and primary site, is possible for children with malignant extracranial germ cell tumors (Table 4). The new classification schema proposed by the Children’s Oncology Group (COG) stratifies patients into 3 risk groups, as follows:

• Low-Risk: Patients with stage I immature teratomas and gonadal malignant germ cell tumors. Surgery and close follow-up observation are indicated to document that a normalization of the tumor markers occurs after resection.^1,3,4,5 Strict guidelines for the evaluation and follow-up of these observation patients are mandated in the current COG study to ensure that disease recurrence or regrowth are detected early.
• Intermediate-Risk: Patients with stages II–IV gonadal tumors (excluding patients aged 15 years or older with stage IV testicular tumors and all stage IV ovarian tumors), and patients with stage I–II extragonadal tumors. These patients have an overall survival outcome greater than 90% with 4 to 6 courses of standard cisplatin, etoposide, and bleomycin (PEB), suggesting that a reduction in therapy could be considered.^6,7 The COG is investigating a modified standard PEB treatment (3 PEB courses given over 3 days) for intermediate-risk patients, with the goal of decreasing the duration and cumulative doses of chemotherapy (25% dose reduction) and lessening the cost of treatment. Studies in adult males with good-risk germ cell cancer demonstrated equivalent outcome for patients treated with 3 or 4 cycles of PEB chemotherapy that was administered in 3 days versus 5 days.⁸ Because of the decreased bleomycin dosing in pediatric PEB and the potential difference in clinical response of pediatric germ cell tumors to this decreased chemotherapy approach, the modified standard PEB treatment approach should be utilized in pediatric patients only in the context of the COG-controlled clinical trial. The outcome for these intermediate-risk patients is also excellent using 4 to 6 cycles of carboplatin, etoposide, and bleomycin (JEB).^1,
• High-Risk: Patients with advanced (stages III and IV) extragonadal tumors. For these patients, survival with the standard platinum-based regimens (PEB or JEB) is approximately 80%. The POG/CCG intergroup protocol showed that patients receiving high-dose PEB (HD-PEB) had better event-free survival (EFS) than patients receiving standard PEB,⁷ though the incidence and severity of long-term toxicities in the HD-PEB group was significantly higher. A subsequent COG study explored the use of amifostine to diminish the platinum-related toxicity of HD-PEB. The preliminary results of this study, however, do not show any benefit from the addition of amifostine, and approximately 70% of the patients continue to develop severe hearing loss.⁹ New strategies are needed for these patients, and the current COG study is investigating the addition of cyclophosphamide to standard PEB.

Table 4: Type of Germ Cell Tumor by Stage and by Risk Group*

OvarianTesticularExtragonadal* Adapted from Rogers PC et al. ⁶ and Cushing B et al.^7,** Stage 4 ovarian tumors in children and adolescents continue to be treated with 4 courses of pediatric PEB; these patients are not eligible for either a possible reduction in treatment courses, as are the intermediate-risk patients, or the high-risk protocol that includes the potential of greater toxicity.Stage 1LowLowIntermediateStage 2IntermediateIntermediateIntermediateStage 3IntermediateIntermediateHighStage 4High**IntermediateHigh

¹ Mann JR, Raafat F, Robinson K, 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. J Clin Oncol 18 (22): 3809-18, 2000.

² Baranzelli MC, Kramar A, Bouffet E, et al.: Prognostic factors in children with localized malignant nonseminomatous germ cell tumors. J Clin Oncol 17 (4): 1212, 1999.

³ Marina NM, Cushing B, Giller R, et al.: Complete surgical excision is effective treatment for children with immature teratomas with or without malignant elements: A Pediatric Oncology Group/Children's Cancer Group Intergroup Study. J Clin Oncol 17 (7): 2137-43, 1999.

⁴ Baranzelli MC, Bouffet E, Quintana E, et al.: Non-seminomatous ovarian germ cell tumours in children. Eur J Cancer 36 (3): 376-83, 2000.

⁵ 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 38 (3): 319-24; discussion 319-24, 2003.

⁶ Rogers PC, Olson TA, Cullen JW, 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 22 (17): 3563-9, 2004.

⁷ Cushing B, Giller R, Cullen JW, 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 22 (13): 2691-700, 2004.

⁸ de Wit R, Roberts JT, Wilkinson PM, et al.: Equivalence of three or four cycles of bleomycin, etoposide, and cisplatin chemotherapy and of a 3- or 5-day schedule in good-prognosis germ cell cancer: a randomized study of the European Organization for Research and Treatment of Cancer Genitourinary Tract Cancer Cooperative Group and the Medical Research Council. J Clin Oncol 19 (6): 1629-40, 2001.

⁹ Marina N, Malogolowkin M, London WB, et al.: Amifostine does not protect against the ototoxicity associated with high-dose cisplatin, etoposide and bleomycin (HD-PEB) in pediatric germ cell tumors (PGCT): A PGCT Intergroup Study. [Abstract] Proceedings of the American Society of Clinical Oncology 22: A-3208, 798, 2003.

Sacrococcygeal Tumors in Children

The sacrococcygeal region is the primary tumor site for the majority of benign and malignant germ cell tumors diagnosed in neonates, infants, and children younger than 4 years. These tumors occur more often in girls than in boys; ratios of 3:1 to 4:1 have been reported.¹ Sacrococcygeal tumors present in 2 clinical patterns related to the child’s age, tumor location, and likelihood of tumor malignancy. Neonatal tumors present at birth protruding from the sacral site and are usually mature or immature teratomas. Among infants and young children, the tumor presents as a palpable mass in the sacropelvic region compressing the bladder or rectum.² These pelvic tumors have a greater likelihood of being malignant. An early survey found that the rate of tumor malignancy was 48% for girls and 67% for boys older than 2 months at the time of sacrococcygeal tumor diagnosis, compared with a malignant tumor incidence of 7% for girls and 10% for boys younger than 2 months at the time of diagnosis.³ The pelvic site of the primary tumor has been reported to be an adverse prognostic factor, most likely caused by a higher rate of incomplete resection.^3,4,5,6,

After successful resection, neonates diagnosed with benign mature and immature teratomas are observed with close follow-up exams and serial serum alpha-fetoprotein (AFP) determinations for several years to ensure that the expected physiological normalization of AFP levels occurs and to facilitate early detection of tumor relapse.⁷ A significant rate of recurrence among these benign tumors has been reported by several groups, ranging from 10% to 21%, with most relapses occurring within 3 years of resection.^1,7,8 Importantly, 43% to 50% of these recurrent tumors will be malignant and require adjuvant chemotherapy. Complete resection of the coccyx is vital to minimize the likelihood of recurrent tumor.⁹ For older infants and young children presenting with large presacral sacrococcygeal tumors, complete tumor resection is often not feasible, and after initial biopsy, neoadjuvant platinum-based chemotherapy and delayed resection has a survival rate of 80% to 90%, even among patients presenting with metastatic disease.^10,11,

¹ Rescorla FJ, Sawin RS, Coran AG, et al.: Long-term outcome for infants and children with sacrococcygeal teratoma: a report from the Childrens Cancer Group. J Pediatr Surg 33 (2): 171-6, 1998.

² Rescorla FJ: Pediatric germ cell tumors. Semin Surg Oncol 16 (2): 144-58, 1999.

³ Altman RP, Randolph JG, Lilly JR: Sacrococcygeal teratoma: American Academy of Pediatrics Surgical Section Survey-1973. J Pediatr Surg 9 (3): 389-98, 1974.

⁴ Ablin AR, Krailo MD, Ramsay NK, et al.: Results of treatment of malignant germ cell tumors in 93 children: a report from the Childrens Cancer Study Group. J Clin Oncol 9 (10): 1782-92, 1991.

⁵ Marina N, Fontanesi J, Kun L, et al.: Treatment of childhood germ cell tumors. Review of the St. Jude experience from 1979 to 1988. Cancer 70 (10): 2568-75, 1992.

⁶ Baranzelli MC, Kramar A, Bouffet E, et al.: Prognostic factors in children with localized malignant nonseminomatous germ cell tumors. J Clin Oncol 17 (4): 1212, 1999.

⁷ Huddart SN, Mann JR, Robinson K, et al.: Sacrococcygeal teratomas: the UK Children's Cancer Study Group's experience. I. Neonatal. Pediatr Surg Int 19 (1-2): 47-51, 2003.

⁸ Gonzalez-Crussi F, Winkler RF, Mirkin DL: Sacrococcygeal teratomas in infants and children: relationship of histology and prognosis in 40 cases. Arch Pathol Lab Med 102 (8): 420-5, 1978.

⁹ Göbel U, Calaminus G, Engert J, et al.: Teratomas in infancy and childhood. Med Pediatr Oncol 31 (1): 8-15, 1998.

¹⁰ Göbel U, Schneider DT, Calaminus G, et al.: Multimodal treatment of malignant sacrococcygeal germ cell tumors: a prospective analysis of 66 patients of the German cooperative protocols MAKEI 83/86 and 89. J Clin Oncol 19 (7): 1943-50, 2001.

¹¹ Rescorla F, Billmire D, Stolar C, et al.: The effect of cisplatin dose and surgical resection in children with malignant germ cell tumors at the sacrococcygeal region: a pediatric intergroup trial (POG 9049/CCG 8882). J Pediatr Surg 36 (1): 12-7, 2001.

Nonsacrococcygeal Mature and Immature Teratomas in Children

Mature and immature teratomas arise primarily in the sacrococcygeal region of neonates and young children, and in the ovaries of pubescent girls. These tumors are also less commonly found in the testicular region of boys younger than 4 years, the mediastinum of adolescents, and other sites.^1,2,3 Mature teratoma and epidermoid cyst in the prepubertal testis are relatively common benign lesions and may be amenable to testis-sparing surgery.⁴ Children with mature teratomas, including mature teratomas of the mediastinum, can be treated with surgery and observation with an excellent prognosis.^1,5 In a review of 153 children with nontesticular mature teratoma, the 6-year relapse-free survival for completely resected disease was 96% versus 55% for incomplete disease resection.^3,

The benign clinical behavior of immature teratomas in infants and young children has been reported in the literature ^6,7,8 and, though immature teratoma diagnosed in adults, primarily ovarian, reportedly has an aggressive clinical behavior ⁹ requiring surgery and chemotherapy, the benefit of adjuvant chemotherapy for children was questioned. A study by the Pediatric Oncology Group and Children's Cancer Group evaluated the use of surgical resection followed by careful observation for patients with immature teratomas. Surgery alone was curative for most children and adolescents with resected ovarian immature teratoma of any grade, even when elevated levels of serum alpha-fetoprotein or microscopic foci of yolk sac tumor were present.¹⁰ The study demonstrated a 3-year event-free survival of 97.8%, 100%, and 80% for patients with ovarian, testicular, and extragonadal tumors, respectively.¹¹ The majority of patients with resected immature teratoma who develop recurrent disease can be salvaged with subsequent surgery and chemotherapy, and long-term survival is outstanding.¹¹

¹ Rescorla FJ: Pediatric germ cell tumors. Semin Surg Oncol 16 (2): 144-58, 1999.

² Pinkerton CR: Malignant germ cell tumours in childhood. Eur J Cancer 33 (6): 895-901; discussion 901-2, 1997.

³ Göbel U, Calaminus G, Engert J, et al.: Teratomas in infancy and childhood. Med Pediatr Oncol 31 (1): 8-15, 1998.

⁴ Metcalfe PD, Farivar-Mohseni H, Farhat W, et al.: Pediatric testicular tumors: contemporary incidence and efficacy of testicular preserving surgery. J Urol 170 (6 Pt 1): 2412-5; discussion 2415-6, 2003.

⁵ Schneider DT, Calaminus G, Reinhard H, et al.: Primary mediastinal germ cell tumors in children and adolescents: results of the German cooperative protocols MAKEI 83/86, 89, and 96. J Clin Oncol 18 (4): 832-9, 2000.

⁶ Valdiserri RO, Yunis EJ: Sacrococcygeal teratomas: a review of 68 cases. Cancer 48 (1): 217-21, 1981.

⁷ Carter D, Bibro MC, Touloukian RJ: Benign clinical behavior of immature mediastinal teratoma in infancy and childhood: report of two cases and review of the literature. Cancer 49 (2): 398-402, 1982.

⁸ Gonzalez-Crussi F, Winkler RF, Mirkin DL: Sacrococcygeal teratomas in infants and children: relationship of histology and prognosis in 40 cases. Arch Pathol Lab Med 102 (8): 420-5, 1978.

⁹ Norris HJ, Zirkin HJ, Benson WL: Immature (malignant) teratoma of the ovary: a clinical and pathologic study of 58 cases. Cancer 37 (5): 2359-72, 1976.

¹⁰ Cushing B, Giller R, Ablin A, et al.: Surgical resection alone is effective treatment for ovarian immature teratoma in children and adolescents: a report of the pediatric oncology group and the children's cancer group. Am J Obstet Gynecol 181 (2): 353-8, 1999.

¹¹ Marina NM, Cushing B, Giller R, et al.: Complete surgical excision is effective treatment for children with immature teratomas with or without malignant elements: A Pediatric Oncology Group/Children's Cancer Group Intergroup Study. J Clin Oncol 17 (7): 2137-43, 1999.

Childhood Malignant Testicular Germ Cell Tumor

Testicular Germ Cell Tumors in Young Boys

Testicular germ cell tumors in children occur almost exclusively in boys younger than 4 years.¹ The initial approach to evaluate a testicular mass in a young boy is important because a transscrotal biopsy can risk inguinal node metastasis.^2,3 Radical inguinal orchiectomy with initial high ligation of the spermatic cord is the procedure of choice.⁴ Retroperitoneal dissection of lymph nodes is not beneficial in the staging of testicular germ cell tumors in young boys. Computed tomography or magnetic resonance imaging evaluation, with the additional information provided by elevated tumor markers, appears adequate for staging.^2,3 Therefore, there is no reason to risk the potential morbidity (e.g., impotence and retrograde ejaculation) related to this surgery.^5,6,

A Children’s Cancer Group /Pediatric Oncology Group clinical trial evaluated surgery followed by observation for boys with stage I testicular tumors. This treatment strategy has resulted in a 6-year event-free survival (EFS) of 82%; those boys who developed recurrent disease were salvaged by standard-dose cisplatin, etoposide, and bleomycin (PEB), with a 6-year survival of 100%.^2,3 Boys with stage II or recurrent stage I disease were treated with 4 cycles of standard-dose PEB, with a resulting 100% 6-year survival.⁷ Boys and adolescents with stages III and IV testicular tumors were treated with surgical resection followed by 4 courses of standard or high-dose PEB therapy. The 6-year survival outcome for stage III and IV males younger than 15 years was 100%, with 6-year EFS of 100% and 94%, respectively.⁸ The use of high-dose PEB therapy did not improve the outcome for these boys but did cause increased incidence of ototoxicity. Excellent outcomes for boys with testicular germ cell tumors using surgery and observation for stage I tumors and carboplatin, etoposide, and bleomycin (JEB) and other cisplatin-containing chemotherapy regimens for stage II–IV tumors have also been reported by European investigators.^5,9 Thus, surgery followed by standard-dose platinum-based chemotherapy is the recommended approach for stages II–IV testicular germ cell tumors in children younger than 15 years.

Testicular Germ Cell Tumors in Adolescents and Young Adult Males

Testicular germ cell cancers usually occur in adolescents and young adult males older than 15 years. Because the biology of testicular germ cell tumors among adolescents and young adult males is different from that of testicular tumors arising in infants and young boys, the treatment guidelines described above for young boys may not be strictly applicable to the adolescent males.

(Refer to the PDQ summary on Testicular Cancer Treatment for more information.)

¹ Ries LA, Smith MA, Gurney JG, et al., eds.: Cancer incidence and survival among children and adolescents: United States SEER Program 1975-1995. Bethesda, Md: National Cancer Institute, SEER Program, 1999. NIH Pub.No. 99-4649. Also available online. Last accessed April 19, 2007.

² 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 38 (3): 319-24; discussion 319-24, 2003.

³ Canning DA: Excellent outcome in patients with stage I germ cell tumors of the testes: a study of the Children's Cancer Group/Pediatric Oncology Group [Editorial Comment on Schlatter]. J Urol 174 (1): 310, 2005.

⁴ Rescorla FJ: Pediatric germ cell tumors. Semin Surg Oncol 16 (2): 144-58, 1999.

⁵ Haas RJ, Schmidt P, Göbel U, et al.: Treatment of malignant testicular tumors in childhood: results of the German National Study 1982-1992. Med Pediatr Oncol 23 (5): 400-5, 1994.

⁶ Pinkerton CR: Malignant germ cell tumours in childhood. Eur J Cancer 33 (6): 895-901; discussion 901-2, 1997.

⁷ Rogers PC, Olson TA, Cullen JW, 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 22 (17): 3563-9, 2004.

⁸ Cushing B, Giller R, Cullen JW, 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 22 (13): 2691-700, 2004.

⁹ Mann JR, Raafat F, Robinson K, 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. J Clin Oncol 18 (22): 3809-18, 2000.

Childhood Malignant Ovarian Germ Cell Tumor

Germ cell tumors comprise most ovarian neoplasms in children and adolescents.¹ Ovarian germ cell tumors are very rare in young children, but the incidence begins to increase in children at approximately 8 or 9 years, and peaks at the age of 19 years. Childhood malignant ovarian germ cell tumors can be divided into dysgerminomas and nonseminomatous malignant germ cell tumors (i.e., immature teratomas, yolk sac carcinomas, mixed germ cell tumors, and embryonal carcinomas). (For information on childhood mature and immature teratomas arising in the ovary, see the Nonsacrococcygeal Mature and Immature Teratomas in Children section of this summary.) (Refer to the PDQ summary on Ovarian Germ Cell Tumor Treatment for more information.)

For stage I ovarian germ cell tumors and immature teratomas, cure can usually be achieved by unilateral salpingo-oophorectomy, conserving the uterus and opposite ovary, and close follow-up observation.^2,3,4,5,6 Chemotherapy can be implemented if tumor markers do not normalize or if tumors recur.

While advanced-stage ovarian dysgerminomas similar to testicular seminomas are highly curable with surgery and radiotherapy, the effects on growth and fertility in these young patients ^{7 8} make chemotherapy a more attractive adjunct to surgery.^9,10 Complete tumor resection is the goal for advanced dysgerminomas; platinum-based chemotherapy can be given preoperatively to facilitate resection or postoperatively (after debulking surgery) to avoid mutilating surgical procedures.⁶ This approach results in a high rate of cure and the maintenance of menstrual function and fertility in most patients with dysgerminomas.^9,11

For ovarian malignant germ cell tumors other than dysgerminomas or immature teratoma, treatment generally involves surgical resection and adjuvant chemotherapy.^12,13 Platinum-based chemotherapy regimens such as PEB or JEB have been used successfully in children,^2,4,14,15 and PEB is a common regimen in young women with ovarian germ cell tumors.^16,17 This approach results in a high rate of cure and the maintenance of menstrual function and fertility in most patients with nondysgerminomas.¹³

¹ Ries LA, Smith MA, Gurney JG, et al., eds.: Cancer incidence and survival among children and adolescents: United States SEER Program 1975-1995. Bethesda, Md: National Cancer Institute, SEER Program, 1999. NIH Pub.No. 99-4649. Also available online. Last accessed April 19, 2007.

² Baranzelli MC, Bouffet E, Quintana E, et al.: Non-seminomatous ovarian germ cell tumours in children. Eur J Cancer 36 (3): 376-83, 2000.

³ Dark GG, Bower M, Newlands ES, et al.: Surveillance policy for stage I ovarian germ cell tumors. J Clin Oncol 15 (2): 620-4, 1997.

⁴ Mann JR, Raafat F, Robinson K, 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. J Clin Oncol 18 (22): 3809-18, 2000.

⁵ Marina NM, Cushing B, Giller R, et al.: Complete surgical excision is effective treatment for children with immature teratomas with or without malignant elements: A Pediatric Oncology Group/Children's Cancer Group Intergroup Study. J Clin Oncol 17 (7): 2137-43, 1999.

⁶ Gershenson DM: Chemotherapy of ovarian germ cell tumors and sex cord stromal tumors. Semin Surg Oncol 10 (4): 290-8, 1994 Jul-Aug.

⁷ Teinturier C, Gelez J, Flamant F, et al.: Pure dysgerminoma of the ovary in childhood: treatment results and sequelae. Med Pediatr Oncol 23 (1): 1-7, 1994.

⁸ Mitchell MF, Gershenson DM, Soeters RP, et al.: The long-term effects of radiation therapy on patients with ovarian dysgerminoma. Cancer 67 (4): 1084-90, 1991.

⁹ Brewer M, Gershenson DM, Herzog CE, et al.: Outcome and reproductive function after chemotherapy for ovarian dysgerminoma. J Clin Oncol 17 (9): 2670-75, 1999.

¹⁰ Williams SD, Blessing JA, Hatch KD, et al.: Chemotherapy of advanced dysgerminoma: trials of the Gynecologic Oncology Group. J Clin Oncol 9 (11): 1950-5, 1991.

¹¹ Gershenson DM: Menstrual and reproductive function after treatment with combination chemotherapy for malignant ovarian germ cell tumors. J Clin Oncol 6 (2): 270-5, 1988.

¹² Gershenson DM, Morris M, Cangir A, et al.: Treatment of malignant germ cell tumors of the ovary with bleomycin, etoposide, and cisplatin. J Clin Oncol 8 (4): 715-20, 1990.

¹³ Mitchell PL, Al-Nasiri N, A'Hern R, et al.: Treatment of nondysgerminomatous ovarian germ cell tumors: an analysis of 69 cases. Cancer 85 (10): 2232-44, 1999.

¹⁴ Cushing B, Giller R, Cullen JW, 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 22 (13): 2691-700, 2004.

¹⁵ Rogers PC, Olson TA, Cullen JW, 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 22 (17): 3563-9, 2004.

¹⁶ Williams SD: Ovarian germ cell tumors: an update. Semin Oncol 25 (3): 407-13, 1998.

¹⁷ Williams S, Blessing JA, Liao SY, et al.: Adjuvant therapy of ovarian germ cell tumors with cisplatin, etoposide, and bleomycin: a trial of the Gynecologic Oncology Group. J Clin Oncol 12 (4): 701-6, 1994.

Childhood Extragonadal Malignant Germ Cell Tumor

Extragonadal germ cell tumors (i.e., sacrococcygeal, mediastinal, and retroperitoneal) account for greater than 60% of pediatric germ cell tumors, whereas in adults they account for only 5% to 10% of such tumors.¹ Children with extragonadal malignant germ cell tumors, particularly those with advanced stage, have the highest risk of treatment failure for any germ cell tumor presentation.^2,3 In a study of prognostic factors in pediatric extragonadal malignant germ cell tumors, age was the most important prognostic factor. Children 12 years or older with thoracic tumors had 6 times the risk of death compared with children younger than 12 years with primary tumors other than thoracic.⁴ Outcome has improved remarkably, however, since the advent of platinum-based chemotherapy and the use of a multidisciplinary treatment approach.^2,5 Complete resection prior to chemotherapy may be possible in some patients without major morbidity, but for patients with locally advanced sacrococcygeal tumors, mediastinal tumors, or large pelvic tumors, tumor biopsy followed by preoperative chemotherapy can facilitate subsequent complete tumor resection and improve ultimate patient outcome.^5,6,7,8,

Sacrococcygeal germ cell tumors are the most common extragonadal tumors and represent 40% of all childhood germ cell tumors.⁹ They are usually diagnosed at birth, when large external lesions predominate (usually benign or immature teratomas), or later in the first years of life, when presacral lesions with higher malignancy rates predominate.⁹ Malignant sacrococcygeal tumors are usually very advanced at diagnosis; two thirds of patients have locoregional disease and metastases are present in 50% of the patients.^7,10,11 Because of advanced presentation, the management of sacrococcygeal tumors requires a multimodal approach with chemotherapy followed by delayed tumor resection. Platinum-based therapies, with either cisplatin or carboplatin, are the cornerstone of treatment. The cisplatin, etoposide, and bleomycin (PEB) or the carboplatin, etoposide, and bleomycin (JEB) regimen produces event-free survival (EFS) rates of 75% to 85%; overall survival rates of 80% to 90% can be achieved.^7,8 Surgery is usually facilitated by preoperative chemotherapy, and completeness of surgical resection is a very important prognostic factor. Patients with resected tumors with negative microscopic margins have EFS rates greater than 90%. Patients with microscopic margins have EFS rates of 75% to 85%; patients with macroscopic residual disease after surgery have EFS rates less than 40%. In any patient with a sacrococcygeal germ cell tumor, resection of the coccyx is mandatory.^7,8,

Mediastinal germ cell tumors account for 15% to 20% of malignant nongonadal, extracranial germ cell tumors in children.⁵ The histology of mediastinal germ cell tumors is dependent on age, with teratomas predominating among infants and with yolk sac tumor histology predominating among children aged 1 to 4 years.⁶ Children with mediastinal teratomas are treated with tumor resection, which is curative in almost all patients. ⁶ Children with malignant, nonmetastatic mediastinal germ cell tumors who receive cisplatin-based chemotherapy have 5-year EFS and overall survival rates of 90%, but an EFS closer to 70% occurs with metastatic mediastinal tumors.^5,6 As occurs with sacrococcygeal tumors, primary chemotherapy is usually necessary to facilitate surgical resection of mediastinal germ cell tumors, and the completeness of resection is a very important prognostic indicator.^6,12 Survival rates for the older adolescent and young adult population with mediastinal tumors are generally less than 50%.^4,13,14,15 (Refer to the PDQ summary on Extragonadal Germ Cell Tumor Treatment for more information.)

Malignant germ cell tumors located in the retroperitoneum or abdomen usually present in children younger than 5 years; most tumors are of advanced stage and locally unresectable at diagnosis.¹⁶ A limited biopsy followed by platinum-based chemotherapy to shrink tumor bulk can lead to complete tumor resection in most patients. Despite advanced-stage disease in most patients, the 6-year EFS using PEB was 83% in the Pediatric Oncology Group(POG)/Children's Cancer Group (CCG) intergroup study.^16,

The most effective chemotherapy regimens for extragonadal malignant germ cell tumors are the PEB (cisplatin, etoposide, and bleomycin) and the JEB (carboplatin, etoposide, and bleomycin) regimens.^2,5 The 6-year EFS among patients with localized (stage I–II) extragonadal tumors who received either high-dose PEB or standard-dose PEB was 90% for children younger than 15 years in the POG/CCG intergroup germ cell study.² For patients with advanced stage (stage III–IV) extragonadal tumors, 6-year EFS rates of 74% (with standard PEB therapy) and 84% (with high-dose PEB) were attained; however, this survival difference was not significant, and the platinum-associated toxic effects (hearing loss and nephrotoxicity) were severe.² The high-dose PEB regimen is no longer pursued as upfront treatment for the higher-risk extragonadal patients.

¹ Pantoja E, Llobet R, Gonzalez-Flores B: Retroperitoneal teratoma: historical review. J Urol 115 (5): 520-3, 1976.

² Cushing B, Giller R, Cullen JW, 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 22 (13): 2691-700, 2004.

³ Baranzelli MC, Kramar A, Bouffet E, et al.: Prognostic factors in children with localized malignant nonseminomatous germ cell tumors. J Clin Oncol 17 (4): 1212, 1999.

⁴ Marina N, London WB, Frazier AL, et al.: Prognostic factors in children with extragonadal malignant germ cell tumors: a pediatric intergroup study. J Clin Oncol 24 (16): 2544-8, 2006.

⁵ Mann JR, Raafat F, Robinson K, 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. J Clin Oncol 18 (22): 3809-18, 2000.

⁶ Schneider DT, Calaminus G, Reinhard H, et al.: Primary mediastinal germ cell tumors in children and adolescents: results of the German cooperative protocols MAKEI 83/86, 89, and 96. J Clin Oncol 18 (4): 832-9, 2000.

⁷ Göbel U, Schneider DT, Calaminus G, et al.: Multimodal treatment of malignant sacrococcygeal germ cell tumors: a prospective analysis of 66 patients of the German cooperative protocols MAKEI 83/86 and 89. J Clin Oncol 19 (7): 1943-50, 2001.

⁸ Rescorla F, Billmire D, Stolar C, et al.: The effect of cisplatin dose and surgical resection in children with malignant germ cell tumors at the sacrococcygeal region: a pediatric intergroup trial (POG 9049/CCG 8882). J Pediatr Surg 36 (1): 12-7, 2001.

⁹ Altman RP, Randolph JG, Lilly JR: Sacrococcygeal teratoma: American Academy of Pediatrics Surgical Section Survey-1973. J Pediatr Surg 9 (3): 389-98, 1974.

¹⁰ Rescorla FJ, Sawin RS, Coran AG, et al.: Long-term outcome for infants and children with sacrococcygeal teratoma: a report from the Childrens Cancer Group. J Pediatr Surg 33 (2): 171-6, 1998.

¹¹ Calaminus G, Schneider DT, Bökkerink JP, et al.: Prognostic value of tumor size, metastases, extension into bone, and increased tumor marker in children with malignant sacrococcygeal germ cell tumors: a prospective evaluation of 71 patients treated in the German cooperative protocols Maligne Keimzelltumoren (MAKEI) 83/86 and MAKEI 89. J Clin Oncol 21 (5): 781-6, 2003.

¹² Billmire D, Vinocur C, Rescorla F, et al.: Malignant mediastinal germ cell tumors: an intergroup study. J Pediatr Surg 36 (1): 18-24, 2001.

¹³ Vuky J, Bains M, Bacik J, et al.: Role of postchemotherapy adjunctive surgery in the management of patients with nonseminoma arising from the mediastinum. J Clin Oncol 19 (3): 682-8, 2001.

¹⁴ Ganjoo KN, Rieger KM, Kesler KA, et al.: Results of modern therapy for patients with mediastinal nonseminomatous germ cell tumors. Cancer 88 (5): 1051-6, 2000.

¹⁵ Bokemeyer C, Nichols CR, Droz JP, et al.: Extragonadal germ cell tumors of the mediastinum and retroperitoneum: results from an international analysis. J Clin Oncol 20 (7): 1864-73, 2002.

¹⁶ Billmire D, Vinocur C, Rescorla F, et al.: Malignant retroperitoneal and abdominal germ cell tumors: an intergroup study. J Pediatr Surg 38 (3): 315-8; discussion 315-8, 2003.

Recurrent Childhood Malignant Germ Cell Tumor

Only a small number of children and adolescents with extracranial germ cell tumors relapse as a result of the effectiveness of treatment, though 20% to 30% of patients with advanced-stage extragonadal disease and adolescents with advanced gonadal disease may develop recurrent disease.^1,2 The approach to recurrent disease and its success depend on the initial treatment regimen and on the response of the tumor to treatment.

Boys with stage I testicular disease originally treated with surgical resection and observation can usually be salvaged, if relapse occurs, by further surgical excision and standard cisplatin, etoposide and bleomycin (PEB) or JEB chemotherapy.^3,4 Several European studies also have reported encouraging salvage rates for stage I ovarian germ cell tumor patients originally treated with surgery and observation.^5,6,

Most children with recurrent sacrococcygeal tumors will recur locally at the primary tumor site. For these children, complete surgical resection of the recurrent tumor and the coccyx is the basis of salvage treatment; preoperative chemotherapy may assist the surgical resection. In patients in whom a complete salvage resection is not achieved, postoperative local irradiation should be considered.^7,

Despite overall cure rates greater than 80%, children with extracranial germ cell tumors who have disease recurrence after surgery and 3-agent platinum-based combination chemotherapy (PEB or JEB) have an unfavorable prognosis. The Children’s Oncology Group (COG) has not established a standard salvage approach at this time; reports regarding the treatment and outcome of these children include small patient samples.⁷ Reports of salvage treatment strategies used in adult recurrent germ cell tumors include larger numbers of patients, but the differences between children and adults regarding the location of the primary germ cell tumor site, pattern of relapse, and the biology of childhood germ cell tumors may limit the applicability of adult salvage approaches to childhood patients.^8,

In adults, combinations of conventional-dose ifosfamide and cisplatin combined with etoposide or vinblastine (VeIP) have been utilized as initial salvage therapy for patients who did not progress on standard PEB therapy.⁹ These regimens can achieve relatively good disease-free status among patients with primary gonadal germ cell tumors who had a complete response (CR) to previous cisplatin-based chemotherapy; the outcome is poorer for patients who never achieved a CR or patients with mediastinal nonseminomatous germ cell tumors who relapse after a CR.⁹ The combination of paclitaxel, ifosfamide, and cisplatin (TIP) has demonstrated a durable complete response rate greater than 70% among these good-prognosis adults with relapsed nonseminomatous testicular cancer.¹⁰ Given the good results obtained with the TIP regimen, a U.S. multi-institutional study is currently under way to compare VeIP and TIP regimens in a randomized manner in men with recurrent nonseminomatous germ cell tumors.

High-dose chemotherapy with autologous stem cell rescue has been explored in adults using carboplatin and etoposide with and without ifosfamide or cyclophosphamide. This strategy has been of special interest for patients with tumors that respond poorly to initial cisplatin-based therapy or with recurrent extragonadal tumors. In a study of men with primary testicular germ cell tumor relapse, the use of high-dose carboplatin and etoposide with stem cell rescue (2 cycles) as an initial salvage approach demonstrated better survival results than the use of this approach among patients with multiply relapsed germ cell tumor.¹¹ Studies of sequential dose-intensive paclitaxel/ifosfamide and carboplatin/etoposide with stem cell rescue or conventional-dose TIP followed by carboplatin/etoposide/thiotepa with stem cell rescue have demonstrated survival rates of 40% and 30%, respectively, in pilot studies.^12,13 Patients in second relapse with very high human chorionic gonadotropin levels, mediastinal nonseminomatous germ cell tumor, or progression soon after cisplatin-based chemotherapy have demonstrated less benefit from high-dose salvage chemotherapy.^14,15 Salvage attempts using high-dose chemotherapy regimens may be of little benefit if local tumor control is not achieved initially.¹⁶ In one European series, 10 of 23 children with relapsed extragonadal germ cell tumors achieved long-term (median follow-up 66 months) disease-free survival by using high-dose chemotherapy with stem cell support.¹⁷ Further study is needed in children and adolescents.

¹ Mann JR, Raafat F, Robinson K, 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. J Clin Oncol 18 (22): 3809-18, 2000.

² Cushing B, Giller R, Cullen JW, 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 22 (13): 2691-700, 2004.

³ 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 38 (3): 319-24; discussion 319-24, 2003.

⁴ Rogers PC, Olson TA, Cullen JW, 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 22 (17): 3563-9, 2004.

⁵ Baranzelli MC, Bouffet E, Quintana E, et al.: Non-seminomatous ovarian germ cell tumours in children. Eur J Cancer 36 (3): 376-83, 2000.

⁶ Dark GG, Bower M, Newlands ES, et al.: Surveillance policy for stage I ovarian germ cell tumors. J Clin Oncol 15 (2): 620-4, 1997.

⁷ Schneider DT, Wessalowski R, Calaminus G, et al.: Treatment of recurrent malignant sacrococcygeal germ cell tumors: analysis of 22 patients registered in the German protocols MAKEI 83/86, 89, and 96. J Clin Oncol 19 (7): 1951-60, 2001.

⁸ Nichols CR: Treatment of recurrent germ cell tumors. Semin Surg Oncol 17 (4): 268-74, 1999.

⁹ Loehrer PJ Sr, Gonin R, Nichols CR, et al.: Vinblastine plus ifosfamide plus cisplatin as initial salvage therapy in recurrent germ cell tumor. J Clin Oncol 16 (7): 2500-4, 1998.

¹⁰ Motzer RJ, Sheinfeld J, Mazumdar M, et al.: Paclitaxel, ifosfamide, and cisplatin second-line therapy for patients with relapsed testicular germ cell cancer. J Clin Oncol 18 (12): 2413-8, 2000.

¹¹ Bhatia S, Abonour R, Porcu P, et al.: High-dose chemotherapy as initial salvage chemotherapy in patients with relapsed testicular cancer. J Clin Oncol 18 (19): 3346-51, 2000.

¹² Motzer RJ, Mazumdar M, Sheinfeld J, et al.: Sequential dose-intensive paclitaxel, ifosfamide, carboplatin, and etoposide salvage therapy for germ cell tumor patients. J Clin Oncol 18 (6): 1173-80, 2000.

¹³ Rick O, Bokemeyer C, Beyer J, et al.: Salvage treatment with paclitaxel, ifosfamide, and cisplatin plus high-dose carboplatin, etoposide, and thiotepa followed by autologous stem-cell rescue in patients with relapsed or refractory germ cell cancer. J Clin Oncol 19 (1): 81-8, 2001.

¹⁴ Beyer J, Rick O, Siegert W, et al.: Salvage chemotherapy in relapsed germ cell tumors. World J Urol 19 (2): 90-3, 2001.

¹⁵ Beyer J, Kramar A, Mandanas R, et al.: High-dose chemotherapy as salvage treatment in germ cell tumors: a multivariate analysis of prognostic variables. J Clin Oncol 14 (10): 2638-45, 1996.

¹⁶ Rick O, Bokemeyer C, Weinknecht S, et al.: Residual tumor resection after high-dose chemotherapy in patients with relapsed or refractory germ cell cancer. J Clin Oncol 22 (18): 3713-9, 2004.

¹⁷ De Giorgi U, Rosti G, Slavin S, et al.: Salvage high-dose chemotherapy for children with extragonadal germ-cell tumours. Br J Cancer 93 (4): 412-7, 2005.

Changes to This Summary (2/1/2007)

The PDQ cancer information summaries are reviewed regularly and updated as new information becomes available. This section describes the latest changes made to this summary as of the date above.

Treatment Option Overview

Added Marina et al. as reference 17.

Childhood Malignant Testicular Germ Cell Tumor

Added Canning as reference 3.

Childhood Extragonadal Malignant Germ Cell Tumor

Added text about the results of a study of prognostic factors in children with extragonadal malignant germ cell tumors (cited Marina et al. as reference 4).

More Information

About PDQ

• PDQ® - NCI's Comprehensive Cancer Database.
  • Full description of the NCI PDQ database.

Additional PDQ Summaries

• PDQ® Cancer Information Summaries: Adult Treatment
  • Treatment options for adult cancers.
• PDQ® Cancer Information Summaries: Pediatric Treatment
  • Treatment options for childhood cancers.
• PDQ® Cancer Information Summaries: Supportive Care
  • Side effects of cancer treatment, management of cancer-related complications and pain, and psychosocial concerns.
• PDQ® Cancer Information Summaries: Screening/Detection (Testing for Cancer)
  • Tests or procedures that detect specific types of cancer.
• PDQ® Cancer Information Summaries: Prevention
  • Risk factors and methods to increase chances of preventing specific types of cancer.
• PDQ® Cancer Information Summaries: Genetics
  • Genetics of specific cancers and inherited cancer syndromes, and ethical, legal, and social concerns.
• PDQ® Cancer Information Summaries: Complementary and Alternative Medicine
  • Information about complementary and alternative forms of treatment for patients with cancer.

Important:

This information is intended mainly for use by doctors and other health care professionals. If you have questions about this topic, you can ask your doctor, or call the Cancer Information Service at 1-800-4-CANCER (1-800-422-6237) .