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Childhood Extracranial Germ Cell Tumors Treatment (PDQ®)

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Table of Contents

General Information About Childhood Extracranial Germ Cell Tumors (GCTs)

Stage Information for Childhood Extracranial GCTs

Treatment Option Overview for Childhood Extracranial GCTs

Treatment of Mature and Immature Teratomas in Children

Treatment of Malignant Gonadal GCTs in Children

Treatment of Malignant Extragonadal Extracranial GCTs in Children

Treatment of Recurrent Malignant GCTs in Children

Changes to This Summary (06/06/2014)

About This PDQ Summary

Get More Information From NCI

General Information About Childhood Extracranial Germ Cell Tumors (GCTs)

Cancer in children and adolescents is rare, although the overall incidence of childhood cancer has slowly increased since 1975.[1] 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 approach incorporates the skills of the following health care professionals and others to ensure that children receive treatment, supportive care, and rehabilitation that will achieve optimal survival and quality of life:

  • Primary care physicians.
  • Pediatric surgical subspecialists.
  • Radiation oncologists.
  • Pediatric medical oncologists/hematologists.
  • Rehabilitation specialists.
  • Pediatric nurse specialists.
  • Social workers.
  • Child life professionals.
  • Psychologists.

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.[2] At these pediatric cancer centers, clinical trials are available for most of the cancer types 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. Most 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.

Dramatic improvements in survival have been achieved for children and adolescents with cancer.[1] Between 1975 and 2002, childhood cancer mortality decreased by more than 50%. For gonadal extracranial germ cell tumor (GCT), the 5-year survival rate has increased over the same time, from 89% to 98% for children younger than 15 years and from 70% to 95% for adolescents aged 15 to 19 years. Between 1979 and 2002, the extragonadal GCT 5-year survival rate increased from 42% to 83% for children younger than 15 years.[1] Childhood and adolescent cancer survivors require close monitoring because 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.)

GCTs arise from primordial germ cells, which migrate during embryogenesis from the yolk sac through the mesentery to the gonads.[3,4] Childhood extracranial GCTs can be divided into the following two types:

  • Gonadal.
  • Extragonadal.

Most childhood extragonadal GCTs arise in midline sites (i.e., sacrococcygeal, mediastinal, and retroperitoneal); the midline location may represent aberrant embryonic migration of the primordial germ cells.

Childhood extracranial GCTs are broadly classified as the following:

  • Mature teratomas.
  • Immature teratomas.
  • Malignant GCTs.

GCTs comprise a variety of histologic diagnoses and can also be divided into the following histologic types:

  • Germinoma.
    • Germinoma.
    • Dysgerminoma (ovary).
    • Seminoma (testis).
  • Nongerminoma.
    • Teratomas (mature and immature).
    • Yolk sac tumor (endodermal sinus tumor).
    • Choriocarcinoma.
    • Embryonal carcinoma.
    • Gonadoblastoma.
    • Mixed GCT (contains more than one of the histologies above).

(Refer to the PDQ summary on Childhood Central Nervous System Germ Cell Tumors Treatment for information about the treatment of intracranial germ cell tumors.)

Incidence

Childhood GCTs are rare in children younger than 15 years, accounting for approximately 3% of cancers in this age group.[5-7] In the fetal/neonatal age group, most extracranial GCTs are benign teratomas occurring at midline locations, including sacrococcygeal, retroperitoneal, mediastinal, and cervical regions. Despite the small percentage of malignant teratomas that occur in this age group, perinatal tumors have a high morbidity rate caused by hydrops fetalis and premature delivery.[8,9]

Extracranial GCTs (particularly testicular GCTs) are much more common among adolescents aged 15 to 19 years, representing approximately 14% of cancers in this age group.

The incidence of extracranial GCTs by 5-year age group and gender is shown in Table 1.

Table 1. Incidence of Extracranial Germ Cell Tumors by Age Group and Gender (per 106 population)a
 0–4 years 5–9 years 10–14 years  15–19 years 
aRates are per 1 million children from 1986 to 1995 for the nine Surveillance, Epidemiology, and End Results regions plus Los Angeles.
Males70.31.431
Females5.82.47.825.3

Histologic Classification of Childhood Extracranial GCTs

Childhood extracranial GCTs comprise a variety of histologic diagnoses and can be broadly classified as the following:

The histologic and genetic properties of these tumors are heterogeneous and vary by primary tumor site and the gender and age of the patient.[10,11] Histologically identical GCTs that arise in younger children have different biological characteristics from those that arise in adolescents and young adults.[12]

Mature teratomas

Mature teratomas usually occur in the ovary or at extragonadal locations. They are the most common histological subtype of childhood GCT.[13-15] Mature teratomas usually contain well-differentiated tissues from the ectodermal, mesodermal, and endodermal germ cell layers, and any tissue type may be found within the tumor.

Mature teratomas are benign, although some mature teratomas may secrete enzymes or hormones, including insulin, growth hormone, androgens, and prolactin.[16,17]

Immature teratomas

Immature teratomas contain tissues from the ectodermal, mesodermal, and endodermal germ cell layers, but immature tissues, primarily neuroepithelial, are also present. Immature teratomas are graded from 0 to 3 on the basis of the amount of immature neural tissue found in the tumor specimen.[18] Tumors of higher grade are more likely to have foci of yolk sac tumor.[19] Immature teratomas may be classified as malignant tumors.

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.[19,20] Some immature teratomas may secrete enzymes or hormones, such as vasopressin.[21]

Malignant GCTs

GCTs contain frankly malignant tissues of germ cell origin and, rarely, tissues of somatic origin. Isolated malignant elements may constitute a small fraction of a predominantly mature or immature teratoma.[20,22]

Malignant germ cell elements of children, adolescents, and young adults can be grouped broadly by location (refer to Tables 2 and 3).

Table 2. Histology of Malignant Germ Cell Tumors in Young Childrena
Malignant Germ Cell Elements Location 
Yolk sac tumor (endodermal sinus tumor)E, O, T
Dysgerminoma (rare in young children)O

E = extragonadal; O = ovarian; T = testicular.
aModified from Perlman et al.[23]

Table 3. Histology of Malignant Germ Cell Tumors in Adolescents and Young Adultsa
Malignant Germ Cell Elements Location 
SeminomaT
DysgerminomaO
GerminomaE
Yolk sac tumor (endodermal sinus tumor)E, O, T
ChoriocarcinomaE, O, T
Embryonal carcinomaE, T
Mixed germ cell tumorsE, O, T

E = extragonadal; O = ovarian; T = testicular.
aModified from Perlman et al.[23]

Adolescent and young adult males present with more germinomas (testicular and mediastinal seminomas), and females present with more ovarian dysgerminomas.

Pediatric GCT Biology

The following biologically distinct subtypes of GCTs are found in children and adolescents:

It should be emphasized that very few pediatric GCT specimens have been analyzed to date. Biologic distinctions between GCTs in children and GCTs in adults may not be absolute, and biologic factors have not been shown to predict risk.[24-26]

Testicular GCTs
  • Children: During early childhood, both testicular teratomas and malignant testicular GCTs are identified. The malignant tumors are commonly composed of pure yolk sac tumor (also known as endodermal sinus tumor), are generally diploid or tetraploid, and often lack the isochromosome of the short arm of chromosome 12 that characterizes testicular cancer in young adults.[24,27-31] 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.[29-32]

  • Adolescents and young adults: Testicular GCTs typically possess an isochromosome of the short arm of chromosome 12 [33-36] and are aneuploid.[27,36] Although adolescent testicular germ cell patients may be best treated at pediatric oncology centers, the treatment for adolescents older than 14 years follows the regimens used in adults. (Refer to the PDQ summary on Testicular Cancer Treatment for more information.)

Ovarian GCTs

Ovarian GCTs occur primarily in adolescent and young adult females. While most ovarian GCTs are benign mature teratomas, a heterogeneous group of malignant GCTs do occur in females, including immature teratomas, dysgerminomas, yolk sac tumors, and mixed GCTs. The malignant ovarian GCT commonly shows increased copies of the short arm of chromosome 12.[37]

Patients with pediatric ovarian GCTs have an excellent prognosis. One series of 66 patients monitored for more than 44 years reported recurrence rates of 4.5% and mortality rates of 3%.[38]

(Refer to the PDQ summary on Ovarian Germ Cell Tumors Treatment for more information.)

Extragonadal extracranial GCTs

Extragonadal extracranial GCTs occur outside of the brain and gonads.

  • Children: These tumors typically present at birth or during early childhood. Most of these tumors are benign teratomas occurring in the sacrococcygeal region, and thus are not included in Surveillance, Epidemiology, and End Results (SEER) data.[39,40] Malignant yolk sac tumor histology occurs in a minority of these tumors; however, they may have cytogenetic abnormalities similar to those observed for tumors occurring in the testes of young males.[28-30,32]

  • Older children, adolescents, and young adults: The mediastinum is the most common primary site for extragonadal GCTs in older children and adolescents.[14] Mediastinal GCTs in children younger than 8 years share the same genetic gains and losses as sacrococcygeal and testicular tumors in young children.[41-43] The gain in chromosome 12p has been reported in mediastinal tumors in children aged 8 years and older.[43,44]

There are few data about the potential genetic or environmental factors associated with childhood extragonadal extracranial GCTs. Patients with the following syndromes are at an increased risk of extragonadal extracranial GCTs:

  • Klinefelter syndrome—increased risk of mediastinal GCTs.[45-47]

  • Swyer syndrome—increased risk of gonadoblastomas and germinomas.[48,49]

  • Turner syndrome—increased risk of gonadoblastomas and germinomas.[50,51]

Clinical Features

Childhood extracranial GCTs develop at diffuse sites. The clinical features at presentation are specific for each site.

Diagnostic and Staging Evaluation

Diagnostic evaluation of GCTs includes imaging studies and measurement of tumor markers. In suspected cases, tumor markers can suggest the diagnosis before surgery and/or biopsy. This information can be used by the multidisciplinary team to make appropriate treatment choices.

Tumor markers

Yolk sac tumors produce alpha-fetoprotein (AFP), while germinomas (seminomas and dysgerminomas), and especially choriocarcinomas, produce beta-human chorionic gonadotropin (beta-HCG), resulting in elevated serum levels of these substances. Most children with malignant GCTs will have a component of yolk sac tumor and have elevations of AFP levels,[52,53] which are serially monitored during treatment to help assess response to therapy.[20,22,52] Benign teratomas and immature teratomas may produce small elevations of AFP and beta-HCG.

During the first year of life, infants have a wide range of serum AFP levels, which are not associated with the presence of a GCT. Normal ranges have been described but are based on limited data.[54,55] The serum half-life of AFP is 5 to 7 days, and the serum half-life of beta-HCG is 1 to 2 days. Although few pediatric data exist, adult studies have shown that an unsatisfactory decline of elevated tumor markers is a poor prognostic finding.[56] Even though the data are limited, tumor markers are measured with each cycle of chemotherapy for all pediatric patients with malignant GCT. It should be recognized that after initial chemotherapy, tumor markers may show a transient elevation.[57]

Imaging tests

Imaging tests may include the following:

  • Computed tomography (CT) scan of the primary site and chest.
  • Magnetic resonance imaging (MRI) of the primary site.
  • Radionucleotide bone scan or positron emission tomography scan (for postpubertal males).
Follow-up After Treatment

There is little evidence to provide guidance on the follow-up care of children with extracranial GCTs.

The following tests and procedures may be performed at the physician's discretion when tumor markers are elevated at diagnosis:

  • AFP and beta-HCG. Monitor AFP and beta-HCG levels monthly for 6 months (highest risk period) and then every 3 months, for a total of 2 years (3 years for sacrococcygeal teratoma).

  • Imaging tests. MRI/CT may be performed at the completion of therapy. Further imaging intervals have not been defined.

The following tests and procedures may be performed at the physician's discretion when tumor markers are normal at diagnosis:

  • Imaging tests. Ultrasound or CT/MRI may be performed every 3 months for 2 years and then annually for 5 years for germinomas.
References
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  2. 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.  [PUBMED Abstract]

  3. Dehner LP: Gonadal and extragonadal germ cell neoplasia of childhood. Hum Pathol 14 (6): 493-511, 1983.  [PUBMED Abstract]

  4. McIntyre A, Gilbert D, Goddard N, et al.: Genes, chromosomes and the development of testicular germ cell tumors of adolescents and adults. Genes Chromosomes Cancer 47 (7): 547-57, 2008.  [PUBMED Abstract]

  5. Miller RW, Young JL Jr, Novakovic B: Childhood cancer. Cancer 75 (1 Suppl): 395-405, 1995.  [PUBMED Abstract]

  6. 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 October 24, 2014. 

  7. Poynter JN, Amatruda JF, Ross JA: Trends in incidence and survival of pediatric and adolescent patients with germ cell tumors in the United States, 1975 to 2006. Cancer 116 (20): 4882-91, 2010.  [PUBMED Abstract]

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

  9. 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.  [PUBMED Abstract]

  10. Hawkins EP: Germ cell tumors. Am J Clin Pathol 109 (4 Suppl 1): S82-8, 1998.  [PUBMED Abstract]

  11. 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.  [PUBMED Abstract]

  12. Horton Z, Schlatter M, Schultz S: Pediatric germ cell tumors. Surg Oncol 16 (3): 205-13, 2007.  [PUBMED Abstract]

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

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

  15. Harms D, Zahn S, Göbel U, et al.: Pathology and molecular biology of teratomas in childhood and adolescence. Klin Padiatr 218 (6): 296-302, 2006 Nov-Dec.  [PUBMED Abstract]

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

  17. 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.  [PUBMED Abstract]

  18. 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.  [PUBMED Abstract]

  19. 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.  [PUBMED Abstract]

  20. 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.  [PUBMED Abstract]

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

  22. Göbel U, Calaminus G, Schneider DT, et al.: The malignant potential of teratomas in infancy and childhood: the MAKEI experiences in non-testicular teratoma and implications for a new protocol. Klin Padiatr 218 (6): 309-14, 2006 Nov-Dec.  [PUBMED Abstract]

  23. Perlman EJ, Hawkins EP: Pediatric germ cell tumors: protocol update for pathologists. Pediatr Dev Pathol 1 (4): 328-35, 1998 Jul-Aug.  [PUBMED Abstract]

  24. Palmer RD, Foster NA, Vowler SL, et al.: Malignant germ cell tumours of childhood: new associations of genomic imbalance. Br J Cancer 96 (4): 667-76, 2007.  [PUBMED Abstract]

  25. Palmer RD, Barbosa-Morais NL, Gooding EL, et al.: Pediatric malignant germ cell tumors show characteristic transcriptome profiles. Cancer Res 68 (11): 4239-47, 2008.  [PUBMED Abstract]

  26. Poynter JN, Hooten AJ, Frazier AL, et al.: Associations between variants in KITLG, SPRY4, BAK1, and DMRT1 and pediatric germ cell tumors. Genes Chromosomes Cancer 51 (3): 266-71, 2012.  [PUBMED Abstract]

  27. 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.  [PUBMED Abstract]

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

  29. 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.  [PUBMED Abstract]

  30. 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.  [PUBMED Abstract]

  31. Bussey KJ, Lawce HJ, Olson SB, et al.: Chromosome abnormalities of eighty-one pediatric germ cell tumors: sex-, age-, site-, and histopathology-related differences--a Children's Cancer Group study. Genes Chromosomes Cancer 25 (2): 134-46, 1999.  [PUBMED Abstract]

  32. 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.  [PUBMED Abstract]

  33. 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.  [PUBMED Abstract]

  34. 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.  [PUBMED Abstract]

  35. 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.  [PUBMED Abstract]

  36. 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.  [PUBMED Abstract]

  37. 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.  [PUBMED Abstract]

  38. De Backer A, Madern GC, Oosterhuis JW, et al.: Ovarian germ cell tumors in children: a clinical study of 66 patients. Pediatr Blood Cancer 46 (4): 459-64, 2006.  [PUBMED Abstract]

  39. 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.  [PUBMED Abstract]

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

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

  42. 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.  [PUBMED Abstract]

  43. 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.  [PUBMED Abstract]

  44. McKenney JK, Heerema-McKenney A, Rouse RV: Extragonadal germ cell tumors: a review with emphasis on pathologic features, clinical prognostic variables, and differential diagnostic considerations. Adv Anat Pathol 14 (2): 69-92, 2007.  [PUBMED Abstract]

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

  46. 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.  [PUBMED Abstract]

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

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

  49. 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.  [PUBMED Abstract]

  50. Tanaka Y, Sasaki Y, Tachibana K, et al.: Gonadal mixed germ cell tumor combined with a large hemangiomatous lesion in a patient with Turner's syndrome and 45,X/46,X, +mar karyotype. Arch Pathol Lab Med 118 (11): 1135-8, 1994.  [PUBMED Abstract]

  51. Kota SK, Gayatri K, Pani JP, et al.: Dysgerminoma in a female with turner syndrome and Y chromosome material: A case-based review of literature. Indian J Endocrinol Metab 16 (3): 436-40, 2012.  [PUBMED Abstract]

  52. 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.  [PUBMED Abstract]

  53. 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.  [PUBMED Abstract]

  54. Wu JT, Book L, Sudar K: Serum alpha fetoprotein (AFP) levels in normal infants. Pediatr Res 15 (1): 50-2, 1981.  [PUBMED Abstract]

  55. Blohm ME, Vesterling-Hörner D, Calaminus G, et al.: Alpha 1-fetoprotein (AFP) reference values in infants up to 2 years of age. Pediatr Hematol Oncol 15 (2): 135-42, 1998 Mar-Apr.  [PUBMED Abstract]

  56. Motzer RJ, Nichols CJ, Margolin KA, et al.: Phase III randomized trial of conventional-dose chemotherapy with or without high-dose chemotherapy and autologous hematopoietic stem-cell rescue as first-line treatment for patients with poor-prognosis metastatic germ cell tumors. J Clin Oncol 25 (3): 247-56, 2007.  [PUBMED Abstract]

  57. Vogelzang NJ, Lange PH, Goldman A, et al.: Acute changes of alpha-fetoprotein and human chorionic gonadotropin during induction chemotherapy of germ cell tumors. Cancer Res 42 (11): 4855-61, 1982.  [PUBMED Abstract]

Stage Information for Childhood Extracranial GCTs

As with other childhood solid tumors, stage directly impacts the outcome of patients with malignant germ cell tumors (GCTs).[1-3] The most commonly used staging systems in the United States are as follows:[4]

Nonseminoma Testicular GCT Staging From the COG
  • Stage I: Limited to testis; complete resection by high inguinal orchiectomy or transscrotal resection with no tumor spillage. There must be no evidence of disease beyond the testis by radiologic scans or pathology.

  • Stage II: Transscrotal orchiectomy with spillage of tumor; microscopic disease in scrotum or high in spermatic cord (>0.5 cm). Tumor markers fail to normalize or increase.

  • Stage III: Gross residual disease; retroperitoneal lymph node involvement (>2 cm in boys younger than 10 years).

  • Stage IV: Distant metastases, including liver, brain, bone, and lung.

Retroperitoneal lymph node dissection has not been required in pediatric germ cell trials to stage disease in males younger than 15 years. Data on adolescent males with testicular GCTs are limited. Retroperitoneal lymph node dissection is used for both staging and treatment in adult testicular GCT trials.[5] (Refer to the PDQ summary on Testicular Cancer Treatment for more information about the staging of adult testicular GCTs.)

Ovarian GCT Staging From the COG
  • Stage I: Localized disease; completely resected without microscopic disease in the resected margins or evidence of capsular rupture. Negative peritoneal cytology.

  • 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.

  • Stage IV: Disseminated disease involving lungs, liver, brain, or bone.

Ovarian GCT Staging From the FIGO

Another ovarian GCT staging system used frequently by gynecologic oncologists is the FIGO staging system, which is based on an adequate staging operation at the time of diagnosis.[6] (Refer to the PDQ summary on Ovarian Germ Cell Tumors Treatment for more information.) 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 deposit 2 cm or smaller.
  • IIIC: Gross deposits larger than 2 cm or positive nodes.

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

Extragonadal Extracranial GCT Staging From the COG
  • Stage I: Localized disease; complete resection with no microscopic disease at margins or in regional lymph nodes. Tumor markers must normalize in appropriate half-life after resection. Complete coccygectomy for sacrococcygeal site.

  • Stage II: Microscopic residual disease, capsular invasion, and/or microscopic lymph node involvement. Tumor markers fail to normalize or increase.

  • Stage III: Gross residual disease and gross lymph node involvement (>2 cm).

  • Stage IV: Distant metastases, including liver, brain, bone, or lung.

References
  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.  [PUBMED Abstract]

  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.  [PUBMED Abstract]

  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.  [PUBMED Abstract]

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

  5. de Wit R, Fizazi K: Controversies in the management of clinical stage I testis cancer. J Clin Oncol 24 (35): 5482-92, 2006.  [PUBMED Abstract]

  6. Cannistra SA: Cancer of the ovary. N Engl J Med 329 (21): 1550-9, 1993.  [PUBMED Abstract]

Treatment Option Overview for Childhood Extracranial GCTs

Childhood extracranial germ cell tumors (GCTs) are very heterogenous. The benefits and limitations of therapy are related to differences in histology. For example, pediatric GCTs, such as mature and immature teratomas, may not respond to chemotherapy.

Prognosis and appropriate treatment for extracranial GCTs depend on many factors, including the following:[1-4]

  • Histology (e.g., seminomatous vs. nonseminomatous).
  • Age (young children vs. adolescents).
  • Stage of disease.
  • Primary site of disease.

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, and renal dysfunction), children with extracranial malignant GCTs need to be cared for at pediatric cancer centers with experience treating these rare tumors.

On the basis of clinical factors, appropriate treatment for extracranial GCTs may involve one of the following:

  • Surgical resection followed by careful monitoring for disease recurrence.
  • Initial surgical resection followed by platinum-based chemotherapy.
  • Diagnostic tumor biopsy and preoperative platinum-based chemotherapy followed by definitive tumor resection.[5]

For patients with completely resected immature teratomas at any location (even those with malignant elements) and patients with localized, completely resected (stage I) gonadal tumors, additional therapy may not be necessary; however, close monitoring is important.[6,7] 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.

Surgery

Surgery is an essential component of treatment. Specific treatments will be discussed for each tumor type.

Radiation Therapy

Germinomas (testicular and mediastinal seminomas in males and ovarian dysgerminomas in females) are sensitive to radiation, but radiation therapy is rarely recommended. With the advent of effective chemotherapy, it became possible for patients to avoid the toxic effects of radiation.

Chemotherapy

Before effective chemotherapy became available, children with extracranial malignant GCTs had 3-year survival rates of 15% to 20% with surgery and radiation therapy,[8-10] although young boys with localized testicular tumors did well with surgical resection.[11,12] Cisplatin-based chemotherapy has significantly improved the outcome for most children and adolescents with extracranial GCTs; 5-year survival rates are now more than 90%.

The standard chemotherapy regimen for both adults and children with malignant nonseminomatous GCTs includes cisplatin, etoposide, and bleomycin. Adult patients receive weekly bleomycin throughout treatment (bleomycin, etoposide, and cisplatin [BEP]). Pediatric patients do not receive bleomycin during the weeks between cycles (cisplatin, etoposide, and bleomycin [PEB]). (Refer to Table 4 for adult BEP and pediatric PEB and JEB chemotherapy dosing schedules.)[1,2,13-15] The combination of carboplatin, etoposide, and bleomycin (JEB) underwent clinical investigation in the United Kingdom in children younger than 16 years and was reported to have an event-free survival (EFS) by site and stage similar to that of PEB.[3,16] The use of JEB appears to be associated with fewer otologic toxic effects and renal toxic effects than does the use of PEB.[3] PEB and JEB have not been compared in a randomized pediatric GCT trial.

Adult studies have substituted standard-dose carboplatin for cisplatin in combination with etoposide alone and in combination with etoposide and low-dose bleomycin,[17] but the carboplatin regimens demonstrated inferior EFS and overall survival (OS) compared with cisplatin-containing therapy among patients with malignant GCTs. No randomized comparison of PEB versus JEB has been conducted in children.

Refer to Table 4 for adult BEP and pediatric PEB and JEB chemotherapy dosing schedules.

Table 4. Comparison of Adult BEP and Pediatric PEB and JEB Chemotherapy Dosing Schedulesa
Regimen Bleomycin Etoposide Cisplatin Carboplatin 
Adult BEP (every 21 days)b [15,18]30 units/m2, days 1, 8, 15100mg/m2, days 1–520 mg/m2, days 1–5
Pediatric PEB (every 21 days) [1,2]15 units/m², day 1100 mg/m², days 1–520 mg/m², days 1–5
Pediatric JEB (every 21–28 days) [3]15 units/m², day 3120 mg/m², days 1–3600 mg/m² or GFR-based dosing, day 2

BEP = bleomycin, etoposide, and cisplatin; GFR = glomerular filtration rate; JEB = carboplatin, etoposide, and bleomycin; PEB = cisplatin, etoposide, and bleomycin.
aAdult doses of PEB and JEB chemotherapy are different from pediatric doses.
bThe adult BEP regimen is provided here for comparison only; BEP is not used in the treatment of children.

The approach to the management of extracranial GCTs has been derived from the results of several intergroup studies conducted by the Children's Cancer Group (CCG) and the Pediatric Oncology Group (POG).[1,2,6] These studies explored the use of PEB for the treatment of localized gonadal GCT [1] and the benefit of increasing the dose of cisplatin (high-dose [HD]-PEB: 200 mg/m2 vs. PEB: 100 mg/m2 of cisplatin) in a randomized manner in patients with extragonadal and advanced gonadal GCTs.[2] The intensification of cisplatin in the HD-PEB regimen provided some improvement in EFS but no difference in OS; however, the use of HD-PEB was associated with a significantly higher incidence and severity of otologic toxic effects and renal toxic effects. In a subsequent study, amifostine was not effective in preventing hearing loss in patients who received HD-PEB.[19]

Table 5 provides an overview of standard treatment options for children with extracranial GCTs. Specific details of treatment by primary site and clinical condition are described in subsequent sections.

Table 5. Standard Treatment Options for Childhood Extracranial Germ Cell Tumors (GCTs)
Histology Standard Treatment Options 
Mature teratoma (nonsacrococcygeal)Surgery and observation
Immature teratoma (nonsacrococcygeal)Surgery and observation (stage I)
Surgery and chemotherapy (stages II–IV) (refer to the Childhood Malignant Ovarian GCTs section of this summary for specific information about the treatment of ovarian immature teratoma)
Mature and immature teratomas (sacrococcygeal)Surgery and observation
Malignant gonadal GCTs in children:
Childhood malignant testicular GCTs:
Malignant testicular GCTs in prepubertal malesSurgery and observation (stage I)
Surgery and chemotherapy (PEB) (stages II–IV)
Malignant testicular GCTs in postpubertal malesRefer to the PDQ summary on Testicular Cancer Treatment for more information.
Childhood malignant ovarian GCTs:
Dysgerminomas of the ovarySurgery and observation (stage I)
Surgery and chemotherapy (PEB) (stages II–IV)
Malignant nongerminomatous ovarian GCTs (yolk sac and mixed GCTs)Surgery and observation (stage I) (refer to the Childhood Malignant Ovarian GCTs section of this summary for specific information about the treatment of ovarian immature teratoma)
Surgery and chemotherapy (PEB) (stage I and stages II–IV)
Biopsy followed by chemotherapy (PEB) and surgery (initially unresectable tumors)
Malignant extragonadal extracranial GCTs in childrenSurgery and chemotherapy (PEB)
Biopsy followed by chemotherapy (PEB) and possibly surgery
Recurrent malignant GCTs in childrenRefer to the Treatment of Recurrent Malignant GCTs in Children section of this summary for more information.

JEB = carboplatin, etoposide, and bleomycin; PEB = cisplatin, etoposide, and bleomycin.

GCT With Non-GCT Elements

The treatment of GCTs with other non-GCT elements is complex and few data exist to direct treatment. In adolescents, central primitive neuroectodermal tumors and sarcomas have been found in teratomas.[20] The Italian Pediatric Germ Cell Tumor group identified 14 patients with malignant somatic tumors, such as neuroblastoma and rhabdomyosarcoma, imbedded in teratomas (<2% of extracranial GCTs).[21] The optimal treatment strategy for GCT with non-GCT elements has not been determined, and separate treatments for both malignant GCT and non-GCT elements may be required.

References
  1. 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.  [PUBMED Abstract]

  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.  [PUBMED Abstract]

  3. 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.  [PUBMED Abstract]

  4. 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.  [PUBMED Abstract]

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

  6. 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.  [PUBMED Abstract]

  7. 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.  [PUBMED Abstract]

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

  9. 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.  [PUBMED Abstract]

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

  11. 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.  [PUBMED Abstract]

  12. 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.  [PUBMED Abstract]

  13. 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.  [PUBMED Abstract]

  14. 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.  [PUBMED Abstract]

  15. Williams SD, Birch R, Einhorn LH, et al.: Treatment of disseminated germ-cell tumors with cisplatin, bleomycin, and either vinblastine or etoposide. N Engl J Med 316 (23): 1435-40, 1987.  [PUBMED Abstract]

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

  17. 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.  [PUBMED Abstract]

  18. 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.  [PUBMED Abstract]

  19. 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.  [PUBMED Abstract]

  20. Ehrlich Y, Beck SD, Ulbright TM, et al.: Outcome analysis of patients with transformed teratoma to primitive neuroectodermal tumor. Ann Oncol 21 (9): 1846-50, 2010.  [PUBMED Abstract]

  21. Terenziani M, D'Angelo P, Bisogno G, et al.: Teratoma with a malignant somatic component in pediatric patients: the Associazione Italiana Ematologia Oncologia Pediatrica (AIEOP) experience. Pediatr Blood Cancer 54 (4): 532-7, 2010.  [PUBMED Abstract]

Treatment of 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. Less commonly, these tumors are found in the testicular region of boys younger than 4 years, the mediastinum of adolescents, and other sites.[1-3] The primary treatment for teratomas is surgery and depends on whether the tumor forms in a nonsacrococcygeal or sacrococcygeal site. Surgical options for sacrococcygeal teratomas are complex. The number of pediatric patients with postoperative residual mature or immature teratomas is very small.

Mature Teratomas (Nonsacrococcygeal Sites)

Standard treatment options for mature teratomas (nonsacrococcygeal sites)

Standard treatment options for mature teratomas in a nonsacrococcygeal site include the following:

  1. Surgery and observation.

Children with mature teratomas, including mature teratomas of the mediastinum, can be treated with surgery and observation, with an excellent prognosis.[1,4] In a review of 153 children with nontesticular mature teratoma, the 6-year relapse-free survival was 96% for completely resected disease and 55% for incompletely resected disease.[2]

Head and neck germ cell tumors (GCTs) in neonates should be cared for by a multidisciplinary team. Although most head and neck GCTs are benign, they present significant challenges to surgeons. Some tumors develop malignant elements, which may change the treatment strategy.[5]

Mature teratomas in the prepubertal testis are relatively common benign lesions and may be amenable to testis-sparing surgery.[6]

Immature Teratomas (Nonsacrococcygeal Sites)

Standard treatment options for immature teratomas (nonsacrococcygeal sites)

Standard treatment options for immature teratomas in a nonsacrococcygeal site include the following:

  1. Surgery and observation (stage I).
  2. Surgery and chemotherapy (stages II through IV).

The treatment options for immature teratomas at a nonsacrococcygeal site differ by stage of disease.

Stage I

Infants and young children with immature teratomas have an excellent prognosis if the tumor can be completely resected.[7-9] For these patients, the current standard of treatment is surgery and observation.

Evidence (surgery and observation for stage I disease):

  1. The benefit of adjuvant chemotherapy for children was investigated in a study by the Pediatric Oncology Group and Children's Cancer Group. Surgical resection followed by careful observation was used to treat patients with immature teratomas.[10]
    • Surgery alone was curative for most children and adolescents with resected ovarian immature teratomas of any grade, even when elevated levels of serum alpha-fetoprotein (AFP) or microscopic foci of yolk sac tumor were present.

    • The study demonstrated a 3-year event-free survival of 97.8% for patients with ovarian tumors, 100% for patients with testicular tumors, and 80% for patients with extragonadal tumors.

Stages II through IV

There is significant debate on the responsiveness of immature teratomas to chemotherapy. In adults, and perhaps adolescents, immature teratomas (primarily ovarian) reportedly have an aggressive clinical behavior [11] requiring surgery and chemotherapy. The decision to use chemotherapy is based on the tumor stage (II through IV) and grade. Further studies on the treatment of ovarian immature teratomas with chemotherapy are lacking. In a pediatric report from the United Kingdom, immature teratomas did not respond to chemotherapy.[12] This study did not include patients older than 15 years. (Refer to the PDQ summary on Ovarian Germ Cell Tumors Treatment for more information about the treatment of ovarian immature teratomas in postpubertal females.)

Mature and Immature Teratomas (Sacrococcygeal Site)

The sacrococcygeal region is the primary tumor site for most benign and malignant GCTs 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.[13]

Sacrococcygeal tumors present in the following two clinical patterns related to the child’s age, tumor location, and likelihood of tumor malignancy:[1]

  • Neonates: Neonatal tumors present at birth protruding from the sacral site and are usually mature or immature teratomas.

  • Infants and young children: Among infants and young children, the tumor presents as a palpable mass in the sacro-pelvic region compressing the bladder or rectum. These pelvic tumors are more likely to be 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.[14] The pelvic site of the primary tumor has been reported to be an adverse prognostic factor, perhaps as a result of delayed diagnosis because it was unappreciated at birth or incomplete resection at the time of original surgery.[14-17]

Standard treatment options for mature and immature teratomas (sacrococcygeal sites)

Standard treatment options for mature and immature teratomas in a sacrococcygeal site include the following:

  1. Surgery and observation.

Surgery is an essential component of treatment. Complete resection of the coccyx is vital to minimize the likelihood of tumor recurrence;[2] however, one study reported that 11 of 12 patients with microscopic residual benign immature teratomas had no recurrence.[18] After successful resection, neonates diagnosed with benign mature and immature teratomas are closely observed with follow-up exams and serial serum AFP determinations for several years to ensure that the expected physiological normalization of AFP levels occurs and to facilitate early detection of tumor relapse.[19] 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.[9,13,19,20]

While there is no standard follow-up schedule, tumor markers are measured frequently for 3 years. Recurrent tumors will be malignant in 43% to 50% of cases, and yolk sac tumor is the most common histology. With early detection, recurrent malignant GCTs can be treated successfully with surgery and chemotherapy (overall survival, 92%).[21] Long-term survivors are monitored for complications of extensive surgery, which include constipation, fecal and urinary incontinence, and psychologically unacceptable cosmetic scars.[22]

Current Clinical Trials

Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with childhood teratoma. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI Web site.

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

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

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

  4. 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.  [PUBMED Abstract]

  5. Bernbeck B, Schneider DT, Bernbeck B, et al.: Germ cell tumors of the head and neck: report from the MAKEI Study Group. Pediatr Blood Cancer 52 (2): 223-6, 2009.  [PUBMED Abstract]

  6. 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.  [PUBMED Abstract]

  7. Valdiserri RO, Yunis EJ: Sacrococcygeal teratomas: a review of 68 cases. Cancer 48 (1): 217-21, 1981.  [PUBMED Abstract]

  8. 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.  [PUBMED Abstract]

  9. 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.  [PUBMED Abstract]

  10. 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.  [PUBMED Abstract]

  11. 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.  [PUBMED Abstract]

  12. Mann JR, Gray ES, Thornton C, et al.: Mature and immature extracranial teratomas in children: the UK Children's Cancer Study Group Experience. J Clin Oncol 26 (21): 3590-7, 2008.  [PUBMED Abstract]

  13. 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.  [PUBMED Abstract]

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

  15. 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.  [PUBMED Abstract]

  16. 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.  [PUBMED Abstract]

  17. 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.  [PUBMED Abstract]

  18. De Backer A, Madern GC, Hakvoort-Cammel FG, et al.: Study of the factors associated with recurrence in children with sacrococcygeal teratoma. J Pediatr Surg 41 (1): 173-81; discussion 173-81, 2006.  [PUBMED Abstract]

  19. 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.  [PUBMED Abstract]

  20. Gabra HO, Jesudason EC, McDowell HP, et al.: Sacrococcygeal teratoma--a 25-year experience in a UK regional center. J Pediatr Surg 41 (9): 1513-6, 2006.  [PUBMED Abstract]

  21. De Corti F, Sarnacki S, Patte C, et al.: Prognosis of malignant sacrococcygeal germ cell tumours according to their natural history and surgical management. Surg Oncol 21 (2): e31-7, 2012.  [PUBMED Abstract]

  22. Derikx JP, De Backer A, van de Schoot L, et al.: Long-term functional sequelae of sacrococcygeal teratoma: a national study in The Netherlands. J Pediatr Surg 42 (6): 1122-6, 2007.  [PUBMED Abstract]

Treatment of Malignant Gonadal GCTs in Children



Childhood Malignant Testicular GCTs

Malignant testicular GCTs in prepubertal males

Testicular germ cell tumors (GCTs) in children occur almost exclusively in boys younger than 4 years.[1,2] The initial surgical approach to evaluate a testicular mass in a young boy is important because a transscrotal biopsy can risk inguinal node metastasis.[3,4] Radical inguinal orchiectomy with initial high ligation of the spermatic cord is the procedure of choice.[5]

Computed tomography or magnetic resonance imaging evaluation, with the additional information provided by elevated tumor markers, appears adequate for staging. Retroperitoneal dissection of lymph nodes is not beneficial in the staging of testicular GCTs in young boys.[3,4] Therefore, there is no reason to risk the potential morbidity (e.g., impotence and retrograde ejaculation) associated with lymph node dissection.[6,7]

The role of surgery at diagnosis for GCTs is age- and site-dependent and must be individualized. All malignant testicular GCTs should be resected. Primary resection of other areas of disease may be appropriate when feasible, without undue risk of damage to adjacent structures; otherwise, an appropriate strategy is resection of the testis for diagnosis followed by subsequent excision in selected patients who have residual masses after undergoing chemotherapy.

Standard treatment options for malignant GCTs in prepubertal males

Standard treatment options for malignant GCTs in prepubertal males (younger than 15 years) include the following:

  1. Surgery and observation (stage I).
  2. Surgery and chemotherapy (stages II through IV).

The treatment options for malignant GCTs in prepubertal males differ by stage of disease.

Stage I

Surgery and close follow-up observation are indicated to document that a normalization of the tumor markers occurs after resection.[8,3]

Evidence (surgery and observation for stage I disease):

  1. A Children’s Cancer Group (CCG)/Pediatric Oncology Group (POG) clinical trial evaluated surgery followed by observation for boys aged 10 years or younger with stage I testicular tumors.[3,4]
    • This treatment strategy resulted in a 6-year event-free survival (EFS) of 82%.

    • Boys who developed recurrent disease received salvage therapy with four cycles of standard-dose cisplatin, etoposide, and bleomycin (PEB), with a 6-year survival of 100%.

Stages II through IV

Surgery and chemotherapy with four cycles of standard PEB is a common treatment regimen. Patients treated with this regimen have an overall survival (OS) outcome greater than 90%, suggesting that a reduction in therapy could be considered.[9,10]

Surgery and treatment with four to six cycles of carboplatin, etoposide, and bleomycin (JEB) is an alternative treatment regimen.[8]

Evidence (surgery and chemotherapy for stages II–IV disease):

  1. A CCG/POG clinical trial evaluated boys younger than 10 years with stage II tumors who were treated with four cycles of PEB after diagnosis.[9]
    • The 6-year EFS and OS rates were 100%.

  2. In the same CCG/POG clinical trial, boys and adolescents (age not limited to 10 years or younger) with stage III and stage IV testicular tumors were treated with surgical resection followed by four cycles of standard-dose or high-dose (HD)–PEB therapy.[10]
    • The 6-year survival outcome for males younger than 15 years with stage III and stage IV tumors was 100%.

    • The 6-year EFS for males younger than 15 years was 100% for stage III tumors and 94% for stage IV tumors.

    • The use of HD-PEB therapy did not improve the outcome for these boys but did cause increased incidence of otologic toxic effects.

  3. Excellent outcomes for boys with testicular GCTs using surgery and observation for stage I tumors and JEB and other cisplatin-containing chemotherapy regimens for stage II, stage III, and stage IV tumors have also been reported by European investigators.[6,8]

Malignant testicular GCTs in postpubertal males

The treatment options described above for young boys may not be strictly applicable to adolescent males (aged 15 years and older). In particular, the use of retroperitoneal lymph node dissection may play a crucial role in the evaluation of early-stage testicular GCT [11] and for residual disease after chemotherapy for the treatment of metastatic GCT.[12,13]

In this age group, the presence of a sarcomatous component in the primary testis GCT does not alter the prognosis; however, if a sarcomatous component is found in a metastatic lesion, survival is likely to be compromised.[14]

Standard treatment options for malignant testicular GCTs in postpubertal males

Refer to the PDQ summary on Testicular Cancer Treatment for more information about the treatment of malignant testicular GCTs in postpubertal males.

Current Clinical Trials

Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with childhood malignant testicular germ cell tumor. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI Web site.

Childhood Malignant Ovarian GCTs

Most ovarian neoplasms in children and adolescents are of germ cell origin.[1] Ovarian GCTs are very rare in young girls, but the incidence begins to increase in children aged approximately 8 or 9 years and continues to rise throughout adulthood.[1]

Childhood malignant ovarian GCTs can be divided into germinomatous (dysgerminomas) and nongerminomatous malignant GCTs (i.e., yolk sac carcinomas, mixed GCTs, choriocarcinoma, and embryonal carcinomas).

(Refer to the Mature Teratomas [Nonsacrococcygeal Sites] section of this summary for more information about childhood mature and immature teratomas arising in the ovary and the PDQ summary on Ovarian Germ Cell Tumors Treatment for more information on the treatment of ovarian GCT in postpubertal females.)

Dysgerminomas of the ovary

Standard treatment options for dysgerminomas of the ovary

Standard treatment options for dysgerminomas of the ovary include the following:

  1. Surgery and observation (stage I).
  2. Surgery and chemotherapy (stages II through IV).

The treatment options for dysgerminomas of the ovary differ by stage of disease.

Stage I

For stage I ovarian dysgerminomas of the ovary, cure can usually be achieved by unilateral salpingo-oophorectomy, conserving the uterus and opposite ovary, and close follow-up observation.[8,15-18]

Chemotherapy may be given if tumor markers do not normalize or if tumors recur.

Stages II through IV

While advanced-stage ovarian dysgerminomas, like testicular seminomas, are highly curable with surgery and radiation therapy, the effects on growth, fertility, and risk of treatment-induced second malignancy in these young patients [19,20] make chemotherapy a more attractive adjunct to surgery.[21,22] 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.[18] This approach results in a high rate of cure and the preservation of menstrual function and fertility in most patients with dysgerminomas.[21,23]

Malignant nongerminomatous ovarian GCTs

A multidisciplinary approach is essential for treatment of ovarian GCTs. Various surgical subspecialists and the pediatric oncologist must be involved in clinical decisions. The reproductive surgical approach for pediatric GCTs is often guided by the hope that function can be preserved.

Standard treatment options for malignant nongerminomatous ovarian GCTs

Standard treatment options for malignant nongerminomatous ovarian GCTs include the following:

  1. Surgery and observation (stage I).
  2. Surgery and chemotherapy (stage I and stages II through IV).
  3. Biopsy followed by chemotherapy and surgery (initially unresectable tumors).

The treatment of ovarian malignant GCTs that are not dysgerminomas or immature teratomas generally involves surgical resection and adjuvant chemotherapy.[24,25]

The role for surgery at diagnosis is age- and site-dependent and must be individualized. The use of laparoscopy in children with ovarian GCTs has not been well studied.

Pediatric surgical guidelines to determine stage I disease have been published.[26] Adult surgical guidelines to determine stage are more extensive. (Refer to the Stage Information for Ovarian Germ Cell Tumors section of the PDQ summary on Ovarian Germ Cell Tumors Treatment for more information about staging of ovarian GCTs in postpubertal females.) Strict surgical staging guidelines need to be followed to determine true stage I disease. Historically, in both pediatric and adult studies, comprehensive staging guidelines have not been followed. If strict surgical staging guidelines are not followed, surgery followed by chemotherapy, rather than surgery followed by observation, is the standard treatment.[8,27] If conservative surgery is the choice, a high rate of cure can be obtained with adjuvant chemotherapy, and adherence to strict surgical guidelines is not necessary.[28]

Platinum-based chemotherapy regimens such as PEB or JEB have been used successfully in children.[8-10,15] BEP is a common regimen in young women with ovarian GCTs.[29,30] BEP differs from PEB with the addition of weekly bleomycin. This approach results in a high rate of cure and the preservation of menstrual function and fertility in most patients with nondysgerminomas.[25,27] (Refer to Table 4 for more information about the dosing schedules for BEP, PEB, and JEB.)

Stage I

When strict surgical staging guidelines are followed, surgery followed by observation may be an appropriate treatment choice.

Evidence (surgery and observation for stage I disease):

  1. In a Children's Oncology Group (COG) trial, 25 girls with stage I ovarian malignant GCTs were treated with surgery and observation.[26]
    • The 4-year EFS was 52%.

    • Relapse was detected in 12 patients by tumor marker elevation (mean time, 2 months). Eleven patients later underwent salvage therapy with three cycles of PEB. The 4-year OS was 96%.

Similar results have been reported in other international pediatric trials, but the number of patients has been small.[8]

When strict surgical staging guidelines are not followed, surgery followed by chemotherapy is an appropriate treatment choice. Chemotherapy consists of four cycles of PEB.[9,10]

Evidence (surgery and chemotherapy for stage I disease):

  1. A pediatric intergroup trial studied patients with ovarian GCTs (stages I–IV). [9,28]
    • For stage I ovarian cancer, the EFS and OS rates were both 95.1%.

  2. In a previous U.S. intergroup trial where there was incomplete adherence to surgical staging guidelines, all reported stage I patients were given adjuvant chemotherapy and survived.[8,27] Patients had excellent survival with four cycles of PEB and conservative surgery.

Stages II through IV

Surgery and chemotherapy with four to six cycles of standard PEB in younger girls [9,10] and BEP in postpubertal girls are considered standard treatments.[29,30] Patients with normalization of tumor markers are imaged after four cycles of PEB, and any residual tumor is removed. If the tumor is completely resected but the specimen contains viable tumor, two additional cycles of PEB can be given.[10] Any persistent viable tumor that remains indicates that the treatment has failed.

Alternatively, surgery and chemotherapy with four to six cycles of JEB (patients were all younger than 15 years) is also a treatment option.[8]

Initially unresectable tumor

Primary resection of ovarian GCT is usually attempted. In rare instances where primary resection of the ovary is not possible without undue risk of damage to adjacent structures, an appropriate strategy is biopsy for diagnosis followed by subsequent surgery in patients who have residual masses after undergoing chemotherapy.

Current Clinical Trials

Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with childhood malignant ovarian germ cell tumor. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI Web site.

References
  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 October 24, 2014. 

  2. Walsh TJ, Grady RW, Porter MP, et al.: Incidence of testicular germ cell cancers in U.S. children: SEER program experience 1973 to 2000. Urology 68 (2): 402-5; discussion 405, 2006.  [PUBMED Abstract]

  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.  [PUBMED Abstract]

  4. 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. 

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

  6. 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.  [PUBMED Abstract]

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

  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.  [PUBMED Abstract]

  9. 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.  [PUBMED Abstract]

  10. 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.  [PUBMED Abstract]

  11. de Wit R, Fizazi K: Controversies in the management of clinical stage I testis cancer. J Clin Oncol 24 (35): 5482-92, 2006.  [PUBMED Abstract]

  12. Carver BS, Shayegan B, Serio A, et al.: Long-term clinical outcome after postchemotherapy retroperitoneal lymph node dissection in men with residual teratoma. J Clin Oncol 25 (9): 1033-7, 2007.  [PUBMED Abstract]

  13. Carver BS, Shayegan B, Eggener S, et al.: Incidence of metastatic nonseminomatous germ cell tumor outside the boundaries of a modified postchemotherapy retroperitoneal lymph node dissection. J Clin Oncol 25 (28): 4365-9, 2007.  [PUBMED Abstract]

  14. Guo CC, Punar M, Contreras AL, et al.: Testicular germ cell tumors with sarcomatous components: an analysis of 33 cases. Am J Surg Pathol 33 (8): 1173-8, 2009.  [PUBMED Abstract]

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

  16. 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.  [PUBMED Abstract]

  17. 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.  [PUBMED Abstract]

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

  19. 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.  [PUBMED Abstract]

  20. 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.  [PUBMED Abstract]

  21. 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.  [PUBMED Abstract]

  22. 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.  [PUBMED Abstract]

  23. 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.  [PUBMED Abstract]

  24. 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.  [PUBMED Abstract]

  25. 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.  [PUBMED Abstract]

  26. Billmire DF, Cullen JW, Rescorla FJ, 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 32 (5): 465-70, 2014.  [PUBMED Abstract]

  27. Palenzuela G, Martin E, Meunier A, et al.: Comprehensive staging allows for excellent outcome in patients with localized malignant germ cell tumor of the ovary. Ann Surg 248 (5): 836-41, 2008.  [PUBMED Abstract]

  28. Billmire D, Vinocur C, Rescorla F, et al.: Outcome and staging evaluation in malignant germ cell tumors of the ovary in children and adolescents: an intergroup study. J Pediatr Surg 39 (3): 424-9; discussion 424-9, 2004.  [PUBMED Abstract]

  29. Williams SD: Ovarian germ cell tumors: an update. Semin Oncol 25 (3): 407-13, 1998.  [PUBMED Abstract]

  30. 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.  [PUBMED Abstract]

Treatment of Malignant Extragonadal Extracranial GCTs in Children

Extragonadal extracranial germ cell tumors (GCTs) (i.e., sacrococcygeal, mediastinal, and retroperitoneal) are more common in children than in adults.[1] Children with extragonadal malignant GCTs, particularly those with advanced-stage disease, have the highest risk of treatment failure for any GCT presentation.[2,3]

In a study of prognostic factors in pediatric extragonadal malignant GCTs, age older than 12 years was the most important prognostic factor. In a multivariate analysis, children aged 12 years or older with thoracic tumors had six times the risk of death compared with children younger than 12 years with primary nonthoracic tumors.[4]

Standard Treatment Options for Malignant Extragonadal Extracranial GCTs

Standard treatment options for malignant extragonadal extracranial GCTs include the following:

  1. Surgery and chemotherapy.
  2. Biopsy followed by chemotherapy and possibly surgery.

Outcome has improved remarkably since the advent of platinum-based chemotherapy and the use of a multidisciplinary treatment approach.[2,5] Complete resection before chemotherapy may be possible in some patients without major morbidity. 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.[5-8]

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 be primary resection, biopsy before chemotherapy, or no surgery (e.g., mediastinal primary tumor in a patient with a compromised airway and elevated tumor markers). An appropriate strategy may be biopsy at diagnosis followed by chemotherapy and subsequent surgery in selected patients who have residual masses after chemotherapy.

Stages I and II

Surgery and chemotherapy with four to six cycles of standard cisplatin, etoposide, and bleomycin (PEB) is one treatment alternative. Patients treated with this regimen have an overall survival (OS) outcome greater than 90%, suggesting that a reduction in therapy could be considered.[2,9] An alternative treatment option is surgery and chemotherapy with six cycles of carboplatin, etoposide, and bleomycin (JEB).[5]

Stages III and IV

A treatment option for stage III and stage IV disease is surgery and chemotherapy with four to six cycles of standard PEB. These patients have an OS outcome approaching 80% with this regimen.[2] Another treatment option is surgery and chemotherapy with six cycles of JEB, which has a similar OS to the PEB regimen.[5]

A Children's Oncology Group trial investigated the addition of cyclophosphamide to standard-dose PEB. The addition of cyclophosphamide was feasible and well tolerated at all dose levels, but there was no evidence that adding cyclophosphamide improves efficacy.[10]

Malignant Extragonadal Extracranial GCTs (Sacrococcygeal Sites)

Sacrococcygeal GCTs are common extragonadal tumors that occur in very young children, predominantly young females.[11] The tumors are usually diagnosed at birth, when large external lesions predominate (usually mature or immature teratomas), or later in the first years of life, when presacral lesions with higher malignancy rates predominate.[11]

Malignant sacrococcygeal tumors are usually very advanced at diagnosis; two-thirds of patients have locoregional disease, and metastases are present in 50% of patients.[7,12,13] Because of their advanced stage at presentation, the management of sacrococcygeal tumors requires a multimodal approach with platinum-based chemotherapy followed by delayed tumor resection.

Platinum-based therapies, with either cisplatin or carboplatin, are the cornerstone of treatment. The PEB regimen or the JEB regimen produces event-free survival (EFS) rates of 75% to 85% and OS rates of 80% to 90%.[7,8] Surgery may be facilitated by preoperative chemotherapy. In any patient with a sacrococcygeal GCT, resection of the coccyx is mandatory.[7,8]

Completeness of surgical resection is an important prognostic factor, as shown in the following circumstances:[7,8]

  • Resected tumors with negative microscopic margins—EFS rates of greater than 90%.
  • Resected tumors with microscopic margins—EFS rates of 75% to 85%.
  • Resected tumors with macroscopic residual disease—EFS rates of less than 40%.
Malignant Extragonadal Extracranial GCTs (Mediastinal)

Mediastinal GCTs account for 15% to 20% of malignant extragonadal extracranial GCTs in children.[5] The histology of mediastinal GCT is dependent on age, with teratomas predominating among infants and 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 GCTs who receive cisplatin-based chemotherapy have 5-year EFS and OS rates of 90%; however, metastatic mediastinal tumors have an EFS closer to 70%.[5,6]

Most mediastinal GCTs in adolescents and young adults occur in males, and 22% to 50% have cytogenetic changes consistent with Klinefelter syndrome.[14,15] The age of presentation is younger in patients with Klinefelter syndrome.[14,15] As with sacrococcygeal tumors, primary chemotherapy is usually necessary to facilitate surgical resection of mediastinal GCTs, and the completeness of resection is a very important prognostic indicator.[6,16] Survival rates for the older adolescent and young adult population with mediastinal tumors are generally less than 60%.[4,17-19]; [20][Level of evidence: 3iiA]

Patients with a malignant mediastinal primary tumor and extracranial metastases are at the highest risk of developing brain metastases and are monitored closely for signs and symptoms of central nervous system involvement.[21][Level of evidence: 3iiB] (Refer to the PDQ summary on Extragonadal Germ Cell Tumors Treatment for more information about the treatment of adult patients.)

Malignant Extragonadal Extracranial GCTs (Retroperitoneum)

Malignant GCTs located in the retroperitoneum or abdomen usually present in children before the age of 5 years; most tumors are of advanced stage and locally unresectable at diagnosis.[22] A limited biopsy followed by platinum-based chemotherapy to shrink tumor bulk can lead to complete tumor resection in most patients. Despite the advanced-stage disease in most patients, the 6-year EFS using PEB was 83% in the Pediatric Oncology Group/Children's Cancer Group intergroup study.[22]

Malignant Extragonadal Extracranial GCTs (Head and Neck Sites)

Although rare, benign and malignant GCTs can occur in the head and neck region, especially in infants. Often the airway is threatened. Surgery for nonmalignant tumors and surgery plus chemotherapy for malignant tumors can be curative.[23][Level of evidence: 3iiiDii]

Current Clinical Trials

Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with childhood extragonadal germ cell tumor. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI Web site.

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

  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.  [PUBMED Abstract]

  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.  [PUBMED Abstract]

  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.  [PUBMED Abstract]

  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.  [PUBMED Abstract]

  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.  [PUBMED Abstract]

  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.  [PUBMED Abstract]

  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.  [PUBMED Abstract]

  9. 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.  [PUBMED Abstract]

  10. Malogolowkin MH, Krailo M, Marina N, et al.: Pilot study of cisplatin, etoposide, bleomycin, and escalating dose cyclophosphamide therapy for children with high risk germ cell tumors: a report of the children's oncology group (COG). Pediatr Blood Cancer 60 (10): 1602-5, 2013.  [PUBMED Abstract]

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

  12. 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.  [PUBMED Abstract]

  13. 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.  [PUBMED Abstract]

  14. 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.  [PUBMED Abstract]

  15. 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.  [PUBMED Abstract]

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

  17. 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.  [PUBMED Abstract]

  18. 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.  [PUBMED Abstract]

  19. 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.  [PUBMED Abstract]

  20. Kang CH, Kim YT, Jheon SH, et al.: Surgical treatment of malignant mediastinal nonseminomatous germ cell tumor. Ann Thorac Surg 85 (2): 379-84, 2008.  [PUBMED Abstract]

  21. Göbel U, von Kries R, Teske C, et al.: Brain metastases during follow-up of children and adolescents with extracranial malignant germ cell tumors: risk adapted management decision tree analysis based on data of the MAHO/MAKEI-registry. Pediatr Blood Cancer 60 (2): 217-23, 2013.  [PUBMED Abstract]

  22. 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.  [PUBMED Abstract]

  23. Bernbeck B, Schneider DT, Bernbeck B, et al.: Germ cell tumors of the head and neck: report from the MAKEI Study Group. Pediatr Blood Cancer 52 (2): 223-6, 2009.  [PUBMED Abstract]

Treatment of Recurrent Malignant GCTs in Children

Only a small number of children and adolescents with extracranial germ cell tumors (GCTs) have a recurrence.[1,2] However, the approach to the treatment of recurrent disease and its success depend on the initial treatment regimen and on the response of the tumor to treatment.

Treatment Options for Recurrent Malignant GCTs in Children

There are no standard treatment options for recurrent pediatric GCTs. Information about ongoing clinical trials is available from the NCI Web site.

Treatment options for recurrent childhood malignant GCTs include the following:

  1. Surgery followed by chemotherapy.
  2. Chemotherapy followed by surgery and possibly radiation therapy.
  3. High-dose (HD) chemotherapy and hematopoietic stem cell rescue.
  4. Radiation therapy followed by surgery (for brain metastases).

The role for surgery in selected patients who have recurrent GCTs has not been established but should be considered.

Despite overall cure rates greater than 80%, children with extracranial GCTs who have disease recurrence after surgery and three-agent, platinum-based combination chemotherapy (cisplatin, etoposide, and bleomycin [PEB] or carboplatin, etoposide, and bleomycin [JEB]) have an unfavorable prognosis. Reports regarding the treatment and outcome of these children are based on small patient samples.[3]

Reports of salvage treatment strategies used in adult recurrent GCTs include larger numbers of patients, but the differences between children and adults regarding the location of the primary GCT site, pattern of relapse, and the biology of childhood GCTs may limit the applicability of adult salvage approaches to children. Treatments that have been explored in adults include the following:

  • In adults with recurrent GCTs, several chemotherapy combinations have achieved relatively good disease-free status.[4-9] A combination of paclitaxel and gemcitabine has demonstrated activity in adults with testicular GCTs who relapsed after HD chemotherapy and hematopoietic stem cell transplant (HSCT).[10]

Surgery followed by chemotherapy

If a tumor recurs, boys with stage I testicular disease originally treated with surgical resection and observation can usually undergo salvage therapy with further surgical excision and standard PEB or JEB chemotherapy.[11,12]

For stage I ovarian GCT patients originally treated with surgery and observation, several European studies have reported encouraging salvage rates with further surgical excision and chemotherapy.[13,14]

In a Children’s Oncology Group Trial (AGCT0521), patients who relapsed after PEB therapy received two cycles of paclitaxel, ifosfamide, and carboplatin. Study results are pending.

Chemotherapy followed by surgery and possibly radiation therapy

Most children with benign sacrococcygeal tumors experience recurrence with a malignant component at the primary tumor site. For these children, complete surgical resection of the recurrent tumor and coccyx (if not done originally) is the basis of salvage treatment; preoperative chemotherapy with PEB may assist the surgical resection. In patients who had a malignant sacrococcygeal tumor that recurred after PEB treatment, surgery and additional chemotherapy may be warranted; when a complete salvage resection is not achieved, postoperative local radiation therapy may be an option.[3]

HD chemotherapy and hematopoietic stem cell rescue

The role of HD chemotherapy and hematopoietic stem cell rescue for recurrent pediatric GCTs is not established, despite anecdotal reports. (Refer to the Autologous Hematopoietic Cell Transplantation section of the PDQ summary on Childhood Hematopoietic Cell Transplantation for more information about transplantation.) In one European series, 10 of 23 children with relapsed extragonadal GCTs achieved long-term disease-free survival (median follow-up, 66 months) after receiving HD chemotherapy with stem cell support.[15] Further study in children and adolescents is needed.

HD chemotherapy with autologous stem cell rescue has been explored as a treatment for adults with recurrent testicular GCTs. HD chemotherapy plus hematopoietic stem cell rescue has been reported to cure adult patients with relapsed testicular GCTs, even as third-line therapy and in cisplatin-refractory patients.[16] While several other studies support this approach,[17,18,10,19,20] others do not.[21,22] Salvage attempts using HD-chemotherapy regimens may be of little benefit if the patient is not clinically disease free at the time of HSCT.[16,23]

Radiation therapy followed by surgery (for brain metastases)

Patients with nongerminomatous brain metastases may respond to radiation therapy. In the German Maligne Keimzelltümoren (MAKEI) studies, radiation therapy and surgery for patients with brain metastases provided palliation and occasional long-term survival.[24,25][Level of evidence: 3iiiA]

Treatment Options Under Clinical Evaluation for Recurrent Malignant GCTs in Children

Other treatment options that are being investigated include the following:

  1. Hyperthermia. A single-institution study of 44 young people (aged 7 months to 21 years) with refractory or recurrent extracranial GCTs, using cisplatin/etoposide/ifosfamide and regional deep hyperthermia with or without surgery plus radiation therapy for residual tumor, showed a response rate of 86% in 35 patients for whom sufficient data were available. The 5-year event-free survival was 62%, and the 5-year overall survival was 72%.[26][Level of evidence: 3iiDi] However, regional hyperthermia facilities are limited and not readily available for children in the United States. Further study in children and adolescents is needed.

Current Clinical Trials

Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with recurrent childhood malignant germ cell tumor. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI Web site.

References
  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.  [PUBMED Abstract]

  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.  [PUBMED Abstract]

  3. 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.  [PUBMED Abstract]

  4. 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.  [PUBMED Abstract]

  5. 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.  [PUBMED Abstract]

  6. Hartmann JT, Einhorn L, Nichols CR, et al.: Second-line chemotherapy in patients with relapsed extragonadal nonseminomatous germ cell tumors: results of an international multicenter analysis. J Clin Oncol 19 (6): 1641-8, 2001.  [PUBMED Abstract]

  7. Mandanas RA, Saez RA, Epstein RB, et al.: Long-term results of autologous marrow transplantation for relapsed or refractory male or female germ cell tumors. Bone Marrow Transplant 21 (6): 569-76, 1998.  [PUBMED Abstract]

  8. Kondagunta GV, Bacik J, Sheinfeld J, et al.: Paclitaxel plus Ifosfamide followed by high-dose carboplatin plus etoposide in previously treated germ cell tumors. J Clin Oncol 25 (1): 85-90, 2007.  [PUBMED Abstract]

  9. Schmoll HJ, Kollmannsberger C, Metzner B, et al.: Long-term results of first-line sequential high-dose etoposide, ifosfamide, and cisplatin chemotherapy plus autologous stem cell support for patients with advanced metastatic germ cell cancer: an extended phase I/II study of the German Testicular Cancer Study Group. J Clin Oncol 21 (22): 4083-91, 2003.  [PUBMED Abstract]

  10. Einhorn LH, Brames MJ, Juliar B, et al.: Phase II study of paclitaxel plus gemcitabine salvage chemotherapy for germ cell tumors after progression following high-dose chemotherapy with tandem transplant. J Clin Oncol 25 (5): 513-6, 2007.  [PUBMED Abstract]

  11. 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.  [PUBMED Abstract]

  12. 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.  [PUBMED Abstract]

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

  14. 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.  [PUBMED Abstract]

  15. 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.  [PUBMED Abstract]

  16. Einhorn LH, Williams SD, Chamness A, et al.: High-dose chemotherapy and stem-cell rescue for metastatic germ-cell tumors. N Engl J Med 357 (4): 340-8, 2007.  [PUBMED Abstract]

  17. 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.  [PUBMED Abstract]

  18. 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.  [PUBMED Abstract]

  19. 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.  [PUBMED Abstract]

  20. Feldman DR, Sheinfeld J, Bajorin DF, et al.: TI-CE high-dose chemotherapy for patients with previously treated germ cell tumors: results and prognostic factor analysis. J Clin Oncol 28 (10): 1706-13, 2010.  [PUBMED Abstract]

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

  22. 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.  [PUBMED Abstract]

  23. 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.  [PUBMED Abstract]

  24. Göbel U, von Kries R, Teske C, et al.: Brain metastases during follow-up of children and adolescents with extracranial malignant germ cell tumors: risk adapted management decision tree analysis based on data of the MAHO/MAKEI-registry. Pediatr Blood Cancer 60 (2): 217-23, 2013.  [PUBMED Abstract]

  25. Göbel U, Schneider DT, Teske C, et al.: Brain metastases in children and adolescents with extracranial germ cell tumor - data of the MAHO/MAKEI-registry. Klin Padiatr 222 (3): 140-4, 2010.  [PUBMED Abstract]

  26. Wessalowski R, Schneider DT, Mils O, et al.: Regional deep hyperthermia for salvage treatment of children and adolescents with refractory or recurrent non-testicular malignant germ-cell tumours: an open-label, non-randomised, single-institution, phase 2 study. Lancet Oncol 14 (9): 843-52, 2013.  [PUBMED Abstract]

Changes to This Summary (06/06/2014)

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.

This summary was comprehensively reviewed and extensively revised.

This summary is written and maintained by the PDQ Pediatric Treatment Editorial Board, which is editorially independent of NCI. The summary reflects an independent review of the literature and does not represent a policy statement of NCI or NIH. More information about summary policies and the role of the PDQ Editorial Boards in maintaining the PDQ summaries can be found on the About This PDQ Summary and PDQ NCI's Comprehensive Cancer Database pages.

About This PDQ Summary



Purpose of This Summary

This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the treatment of childhood extracranial germ cell tumors. It is intended as a resource to inform and assist clinicians who care for cancer patients. It does not provide formal guidelines or recommendations for making health care decisions.

Reviewers and Updates

This summary is reviewed regularly and updated as necessary by the PDQ Pediatric Treatment Editorial Board, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).

Board members review recently published articles each month to determine whether an article should:

  • be discussed at a meeting,
  • be cited with text, or
  • replace or update an existing article that is already cited.

Changes to the summaries are made through a consensus process in which Board members evaluate the strength of the evidence in the published articles and determine how the article should be included in the summary.

The lead reviewers for Childhood Extracranial Germ Cell Tumors Treatment are:

  • Thomas A. Olson, MD (AFLAC Cancer Center and Blood Disorders Service of Children's Healthcare of Atlanta - Egleston Campus)
  • R. Beverly Raney, MD (Consultant)
  • Stephen J. Shochat, MD (St. Jude Children's Research Hospital)

Any comments or questions about the summary content should be submitted to Cancer.gov through the Web site's Contact Form. Do not contact the individual Board Members with questions or comments about the summaries. Board members will not respond to individual inquiries.

Levels of Evidence

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The preferred citation for this PDQ summary is:

National Cancer Institute: PDQ® Childhood Extracranial Germ Cell Tumors Treatment. Bethesda, MD: National Cancer Institute. Date last modified <MM/DD/YYYY>. Available at: http://cancer.gov/cancertopics/pdq/treatment/extracranial-germ-cell/HealthProfessional. Accessed <MM/DD/YYYY>.

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