Purpose of This PDQ summary
General Information
Histologic Classification

Mature Teratomas Immature Teratomas Malignant Germ Cell Tumors

Pediatric Germ Cell Tumor Biology

Testicular Germ Cell Tumors Ovarian Germ Cell Tumors Extragonadal Extracranial Germ Cell Tumors

Stage Information
Treatment Background for Childhood Extracranial Germ Cell Tumors
Treatment of Mature and Immature Teratomas in Children

Sacrococcygeal Tumors in Children         Standard treatment options Nonsacrococcygeal Teratomas in Children         Standard treatment options Current Clinical Trials

Treatment of Malignant Gonadal Germ Cell Tumors

Childhood Malignant Testicular Germ Cell Tumors         Testicular germ cell tumors in young boys         Treatment options under clinical evaluation for stages I through IV in patients aged 15 years and younger         Testicular germ cell tumors in adolescents and young adult males         Current Clinical Trials Treatment of Childhood Malignant Ovarian Germ Cell Tumors         Standard treatment options         Treatment options under clinical evaluation for stages I through III         Current Clinical Trials

Treatment of Childhood Malignant Extragonadal Germ Cell Tumor

Standard Treatment Options Treatment Options Under Clinical Evaluation Current Clinical Trials

Treatment of Recurrent Childhood Malignant Germ Cell Tumor

Standard Treatment Options Treatment Options Under Clinical Evaluation Current Clinical Trials

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Changes to This Summary (09/24/2008)
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Purpose of This PDQ 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. This summary is reviewed regularly and updated as necessary by the PDQ Pediatric Treatment Editorial Board.

Information about the following is included in this summary:

• Histologic classification.
• Stage information.
• Treatment options.

This summary is intended as a resource to inform and assist clinicians and other health professionals who care for pediatric cancer patients. It does not provide formal guidelines or recommendations for making health care decisions.

Some of the reference citations in this summary are accompanied by a level-of-evidence designation. These designations are intended to help readers assess the strength of the evidence supporting the use of specific interventions or approaches. The PDQ Pediatric and Adult Treatment Editorial Boards use a formal evidence ranking system in developing their level-of-evidence designations. Based on the strength of the available evidence, treatment options are described as either “standard” or “under clinical evaluation.” These classifications should not be used as a basis for reimbursement determinations.

This summary is also available in a patient version, which is written in less technical language, and in Spanish.

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General Information

The National Cancer Institute (NCI) provides the PDQ pediatric cancer treatment information summaries as a public service to increase the availability of evidence-based cancer information to health professionals, patients, and the public.

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

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

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

Childhood extracranial germ cell tumors (GCT) are rare in children younger than 15 years, accounting for approximately 3% of cancer cases in this age group.[2,3] In the fetal/neonatal age group, the majority of extracranial GCT that occur 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 due to hydrops fetalis and premature delivery.[4,5] Extracranial GCT (particularly testicular GCT) are much more common among adolescents aged 15 to 19 years, representing approximately 14% of cancer diagnoses in this age group. The distribution of extracranial GCT by 5-year age group and by gender is shown in Table 1 below.

Germ cell tumors develop from primordial germ cells, which migrate during embryogenesis from the yolk sac through the mesentery to the gonads.[6] Childhood extracranial GCT can be divided into gonadal and extragonadal types. Most childhood extragonadal GCT arise in midline sites (i.e., sacrococcygeal, mediastinal, retroperitoneal), and the midline location may represent aberrant embryonic migration of the primordial germ cells.

The histologic and genetic properties of these tumors are heterogeneous and vary by primary tumor site and the sex and age of the patient.[7,8] Histologically identical GCT that arise in younger children have different biological characteristics from those that arise in adolescents and young adults.

References

1. Guidelines for the pediatric cancer center and role of such centers in diagnosis and treatment. American Academy of Pediatrics Section Statement Section on Hematology/Oncology. Pediatrics 99 (1): 139-41, 1997.  [PUBMED Abstract]
   
   
2. Miller RW, Young JL Jr, Novakovic B: Childhood cancer. Cancer 75 (1 Suppl): 395-405, 1995.  [PUBMED Abstract]
   
   
3. Ries LA, Smith MA, Gurney JG, et al., eds.: Cancer incidence and survival among children and adolescents: United States SEER Program 1975-1995. Bethesda, Md: National Cancer Institute, SEER Program, 1999. NIH Pub.No. 99-4649. Also available online. Last accessed April 19, 2007. 
   
   
4. Isaacs H Jr: Perinatal (fetal and neonatal) germ cell tumors. J Pediatr Surg 39 (7): 1003-13, 2004.  [PUBMED Abstract]
   
   
5. 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]
   
   
6. Dehner LP: Gonadal and extragonadal germ cell neoplasia of childhood. Hum Pathol 14 (6): 493-511, 1983.  [PUBMED Abstract]
   
   
7. Hawkins EP: Germ cell tumors. Am J Clin Pathol 109 (4 Suppl 1): S82-8, 1998.  [PUBMED Abstract]
   
   
8. 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]
   
   

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Histologic Classification

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

Mature teratomas generally occur in the ovary or at extragonadal locations and are the most common histological subtype of childhood GCT.[1-3] These teratomas usually contain well-differentiated tissues from the ectodermal, mesodermal, and endodermal germ cell layers, and any tissue type may be found among the tumor. Mature teratomas are benign, though some mature and immature teratomas may secrete enzymes or hormones, including insulin, growth hormone, androgens, prolactin, and vasopressin.[4-6]

Immature teratomas also contain tissues from all three germ cell layers, but immature tissues, primarily neuroepithelial, are present. Immature teratomas can be graded from 0 to 3 based on the amount of immature tissue found in the tumor specimen.[7] Tumors of higher grade are more likely to have foci of yolk sac tumor.[8] 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.[8,9]

GCT outside the central nervous system contain frankly malignant tissues of germ cell origin, or rarely, tissues of somatic origin. Isolated malignant elements may constitute a small fraction of a predominantly immature teratoma.[9,10] Malignant germ cell elements of children, adolescents, and young adults can broadly be classified by location (see Tables 2 and 3).

 [Note: Modified from (Perlman EJ and Hawkins EP. Pediatric and Developmental Pathology 1, 328-335, 1998.)]

 [Note: Modified from (Perlman EJ and Hawkins EP. Pediatric and Developmental Pathology 1, 328-335, 1998.)]

Yolk sac tumors produce alpha-fetoprotein (AFP), while germinomas (seminomas and dysgerminomas), and especially choriocarcinomas, produce beta-human chorionic gonadotropin, resulting in the elevated serum levels of these substances. Most children with malignant GCT will have a component of yolk sac tumor and have elevations of AFP,[11,12] which is serially monitored during treatment to help assess response to therapy.[9-11]

Adolescents and young adults present with more germinomas (testicular and mediastinal seminomas in males and ovarian dysgerminomas in females). These tumors are usually treated with chemotherapy but are also sensitive to radiation therapy.

References

1. Göbel U, Calaminus G, Engert J, et al.: Teratomas in infancy and childhood. Med Pediatr Oncol 31 (1): 8-15, 1998.  [PUBMED Abstract]
   
   
2. Rescorla FJ: Pediatric germ cell tumors. Semin Surg Oncol 16 (2): 144-58, 1999.  [PUBMED Abstract]
   
   
3. 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]
   
   
4. 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]
   
   
5. 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]
   
   
6. 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]
   
   
7. 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]
   
   
8. 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]
   
   
9. 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]
   
   
10. 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]
    
    
11. 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]
    
    
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]
    
    

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Pediatric Germ Cell Tumor Biology

The following paragraphs describe the biologically distinct subtypes of germ cell tumors (GCT)found in children and adolescents. It should be emphasized that very few pediatric GCT specimens have been analyzed to date. Biologic distinctions between GCT in children versus adults may not be absolute.[1]

• Children: These GCT typically present during early childhood. The tumors commonly present with yolk sac tumor (endodermal sinus tumor) histology, are generally diploid or tetraploid, and may lack the isochromosome of the short arm of chromosome 12 that characterizes testicular cancer in young adults.[1-5] 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.[4-6]



• Adolescents and young adults: These tumors typically possess an isochromosome of the short arm of chromosome 12 [7-10] and are aneuploid.[2,10] Testicular cancer is broadly divided into seminomatous and nonseminomatous tumors, which is an important distinction for treatment planning because seminomas are more sensitive to radiation therapy. Although adolescent testicular germ cell patients may be best treated at pediatric oncology centers, the treatment regimens for adolescents older than 14 years follow regimens used in adults. (Refer to the PDQ summary on Testicular Cancer Treatment for more information.)

Ovarian GCT occur primarily in adolescent and young adult females. While the majority of ovarian GCT are benign mature teratomas, a heterogeneous group of malignant GCT occur in females, including immature teratomas, dysgerminomas, yolk sac tumors, and mixed GCT. Patients with pediatric ovarian GCT have an excellent prognosis with one series of 66 patients followed over 44 years, reporting recurrence and mortality rates of 4.5% and 3%, respectively.[11] The malignant ovarian GCT commonly show increased copies of the short arm of chromosome 12.[12] (Refer to the PDQ summary on Ovarian Germ Cell Tumor Treatment for more information.)

• Children: These tumors typically present at birth or during early childhood. The majority of these tumors are benign teratomas occurring in the sacrococcygeal region, and hence SEER areas do not report them.[13,14] Malignant yolk sac tumor histology occurs in a minority of these tumors, however, with cytogenetic abnormalities similar to those observed for tumors occurring in the testes of young males.[3-6]



• Older children, adolescents, and young adults: The mediastinum is the most common primary site for extragonadal GCT in older children and adolescents.[15] Mediastinal GCT in children younger than 8 years share the same genetic gains and losses as sacrococcygeal and testicular tumors in young children.[16-18] The gain in chromosome 12p has been reported in mediastinal tumors in children aged 8 years and older.[18,19]

Very little is known about the potential genetic or environmental factors associated with childhood extracranial GCT. Patients with Klinefelter syndrome [20-22] appear to be at increased risk for mediastinal GCT, while patients with Swyer syndrome [23,24] appear to be at increased risk for gonadoblastomas and germinomas.

References

1. 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]
   
   
2. 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]
   
   
3. Silver SA, Wiley JM, Perlman EJ: DNA ploidy analysis of pediatric germ cell tumors. Mod Pathol 7 (9): 951-6, 1994.  [PUBMED Abstract]
   
   
4. 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]
   
   
5. 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]
   
   
6. 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]
   
   
7. 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]
   
   
8. 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]
   
   
9. 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]
   
   
10. 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]
    
    
11. 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]
    
    
12. 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]
    
    
13. 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]
    
    
14. 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]
    
    
15. Rescorla FJ: Pediatric germ cell tumors. Semin Surg Oncol 16 (2): 144-58, 1999.  [PUBMED Abstract]
    
    
16. 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]
    
    
17. 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]
    
    
18. 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]
    
    
19. 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]
    
    
20. 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]
    
    
21. 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]
    
    
22. Lachman MF, Kim K, Koo BC: Mediastinal teratoma associated with Klinefelter's syndrome. Arch Pathol Lab Med 110 (11): 1067-71, 1986.  [PUBMED Abstract]
    
    
23. 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]
    
    
24. 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]
    
    

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Stage Information

As with other childhood solid tumors, stage directly impacts the outcome of patients with malignant germ cell tumors (GCT).[1-3] The most commonly used staging system in the United States is described below.[4] Retroperitoneal lymph node dissection (RPLND) has not been required in pediatric germ cell trials to stage males younger than 15 years. Data on adolescent males with testicular GCT are limited. RPLND 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 GCT.

• Stage I: localized disease, completely resected without microscopic disease in the resected margins or in regional lymph nodes.



• Stage II: microscopic residual disease, capsular invasion, or microscopic lymph node involvement.



• Stage III: gross residual disease, gross lymph node involvement (>2 cm), or cytologic evidence of tumor cells in ascites or pleural fluid.



• Stage IV: disseminated disease involving lungs, liver, brain, bone, distant nodes, or other sites.

Another staging system used most frequently by gynecologic oncologists is the International Federation of Gynecologic Oncologists (FIGO) staging system, which is based on an adequate staging operation at the time of diagnosis.[6] (Refer to the PDQ summary on Ovarian Germ Cell Tumor 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.
• IIIC: gross deposits larger than 2 cm or positive nodes.

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

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]
   
   

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Treatment Background for Childhood Extracranial Germ Cell Tumors

Prior to effective chemotherapy, children with extracranial malignant germ cell tumors (GCT) had 3-year survival rates of 15% to 20% with surgery and radiation therapy,[1-3] though boys with localized testicular tumors did well with surgical resection.[4,5] The outcome for most children and adolescents with extracranial GCT is now favorable when appropriate treatment is provided.[6] Prognosis and appropriate treatment depend on factors such as histology (e.g., seminomatous vs. nonseminomatous), age (young children vs. adolescents), stage of disease, and primary site.[7,8] To maximize the likelihood of long-term survival while minimizing the likelihood of treatment-related long-term sequelae (e.g., secondary leukemias, infertility, hearing loss, renal dysfunction), it is important that children with extracranial malignant GCT be cared for at pediatric cancer centers with experience treating these rare tumors. Based on clinical factors, appropriate treatment may involve: surgical resection followed by careful monitoring for disease recurrence; diagnostic tumor biopsy and preoperative platinum-based chemotherapy followed by definitive tumor resection; or initial surgical resection followed by a platinum-based chemotherapy.[9] For patients with completely resected immature teratomas at any location (even those with malignant elements) and patients with completely resected (stage I) gonadal tumors, additional therapy may not be necessary; however, close follow-up is important.[10] 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.

Cisplatin-based chemotherapy has dramatically improved the outcome for children with extracranial GCT, with 5-year survival rates of more than 90%.[11-14] The standard chemotherapy regimen for both adults and children with malignant nonseminomatous GCT includes cisplatin, etoposide, and bleomycin (PEB), though children receive fewer doses of bleomycin than adults.[11,12,15-17] The combination of carboplatin, etoposide, and bleomycin (JEB) has undergone clinical investigation in the United Kingdom in children younger than 16 years and is reported to have a similar event-free survival (EFS) by site and stage as PEB;[13,18] however, these were not randomized trials. The use of JEB appears to be associated with less ototoxicity and nephrotoxicity than PEB.[13] Adult studies have substituted standard-dose carboplatin for cisplatin in combination with etoposide alone and in combination with etoposide and low-dose bleomycin,[19] but the carboplatin regimens demonstrated inferior EFS and overall survival compared with cisplatin-containing therapy among patients with malignant GCT. No randomized comparison of PEB versus JEB has been conducted in children.  [Note: See Table 4 for pediatric PEB and JEB chemotherapy dosing schedules.]

The current approach to the management of extracranial GCT has been informed by the results of two intergroup studies conducted by the Children's Cancer Group (CCG) and the Pediatric Oncology Group (POG).[10-12] These studies explored the use of PEB for the treatment of localized gonadal GCT [11]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 GCT.[12]

The intensification of cisplatin in the HD-PEB regimen provided some improvement in EFS; however, the use of HD-PEB was associated with a significantly higher incidence and severity of ototoxicity and nephrotoxicity. In a subsequent study, amifostine was not effective in preventing hearing loss in patients who received HD-PEB.[20]

 [Note: Adult doses of PEB and JEB chemotherapy are different than pediatric doses.]

Table 5 provides an overview of standard treatment options for extracranial GCT of children. Treatment requires a multidisciplinary approach with various surgical subspecialties and pediatric oncologists. Specific details of treatment by primary site and clinical condition are described in subsequent sections.

References

1. Kurman RJ, Norris HJ: Endodermal sinus tumor of the ovary: a clinical and pathologic analysis of 71 cases. Cancer 38 (6): 2404-19, 1976.  [PUBMED Abstract]
   
   
2. Chretien PB, Milam JD, Foote FW, et al.: Embryonal adenocarcinomas (a type of malignant teratoma) of the sacrococcygeal region. Clinical and pathologic aspects of 21 cases. Cancer 26 (3): 522-35, 1970.  [PUBMED Abstract]
   
   
3. Billmire DF, Grosfeld JL: Teratomas in childhood: analysis of 142 cases. J Pediatr Surg 21 (6): 548-51, 1986.  [PUBMED Abstract]
   
   
4. Hawkins EP, Finegold MJ, Hawkins HK, et al.: Nongerminomatous malignant germ cell tumors in children. A review of 89 cases from the Pediatric Oncology Group, 1971-1984. Cancer 58 (12): 2579-84, 1986.  [PUBMED Abstract]
   
   
5. Marina N, Fontanesi J, Kun L, et al.: Treatment of childhood germ cell tumors. Review of the St. Jude experience from 1979 to 1988. Cancer 70 (10): 2568-75, 1992.  [PUBMED Abstract]
   
   
6. Toner GC: Early identification of therapeutic failure in nonseminomatous germ cell tumors by assessing serum tumor marker decline during chemotherapy: still not ready for routine clinical use. J Clin Oncol 22 (19): 3842-5, 2004.  [PUBMED Abstract]
   
   
7. 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]
   
   
8. 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]
   
   
9. Rescorla FJ: Pediatric germ cell tumors. Semin Surg Oncol 16 (2): 144-58, 1999.  [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. 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]
    
    
12. 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]
    
    
13. 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]
    
    
14. 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]
    
    
15. 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]
    
    
16. 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]
    
    
17. 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]
    
    
18. 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]
    
    
19. 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]
    
    
20. Marina N, Chang KW, Malogolowkin M, et al.: Amifostine does not protect against the ototoxicity of high-dose cisplatin combined with etoposide and bleomycin in pediatric germ-cell tumors: a Children's Oncology Group study. Cancer 104 (4): 841-7, 2005.  [PUBMED Abstract]
    
    

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Treatment of Mature and Immature Teratomas in Children

Sacrococcygeal Tumors in Children

Standard treatment options

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

After successful resection, neonates diagnosed with benign mature and immature teratomas are observed with close follow-up exams and serial serum alpha-fetoprotein (AFP) determinations for several years to ensure that the expected physiological normalization of AFP levels occurs and to facilitate early detection of tumor relapse.[7] A significant rate of recurrence among these benign tumors has been reported by several groups, ranging from 10% to 21%, with most relapses occurring within 3 years of resection.[1,7-9] While there is no standard follow-up schedule, follow-up should include scans and tumor markers for 3 years. Importantly, 43% to 50% of these recurrent tumors will be malignant and require adjuvant chemotherapy. Complete resection of the coccyx is vital to minimize the likelihood of recurrent tumor.[10] However, one study reported that 11/12 patients with microscopic residual benign immature teratoma had no recurrence.[11] Long-term survivors should be followed for complications of extensive surgery, which include, constipation, fecal and urinary incontinence, and psychologically unacceptable cosmetic scars.[12]

Mature and immature teratomas arise primarily in the sacrococcygeal region of neonates and young children, and in the ovaries of pubescent girls. These tumors are also less commonly found in the testicular region of boys younger than 4 years, the mediastinum of adolescents, and other sites.[2,10,13] Mature teratoma and epidermoid cyst in the prepubertal testis are relatively common benign lesions and may be amenable to testis-sparing surgery.[14] Children with mature teratomas, including mature teratomas of the mediastinum, can be treated with surgery and observation with an excellent prognosis.[2,15] In a review of 153 children with nontesticular mature teratoma, the 6-year relapse-free survival for completely resected disease was 96% versus 55% for incomplete disease resection.[10]

In infants and young children, immature teratomas have benign clinical behavior; [8,16,17] however, in adults immature teratomas (primarily ovarian) reportedly have an aggressive clinical behavior [18] requiring surgery and chemotherapy. The benefit of adjuvant chemotherapy for children was questioned in a study by the Pediatric Oncology Group and Children's Cancer Group that evaluated the use of surgical resection followed by careful observation for patients with immature teratomas. Surgery alone was curative for most children and adolescents with resected ovarian immature teratoma of any grade, even when elevated levels of serum AFP or microscopic foci of yolk sac tumor were present. The study demonstrated a 3-year event-free survival of 97.8%, 100%, and 80% for patients with ovarian, testicular, and extragonadal tumors, respectively.[19] It is important to emphasize that the number of pediatric patients with residual teratomas and immature teratomas is very small. There may be a role for surgical removal of residual benign lesions.

Check for U.S. clinical trials from NCI's PDQ Cancer Clinical Trials Registry 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, 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]
   
   
2. Rescorla FJ: Pediatric germ cell tumors. Semin Surg Oncol 16 (2): 144-58, 1999.  [PUBMED Abstract]
   
   
3. Altman RP, Randolph JG, Lilly JR: Sacrococcygeal teratoma: American Academy of Pediatrics Surgical Section Survey-1973. J Pediatr Surg 9 (3): 389-98, 1974.  [PUBMED Abstract]
   
   
4. Ablin AR, Krailo MD, Ramsay NK, et al.: Results of treatment of malignant germ cell tumors in 93 children: a report from the Childrens Cancer Study Group. J Clin Oncol 9 (10): 1782-92, 1991.  [PUBMED Abstract]
   
   
5. Marina N, Fontanesi J, Kun L, et al.: Treatment of childhood germ cell tumors. Review of the St. Jude experience from 1979 to 1988. Cancer 70 (10): 2568-75, 1992.  [PUBMED Abstract]
   
   
6. Baranzelli MC, Kramar A, Bouffet E, et al.: Prognostic factors in children with localized malignant nonseminomatous germ cell tumors. J Clin Oncol 17 (4): 1212, 1999.  [PUBMED Abstract]
   
   
7. Huddart SN, Mann JR, Robinson K, et al.: Sacrococcygeal teratomas: the UK Children's Cancer Study Group's experience. I. Neonatal. Pediatr Surg Int 19 (1-2): 47-51, 2003.  [PUBMED Abstract]
   
   
8. Gonzalez-Crussi F, Winkler RF, Mirkin DL: Sacrococcygeal teratomas in infants and children: relationship of histology and prognosis in 40 cases. Arch Pathol Lab Med 102 (8): 420-5, 1978.  [PUBMED Abstract]
   
   
9. 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]
   
   
10. Göbel U, Calaminus G, Engert J, et al.: Teratomas in infancy and childhood. Med Pediatr Oncol 31 (1): 8-15, 1998.  [PUBMED Abstract]
    
    
11. 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]
    
    
12. 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]
    
    
13. Pinkerton CR: Malignant germ cell tumours in childhood. Eur J Cancer 33 (6): 895-901; discussion 901-2, 1997.  [PUBMED Abstract]
    
    
14. 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]
    
    
15. 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]
    
    
16. Valdiserri RO, Yunis EJ: Sacrococcygeal teratomas: a review of 68 cases. Cancer 48 (1): 217-21, 1981.  [PUBMED Abstract]
    
    
17. 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]
    
    
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. 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]
    
    

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Treatment of Malignant Gonadal Germ Cell Tumors

Childhood Malignant Testicular Germ Cell Tumors

Testicular germ cell tumors in young boys

Testicular GCT in children occur almost exclusively in boys younger than 4 years.[1,2] The initial 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] Retroperitoneal dissection of lymph nodes is not beneficial in the staging of testicular GCT in young boys. Computed tomography or magnetic resonance imaging evaluation, with the additional information provided by elevated tumor markers, appears adequate for staging.[3,4] Therefore, there is no reason to risk the potential morbidity (e.g., impotence and retrograde ejaculation) related to this surgery.[6,7]

A Children’s Cancer Group/Pediatric Oncology Group clinical trial evaluated surgery followed by observation for boys with stage I testicular tumors. This treatment strategy resulted in a 6-year event-free survival (EFS) of 82%; those boys who developed recurrent disease were salvaged by standard-dose cisplatin, etoposide, and bleomycin (PEB), with a 6-year survival of 100%.[3,4] Boys with stage II or recurrent stage I disease were treated with four cycles of standard-dose PEB, with a resulting 100% 6-year survival.[8] Boys and adolescents with stages III and IV testicular tumors were treated with surgical resection followed by four courses of standard or high-dose (HD) PEB therapy. The 6-year survival outcome for males younger than 15 years with stage III and IV tumors was 100%, with 6-year EFS of 100% and 94%, respectively.[9] The use of HD-PEB therapy did not improve the outcome for these boys but did cause increased incidence of ototoxicity. Excellent outcomes for boys with testicular GCT using surgery and observation for stage I tumors and carboplatin, etoposide, and bleomycin (JEB) and other cisplatin-containing chemotherapy regimens for stage II, III, and IV tumors have also been reported by European investigators.[6,10] Thus, surgery followed by standard-dose platinum-based chemotherapy is the recommended approach for stages II, III, and IV testicular GCT in children younger than 15 years.

Surgery: The role of surgery at diagnosis for GCT is age- and site-dependent and must be individualized. Depending on the clinical setting, the appropriate surgical approach may range from no surgery, to biopsy, to primary resection. In some cases, an appropriate strategy is biopsy at diagnosis followed by subsequent surgery in selected patients who have residual masses following chemotherapy.

Stage I

• Surgery and close follow-up observation are indicated to document that a normalization of the tumor markers occurs after resection.[10,3]

Stages II through IV

• Surgery and treatment with four to six courses of standard PEB. These patients have an overall survival outcome greater than 90% with this regimen, suggesting that a reduction in therapy could be considered.[8,9]



• Surgery and treatment with six courses of JEB.[10]

The following are examples of national and/or institutional clinical trials that are currently being conducted. Information about ongoing clinical trials is available from the NCI Web site.

• The Children’s Oncology Group trial, AGCT0132, is currently studying the effect of surgery and observation (stage I) and decreased chemotherapy for stage II-IV (three courses of PEB over 3 days) with the goal of decreasing the duration and cumulative doses of chemotherapy (25% dose reduction) and lessening the cost of treatment. Strict guidelines for the evaluation and follow-up of the "observation" patients are mandated to ensure that disease recurrence or regrowth is detected early.



• A United Kingdom Childhood Cancer Group trial is also studying the reduction of total JEB cycles.

Because the biology of testicular GCT among adolescents and young adult males is different from that of testicular tumors arising in infants and young boys, the treatment guidelines described above for young boys may not be strictly applicable to the adolescent males. In particular, the use of retroperitoneal lymph node dissection may play a crucial role both in early stage testicular GCT [11] and for residual disease after chemotherapy for the treatment of metastatic GCT.[12,13]

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

Check for U.S. clinical trials from NCI's PDQ Cancer Clinical Trials Registry that are now accepting patients with childhood malignant testicular germ cell tumor and 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.

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

For stage I ovarian GCT and immature teratomas, cure can usually be achieved by unilateral salpingo-oophorectomy, conserving the uterus and opposite ovary, and close follow-up observation.[10,14-17] Chemotherapy can be implemented if tumor markers do not normalize or if tumors recur.

While advanced-stage ovarian dysgerminomas similar to testicular seminomas are highly curable with surgery and radiation therapy, the effects on growth and fertility in these young patients [18,19] make chemotherapy a more attractive adjunct to surgery.[20,21] 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.[17] This approach results in a high rate of cure and the maintenance of menstrual function and fertility in most patients with dysgerminomas.[20,22]

For ovarian malignant GCT other than dysgerminomas or immature teratoma, treatment generally involves surgical resection and adjuvant chemotherapy.[23,24] Platinum-based chemotherapy regimens such as cisplatin, etoposide, and bleomycin (PEB) or the carboplatin, etoposide, and bleomycin (JEB) have been used successfully in children,[8-10,14] and PEB is a common regimen in young women with ovarian GCT.[25,26] This approach results in a high rate of cure and the maintenance of menstrual function and fertility in most patients with nondysgerminomas.[24]

A multidisciplinary approach is essential for treatment of ovarian GCT. Various surgical subspecialties and the pediatric oncologist must be involved in clinical decisions. The reproductive surgical approach for pediatric GCT is often guided by the hope that function can be preserved. In a completed pediatric intergroup trial, pediatric patients with ovarian GCT (stages I-IV) had excellent survival with PEB and conservative surgery, rather than the strict guidelines proposed originally in the study.[27] The role of laparoscopy in children with ovarian GCT has not been well studied.

Surgery: The role