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NCI/PDQ^® Health professionals: Childhood Extracranial Germ Cell Tumors Treatment (PDQ®)

National Cancer Institute
Ultima Vez Modificado: 27 de noviembre del 2012

TABLE OF CONTENTS

• General Information About Childhood Extracranial Germ Cell Tumors (GCTs)

• Histologic Classification of Childhood Extracranial GCTs
  • Mature Teratomas
  • Immature Teratomas
  • Malignant GCTs

• Pediatric GCT Biology
  • Testicular GCTs
  • Ovarian GCTs
  • Extragonadal Extracranial GCTs

• Stage Information for Childhood Extracranial GCTs
  • Nonseminoma Testicular GCT Staging From Children's Oncology Group
  • Ovarian GCT Staging From Children's Oncology Group
  • Ovarian GCT Staging From FIGO
  • Extragonadal Extracranial GCT Staging From Children's Oncology Group

• Treatment Background for Childhood Extracranial GCTs
  • Non-GCT Malignant Elements

• 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 GCTs
  • Childhood Malignant Testicular GCTs
    • Testicular GCTs in young boys
      • Standard treatment options
      • Treatment options under clinical evaluation for stages I through IV in patients younger than 15 years
    • Testicular GCTs in adolescents and young adult males
    • Current Clinical Trials
  • Childhood Malignant Ovarian GCT
    • Standard treatment options
    • Treatment options under clinical evaluation for stages I through III
    • Current Clinical Trials

• Treatment of Childhood Malignant Extragonadal GCTs
  • Standard Treatment Options
  • Treatment Options Under Clinical Evaluation
  • Current Clinical Trials

• Treatment of Recurrent Childhood Malignant GCTs
  • Standard Treatment Options
  • Current Clinical Trials

• Changes to This Summary (11/27/2012)

• About This PDQ® Summary
  • Purpose of This Summary
  • Reviewers and Updates
  • Levels of Evidence
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General Information About Childhood Extracranial Germ Cell Tumors (GCTs)

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Fortunately, cancer in children and adolescents is rare, although the overall incidence of childhood cancer has been slowly increasing 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 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 and Palliative 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. 2 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.

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. For extragonadal GCT, the 5-year survival rate from 1979 to 2002 increased from 42% to 83% for children younger than 15 years. 1 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 GCTs are rare in children younger than 15 years, accounting for approximately 3% of cancer cases in this age group. 3 4 5 In the fetal/neonatal age group, the majority of extracranial GCTs 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 rate due to hydrops fetalis and premature delivery. 6 7 Extracranial GCTs (particularly testicular GCTs) 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 GCTs by 5-year age group and by gender is shown in Table 1 below.

Table 1. Extracranial Germ Cell Tumors by Age Group and Gender^a

^aRates are per million children from 1986 to 1995 for the nine SEER regions plus Los Angeles.

	04 years	59 years	1014 years	1519 years
Males	7	0.3	1.4	31
Females	5.8	2.4	7.8	25.3

GCTs develop from primordial germ cells, which migrate during embryogenesis from the yolk sac through the mesentery to the gonads. 8 9 Childhood extracranial GCTs can be divided into gonadal and extragonadal types. 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.

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

References:

1. Smith MA, Seibel NL, Altekruse SF, et al.: Outcomes for children and adolescents with cancer: challenges for the twenty-first century. J Clin Oncol 28 (15): 2625-34, 2010. [PUBMED Abstract]
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. Miller RW, Young JL Jr, Novakovic B: Childhood cancer. Cancer 75 (1 Suppl): 395-405, 1995. [PUBMED Abstract]
4. 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. [PUBMED Abstract]
5. 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]
6. Isaacs H Jr: Perinatal (fetal and neonatal) germ cell tumors. J Pediatr Surg 39 (7): 1003-13, 2004. [PUBMED Abstract]
7. 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]
8. Dehner LP: Gonadal and extragonadal germ cell neoplasia of childhood. Hum Pathol 14 (6): 493-511, 1983. [PUBMED Abstract]
9. 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]
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]

Histologic Classification of Childhood Extracranial GCTs

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

Mature Teratomas

Mature teratomas usually occur in the ovary or at extragonadal locations and are the most common histological subtype of childhood GCT. 1 2 3 These 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, though some mature and immature teratomas may secrete enzymes or hormones, including insulin, growth hormone, androgens, prolactin, and vasopressin. 4 5 6

Immature Teratomas

Immature teratomas contain tissues from all three germ cell layers, but immature tissues, primarily neuroepithelial, are also present. Immature teratomas are graded from 0 to 3 based on the amount of immature neural 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

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. 9 10 Malignant germ cell elements of children, adolescents, and young adults can broadly be classified by location (see Tables 2 and 3).

Table 2. Histology of Malignant Germ Cell Tumors in Young Children^a

^aModified from Perlman et al.

Malignant Germ Cell Elements	Location
Yolk sac tumor	E, O, T
Dysgerminoma (rare in young children)	O
E = extragonadal; O = ovarian; T = testicular.
11

Table 3. Histology of Malignant Germ Cell Tumors in Adolescents and Young Adults^a

^aModified from Perlman et al.

Malignant Germ Cell Elements	Location
Seminoma	T
Dysgerminoma	O
Germinoma	E
Yolk sac tumor	E, O, T
Choriocarcinoma	E, O, T
Embryonal carcinoma	T
Mixed germ cell tumors	E, O
E = extragonadal; O = ovarian; T = testicular.
11

Yolk sac tumors produce alpha-fetoprotein (AFP), while germinomas (seminomas and dysgerminomas), and especially choriocarcinomas, produce beta-human chorionic gonadotropin, 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, 12 13 which is serially monitored during treatment to help assess response to therapy. 9 10 12

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. They are also sensitive to radiation therapy, but radiation is rarely recommended. Radiation therapy and surgery for the patient with brain metastases may provide palliation and occasionally, long-term survival. 14[Level of evidence: 3iiiA]

References:

1. Gíbel 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, Gíbel 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. Gíbel 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. Perlman EJ, Hawkins EP: Pediatric germ cell tumors: protocol update for pathologists. Pediatr Dev Pathol 1 (4): 328-35, 1998 Jul-Aug. [PUBMED Abstract]
12. 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]
13. 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]
14. Gíbel 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]

Pediatric GCT Biology

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The following paragraphs describe the biologically distinct subtypes of GCTs 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 versus adults may not be absolute. 1 2

Testicular GCTs

• Children: These GCTs typically present during early childhood. The tumors are commonly composed of pure yolk sac tumor (also known as endodermal sinus tumor), are generally diploid or tetraploid, and usually lack the isochromosome of the short arm of chromosome 12 that characterizes testicular cancer in young adults. 1 3 4 5 6 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. 5 6 7
• Adolescents and young adults: These tumors typically possess an isochromosome of the short arm of chromosome 12 8 9 10 11 and are aneuploid. 3 11 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 GCTs

Ovarian GCTs occur primarily in adolescent and young adult females. While the majority of ovarian GCTs are benign mature teratomas, a heterogeneous group of malignant GCTs occur in females, including immature teratomas, dysgerminomas, yolk sac tumors, and mixed GCTs. Patients with pediatric ovarian GCTs have an excellent prognosis. One series of 66 patients followed over 44 years reported recurrence and mortality rates of 4.5% and 3%, respectively. 12 The malignant ovarian GCT commonly shows increased copies of the short arm of chromosome 12. 13 (Refer to the PDQ® summary on Ovarian Germ Cell Tumors Treatment for more information.)

Extragonadal Extracranial GCTs

• 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 data do not include them. 14 15 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. 4 5 6 7
• Older children, adolescents, and young adults: The mediastinum is the most common primary site for extragonadal GCTs in older children and adolescents. 16 Mediastinal GCTs in children younger than 8 years share the same genetic gains and losses as sacrococcygeal and testicular tumors in young children. 17 18 19 The gain in chromosome 12p has been reported in mediastinal tumors in children aged 8 years and older. 19 20

There is very little data about the potential genetic or environmental factors associated with childhood extracranial GCTs. Patients with Klinefelter syndrome 21 22 23 are at increased risk for mediastinal GCTs, while patients with Swyer syndrome 24 25 are 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. 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]
3. 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]
4. Silver SA, Wiley JM, Perlman EJ: DNA ploidy analysis of pediatric germ cell tumors. Mod Pathol 7 (9): 951-6, 1994. [PUBMED Abstract]
5. 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]
6. 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]
7. 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]
8. 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]
9. 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]
10. 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]
11. 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]
12. 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]
13. 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]
14. 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]
15. 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]
16. Rescorla FJ: Pediatric germ cell tumors. Semin Surg Oncol 16 (2): 144-58, 1999. [PUBMED Abstract]
17. 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]
18. 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]
19. 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]
20. 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]
21. 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]
22. 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]
23. Lachman MF, Kim K, Koo BC: Mediastinal teratoma associated with Klinefelter's syndrome. Arch Pathol Lab Med 110 (11): 1067-71, 1986. [PUBMED Abstract]
24. 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]
25. 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]

Stage Information for Childhood Extracranial GCTs

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As with other childhood solid tumors, stage directly impacts the outcome of patients with malignant germ cell tumors (GCTs). 1 2 3 The most commonly used staging system in the United States is described below. 4 Retroperitoneal lymph node dissection has not been required in pediatric germ cell trials to stage 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.)

Nonseminoma Testicular GCT Staging From Children's Oncology Group

• Stage I: Limited to testis, complete resection by high inguinal orchiectomy or transscrotally with no tumor spillage. There must be no evidence of disease beyond the testis by radiologic scans or pathology. Tumor markers must normalize in appropriate half-life after resection.
• 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 < age 10 years).
• Stage IV: Distant metastases, including liver.

Ovarian GCT Staging From Children's Oncology Group

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

Ovarian GCT Staging From FIGO

Another staging system used 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 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 Children's Oncology Group

• 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.

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 Background for Childhood Extracranial GCTs

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Prior to effective chemotherapy, children with extracranial malignant germ cell tumors (GCTs) had 3-year survival rates of 15% to 20% with surgery and radiation therapy, 1 2 3 though young 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. 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. 6 7 8 9 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), it is important that children with extracranial malignant GCTs 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 platinum-based chemotherapy. 10 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 follow-up is important. 11 12 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 GCTs, with 5-year survival rates of more than 90%. 6 7 8 9 The standard chemotherapy regimen for both adults and children with malignant nonseminomatous GCTs includes cisplatin, etoposide, and bleomycin (PEB), though children receive fewer doses of bleomycin than adults. 6 7 13 14 The combination of carboplatin, etoposide, and bleomycin (JEB) has undergone clinical investigation in the United Kingdom in children younger than 16 years and is reported to have a similar event-free survival (EFS) by site and stage as PEB. 8 15 The use of JEB appears to be associated with less ototoxicity and nephrotoxicity than PEB. 8 Adult studies have substituted standard-dose carboplatin for cisplatin in combination with etoposide alone and in combination with etoposide and low-dose bleomycin, 16 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. [Note: See Table 4 for pediatric PEB and JEB chemotherapy dosing schedules.]

The approach to the management of extracranial GCTs has been informed by the results of two intergroup studies conducted by the Children's Cancer Group (CCG) and the Pediatric Oncology Group (POG). 6 7 11 These studies explored the use of PEB for the treatment of localized gonadal GCT 6 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. 7

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 ototoxicity and nephrotoxicity. In a subsequent study, amifostine was not effective in preventing hearing loss in patients who received HD-PEB. 17

Table 4. Comparison of Pediatric PEB and JEB Chemotherapy Dosing Schedules^a

^aAdult doses of PEB and JEB chemotherapy are different from pediatric doses.

Regimen	Bleomycin	Etoposide	Cisplatin	Carboplatin	References
Pediatric PEB (every 21 days)	15 units/m, day 1	100 mg/m, days 15	20 mg/m, days 15
Pediatric JEB (every 2128 days)	15 units/m, day 3	120 mg/m, days 13		600 mg/m or GFR-based dosing, day 2
GFR = glomerular filtration rate; JEB = carboplatin, etoposide, and bleomycin; PEB = cisplatin, etoposide, and bleomycin.

Table 5 provides an overview of standard treatment options for children with extracranial GCTs. 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.

Table 5. Standard Treatment Approaches for Infants and Children Younger Than 15 Years With Germ Cell Tumors by Histology, Stage, and Primary Site

^aPatients aged 15 years and older with stage IV testicular tumors and all patients with stages III and IV extragonadal tumors treated with PEB have suboptimal outcome and should be considered for more intensive therapies.^bThe role for observation after surgery has not been well established for stage I ovarian germ cell tumors and should be reserved for a clinical trial.^cThe role for surgery at diagnosis for extragonadal tumors is age- and site-dependent and must be individualized. Depending on the clinical setting, the appropriate surgical approach may range from no surgery (e.g., mediastinal primary tumor in a patient with a compromised airway and elevated tumor markers), to biopsy, to primary resection. In some cases, an appropriate strategy is biopsy at diagnosis followed by subsequent surgery in selected patients who have residual masses following chemotherapy.

Histology	Primary Site	Stage	Treatment
Mature teratoma	All sites	Localized	Surgery + Observation
Immature teratoma	All sites	Localized	Surgery + Observation
Malignant germ cell tumors	Testicular	Stage I	Surgery + Observation
		Stages IIIVa	Surgery + PEB
	Ovarian	Stage Ib	Surgery + PEB
		Stages IIIV	Surgery + PEB
	Extragonadal	Stages III	Surgeryc + PEB
		Stages IIIIVa	Surgeryc + PEB
PEB = cisplatin, etoposide, and bleomycin.

Non-GCT Malignant Elements

The treatment of GCTs with other non-GCT elements is complex and scant data exist to inform treatment. Specific treatment for both the malignant GCT and non-GCT elements may be required. 18 However, the optimal treatment strategy for other malignant elements found in GCT has not been determined.

References:

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Treatment of Mature and Immature Teratomas in Children

Back Up

Mature and immature teratomas arise primarily in the sacrococcygeal region of neonates and young children and in the ovaries of pubescent girls. These tumors are also less commonly found in the testicular region of boys younger than 4 years, the mediastinum of adolescents, and other sites. 1 2 3

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 (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. 4 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