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Childhood Extracranial Germ Cell Tumors Treatment (PDQ®)

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General Information About Childhood Extracranial Germ Cell Tumors (GCTs)

Incidence
Histologic Classification of Childhood Extracranial GCTs
        Mature teratomas
        Immature teratomas
        Malignant GCTs
Pediatric GCT Biology
        Testicular GCTs
        Ovarian GCTs
        Extragonadal extracranial GCTs
Clinical Features
Diagnostic and Staging Evaluation
        Tumor markers
        Imaging tests
Follow-up After Treatment

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.
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