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Dramatic improvements in survival have been achieved for children and adolescents with cancer. Between 1975 and 2010, childhood cancer mortality decreased by more than 50%. During the period from 2002 to 2010, cancer mortality continued to decrease by 2.4% per year for children and adolescents with acute lymphoblastic leukemia, acute myeloid leukemia, Hodgkin and non-Hodgkin lymphoma, neuroblastoma, central nervous system tumors, and gonadal tumors, as compared with the period from 1975 to 1998 (plateauing from 1998 to 2001). Childhood and adolescent cancer survivors require close monitoring because late effects of cancer therapy 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.[2,3] Childhood extracranial GCTs can be divided into the following two types:
Most childhood extragonadal GCTs arise in midline sites (i.e., head and neck, 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:
(Refer to the PDQ summary on Childhood Central Nervous System Germ Cell Tumors Treatment for information about the treatment of intracranial GCTs.)
Childhood GCTs are rare in children younger than 15 years, accounting for approximately 3% of cancers in this age group.[4,5,6,7] In the fetal/neonatal age group, most extracranial GCTs are benign teratomas occurring at midline locations, including the head and neck, sacrococcyx, and retroperitoneum. 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.[9,10,11]
The incidence of extracranial GCTs with the onset of puberty represents approximately 14% of cancers in adolescents aged 15 to 19 years.
The incidence of extracranial GCTs according to 5-year age group and sex is shown in Table 1.
The presence of an abdominal undescended testis (cryptorchidism) has been associated with a risk of developing testicular cancer that is 3.7 to 7.5 times higher than in those with normal testes. The presence of Y-chromosome material in an abdominal gonad, as seen in gonadal dysgenesis, also increases the risk of developing a gonadal GCT, especially gonadoblastoma.[13,14]
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 properties of extracranial GCTs are heterogeneous and vary by primary tumor site and the sex and age of the patient.[15,16] Histologically identical GCTs that arise in younger children have different biological characteristics from those that arise in adolescents and young adults.
Mature teratomas can occur at gonadal or at extragonadal locations. They are the most common histological subtype of childhood GCT.[11,18,19,20] 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.[21,22]
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. Tumors of higher grade are more likely to have foci of yolk sac tumor. Immature teratomas can exhibit malignant behavior and metastasize.
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.[24,25] Some immature teratomas may secrete enzymes or hormones such as vasopressin.
GCTs contain 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.[25,27]
Malignant germ cell elements of children, adolescents, and young adults can be grouped broadly by location (refer to Table 2). Adolescent and young adult males present with more germinomas (testicular and mediastinal seminomas), and females present with more ovarian dysgerminomas.
The following biologically distinct subtypes of GCTs are found in children and adolescents:
Very few pediatric GCT specimens have been analyzed. Biologic distinctions between GCTs in children and GCTs in adults may not be absolute, and biologic factors have not been shown to predict risk.[29,30,31]
Ovarian GCTs occur primarily in adolescent and young adult females. While most ovarian GCTs are benign mature teratomas (dermoid cysts), a heterogeneous group of malignant GCTs, including immature teratomas, dysgerminomas, yolk sac tumors, and mixed GCTs, do occur in females. The malignant ovarian GCT commonly shows increased copies of the short arm of chromosome 12.
Extragonadal extracranial GCTs
Extragonadal extracranial GCTs occur outside of the brain and gonads.
There are few data about the potential genetic or environmental risk factors associated with childhood extragonadal extracranial GCTs. Patients with the following syndromes are at an increased risk of extragonadal extracranial GCTs:
Childhood extracranial GCTs develop at many sites, including testicles, ovaries, mediastinum, retroperitoneum, sacrum, coccyx, and head and neck (refer to Figure 1). The clinical features at presentation are specific for each site.
Benign teratomas and immature teratomas can cause morbidity and mortality through obstruction (i.e., head and neck teratomas). In preterm infants and neonates, head and neck teratomas and immature teratomas can cause significant airway compromise. In a single-institutional report, airway obstruction was overcome by using the ex utero intrapartum treatment (EXIT) procedure. Complete resection of a teratoma can be achieved.
Figure 1. Extracranial germ cell tumors form in parts of the body other than the brain. This includes the testicles, ovaries, sacrococcyx (usually originating from the coccyx and including the sacrum), mediastinum, and retroperitoneum.
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.
Yolk sac tumors produce alpha-fetoprotein (AFP), and beta-human chorionic gonadotropin (beta-hCG) is produced by all choriocarcinomas and by some germinomas (seminomas and dysgerminomas) and embryonal carcinomas, 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,[56,57] which are serially monitored during treatment to help assess response to therapy.[25,27,56] Benign teratomas and immature teratomas may produce small elevations of AFP and beta-hCG.
The fetal liver produces AFP, and during the first year of life, infants have elevated serum AFP levels, which are not associated with the presence of a GCT. Normal ranges have been described.[58,59] The serum half-life of AFP is 5 to 7 days, and the serum half-life of beta-hCG is 1 to 2 days. Even though the data are limited, tumor markers are measured with each cycle of chemotherapy for all pediatric patients with malignant GCTs. After initial chemotherapy, tumor markers may show a transient elevation. A COG study measured AFP levels in children who received chemotherapy for GCTs. AFP decline was defined as automatically satisfactory if AFP normalized after two cycles of chemotherapy and was calculated satisfactory if the AFP half-life decline was less than or equal to 7 days after the start of chemotherapy. Other decline in AFP was defined as unsatisfactory. The cumulative incidence of relapse was 11% for patients with a satisfactory decline in AFP (n = 117) and 38% for patients with an unsatisfactory decline in AFP (n = 14).[Level of evidence: 3iiA]
Imaging tests may include the following:
Prognostic factors for extracranial GCTs depend on many circumstances and include the following (obtained from historical national GCT trials):[56,62,63,64]
To better identify prognostic factors, data from five U.S. trials and two U.K. trials for malignant extracranial GCTs in children and adolescents were merged by the Malignant Germ Cell Tumor International Collaborative. The goal was to ascertain the important prognostic factors in 519 young patients who received chemotherapy, incorporating age at diagnosis, stage, and site of primary tumor, along with pretreatment AFP level and histology.[Level of evidence: 3iiiDii] In this age-focused investigation of these factors in young children and adolescents, prognostic factors included the following:
The presence of gonadal dysgenesis in patients with ovarian nondysgerminomatous tumors is associated with worse outcomes. In a report from the COG AGCT0132 study, seven patients with gonadal dysgenesis and ovarian nondysgerminoma had an estimated 3-year event-free survival rate of 67%, compared with 89% for 100 patients with nondysgerminoma ovarian tumors who did not have gonadal dysgenesis. These dysgenetic gonads contain Y-chromosome material, and intra-abdominal gonads with Y-chromosome material are at increased risk of tumor development.[12,13] In contrast to nondysgerminomas, gonadal dysgenesis was identified in 7 of 48 patients with ovarian dysgerminomas in a report from the French Society of Pediatric Oncology. With a medium follow-up of 14 years, all patients survived.
Although few pediatric data exist, adult studies have shown that an unsatisfactory decline of elevated tumor markers after the first cycle of chemotherapy is a poor prognostic finding.[68,69]
(Refer to the Treatment of Mature and Immature Teratomas in Children, Treatment of Malignant Gonadal GCTs in Children, and Treatment of Malignant Extragonadal Extracranial GCTs in Children sections of this summary for more information about prognosis and prognostic factors for childhood extragonadal extracranial GCTs.)
Follow-up After Treatment
The following tests and procedures may be performed at the physician's discretion for monitoring children with extracranial GCTs:
The following tests and procedures may be performed at the physician's discretion when tumor markers are normal at diagnosis:
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 systems in the United States are as follows:
Testicular GCT Staging From COG (Patients Aged <11 Years)
Table 3 describes the testicular GCT staging from the COG AGCT1531 (NCT03067181) trial.
Testicular GCT Staging (Patients Aged ≥11 Years)
Refer to the PDQ summary on Testicular Cancer Treatment for more information about the American Joint Committee on Cancer staging criteria for testicular GCT in males aged 11 years and older.
Retroperitoneal lymph node dissection has not been required in pediatric germ cell trials to stage disease in males younger than 15 years. Data on adolescent males with testicular GCTs are limited. Retroperitoneal lymph node dissection is used for both staging and treatment in adult testicular GCT trials.
In males older than 15 years, there are only stage I tumors and metastatic tumors. Metastatic tumors are assigned risk according to the IGCCC.
Ovarian GCT Staging From COG
Table 4 describes the ovarian GCT staging from the COG AGCT1531 (NCT03067181) trial.
Ovarian GCT Staging From FIGO
Another ovarian GCT staging system used frequently by gynecologic oncologists is the FIGO staging system, which is based on adequate surgical staging at the time of diagnosis. (Refer to the PDQ summary on Ovarian Germ Cell Tumors Treatment for more information.) This system has also been used by some pediatric centers  and is described in Table 5.
The ovarian staging systems described above require adherence to specific guidelines. However, in a pediatric intergroup trial, guidelines were followed in only 2 of 131 patients with ovarian tumors. In a single-institution retrospective study, guidelines were followed in only 2 of 44 patients with ovarian tumors.
Extragonadal Extracranial GCT Staging From COG
Table 6 describes the extragonadal extracranial GCT staging from the COG AGCT1531 (NCT03067181) trial.
Childhood extracranial germ cell tumors (GCTs) are very heterogenous. The benefits and limitations of therapy are related to differences in histology. For example, pediatric GCTs such as mature and immature teratomas may not respond to chemotherapy.
On the basis of clinical factors, appropriate treatment for extracranial GCTs may involve one of the following:
To maximize the likelihood of long-term survival while minimizing the likelihood of treatment-related long-term sequelae (e.g., secondary leukemias, infertility, hearing loss, and renal dysfunction), children with extracranial malignant GCTs need to be cared for at pediatric cancer centers with experience treating these rare tumors.
Surgery is an essential component of treatment. Specific treatments will be discussed for each tumor type.
Surgery and Observation
For patients with completely resected immature teratomas of all grades and at any location, and for patients with localized, completely resected (stage I) seminomatous and nonseminomatous GCTs (testicular and ovarian), additional therapy may not be necessary; however, close monitoring is important.[2,3] 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.
Before effective chemotherapy became available, children with extracranial malignant GCTs had 3-year survival rates of 15% to 20% with surgery and radiation therapy,[4,5,6] although young boys with localized testicular tumors did well with surgical resection alone.[7,8] Cisplatin-based chemotherapy has significantly improved outcomes for most children and adolescents with extracranial GCTs; 5-year survival rates now approach 85%.
In the United States, the standard chemotherapy regimen for both adults and children with malignant nonseminomatous GCTs includes cisplatin, etoposide, and bleomycin. Adult patients receive weekly bleomycin throughout treatment (bleomycin, etoposide, and cisplatin [BEP]).[9,10,11,12] U.S. pediatric trials included patients aged 15 years and younger with testicular GCTs and patients aged 21 years and younger with ovarian and extragonadal GCTs. Patients received bleomycin only on day 1 of each cycle (cisplatin, etoposide, and bleomycin [PEb]).[13,14] The combination of carboplatin, etoposide, and bleomycin (JEb) underwent clinical investigation in the United Kingdom in children younger than 16 years and was reported to have an event-free survival (EFS) by site and stage similar to that of PEb.[15,16] Refer to Table 7 for adult BEP and pediatric PEb and JEb chemotherapy dosing schedules.[9,10,11,13,14] In both adult and pediatric trials, the number of adolescent subjects was small; the optimal therapy for adolescents (aged ≥11 years) is not clear.
The use of JEb appears to be associated with fewer otologic toxic effects and renal toxic effects than does the use of PEb. In a retrospective meta-analysis of data from the Children's Oncology Group (COG) and the Children's Cancer and Leukaemia Group germ cell studies conducted contemporaneously, the multivariate cure model showed no difference in 4-year EFS rates. The 4-year EFS rate was 86% (95% confidence interval [CI], 83%–89%) for patients who received the cisplatin regimen (n = 620) and 86% (95% CI, 79%–90%) for patients who received the carboplatin regimen (n = 163) (P = .87).[Level of evidence: 3iiA] However, PEb and JEb have not been compared in a randomized pediatric GCT trial.
Several trials were conducted by the COG (previously the Children's Cancer Group and the Pediatric Oncology Group ).[2,13,14] These trials explored the use of PEb for the treatment of localized gonadal GCT  and intensified regimens for patients with poor-risk features. The strategies included high-dose cisplatin (200 mg/m2) and cyclophosphamide or the protective agent amifostine.[14,20] None of these strategies had a significant effect on survival or decreased toxicity.
Testicular and mediastinal seminomas in males and ovarian dysgerminomas in females are sensitive to radiation, but radiation therapy is rarely recommended because of the known late effects.
Treatment Options for Childhood Extracranial GCTs by Histologic Type
Table 8 provides an overview of treatment options for children with extracranial GCTs. Specific details of treatment by primary site and clinical condition are described in subsequent sections.
GCT with non-GCT elements (teratoma with malignant transformation)
The treatment of GCTs with other non-GCT somatic elements is complex, and few data exist to direct treatment. In adolescents, central primitive neuroectodermal tumors and sarcomas have been found in teratomas.[22,23] The Italian Pediatric Germ Cell Tumor group identified 14 patients with malignant GCTs with a somatic malignancy, such as neuroblastoma or rhabdomyosarcoma, embedded in teratomas (<2% of extracranial GCTs).
The optimal treatment strategy for GCTs with non-GCT elements has not been determined, and separate treatments for both malignant GCTs and non-GCT elements may be required.
Special Considerations for the Treatment of Children With Cancer
Cancer in children and adolescents is rare, although the overall incidence of childhood cancer has slowly increased since 1975. 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:
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. 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 and 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 website.
Mature and immature teratomas arise primarily in the sacrococcygeal region of neonates and young children and in the ovaries of pubescent girls. Less commonly, these tumors are found in the testicular region of boys younger than 4 years, the mediastinum of adolescents, and other sites.[1,2,3]
The primary treatment for teratomas is surgery and depends on whether the tumor forms in a nonsacrococcygeal or sacrococcygeal site. Surgical options for sacrococcygeal teratomas are complex. The number of pediatric patients with postoperative residual mature or immature teratomas is very small.
Treatment of Mature Teratomas
Standard treatment options for mature teratomas (nonsacrococcygeal sites)
Standard treatment options for mature teratomas in a nonsacrococcygeal site include the following:
Children with mature teratomas, including mature teratomas of the mediastinum, can be treated with surgery and observation, with an excellent prognosis.[1,4] In a review of 153 children with nontesticular mature teratoma, the 6-year relapse-free survival was 96% for completely resected disease and 55% for incompletely resected disease.
Head and neck germ cell tumors (GCTs) in neonates should be cared for by a multidisciplinary team. Although most head and neck GCTs are benign, they can be life-threatening and present significant challenges to surgeons, especially in newborns. Some tumors develop malignant elements, which may change the treatment strategy.[6,7]
Mature teratomas in the prepubertal testis are relatively common benign lesions and may be amenable to testis-sparing surgery.
Standard treatment options for mature teratomas (sacrococcygeal sites)
The sacrococcygeal region is the primary tumor site for most benign and malignant GCTs diagnosed in neonates, infants, and children younger than 4 years. These tumors occur more often in girls than in boys; ratios of 3:1 to 4:1 have been reported.
Sacrococcygeal tumors present in the following two clinical patterns related to the child's age, tumor location, and likelihood of tumor malignancy:
The older the child at presentation, the more likely a malignant component is present in addition to the teratoma. 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. The pelvic site of the primary tumor has been reported to be an adverse prognostic factor, perhaps as a result of delayed diagnosis because it was overlooked at birth or because of incomplete resection at the time of original surgery.[10,11,12,13]
Standard treatment options for mature teratomas in a sacrococcygeal site include the following:
Surgery is an essential component of treatment. Complete resection of the coccyx is vital to minimize the likelihood of tumor recurrence.
After successful resection, neonates diagnosed with benign mature and immature teratomas are closely observed with 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.[14,15] A significant rate of recurrence among these benign tumors, ranging from 10% to 21%, has been reported by several groups, with most relapses occurring within 3 years of resection.[9,14,16,17]
While there is no standard follow-up schedule, tumor markers are measured frequently for 3 years in all children. Recurrent tumors will be malignant in 43% to 50% of cases, and yolk sac tumor is the most common histology. With early detection, recurrent malignant GCTs can be treated successfully with surgery and chemotherapy (overall survival rate, 92%). Long-term survivors are monitored for complications of extensive surgery, which include constipation, fecal and urinary incontinence, and psychologically unacceptable cosmetic scars.
Treatment of Immature Teratomas
Treatment options for immature teratomas
Treatment options for immature teratomas include the following:
The treatment options for immature teratomas differ by stage of disease.
Infants and young children with immature teratomas have an excellent prognosis if the tumor can be completely resected.[16,20,21] For these patients, the current standard of treatment is surgery and observation.
Evidence (surgery and observation for stage I disease):
Stages II through IV
There are no clinical trials supporting the use of chemotherapy in children, as this area has not been well studied. Immature teratomas in children are primarily managed with surgery and observation. In adults, surgery followed by chemotherapy has been the standard treatment approach since 1976. As in children, there are no clinical trials supporting the use of chemotherapy in adults.
Evidence (role of chemotherapy for immature teratomas):
Additional studies on the treatment of ovarian immature teratomas with chemotherapy are needed. (Refer to the PDQ summary on Ovarian Germ Cell Tumors Treatment for more information about the treatment of ovarian immature teratomas in postpubertal females.)
Treatment options under clinical evaluation for immature teratomas
Information about National Cancer Institute (NCI)–supported clinical trials can be found on the NCI website. For information about clinical trials sponsored by other organizations, refer to the ClinicalTrials.gov website.
The following is an example of a national and/or institutional clinical trial that is currently being conducted:
Current Clinical Trials
Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.
Childhood Malignant Testicular GCTs
Malignant testicular GCTs in prepubertal males
Testicular germ cell tumors (GCTs) in children occur almost exclusively in boys younger than 4 years.[1,2] The initial surgical approach to evaluate a testicular mass in a young boy is important because a trans-scrotal biopsy can risk inguinal node metastasis.[3,4] Radical inguinal orchiectomy with initial high ligation of the spermatic cord is the procedure of choice.
Computed tomography or magnetic resonance imaging evaluation, with the additional information provided by elevated tumor markers, appears adequate for staging. Retroperitoneal dissection of lymph nodes is not beneficial in the staging of testicular GCTs in young boys.[3,4] Therefore, there is no reason to risk the potential morbidity (e.g., impotence and retrograde ejaculation) associated with lymph node dissection.[6,7]
The role of surgery at diagnosis for GCTs is age- and site-dependent and must be individualized. All malignant testicular GCTs should be resected. Resection should be followed by subsequent excision of residual masses after chemotherapy.
Standard treatment options for malignant GCTs in prepubertal males
Standard treatment options for malignant GCTs in prepubertal males (aged <11 years) include the following:
The treatment options for malignant GCTs in prepubertal males differ by stage of disease.
Surgery and close follow-up observation are indicated to document that a normalization of the tumor markers occurs after resection.[3,8]
Evidence (surgery and observation for stage I disease in prepubertal males):
Surgery and chemotherapy with four cycles of standard PEb is a common treatment regimen for prepubertal males with stages II through IV disease. Patients treated with this regimen have an OS outcome greater than 90%, suggesting that a reduction in therapy could be considered.[11,12]
Surgery and treatment with four to six cycles of carboplatin, etoposide, and bleomycin (JEb) is an alternative treatment regimen.
A revised risk stratification was developed by the Malignant Germ Cell Tumor International Consortium.
Evidence (surgery and chemotherapy for stages II–IV disease in prepubertal males):
Malignant testicular GCTs in postpubertal males
The treatment options described for prepubertal males may not be strictly applicable to postpubertal males. In particular, retroperitoneal lymph node dissection may play a crucial role  in the treatment of patients with residual disease after chemotherapy for the treatment of metastatic testicular GCT.[15,16] A meta-analysis showed that patients older than 11 years were at higher risk of recurrence. The number of males aged 11 to 15 years with GCT is small; it is possible that these patients should be treated according to adult standards. (Refer to the PDQ summary on Testicular Cancer Treatment for more information about the treatment of malignant testicular GCTs in postpubertal males.)
Standard treatment options for malignant testicular GCTs in postpubertal males
Refer to the PDQ summary on Testicular Cancer Treatment for information about the treatment of malignant testicular GCTs in postpubertal males.
Treatment options under clinical evaluation for malignant testicular GCTs
The following are examples of national and/or institutional clinical trials that are currently being conducted:
Childhood Malignant Ovarian GCTs
Most ovarian neoplasms in children and adolescents are of germ cell origin. Ovarian GCTs are very rare in young girls, but the incidence begins to increase in children aged approximately 8 or 9 years and continues to rise throughout adulthood.
Childhood malignant ovarian GCTs can be divided into germinomatous (dysgerminomas) and nongerminomatous malignant GCTs (i.e., yolk sac carcinomas, mixed GCTs, choriocarcinoma, and embryonal carcinomas).
(Refer to the Treatment of Mature Teratomas section of this summary for more information about childhood mature and immature teratomas arising in the ovary and the PDQ summary on Ovarian Germ Cell Tumors Treatment for more information about the treatment of ovarian GCT in postpubertal females.)
Dysgerminomas of the ovary
Standard treatment options for dysgerminomas of the ovary
Standard treatment options for dysgerminomas of the ovary include the following:
The treatment options for dysgerminomas of the ovary differ by stage of disease.
For stage I ovarian dysgerminomas, a cure can usually be achieved by unilateral salpingo-oophorectomy, conserving the uterus and opposite ovary, and close follow-up observation.[8,18,19,20,21] In three successive French Society of Pediatric Oncology studies (TGM-85, TGM-90, and TGM-95), 15 patients were identified as stage I, and all patients survived. Before 1998, eight patients were treated with adjuvant radiation or chemotherapy. After a practice change (after 1998), seven patients underwent surgery and observation. One of the seven patients (14%) had a tumor event and responded to treatment with chemotherapy.[Level of evidence: 3iiA]
While advanced-stage ovarian dysgerminomas, like testicular seminomas, are highly curable with surgery and radiation therapy, the effects on growth, fertility, and risk of treatment-induced second malignancy in these young patients [23,24] make chemotherapy a more attractive adjunct to surgery.[25,26] 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. In a report from the French Society of Pediatric Oncology, 48 girls younger than 19 years (median age, 12.8 years) were registered; 20 patients had localized disease, 28 patients had locoregional disease, and no patients had metastases. Seven patients had positive para-aortic lymph nodes. Forty-seven patients underwent primary surgery. Before 1998, all patients with advanced disease received radiation therapy. After a practice change (after 1998), patients were treated with platinum-based chemotherapy. The 5-year EFS rate was 91%, and the 5-year OS rate was 100%. Side effects were not severe, and several patients became pregnant in later years.[Level of evidence: 3iiA] This approach results in a high rate of cure and the preservation of menstrual function and fertility in most patients with dysgerminomas.[25,27] In a meta-analysis of patients with dysgerminoma by the Malignant Germ Cell Tumor International Consortium, no difference was seen between patients who were treated with cisplatin (n = 70) (5-year EFS rate, 93%; OS rate, 96%) and patients who were treated with carboplatin (n = 56) (5-year EFS rate, 96%; OS rate, 96%).
Malignant nongerminomatous ovarian GCTs
A multidisciplinary approach is essential for treatment of ovarian GCTs. Various surgical subspecialists and the pediatric oncologist must be involved in clinical decisions. The surgical approach for pediatric ovarian GCTs is often guided by the expectation that reproductive function can be preserved.
Standard treatment options for malignant nongerminomatous ovarian GCTs
Standard treatment options for malignant nongerminomatous ovarian GCTs in prepubertal females include the following:
Standard treatment options for malignant nongerminomatous ovarian GCTs in postpubertal females include the following:
Standard treatment options for malignant nongerminomatous ovarian GCTs that cannot be resected initially include the following:
The treatment of ovarian malignant GCTs that are not dysgerminomas or immature teratomas generally involves surgical resection and adjuvant chemotherapy.[29,30]
The role for surgery at diagnosis is age- and site-dependent and must be individualized. The use of laparoscopy in children with ovarian GCTs has not been well studied.
Pediatric surgical guidelines to determine stage I disease have been published. Adult surgical guidelines to determine stage are more extensive. (Refer to the Stage Information for Ovarian Germ Cell Tumors section of the PDQ summary on Ovarian Germ Cell Tumors Treatment for more information about staging of ovarian GCTs in postpubertal females.) Strict surgical staging guidelines need to be followed to determine true stage I disease. Historically, in both pediatric and adult studies, comprehensive staging guidelines have not been followed. If strict surgical staging guidelines are not followed, surgery followed by chemotherapy, rather than surgery followed by observation, is the standard treatment.[8,11,32] A goal of surgical therapy for pediatric GCTs is to preserve reproductive function. If conservative surgery is the choice, a high rate of cure can be obtained with adjuvant chemotherapy, and adherence to strict surgical guidelines is not necessary.
Chemotherapy regimens with cisplatin (PEb) or carboplatin (JEb) have been used successfully in children.[8,11,12,18] BEP is a common regimen in young women with ovarian GCTs.[34,35] BEP differs from PEb with the addition of weekly bleomycin. This approach results in a high rate of cure and the preservation of menstrual function and fertility in most patients with nondysgerminomas.[30,32] (Refer to Table 7 for more information about the dosing schedules for BEP, PEb, and JEb.)
Surgery and observation
When strict surgical staging guidelines are followed, surgery followed by observation may be an appropriate treatment choice for prepubertal females with stage I disease.
Evidence (surgery and observation for stage I disease in prepubertal females):
Surgery and chemotherapy
In prepubertal females with purported stage I ovarian tumors, when strict surgical staging guidelines are not followed, surgery followed by chemotherapy (four cycles of PEb) is an appropriate treatment choice and results in EFS and OS rates of 95%.[11,12]
In postpubertal females with purported stage I ovarian tumors, chemotherapy after resection remains the standard treatment. In postpubertal females, the strategy of observation after surgery has not been established; this treatment strategy is under investigation in the AGCT1531 (NCT03067181) trial.
In prepubertal and postpubertal females with stages II, III, or IV ovarian tumors, surgery and chemotherapy are considered standard treatments. Surgery and chemotherapy with four to six cycles of standard PEb is used to treat younger (prepubertal) girls,[11,12] and BEP is used to treat postpubertal girls.[34,35] Patients with normalization of tumor markers undergo imaging after four cycles of PEb, and any residual tumor is removed. Patients with residual viable tumor after surgery are considered refractory.
Alternatively, surgery and chemotherapy with four to six cycles of JEb is a treatment option (as demonstrated in one study in which all patients were younger than 15 years).
Initially unresectable tumor
Primary resection of ovarian GCT is usually attempted. In rare instances in which primary resection of the ovary is not possible without undue risk of damage to adjacent structures, an appropriate strategy is biopsy for diagnosis followed by subsequent surgery in patients who have residual masses after undergoing chemotherapy.
Treatment options under clinical evaluation for malignant ovarian GCTs
Extragonadal extracranial germ cell tumors (GCTs) (i.e., sacrococcygeal, mediastinal, and retroperitoneal) are more common in children than in adults. In initial reports, children with extragonadal malignant GCTs, particularly those with advanced-stage (stage III or stage IV) disease, had the highest risk of treatment failure for any GCT presentation.[2,3] Subsequently, an analysis of data from 25 years of pediatric GCT studies in the United States and United Kingdom reported that children younger than 11 years with extragonadal stage III and stage IV GCTs had an event-free survival (EFS) rate of 85%, and adolescents with stage III and stage IV extragonadal disease had poorer outcomes (expected EFS rate, <70%).
Standard Treatment Options for Malignant Extragonadal Extracranial GCTs in Prepubertal Children
Standard treatment options for malignant extragonadal extracranial GCTs in prepubertal children include the following:
The treatment of malignant extragonadal extracranial GCTs also depends on the site of disease. (Refer to the Site-specific considerations for malignant extragonadal extracranial GCTs section of this summary for more information.)
Outcome has improved remarkably since the advent of platinum-based chemotherapy and the use of a multidisciplinary treatment approach.[2,5] Complete resection before chemotherapy may be possible in some patients without major morbidity. For patients with locally advanced sacrococcygeal tumors, mediastinal tumors, or large pelvic tumors, tumor biopsy followed by preoperative chemotherapy can facilitate subsequent complete tumor resection and improve ultimate patient outcome. There is no decrease in overall survival (OS) in patients with extragonadal GCT who have had delayed resection after receiving chemotherapy.[5,6,7,8]
The role of surgery at diagnosis for extragonadal tumors is age- and site-dependent and must be individualized. Depending on the clinical setting, the appropriate surgical approach may be primary resection, biopsy before chemotherapy, or no surgery (e.g., for a mediastinal primary tumor in a patient with a compromised airway and elevated tumor markers). An appropriate strategy may be biopsy at diagnosis followed by chemotherapy and subsequent surgery in selected patients who have residual masses after chemotherapy.
Stages I and II
Surgery and chemotherapy with four cycles of standard cisplatin, etoposide, and bleomycin (PEb) is one treatment option. Patients treated with this regimen have an OS rate of 90%, suggesting that a reduction in therapy might be considered.[2,9] An alternative treatment option is surgery and chemotherapy with carboplatin, etoposide, and bleomycin (JEb).
Stages III and IV
A treatment option for stage III and stage IV disease is surgery and chemotherapy with four cycles of standard PEb. Patients have OS rates of higher than 80% with this regimen. Another treatment option is surgery and chemotherapy with JEb, which has an OS rate similar to that of the PEb regimen.
Two pediatric intergroup trials investigated the use of high-dose cisplatin (200 mg/m2) in a randomized study and a subsequent study that added amifostine to high-dose cisplatin. No benefit in OS was observed, and 75% of patients required hearing aids. A Children's Oncology Group (COG) trial investigated the addition of cyclophosphamide to standard-dose PEb. The addition of cyclophosphamide was feasible and well tolerated at all dose levels, but there was no evidence that adding cyclophosphamide improved efficacy.
Site-specific considerations for malignant extragonadal extracranial GCTs
The treatment of malignant extragonadal extracranial GCTs depends in part on the site of disease.
Sacrococcygeal GCTs are common extragonadal tumors that occur in very young children, predominantly young females. The tumors are usually diagnosed at birth, when large external lesions predominate (usually mature or immature teratomas), or later in the first years of life, when presacral lesions with higher malignancy rates predominate.
Malignant sacrococcygeal tumors are usually very advanced at diagnosis; two-thirds of patients have locoregional disease, and metastases are present in 50% of patients.[7,12,13] Because of their advanced stage at presentation, the management of sacrococcygeal tumors requires a multimodal approach with platinum-based chemotherapy followed by delayed tumor resection.
Platinum-based therapies, with either cisplatin or carboplatin, are the cornerstone of treatment. The PEb regimen or the JEb regimen produces EFS rates of 85%.[7,8] Surgery may be facilitated by preoperative chemotherapy. In any patient with a sacrococcygeal GCT, resection of the coccyx is mandatory.[7,8]
Completeness of surgical resection is an important prognostic factor, as shown in the following circumstances:[7,8,14]
Mediastinal GCTs account for 15% to 20% of malignant extragonadal extracranial GCTs in children. The histology of mediastinal GCT is dependent on age, with teratomas predominating among infants and yolk sac tumor histology predominating among children aged 1 to 4 years.
Prepubertal children with mediastinal malignant teratomas are treated with tumor resection, which is curative in almost all patients. Children with stage I to stage III nonmetastatic mediastinal GCTs who receive cisplatin-based chemotherapy have 5-year EFS and OS rates of 90%; however, patients with stage IV mediastinal tumors have EFS rates closer to 80%.[4,5,6]; [Level of evidence: 3iiA]
Malignant GCTs located in the retroperitoneum or abdomen usually present in children younger than 5 years; most tumors are advanced stage and locally unresectable at diagnosis. A limited biopsy followed by platinum-based chemotherapy to shrink tumor bulk can lead to complete tumor resection in most patients. Despite the advanced-stage disease in most patients, the 6-year EFS rate using PEb was 83% in the Pediatric Oncology Group/Children's Cancer Group intergroup study.
Head and neck site
Although rare, benign and malignant GCTs can occur in the head and neck region, especially in infants. The airway is often threatened. Surgery for nonmalignant tumors and surgery plus chemotherapy for malignant tumors can be curative.[Level of evidence: 3iiiDii]
Standard Treatment Options for Malignant Extragonadal Extracranial GCTs in Postpubertal Children
In a study of prognostic factors in pediatric extragonadal malignant GCTs, age older than 12 years was the most important prognostic factor. In a multivariate analysis, children aged 12 years and older with thoracic tumors had six times the risk of death compared with children younger than 12 years with primary nonthoracic tumors. In a subsequent meta-analysis, adolescents with stage III and stage IV extragonadal disease had poor outcomes (expected EFS rate, <70%). Extragonadal disease of any stage is considered a poor risk factor in adolescents and young adults.
Standard treatment options for malignant extragonadal extracranial GCTs in postpubertal children include the following:
Most mediastinal GCTs in adolescents and young adults occur in males, and 22% to 50% have cytogenetic changes consistent with Klinefelter syndrome.[20,21] The age of presentation is younger in patients with Klinefelter syndrome, and testing all younger males for Klinefelter syndrome should be considered.[20,21] (Refer to the GCT Biology section of this summary for more information.) As with sacrococcygeal tumors, primary chemotherapy is usually necessary to facilitate surgical resection of mediastinal GCTs, and the completeness of resection is a very important prognostic indicator.[6,22] Survival rates for the older adolescent and young adult population with mediastinal tumors are generally lower than 60%.[4,18,23,24,25]; [Level of evidence: 3iiA]
Patients with Klinefelter syndrome have an increased risk of developing mediastinal GCTs.[20,27,28] Patients with GCTs were identified from the COG Childhood Cancer Research Network. Twenty-nine patients in the study had mediastinal primary tumors, and nine patients (31%) had Klinefelter syndrome. In the Centers for Disease Control and Prevention's large 2013 WONDER database, 3% of patients with GCT had Klinefelter syndrome (70% were mediastinal), compared with 0.2% of males in the general population with reported Klinefelter syndrome.
Patients with a malignant mediastinal primary tumor and extracranial metastases are at the highest risk of developing brain metastases and are monitored closely for signs and symptoms of central nervous system involvement.[Level of evidence: 3iiB] (Refer to the PDQ summary on Extragonadal Germ Cell Tumors Treatment for more information about the treatment of adult patients.)
Treatment Options Under Clinical Evaluation for Malignant Extragonadal Extracranial GCTs
Only a small number of children and adolescents with extracranial germ cell tumors (GCTs) have a recurrence.[1,2] Reports regarding the treatment and outcome of these children are based on small studies.
Treatment options for recurrent pediatric GCTs are modeled after treatment options in adult clinical trials. Information about ongoing National Cancer Institute (NCI)–supported clinical trials is available from the NCI website.
Standard Treatment Options for Recurrent Malignant GCTs in Children
Standard treatment options for recurrent childhood malignant GCTs include the following:
Refer to the following sections for information about salvage therapy after observation for patients with stage I disease:
Surgery with neoadjuvant or adjuvant chemotherapy
Reports of salvage treatment strategies used in adult recurrent GCTs include larger numbers of patients, but the differences between children and adults regarding the location of the primary GCT site, pattern of relapse, and the biology of childhood GCTs may limit the applicability of adult salvage approaches to children. In adults with recurrent GCTs, several chemotherapy combinations (most include the addition of paclitaxel and ifosfamide to a platinum compound) have achieved relatively good disease-free status.[4,5,6,7,8,9] A combination of paclitaxel and gemcitabine has demonstrated activity in adults with testicular GCTs who relapsed after high-dose chemotherapy and hematopoietic stem cell transplant (HSCT).
Among children with benign sacrococcygeal tumors who recur, a malignant component may be present at the primary tumor site. For these children, complete surgical resection of the recurrent tumor and coccyx (if not done originally) is the basis of salvage treatment; preoperative chemotherapy with cisplatin, etoposide, and bleomycin (PEb) may assist the surgical resection. In patients who had a malignant sacrococcygeal tumor that recurred after PEb treatment, surgery and additional chemotherapy may be warranted.
In a phase II Children's Oncology Group (COG) trial (AGCT0521 [NCT00467051]), 20 patients younger than 21 years who relapsed after PEb therapy received two cycles of paclitaxel, ifosfamide, and carboplatin (TIC). Responses were then assessed by a combination of Response Evaluation Criteria In Solid Tumors (RECIST) criteria and marker decline. Eight patients had partial responses, ten patients had stable disease, and two patients had progressive disease. This chemotherapy regimen produced a combined response rate of 44%.
Nonstandard Treatment Options for Recurrent Malignant GCTs in Children
High-dose (HD) chemotherapy and hematopoietic stem cell rescue
The role of HD chemotherapy and hematopoietic stem cell rescue for recurrent pediatric GCTs is not established, despite anecdotal reports. (Refer to the Autologous Hematopoietic Cell Transplantation section of the PDQ summary on Childhood Hematopoietic Cell Transplantation for more information about transplantation.) In one European series, 10 of 23 children with relapsed extragonadal GCTs achieved long-term disease-free survival (median follow-up, 66 months) after receiving HD chemotherapy with stem cell support. Additional study in children and adolescents is needed.
HD chemotherapy with autologous stem cell rescue has been explored as a treatment for adults with recurrent testicular GCTs. HD chemotherapy plus hematopoietic stem cell rescue has been reported to cure adult patients with relapsed testicular GCTs, even as third-line therapy and in cisplatin-refractory patients.[10,13,14,15] A small study also demonstrated efficacy in adolescents and women with ovarian GCTs.[Level of evidence: 3iiiA] While some studies support this approach,[10,14,15,17,18] others do not.[19,20] Salvage attempts using HD chemotherapy regimens may be of little benefit if the patient is not clinically disease free at the time of HSCT.[13,21]
Radiation therapy followed by surgery (for brain metastases)
In a very small pediatric study, patients with nongerminomatous brain metastases responded to radiation therapy. In the German Maligne Keimzelltümoren (MAKEI) studies, radiation therapy and surgery for patients with brain metastases provided palliation and occasional long-term survival.[22,23][Level of evidence: 3iiiA] A meta-analysis showed that radiation therapy did not improve outcome compared with surgery and radiation. However, the number of patients treated with radiation therapy was too small to accurately assess outcome.
Treatment Options Under Clinical Evaluation for Recurrent Malignant GCTs in Children and Adolescents
Information about NCI-supported clinical trials can be found on the NCI website. For information about clinical trials sponsored by other organizations, refer to the ClinicalTrials.gov website.
Tumor tissue from progressive or recurrent disease must be available for molecular characterization. Patients with tumors that have molecular variants addressed by treatment arms included in the trial will be offered treatment on Pediatric MATCH. Additional information can be obtained on the NCI website and ClinicalTrials.gov website.
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This summary is written and maintained by the PDQ Pediatric Treatment Editorial Board, which is editorially independent of NCI. The summary reflects an independent review of the literature and does not represent a policy statement of NCI or NIH. More information about summary policies and the role of the PDQ Editorial Boards in maintaining the PDQ summaries can be found on the About This PDQ Summary and PDQ® - NCI's Comprehensive Cancer Database pages.
Purpose of This Summary
This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the treatment of childhood extracranial germ cell tumors. It is intended as a resource to inform and assist clinicians who care for cancer patients. It does not provide formal guidelines or recommendations for making health care decisions.
Reviewers and Updates
This summary is reviewed regularly and updated as necessary by the PDQ Pediatric Treatment Editorial Board, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).
Board members review recently published articles each month to determine whether an article should:
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The lead reviewers for Childhood Extracranial Germ Cell Tumors Treatment are:
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Levels of Evidence
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PDQ® Pediatric Treatment Editorial Board. PDQ Childhood Extracranial Germ Cell Tumors Treatment. Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at: https://www.cancer.gov/types/extracranial-germ-cell/hp/germ-cell-treatment-pdq. Accessed <MM/DD/YYYY>. [PMID: 26389316]
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Last Revised: 2020-02-04
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