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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.
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 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.[4,5] Childhood extracranial GCTs can be divided into the following two 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.
Childhood extracranial GCTs are broadly classified as the following:
GCTs comprise a variety of histologic diagnoses and can also be divided into the following histologic types:
(Refer to the PDQ summary on Childhood Central Nervous System Germ Cell Tumors Treatment for information about the treatment of intracranial germ cell tumors.)
Childhood GCTs are rare in children younger than 15 years, accounting for approximately 3% of cancers in this age group.[6,7,8] 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.[9,10]
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.
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 these tumors are heterogeneous and vary by primary tumor site and the gender and age of the patient.[11,12] Histologically identical GCTs that arise in younger children have different biological characteristics from those that arise in adolescents and young adults.
Mature teratomas usually occur in the ovary or at extragonadal locations. They are the most common histological subtype of childhood GCT.[14,15,16] 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.[17,18]
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 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.[20,21] Some immature teratomas may secrete enzymes or hormones, such as vasopressin.
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.[21,23]
Malignant germ cell elements of children, adolescents, and young adults can be grouped broadly by location (refer to Tables 2 and 3).
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.[25,26,27]
Ovarian GCTs occur primarily in adolescent and young adult females. While most ovarian GCTs are benign mature teratomas, 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.
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%.
(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.
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:
Childhood extracranial GCTs develop at diffuse sites that include the testicles, ovaries, mediastinum, retroperitoneum, sacrum, and coccyx. The clinical features at presentation are specific for each site.
Figure 1. Extracranial germ cell tumors form in parts of the body other than the brain. This includes the testicles, ovaries, sacrum (lower part of the spine), coccyx (tailbone), mediastinum (area between the lungs), and retroperitoneum (the back wall of the abdomen).
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), 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,[53,54] which are serially monitored during treatment to help assess response to therapy.[21,23,53] 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.[55,56] 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. It should be recognized that after initial chemotherapy, tumor markers may show a transient elevation.
Although few pediatric data exist, adult studies have shown that an unsatisfactory decline of elevated tumor markers is a poor prognostic finding.
Imaging tests may include the following:
Prognosis and Prognostic Factors
Prognosis and prognostic factors for extracranial GCTs depend on many circumstances, including the following:
(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
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:
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:
Nonseminoma Testicular GCT Staging From the COG
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. (Refer to the PDQ summary on Testicular Cancer Treatment for more information about the staging of adult testicular GCTs.)
Ovarian GCT Staging From the COG
Ovarian GCT Staging From the FIGO
Another ovarian GCT staging system used frequently by gynecologic oncologists is the FIGO staging system, which is based on 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 as follows:
Extragonadal Extracranial GCT Staging From the COG
Childhood extracranial germ cell tumors (GCTs) are very heterogenous. The benefits and limitations of therapy are related to differences in histology. For example, pediatric GCTs, such as mature and immature teratomas, may not respond to chemotherapy.
Prognosis and appropriate treatment for extracranial GCTs depend on many factors, including the following:[1,2,3,4]
To maximize the likelihood of long-term survival while minimizing the likelihood of treatment-related long-term sequelae (e.g., secondary leukemias, infertility, hearing loss, and renal dysfunction), children with extracranial malignant GCTs need to be cared for at pediatric cancer centers with experience treating these rare tumors.
On the basis of clinical factors, appropriate treatment for extracranial GCTs may involve one of the following:
For patients with completely resected immature teratomas at any location (even those with malignant elements) and patients with localized, completely resected (stage I) gonadal tumors, additional therapy may not be necessary; however, close monitoring is important.[6,7] The watch-and-wait approach requires scheduled serial physical examination, tumor marker determination, and primary tumor imaging to ensure that a recurrent tumor is detected without delay.
Surgery is an essential component of treatment. Specific treatments will be discussed for each tumor type.
Testicular and mediastinal seminomas in males and ovarian dysgerminomas in females are sensitive to radiation, but radiation therapy is rarely recommended. With the advent of effective chemotherapy, it became possible for patients to avoid the toxic effects of radiation.
Before effective chemotherapy became available, children with extracranial malignant GCTs had 3-year survival rates of 15% to 20% with surgery and radiation therapy,[8,9,10] although young boys with localized testicular tumors did well with surgical resection.[11,12] Cisplatin-based chemotherapy has significantly improved outcomes for most children and adolescents with extracranial GCTs; 5-year survival rates now exceed 90%.
The standard chemotherapy regimen for both adults and children with malignant nonseminomatous GCTs includes cisplatin, etoposide, and bleomycin. Adult patients receive weekly bleomycin throughout treatment (bleomycin, etoposide, and cisplatin [BEP]). Pediatric patients do not receive bleomycin during the weeks between cycles (cisplatin, etoposide, and bleomycin [PEB]). (Refer to Table 5 for adult BEP and pediatric PEB and JEB chemotherapy dosing schedules.)[1,2,13,14,15] The combination of carboplatin, etoposide, and bleomycin (JEB) underwent clinical investigation in the United Kingdom in children younger than 16 years and was reported to have an event-free survival (EFS) by site and stage similar to that of PEB.[3,16] The use of JEB appears to be associated with fewer otologic toxic effects and renal toxic effects than does the use of PEB. PEB and JEB have not been compared in a randomized pediatric GCT trial.
Adult studies have substituted standard-dose carboplatin for cisplatin in combination with etoposide alone and in combination with etoposide and low-dose bleomycin, but the carboplatin regimens demonstrated inferior EFS and overall survival (OS) compared with cisplatin-containing therapy among patients with malignant GCTs.
Refer to Table 5 for adult BEP and pediatric PEB and JEB chemotherapy dosing schedules.
The approach to the management of extracranial GCTs has been derived from the results of several intergroup studies conducted by the Children's Cancer Group (CCG) and the Pediatric Oncology Group (POG).[1,2,6] These studies explored the use of PEB for the treatment of localized gonadal GCT  and the benefit of increasing the dose of cisplatin (high-dose PEB [HD-PEB]: a cisplatin concentration of 200 mg/m2 vs. PEB: a cisplatin concentration of 100 mg/m2) in a randomized manner in patients with extragonadal and advanced gonadal GCTs. The intensification of cisplatin in the HD-PEB regimen provided some improvement in EFS but no difference in OS; however, the use of HD-PEB was associated with a significantly higher incidence and severity of otologic toxic effects and renal toxic effects. In a subsequent study, amifostine was not effective in preventing hearing loss in patients who received HD-PEB.
Table 6 provides an overview of standard treatment options for children with extracranial GCTs. Specific details of treatment by primary site and clinical condition are described in subsequent sections.
GCT With Non-GCT Elements
The treatment of GCTs with other non-GCT elements is complex, and few data exist to direct treatment. In adolescents, central primitive neuroectodermal tumors and sarcomas have been found in teratomas.[20,21] The Italian Pediatric Germ Cell Tumor group identified 14 patients with malignant somatic tumors, such as neuroblastoma and 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.
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.
Mature Teratomas (Nonsacrococcygeal Sites)
Standard treatment options for mature teratomas (nonsacrococcygeal sites)
Standard treatment options for mature teratomas in a nonsacrococcygeal site include the following:
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 present significant challenges to surgeons. Some tumors develop malignant elements, which may change the treatment strategy.
Mature teratomas in the prepubertal testis are relatively common benign lesions and may be amenable to testis-sparing surgery.
Immature Teratomas (Nonsacrococcygeal Sites)
Standard treatment options for immature teratomas (nonsacrococcygeal sites)
Standard treatment options for immature teratomas in a nonsacrococcygeal site include the following:
The treatment options for immature teratomas at a nonsacrococcygeal site differ by stage of disease.
Infants and young children with immature teratomas have an excellent prognosis if the tumor can be completely resected.[7,8,9] 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 is significant debate on the responsiveness of immature teratomas to chemotherapy. In adults, and perhaps adolescents, immature teratomas (primarily ovarian) reportedly have an aggressive clinical behavior  requiring surgery and chemotherapy. The decision to use chemotherapy is based on the tumor stage (II through IV) and grade. In a pediatric report from the United Kingdom, immature teratomas did not respond to chemotherapy. This study did not include patients older than 15 years. Further 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.)
Mature and Immature Teratomas (Sacrococcygeal Site)
The sacrococcygeal region is the primary tumor site for most benign and malignant GCTs diagnosed in neonates, infants, and children younger than 4 years. These tumors occur more often in girls than in boys; ratios of 3:1 to 4:1 have been reported.
Sacrococcygeal tumors present in the following two clinical patterns related to the child's age, tumor location, and likelihood of tumor malignancy:
Standard treatment options for mature and immature teratomas (sacrococcygeal sites)
Standard treatment options for mature and immature teratomas in a sacrococcygeal site include the following:
Surgery is an essential component of treatment. Complete resection of the coccyx is vital to minimize the likelihood of tumor recurrence; however, one study reported that 11 of 12 patients with microscopic residual benign immature teratomas had no recurrence.
After successful resection, neonates diagnosed with benign mature and immature teratomas are closely observed with follow-up exams and serial serum AFP determinations for several years to ensure that the expected physiological normalization of AFP levels occurs and to facilitate early detection of tumor relapse. 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.[9,13,19,20]
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, 92%). Long-term survivors are monitored for complications of extensive surgery, which include constipation, fecal and urinary incontinence, and psychologically unacceptable cosmetic scars.
Current Clinical Trials
Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with childhood teratoma. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.
General information about clinical trials is also available from the NCI Web site.
Childhood Malignant Testicular GCTs
Malignant testicular GCTs in prepubertal males
Testicular germ cell tumors (GCTs) in children occur almost exclusively in boys younger than 4 years.[1,2] The initial surgical approach to evaluate a testicular mass in a young boy is important because a transscrotal biopsy can risk inguinal node metastasis.[3,4] Radical inguinal orchiectomy with initial high ligation of the spermatic cord is the procedure of choice.
Computed tomography or magnetic resonance imaging evaluation, with the additional information provided by elevated tumor markers, appears adequate for staging. Retroperitoneal dissection of lymph nodes is not beneficial in the staging of testicular GCTs in young boys.[3,4] Therefore, there is no reason to risk the potential morbidity (e.g., impotence and retrograde ejaculation) associated with lymph node dissection.[6,7]
The role of surgery at diagnosis for GCTs is age- and site-dependent and must be individualized. All malignant testicular GCTs should be resected. Primary resection of other areas of disease may be appropriate when feasible, without undue risk of damage to adjacent structures; otherwise, an appropriate strategy is resection of the testis for diagnosis followed by subsequent excision in selected patients who have residual masses after undergoing chemotherapy.
Standard treatment options for malignant GCTs in prepubertal males
Standard treatment options for malignant GCTs in prepubertal males (younger than 15 years) include the following:
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]
Surgery and chemotherapy with four cycles of standard PEB is a common treatment regimen. Patients treated with this regimen have an overall survival (OS) outcome greater than 90%, suggesting that a reduction in therapy could be considered.[10,11]
Surgery and treatment with four to six cycles of carboplatin, etoposide, and bleomycin (JEB) is an alternative treatment regimen.
Evidence (surgery and chemotherapy for stages II–IV disease):
Malignant testicular GCTs in postpubertal males
The treatment options described above for young boys may not be strictly applicable to adolescent males (aged 15 years and older). In particular, the use of retroperitoneal lymph node dissection may play a crucial role in the evaluation of early-stage testicular GCT  and for residual disease after chemotherapy for the treatment of metastatic GCT.[13,14]
In this age group, the presence of a sarcomatous component in the primary testis GCT does not alter the prognosis; however, if a sarcomatous component is found in a metastatic lesion, survival is likely to be compromised.
Standard treatment options for malignant testicular GCTs in postpubertal males
Refer to the PDQ summary on Testicular Cancer Treatment for more information about the treatment of malignant testicular GCTs in postpubertal males.
Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with childhood malignant testicular germ cell tumor. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.
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 Mature Teratomas [Nonsacrococcygeal Sites] section of this summary for more information about childhood mature and immature teratomas arising in the ovary and the PDQ summary on Ovarian Germ Cell Tumors Treatment for more information 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 of the ovary, cure can usually be achieved by unilateral salpingo-oophorectomy, conserving the uterus and opposite ovary, and close follow-up observation.[8,16,17,18,19]
Chemotherapy may be given if tumor markers do not normalize or if the tumor recurs.
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 [20,21] make chemotherapy a more attractive adjunct to surgery.[22,23] 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. This approach results in a high rate of cure and the preservation of menstrual function and fertility in most patients with dysgerminomas.[22,24]
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 hope that reproductive function can be preserved.
Standard treatment options for malignant nongerminomatous ovarian GCTs
Standard treatment options for malignant nongerminomatous ovarian GCTs include the following:
The treatment of ovarian malignant GCTs that are not dysgerminomas or immature teratomas generally involves surgical resection and adjuvant chemotherapy.[25,26]
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.[8,28] 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.
Platinum-based chemotherapy regimens such as PEB or JEB have been used successfully in children.[8,10,11,16] BEP is a common regimen in young women with ovarian GCTs.[30,31] 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.[26,28] (Refer to Table 5 for more information about the dosing schedules for BEP, PEB, and JEB.)
When strict surgical staging guidelines are followed, surgery followed by observation may be an appropriate treatment choice.
Similar results have been reported in other international pediatric trials, but the number of patients has been small.
When strict surgical staging guidelines are not followed, surgery followed by chemotherapy is an appropriate treatment choice. Chemotherapy consists of four cycles of PEB.[10,11]
Evidence (surgery and chemotherapy for stage I disease):
Surgery and chemotherapy with four to six cycles of standard PEB in younger girls [10,11] and BEP in postpubertal girls are considered standard treatments.[30,31] Patients with normalization of tumor markers are imaged after four cycles of PEB, and any residual tumor is removed. If the tumor is completely resected but the specimen contains viable tumor, two additional cycles of PEB can be given. Any persistent viable tumor that remains indicates that the treatment has failed.
Alternatively, surgery and chemotherapy with four to six cycles of JEB is also a treatment option (patients were all younger than 15 years).
Initially unresectable tumor
Primary resection of ovarian GCT is usually attempted. In rare instances where primary resection of the ovary is not possible without undue risk of damage to adjacent structures, an appropriate strategy is biopsy for diagnosis followed by subsequent surgery in patients who have residual masses after undergoing chemotherapy.
Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with childhood malignant ovarian germ cell tumor. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.
Extragonadal extracranial germ cell tumors (GCTs) (i.e., sacrococcygeal, mediastinal, and retroperitoneal) are more common in children than in adults. Children with extragonadal malignant GCTs, particularly those with advanced-stage disease, have the highest risk of treatment failure for any GCT presentation.[2,3]
In a study of prognostic factors in pediatric extragonadal malignant GCTs, age older than 12 years was the most important prognostic factor. In a multivariate analysis, children aged 12 years or older with thoracic tumors had six times the risk of death compared with children younger than 12 years with primary nonthoracic tumors.
Standard Treatment Options for Malignant Extragonadal Extracranial GCTs
Standard treatment options for malignant extragonadal extracranial GCTs include the following:
Outcome has improved remarkably since the advent of platinum-based chemotherapy and the use of a multidisciplinary treatment approach.[2,5] Complete resection before chemotherapy may be possible in some patients without major morbidity. For patients with locally advanced sacrococcygeal tumors, mediastinal tumors, or large pelvic tumors, tumor biopsy followed by preoperative chemotherapy can facilitate subsequent complete tumor resection and improve ultimate patient outcome.[5,6,7,8]
The role for surgery at diagnosis for extragonadal tumors is age- and site-dependent and must be individualized. Depending on the clinical setting, the appropriate surgical approach may be primary resection, biopsy before chemotherapy, or no surgery (e.g., mediastinal primary tumor in a patient with a compromised airway and elevated tumor markers). An appropriate strategy may be biopsy at diagnosis followed by chemotherapy and subsequent surgery in selected patients who have residual masses after chemotherapy.
Stages I and II
Surgery and chemotherapy with four to six cycles of standard cisplatin, etoposide, and bleomycin (PEB) is one treatment alternative. Patients treated with this regimen have an overall survival (OS) outcome greater than 90%, suggesting that a reduction in therapy could be considered.[2,9] An alternative treatment option is surgery and chemotherapy with six cycles of carboplatin, etoposide, and bleomycin (JEB).
Stages III and IV
A treatment option for stage III and stage IV disease is surgery and chemotherapy with four to six cycles of standard PEB. Patients have an OS outcome approaching 80% with this regimen. Another treatment option is surgery and chemotherapy with six cycles of JEB, which has an OS similar to that of the PEB regimen.
A Children's Oncology Group trial investigated the addition of cyclophosphamide to standard-dose PEB. The addition of cyclophosphamide was feasible and well tolerated at all dose levels, but there was no evidence that adding cyclophosphamide improves efficacy.
Malignant Extragonadal Extracranial GCTs (Sacrococcygeal Sites)
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 event-free survival (EFS) rates of 75% to 85% and OS rates of 80% to 90%.[7,8] Surgery may be facilitated by preoperative chemotherapy. In any patient with a sacrococcygeal GCT, resection of the coccyx is mandatory.[7,8]
Completeness of surgical resection is an important prognostic factor, as shown in the following circumstances:[7,8]
Malignant Extragonadal Extracranial GCTs (Mediastinal)
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.
Children with mediastinal teratomas are treated with tumor resection, which is curative in almost all patients. Children with malignant, nonmetastatic mediastinal GCTs who receive cisplatin-based chemotherapy have 5-year EFS and OS rates of 90%; however, metastatic mediastinal tumors have an EFS closer to 70%.[5,6]
Most mediastinal GCTs in adolescents and young adults occur in males, and 22% to 50% have cytogenetic changes consistent with Klinefelter syndrome.[14,15] The age of presentation is younger in patients with Klinefelter syndrome.[14,15] As with sacrococcygeal tumors, primary chemotherapy is usually necessary to facilitate surgical resection of mediastinal GCTs, and the completeness of resection is a very important prognostic indicator.[6,16] Survival rates for the older adolescent and young adult population with mediastinal tumors are generally lower than 60%.[4,17,18,19]; [Level of evidence: 3iiA]
Patients with a malignant mediastinal primary tumor and extracranial metastases are at the highest risk of developing brain metastases and are monitored closely for signs and symptoms of central nervous system involvement.[Level of evidence: 3iiB] (Refer to the PDQ summary on Extragonadal Germ Cell Tumors Treatment for more information about the treatment of adult patients.)
Malignant Extragonadal Extracranial GCTs (Retroperitoneum)
Malignant GCTs located in the retroperitoneum or abdomen usually present in children 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 using PEB was 83% in the Pediatric Oncology Group/Children's Cancer Group intergroup study.
Malignant Extragonadal Extracranial GCTs (Head and Neck Sites)
Although rare, benign and malignant GCTs can occur in the head and neck region, especially in infants. The airway is often threatened. Surgery for nonmalignant tumors and surgery plus chemotherapy for malignant tumors can be curative.[Level of evidence: 3iiiDii]
Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with childhood extragonadal germ cell tumor. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.
Only a small number of children and adolescents with extracranial germ cell tumors (GCTs) have a recurrence.[1,2] However, the approach to the treatment of recurrent disease and its success depend on the initial treatment regimen and on the response of the tumor to treatment.
There are no standard treatment options for recurrent pediatric GCTs. Information about ongoing clinical trials is available from the NCI website.
Treatment Options for Recurrent Malignant GCTs in Children
Treatment options for recurrent childhood malignant GCTs include the following:
Despite overall cure rates higher than 80%, children with extracranial GCTs who have disease recurrence after surgery and three-agent, platinum-based combination chemotherapy (cisplatin, etoposide, and bleomycin [PEB] or carboplatin, etoposide, and bleomycin [JEB]) have an unfavorable prognosis. Reports regarding the treatment and outcome of these children are based on small studies.
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 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 HD chemotherapy and hematopoietic stem cell transplant (HSCT).
Surgery followed by chemotherapy
If a tumor recurs, boys with stage I testicular disease originally treated with surgical resection and observation can usually undergo salvage therapy with further surgical excision and standard PEB or JEB chemotherapy.[11,12]
For stage I ovarian GCT patients originally treated with surgery and observation, several European studies have reported encouraging salvage rates with further surgical excision and chemotherapy.[13,14]
In a Children's Oncology Group trial (AGCT0521 [NCT00467051]), patients who relapsed after PEB therapy received two cycles of paclitaxel, ifosfamide, and carboplatin. Study results are pending.
Chemotherapy followed by surgery and possibly radiation therapy
Most children with benign sacrococcygeal tumors experience recurrence with a malignant component at the primary tumor site. For these children, complete surgical resection of the recurrent tumor and coccyx (if not done originally) is the basis of salvage treatment; preoperative chemotherapy with PEB may assist the surgical resection. In patients who had a malignant sacrococcygeal tumor that recurred after PEB treatment, surgery and additional chemotherapy may be warranted; when a complete salvage resection is not achieved, postoperative local radiation therapy may be an option.
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. Further study in children and adolescents is needed.
HD chemotherapy with autologous stem cell rescue has been explored as a treatment for adults with recurrent testicular GCTs. HD chemotherapy plus hematopoietic stem cell rescue has been reported to cure adult patients with relapsed testicular GCTs, even as third-line therapy and in cisplatin-refractory patients. While several other studies support this approach,[10,17,18,19,20] others do not.[21,22] Salvage attempts using HD-chemotherapy regimens may be of little benefit if the patient is not clinically disease free at the time of HSCT.[16,23]
Radiation therapy followed by surgery (for brain metastases)
Patients with nongerminomatous brain metastases may respond to radiation therapy. In the German Maligne Keimzelltümoren (MAKEI) studies, radiation therapy and surgery for patients with brain metastases provided palliation and occasional long-term survival.[24,25][Level of evidence: 3iiiA]
Treatment Options Under Clinical Evaluation for Recurrent Malignant GCTs in Children
Treatment options under clinical evaluation for recurrent malignant GCTs in children include the following:
Information about ongoing clinical trials is available from the NCI website.
Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with recurrent childhood malignant germ cell tumor. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.
The PDQ cancer information summaries are reviewed regularly and updated as new information becomes available. This section describes the latest changes made to this summary as of the date above.
This summary was reformatted.
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:
Changes to the summaries are made through a consensus process in which Board members evaluate the strength of the evidence in the published articles and determine how the article should be included in the summary.
The lead reviewers for Childhood Extracranial Germ Cell Tumors Treatment are:
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Levels of Evidence
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National Cancer Institute: PDQ® Childhood Extracranial Germ Cell Tumors Treatment. Bethesda, MD: National Cancer Institute. Date last modified <MM/DD/YYYY>. Available at: http://www.cancer.gov/types/extracranial-germ-cell/hp/germ-cell-treatment-pdq. Accessed <MM/DD/YYYY>.
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