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Fortunately, cancer in children and adolescents is rare, although the overall incidence of childhood cancer has been slowly increasing since 1975. Children and adolescents with cancer should be referred to medical centers that have a multidisciplinary team of cancer specialists with experience treating the cancers that occur during childhood and adolescence. This multidisciplinary team incorporates the skills of the primary care physician, pediatric surgical subspecialists, radiation therapists, pediatric oncologists/hematologists, rehabilitation specialists, pediatric nurse specialists, social workers, and others to ensure that children receive treatment, supportive care, and rehabilitation that will achieve optimal survival and quality of life. Specific information about supportive care for children and adolescents with cancer can be found in the PDQ Supportive and Palliative Care summaries.
Guidelines for pediatric cancer centers and their role in the treatment of pediatric patients with cancer have been outlined by the American Academy of Pediatrics. At these pediatric cancer centers, clinical trials are available for most of the types of cancer that occur in children and adolescents, and the opportunity to participate in these trials is offered to most patients/families. Clinical trials for children and adolescents with cancer are generally designed to compare potentially better therapy with therapy that is currently accepted as standard. The majority of the progress made in identifying curative therapies for childhood cancers has been achieved through clinical trials. Information about ongoing clinical trials is available from the NCI Web site.
Dramatic improvements in survival have been achieved for children and adolescents with cancer. Between 1975 and 2002, childhood cancer mortality decreased by more than 50%. For gonadal extracranial germ cell tumor (GCT), the 5-year survival rate has increased over the same time from 89% to 98% for children younger than 15 years and from 70% to 95% for adolescents aged 15 to 19 years. For extragonadal GCT, the 5-year survival rate from 1979 to 2002 increased from 42% to 83% for children younger than 15 years. Childhood and adolescent cancer survivors require close follow-up since cancer therapy side effects may persist or develop months or years after treatment. (Refer to the PDQ summary on Late Effects of Treatment for Childhood Cancer for specific information about the incidence, type, and monitoring of late effects in childhood and adolescent cancer survivors.)
Childhood GCTs are rare in children younger than 15 years, accounting for approximately 3% of cancer cases in this age group.[3,4,5] In the fetal/neonatal age group, the majority of extracranial GCTs that occur are benign teratomas occurring at midline locations including sacrococcygeal, retroperitoneal, mediastinal, and cervical regions. Despite the small percentage of malignant teratomas that occur in this age group, perinatal tumors have a high morbidity rate due to hydrops fetalis and premature delivery.[6,7] Extracranial GCTs (particularly testicular GCTs) are much more common among adolescents aged 15 to 19 years, representing approximately 14% of cancer diagnoses in this age group. The incidence of extracranial GCTs by 5-year age group and by gender is shown in Table 1 below.
GCTs develop from primordial germ cells, which migrate during embryogenesis from the yolk sac through the mesentery to the gonads.[8,9] Childhood extracranial GCTs can be divided into gonadal and extragonadal types. Most childhood extragonadal GCTs arise in midline sites (i.e., sacrococcygeal, mediastinal, and retroperitoneal); the midline location may represent aberrant embryonic migration of the primordial germ cells.
The histologic and genetic properties of these tumors are heterogeneous and vary by primary tumor site and the gender and age of the patient.[10,11] Histologically identical GCTs that arise in younger children have different biological characteristics from those that arise in adolescents and young adults.
Childhood extracranial germ cell tumors (GCTs) comprise a variety of histologic diagnoses and can be broadly classified into mature or immature teratomas and malignant GCTs.
Mature teratomas usually occur in the ovary or at extragonadal locations and are the most common histological subtype of childhood GCT.[1,2,3] These teratomas usually contain well-differentiated tissues from the ectodermal, mesodermal, and endodermal germ cell layers, and any tissue type may be found within the tumor. Mature teratomas are benign, though some mature and immature teratomas may secrete enzymes or hormones, including insulin, growth hormone, androgens, prolactin, and vasopressin.[4,5,6]
Immature teratomas contain tissues from all three germ cell layers, but immature tissues, primarily neuroepithelial, are also present. Immature teratomas are graded from 0 to 3 based on the amount of immature neural tissue found in the tumor specimen. Tumors of higher grade are more likely to have foci of yolk sac tumor. Immature teratomas occur primarily in young children at extragonadal sites and in the ovaries of girls near the age of puberty, but there is no correlation between tumor grade and patient age.[8,9]
GCTs contain frankly malignant tissues of germ cell origin, and rarely, tissues of somatic origin. Isolated malignant elements may constitute a small fraction of a predominantly mature or immature teratoma.[9,10] Malignant germ cell elements of children, adolescents, and young adults can broadly be classified by location (see Tables 2 and 3).
Yolk sac tumors produce alpha-fetoprotein (AFP), while germinomas (seminomas and dysgerminomas), and especially choriocarcinomas, produce beta-human chorionic gonadotropin, resulting in elevated serum levels of these substances. Most children with malignant GCTs will have a component of yolk sac tumor and have elevations of AFP,[12,13] which is serially monitored during treatment to help assess response to therapy.[9,10,12]
Adolescents and young adults present with more germinomas (testicular and mediastinal seminomas in males and ovarian dysgerminomas in females). These tumors are usually treated with chemotherapy. They are also sensitive to radiation therapy, but radiation is rarely recommended. Radiation therapy and surgery for the patient with brain metastases may provide palliation and occasionally, long-term survival.[14,15][Level of evidence: 3iiiA]
The following paragraphs describe the biologically distinct subtypes of GCTs found in children and adolescents. It should be emphasized that very few pediatric GCT specimens have been analyzed to date. Biologic distinctions between GCTs in children versus adults may not be absolute.[1,2,3]
Ovarian GCTs occur primarily in adolescent and young adult females. While the majority of ovarian GCTs are benign mature teratomas, a heterogeneous group of malignant GCTs occur in females, including immature teratomas, dysgerminomas, yolk sac tumors, and mixed GCTs. Patients with pediatric ovarian GCTs have an excellent prognosis. One series of 66 patients followed over 44 years reported recurrence and mortality rates of 4.5% and 3%, respectively. The malignant ovarian GCT commonly shows increased copies of the short arm of chromosome 12. (Refer to the PDQ summary on Ovarian Germ Cell Tumors Treatment for more information.)
Extragonadal Extracranial GCTs
There is very little data about the potential genetic or environmental factors associated with childhood extracranial GCTs. Patients with Klinefelter syndrome [22,23,24] are at increased risk for mediastinal GCTs, while patients with Swyer syndrome [25,26] are at increased risk for gonadoblastomas and germinomas.
As with other childhood solid tumors, stage directly impacts the outcome of patients with malignant germ cell tumors (GCTs).[1,2,3] The most commonly used staging system in the United States is described below. Retroperitoneal lymph node dissection has not been required in pediatric germ cell trials to stage males younger than 15 years. Data on adolescent males with testicular GCTs are limited. Retroperitoneal lymph node dissection is used for both staging and treatment in adult testicular GCT trials. (Refer to the PDQ summary on Testicular Cancer Treatment for more information about the staging of adult testicular GCTs.)
Nonseminoma Testicular GCT Staging From Children's Oncology Group
Ovarian GCT Staging From Children's Oncology Group
Ovarian GCT Staging From FIGO
Another staging system used frequently by gynecologic oncologists is the International Federation of Gynecologic Oncologists (FIGO) staging system, which is based on an adequate staging operation at the time of diagnosis. (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:
Stage I: Tumor limited to the ovaries
Stage II: Ovarian tumor with pelvic extension
Stage III: Tumor outside the pelvis, or positive nodes
Stage IV: Distant organ involvement, including liver parenchyma or pleural space
Extragonadal Extracranial GCT Staging From Children's Oncology Group
Prior to effective chemotherapy, children with extracranial malignant germ cell tumors (GCTs) had 3-year survival rates of 15% to 20% with surgery and radiation therapy,[1,2,3] though young boys with localized testicular tumors did well with surgical resection.[4,5] The outcome for most children and adolescents with extracranial GCT is now favorable when appropriate treatment is provided. Prognosis and appropriate treatment depend on factors such as histology (e.g., seminomatous vs. nonseminomatous), age (young children vs. adolescents), stage of disease, and primary site.[6,7,8,9] To maximize the likelihood of long-term survival while minimizing the likelihood of treatment-related long-term sequelae (e.g., secondary leukemias, infertility, hearing loss, and renal dysfunction), it is important that children with extracranial malignant GCTs be cared for at pediatric cancer centers with experience treating these rare tumors. Based on clinical factors, appropriate treatment may involve: surgical resection followed by careful monitoring for disease recurrence; diagnostic tumor biopsy and preoperative platinum-based chemotherapy followed by definitive tumor resection; or initial surgical resection followed by platinum-based chemotherapy. For patients with completely resected immature teratomas at any location (even those with malignant elements) and patients with localized, completely resected (stage I) gonadal tumors, additional therapy may not be necessary; however, close follow-up is important.[11,12] The watch-and-wait approach requires scheduled serial physical examination, tumor marker determination, and primary tumor imaging to ensure that a recurrent tumor is detected without delay.
Cisplatin-based chemotherapy has dramatically improved the outcome for children with extracranial GCTs, with 5-year survival rates of more than 90%.[6,7,8,9] The standard chemotherapy regimen for both adults and children with malignant nonseminomatous GCTs includes cisplatin, etoposide, and bleomycin (PEB), though children receive fewer doses of bleomycin than adults.[6,7,13,14] The combination of carboplatin, etoposide, and bleomycin (JEB) has undergone clinical investigation in the United Kingdom in children younger than 16 years and is reported to have a similar event-free survival (EFS) by site and stage as PEB.[8,15] The use of JEB appears to be associated with less ototoxicity and nephrotoxicity than PEB. 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. No randomized comparison of PEB versus JEB has been conducted in children. See Table 4 for pediatric PEB and JEB chemotherapy dosing schedules.
The approach to the management of extracranial GCTs has been informed by the results of two intergroup studies conducted by the Children's Cancer Group (CCG) and the Pediatric Oncology Group (POG).[6,7,11] These studies explored the use of PEB for the treatment of localized gonadal GCT  and the benefit of increasing the dose of cisplatin (high-dose [HD]-PEB: 200 mg/m2 vs. PEB: 100 mg/m2 of cisplatin) in a randomized manner in patients with extragonadal and advanced gonadal GCTs.
The intensification of cisplatin in the HD-PEB regimen provided some improvement in EFS but no difference in OS; however, the use of HD-PEB was associated with a significantly higher incidence and severity of ototoxicity and nephrotoxicity. In a subsequent study, amifostine was not effective in preventing hearing loss in patients who received HD-PEB.
Table 5 provides an overview of standard treatment options for children with extracranial GCTs. Treatment requires a multidisciplinary approach with various surgical subspecialties and pediatric oncologists. Specific details of treatment by primary site and clinical condition are described in subsequent sections.
Non-GCT Malignant Elements
The treatment of GCTs with other non-GCT elements is complex and scant data exist to inform treatment. Specific treatment for both the malignant GCT and non-GCT elements may be required. However, the optimal treatment strategy for other malignant elements found in GCT has not been determined.
Mature and immature teratomas arise primarily in the sacrococcygeal region of neonates and young children and in the ovaries of pubescent girls. These tumors are also less commonly found in the testicular region of boys younger than 4 years, the mediastinum of adolescents, and other sites.[1,2,3]
Sacrococcygeal Tumors in Children
Standard treatment options
The sacrococcygeal region is the primary tumor site for the majority of benign and malignant germ cell tumors (GCTs) diagnosed in neonates, infants, and children younger than 4 years. These tumors occur more often in girls than in boys; ratios of 3:1 to 4:1 have been reported. Sacrococcygeal tumors present in two clinical patterns related to the child's age, tumor location, and likelihood of tumor malignancy. Neonatal tumors present at birth protruding from the sacral site are usually mature or immature teratomas. Among infants and young children, the tumor presents as a palpable mass in the sacropelvic region compressing the bladder or rectum. These pelvic tumors have a greater likelihood of being malignant. An early survey found that the rate of tumor malignancy was 48% for girls and 67% for boys older than 2 months at the time of sacrococcygeal tumor diagnosis, compared with a malignant tumor incidence of 7% for girls and 10% for boys younger than 2 months at the time of diagnosis. The pelvic site of the primary tumor has been reported to be an adverse prognostic factor, which may be due to either delayed diagnosis because it was unappreciated at birth or incomplete resection at the time of original surgery.[5,6,7,8]
After successful resection, neonates diagnosed with benign mature and immature teratomas are observed with close follow-up exams and serial serum alpha-fetoprotein (AFP) determinations for several years to ensure that the expected physiological normalization of AFP levels occurs and to facilitate early detection of tumor relapse. A significant rate of recurrence among these benign tumors has been reported by several groups, ranging from 10% to 21%, with most relapses occurring within 3 years of resection.[4,9,10,11] While there is no standard follow-up schedule, follow-up should include scans and tumor markers for 3 years. Importantly, 43% to 50% of these recurrent tumors will be malignant and require adjuvant chemotherapy. With early detection, these malignant GCTs can be treated successfully with surgery and chemotherapy (overall survival, 92%). Complete resection of the coccyx is vital to minimize the likelihood of tumor recurrence; however, one study reported that 11 out of 12 patients with microscopic residual benign immature teratoma had no recurrence. Long-term survivors should be monitored for complications of extensive surgery, which include constipation, fecal and urinary incontinence, and psychologically unacceptable cosmetic scars.
Nonsacrococcygeal Teratomas in Children
Mature teratoma and epidermoid cyst in the prepubertal testis are relatively common benign lesions and may be amenable to testis-sparing surgery. Children with mature teratomas, including mature teratomas of the mediastinum, can be treated with surgery and observation with an excellent prognosis.[1,16] In a review of 153 children with nontesticular mature teratoma, the 6-year relapse-free survival for completely resected disease was 96% versus 55% for incomplete resection. Head and neck GCTs in neonates should be cared for by a multidisciplinary team. While most are benign, they do present significant challenges to surgeons. Some tumors develop malignant elements, which may change the treatment strategy.
In infants and young children, immature teratomas have benign clinical behavior if they can be resected.[10,18,19] In a single institution retrospective study, immature teratomas had a mortality rate (16.2%) twice that of yolk sac tumors (7.4%) and reflects the few patients with immature teratomas (unfavorable sites) that could not be resected. Immature teratomas generally do not respond to chemotherapy. In adults, immature teratomas (primarily ovarian) reportedly have an aggressive clinical behavior  requiring surgery and chemotherapy. The benefit of adjuvant chemotherapy for children was questioned in a study by the Pediatric Oncology Group and Children's Cancer Group that evaluated the use of surgical resection followed by careful observation for patients with immature teratomas. Surgery alone was curative for most children and adolescents with resected ovarian immature teratoma of any grade, even when elevated levels of serum AFP or microscopic foci of yolk sac tumor were present. The study demonstrated a 3-year event-free survival of 97.8%, 100%, and 80% for patients with ovarian, testicular, and extragonadal tumors, respectively. It is important to emphasize that the number of pediatric patients with residual teratomas and immature teratomas is very small. There may be a role for surgical removal of residual benign lesions.
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
Testicular GCTs in young boys
Testicular germ cell tumors (GCTs) in children occur almost exclusively in boys younger than 4 years.[1,2] The initial approach to evaluate a testicular mass in a young boy is important because a transscrotal biopsy can risk inguinal node metastasis.[3,4] Radical inguinal orchiectomy with initial high ligation of the spermatic cord is the procedure of choice. Retroperitoneal dissection of lymph nodes is not beneficial in the staging of testicular GCTs in young boys. Computed tomography or magnetic resonance imaging evaluation, with the additional information provided by elevated tumor markers, appears adequate for staging.[3,4] Therefore, there is no reason to risk the potential morbidity (e.g., impotence and retrograde ejaculation) related to lymph node dissection.[6,7]
A Children's Cancer Group (CCG)/Pediatric Oncology Group (POG) clinical trial evaluated surgery followed by observation for boys aged 10 years or younger with stage I testicular tumors. This treatment strategy resulted in a 6-year event-free survival (EFS) of 82%; those boys who developed recurrent disease were salvaged with four cycles of standard-dose cisplatin, etoposide, and bleomycin (PEB), with a 6-year survival of 100%.[3,4] Boys younger than 10 years with stage II tumors were treated after diagnosis with four cycles of PEB. Boys and adolescents (age not limited to 10 years or younger) with stage III and IV testicular tumors were treated with surgical resection followed by four cycles of standard or high-dose (HD)-PEB therapy. The 6-year survival outcome for males younger than 15 years with stage III and IV tumors was 100%, with 6-year EFS of 100% and 94%, respectively. The use of HD-PEB therapy did not improve the outcome for these boys but did cause increased incidence of ototoxicity. Excellent outcomes for boys with testicular GCTs using surgery and observation for stage I tumors and carboplatin, etoposide, and bleomycin (JEB) and other cisplatin-containing chemotherapy regimens for stage II, III, and IV tumors have also been reported by European investigators.[6,10] Thus, surgery followed by standard-dose platinum-based chemotherapy is the recommended approach for stages II, III, and IV testicular GCTs in children younger than 15 years.
Surgery: The role of surgery at diagnosis for GCTs is age- and site-dependent and must be individualized. Primary resection is appropriate when feasible without undue risk of damage to adjacent structures; otherwise, an appropriate strategy is biopsy for diagnosis followed by subsequent excision in selected patients who have residual masses following chemotherapy.
Stages II through IV
Treatment options under clinical evaluation for stages I through IV in patients younger than 15 years
The following is an example of a national and/or institutional clinical trial that is currently being conducted. Information about ongoing clinical trials is available from the NCI Web site.
Testicular GCTs in adolescents and young adult males
Because the biology of testicular GCTs among adolescents and young adult males is different from that of testicular tumors arising in infants and young boys, the treatment guidelines described above for young boys may not be strictly applicable to adolescent males. In particular, the use of retroperitoneal lymph node dissection may play a crucial role both in early stage testicular GCT  and for residual disease after chemotherapy for the treatment of metastatic GCT.[12,13] In this age group, the presence of a sarcomatous component in the primary testis GCT does not alter the prognosis, but if a sarcomatous component is found in a metastatic lesion, survival is likely to be compromised.
(Refer to the PDQ summary on Testicular Cancer Treatment for more information.)
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 and childhood malignant ovarian germ cell tumor. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.
Childhood Malignant Ovarian GCT
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 dysgerminomas (seminomatous) and nonseminomatous malignant GCTs (i.e., immature teratomas, yolk sac carcinomas, mixed GCTs, choriocarcinoma, and embryonal carcinomas). (For information on childhood mature and immature teratomas arising in the ovary, see the Nonsacrococcygeal Teratomas in Children section of this summary. Refer to the PDQ summary on Ovarian Germ Cell Tumors Treatment for more information.)
For stage I ovarian dysgerminomas and immature teratomas, cure can usually be achieved by unilateral salpingo-oophorectomy, conserving the uterus and opposite ovary, and close follow-up observation.[10,15,16,17,18] Chemotherapy can be given if tumor markers do not normalize or if tumors recur.
While advanced-stage ovarian dysgerminomas similar to testicular seminomas are highly curable with surgery and radiation therapy, the effects on growth, fertility, and risk of treatment-induced second malignancy in these young patients [19,20] make chemotherapy a more attractive adjunct to surgery.[21,22] 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 maintenance of menstrual function and fertility in most patients with dysgerminomas.[21,23]
For ovarian malignant GCTs other than dysgerminomas or immature teratomas, treatment generally involves surgical resection and adjuvant chemotherapy.[24,25] Platinum-based chemotherapy regimens such as PEB or JEB have been used successfully in children,[8,9,10,15] and PEB is a common regimen in young women with ovarian GCTs.[26,27] This approach results in a high rate of cure and the maintenance of menstrual function and fertility in most patients with nondysgerminomas.[25,28] A few small studies have suggested that observation after surgery may be an option, but only as part of a clinical trial with strict adherence to surgical guidelines.[10,28]
A multidisciplinary approach is essential for treatment of ovarian GCTs. Various surgical subspecialties and the pediatric oncologist must be involved in clinical decisions. The reproductive surgical approach for pediatric GCTs is often guided by the hope that function can be preserved. In a completed pediatric intergroup trial, pediatric patients with ovarian GCTs (stages I-IV) had excellent survival with PEB and conservative surgery, rather than the strict guidelines proposed originally in the study. The role of laparoscopy in children with ovarian GCTs has not been well studied.
Surgery: The role for surgery at diagnosis is age- and site-dependent and must be individualized. Primary resection is appropriate when feasible without undue risk of damage to adjacent structures; otherwise, an appropriate strategy is biopsy for diagnosis followed by subsequent surgery in selected patients who have residual masses following chemotherapy.
Stages I through IV
Treatment options under clinical evaluation for stages I through III
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 germ cell tumors (GCTs) (i.e., sacrococcygeal, mediastinal, and retroperitoneal) are more common in children than adults. Children with extragonadal malignant GCTs, particularly those with advanced stage, 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. Outcome has improved remarkably, however, since the advent of platinum-based chemotherapy and the use of a multidisciplinary treatment approach.[2,5] Complete resection prior to chemotherapy may be possible in some patients without major morbidity, but 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]
Sacrococcygeal GCTs are very common extragonadal tumors that occur in very young children, predominately young females. They are usually diagnosed at birth, when large external lesions predominate (usually benign 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 the patients.[7,10,11] Because of advanced presentation, the management of sacrococcygeal tumors requires a multimodal approach with chemotherapy followed by delayed tumor resection. Platinum-based therapies, with either cisplatin or carboplatin, are the cornerstone of treatment. The cisplatin, etoposide, and bleomycin (PEB) regimen or the carboplatin, etoposide, and bleomycin (JEB) regimen produces event-free survival (EFS) rates of 75% to 85%; overall survival (OS) rates of 80% to 90% can be achieved.[7,8] Surgery is usually facilitated by preoperative chemotherapy, and completeness of surgical resection is a very important prognostic factor. Patients with resected tumors with negative microscopic margins have EFS rates greater than 90%; patients with microscopic margins have EFS rates of 75% to 85%; and patients with macroscopic residual disease after surgery have EFS rates less than 40%. In any patient with a sacrococcygeal GCT, resection of the coccyx is mandatory.[7,8]
Mediastinal GCTs account for 15% to 20% of malignant nongonadal, extracranial GCTs in children. The histology of mediastinal GCT is dependent on age, with teratomas predominating among infants and with 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%, but an EFS closer to 70% occurs with metastatic mediastinal tumors.[5,6] Most mediastinal GCTs in adolescents and young adults occur in males and 50% have cytogenetic changes consistent with Klinefelter syndrome. The age of presentation is younger in patients with Klinefelter syndrome.[12,13] 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.[6,14] Survival rates for the older adolescent and young adult population with mediastinal tumors are generally less than 60%.[4,15,16,17]; 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 followed 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.)
Malignant GCTs located in the retroperitoneum or abdomen usually present in children before age 5 years; most tumors are of 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 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.
Though rare, benign and malignant GCTs can occur in the head and neck region, especially in infants. Often the airway is threatened. Surgery for nonmalignant tumors plus chemotherapy for malignant tumors can be curative.[Level of evidence: 3iiiDii]
Standard Treatment Options
Surgery: 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 range from no surgery (e.g., mediastinal primary tumor in a patient with a compromised airway and elevated tumor markers), to biopsy, to primary resection. In some cases, an appropriate strategy is biopsy at diagnosis followed by subsequent surgery in selected patients who have residual masses following chemotherapy.
Stages I and II
Stages III and IV
Treatment Options Under Clinical Evaluation
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) relapse.[1,2] However, the approach to recurrent disease and its success depend on the initial treatment regimen and on the response of the tumor to treatment.
Boys with stage I testicular disease originally treated with surgical resection and observation can usually be salvaged, if relapse occurs, by further surgical excision and standard cisplatin, etoposide, and bleomycin (PEB) or carboplatin, etoposide, and bleomycin (JEB) chemotherapy.[3,4] Several European studies also have reported encouraging salvage rates for stage I ovarian GCT patients originally treated with surgery and observation.[5,6]
Most children with recurrent sacrococcygeal tumors will recur locally at the primary tumor site. For these children, complete surgical resection of the recurrent tumor and the coccyx is the basis of salvage treatment; preoperative chemotherapy may assist the surgical resection. In patients in whom a complete salvage resection is not achieved, postoperative local irradiation should be considered.
Despite overall cure rates greater than 80%, children with extracranial GCTs who have disease recurrence after surgery and three-agent platinum-based combination chemotherapy (PEB or JEB) have an unfavorable prognosis. Reports regarding the treatment and outcome of these children include small patient samples. 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.[8,9,10,11,12,13] A combination of paclitaxel and gemcitabine has demonstrated activity in adults with testicular GCTs who relapsed after high-dose (HD) chemotherapy and hematopoietic stem cell transplant (SCT).
HD chemotherapy with autologous stem cell rescue has been explored in 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,[16,17,14,18,19] others do not.[20,21] Salvage attempts using HD-chemotherapy regimens may be of little benefit if the patient is not clinically disease free at the time of hematopoietic SCT.[15,22]
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 (median follow-up 66 months) disease-free survival by using HD chemotherapy with stem cell support. Further study is needed in children and adolescents.
A single-institution study of 44 young people (aged 7 months to 21 years) with refractory or recurrent extracranial GCTs, using cisplatin/etoposide/ifosfamide and regional deep hyperthermia with or without surgery plus radiation therapy for residual tumor, showed a response rate of 86% in 35 patients who had sufficient data available; the 5-year event-free survival was 62% and the 5-year overall survival was 72%.[Level of evidence: 3iiDi] However, regional hyperthermia facilities are limited and not readily available for children in the United States. Further study is needed in children and adolescents.
There are no standard treatment options for recurrent pediatric GCTs. The role for surgery in selected patients who have recurrent GCTs has not been established but should be considered. Information about ongoing clinical trials is available from the NCI Web site.
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.
Histologic Classification of Childhood Extracranial GCTs
Added Göbel et al. as reference 14.
Treatment of Childhood Malignant Extragonadal GCTs
Added text to state that patients with a malignant mediastinal primary tumor and extracranial metastases are at the highest risk of developing brain metastases and are followed closely for signs and symptoms of central nervous system involvement (cited Göbel et al. as reference 19 and level of evidence 3iiB).
Treatment of Recurrent Childhood Malignant GCTs
Added text to state that a single-institution study of 44 young people with refractory or recurrent extracranial GCTs, using cisplatin/etoposide/ifosfamide and regional deep hyperthermia with or without surgery plus radiation therapy for residual tumor, showed a response rate of 86% in 35 patients who had sufficient data available; the 5-year event-free survival was 62% and the 5-year overall survival was 72%. However, regional hyperthermia facilities are limited and not readily available for children in the United States. Further study is needed in children and adolescents (cited Wessalowski et al. as reference 24 and level of evidence 3iiDi).
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.
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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://cancer.gov/cancertopics/pdq/treatment/extracranial-germ-cell/HealthProfessional. Accessed <MM/DD/YYYY>.
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Last Revised: 2014-01-27
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