Our Health Library information does not replace the advice of a doctor. Please be advised that this information is made available to assist our patients to learn more about their health. Our providers may not see and/or treat all topics found herein. This information is produced and provided by the National Cancer Institute (NCI). The information in this topic may have changed since it was written. For the most current information, contact the National Cancer Institute via the Internet web site at http://cancer.gov or call 1-800-4-CANCER. GCTs arise from primordial germ cells, which migrate during embryogenesis from the yolk sac through the mesentery to the gonads (see Figure 1).[1,2] Childhood extracranial GCTs can generally be divided into gonadal and extragonadal. These tumors can also be broadly classified as teratomas, malignant GCTs, or mixed GCTs. Incidence Childhood GCTs are rare in children younger than 15 years, accounting for approximately 3% of cancers in this age group.[3,4,5,6] In the fetal/neonatal age group, most extracranial GCTs are benign teratomas occurring at midline locations, including the head and neck, sacrococcyx, and retroperitoneum.[7,8] Despite the small percentage of malignant teratomas that occur in this age group, perinatal tumors have a high morbidity rate caused by hydrops fetalis and premature delivery.[8,9,10] The incidence of malignant extracranial GCTs increases with the onset of puberty. These tumors represent approximately 15% of cancers in male adolescents aged 15 to 19 years and 4% of cancers in female adolescents aged 15 to 19 years.[3] Figure 2 shows the age-incidence profile by sex for malignant extracranial/extragonadal GCTs (left panel) and malignant gonadal GCTs (right panel) between 2014 and 2018 for 23 U.S. Cancer registries that represent 66% of all U.S. children, adolescents, and young adults (blue triangles, females; green triangles, males).[3] For males, there is a peak in incidence in children younger than 2 years for both extragonadal and gonadal sites, which is followed by low rates between the ages of 2 and 12 years, and then higher rates throughout adolescence. For females, the peak in young children is present only for extragonadal tumors, with rates increasing after the age of puberty for both extragonadal and gonadal sites. However, the incidence of each tumor is lower for females during adolescence than for males during adolescence. The incidence of extracranial GCTs according to age group, sex, and gonadal versus extragonadal primary site is shown in Table 1.[3] Risk Factors Cryptorchidism, the presence of an abdominal undescended testis, has been associated with a 10.8-fold increased risk of developing a GCT.[11] Gonadal dysgenesis, as well as the presence of Y-chromosome material in an abdominal gonad, also increases the risk of developing a gonadal GCT, especially gonadoblastoma. Gonadoblastoma is a rare gonadal tumor consisting of a mixture of germ cells and sex-cord stromal derivatives resembling immature granulosa and Sertoli cells.[12,13] 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: Most mediastinal GCTs in adolescents and young adults occur in males, and 22% to 50% have cytogenetic changes consistent with Klinefelter syndrome.[15,18] The age of tumor presentation is younger in patients with Klinefelter syndrome, and testing all younger males for Klinefelter syndrome should be considered.[15,18] Patients with GCTs were identified from the Children's Oncology Group (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 GCTs had Klinefelter syndrome (70% were mediastinal). In comparison, 0.2% of males in the general population have Klinefelter syndrome.[17] Histological Classification of Childhood Extracranial GCTs Childhood extracranial GCTs comprise a variety of histological diagnoses and can be broadly classified as the following: The histological properties of extracranial GCTs are heterogeneous and vary by primary tumor site and the sex and age of the patient.[23,24] Histologically identical GCTs that arise in younger children have different biological characteristics from those that arise in adolescents and young adults.[25] Mature teratoma Mature teratomas can occur at gonadal or at extragonadal locations. They are the most common histological subtype of childhood GCT.[10,26,27,28] Mature teratomas usually contain well-differentiated tissues from the ectodermal, mesodermal, and endodermal germ cell layers. Any tissue type may be found within this tumor. Mature teratomas are benign, although some mature teratomas may secrete enzymes or hormones, including insulin, growth hormone, androgens, and prolactin.[29,30] Immature teratoma Immature teratomas contain tissues from the ectodermal, mesodermal, and endodermal germ cell layers. 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.[31,32] Tumors of higher grade are more likely to have foci of yolk sac tumor.[33] 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. However, there is no correlation between tumor grade and patient age.[33,34] Some immature teratomas may secrete enzymes or hormones such as vasopressin.[35] Malignant GCTs 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. 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.[34,36] Malignant germ cell elements of children, adolescents, and young adults can be grouped broadly by location (see Table 2). GCT Biology Childhood extracranial GCTs develop at many sites, including testicles, ovaries, mediastinum, retroperitoneum, sacrum, coccyx, and head and neck (see Figure 3).[7] The clinical features at presentation are specific for each site. The following biologically distinct subtypes of GCTs are found in children and adolescents: Biological distinctions between GCTs in children and GCTs in adults may not be absolute, and biological factors have not been shown to predict risk.[38,39,40] Testicular GCTs Ovarian GCTs 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.[51] Extragonadal extracranial GCTs Extragonadal extracranial GCTs occur outside of the brain and gonads. For information about the treatment of intracranial GCTs, see Childhood Central Nervous System Germ Cell Tumors Treatment. Diagnostic and Staging Evaluation Diagnostic evaluation of GCTs includes measurement of serum tumor markers and imaging studies. In suspected cases, tumor markers can suggest the diagnosis before surgery and/or biopsy. This information can be used by the multidisciplinary team to make appropriate treatment choices. Tumor markers 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.[56] Common tumor markers include the following: 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.[57,58] The serum half-life of AFP is 5 to 7 days. Yolk sac tumors produce AFP. Most children with malignant GCTs will have a component of yolk sac tumor and have elevations of AFP levels,[59,60] which are serially monitored during treatment to help assess response to therapy.[34,36,59] Benign teratomas and immature teratomas may produce small elevations of AFP and beta-human chorionic gonadotropin (beta-hCG). 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.[61][Level of evidence C1] 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. The serum half-life of beta-hCG is 1 to 2 days. In a prospective multicentric study, the serum level of microRNA-371a-3p was shown to be a sensitive and specific biomarker for adult testicular GCTs.[62] The study included 616 patients with GCTs of varying histologies and 258 controls without malignant GCTs. Elevation of microRNA-371a-3p levels was noted in all malignant histologies, including seminomas. Normal controls and patients with benign teratomas did not have the biomarker elevation. MicroRNA-371a-3p levels were related to tumor volume, and the levels decreased in response to chemotherapy. More studies about microRNA-371a-3p are needed to assess its use in patients with pediatric GCTs. Imaging tests Imaging tests may include the following: Prognostic Factors Prognostic factors for extracranial GCTs depend on many patient and tumor characteristics and include the following (obtained from historical national GCT trials):[59,63,64,65] 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.[66][Level of evidence C2] In this age-focused investigation of these factors in young children and adolescents, outcomes included the following (see Figure 4):[66] A subsequent study used a database of 11 GCT trials and identified 593 patients with metastatic testicular, mediastinal, or retroperitoneal GCTs. The distribution of patients by age groups included 90 children (aged 0 to <11 years), 109 adolescents (aged 11 to <18 years), and 394 young adults (aged 18 to ≤30 years).[67]; [68][Level of evidence C1] 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.[69,70] The presence of gonadal dysgenesis in patients with ovarian nondysgerminomas is associated with worse outcomes. In a report from the COG AGCT0132 study, seven patients with gonadal dysgenesis and ovarian nondysgerminomas had an estimated 3-year EFS rate of 67%, compared with 89% for 100 patients with nondysgerminoma ovarian tumors who did not have gonadal dysgenesis.[13] These dysgenetic gonads contain Y-chromosome material, and intra-abdominal gonads with Y-chromosome material are at increased risk of tumor development.[12,71] 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.[72] For more information about prognosis and prognostic factors for childhood extragonadal extracranial GCTs, see the sections on Treatment of Mature and Immature Teratomas in Children, Treatment of Malignant Gonadal GCTs in Children, and Treatment of Malignant Extragonadal Extracranial GCTs in Children. Follow-up After Treatment The following tests and procedures may be performed at the physician's discretion for monitoring children with extracranial GCTs: A COG trial of patients with low-risk and intermediate-risk GCTs reported the following results:[73][Level of evidence C2] Dramatic improvements in survival have been achieved for children and adolescents with cancer.[74] Between 1975 and 2020, childhood cancer mortality decreased by more than 50%.[3,74,75] During the period from 2002 to 2010, cancer mortality continued to decrease by 2.4% per year for children and adolescents with gonadal tumors, as compared with the period from 1975 to 1998 (plateauing from 1998 to 2001).[74] Childhood and adolescent cancer survivors require close monitoring because late effects of cancer therapy may persist or develop months or years after treatment. For information about the incidence, type, and monitoring of late effects of childhood and adolescent cancer survivors, see Late Effects of Treatment for Childhood Cancer. References: As with other childhood solid tumors, stage of disease at diagnosis 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:[4] Testicular GCT Staging From COG (Patients Aged <11 Years) Table 3 describes the testicular GCT staging for males younger than 11 years from the COG AGCT1531 (NCT03067181) trial. Testicular GCT Staging (Patients Aged ≥11 Years) 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.[5] In males older than 15 years, there are only stage I tumors and metastatic tumors. Metastatic tumors are assigned risk according to the International Germ Cell Consensus Classification.[6] For more information about the American Joint Committee on Cancer staging criteria for testicular GCT in males aged 11 years and older, see Testicular Cancer Treatment. Ovarian GCT Staging From COG Table 4 describes the ovarian GCT staging for females younger than 11 years 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.[7] This system has also been used by some pediatric centers,[2] is most applicable to females older than 11 years, and is described in Table 5. For more information about the FIGO staging system, see Ovarian Germ Cell Tumors Treatment. The ovarian staging systems described above require adherence to specific surgical guidelines. However, in a pediatric intergroup trial, guidelines were followed in only 2 of 131 patients with ovarian tumors.[9] In a single-institution retrospective study, guidelines were followed in only 2 of 44 patients with ovarian tumors.[10] Extragonadal Extracranial GCT Staging From COG Table 6 describes the extragonadal extracranial GCT staging from the COG AGCT1531 (NCT03067181) trial. References: Childhood extracranial germ cell tumors (GCTs) are very heterogenous. On the basis of clinical factors and tumor histology, appropriate treatment for extracranial GCTs may involve one of the following: To maximize long-term survival while minimizing 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. Treatment Options for Childhood Extracranial GCTs by Histological Type Table 7 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. GCTs 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.[4,5] 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).[6] The optimal treatment strategy for GCTs with non-GCT elements has not been determined. Separate treatments for both malignant GCTs and non-GCT elements may be required. Surgery 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 of patients is important.[7,8] 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. Chemotherapy 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]).[3,13] The combination of carboplatin, etoposide, and bleomycin (JEb) underwent clinical investigation in the United Kingdom in children younger than 16 years. Treatment with this regimen produced event-free survival (EFS) rates by site and stage similar to those produced using treatment with PEb.[14,15]; [16][Level of evidence C1] For information about adult BEP and pediatric PEb and JEb chemotherapy dosing schedules, see Table 8.[3,9,10,11,13] In both adult and pediatric trials, the number of adolescent subjects was small. The optimal therapy for adolescents (aged ≥11 years) is not clear.[17] The use of JEb appears to be associated with fewer otologic toxic effects and renal toxic effects than does the use of PEb.[14] 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).[18][Level of evidence C1] 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).[3,7,13] These trials explored the use of PEb for the treatment of localized gonadal GCT [3] 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.[13,20] None of these strategies had a significant effect on survival or decreased toxicity. The COG conducted a trial of compressed and reduced PEb chemotherapy (three cycles in 3 days) for patients with low-risk or intermediate-risk malignant GCTs. This study was designed as a noninferior trial with a P value of .1. The 4-year EFS rate of 89% was significantly lower than the rate for the historical control model (92%; P = .08).[21] However, the number of patients in each stratum was small, and further investigation in patients with lower-stage disease may be warranted. Radiation Therapy 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. References: Cancer in children and adolescents is rare, although the overall incidence has slowly increased since 1975.[1] Children and adolescents with cancer should be referred to medical centers that have a multidisciplinary team of cancer specialists with experience treating the cancers that occur during childhood and adolescence. This multidisciplinary team approach incorporates the skills of the following health care professionals and others to ensure that children receive treatment, supportive care, and rehabilitation that will achieve optimal survival and quality of life: The American Academy of Pediatrics has outlined guidelines for pediatric cancer centers and their role in the treatment of pediatric patients with cancer.[2] At these pediatric cancer centers, clinical trials are available for most of the cancer types that occur in children and adolescents, and the opportunity to participate is offered to most patients and families. Clinical trials for children and adolescents with cancer are generally designed to compare potentially better therapy with current standard therapy. 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. References: 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 with complete resection. Surgical options for sacrococcygeal teratomas are complex. Benign head and neck teratomas and immature teratomas can cause morbidity and mortality through obstruction. 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.[4] Complete resection of a teratoma can be achieved. Treatment of Mature Teratomas Standard treatment options for mature teratomas (sacrococcygeal sites) The sacrococcygeal region is the primary tumor site for most 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.[5] Sacrococcygeal tumors present in the following two clinical patterns related to the child's age, tumor location, and likelihood of tumor malignancy:[1] 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.[6] The pelvic primary tumor site has been reported to be an adverse prognostic factor. This could be due to a delayed diagnosis because it was overlooked at birth or incomplete resection at the time of original surgery.[6,7,8,9] 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.[2] 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 and have an excellent prognosis.[1,10] In a review of 153 children with nontesticular mature teratomas, the 6-year relapse-free survival rate was 96% for patients with completely resected disease and 55% for patients with incompletely resected disease.[2] Another series included 57 girls with mature teratomas of the ovary. Two patients experienced tumor recurrences (8 and 12 months after ovarian-sparing surgery), and seven patients developed metachronous tumors (as late as 79 months after initial diagnosis).[11][Level of evidence C1] A multidisciplinary team should treat and monitor neonates with head and neck GCTs. Although most head and neck GCTs are benign, they can be life-threatening and present significant challenges to surgeons, especially in newborns.[4] Some tumors develop malignant elements, which may change the treatment strategy.[12,13] Mature teratomas in the prepubertal testis are relatively common benign lesions and may be amenable to testis-sparing surgery.[14] Treatment of Immature Teratomas Treatment options for immature teratomas Treatment options for immature teratomas include the following: Surgery and observation (stage I) Immature teratomas in children are primarily managed with surgery and observation. Evidence (surgery and observation for stage I disease): Surgery and observation or chemotherapy (stages I–IV) The use of chemotherapy is controversial in the treatment of immature teratomas. There are no clinical trials supporting the use of chemotherapy in children. In adult women with ovarian tumors, surgery followed by chemotherapy has been the standard treatment approach since 1976.[16] 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. For more information about the treatment of ovarian immature teratomas in postpubertal females, see Ovarian Germ Cell Tumors Treatment. 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, see the ClinicalTrials.gov website. The following is an example of a national and/or institutional clinical trial that is currently being conducted: Follow-up After Treatment of Mature and Immature Teratomas After successful resection, neonates diagnosed with benign mature and immature teratomas are closely observed with follow-up exams and serial serum AFP determinations. These tests are done for several years to ensure that AFP measurements normalize to expected physiological levels and to facilitate early detection of tumor relapse.[19,20] Several oncology groups have reported significant rates of recurrence among these benign tumors, ranging from 10% to 21%. Most relapses occur within 3 years of resection.[5,19,21,22] While there is no standard follow-up schedule, tumor markers are measured frequently for 3 years in all children. With early detection, recurrent malignant GCTs can be treated successfully with surgery and chemotherapy (OS rate, 92%).[23] Long-term survivors are monitored for complications of extensive surgery, which include constipation, fecal and urinary incontinence, and psychologically unacceptable cosmetic scars.[24] 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. References: Childhood Malignant Testicular GCTs Malignant testicular GCTs in prepubertal males The role of surgery at diagnosis for germ cell tumors (GCTs) depends on patient age and tumor site, and treatment must be individualized. All malignant testicular GCTs should be resected. Resection may be followed by subsequent excision of residual masses after chemotherapy. Testicular GCTs in children occur almost exclusively in boys younger than 5 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.[5] 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 may be no reason to risk the potential morbidity (e.g., impotence and retrograde ejaculation) associated with lymph node dissection.[6,7] A revised risk stratification was developed by the Malignant Germ Cell Tumor International Consortium (see Figure 4).[8] 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 observation (stage I) Surgery and close follow-up observation are indicated to document that tumor marker levels normalize after resection.[3,9] Evidence (surgery and observation for stage I disease in prepubertal males): Surgery and chemotherapy (stages II–IV) 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 OS rates exceeding 90%, suggesting that a reduction in therapy could be considered.[13,14] Surgery and treatment with four to six cycles of carboplatin, etoposide, and bleomycin (JEb) is an alternative treatment regimen.[9] 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 is a treatment option and may play a crucial role [16] in the initial treatment of patients or in subsequent treatment of patients with residual disease after chemotherapy for metastatic testicular GCT.[17,18] A meta-analysis showed that patients older than 11 years were at higher risk of recurrence.[8] 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. For more information about the treatment of malignant testicular GCTs in postpubertal males, see Testicular Cancer Treatment. Standard treatment options for malignant testicular GCTs in postpubertal males For information about the treatment of malignant testicular GCTs in postpubertal males, see Testicular Cancer Treatment. Treatment options under clinical evaluation for malignant testicular GCTs 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, see 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 Ovarian GCTs Most ovarian neoplasms in children and adolescents are of germ cell origin.[19] 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.[1] 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). For more information about childhood mature and immature teratomas arising in the ovary, see the Treatment of Mature Teratomas section. For more information about the treatment of ovarian GCT in postpubertal females, see Ovarian Germ Cell Tumors Treatment. 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. Surgery and observation (stage I) 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.[9,20,21,22,23] Evidence (surgery and observation for stage I dysgerminomas): Surgery and chemotherapy (stages II–IV) 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 [25,26] make chemotherapy a more attractive adjunct to surgery.[27,28] 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.[23] Evidence (surgery and chemotherapy for stage II–IV dysgerminomas): This approach results in a high rate of cure and the preservation of menstrual function and fertility in most patients with dysgerminomas.[27,30] 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. The treatment of ovarian malignant GCTs that are not dysgerminomas or immature teratomas generally involves surgical resection and adjuvant chemotherapy.[31,32] The role for surgery at diagnosis depends on patient age and tumor site, and treatment must be individualized. The use of laparoscopy in children with ovarian GCTs has not been well studied. The use of intraoperative frozen biopsy in pediatric and adolescent patients to determine the presence of malignancy to allow an ovarian-sparing procedure has been questioned. In a retrospective analysis from the COG AGCT0132 (NCT00053352) study, 60 of 131 eligible patients with ovarian tumors had both intraoperative frozen section and final paraffin section diagnoses available.[33] Intraoperative frozen section biopsy was incorrect 38% of the time (23 patients), and it confirmed the final diagnosis 76% of the time. In addition, central pathological review detected additional germ cell components in 23.7% of patients. Pediatric surgical guidelines to determine stage I disease have been published.[34] Adult surgical guidelines to determine stage are more extensive. For more information about staging of ovarian GCTs in postpubertal females, see the Stage Information for Ovarian Germ Cell Tumors section in Ovarian Germ Cell Tumors Treatment. 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.[9,13,35] 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.[36] 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: Surgery and observation for prepubertal females (stage I following strict surgical staging guidelines) 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 prepubertal females with stage I disease): Surgery and chemotherapy for prepubertal and postpubertal females (purported stage I and stages II–IV) A revised risk stratification was developed by the Malignant Germ Cell Tumor International Consortium (see Figure 4).[8] Chemotherapy regimens with cisplatin (PEb) or carboplatin (JEb) have been used successfully in children.[9,13,14,20] BEP is a common regimen in young women with ovarian GCTs.[37,38] 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.[32,35] For more information about the dosing schedules for BEP, PEb, and JEb, see Table 8. 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%.[13,14] 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 and 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,[13,14] and BEP is used to treat postpubertal girls.[37,38] Patients with normalization of tumor markers undergo imaging after four cycles of PEb, and any residual tumor is resected. 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).[9] Initially unresectable ovarian GCT Primary resection of ovarian GCT is usually attempted. However, in rare instances, primary resection of the ovary is not possible without undue risk of damage to adjacent structures. In these cases, an appropriate strategy is biopsy for diagnosis, followed by chemotherapy and then subsequent surgery for patients who have residual masses after undergoing chemotherapy. Treatment options under clinical evaluation for malignant ovarian GCTs 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, see 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. References: In initial reports, children with extragonadal malignant germ cell tumors (GCTs), particularly those with advanced-stage (stage III or stage IV) disease, had the highest risk of treatment failure for any GCT presentation.[1,2] 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%).[3] The role of surgery at diagnosis for extragonadal tumors depends on patient age and tumor site, and treatment 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. 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. For more information, see the Site-specific considerations for malignant extragonadal extracranial GCTs section. Surgery and chemotherapy (stages I–IV) Surgery and chemotherapy with four cycles of standard cisplatin, etoposide, and bleomycin (PEb) is one treatment option. Patients with stage I and stage II disease treated with this regimen had an overall survival (OS) rate of 90%, suggesting that a reduction in therapy may be considered.[1,4] Patients with stage III and stage IV disease had OS rates of higher than 80%.[1] An alternative treatment option is surgery and chemotherapy with carboplatin, etoposide, and bleomycin (JEb).[5] Stage III and stage IV patients treated with JEb had an OS rate similar to that with the PEb regimen.[5] Two pediatric intergroup trials for patients with high-risk disease 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.[1] No benefit in OS was observed, and 75% of patients required hearing aids. A Children's Oncology Group (COG) trial of patients with high-risk disease 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.[6] Biopsy followed by chemotherapy with or without surgery (stages III and IV) While outcomes have improved remarkably since the advent of platinum-based chemotherapy and the use of a multidisciplinary treatment approach, complete resection before chemotherapy may be possible in some patients without major morbidity.[1,5] However, for patients with locally advanced sacrococcygeal tumors, mediastinal tumors, or large pelvic tumors, tumor biopsy followed by preoperative chemotherapy may facilitate subsequent complete tumor resection and improve ultimate patient outcome. No decrease in OS has been noted for patients with malignant extragonadal GCTs who have had delayed resection after receiving chemotherapy.[5,7,8,9] Site-specific considerations for malignant extragonadal extracranial GCTs The treatment of malignant extragonadal extracranial GCTs depends in part on the site of disease. Sacrococcygeal site Sacrococcygeal GCTs are common extragonadal tumors that occur in very young children, predominantly young females.[10] 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.[10] Malignant sacrococcygeal tumors are usually very advanced at diagnosis. Two-thirds of patients have locoregional disease, and metastases are present in 50% of patients.[8,11,12] 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%.[8,9] Surgery may be facilitated by preoperative chemotherapy. In any patient with a sacrococcygeal GCT, resection of the coccyx is mandatory.[8,9] Completeness of surgical resection is an important prognostic factor, as shown in the following circumstances:[8,9,13] Mediastinal site Mediastinal GCTs account for 15% to 20% of malignant extragonadal extracranial GCTs in children.[5] The histology of mediastinal GCT is dependent on age, with teratomas predominating among infants and yolk sac tumors predominating among children aged 1 to 4 years.[7] Prepubertal children with mediastinal malignant teratomas are treated with tumor resection, which is curative in almost all patients.[7] 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%.[3,5,7]; [14][Level of evidence C1] Retroperitoneal site Malignant GCTs located in the retroperitoneum or abdomen usually present in children younger than 5 years. Most of these tumors are advanced stage and locally unresectable at diagnosis.[15] 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.[15] 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.[16][Level of evidence C2] 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.[17] In a subsequent meta-analysis, adolescents with stage III and stage IV extragonadal disease had poor outcomes (expected EFS rate, <70%).[3] Extragonadal disease of any stage is considered a poor risk factor in adolescents and young adults.[18] Standard treatment options for malignant extragonadal extracranial GCTs in postpubertal children include the following: 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.[7,19] Survival rates for the older adolescent and young adult population with mediastinal tumors are generally lower than 60%.[3,17,20,21,22]; [23][Level of evidence C1] 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.[24][Level of evidence C1] For more information about the treatment of adult patients, see Extragonadal Germ Cell Tumors Treatment. Treatment Options Under Clinical Evaluation for Malignant Extragonadal Extracranial GCTs 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, see 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. References: 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.[3] 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: For information about salvage therapy after observation for patients with stage I disease, see the following sections: 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).[10] 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.[3] 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%.[11] 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. 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.[12] Additional study in children and adolescents is needed. For more information about transplant, see Pediatric Autologous Hematopoietic Stem Cell Transplant and Pediatric Hematopoietic Stem Cell Transplant and Cellular Therapy for Cancer. 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.[16][Level of evidence C1] 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 C1] 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.[24] 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, see the ClinicalTrials.gov website. 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. References: 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. Editorial changes were made to this summary. 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® Cancer Information for Health Professionals 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 in the care of their 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. 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Childhood Extracranial Germ Cell Tumors Treatment (PDQ®): Treatment - Health Professional Information [NCI]
General Information About Childhood Extracranial Germ Cell Tumors (GCTs)
Figure 1. Extracranial germ cell development from primordial germ cells. Credit: Thomas Olson, M.D.
Figure 2. Age-incidence profiles for extracranial, extragonadal germ cell tumors (left graph) and for gonadal germ cell tumors (right graph). The blue triangles represent females, and the green triangles represent males. (See text for details.)Tumor Site Sex Age <1 y Ages 1–4 y Ages 5–9 y Ages 10–14 y Ages 15–19 y a Rates are per 1 million children from 2014 to 2018 for NCCR Registries, 23 U.S. Cancer registries that represent 66% of all U.S. children, adolescents, and young adults. b Data from National Cancer Institute; National Childhood Cancer Registry: NCCR*Explorer.[3] Extragonadal Female 17.7 2.1 0.1 0.1 0.7 Male 8.8 0.7 0 0.6 2.2 Gonadal Female 0.6 0.7 2.1 7.6 8.3 Male 7 2.5 0.1 1.5 36.1 Malignant Germ Cell Elements Location E = extragonadal; O = ovarian; T = testicular. a Modified from Perlman et al.[37] Seminomatous Seminoma T Dysgerminoma O Germinoma E Nonseminomatous Yolk sac tumor (endodermal sinus tumor) E, O, T Choriocarcinoma E, O, T Embryonal carcinoma E, T Gonadoblastoma O Mixed Germ Cell Tumors Mixed germ cell tumors E, O, T
Figure 3. 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.
Figure 4. Predicted fraction of pediatric germ cell tumors cured by site, age, and stage using parameter estimates from cure model. Reprinted with permission. © 2015 American Society of Clinical Oncology. All rights reserved. Frazier AL, Hale JP, Rodriguez-Galindo C, et al: Revised risk classification for pediatric extracranial germ cell tumors based on 25 years of clinical trial data from the United Kingdom and United States. J Clin Oncol, Vol. 33 (Issue 2), 2015: 195-201.Stage Information for Childhood Extracranial GCTs
Stage Extent of Disease COG = Children's Oncology Group; CT = computed tomography; GCT = germ cell tumor. a Males younger than 50 years are eligible for the AGCT1531 trial. b COG trials include patients younger than 15 years with testicular GCT. Although data are scarce, patients between the ages of 11 years and 15 years might be more appropriately staged according to adult testicular guidelines. For more information about the staging of adult testicular GCTs, see Testicular Cancer Treatment. I (1) Tumor limited to testis (testes) with negative microscopic margins, completely resected by high inguinal orchiectomy; (2) Tumor capsule cannot have been violated by needle biopsy, incisional biopsy, or tumor rupture. Patients who have undergone scrotal orchiectomy without violation of the tumor capsule and with removal of the spermatic cord to the level of the internal ring are stage I. Patients who have undergone excisional biopsy for frozen section analysis with complete orchiectomy and cord excision at the same operation can be designated stage I; (3) No clinical, radiographic, or histological evidence of disease beyond the testes; (4) Lymph nodes all <1 cm maximum short-axis diameter on multiplanar imaging. (Note: Nodes 1–2 cm require short-interval follow-up in 4–6 weeks. If nodes are unchanged at 4–6 weeks [1–2 cm], consider biopsy or transfer to chemotherapy arm. If growing, transfer to chemotherapy arm.) II (1) Complete orchiectomy with violation of the tumor capsulein situ(includes preoperative needle biopsy and incisional biopsy or intraoperative tumor capsule rupture); (2) Microscopic disease in scrotum or high in spermatic cord (<5 cm from proximal end). Failure of tumor markers to normalize or decrease with an appropriate half-life; (3) Lymph nodes negative. III (1) Retroperitoneal lymph node involvement, but no visceral or extra-abdominal involvement; (2) Lymph nodes ≥2 cm or lymph nodes >1 cm but <2 cm on short axis by multiplanar imaging CT that fail to resolve on re-imaging at 4–6 weeks. IV (1) Distant metastases, including liver, lung, bone, and brain. Stage Extent of Disease COG = Children's Oncology Group; CT = computed tomography; GCT = germ cell tumor. a Bilateral ovarian tumors may be any stage as long as other stage criteria are met. Tumor staged according to ovary with most advanced features. I (1) Ovarian tumor removed without violation of the tumor capsule; (2) No evidence of partial or complete capsular penetration; (3) Peritoneal cytology negative for malignant cells; (4) Peritoneal surfaces and omentum documented to be free of disease in operative note or biopsied with negative histology if abnormal in appearance; (5) Lymph nodes all <1 cm by short-axis diameter on multiplanar imaging or biopsy proven negative. (Note: Nodes 1–2 cm require short-interval follow-up in 4–6 weeks. If nodes are unchanged at 4–6 weeks [1–2 cm], consider biopsy or transfer to chemotherapy arm. If growing, transfer to chemotherapy arm.) II (1) Ovarian tumor completely removed but with preoperative biopsy, violation of tumor capsulein situ, or presence of partial or complete capsule penetration at histology; (2) Tumor >10 cm removed laparoscopically; (3) Tumor morcellated for removal so that capsule cannot be assessed for penetration; (4) Peritoneal cytology must be negative for malignant cells; (5) Lymph nodes, peritoneal surfaces, and omentum documented to be free of disease in operative note or biopsied with negative histology if abnormal in appearance. III (1) Lymph nodes ≥2 cm or lymph nodes >1 cm but <2 cm on short axis by multiplanar imaging CT that fail to resolve on re-imaging at 4–6 weeks; (2) Ovarian tumor biopsy or removal with gross residual; (3) Positive peritoneal fluid cytology for malignant cells, including immature teratoma; (4) Lymph nodes positive for malignant cells, including immature teratoma; (5) Peritoneal implants positive for malignant cells, including immature teratoma. III–X Patients otherwise stage I or II by COG criteria but with the following: (1) Failure to collect peritoneal cytology; (2) Failure to biopsy lymph nodes >1 cm on short axis by multiplanar imaging; (3) Failure to sample abnormal peritoneal surfaces or omentum; or (4) Delayed completion of surgical staging at a second procedure for patients who had only oophorectomy at first procedure. IV (1) Metastatic disease to the parenchyma of the liver (surface implants are stage III) or metastases outside the peritoneal cavity to any other viscera (bone, lung, or brain) and pleural fluid with positive cytology. Stage Description FIGO = International Federation of Gynecology and Obstetrics. a Adapted from Berek et al.[8] I Tumor confined to the ovary. IA Tumor limited to one ovary (capsule intact); no tumor on surface of the ovary; no malignant cells in the ascites or peritoneal washings. IB Tumor limited to both ovaries (capsules intact); no tumor on surface of the ovary; no malignant cells in the ascites or peritoneal washings. IC Tumor limited to one or both ovaries, with any of the following: IC1 Surgical spill. IC2 Capsule ruptured before surgery or tumor on the surface of the ovary. IC3 Malignant cells in the ascites or peritoneal washings. II Tumor involves one or both ovaries with pelvic extension (below pelvic brim) or primary peritoneal cancer. IIA Extension and/or implants on uterus and/or fallopian tubes. IIB Extension to other pelvic intraperitoneal tissues. III Tumor involves one or both ovaries or primary peritoneal cancer, with cytologically or histologically confirmed spread to the peritoneum outside the pelvis and/or metastasis to the retroperitoneal lymph nodes. IIIA1 Positive retroperitoneal lymph nodes only (cytologically or histologically proven): IIIA1(i) Lymph nodes ≤10 mm in greatest dimension. IIIA1(ii) Lymph nodes >10 mm in greatest dimension. IIIA2 Microscopic extrapelvic (above the pelvic brim) peritoneal involvement with or without positive retroperitoneal lymph nodes. IIIB Macroscopic peritoneal metastasis beyond the pelvis ≤2 cm in greatest dimension, with or without metastasis to the retroperitoneal lymph nodes IIIC Macroscopic peritoneal metastasis beyond the pelvis >2 cm in greatest dimension, with or without metastasis to the retroperitoneal lymph nodes (includes extension of tumor to capsule of liver and spleen without parenchymal involvement of either organ). IV Distant metastasis excluding peritoneal metastases. IVA Pleural effusion with positive cytology. IVB Parenchymal metastases and metastases to extra-abdominal organs (including inguinal lymph nodes and lymph nodes outside of the abdominal cavity). Stage Extent of Disease COG = Children's Oncology Group; CT = computed tomography; GCT = germ cell tumor. I (1) Complete resection at any site, including coccygectomy for sacrococcygeal site; (2) Must have negative tumor margins and intact capsule; (3) For any tumors involving abdominal cavity or retroperitoneum, peritoneal fluid or washings must be done for cytology and be negative for malignant cells; (4) Lymph nodes ≤1 cm by imaging of abdomen, pelvis, and chest. (Note: Nodes 1–2 cm require short-interval follow-up in 4–6 weeks. If nodes are unchanged at 4–6 weeks [1–2 cm], consider biopsy or transfer to chemotherapy arm. If growing, transfer to chemotherapy arm. For any tumors involving abdominal cavity or retroperitoneum, peritoneal fluid or washings must be done for cytology and be negative for malignant cells.) II (1) Microscopic residual disease; (2) Gross-total resection with preoperative biopsy, intraoperative biopsy, microscopic residual disease, or pathological evidence of capsular disruption; (3) Lymph nodes negative by abdomen, pelvic, and chest imaging. Peritoneal fluid negative. III (1) Gross residual disease or biopsy only; (2) Lymph nodes positive with tumor resection. Lymph nodes ≥2 cm or lymph nodes >1 cm but <2 cm on short axis by multiplanar imaging CT that fail to resolve on re-imaging at 4–6 weeks. IV Distant metastases, including liver, lung, bone, and brain. Treatment Option Overview for Childhood Extracranial GCTs
Histology Treatment Options BEP = bleomycin (weekly), etoposide, and cisplatin; JEb = carboplatin, etoposide, and bleomycin; PEb = cisplatin, etoposide, and bleomycin (bleomycin only on day 1 of each cycle). a Chemotherapy has not been shown to be effective in the treatment of children with stages II–IV immature teratoma. However, the role of chemotherapy in these patients has not been systematically studied. In postpubertal patients, chemotherapy remains the standard treatment, although studies are limited.[2] b In prepubertal females with reported stage I disease, but in whom strict surgical staging guidelines were not followed, chemotherapy (PEb) can be considered standard treatment.[3] c In postpubertal females with stage I disease, the strategy of observation after surgery has not been established. This treatment strategy is under investigation in a clinical trial (AGCT1531 [NCT03067181]). Mature teratoma Sacrococcygeal site Surgery and observation Nonsacrococcygeal site Surgery and observation Immature teratoma Surgery and observation (stage I) Surgery and observation or chemotherapy (stages I–IV) a Malignant gonadal GCTs in children: Childhood malignant testicular GCTs: Malignant testicular GCTs in prepubertal males Surgery and observation (stage I) Surgery and chemotherapy (PEb) (stages II–IV) Malignant testicular GCTs in postpubertal males For information, see Testicular Cancer Treatment. Childhood malignant ovarian GCTs: Dysgerminomas of the ovary Surgery and observation (stage I) Surgery and chemotherapy (PEb) (stages II–IV) Malignant nongerminomatous ovarian GCTs (yolk sac and mixed GCTs) in prepubertal females Surgery and observation for prepubertal females (stage I following strict surgical staging guidelines) b. For information about the treatment of ovarian mature teratoma, see the Childhood Malignant Ovarian GCTssection. Surgery and chemotherapy (PEb) for prepubertal and postpubertal females (purported stage I and stages II–IV) Malignant nongerminomatous ovarian GCTs (yolk sac and mixed GCTs) in postpubertal females Surgery and chemotherapy (BEP) for prepubertal and postpubertal females (purported stage I and stages II–IV) c Malignant nongerminomatous ovarian GCTs (yolk sac and mixed GCTs) that are initially unresectable Biopsy followed by chemotherapy and surgery (initially unresectable ovarian GCT) Malignant extragonadal extracranial GCTs in children: Malignant extragonadal extracranial GCTs in prepubertal children Surgery and chemotherapy (PEb or JEb) (stages I –IV) Biopsy followed by chemotherapy with or without surgery (stages III and IV) Malignant extragonadal extracranial GCTs in postpubertal children Surgery Chemotherapy (BEP) Chemotherapy followed by surgery to remove residual tumor Enrollment in a clinical trial Recurrent malignant GCTs in children Surgery alone Surgery with neoadjuvant or adjuvant chemotherapy Regimen Bleomycin Etoposide Cisplatin Carboplatin BEP = bleomycin, etoposide, and cisplatin; GFR = glomerular filtration rate; JEb = carboplatin, etoposide, and bleomycin; PEb = cisplatin, etoposide, and bleomycin. Adult BEP (every 21 days)[11,19] 30 units/m2, days 1, 8, 15 (maximum 30 units) 100 mg/m2, days 1–5 20 mg/m2, days 1–5 Pediatric PEb (every 21 days)[3,13] 15 units/m2, day 1 (maximum 30 units) 100 mg/m2, days 1–5 20 mg/m2, days 1–5 Pediatric JEb (every 21–28 days)[14] 15 units/m2, day 3 (maximum 30 units) 120 mg/m2, days 1–3 600 mg/m2 or GFR-based dosing, day 2 Special Considerations for the Treatment of Children With Cancer
Treatment of Mature and Immature Teratomas in Children
Treatment of Malignant Gonadal GCTs in Children
Treatment of Malignant Extragonadal Extracranial GCTs in Children
Treatment of Recurrent Malignant GCTs in Children
Latest Updates to This Summary (04 / 03 / 2024)
About This PDQ Summary
Our Health Library information does not replace the advice of a doctor. Please be advised that this information is made available to assist our patients to learn more about their health. Our providers may not see and/or treat all topics found herein.Childhood Extracranial Germ Cell Tumors Treatment (PDQ®): Treatment - Health Professional Information [NCI]