Chapter 459. Germ Cell Tumors

Germ cell tumors are infrequent tumors in childhood and adolescence. These neoplasms comprise 2% to 3% of all tumors diagnosed in children and adolescents ages 0 to 15 years,1 with an annual incidence of approximately 3 per million. Extracranial germ cell tumors are more common in adolescents 15 to 19 years of age, accounting for 16% of cancer diagnoses in this age group (Fig. 459-1). Ninety percent of germ cell tumors diagnosed during adult life are gonadal, whereas two thirds of childhood germ cell tumors are extragonadal. The age distribution for childhood germ cell tumors is bimodal, with a peak at 3 years of age and a second peak during adolescence. One third of germ cell tumors of childhood are malignant, but most neonatal germ cell tumors, irrespective of location, are benign. However, despite the relative infrequency of malignant tissue, there is a high associated morbidity due to obstruction of airway, hydrops fetalis, and premature delivery.2,3 With advancing age, the proportion of malignant germ cell tumors increases.

Germ cell tumors are thought to develop from a common primordial or embryonic germ cell.4 However, there is great heterogeneity in location, histopathology, and genetics.5,6 Tumor development is not well understood but may be related to the stage of germ cell development, the location of stem cells at time of tumorigenesis, and the sex of the individual. During normal development, primordial germ cells migrate from the yolk sac through the mesentery to the gonadal ridge.7 The c-kit receptor and its ligand, stem cell factor-8, have been shown to affect primitive germ cell directional migration to the gonadal ridge. Extragonadal germ cell tumors may develop from primordial germ cells that display an abnormal migration pattern.

Germ cells may give rise to tumors at any point in their migration path or at any stage of differentiation. The pluripotential cells can differentiate into various embryonic or extraembryonic tissues, which can be either benign or malignant. A mixture of benign and malignant components is common in germ cell tumors, lending support to the notion that different classes of germ cell tumors have a common progenitor. Although there is little doubt that gonadal germ cell tumors are derived from pluripotent descendants of activated germ cells, the origin of extragonadal germ cell tumors is controversial. Cytogenetic studies suggest that such extragonadal tumors may arise from either misplaced pluripotent embryonic tissue or activated germ cells.

A classification of pediatric germ cell tumors is shown in Table 459-1. Germ cell tumors can be classified into mature or immature teratomas and malignant germ cell tumors.

Mature Teratoma and Immature Teratoma

Mature teratomas are the most common histological subtype of childhood germ cell tumors.8,9 They most often occur in the ovary or extragonadal sites. They usually contain differentiated ectodermal, mesodermal, and endodermal tissue.

Immature teratomas often occur in the ovary near puberty and at extragonadal sites. All three 3 cell layers are often found, but immature tissue (usually neuroepithelial) is present. These are graded 0 to 3 according to immature elements.10

Malignant Germ Cell Tumor

Germinoma

Germinomas are also called seminomas (testicle) or dysgerminomas (ovary). The histology is identical. Germinomas stain strongly for placental alkaline phosphatase. If syncytiotrophoblasts are present, these cells will stain positively for human chorionic gonadotropin beta-subunit (β-HCG). Pure germinomas are the most common malignant germ cell tumor occurring in the central nervous system and ovary.11 Ovarian germinomas are rarely encountered in prepubertal girls.

Yolk Sac Tumor

This is the most common malignant form of childhood germ cell tumor and the only malignant germ cell tumor that occurs in the sacrococcygeal area in infants.12,13 Four histologic patterns have been described, and they often contain Schiller-Duval bodies. Most yolk sac tumors stain positive for alpha-fetoprotein (AFP).

Embryonal Carcinoma

The tumor cells appear epithelial and form large nests. The cells are AFP negative but CD30 positive by immunostaining. Embryonal carcinoma is often found with other malignant elements as part of a mixed germ cell tumor. It is common in adolescent testicular tumors and rarely occurs in children younger than 15 years.

Choriocarcinoma

This malignant tumor is characterized by the presence of cytotrophoblasts and syncytiotrophoblast (syntitial cells) tissue. The syncytiotrophoblasts stain positively for β-HCG. Pure choriocarcinoma is rare in children but may be encountered occasionally in intracranial sites, the mediastinum, or the gonads.

Mixed Germ Cell Tumor

Teratomas and immature teratomas can occur in combination with 1 or more of the malignant germ cell tumors, such as germinoma, embryonal carcinoma, endodermal sinus tumor, and choriocarcinoma. In children, a tumor of predominately yolk sac histology may also contain small elements of embryonal carcinoma or choriocarcinoma.

Malignant Teratoma

Malignant teratomas contain malignant epithelial elements or other malignant non–germ cell tumor elements such as premature neuroectodermal tumors or rhabdomyosarcomas.

Other Gonadal Tumors

Gonadoblastoma

This tumor occurs almost exclusively in dysgenetic gonads. Most of the affected persons have either a 46XY or 46XY/45XO karyotype, and 80% have the female phenotype. This tumor can occur in association with cryptorchidism. Gonadoblastoma is regarded as cancer in situ and has a low propensity for spread. However, gonadoblastoma frequently occurs in combination with germinoma, which can metastasize.

Sex Cord Tumors

Although not true germ cell tumors, sex cord tumors deserve mention because they should be considered in the differential diagnosis of gonadal tumors. Sex cord tumors arise from the supportive, often hormonally active cells within the ovary or the testis from the nongerminative cells (granulosa, Leydig or Sertoli cells).

The embryonic and extraembryonic components of germ cell tumors produce secreted or intracellular antigens useful in diagnosis and surveillance. The 2 most commonly used germ cell tumor markers in serum are AFP and β-HCG. Malignant yolk sac tumors produce elevated serum AFP levels. AFP is elevated in utero with a peak level at 14 weeks’ gestation. A gradual decline then occurs, and normal adult levels are reached by 1 year of age. AFP is also produced in the liver. An elevated serum AFP (corrected for age in children < 1 year) may suggest the diagnosis of yolk sac tumor or hepatoblastoma. Biopsy should be obtained for confirmation. Decay in serum AFP levels can be used as a measure of effectiveness of therapy. Increasing levels of AFP may not always be related to tumor progression, as minor hepatic damage can also lead to elevated serum AFP. Syncytiotrophoblast tissue in choriocarcinomas produces elevated serum levels of β-HCG.

β-HCG can be detected occasionally in the cerebrospinal fluid of patients with intracerebral germinoma. Placental alkaline phosphatase and β-HCG can be detected in germinomas. Levels of several other tumor markers, including the carbohydrate antigens CA-125 and CA-19-9, may be elevated in certain germ cell tumors. Serum markers are useful for differentiating gonadal germ cell tumors from sex cord–derived tumors. For example, an elevated serum level of estradiol is associated with granulosa cell tumors, whereas the level of the bioactive peptide inhibin is elevated in the serum of patients with Sertoli cell tumors.

Pediatric Germ Cell Tumor Biology

Biologic differences have been noted in germ cell tumors from children and adults. Testicular germ cell tumors in prepubertal boys usually contain yolk sac histology with deletions of chromosomes 1p and 6q.14-16 Testicular germ cell tumors in adolescents and adults usually have an isochromosome on the short arm of chromosome 12.17 Isochromosome 12p is also identified in postpubertal girls with ovarian germ cell tumor. Extragonadal tumors in children usually express deletions of 1p and 6q, while isochromosome 12p has been identified in children 8 years and older.18 Although not absolute, studies have revealed more biologic differences in pediatric germ cell tumors than in adult tumors.19-21 Males with Klinefelter syndrome have increased risk for mediastinal germ cell tumors.22-24

The clinical manifestations of germ cell tumors are related to the tumor location.

Testicular Tumors

Testicular germ cell tumor usually manifests as a painless scrotal mass. When metastatic to retroperitoneal nodes, an abdominal mass or pain may present.

Ovarian Tumors

Patients with ovarian germ cell tumors typically have pain, nausea, vomiting, or other signs of an acute abdomen because of torsion of the ovary caused by the tumor.

Extragonadal Tumors

Sacrococcygeal teratoma is frequently detected at birth as a mass in the region of the sacrum or buttocks, sometimes accompanied by obstruction of the rectum or urinary tract. These tumors are most often postsacral but occasionally are presacral. Vertebral anomalies can occur in patients with sacrococcygeal teratoma. Mediastinal tumors can produce a combination of symptoms that are manifestations of tracheal compression or secondary infection, such as dyspnea, cough, wheezing, fever, or chest pain. Intracranial germ cell tumors in the midline cause signs of increased intracranial pressure, ataxia, or diabetes insipidus.

Tumor staging systems have been developed by several international pediatric germ cell tumor study groups. The common staging system used by the Children’s Oncology Group utilizes a standard pediatric surgical staging system, as shown in Table 459-2.25,26,27 Ovarian germ cell tumors in adolescents and young adults are often staged according to the International Federation of Gynecologic Oncologists (FIGO) staging system.28

Pediatric and adolescent germ cell tumors show great heterogeneity in location, histology, and malignant potential. The successful treatment of these diverse tumors often involves a multidisciplinary strategy with surgery and chemotherapy. Surgery may be the most essential therapy for germ cell tumors, irrespective of histologic features or location, but chemotherapy has evolved as an essential element in the last 3 decades. Germ cell tumors are very sensitive to radiation therapy, which is usually reserved for germinomas as chemotherapy has become the preferred adjuvant therapy. Initially, cyclophosphamide-based therapy improved survival somewhat, but the introduction of cisplatin-based therapy29 has led to significant improvement in survival and has diminished the need for extensive surgery in some children with malignant germ cell tumors. With the advent of cisplatin, bleomycin, and etoposide chemotherapy, the overall survival for children with malignant germ cell tumor is approaching 90%. Prognosis may be related to location and age.30 Children older than 12 years and mediastinal primaries may have a poorer prognosis.

Treatment of Mature and Immature Teratomas

Surgery is the standard therapy for mature and immature teratomas. The benefit of chemotherapy for mature and immature teratomas of childhood has not been demonstrated. The sacrococcygeal region is the most common site for benign and malignant germ cell tumors in neonates, infants, and children under 4 years of age.31 During resection of sacrococcygeal teratoma, the coccyx must be removed to minimize the risk of recurrence. Many sacrococcygeal teratomas contain small amounts of yolk sac tumor. The rate of recurrence as malignant germ cell tumor is approximately 10% for children under 2 months of age and 50% for children diagnosed later than 2 months of age.32 Complete excision of immature teratomas at any nontesticular site is associated with excellent outcome (96% 6-year relapse-free survival versus 55% for incomplete resection).9

Malignant Testicular Germ Cell Tumors

Malignant germ cell tumors of the testis present in boys younger than 4 years with another peak that occurs in adolescent males.1 The treatment approach may be different because the latter group should be treated according to adult testicular cancer guidelines. In young boys, an inguinal approach should be used to resect the tumor. Computer tomography imaging can be used to determine the presence of metastatic disease in retroperitoneal lymph nodes and in the lungs. Retroperitoneal lymph node resection is often standard in adult testicular cancer therapy but is not indicated in boys younger than 4 years of age.33

Stage I testicular germ cell tumors are treated with surgery and observation. Patients with recurrence are treated with standard pediatric cisplatin, bleomycin, and etoposide (CEB25) or carboplatin, bleomycin, and etoposide (CEB).34 Surgery, observation, and PEB (for recurrence) has yielded a 6-year event-free survival of 82% with 6-year survival of 100%.33 Young boys with stage II to IV testicular tumors can be successfully treated with either PEB or JEB with 6-year event-free survival of greater than 94%.25,27,34 Adolescent patients with testicular germ cell tumors had event-free survival of 85% and should follow adult germ cell tumor surgical guidelines.

Ovarian Germ Cell Tumors

Surgery is essential for treatment of malignant ovarian germ cell tumors. The standard surgery for young girls is unilateral salpingo-oophorectomy with sparing of the uterus. Because 15% of ovarian germ cell tumors are bilateral, examination or biopsy of the contralateral ovary is indicated at the time of initial surgical resection. Most children with ovarian germ cell tumors are treated with surgery and PEB or JEB chemotherapy. Chemotherapy can often decrease the need for mutilating therapy. The approach often leads to 6-year survival of 95% for all stages.25,27

Extragonadal Germ Cell Tumors

Extragonadal malignant germ cell tumors account for approximately 60% of all pediatric germ cell tumors. Sacrococcygeal tumors are most common, and when they are seen in children older than 2 months, the disease is often advanced and may not be amenable to resection. Yolk sac tumor is the most common malignant element in these tumors. Treatment should include chemotherapy and, often, delayed resection. Survival rates of 85% can be achieved.35,36 Mediastinal germ cell tumors are often mature and immature teratomas with malignant elements. Yolk sac tumor morphology is seen most often in children under 4 years of age. Other histologic subtypes, embryonal carcinoma and choriocarcinoma, are seen with adolescent patients with mediastinal tumors. Surgical treatment is essential either at diagnosis or after chemotherapy reduction. Children with nonmetastatic mediastinal germ cell tumors have 6-year event-free survival of 90% with surgery and PEB or JEB. If tumor is metastatic at presentation, event-free survival is 70%.34,37 Survival rates of 40% to 50% have been reported for adolescents and young adults with mediastinal germ cell tumors.30

Follow-Up and Adverse Late Effects

Tumor recurrence is unusual in children under 12 years of age with germ cell tumors treated with chemotherapy. However, careful evaluation should be conducted. Many of these tumors have tumor markers whose elevation can signal a recurrence prior to findings on imaging studies. This is especially true with yolk sac tumor (AFP) and choriocarcinoma (β-HCG). Computer tomography studies should be done at regular intervals after completion of treatment.

Long-term survivors of germ cell tumors may have a variety of sequelae. Functional anorectal and urinary impairment occur among as many as 30% of patients with sacrococcygeal teratoma B. Growth hormone deficiency or other pituitary problems may follow treatment of intracranial germinomas with surgery or radiation therapy. Among older male adolescents, testicular dysfunction after chemotherapy is common. However, fertility problems have occurred among patients with a history of teratoma treated with surgery alone, suggesting that an underlying germ cell defect may contribute to infertility.

Chemotherapy has led to some significant adverse late effects. Cisplatin has been associated with hearing loss, leading to need for hearing aides in some patients.25 In this study, severe otoxicity was reported in 14% of patients treated with high-dose cisplatin. However, when audiograms were reviewed centrally, the true incidence approached 67% for high-dose cisplatin and 10% for standard cisplatin C. Carboplatin may affect hearing, but the findings are not often identified by standard audiometry and have not been reported in the pediatric literature. Bleomycin has been associated with significant pulmonary toxicity in adults. Two large pediatric germ cell trials did not report significant pulmonary toxicity.25,27,34 In the UK study, only 1 in 192 patients had severe, irreversible pulmonary toxicity, and that was in a patient with a primary mediastinal tumor.34 One limitation may be the difficulty in obtaining accurate pulmonary function testing in children. The use of chemotherapy has been associated with secondary acute myelogenous leukemia in patients with germ cell tumors. In the US intergroup studies, 4 in 373 patients treated with chemotherapy developed secondary acute myelogenous leukemia not associated with 11q23 abnormalities.25,27