Pediatric Teratomas and Other Germ Cell Tumors 

Updated: Jul 31, 2019
Author: E Stanton Adkins, III, MD; Chief Editor: Max J Coppes, MD, PhD, MBA 

Overview

Background

Teratomas (from Greek teras, meaning "monster," and -oma, a suffix denoting a tumor or neoplasm) and other germ cell tumors are relatively common solid neoplasms in children. They may occur in both gonadal and extragonadal locations. Locations and specific tumor types depend on the age of the child. These tumors are grouped together because they all appear to arise from postmeiotic germ cells. Most of the malignant tumors produce markers that can be serologically assessed.[1, 2, 3, 4, 5, 6, 7]

Pathophysiology

Several theories about the origin of these tumors are recognized. The best evidence suggests that most are due to abnormal differentiation of fetal germ cells that arise from the fetal yolk sac. Normal migration of these germ cells may cause gonadal tumors, whereas abnormal migration produces extragonadal tumors.[8] Teratomas are typically found in the midline or gonads. Frequencies of the most common sites are as follows:

  • Sacrococcygeal - 40%
  • Ovary - 25%
  • Testicle - 12%
  • Brain - 5%
  • Other (including the neck and mediastinum) - 18%

By definition, teratomas include components derived from all three embryonic layers: ectoderm, endoderm, and mesoderm. These tissues are foreign to the location in which they are found.

Teratomas may be classified as mature or immature on the basis of the presence of immature neuroectodermal elements within the tumor. Mature tumors (grade 0) have no immature elements. In grade 1 tumors, immature elements are limited to one low-power field per slide; in grade 2 tumors, fewer than four fields are present per slide; and in grade 3 tumors, more than four fields are present per slide.

In the past, survival was linked to the degree of immaturity in the teratoma. Close histologic evaluation of immature teratomas reveals a good correlation between the degree of immaturity and the presence of microscopic foci of frankly malignant elements. These malignant elements are typically yolk sac tumors but may also represent primitive neuroectodermal tumors (PNETs). Charoenkwan et al found overexpression of p53 in the more aggressive immature teratomas at all sites.[9]

The risk of recurrence also appears to be related to the degree of immaturity. Recurrence in a completely resected mature teratoma is less than 10%; in an immature teratoma, recurrence may be as high as 33%.

The likelihood of recurrence depends on the site of the tumor as well as the completeness of resection. The German MAKEI trials suggested that the recurrence rate for immature teratomas can be decreased to 9.5% with chemotherapy.[10] Sacrococcygeal teratomas are more likely to recur than those in the ovary or other sites. Molecular biologic and cytogenetic studies are providing a firmer scientific basis to these observations.

In 1965, Teilum first suggested the germ cell origin of gonadal tumors.[11] Since that time, the pathologic classification scheme has evolved to its present state. Germ cells undergo neoplastic transformation as follows:

  • Suppressed differentiation - Seminoma; dysgerminoma
  • Differentiation - Initial (embryonal carcinoma); embryonic (mature teratoma and immature teratoma); extraembryonic (choriocarcinoma and endodermal sinus tumor [yolk sac tumor])

Mutter described genetic imprinting as a major factor in the development of some of these tumors.[12] The developmentally expressed genes insulinlike growth factor 2 (IGF II) and its receptor RNA (H-19); small nuclear riboprotein (SNRPN); mas proto-oncogene; and the tumor suppressor genes WT1 and MASH2 are imprinted, depending on their maternal or paternal origin.

Mutter suggested that these genes or the cells have only the maternal imprint because many teratomas arise from a parthenogenetically activated egg. Therefore, maternally active genes are present in higher than usual concentrations, and maternally inactive products are present at lesser concentrations if at all. These abnormalities may account for the lack of organization of the three germ cell layers.

Oosterhuis et al suggested that tumors may be grouped on the basis of their chromosomal abnormalities as follows[13] :

  • Group 1, including immature teratomas and yolk sac tumors - Immature teratomas are usually diploid, whereas yolk sac tumors may be diploid, tetraploid, or aneuploidy; chromosomal aberrations include overrepresentation of chromosomes X, 1, 3, 8, 12, and 14 and underrepresentation of Y and X; deletions in 1p and rearrangements of 3q and 6q may be present; isochromosome 12p (i12p) has been found; an abnormal number of centromeres is frequent in both diploid and aneuploid tumors
  • Group 2, including most nonseminomatous malignant germ cell tumors and typically including numeric abnormalities in X, 7, 8, 12, and 21 as excess and deletions of Y, 11, 13, or 18 - Once again, isochromosomes 12p with other aberrations of 12p and 1p are present
  • Group 3, including mature teratomas or mature cystic teratomas - Numeric abnormalities, including extra X, 7, 12, and 15, have been found; no chromosomal structural anomalies have been found
  • Group 4, including spermatocytic seminoma, a type usually confined to older men - The cytogenetics of this group have not been characterized; as with abnormalities and imprinting patterns, these chromosomal rearrangements can lead to overproduction of certain gene products and underproduction of others; these lead to the abnormal growth characteristics of the tumor

Hara et al suggested that the MAGE gene family of tumor rejection antigens may also be involved in the pathogenesis of these tumors.[14] These genes appear to be more active in pure seminoma or mixed type of seminomatous elements than in other germ cell tumors. In their limited study of 22 patients, MAGE expression was not correlated with disease progression. It is likely to be only an indicator of maturity or differentiation of the tissues.

The concept of teratoma with malignant transformation indicates the development of non–germ cell malignancies within a teratoma. Among 641 patients in the MAKEI protocols 83/86/89/96, nine patients were identified with this finding.[15] Five patients presented with a carcinoma, two with glial tumors, and two with embryonal tumors. Resection and chemotherapy were typically used. Because these tumors are quite rare, response to treatment is difficult to generalize.[16]

When platinum-based chemotherapy–resistant tumors are evaluated, between one third and one half of tumors exhibit microsatellite instability.

Etiology

With sacrococcygeal teratomas, no causative agents are known. With respect to ovarian germ cell tumors, a familial predilection may be present. Cases in seven families have been reported in which female first-degree relatives had germ cell tumors. In an additional seven families, males had germ cell tumors. This observation suggests that certain genes may be present in these families, predisposing them to germ cell malignancy.

One study that examined the effect of diet on the development of ovarian tumors revealed that diets high in polyunsaturated fat were associated with the development of teratomas.[17]  Likely, plant estrogens, and not the polyunsaturated fat, are associated with an increased tumor risk.

The risk factors and epidemiologic features of testicular cancer suggest that cryptorchidism increases the risk of germ cell tumor by a factor of 3.7 to 7.5.[18] Tumors may appear in the ipsilateral or contralateral testicle. Hernia is similarly associated with germ cell tumors. One study also revealed that a history of pyloric stenosis leads to a fourfold risk of germ cell malignancy.[19]  

Boys whose father or brother has had a teratoma have a 5-15% increased risk for teratoma. Whether this is due to genetic causes or is a consequence of shared environment remains to be defined.[20]

No major high-penetrance susceptibility gene for testicular germ cell tumors has been identified; inheritance is likely driven by a complex polygenic model.[21] The most common genomic alterations associated with these tumors include gains in chromosome 12p and mutations in KIT, KRAS, and NRAS, particularly in seminomas.

Disorders of sex development (DSDs) have also been associated with development of germ cell tumors. Gonadoblastoma is observed in roughly one third of patients with DSDs. Although gonadoblastoma is a carcinoma in situ, it frequently evolves into dysgerminoma; yolk sac tumors, immature teratomas, and choriocarcinomas are possible as well.[22]

Turner syndrome is similarly a risk factor for gonadoblastoma. Klinefelter syndrome has been linked with an increased risk of extragonadal malignant germ cell tumors.[23] The highest risk seems to be among patients who carry some Y-chromosome genes in ectopic locations where they may not be normally regulated.

Children with DSDs are typically male pseudohermaphrodites with antigen insensitivity or 5-alpha reductase deficiency. These patients with testicular feminization are sometimes discovered serendipitously during a hernia repair.

Optimal timing for gonadal resection in these situations is a matter of debate. Gonadal estrogen production may benefit the patient in terms of growth and development. However, gonadoblastoma has been observed in patients as young as 2 months, and frank tumors have been observed in those younger than 2 years. The decision to leave or remove the gonads early should be made with the family after thorough discussion of these risks and potential benefits.

Epidemiology

United States statistics

Sacrococcygeal teratoma occurs in 1 in 30,000-70,000 live births. Ovarian teratomas are almost as common, whereas testicular teratomas are about one third less frequent. The overall incidence of malignant germ cell tumors is approximately 3% of all childhood malignancies, or approximately 3 cases per million population per year. The frequency of all germ cell tumors has increased over the last several decades.

International statistics

A study assessing the global incidence of ovarian germ cell tumors in three age groups (0-9, 10-19, and 20-39 years) found that the highest frequency was in 10- to 19-year-olds and that the incidence was generally highest in Eastern Asia, Central America, and North America.[24] Less geographic variation in incidence was noted in 0- to 9-year-olds than in the other two groups. Overall, the highest incidence figures and the largest increases in incidence were seen in Eastern Asia.

Age-related demographics

Sacrococcygeal teratomas

Sacrococcygeal teratomas are congenital. Those with a significant external component (see the image below) are identified at birth. Tumors without an external component (Altman type 4) are discovered later. When the tumors are resected before the patient is aged 2 months, 7-10% are malignant. After that age, the risk of malignancy increases greatly, exceeding 50% by age 1 year.

Sacrococcygeal teratoma in a female neonate. This Sacrococcygeal teratoma in a female neonate. This particular tumor is largely external with no intrapelvic extension.

Ovarian tumors

The incidence of ovarian germ cell tumors (see the image below) increases with age and peaks around age 15-19 years. When girls younger than 15 years were examined, fewer than 10% of tumors occurred in girls younger than 5 years, 20% were found in girls aged 5-9 years, and more than 70% were found in girls aged 10-14 years.[25]

This is an ovarian mixed germ cell tumor in a 13-y This is an ovarian mixed germ cell tumor in a 13-year-old girl. This tumor caused right lower quadrant pain. It is largely cystic in composition. No calcifications are observed within the mass.

Benign ovarian tumors, largely teratomas, predominate. Roughly 70% of malignant ovarian tumors in childhood are germ cell tumors, one quarter are epithelial, and the remainder are stromal tumors. The ratio of germ cell tumors to epithelial malignancies decreases with increasing patient age.

Chromosomal abnormalities also appear to be related to age at presentation for teratomas. In girls younger than 5 years, no chromosomal abnormalities were found, whereas older girls often have gains of 12p and chromosomes 7 and 8.

Testicular tumors

Testicular germ cell tumors in childhood are split between teratomas and yolk sac tumors (see the image below). They are more common from birth to age 5 years. From age 6 years until puberty, testicular tumors are exceedingly uncommon. Thereafter, the incidence increases, with a more adultlike tumor pattern with seminomas gradually becoming the predominant histology.

Yolk sac tumor of the testis. The tumor is metasta Yolk sac tumor of the testis. The tumor is metastatic to the retroperitoneum. It encases the aorta and renal arteries. The vena cava and renal veins are displaced anteriorly by the mass.

Both teratomas and yolk sac tumors may be associated with contralateral in-situ dysgenesis in 9% of patients compared with 0.5% of otherwise healthy males. Contralateral tumors are often found. These are occasionally synchronous but are more often metachronous. Ongoing surveillance of the contralateral testis is therefore needed.

Among malignant germ cell tumors, yolk sac tumors predominate until the age of 14 years. Few tumors of any type are diagnosed in children aged 5-9 years. For malignant teratomas, yolk sac tumors, and all germ cell tumors, respective rates by age group are as follows:

  • Age group 0-4 years - 0.45 case, 3.66 cases, and 4.16 cases per million population
  • Age group 5-9 years - 0.12 case, 0.12 case, and 0.12 case per million population
  • Age group 10-14 years - 0.05 case, 1.30 case, and 1.77 case per million population

Sex-related demographics

Sacrococcygeal teratoma has a 4:1 female-to-male predominance. In other germ cell tumors, the female-to-male ratio is roughly 2:1 in children.

Race-related demographics

Overall racial predispositions for these tumors have not been established. However, a population-based case-control study using figures from the California Cancer Registry, which included 451 cases of malignant germ cell tumors in children aged 0-5 years, found that Asian and Pacific Islander children were at higher risk for developing these tumors than non-Hispanic white children were.[26]

Prognosis

Mortality for congenital teratomas depends on gestational age and the size and location of the tumors. Survival of preterm infants younger than 30 weeks' gestation with sacrococcygeal teratoma is only 7%, whereas the survival for infants older than 30 weeks' gestation is 75%.

Rapid early growth is associated with the yolk-sac phenotype and carries a poorer prognosis.[27]  Early tumors are frequently large relative to the size of the infant and may induce congestive heart failure. Cervical teratomas may frequently lead to airway problems and death when they are large.

Before current developments in chemotherapy, the 10-year survival rate for malignant germ cell tumors ranged from 25% for embryonal carcinoma to 75% for dysgerminoma. Today, overall survival rates are higher than 90%.

Now that survival of most patients is approaching 100%, the morbidity of treatment, particularly with respect to fertility,[28] must be addressed. Because these patients are often prepubertal, standard means of collecting and preserving sperm or ova are not applicable. Techniques for preserving normal gonadal tissue and maturing it to produce viable sperm and ova must be developed.

Long-term follow-up of these patients is necessary because of the possibility of chronic pulmonary disease, hearing loss, and other long-term toxicities of the chemotherapy used in treating these lesions.

In a single-center retrospective study evaluating long-term outcomes in 25 pediatric patients with a primary mediastinal germ cell tumor, six patients were treated with resection alone and were cured without disease recurrence or progression, whereas 19 were treated for malignancy and had a 5-year overall survival of 0.39 ± 0.12.[29] Localized disease, complete resection, and platinum-based chemotherapy were identified as factors linked with improved survival in malignant nonseminomatous mediastinal germ cell tumors, and neoadjuvant platinum-based three-drug therapy followed by delayed surgical resection was found to be the appropriate treatment modality for these tumors.

Pediatric Intergroup Study findings

Intermediate risk

The results of the 2004 Intergroup germ-cell tumor study showed excellent event-free survival (EFS) and overall survival (OS).[30, 31]

Treatment with four cycles of standard-dose PEB (cisplatin-etoposide-bleomycin) resulted in 6-year EFS of 95% and OS of 95.7%. Results for specific tumors and stages included the following:

  • Stage II testicular tumors - 100% EFS and 100% OS
  • Stage I ovarian tumors - 95.1% EFS and 95.1% OS
  • Stage II ovarian tumors - 87.5% EFS and 93.8% OS

Two patients died of recurrent disease, and one patient died of secondary acute myelocytic leukemia. Toxicity was limited with this drug regimen; occasional low-grade toxicity to the renal, pulmonary, and auditory systems were reported. More severe hematologic toxicities were reported.

High risk

The 2004 Intergroup high-risk germ cell trial compared standard-dose PEB treatment with high-dose PEB treatment.[30, 31]  Although substantial improvement in EFS was noted in the high-dose arm, OS was not significantly improved, and serious renal toxicity (7% reduced creatinine clearance) and ototoxicity (14% testable hearing loss) were frequent.

Survival rates were as follows:

  • High-dose PEB - 89.6% EFS and 91.7% OS
  • PEB - 80.5% EFS and 86.0% OS
  • Gonadal stage III tumors - 94-96% EFS and 98-100% OS
  • Gonadal stage IV tumors - 86-88% EFS and 90-93% OS
  • Extragonadal stage I and II tumors - 89% EFS and 93% OS
  • Extragonadal stage III and IV tumors - 75-78% EFS and 81% OS

Because the high-stage extragonadal germ-cell tumors had substantially reduced survival compared with all other groups, more aggressive therapy may be warranted in those patients.

 

Presentation

History and Physical Examination

The clinical presentation of pediatric germ cell tumors depends on the location of the tumor.

Sacrococcygeal teratomas may be diagnosed antenatally as an incidental finding on ultrasonography (US); they may occur in an infant who is large for age, is premature, or has fetal hydrops. Fetal hydrops is an ominous sign, typically due to high flow through the tumor with high-output cardiac failure and placentomegaly. A teratoma larger than 5 cm is likely to cause dystocia and possible rupture; elective cesarean delivery should be performed. Sacrococcygeal teratomas that are not diagnosed antenatally may be noted at delivery, within the first few weeks after birth, or discovered late.

Ovarian masses typically cause abdominal pain, mass, distention, or emesis. Two thirds of affected girls present with pain as their primary symptom. Acute and chronic pain occur with equal frequency. In situations of acute pain, the diagnosis is often related to torsion of the ovary with consequent compromise of the blood supply. Palpable masses are less frequent and appear later in the clinical course.

Testicular tumors typically occur as a scrotal mass with or without pain. The differential diagnosis may include hydrocele because some cystic teratomas may transilluminate. In some situations, the tumor may cause symptomatic metastasis; this is more common in older patients.

The distribution of the patients' age at presentation for testicular tumors is bimodal. In the youngest children (0-4 years), teratomatous lesions and yolk sac tumors are predominant. In children older than 10 years, teratomas are increasingly rare. Yolk sac tumors are still predominant, but other malignant germ cell types start to become clinically relevant.

 

DDx

Diagnostic Considerations

In addition to the conditions listed in the differential diagnosis, other problems to be considered include the following:

Differential Diagnoses

 

Workup

Laboratory Studies

When a germ cell malignancy is suspected, tumor markers should be assessed prior to surgery. If the diagnosis is made after resection, marker studies should be performed as soon as possible thereafter. When tumor marker findings are positive, they should be monitored before each cycle of chemotherapy to determine the response to therapy and check for relapse.

Alpha-fetoprotein (AFP) is present in tumors with the following histologic features:

  • Fetal liver or endodermal sinus tumor elements
  • Embryonic carcinoma
  • Endodermal sinus tumor
  • Teratoma

Beta–human chorionic gonadotropin (β-HCG) is present in tumors with the following histologic features:

  • Embryonal carcinoma
  • Choriocarcinoma
  • Teratoma

The lactate dehydrogenase (LDH) isoenzyme LDH-1 is present in many tumors with the histologic features of an endodermal sinus tumor.

Once the diagnosis has been histologically confirmed, and if chemotherapy is needed, the following tests should be performed:

  • Complete blood count (CBC), differential, and platelet count
  • Glomerular filtration rate (GFR) or creatinine clearance rate - These are used to establish baseline renal function prior to platinum-based chemotherapy
  • Uric acid levels - These are used are used to assess the added risk from tumor lysis
  • Liver function tests - These include assessment of bilirubin, alkaline phosphatase, alanine aminotransferase, total protein, and albumin levels; they are used to assess possible metastases and determine baseline results prior to chemotherapy
  • Electrolytes, calcium, and magnesium levels - These should be monitored daily during chemotherapy, and deficiencies should be treated with supplements or changes in intravenous therapy

Imaging Studies

Diagnostic imaging is an essential part of initial staging, monitoring the response to therapy, and detecting relapse. Different modalities are appropriate at different points in the therapeutic course.

Chest radiography may be used at diagnosis to detect metastasis.

Computed tomography (CT) of the abdomen and pelvis is essential for the staging of abdominal and pelvic tumors at presentation.[32] Follow-up studies may be performed after the third course of chemotherapy, at the conclusion of induction therapy, and at the conclusion of maintenance therapy to monitor the response. CT is needed at relapse to determine the extent and location of the disease.

Magnetic resonance imaging (MRI) of the abdomen and pelvis may be substituted for CT.[32] If so, it should be used throughout therapy to maintain consistency in imaging studies. Yamaoka et al reported that among ovarian teratomas, mature tumors had imaging appearances typical of sebaceous fluid, whereas immature teratomas had multiple foci of fat as well as simple fluid-containing cysts.[33] MRI has also been used to characterize cardiac tumors.[34]

At diagnosis, chest CT is necessary to evaluate the presence and extent of metastatic disease that originates in the abdomen or pelvis. If a thoracic primary tumor is present, CT is used to assess the location and extent of the primary disease.

Bone scanning is a nuclear medicine test that is used to detect metastatic disease. It should be performed at presentation, as well as after the third course of chemotherapy, at the conclusion of induction therapy, and at the conclusion of maintenance therapy.

The remaining tests are optional and may be used as the clinical situation dictates.

CT or MRI of the brain should be performed whenever brain metastases are suspected.

Ultrasonography (US) of the abdomen and pelvis may aid in the detection of ovarian tumor spread and in monitoring certain masses without the risk of ionizing radiation. Testicular US may be useful for detecting microliths in testes contralateral to known tumors. These findings signify a high likelihood of neoplasia in situ.

Fluorodeoxyglucose (FDG) positron emission tomography (PET) appears to be most useful in the detection of relapse because other modalities cannot be used to detect the activity of the disease. The presence of elevated tumor marker levels, without the depiction of new disease on CT or MRI, is an indication for FDG-PET.

Other Tests

Pulmonary function studies, including diffusing capacity tests, are used to establish baseline function and determine the risk of bleomycin toxicity.

Brainstem auditory evoked responses (BAERs) or audiograms are assessed, depending on the patient's age, to establish baseline values prior to platinum-based chemotherapy.

Because germ cell tumors may be associated with chromosomal abnormalities (eg, Klinefelter syndrome[23] and mediastinal germ cell tumors), genetic screening is advisable in many cases.[35]

Histologic Findings

With mature teratoma, sampling of the entire tumor is necessary to ensure that no immature neural elements or occult foci of malignancy are present. The pathologist should evaluate the tumor at 1-cm intervals.

Histologic findings may include the following:

  • Immature teratoma - Grade 1, one low-power immature region per slide; grade 2, immaturity in four or fewer low-power fields per slide; grade 3, immaturity in more than four low-power fields per slide
  • Gliomatosis peritonei - These must be thoroughly evaluated at biopsy; if all glial elements are mature, no added risk is present
  • Germinoma, dysgerminoma, or seminoma - Sheets of polygonal cells separated by fibrous bands; stains with placental alkaline phosphatase in more than 80% of cases
  • Yolk sac tumor and endodermal sinus tumor - Most common malignancy within a teratoma; infiltrative tumor composed of pseudopapillary, reticular, solid, or vitelline cellular patterns
  • Choriocarcinoma - Syncytiotrophoblasts and cytotrophoblasts are present; heterozygosity is often absent
  • Embryonal carcinoma - Grossly smooth with cystic necrosis; anaplasia, mitotic figures, hemorrhage, necrosis; lack of Schiller-Duval bodies

Differentiation of the various subtypes of testicular germ cell tumors may be facilitated by immunohistochemical testing for molecular markers such as Aurora B, GPR30, Nek2, HMGA1, HMGA2, and others.[36] Such markers could represent also useful novel molecular targets for antineoplastic strategies.

Staging

Staging of these tumors depends on the organ of origin.

Ovarian tumors are staged according to two different systems. The International Federation of Gynecology and Obstetrics/American Joint Committee on Cancer (FIGO/AJCC) staging system[37] was initially developed for use in adults, and it is most relevant for epithelial malignancies. The Children's Oncology Group (COG) system is specific to germ cell tumors; it was developed specifically for pediatric tumors.

Testicular tumors are staged and treated according to a COG-specific system. Boys who have achieved sexual maturity have tumors that are staged and treated according to adult protocols.

FIGO/AJCC staging

In FIGO/AJCC stage I ovarian cancers, growth is limited to the ovaries or fallopian tubes. Subcategories are as follows:

  • IA - Limited to the inside of one ovary or the inside of one fallopian tube, with no tumor on the external surface; no cancer cells in ascites or abdominal/pelvic washings
  • IB - Limited to the insides of both ovaries or fallopian tubes, with no tumor on the external surfaces; no cancer cells in ascites or abdominal/pelvic washings
  • IC - Stage IA or IB with any of the following: (1) capsule around the tumor broken during surgery (stage IC1); (2) cancer on the outer surface of at least one ovary or fallopian tube, or capsule ruptured before surgery (stage IC2); (3) cancer cells found in ascites or abdominal/pelvic washings (stage IC3)

In stage II, cancer is in one or both ovaries or fallopian tubes and has spread to other pelvic organs, or there is primary peritoneal cancer; there is no spread to nearby lymph nodes (N0) or to distant sites (M0). Stage II may be subcategorized as follows:

  • IIA - The cancer has spread to or has invaded (grown into) the uterus or the fallopian tubes, or the ovaries
  • IIB - The cancer is on the outer surface of or has grown into other nearby pelvic organs such as the bladder, the sigmoid colon, or the rectum

In stage III, tumor involves one or both ovaries or fallopian tubes, with spread or growth into other organs and lymph nodes but with no distant metastases (M0). It may be subcategorized as follows:

  • IIIA1 - Cancer is in one or both ovaries or fallopian tubes, or there is primary peritoneal cancer (T1) and it may have spread or grown into nearby pelvic organs; spread is to retroperitoneal lymph nodes only
  • IIIA2 - Cancer is in one or both ovaries or fallopian tubes, or there is primary peritoneal cancer and it has spread or grown into organs outside the pelvis; no cancer is visible to the naked eye in the abdomen (outside the pelvis), but tiny deposits are found in the abdominal lining on laboratory examination; there is possible spread to retroperitoneal lymph nodes
  • IIIB - Cancer is in one or both ovaries or fallopian tubes, or there is primary peritoneal cancer and it has spread or grown into extrapelvic organs; cancer deposits of cancer are large enough to be visible but ≤ 2 cm across; there is possible spread to retroperitoneal lymph nodes but no spread to the inside of the liver or spleen or to distant sites
  • IIIC - The cancer is in one or both ovaries or fallopian tubes, or there is primary peritoneal cancer and it has spread or grown into extrapelvic organs; cancer deposits of cancer are >2 cm across and may be on the outside of the liver or spleen; there is possible spread to retroperitoneal lymph nodes but no spread to the inside of the liver or spleen or to distant sites

In stage IV, growth involves one or both ovaries or fallopian tubes, with lymph node spread and distant metastases. Subcategories are as follows:

  • IVA - Cancer cells are in the fluid around the lungs, with no other areas of cancer spread (eg, liver, spleen, intestine, or extra-abdominal lymph nodes)
  • IVB - Cancer has spread to the inside of the spleen or liver, to lymph nodes other than retroperitoneal, or to other organs or tissues outside the peritoneal cavity (eg, lungs or bones)

COG staging

In the COG system, ovarian tumors are staged as follows:

  • Stage I - Tumor is limited to one or both ovaries; peritoneal fluid and washings are negative for tumor; no clinical, radiographic, or histologic evidence of disease is present beyond the ovaries; tumor marker levels return to the reference range after an appropriate postsurgical half-life decline; the presence of gliomatosis peritonei does not worsen the stage
  • Stage II - Microscopic residual or positive lymph nodes (< 2 cm as measured by pathologist) are present; peritoneal fluid or washings are negative for malignant cells; tumor markers are positive or negative
  • Stage III - Lymph node or nodes with malignant metastatic nodule (>2 cm as measured by a pathologist) are present; gross residual or biopsy only; contiguous visceral involvement (omentum, intestine, or bladder) is observed; peritoneal washings are positive for malignant cells; tumor markers are positive or negative
  • Stage IV - Distant metastases, including liver metastases, are present

Testicular tumors are staged as follows:

  • Stage I - Limited to testis; tumor markers normal after appropriate half-life decline
  • Stage II - Transscrotal orchiectomy; microscopic disease in scrotum or high in spermatic cord (< 5 cm from proximal end); retroperitoneal lymph node involvement (< 2 cm); increased tumor marker levels after appropriate half-life decline
  • Stage III - Retroperitoneal lymph node involvement (>2 cm); no visceral or extra-abdominal involvement
  • Stage IV - Distant metastases; liver metastases

Extragonadal germ cell tumors are staged as follows:

  • Stage I - Complete resection at any site; en-bloc coccygectomy for sacrococcygeal site; normal tumor margins; tumor marker levels normal or elevated
  • Stage II - Microscopic residual disease; lymph nodes normal; tumor marker levels normal or elevated
  • Stage III - Gross residual disease or biopsy only; retroperitoneal nodes normal or involved with metastatic disease; tumor marker levels normal or elevated
  • Stage IV - Distant metastases, including those to the liver

The COG has proposed modifying their risk classification system to more accurately reflect current knowledge of pediatric germ cell tumors. Those modifications are being tested in current protocols. Treatment groups will undoubtedly be revised as more knowledge is obtained.

As more is learned about the molecular biology of these tumors, risk stratification is likely to be based less on the site of origin or tumor type and more on the molecular abnormalities of each specific tumor.

 

Treatment

Approach Considerations

For children with extracranial germ cell tumors, surgery is an essential component of treatment. Depending on the clinical factors present, appropriate treatment may involve one of the following[18] :

  • Surgical resection followed by careful monitoring for disease recurrence
  • Initial surgical resection followed by platinum-based chemotherapy
  • Diagnostic tumor biopsy and preoperative platinum-based chemotherapy followed by definitive tumor resection

Medical Care

In the United States, the standard chemotherapy regimen for both adults and children with malignant nonseminomatous germ cell tumors includes cisplatin, etoposide, and bleomycin (PEB). An every-21-days regimen that has been used is as follows[18] : 

  • Bleomycin - 15 units/m2 on day 1 (maximum, 30 units)
  • Etoposide - 100 mg/m2 on days 1-5
  • Cisplatin - 20 mg/m2 on days 1-5

The combination of carboplatin, etoposide, and bleomycin has been studied in the United Kingdom but has not been compared with PEB in a trial focusing on pediatric germ cell tumors.[18]

Radiation therapy is rarely recommended.[18]

Surgical Care

In general, gross total resection of tumor is the goal. The tumor and involved adjacent structures should be resected en bloc, if this is possible and does not lead to disfigurement.

Sacrococcygeal tumor

Typically, the surgeon approaches this tumor through a posterior transsacral route. The coccyx must be resected en bloc with the tumor to minimize the risk of recurrence. Control and division of the middle sacral artery early in the procedure is advisable. If the sacrum or rectum is invaded by the tumor, complete resection may not be advisable at the initial operation. Treating these tumors with chemotherapy is reasonable, with resection after the maximum response is obtained.

When the tumor extends high into the pelvis and abdomen, laparotomy or laparoscopy is required in addition to the posterior incision. Ascitic fluid should be collected or peritoneal washings obtained. The tumor may then be mobilized for removal from below or above, depending on the anatomy. Samples should be obtained in lymph nodes from the retroperitoneum. In tumors with a moderate pelvic component, laparoscopy may allow clip placement in the middle sacral artery and mobilization of the pelvic portion of the tumor.

Cowles et al reported preoperative embolization of the major vessels that supply a large teratoma followed by radiofrequency ablation (RFA) of the zone between normal tissue and tumor.[38] Damage to the nerves supplying the leg has been reported with antenatal RFA.

Ovarian tumor

Open resection is the preferred approach to these tumors. (See the image below.) Typically, laparoscopy requires morcellation of the tumor in a bag. The consequent destruction of the tumor capsule prevents pathologic staging; thus, patients must be treated as stage II. Appropriate measures should be taken to minimize tissue dispersion and the potential for tumor dissemination.[39]

Ovarian yolk sac tumor at surgery. Ovarian yolk sac tumor at surgery.

Ascitic fluid or peritoneal washings should undergo cytologic analysis. The entire peritoneal cavity should be inspected. Any suspicious implants should be sampled or resected. Gliomatosis peritonei does not worsen the stage of a tumor, but all implants must have mature glial tissue. Immature tissue suggests metastatic disease and requires more intensive therapy. The omentum must be inspected. If disease is possible (eg, adherence, nodules, implants), the affected area should be resected at this time.

Ipsilateral oophorectomy or salpingo-oophorectomy should be performed. Uninvolved fallopian tubes should be preserved if possible. In cases of mature teratoma, the contralateral ovary should be inspected. If it appears normal, it should be left alone. Bilateral malignant tumors require bilateral oophorectomy, but hysterectomy is unnecessary for germ cell tumors. Some authors advocate ovary-sparing resection of mature teratomas. This is not always possible.

Samples of suspicious and involved lymph nodes should be obtained. Random bilateral sampling is no longer required because it did not have an impact on survival in the last Intergroup study.[30]

Testicular tumor

Testicular teratomas may be treated with local resection in prepubertal patients. The tumor should be removed with a small rim of normal testicle. If the testicular tissue shows signs of pubertal change, radical inguinal orchiectomy should be performed.

In all malignant cases, radical inguinal orchiectomy should be performed with high ligation of the spermatic cord. For very large tumors, the incision may be enlarged by extending the medial portion of the incision downward into the upper scrotum.

Transscrotal resection with intact capsule is now treated as a stage I tumor, provided that the cord structures are completely removed and are uninvolved. If transscrotal biopsy was performed prior to resection, the stage is at least stage II. Because most of these preadolescent tumors are responsive to chemotherapy, hemiscrotectomy is rarely necessary.

If images do not reveal lymph node enlargement, sampling of ipsilateral retroperitoneal lymph nodes is not required. When images show positive findings of nodal enlargement of 2-4 cm, perform a biopsy of the enlarged nodes. Nodes with a diameter exceeding 4 cm are treated as stage III metastatic disease and do not require biopsy. Tumor debulking is no longer recommended.

Mediastinal tumor

The approach to the resection may be via median sternotomy or lateral thoracotomy. Small lesions have been resected by using video-assisted thoracoscopic surgery (VATS). Large lesions may cause airway compromise and require intubation and care in the intensive care unit (ICU). Many of these large tumors are best managed with initial biopsy, neoadjuvant chemotherapy, and delayed complete resection.[40]

Adherent nonvital structures (eg, pericardium and thymus) should be removed en bloc with the tumor. Lymph nodes should be sampled.

A study of children and adolescents with primary mediastinal and retroperitoneal germ cell tumors, conducted by the French Society of Pediatric Oncology, found that a strategy of delayed aggressive surgery after cisplatin-based chemotherapy yielded a favorable prognosis in children.[41] ​ With aggressive surgery, a microscopic complete resection was achieved in 12 of the 15 patients in the primary mediastinal group and in four of the five in the retroperitoneal group. Overall survival as 88% (14/16) for the former group and 80% (4/5) for the latter. The prognosis was better in younger patients; three adolescents died of tumor progression.

Neck tumor

These lesions present special surgical challenges. In large congenital lesions, the airway may be compromised, and intubation may be difficult. The ex-utero intrapartum treatment (EXIT) procedure, in which a cesarean delivery is performed and the neonate remains attached to the placenta, may allow enough time for bronchoscopic airway placement.

Resection should be total but not at the expense of vital structures. A staged procedure is acceptable in this circumstance. Complete resection may then be possible after chemotherapy.

Recurrent disease

Recurrent disease must be surgically staged. The extent of disease is an important prognostic factor. Surgically resectable recurrent disease has a far more favorable prognosis than unresectable disease. The best prognosis exists when complete surgical resection is accompanied by high-intensity chemotherapy with autologous stem cell rescue.

Additionally, recurrent disease may have a different tissue type than that of the original tumor. PNET, for example, is a frequent component of germ cell tumors that may not respond to bleomycin-etoposide-cisplatin (BEP) therapy.

Metastatic disease

When these tumors are metastatic, initial chemotherapy may lead to resolution of metastatic disease. If resolution is not achieved, residual disease may be necrotic tumor, mature teratoma, persistent malignant disease, or combinations of the above. No current radiologic test reliably distinguishes between these possibilities. Surgical biopsy may help guide therapy. Resection is recommended when possible.[42]

Complications

Complications of chemotherapy include, but are not limited to, the following:

  • Myelosuppression
  • Nephrotoxicity
  • Ototoxicity
  • Pulmonary failure
  • Neurotoxicity
  • Infertility
  • Secondary malignancy

Fertility is of particular importance for these patients. Adult males treated with chemotherapy and surgery similar to current pediatric protocols face a 20-30% reduction in fertility with standard-dose BEP.[43]  Among adult females, the results may be worse. In one study, only three of 26 patients were able to conceive, and none of these conceptions led to live births.[44]

Park et al analyzed oncologic and reproductive outcomes of 42 pediatric and young adolescents with malignant ovarian germ cell tumors treated with fertility-sparing surgery, of whom 31 received adjuvant BEP therapy.[45]  The 5-year disease-free survival (DFS) and overall survival (OS) rates were 85% and 97%, respectively. Seven of the surviving 41 patients were premenarchal, 30 had regular menstruation, and three had irregular menstruation. No patient had premature ovarian failure.

Diet

Maintaining adequate nutrition is often difficult during chemotherapy. Additionally, intestinal obstruction may be a consequence of an abdominal tumor. Nutritional supplements or parenteral nutrition may be necessary. In cases other than those involving frank obstruction, enteral tube feeding has proven useful.

Consultations

Psychological support is important for both the patient and the family after any diagnosis of cancer. For older patients, fertility issues, as well as issues of sexual identity, may also be important.

Long-Term Monitoring

All patients with sacrococcygeal teratomas should be monitored with serial rectal examinations and serum markers every 3 months for the first 3 years to detect signs of recurrence.

Computed tomography (CT) or magnetic resonance imaging (MRI) may also be helpful, especially in cases of questionable masses found during rectal examination, increased serum markers, or inadequate resection margins.

 

Medication

Medication Summary

Since the introduction of platinum-based therapy for this disease, the survival rate has improved considerably. First-line therapy includes the use of bleomycin, etoposide, and cisplatin (BEP). Survival with carboplatin-containing regimens has not been as favorable. For low-risk tumors (testicular stage II; ovarian stage I and II), four cycles of BEP has a survival rate of 94-100%. For high-risk tumors (testicular and ovarian stage III and IV; extragonadal stage I-IV), high-dose BEP has better overall survival at the cost of some increase in toxicity.

Salvage therapy typically consists of a combination of paclitaxel, ifosfamide, carboplatin, etoposide, and vinblastine or vincristine plus peripheral blood stem cell (PBSC) transplantation. Gemcitabine has been used as salvage therapy in a phase 2 protocol.

Kollmannsberger et al reported improved 2-year survival with a second course of high-dose chemotherapy with stem cell rescue and complete surgical resection in high-risk patients who failed initial ablative chemotherapy and autologous stem cell transplant.[46]

Antineoplastic agents

Class Summary

Cancer chemotherapy is based on an understanding of tumor cell growth and how drugs affect this growth. After cells divide, they enter a period of growth (ie, phase G1), followed by DNA synthesis (ie, phase S). The next phase is a premitotic phase (ie, G2). Finally, a mitotic cell division occurs (ie, phase M). Cell division rates vary for different tumors.

Antineoplastic agents interfere with cell reproduction. Some agents are cell cycle specific, while others (eg, alkylating agents, anthracyclines, cisplatin) are not phase specific. Cellular apoptosis (ie, programmed cell death) is also a potential mechanism of many antineoplastic agents.

Current protocols use these agents in combinations that exploit differences in growth and recovery between tumors and normal tissues.

Bleomycin (Blenoxane)

Glycopeptide antibiotic that inhibits DNA synthesis. For palliation in the management of several neoplasms.

Etoposide (Toposar, VePesid)

Inhibits topoisomerase II and causes DNA strand breakage, which arrests cell proliferation in the late S or early G2 portion of the cell cycle.

Vinblastine (Velban)

Inhibits microtubule formation, which, in turn, disrupts the formation of the mitotic spindle, causing cell proliferation to arrest at metaphase.

Cisplatin (Platinol)

Inhibits DNA synthesis and, thus, cell proliferation by causing DNA cross-linking and denaturation of the double helix.

Carboplatin (Paraplatin)

Analog of cisplatin. Has same efficacy as cisplatin but with a better toxicity profile. Dose is based on the following formula: total dose (mg) = (target AUC) X (GFR + 25), where AUC is the area under plasma concentration-time curve expressed in mg/mL/min, and GFR is expressed in mL/min.

Paclitaxel (Taxol)

Mechanisms of action are tubulin polymerization and microtubule stabilization.

Ifosfamide (Ifex)

Inhibits DNA and protein synthesis and, thus, cell proliferation by causing DNA cross-linking and denaturation of the double helix.

Gemcitabine (Gemzar)

Cytidine analog. After it is intracellularly metabolized to become an active nucleotide, it inhibits ribonucleotide reductase and competes with deoxycytidine triphosphate for incorporation into DNA.

This drug has been shown to have activity in a phase 2 trial against relapsed germ cell tumors.

Vincristine (Vincasar PFS, Oncovin)

Mechanism of action is uncertain. May involve a decrease in reticuloendothelial cell function or an increase in platelet production. However, neither of these mechanisms fully explains the effect in TTP and HUS.

Antibiotic agents

Class Summary

Trimethoprim and sulfamethoxazole (TMP-SMZ) is indicated for prophylaxis of Pneumocystis carinii infection.

Trimethoprim and sulfamethoxazole (Septra, Bactrim)

Dihydrofolate reductase inhibitor that prevents tetrahydrofolic acid production in bacteria. Active in vitro against a broad range of gram-positive and gram-negative bacteria, including uropathogens (eg, Enterobacteriaceae species, Staphylococcus saprophyticus). Resistance is usually mediated by decreased cell permeability or alterations in amount or structure of dihydrofolate reductase. Demonstrates synergy with sulfonamides, potentiating inhibition of bacterial tetrahydrofolate production.

Uroprotective antidotes

Class Summary

Mesna is a prophylactic detoxifying agent used to inhibit hemorrhagic cystitis caused by ifosfamide and cyclophosphamide. In the kidney, mesna disulfide is reduced to free mesna. Free mesna has thiol groups that react with acrolein, the ifosfamide and cyclophosphamide metabolite considered responsible for urotoxicity.

Mesna (Mesnex)

Inactivates acrolein and prevents urothelial toxicity without affecting cytostatic activity.

Antiemetic agents

Class Summary

Antiemetics should be administered before, during, and for 6 hours after chemotherapy. Antineoplastic-induced vomiting is stimulated through the chemoreceptor trigger zone (CTZ), which then stimulates the vomiting center (VC) in the brain. Increased activity of the central neurotransmitters dopamine in CTZ or acetylcholine in VC appears to be a major mediator for inducing vomiting. After the administration of antineoplastic agents, serotonin (5-HT) is released from enterochromaffin cells in the GI tract. With serotonin release and subsequent binding to 5-HT3-receptors, vagal neurons are stimulated; they transmit signals to the VC, resulting in nausea and vomiting.

Antineoplastic agents may cause nausea and vomiting so intolerable that patients may refuse further treatment. Some antineoplastic agents are more emetogenic than others. Prophylaxis with antiemetic agents prior to and after cancer treatment is often essential to ensure administration of the entire chemotherapy regimen.

Ondansetron (Zofran)

Selective 5-HT3-receptor antagonist that blocks serotonin both peripherally and centrally. Prevents nausea and vomiting associated with emetogenic cancer chemotherapy (eg, high-dose cisplatin) and complete-body radiotherapy.