AUTHOR AND EDITOR INFORMATION

Section 1 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

INTRODUCTION

Section 2 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Background

Teratomas (from Greek terato meaning "a monster" and onkoma meaning "swelling or mass") 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. The 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.

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. 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 3 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, less than 4 fields are present per slide; and in grade 3 tumors, more than 4 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 tumor (PNET). Charoenkwan et al (2002) found overexpression of p53 in the more aggressive immature teratomas at all sites.¹

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 suggest that the recurrence rate for immature teratomas can be decreased to 9.5% with chemotherapy.² 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.³ 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 describes genetic imprinting as a major factor in the development of some of these tumors.⁴ 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 suggests 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 3 germ cell layers.

Oosterhuis et al suggest that tumors may be grouped on the basis of their chromosomal abnormalities as follows:⁵

• Group 1 includes immature teratomas and yolk sac tumors. The immature teratomas are usually diploid, whereas yolk sac tumors may be diploid, tetraploid, or aneuploid. The 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 includes most nonseminomatous malignant germ cell tumors and typically includes 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 includes 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 includes 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 suggest that the MAGE gene family of tumor rejection antigens may also be involved in the pathogenesis of these tumors.⁶ 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, 9 patients were identified with this finding.⁷ Five patients presented with a carcinoma, 2 patients presented with glial tumors, and 2 patients presented with embryonal tumors. Resection and chemotherapy were typically used. Because these tumors are quite rare, response to treatment is difficult to generalize.

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

Frequency

United States

Sacrococcygeal teratoma occurs in 1 in 30,000-70,000 live births. The female-to-male predominance is 4:1. 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

No significant geographic predilection is recognized.

Mortality/Morbidity

The mortality rate 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.⁸ 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.

Prior to recent chemotherapeutic successes, 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 greater than 90%.

Race

No racial predispositions for these tumors are known.

Sex

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.

Age

• Sacrococcygeal teratomas
• • Sacrococcygeal teratomas are congenital.
  • Those with a significant external component 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 greatly increases to more than 50% by age one year.
• Ovarian tumors
• • The incidence of ovarian germ cell tumors 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% of tumors were found in girls aged 5-9 years, and more than 70% of tumors were found in girls aged 10-14 years.⁹
  • 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 less than 5 years old, 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. 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.
  • 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 patients are aged 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, 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

CLINICAL

Section 3 of 11  

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• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

History

The clinical presentation of these tumors depends on the location of the tumor.

Sacrococcygeal teratomas may be prenatally diagnosed as an incidental ultrasonographic finding; they may occur in an infant who is large for age, in premature infants, or in infants with fetal hydrops. Fetal hydrops is an ominous sign. It is 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 prenatally diagnosed 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 (aged 0-4 y), 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.

Causes

The epidemiology of the tumors suggests that they are increasing in frequency. With sacrococcygeal teratomas, no causative agents are known. With respect to ovarian germ cell tumors, a familial predilection may be present. Cases in 7 families have been reported in which female first-degree relatives had germ cell tumors. In an additional 7 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.¹⁰ 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 10. 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 4-fold risk of germ cell malignancy.¹¹ Boys whose father or brother has had a teratoma have a 5-15% increased risk for developing a teratoma. Whether this is due to genetic causes or is a consequence of shared environment is unclear.

Intersex anomalies have also been associated with development of germ cell tumors. Gonadoblastoma is observed in roughly one third of patients with intersex anomalies. Although gonadoblastoma is a carcinoma in situ, it frequently evolves into dysgerminoma; yolk sac tumors, immature teratomas, and choriocarcinomas are possible as well. Turner syndrome is similarly a risk factor for gonadoblastoma. Klinefelter syndrome has been linked with an increased risk of extragonadal malignant germ cell tumors. 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 intersex anomalies 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. Debate surrounds the optimal timing for gonadal resection in these situations. 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.

DIFFERENTIALS

Section 4 of 11  

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Other Problems to be Considered

Ovarian epithelial malignancy
Ovarian cyst
Ovarian torsion
Testicular torsion

WORKUP

Section 5 of 11  

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• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
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Lab 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 prior to 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 (b-HCG) is present in tumors with the following histologic features:
• • Embryonal carcinoma
  • Choriocarcinoma
  • Teratoma
• Lactate dehydrogenase (LDH) isomer of 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.
• • The CBC count, differential, and platelet count should be evaluated.
  • The glomerular filtration rate (GFR) or creatinine clearance rate is used to establish baseline renal function prior to platinum-based chemotherapy.
  • Uric acid levels are used to assess the added risk from tumor lysis.
  • Liver function tests should be performed to assess possible metastases and determine baseline results prior to chemotherapy. These include assessment of bilirubin, alkaline phosphatase, alanine aminotransferase (SGPT), total protein, and albumin levels.
  • Electrolytes, calcium, and magnesium levels should be monitored daily during chemotherapy. 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.
• CT scanning of the abdomen and pelvis is essential for the staging of abdominal and pelvic tumors at presentation. 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 scanning is needed at relapse to determine the extent and location of the disease.
• MRI of the abdomen and pelvis may be substituted for CT scanning. 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.¹²
• At diagnosis, chest CT scanning 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 scanning 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 scanning or MRI of the brain should be performed whenever brain metastases are suspected.
  • Ultrasonography 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 ultrasound may be useful to detect microliths in testes contralateral to known tumors. These findings signify a high likelihood of in situ neoplasia.
  • Fluorodeoxyglucose (FDG) positron emission tomography (PET) scanning 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 scans or MRIs, is an indication for FDG PET scanning.

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, mediastinal germ cell tumors), genetic screening is advisable in many cases.

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 4 or fewer low-power fields per slide
  • Grade 3 - Immaturity in more than 4 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

Staging

Staging of these tumors depends on the organ of origin. Ovarian tumors are staged using 2 staging systems. The International Federation of Gynecology and Obstetrics/American Joint Committee on Cancer (FIGO/AJCC) staging system was initially developed for use in adults, and it is most relevant for epithelial malignancies. The Children's Oncology Group (COG) system is germ-cell tumor specific; 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 for ovarian tumors
• • Stage I: Growth is limited to the ovaries.
  • • IA - Limited to one ovary, no tumor on the external surface, capsule intact
    • IB - Limited to both ovaries, no tumor on the external surface, capsule intact
    • IC - Stage IA or IB with ascites or peritoneal washings that contain malignant cells, tumor on the surface, or ruptured capsule
  • Stage II: Growth involves one or both ovaries, with pelvic extension.
  • Stage III: Tumor involves one or both ovaries, with peritoneal implants outside the pelvis or positive retroperitoneal or inguinal nodes. Superficial liver metastasis indicates stage III disease. Tumor is limited to the true pelvis, but histologically proven malignant extension to small bowel or omentum is present.
  • Stage IV: Growth involves one or both ovaries, with distant metastases. If pleural effusion is present, cytologic findings must be positive to indicate stage IV disease. Parenchymal liver metastasis indicates stage IV disease.
• COG staging for ovarian tumors
• • 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.
• COG stages for testicular tumors
• • 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
• COG stages for extragonadal germ cell tumors
• • 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

TREATMENT

Section 6 of 11  

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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 trans-sacral 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 (2006) reported preoperative embolization of the major vessels that supply a large teratoma followed by radiofrequency ablation of the zone between normal tissue and tumor.¹³ Damage to the nerves supplying the leg has been reported with prenatal radiofrequency ablation.
• Ovarian tumor
• • Open resection is the preferred approach to these tumors. Typically, laparoscopy requires morcellation of the tumor in a bag. The consequent destruction of the tumor capsule prevents pathological staging; thus, patients must be treated as stage II. Ascites or peritoneal washings should be 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.¹⁴
• 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 the cord structures are completely removed and are uninvolved. If trans-scrotal 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 larger than 4 cm diameter 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 thoracic surgery (VATS). Large lesions may cause airway compromise and require intubation and care in the intensive care unit. Many of these large tumors are best managed with initial biopsy, neoadjuvant chemotherapy, and delayed complete resection.
  • Adherent nonvital structures such as the pericardium and thymus should be removed en bloc with the tumor. Lymph nodes should be sampled
• 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, and cisplatin (BEP)–type therapy.
• Metastatic disease: When these tumors are metastatic, initial chemotherapy may lead to resolution of metastatic disease. When it does not, 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.

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.

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.

MEDICATION

Section 7 of 11  

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• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Since the introduction of platinum-based therapy for this disease, the survival rate has improved considerably. First-line therapy includes the use of cisplatin, etoposide, and bleomycin. Survival with carboplatin containing regimens has not been as favorable. For low risk tumors (testicular stage II, and ovarian stage I and II) 4 cycles of BEP has a survival rate of 94-100%. For high risk tumors (stage III and IV testicular and ovarian tumors and stage I-IV extragonadal tumors) 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 (2003) 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.¹⁵

Drug Category: Antineoplastic agents

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.

Drug Category: Antibiotic agents

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

Drug Category: Uroprotective antidotes

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.

Drug Category: Antiemetic agents

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.

FOLLOW-UP

Section 8 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Further Outpatient Care

• Monitor all patients with sacrococcygeal teratomas with serial rectal examinations and serum markers every 3 months for the first 3 years to detect signs of recurrence.
• CT scanning or MRI studies may also be helpful, especially in cases of questionable masses found during rectal examination, increased serum markers, or inadequate resection margins.

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.¹⁶ Among adult females, the results may be worse. In one study, only 3 of 26 patients were able to conceive, and none of these conceptions led to live births.¹⁷

Prognosis

• Intermediate risk: The results of the last Intergroup germ-cell tumor study show excellent event-free survival (EFS) and overall survival (OS).^{14, 18}
• • Treatment with 4 cycles of standard-dose BEP resulted in 6-year event-free survival (EFS) of 95% and overall survival (OS) of 95.7%.
  • • 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 from 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 hematological toxicities were reported.
• High risk: The last Intergroup high-risk germ cell trial compared standard-dose BEP treatment with high-dose BEP treatment.^{14, 18} 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 BEP - 89.6% EFS and 91.7% OS
    • BEP - 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.

MISCELLANEOUS

Section 9 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Special Concerns

• 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.
• Now that survival of most patients is approaching 100%, the morbidity of treatment, particularly fertility, needs to be addressed. Because these patients are often prepubertal, standard means of collecting and preserving sperm or ova are not applicable. Techniques to preserve normal gonadal tissue and mature it to produce viable sperm and ova need to 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.

MULTIMEDIA

Section 10 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Media file 1:  Sacrococcygeal teratoma in a female neonate. This particular tumor is largely external with no intrapelvic extension.
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Media type:  CT

Media file 2:  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.
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Media type:  CT

Media file 3:  Ovarian yolk sac tumor at surgery.
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Media type:  Photo

Media file 4:  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.
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Media type:  CT

Media file 5:  Esophagram in an infant with massive thoracic germ cell tumor. Note how the esophagus is displaced posteriorly and laterally by the left mediastinal tumor.
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Media type:  Radiograph

Media file 6:  Chest radiograph of the patient in Media file 5 after treatment with chemotherapy. The size of the tumor has not decreased.
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Media type:  Radiograph

Media file 7:  CT scan of the chest in the patient in Media file 6. The carina is displaced posteriorly and to the right. The vena cava is displaced anteriorly, and the aorta is compressed between the mass and the spine.
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Media type:  CT

REFERENCES

Section 11 of 11

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

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