eMedicine - Teratomas and Other Germ Cell Tumors : Article by E Stanton Adkins III, MD

You are in: eMedicine Specialties > Pediatrics > General Surgery

Teratomas and Other Germ Cell Tumors

Last Updated: May 25, 2006

Synonyms and related keywords: teratomas, germ cell tumors, dermoid, sacrococcygeal teratoma, seminoma, dysgerminoma, yolk sac tumor, endodermal sinus tumor, choriocarcinoma, embryonal carcinoma, gonadoblastoma

AUTHOR INFORMATION Section 1 of 11

Author Information Introduction Clinical Differentials Workup Treatment Medication Follow-up Miscellaneous Pictures Bibliography

Author: E Stanton Adkins III, MD, Clinical Assistant Professor, Departments of Pediatrics and Surgery, University of South Carolina School of Medicine

E Stanton Adkins III, MD, is a member of the following medical societies: American Academy of Pediatrics, American College of Surgeons, American Medical Association, and American Pediatric Surgical Association

Editor(s): Rebeccah Brown, MD, Assistant Director of Trauma Services, Assistant Professor, Department of Clinical Surgery and Pediatrics, University of Cincinnati Medical Center and Children's Hospital; Mary L Windle, PharmD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy, Pharmacy Editor, eMedicine.com, Inc; Deborah F Billmire, MD, Associate Professor, Department of Surgery, Indiana University Medical Center; H Biemann Othersen, MD, Emeritus Chief of Pediatric Surgery, Professor, Departments of Surgery and Pediatrics, Medical University of South Carolina; and Max J Coppes, MD, PhD, MBA, Executive Director, Center for Cancer and Blood Disorders, Children's National Medical Center

Disclosure

INTRODUCTION

Section 2 of 11

Author Information Introduction Clinical Differentials Workup Treatment Medication Follow-up Miscellaneous Pictures Bibliography

Background: Teratomas (from Greek terato meaning a monster and onkoma meaning swelling or mass) and other germ cell tumors are 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 assessed serologically.

Pathophysiology: Several theories about the origin of these tumors exist. 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 sacrococcygeal, 40%; ovary, 25%, testicle, 12%; brain, 5%; and other, 18%. These other sites include the neck and mediastinum.

By definition, teratomas include components derived from all 3 embryonic layers: ectoderm, endoderm, and mesoderm. These tissues are foreign to the location where 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 1 low-power field per slide; in grade 2, fewer than 4 fields are present per slide; in grade 3, 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 shows 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 tumor, but they may also represent primitive neuroectodermal tumor (PNET). Charoenkwan (2002) found overexpression of p53 in the more aggressive immature teratomas at all sites.

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%, whereas that in an immature teratoma may be as high as 33%. The likelihood of recurrence depends on the site of the tumor as well as the completeness of resection. 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. 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. The developmentally expressed genes insulinlike growth factor 2 (IGF II) and its receptor, RNA (H-19); small nuclear riboprotein (SNRPN); mas proto-oncogene; and tumor suppressor genes WT1 and MASH2 are imprinted, depending on their maternal or paternal origin. He 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 (Mutter, 1997).

Oosterhuis et al suggest that tumors may be grouped on the basis of their chromosomal abnormalities (Oosterhuis, 1997).

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. 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 (Hara, 1999).

When platinum-based chemotherapy–resistant tumors are evaluated, between 1/3 and 1/2 of tumors exhibit microsatellite instability.

Frequency:

In the US: Sacrococcygeal teratoma occurs in 1 in 30,000-70,000 live births. The female-to-male predominance is 4:1. 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 been increasing over the last several decades.

Internationally: No significant geographic predilection exists.

Mortality/Morbidity: The mortality rate for congenital teratomas is dependent on gestational age and the size and location of the tumors. Survival of preterm infants younger than 30 weeks GA with sacrococcygeal teratoma is only 7%, while the survival for infants older than 30 weeks GA is 75%. Rapid early growth is associated with the yolk-sac phenotype and carries a poorer prognosis (Herrmann 2000). 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: With sacrococcygeal teratoma, a 4:1 female-to-male predominance exists. For 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 increases greatly to more than 50% by one year.

Ovarian tumors

The incidence of ovarian germ cell tumors increases with age, peaking around 15-19 years of age. 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. Benign ovarian tumors, largely teratomas, predominate. Of malignant ovarian tumors in childhood, roughly 70% 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.

Testicular tumors

Testicular germ cell tumors in childhood are split between teratomas and yolk sac tumors. They are more common from birth to 5 years of age. From age 6 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 to 0.5% of otherwise healthy males. Contralateral tumors are often found. These are occasionally synchronous, but 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

Author Information Introduction Clinical Differentials Workup Treatment Medication Follow-up Miscellaneous Pictures Bibliography

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

Sacrococcygeal teratomas may be diagnosed prenatally as an incidental ultrasonographic finding, or they may occur in an infant who is large for his or her age, is in premature labor, and is in 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 diagnosed prenatally 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. In some situations, the tumor may cause symptomatic metastasis; this is more common in older patients. The distribution of patients' age at presentation for testicular tumors is bimodal. In the youngest children aged 0-4 years, teratomatous lesions and yolk sac tumors are predominant. In those 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 exist. 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.

A single 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. 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 recent study also revealed that a history of pyloric stenosis leads to a 4-fold risk of germ cell malignancy. 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. 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 exists about 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

Author Information Introduction Clinical Differentials Workup Treatment Medication Follow-up Miscellaneous Pictures Bibliography

Appendicitis
Ewing Sarcoma and Primitive Neuroectodermal Tumors
Lymphoproliferative Disorders
Neural Tube Defects in the Neonatal Period
Neuroblastoma
Rhabdomyosarcoma

Other Problems to be Considered:

Ovarian epithelial malignancy
Ovarian cyst
Ovarian torsion
Testicular torsion

Quick Find

Author Information
Introduction
Clinical
Differentials
Workup
Treatment
Medication
Follow-up
Miscellaneous
Pictures
Bibliography

Click for related images.

Related Articles

Appendicitis

Ewing Sarcoma and Primitive Neuroectodermal Tumors

Lymphoproliferative Disorders

Neural Tube Defects in the Neonatal Period

Neuroblastoma

Rhabdomyosarcoma

Patient Education

Click here for patient education.

WORKUP

Section 5 of 11

Author Information Introduction Clinical Differentials Workup Treatment Medication Follow-up Miscellaneous Pictures Bibliography

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 confirmed histologically, and if chemotherapy is needed, the following tests should be performed.

The CBC, 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.

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, it 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.

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 by 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 stages for ovarian tumors

Stage I: Growth is limited to the ovaries.
- IA - Limited to 1 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 1 or both ovaries, with pelvic extension.
Stage III: Tumor involves 1 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 1 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 stages for ovarian tumors

Stage I: Tumor is limited to 1 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

Author Information Introduction Clinical Differentials Workup Treatment Medication Follow-up Miscellaneous Pictures Bibliography

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.

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, so the patients must be treated as stage II. Ascites or peritoneal washings should be sent for 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 any question of disease exists (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 (Rogers, 2004).

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 demonstrate lymph node enlargement, sampling of ipsilateral retroperitoneal lymph nodes is not required. When images show positive findings of nodal enlargement between 2 and 4 cm, biopsy the enlarged nodes. Nodes greater 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 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 staged surgically. 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. Primitive neuroectodermal 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 when possible is recommended.

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

Author Information Introduction Clinical Differentials Workup Treatment Medication Follow-up Miscellaneous Pictures Bibliography

Since the introduction of platinum-based therapy for this disease, the survival rate has improved considerably. The overall survival rate is now 95-100%. First-line therapy includes the use of bleomycin, etoposide, and cisplatin. Survival with carboplatin containing regimens has not been as favorable.

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) report improved 2-year survival with a second course of high-dose chemotherapy with stem cell rescue and complete surgical resection for high-risk patients who failed initial ablative chemotherapy and autologous stem cell transplant.

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.

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.
Drug Name
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.
Adult Dose 8 mg PO 1-2 h before radiotherapy and 8 mg bid for chemotherapy prophylaxis
Alternatively, three 0.15-mg/kg IV doses or 32 mg IV once
Pediatric Dose 4-11 years: 4 mg PO 30 min before chemotherapy; may repeat q8h for 2 doses
>11 years: Administer as in adults
Contraindications Documented hypersensitivity
Interactions Potential for CYP450 inducers (eg, barbiturates, rifampin, carbamazepine, phenytoin) to change half-life and clearance, but dose adjustment not usually required
Pregnancy B - Usually safe but benefits must outweigh the risks.
Precautions For prevention of nausea and vomiting, not for rescue of nausea and vomiting

FOLLOW-UP Section 8 of 11

Author Information Introduction Clinical Differentials Workup Treatment Medication Follow-up Miscellaneous Pictures Bibliography

Further Outpatient Care:

Sacrococcygeal teratomas: Monitor all patients 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 mass on 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 (Huyghe, 2004). 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 (Sugae, 2003).

MISCELLANEOUS

Section 9 of 11

Author Information Introduction Clinical Differentials Workup Treatment Medication Follow-up Miscellaneous Pictures Bibliography

Special Concerns:

Future directions

The proposed risk classification system is being tested. 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 will 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.

PICTURES

Section 10 of 11

Author Information Introduction Clinical Differentials Workup Treatment Medication Follow-up Miscellaneous Pictures Bibliography

Caption: Picture 1. Teratomas and other germ cell tumors. Sacrococcygeal teratoma in a female neonate. This particular tumor is largely external with no intrapelvic extension.
Click to see detail View Full Size Image

Picture Type: CT

Caption: Picture 2. Teratomas and other germ cell tumors. 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.
Click to see detail View Full Size Image

Picture Type: CT

Caption: Picture 3. Teratomas and other germ cell tumors. Ovarian yolk sac tumor at surgery.
View Full Size Image

Picture Type: Photo

Caption: Picture 4. Teratomas and other germ cell tumors. 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.
Click to see detail View Full Size Image

Picture Type: CT

Caption: Picture 5. Teratomas and other germ cell tumors. Esophagram in an infant with massive thoracic germ cell tumor. Note how the esophagus is displaced posteriorly and laterally by the left mediastinal tumor.
View Full Size Image

Picture Type: X-RAY

Caption: Picture 6. Teratomas and other germ cell tumors. Chest radiograph of the patient in Image 5 after treatment with chemotherapy. The size of the tumor has not decreased.
Click to see detail View Full Size Image

Picture Type: X-RAY

Caption: Picture 7. Teratomas and other germ cell tumors. CT scan of the chest in the patient in Image 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.
Click to see detail View Full Size Image

Picture Type: CT

BIBLIOGRAPHY Section 11 of 11

Author Information Introduction Clinical Differentials Workup Treatment Medication Follow-up Miscellaneous Pictures Bibliography

Adkins ES: Female genital system. Prob Gen Surg 1999; 16(1): 131-45.

Alexandre J, Fizazi K, Mahe C, et al: Stage I non-seminomatous germ-cell tumours of the testis: identification of a subgroup of patients with a very low risk of relapse. Eur J Cancer 2001 Mar; 37(5): 576-82 [Medline].
Baker BA, Frickey L, Yu IT, et al: DNA content of ovarian immature teratomas and malignant germ cell tumors. Gynecol Oncol 1998 Oct; 71(1): 14-8[Medline].
Bakri YN, Ezzat A, Akhtar, et al: Malignant germ cell tumors of the ovary. Pregnancy considerations. Eur J Obstet Gynecol Reprod Biol 2000 May; 90(1): 87-91[Medline].
Bax NM, van der Zee DC: The laparoscopic approach to sacrococcygeal teratomas. Surg Endosc 2004 Jan; 18(1): 128-30[Medline].
Billmire D, Vinocur C, Rescorla F: Malignant retroperitoneal and abdominal germ cell tumors: an intergroup study. J Pediatr Surg 2003 Mar; 38(3): 315-8; discussion 315-8[Medline].
Billmire D, Vinocur C, Rescorla F: Outcome and staging evaluation in malignant germ cell tumors of the ovary in children and adolescents: an intergroup study. J Pediatr Surg 2004 Mar; 39(3): 424-9; discussion 424-9[Medline].
Billmire D, Vinocur C, Rescorla F: Malignant mediastinal germ cell tumors: an intergroup study. J Pediatr Surg 2001 Jan; 36(1): 18-24[Medline].
Brace V, Grant SR, Brackley KJ, et al: Prenatal diagnosis and outcome in sacrococcygeal teratomas: a review of cases between 1992 and 1998. Prenat Diagn 2000 Jan; 20(1): 51-5[Medline].
Britton JA, Westhoff C, Howe G, Gammon MD: Diet and benign ovarian tumors (United States). Cancer Causes Control 2000 May; 11(5): 389-401[Medline].
Bromen K, Stang A, Baumgardt-Elms C: Testicular, other genital, and breast cancers in first-degree relatives of testicular cancer patients and controls. Cancer Epidemiol Biomarkers Prev 2004 Aug; 13(8): 1316-24[Medline].
Brown DL, Doubilet PM, Miller FH, et al: Benign and malignant ovarian masses: selection of the most discriminating gray-scale and Doppler sonographic features. Radiology 1998 Jul; 208(1): 103-10[Medline].
Busmanis I, Tay SK: Recurrent immature teratoma: lack of correlation between serum level and immunohistochemical detection of serum alpha-fetoprotein. Pathology 1998 Feb; 30(1): 77-9[Medline].
Canto P, Kofman-Alfaro S, Jiménez AL: Gonadoblastoma in Turner syndrome patients with nonmosaic 45,X karyotype and Y chromosome sequences. Cancer Genet Cytogenet 2004 Apr 1; 150(1): 70-2[Medline].
Charoenkwan P, Senger C, Weitzman S: Significance of p53 expression in immature teratomas. Pediatr Dev Pathol 2002 Sep-Oct; 5(5): 499-507[Medline].
Chen Z, Robison L, Giller R: Risk of childhood germ cell tumors in association with parental smoking and drinking. Cancer 2005 Mar 1; 103(5): 1064-71[Medline].
Chou JS, Wu HP, Yu FT, Hu WM: Pathological case of the month. Immature ovarian teratoma with gliomatosis peritonei. Arch Pediatr Adolesc Med 1998 Mar; 152(3): 301-2[Medline].
Cochran PK, Chauvenet AR, Hart PS, et al: Hereditary persistence of alpha-fetoprotein in a child with testicular germ cell tumor. Med Pediatr Oncol 1999 Jun; 32(6): 436-7[Medline].
Comiter CV, Kibel AS, Richie JP, et al: Prognostic features of teratomas with malignant transformation: a clinicopathological study of 21 cases. J Urol 1998 Mar; 159(3): 859-63[Medline].
Cushing B, Giller R, Ablin A, et al: Surgical resection alone is effective treatment for ovarian immature teratoma in children and adolescents: a report of the pediatric oncology group and the children's cancer group. Am J Obstet Gynecol 1999 Aug; 181(2): 353-8[Medline].
Cushing B, Giller R, Cullen JW: Randomized comparison of combination chemotherapy with etoposide, bleomycin, and either high-dose or standard-dose cisplatin in children and adolescents with high-risk malignant germ cell tumors: a pediatric intergroup study--Pediatric Oncology Group 904. J Clin Oncol 2004 Jul 1; 22(13): 2691-700[Medline].
De Giorgi U, Rosti G, Slavin S: Salvage high-dose chemotherapy for children with extragonadal germ-cell tumours. Br J Cancer 2005 Aug 22; 93(4): 412-7[Medline].
dos Santos Silva I, Swerdlow AJ, Stiller CA, Reid A: Incidence of testicular germ-cell malignancies in England and Wales: trends in children compared with adults. Int J Cancer 1999 Nov 26; 83(5): 630-4[Medline].
dos Santos Silva I, Swerdlow AJ: Ovarian germ cell malignancies in England: epidemiological parallels with testicular cancer. Br J Cancer 1991 May; 63(5): 814-8[Medline].
Dreifaldt AC, Carlberg M, Hardell L: Increasing incidence rates of childhood malignant diseases in Sweden during the period 1960-1998. Eur J Cancer 2004 Jun; 40(9): 1351-60[Medline].
Einhorn LH, Stender MJ, Williams SD: Phase II trial of gemcitabine in refractory germ cell tumors. J Clin Oncol 1999 Feb; 17(2): 509-11[Medline].
English PB, Goldberg DE, Wolff C: Parental and birth characteristics in relation to testicular cancer risk among males born between 1960 and 1995 in California (United States). Cancer Causes Control 2003 Nov; 14(9): 815-25[Medline].
Ezzat A, Raja M, Bakri Y, et al: Malignant ovarian germ cell tumours -- a survival and prognostic analysis. Acta Oncol 1999; 38(4): 455-60[Medline].
Garcia AM, Morgan WM III, Bruner JP: In utero decompression of a cystic grade IV sacrococcygeal teratoma. Fetal Diagn Ther 1998 Sep-Oct; 13(5): 305-8[Medline].
Gobel U, Calaminus G, Engert J, et al: Teratomas in infancy and childhood. Med Pediatr Oncol 1998 Jul; 31(1): 8-15[Medline].
Gobel U, Schneider DT, Calaminus G, et al: Multimodal treatment of malignant sacrococcygeal germ cell tumors: a prospective analysis of 66 patients of the German cooperative protocols MAKEI 83/86 and 89. J Clin Oncol 2001 Apr 1; 19(7): 1943-50[Medline].
Gupta DK, Kataria R, Sharma MC: Prepubertal testicular teratomas. Eur J Pediatr Surg 1999 Jun; 9(3): 173-6[Medline].
Hain SF, O'Doherty MJ, Timothy AR, et al: Fluorodeoxyglucose positron emission tomography in the evaluation of germ cell tumours at relapse. Br J Cancer 2000 Oct; 83(7): 863-9[Medline].
Hamada Y, Tanano A, Sato M, et al: Ovarian teratoma with gliomatosis peritonei: report of two cases. Surg Today 1998; 28(2): 223-6[Medline].
Han SJ, Yoo S, Choi SH, Hwang EH: Actual half-life of alpha-fetoprotein as a prognostic tool in pediatric malignant tumors. Pediatr Surg Int 1997; 12(8): 599-602[Medline].
Hara I, Hara S, Miyake H, et al: Expression of MAGE genes in testicular germ cell tumors. Urology 1999 Apr; 53(4): 843-7[Medline].
Hartmann JT, Rick O, Oechsle K: Role of postchemotherapy surgery in the management of patients with liver metastases from germ cell tumors. Ann Surg 2005 Aug; 242(2): 260-6[Medline].
Hassan AB, Mead GM: Germ cell cancers in adult males are associated with a history of infantile pyloric stenosis. Eur J Cancer 1997 May; 33(6): 970-2[Medline].
Hautkappe AL, Lu M, Mueller H, et al: Detection of germ-cell tumor cells in the peripheral blood by nested reverse transcription-polymerase chain reaction for alpha-fetoprotein messenger RNA and beta human chorionic gonadotropin-messenger RNA. Cancer Res 2000 Jun 15; 60(12): 3170-4[Medline].
Herrmann ME, Thompson K, Wojcik EM: Congenital sacrococcygeal teratomas: effect of gestational age on size, morphologic pattern, ploidy, p53, and ret expression. Pediatr Dev Pathol 2000 May-Jun; 3(3): 240-8[Medline].
Hoehn T, Krause MF, Wilhelm C, et al: Fatal rupture of a sacrococcygeal teratoma during delivery. J Perinatol 1999 Dec; 19(8 Pt 1): 596-8[Medline].
Hoei-Hansen CE, Holm M, Rajpert-De Meyts E: Histological evidence of testicular dysgenesis in contralateral biopsies from 218 patients with testicular germ cell cancer. J Pathol 2003 Jul; 200(3): 370-4[Medline].
Holm M, Hoei-Hansen CE, Rajpert-De Meyts E: Increased risk of carcinoma in situ in patients with testicular germ cell cancer with ultrasonic microlithiasis in the contralateral testicle. J Urol 2003 Oct; 170(4 Pt 1): 1163-7[Medline].
Huyghe E, Matsuda T, Daudin M: Fertility after testicular cancer treatments: results of a large multicenter study. Cancer 2004 Feb 15; 100(4): 732-7[Medline].
Janetschek G, Hobisch A, Hittmair A, et al: Laparoscopic retroperitoneal lymphadenectomy after chemotherapy for stage IIB nonseminomatous testicular carcinoma. J Urol 1999 Feb; 161(2): 477-81[Medline].
Jawad AJ, Al-Meshari A: Laparoscopy for ovarian pathology in infancy and childhood. Pediatr Surg Int 1998 Nov; 14(1-2): 62-5[Medline].
Jona JZ: Progressive tumor necrosis and lethal hyperkalemia in a neonate with sacrococcygeal teratoma (SCT). J Perinatol 1999 Oct-Nov; 19(7): 538-40[Medline].
Kato K, Ijiri R, Tanaka Y, et al: Testicular immature teratoma with primitive neuroectodermal tumor in early childhood. J Urol 2000 Dec; 164(6): 2068-9[Medline].
Kaye SB, Mead GM, Fossa S, et al: Intensive induction-sequential chemotherapy with BOP/VIP-B compared with treatment with BEP/EP for poor-prognosis metastatic nonseminomatous germ cell tumor: a Randomized Medical Research Council/European Organization for Research and Treatment of Can. J Clin Oncol 1998 Feb; 16(2): 692-701[Medline].
Kildal W, Kaern J, Kraggerud SM: Evaluation of genomic changes in a large series of malignant ovarian germ cell tumors--relation to clinicopathologic variables. Cancer Genet Cytogenet 2004 Nov; 155(1): 25-32[Medline].
Kokoska ER, Keller MS, Weber TR: Acute ovarian torsion in children. Am J Surg 2000 Dec; 180(6): 462-5[Medline].
Kollmannsberger C, Schleucher N, Rick O: Analysis of salvage treatments for germ cell cancer patients who have relapsed after primary high-dose chemotherapy plus autologous stem cell support. Eur J Cancer 2003 Apr; 39(6): 775-82[Medline].
Kruslin B, Visnjic A, Cizmic A, et al: DNA ploidy analysis and cell proliferation in congenital sacrococcygeal teratomas. Cancer 2000 Aug 15; 89(4): 932-7[Medline].
Kusumakumary P, Mathew BS, Hariharan S, et al: Testicular germ cell tumors in prepubertal children. Pediatr Hematol Oncol 2000 Jan-Feb; 17(1): 105-11[Medline].
Köhn FM, Schroeder-Printzen I, Weidner W: Testicular sperm extraction in a patient with metachronous bilateral testicular cancer. Hum Reprod 2001 Nov; 16(11): 2343-6[Medline].
La Vecchia C, Morris HB, Draper GJ: Malignant ovarian tumours in childhood in Britain, 1962-78. Br J Cancer 1983 Sep; 48(3): 363-74[Medline].
Lazar EL, Stolar CJ: Evaluation and management of pediatric solid ovarian tumors. Semin Pediatr Surg 1998 Feb; 7(1): 29-34[Medline].
Lee SD: Epidemiological and clinical behavior of prepubertal testicular tumors in Korea. J Urol 2004 Aug; 172(2): 674-8