Extragonadal Germ Cell Tumors

Synonyms and related keywords: EGGCT, seminomas, germinomas, nonseminomatous germ cell tumors, NS-GCT, nongerminomas, nongerminomatous germ cell tumors, mediastinal germ cell tumors, MGCT, retroperitoneal germ cell tumors, RGCT, sacrococcygeal germ cell tumors, SCGCT, intracranial germ cell tumors, ICGCT



INTRODUCTION

Background: Extragonadal germinal cell syndromes are rare tumors affecting predominantly young males. They are characterized by their location on the midline from the pineal gland to the coccyx. They produce a rich symptomatology and may reach large volumes if they arise in silent areas. Histologically, they mirror their gonadal counterparts with which they share the same chemosensitivity and radiosensitivity. Modern approaches to diagnosis and treatment can result in high rates of long-term survival and even cure.

Pathophysiology: Controversy remains regarding the origin of extragonadal germ cell tumors (EGGCTs). These tumors can be found anywhere on the midline, particularly the retroperitoneum, the anterior mediastinum, the sacrococcyx, and the pineal gland. Other less common sites include the orbit, suprasellar area, palate, thyroid, submandibular region, anterior abdominal wall, stomach, liver, vagina, and prostate. The classical theory suggests that germ cell tumors (GCTs) in these areas are derived from local transformation of primordial germ cells misplaced during embryogenesis.

A recent alternative theory suggests that primary mediastinal presentations represent reverse migration of occult carcinoma in situ (CIS) lesions in the gonad; hence, they may be gonadal in origin. According to this theory, the differences in phenotypes expressed by mediastinal germ cell tumors (MGCTs) and gonadal GCTs may be explained by differences in the cellular environment between the gonad and the anterior mediastinum. Some retroperitoneal EGGCTs may represent metastases from a testicular cancer, with subsequent spontaneous necrosis of the primary tumour.

To explain the origin of CIS cells, 2 models have been proposed. The first suggests that fetal gonocytes whose development into spermatogonia is blocked may undergo abnormal cell division and then invasive growth mediated by postnatal and pubertal gonadotrophin stimulation. The second model postulates that the most likely target cell for transformation is the zygotene-pachytene spermatocyte. During this stage of germ cell development, aberrant chromatid exchange events associated with crossing over can occur. Normally, these cells are eliminated by apoptosis. In occasional cells this crossing over may lead to increased 12p copy number and overexpression of cyclin D2. The cell carrying this abnormality is relatively protected against apoptotic death because of the oncogenic effect of CCND2, leading to re-initiation of cell cycle and genomic instability.

Malignant transformation of germ cells is the result of a multistep process of genetic changes. One of the earliest events is the increased copy number of 12p, either as 1 or more copies of i(12p) or as tandem duplications of chromosome arm 12p. This abnormality is found in CIS lesions as well as more advanced disease. Further studies indicate that the CCND2 gene is present at chromosome band 12p13 and CCND2 is overexpressed in most GCTs, including CIS. Amplification of CCND2 activates cdk4/6, allowing the cell to progress through the G1-S checkpoint.

Hematologic malignancies frequently are associated with MGCTs. Embryologically, hematopoietic stem cells arise in the yolk sac. Highly differentiated yolk-sac tumors make up 30% of MGCTs, providing a possible basis for this association.

Recently the balance of the p53-mdm2 interaction was shown to be disrupted in intracranial germ cell tumors (ICGCTs). mdm2 sequesters p53 and inhibits its function as G1-S checkpoint controller and apoptosis inducer. In normal cells, mdm2 availability is controlled by ARF, the product of the p14ARF gene located on INK4a/ARF locus, which binds with mdm2 and induces its degradation. Mutation of ARF, reported in 71% of ICGCTs, results in mdm2 accumulation and functional impairment of p53. This abnormality was reported in 90% of seminomatous and 55% of nonseminomatous intracranial germ cell tumors (NS-ICGCTs) examined.

Frequency:

• In the US: EGGCTs represent 5-10% of all GCTs.

• Internationally: In Norway, a recent study by Dueland et al estimated the incidence of EGGCTs at 0.5 per 100,000 per year. This represents about 2% of the number of testicular cancers reported for the same period. ICGCTs represent 0.3-3.4% of primary intracranial tumors in Western countries and 2.1-12.7% in Japan.

Mortality/Morbidity: For patients receiving intensive chemotherapy, 5-year survival rates of 40-65% have been reported. Extragonadal seminomas carry the best survival rates. Mortality due to the treatment may be seen in as many as 12% of patients with nonseminomatous extragonadal germ cell tumors (NS-EGGCTs).

• Seminomas account for 30-40% of these tumors, and nonseminomatous germ cell tumors (NS-GCTs) 60-70%. NS-GCTs include yolk-sac tumors, embryonal carcinomas, choriocarcinomas, teratomas, and nonteratomatous combined GCTs.

• The most common site of EGGCTs is the mediastinum (50-70%) followed by the retroperitoneum (30-40%), the pineal gland (5%), and the sacrococcygeal area (less than 5%).

• Pathology of postchemotherapy residual masses reveals necrosis in 24%, teratoma in 45%, sarcoma in 5%, and viable germ cell cancer in 26%. However, the smaller the residual mass, the lower the chance that it harbors viable tumor cells.

Sex: In children, benign and malignant EGGCTs occur equally in males and females. In adults, only benign EGGCTs (teratomas) occur at equal frequency in both sexes; more than 90% of malignant EGGCTs occur in males.

CLINICAL

History: Symptoms vary depending on the site and the size of the tumor. Those arising in nonvital organs can reach large sizes before becoming symptomatic, but small tumors may result in significant symptoms if they obstruct, compress, or rupture into important structures.

• Mediastinal germ cell tumors

• The mediastinum is the most common site of EGGCTs (50-70%). MGCTs account for 1-15% of adult anterior mediastinal tumors. Mature teratomas represent 60-70% of MGCTs. Malignant MGCTs (30-40%) are divided between seminomas (40%) and NS-GCTs (60%). Although 90-100% of malignant GCTs are symptomatic, only 50% of teratomas produce symptoms. Nonseminomatous mediastinal germ cell tumors (NS-MGCTs) are faster growing and metastasize earlier than mediastinal seminomas.

• Although their incidence peaks in the third decade, several cases have been reported in patients older than 60 years.

• MGCT patients may present with (in decreasing order) chest pain, dyspnea, superior vena cava syndrome, cough, postobstructive pneumonia, weight loss, fever, night sweats, dysphagia, shoulder or arm pain, vocal cord paralysis, and hoarseness. In one third of patients the anterior mediastinal mass is an incidental finding of a routine chest x-ray (in most of these cases a benign tumor is found).

• Metastases to locoregional lymph nodes or to distant sites, such as the lungs, liver, or bone, may be present in 20-50% of cases on presentation. Distant metastases are seen only in malignant MGCTs.

• Mature teratoma rupture, teratoma with malignant transformation, and hematologic malignancies may complicate MGCTs (see Complications).

• Retroperitoneal germ cell tumors

• The second most common site of EGGCTs (30-40%), after the mediastinum, is the retroperitoneum. Retroperitoneal germ cell tumors (RGCTs) represent 10% of all malignant primary retroperitoneal tumors.

• Often patients with RGCTs present late, after their tumors have reached large dimensions.

• Presenting symptoms are abdominal mass with or without pain, backache, and weight loss. Loss of ejaculation was reported in one case.

• Intracranial germ cell tumors

• Very rare tumors of the adolescent and young adult, ICGCTs are localized preferentially to the pineal and suprasellar regions. However, other midline structures can be involved. Although seminomas (60% of ICGCTs) have a predilection for the suprasellar region, embryonal carcinomas, yolk-sac tumors, and choriocarcinomas mainly occur in the pineal region.

• Pineal tumors present with headache, nausea, and vomiting because of increased intracranial pressure; they require early ventriculoperitoneal (VP) shunting. Deterioration of intellectual functions, gait abnormalities with frequent falls, and sphincteric incontinence are common. Choreic movements and ataxia of the limbs with spastic weakness appear in later stages of Parinaud syndrome.

• In suprasellar tumors, precocious pseudopuberty, diabetes insipidus with or without anterior pituitary dysfunctions (eg, adrenocorticotropic hormone [ACTH] deficiency), central hypothyroidism, growth hormone (GH) deficiency, and hypogonadism may be seen. Decreased visual acuity, visual field defect, diplopia, obesity, psychosis, and obsessive-compulsive symptoms also have been reported.

• Recently, a case of primary spinal seminoma was reported in a patient with Klinefelter syndrome.

• Sacrococcygeal germ cell tumors

• In the literature to date, 17 cases have been reported.

• Pain and bowel habit change are the main symptoms. Severe arthropathy of peripheral joints and evidence of hypertrophic osteoarthropathy were reported in one case.

• Extragonadal germ cell cancer syndrome

• Midline fast-growing tumors (eg, of the mediastinum, retroperitoneum) occur in young males. Histologically, these tumors are poorly differentiated carcinomas with atypical features.
• The germ cell origin of these tumors is suggested by the typical abnormalities of chromosome 12 and the elevation of beta human chorionic gonadotropin (bhCG) and/or alpha-fetoprotein (AFP).

Physical: Complete physical examination is required.

• MGCTs may be silent. Dullness caused by atelectasis or pleural effusion and localized wheezes because of airway compression may be present.

• A large abdominal mass may be palpated in RGCTs.

• In suprasellar ICGCTs, decreased visual acuity and visual field defects, obesity, or signs of endocrine deficiencies may be present.

• In pineal tumors, Parinaud syndrome (ie, paralysis of conjugate upward gaze, slightly dilated pupils that react on accommodation but not to light, with a lesion at the level of the superior colliculi) can be present. Gait abnormalities, papilledema, and grasp reflex because of hydrocephalus are present variably. Plantar reflexes are sometimes extensor.

Causes: See Pathophysiology.

DIFFERENTIALS

Lymphoma, Mediastinal
Lymphoma, Non-Hodgkin
Thymoma

Other Problems to be Considered:

Mediastinal germ cell tumors
Thymic tumors
Mesenchymal tumors
Lymphomas
Neurogenic tumors


Retroperitoneal germ cell tumors
Soft tissue sarcoma
Poorly differentiated carcinoma
Lymphomas


Intracranial germ cell tumors
Pinealoma (pinealocytoma and pinealoblastoma)
Glioma

WORKUP

Lab Studies:

• Tumor markers bhCG and AFP

• These tumor markers provide diagnostic, staging, and prognostic information. Check these levels before and then at regular intervals after therapy.

• Choriocarcinoma, embryonal carcinoma, and a minority of seminomas (less than 10%) produce bhCG. Neoplasms with which bhCG elevation can be seen are prostate, bladder, ureteral, and renal cancers. The levels of bhCG in the cerebrospinal fluid of patients with primary ICGCT were elevated more frequently than in the plasma before treatment and became detectable prior to any increase of the serum values in case of relapse.

• AFP elevations are seen in yolk-sac tumors and embryonal carcinoma. Pure seminomas and pure choriocarcinomas do not produce AFP. Pregnancy, hepatocellular carcinoma, cirrhosis, and hepatitis also may be associated with increased levels of AFP.

• The half-life of bhCG is 24 hours, and that of AFP is 4-6 days.

• AFP, bhCG, or both are elevated in approximately 85% of NS-GCTs.

• Lactate dehydrogenase (LDH) is a nonspecific marker. Its level correlates well with the tumor burden and with the number of i(12p) copies.

• Placental alkaline phosphatase is used in some centers as a marker and is useful in the immunohistochemical characterization of midline tumors.

• Cytogenetic analysis of patients with MGCTs reveals trisomy 8 in 16% of cases and Klinefelter syndrome (XXY) in 14-20% of cases. However, the most common karyotype abnormality is i(12p), present in 38% of patients. The presence of this abnormality helps identify midline GCTs presenting as poorly differentiated carcinomas with atypical features.

• Obtain baseline evaluation of pituitary function (ie, thyroid-stimulating hormone, cortisol, GH, follicle-stimulating hormone, luteinizing hormone, prolactin) before treatment and then at regular intervals in patients with ICGCTs.

• Evaluation of blood counts, liver function tests, and kidney functions before therapy and after recovery is necessary.

Imaging Studies:

• Testicular ultrasound: This should be ordered whenever a malignant GCT is diagnosed to rule out a gonadal primary.

• CT scan of the chest, abdomen, and pelvis

• Mature teratomas appear as heterogeneous cystic, well-defined, anterior mediastinal masses with walls of different thicknesses. Calcifications are present in approximately one quarter, with a bone or a tooth rarely identifiable. The combination of fluid, soft tissue, calcium, and/or fat attenuation in an anterior mediastinal mass is highly specific for mature teratoma.

• Seminomas present as bulky, lobulated, homogeneous, anterior mediastinal masses. Although invasion of adjacent organs is uncommon, metastases to regional lymph nodes and bone can be seen. Calcifications are rare.

• NS-MGCTs appear as irregular, anterior mediastinal masses, often with extensive, central heterogeneous areas of low attenuation caused by necrosis, hemorrhage, and/or cyst formation. Adjacent organ involvement and metastases to regional lymph nodes as well as to distant sites may occur.

• Chest x-ray shows enlargement of the mediastinum on the anteroposterior view. The lateral view reveals the anterior location of the mass.

• CT scan or MRI of the brain shows pineal seminoma as a discrete mass that usually reaches 3-4 cm in diameter. It compresses the superior colliculi and sometimes the superior surface of the cerebellum and narrows the sylvian aqueduct. Obstructive hydrocephalus may be evinced by the presence of dilated ventricles and interstitial edema.

Other Tests:

• Assess neuropsychologic status in children before they undergo cranial radiation and at regular intervals thereafter.

• Perform formal visual examination in patients with suprasellar/hypothalamic tumors.

• Biopsy of the tumor mass

• Histologic confirmation of GCT may be obtained by open biopsy of an abdominal mass, anterior median sternotomy of a mediastinal mass, and neuroendoscopy of a pineal tumor. Fine-needle aspiration frequently establishes the diagnosis, obviating the need for open biopsy. Pathologic studies help determine the histologic subtype, the presence of non–germ cell elements, or the rare cases of marker-positive non–small cell lung cancer.

• Tumor marker elevation in the appropriate clinical setting makes the diagnosis of GCTs highly likely. Chemotherapy can be initiated in these cases without tissue diagnosis if a need for immediate treatment is present.

Histologic Findings: EGGCTs show the same histologic features as gonadal GCTs.

Staging: Clinical staging of MGCT

• Stage I - Well-circumscribed tumor with or without focal adhesions to the pleura or pericardium but without microscopic evidence of invasion into adjacent organ

• Stage II - Tumor confined to the mediastinum with macroscopic and/or microscopic evidence of infiltration into adjacent structures

• Stage III - Tumor with metastases

• Stage IIIA - With metastases to intrathoracic organs

• Stage IIIB - With extrathoracic metastases

TREATMENT

Medical Care: Treatment modality is determined by the site and the histologic type of the primary tumor. Seminomas are very sensitive to chemotherapy and radiotherapy. NS-GCTs are less sensitive to these modalities and may require surgery for resection of a postchemotherapy residual mass. Prior to the availability of cisplatin-based chemotherapy, cure rates for NS-GCTs were less than 10%. Surgery is the only treatment for teratomas.

• MGCTs: Cisplatin-based chemotherapy has made a significant improvement in treatment of seminoma of the mediastinum.

• Treatment with 4 cycles of bleomycin, etoposide, and cisplatin (BEP) is the current standard of care. Radiotherapy can be used after chemotherapy in bulky mediastinal seminomas.
• In NS-MGCT, 4 cycles of BEP also are recommended. If the serum tumor markers remain elevated, give salvage chemotherapy. If the CT scan shows residual disease with or without tumor marker elevation, perform surgical resection followed by 2 cycles of chemotherapy. The nature of the salvage and postsurgical chemotherapy remains debated. Intensive cisplatin-based chemotherapy followed by resection of residual tumor was shown to yield survival rates of 48-73% in NS-MGCTs.
• Walsh et al reported on the experience at M. D. Anderson Cancer Center over 5 years with 20 patients treated for NS-MGCTs. Of those treated, 11 patients had received no prior chemotherapy, and 9 patients were referred following treatment at other facilities for salvage therapy after progression of their tumors.
  • Patients received combination chemotherapy with alternating sequential courses comprising, first, bleomycin, vincristine, and cisplatin (BOP); followed in 7 days by cisplatin, cyclophosphamide, doxorubicin (Adriamycin) (CISCA); followed in 14 days by cisplatin, vincristine, methotrexate, and bleomycin (POMB); followed in 10 days by actinomycin, cyclophosphamide, and etoposide (ACE).
  • In addition to this regimen, etoposide, ifosfamide, and cisplatin (VIP) also were used in the salvage group.
  • Major toxic effects occurred in all these patients, including neuropathy, ototoxicity, mucositis, cytopenias, and renal toxicity.
  • The 2-year survival rate of the entire group was 58%. However, the 2-year survival rate for the previously untreated group was 72%, whereas it was 39% for the salvage group.
  • Intensification of the chemotherapy was achieved by decreasing the interval between cycles and by alternating drugs from course to course. This was made possible by the systemic use of hematopoietic growth factors. Stem cell rescue has been used in certain centers to achieve dose intensification.
• Recently, data from 75 patients treated at Indiana University for NS-MGCTs were analyzed.
  • Of those treated, 48 patients received BEP, 9 patients received VIP, 9 patients received VIP/Velban (vinblastine) and bleomycin (VeB), and the rest were treated with different cisplatin-containing regimens.
  • No significant difference in survival was reported between those who received BEP and those who received VIP.
  • Of the 62 patients (58%) who underwent surgical resection of a residual mass, 36 are long-term survivors. Overall survival rate for the group is 48%.
  • None of the 17 patients whose disease relapsed after or progressed on first-line chemotherapy and surgery could achieve complete remission despite salvage therapy with cisplatin-based regimens, high-dose chemotherapy, paclitaxel, or oral etoposide.

• ICGCTs: The standard treatment for ICGCTs has been radiotherapy, either alone (seminomas) or in combination with chemotherapy (NS-GCTs).
  • A wide range of survival rates (37-100%) is reported after radiation. However, because of its long-term toxicity, attempts were made to use lower doses of craniospinal irradiation (CSI) in combination with chemotherapy. Regardless of the type of the initial treatment, combined modality therapy comprising radiation and chemotherapy is the recommended salvage therapy for relapse.
  • Radiation therapy varies in intensity from CSI with boost (the most intense), to whole brain irradiation with boost, ventricular irradiation with boost, and focal irradiation alone (the least intense).
  • Event-free survival rate (EFS) of 90% for patients with seminomas who received only CSI was reported by Calaminus et al. Chemotherapy alone resulted in an EFS of 53%, although the follow-up period was short and the number of patients was limited in this group. Patients receiving combined modality achieved an EFS of about 92%. In nonseminomas, EFS was affected by the cumulative dose of cisplatin. Patients who received a cumulative dose of 400 mg/m² had an EFS of 86%. Those who received 200 mg/m² had a significantly lower EFS, 56%. The 2 groups were observed for 46 and 65 months, respectively.
  • Balmaceda and colleagues reported on 71 patients treated by chemotherapy alone for ICGCTs (45 seminomas and 26 NS-GCTs). Diagnosis was established by resection (approximately 50% of patients) or biopsy. Patients were evaluated after 4 cycles of carboplatin, etoposide, and bleomycin. If complete response (CR) was achieved, 2 more cycles were given. Surgery alone resulted in 3 CR. Of 68 patients, 39 achieved CR after chemotherapy alone. Of the 29 patients with partial response (PR), 10 achieved CR with intensified chemotherapy and 3 more after second surgery, bringing the number of CRs to 55 (78%). Although response to chemotherapy was not affected by the histologic type (81% for nonseminomas vs 82% for seminomas), long-term survival differed significantly by histologic type (84% for seminomas vs 62% for nonseminomas). Treatment mortality rate was 10%.
  • The optimal role for surgery remains to be defined. Because of the risk of intraspinal metastases related to surgery or even to stereotactic biopsy, a sandwich protocol using preoperative chemotherapy, followed by surgery, then postoperative chemotherapy was suggested. Surgery is indicated only if a residual mass is present after chemotherapy. Such a protocol uses BEP preoperatively and VIP postoperatively. The tumor marker elevation in NS-GCT obviates the need for surgical biopsies.
  • Third ventriculostomy via neuroendoscopy can be performed to drain obstructive hydrocephalus. This procedure prevents peritoneal seeding related to VP shunt.

• RGCTs: Primary chemotherapy with 4 cycles of BEP is recommended for both seminomas and nonseminomas, with excision of residual mass in nonseminomas.

• Pectasides reported on 16 patients with RGCTs, 11 with NS-GCTs and 5 with seminomatous GCTs. Cisplatin-based (or carboplatin-based) chemotherapy resulted in complete or PR in 14 patients. Ten patients underwent surgery, bringing the number of patients with CR to 14 (87.5%); 9 of them are long-term survivors (56.25%).
• Nichols recommends primary abdominal radiotherapy for patients with small-volume retroperitoneal seminomas (abdominal mass less than 5 cm) and chemotherapy for patients with larger volume disease (abdominal mass >10 cm). Patients with intermediate disease may be treated with either modality.

• Sacrococcygeal GCTs have a poor prognosis. Long-standing remission is attained in only 31% of patients treated with multiagent chemotherapy.

Surgical Care: Surgery is the primary and only effective modality in teratomas. It also is used as primary or secondary treatment of NS-EGGCTs. The current standard of care is surgery if a residual mass is present after neoadjuvant chemotherapy. Used in this setting, chemotherapy allows translation of PRs into CRs and evaluation of the chemosensitivity of the tumor.

However, the size of residual mass for which surgery is indicated remains controversial. In the experience at the Memorial Sloan-Kettering Cancer Center, 5 of 20 patients underwent surgery for residual mass after receiving chemotherapy or radiotherapy for retroperitoneal seminoma. No viable seminoma was found in masses less than 3 cm. Therefore, they recommend surgical resection for residual tumors greater than 3 cm to ascertain the need for subsequent chemotherapy.

No further chemotherapy is recommended if the final pathology is consistent with mature teratoma or necrotic tissue. Additional postoperative chemotherapy is given if the patient is found to have viable tumors. Although the same chemotherapy used preoperatively may be used after surgery, it is reasonable to switch to another drug combination.

The surgical resection should include all gross disease with en bloc resection of all involved structures that can be sacrificed. Orchiectomy or testicular biopsy is not required unless testicular examination and/or ultrasound findings are suggestive or frankly abnormal.

• MGCT: Midline sternotomy is the most common approach, followed by posterolateral thoracotomy. Partial pericardial resection is required in most cases. Thymectomy is performed routinely because the thymus often is replaced totally by tumor. Dissection of the aorta and sometimes resection of certain veins occasionally are required to achieve complete resection.

• RGCT: Midline, transverse, or oblique transperitoneal approaches have been used to remove RGCTs. Excision via a thoracoabdominal extraperitoneal approach has been suggested recently. The alleged benefits of this approach are more ready removal of the primary tumor and its possible intrathoracic extensions, avoidance of paralytic ileus, and decreased risk of ejaculatory dysfunction.

• Pineal GCT: En bloc resection of the pineal mass is performed via the supracerebellar infratentorial approach.

MEDICATION

The goals of pharmacotherapy are to induce remission, reduce morbidity, and prevent complications.

Drug Category: Chemotherapeutic agents -- Regardless of the tumor location and whenever chemotherapy is considered, a BEP combination is the treatment of choice (BEP for 4 cycles at 3-wk intervals). VIP has been used as salvage therapy for progressive disease or as postoperative therapy following resection of residual mass containing viable tumor. Vinblastine occasionally has replaced etoposide if the latter was used in the initial regimen.

Drug Name	Cisplatin (Platinol) -- Platinum-containing compound that exerts antineoplastic effect by covalently binding to DNA with preferential binding to N-7 position of guanine and adenosine. Can react with 2 different sites on DNA to produce cross-links. Platinum complex also can bind to nucleus and cytoplasmic protein. A bifunctional alkylating agent, once activated to aquated form in cell it binds to DNA, resulting in interstrand and intrastrand cross-linking. Modify dose on basis of CrCl. Avoid use if CrCl less than 60 mL/min.
Adult Dose	20 mg/m2/d IV infusion over 20-60 min for 5 d q21d
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity; preexisting renal insufficiency; myelosuppression; hearing impairment
Interactions	Increases toxicity of bleomycin and ethacrynic acid; aminoglycosides and amphotericin B increase nephrotoxicity; bleomycin, cytarabine, methotrexate, and ifosfamide may accumulate because of decreased renal excretion; may enhance cytotoxicity of etoposide; mesna and sodium thiosulfate directly inactivate cisplatin; dipyridamole increases cytotoxicity by enhancing cellular uptake
Pregnancy	D - Unsafe in pregnancy
Precautions	Administer adequate hydration before and for 24 h after dosing to reduce risk of nephrotoxicity; adverse effects include bone marrow suppression, nausea, vomiting, mucositis, and high-frequency hearing loss; major dose-limiting toxic effect is peripheral neuropathy; can cause acute or chronic renal failure in as many as one third of patients treated, but usually can be prevented by vigorous hydration and saline diuresis; renal tubular wasting of potassium and magnesium are common (monitor closely); cellulitis and fibrosis rarely have occurred after extravasation; avoid aluminum needles

Drug Name	Etoposide (Toposar, VePesid) -- Inhibits topoisomerase II and causes DNA strand breakage, causing cell proliferation to arrest in late S or early G2 portion of cell cycle. Prodrug activated by dephosphorylation. Reduce dose in hepatic (increased total bilirubin [TB]) and renal (decreased CrCl) impairment.
Adult Dose	100 mg/m2 IV daily for 5 d; repeat cycle every 3 wk TB 1.5-3 mg/dL: 50% dose reduction TB 3.1-4.9 mg/dL: 75% dose reduction TB >5 mg/dL: Avoid use CrCl 15-50 mL/min: 25% dose reduction
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity; IT administration may cause death
Interactions	May prolong effects of warfarin and increase clearance of methotrexate; has additive effects with cyclosporine in cytotoxicity of tumor cells; clearance decreased by high dose of cyclosporine (serum concentration >2000 ng/mL), leading to increased risk of neutropenia; zidovudine increases serum concentration, resulting in increased toxicity
Pregnancy	D - Unsafe in pregnancy
Precautions	Bleeding, severe myelosuppression, nausea, vomiting, hypotension, allergic reaction, and alopecia may occur

Drug Name	Bleomycin (Blenoxane) -- Glycopeptide antibiotic that acts by intercalating and binding to guanosine and cytosine portions of DNA. May induce single- or double-stranded DNA breaks by ability to form oxygen free radicals. Test dose is optional: 1-2 U IV/IM prior to full dose.
Adult Dose	30 U IV bolus weekly on days 2, 9, and 16; repeat q21d; modify dose based on CrCl CrCl 20-30 mL/min: 50% of normal dose CrCl less than 20 mL/min: 40% of normal dose
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity; significant renal function impairment; compromised pulmonary function
Interactions	May decrease plasma levels of digoxin and phenytoin; cisplatin may increase toxicity
Pregnancy	D - Unsafe in pregnancy
Precautions	Caution in renal impairment; possibly secreted in breast milk; may cause mutagenesis and pulmonary toxicity (10%); idiosyncratic reactions similar to anaphylaxis (1%) may occur; monitor for adverse effects during and after treatment; erythema, rash, vesiculations, hyperpigmentation, stomatitis, alopecia, and nail changes may occur

Drug Name	Ifosfamide (Ifex) -- Alkylating agent—2 major metabolites are produced after its activation in liver. Ifosfamide mustard, by its ability to cross-link DNA strands, responsible for therapeutic effect. Acrolein related to bladder toxicity.
Adult Dose	1200 mg/m2/d IV continuous infusion d 1-5
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity; depressed bone marrow function; uncontrolled infection
Interactions	Phenobarbital, phenytoin, chloral hydrate, and other drugs that interfere with cytochrome P-450 activity may alter effects
Pregnancy	D - Unsafe in pregnancy
Precautions	May cause hemorrhagic cystitis and severe myelosuppression; caution in renal function impairment or compromised bone marrow reserve; nausea, vomiting, diarrhea, and occasionally constipation may occur; CNS toxic effects include somnolence, confusion, depressive psychosis, and hallucinations; seizures and coma occasionally may occur; use mesna concomitantly at dose of 1200 mg/m2/d IV continuous infusion days 1-6

Drug Name	Vinblastine (Velban) -- Vinca alkaloid, inhibits microtubule formation, which in turn disrupts formation of mitotic spindle, causing cell proliferation to arrest at metaphase. Reduce dose by 50% in patients with TB >3 mg/dL. Dose reduction not required in impaired renal function.
Adult Dose	0.11 mg/kg IV days 1 and 2
Pediatric Dose	3 mg/m2 IVP every 2-4 wk
Contraindications	Documented hypersensitivity; bone marrow suppression
Interactions	May reduce plasma phenytoin levels; mitomycin-C may increase toxicity significantly; avoid heparin and furosemide
Pregnancy	D - Unsafe in pregnancy
Precautions	Caution in impaired liver function and neurotoxicity; when patient is receiving mitomycin-C, monitor closely for shortness of breath and bronchospasm; very irritating (a vesicant) and should be given exclusively via side port of freely flowing IV; if extravasation occurs, antidote is hyaluronidase (Wydase); warm compresses should be applied at site of extravasation; adverse effects include myelosuppression, alopecia, nausea, vomiting, anorexia, constipation, and paresthesia

FOLLOW-UP

Further Outpatient Care:

• Detection of late recurrences (>2 y after treatment discontinuation), development of testicular tumors several years after the initial diagnosis of EGGCTs, and treatment-related complications justify prolonged periods of follow-up care with clinical evaluation, tumor markers, and imaging studies.

• In children (and probably in adults) with ICGCTs, obtain baseline intelligence quotient (IQ) and achievement tests before starting radiotherapy. Perform follow-up intellectual assessments at 1 year after completion of radiation, then at 2, 3, and 5 years, and if any intellectual deterioration is noted. Evaluate hearing if intellectual deterioration occurs. Evaluation of thyroid, corticotropin, gonadotropin, prolactin, and GH functions is obtained before and regularly after radiation therapy.

Complications:

• Growing teratoma syndrome is the increase in tumor size during or after chemotherapy for MGCT or RGCT and only mature teratoma at histologic analysis of the resected tumor specimen. Mature teratoma component is present in the majority of the primary tumors (86%). The major risk factor for this complication is the completeness of the surgical resection of the primary tumor, because it was seen in only 4% of the patients who underwent complete resection compared to 83% of those patients who had partial resection. Complete surgical resection is the treatment of choice.

• Rupture of a mature teratoma as a result of the digestive enzymes secreted by intestinal mucosa or pancreatic tissue into the bronchi or lung may result in hemoptysis or expectoration of hair or sebum. Rupture into the pleura or pericardium leads to pericardial or pleural effusion.

• Teratoma with malignant transformation is a rare complication of MGCT. The most common transformations are different kinds of sarcomas, glioblastomas, nephroblastomas, neuroblastomas, adenocarcinomas, and hematologic malignancies.

• The incidence of hematologic malignancies in patients with NS-MGCTs is 200- to 300-fold higher than in matched controls.

• The median time from the diagnosis of the GCT to the diagnosis of the hematologic malignancy is 6 months (range 0-47 mo). Acute myelogenous leukemia and myelodysplasia with megakaryocyte lineage abnormalities are the most common disorders.

• Patients present with pancytopenia, isolated thrombocytopenia, splenomegaly, and/or hepatomegaly. Flushing and syncope are suggestive of systemic mastocytosis, another unusual hematologic malignancy complicating MGCTs.

• The clinical course is very aggressive, with a median survival of 5 months. Predictors of the subsequent occurrence of leukemia are mediastinal localization of the GCT and endodermal sinus tumor and teratocarcinoma histologic types. Bone marrow biopsy should not be delayed if cytopenia persists or recurs after the initial chemotherapy period.

• Chemotherapy-related complications may be immediate or delayed.

• Nausea and vomiting became less common with the advent of 5-hydroxytryptamine 3 (5-HT3) antagonists. Postcisplatin delayed emesis is better treated by oral administration of metoclopramide, benzodiazepine, and dexamethasone for 2-4 days.
• A certain degree of cisplatin-related nephrotoxicity is almost always present and is cumulative. Hypomagnesemia is common, requiring supplementation for prolonged periods of time in some patients.
• Arthralgias, myalgias, peripheral neuropathy, and paralytic ileus are common toxic effects of vinblastine. However, since replacement of vinblastine with etoposide in first-line therapy began, these complications are no longer seen. Auditory toxicity with reduced high-tone hearing may be seen after cisplatin. It rarely requires hearing aids.
• Neutropenic fever and severe thrombocytopenia are relatively uncommon with etoposide and cisplatin (EP) as first-line chemotherapy. The addition of bleomycin and salvage chemotherapy results in significant increase of these complications (50%), requiring the prophylactic use of hematopoietic growth factors after the first episode of neutropenic fever.
• Pulmonary toxicity from bleomycin is unpredictable and rare (10% of treated patients) and is dose and age dependent (rate is higher in patients >70 y and after a cumulative dose >1200 IU or 400 mg). The progression to pulmonary fibrosis is uncommon and occasionally fatal (1%). Although carbon monoxide diffusing capacity may not predict clinically significant lung damage, its use was recommended along with chest x-ray as a screening test in patients treated with bleomycin. If radiographic changes or a decrease of diffusing capacity of lung for carbon monoxide (D_LCO) greater than 30% is detected, discontinue the drug.
• Raynaud phenomenon and, to a lesser degree, stroke and myocardial infarction were reported after use of bleomycin.
• Accelerated coronary artery disease is a well-recognized complication of mediastinal radiotherapy.
• Infertility is seen in as many as 50% of patients after chemotherapy. Standard bilateral retroperitoneal lymph node dissection almost always is associated with retrograde ejaculation. Nerve-dissecting, nerve-avoiding, and posterior approaches decrease, but do not abolish, this adverse effect.
• The frequency of etoposide-related secondary leukemia is dose dependent. It is seen in less than 0.5% of patients who received a total dose less than 2000 mg/m² and in about 6% of those who received more than 3000 mg/m². Abnormalities of chromosome band 11q23 are very common in this setting. Latency period varies from 2-4 years. The incidence of gastrointestinal malignancies, especially gastric cancers, and soft-tissue sarcomas is increased slightly after combined radiation and chemotherapy. Latency period is about 10 years or more.
• Weijl et al reported a high rate of thromboembolic events (8.4%) during chemotherapy in 179 patients with GCTs. Liver metastases and high-dose corticosteroids were identified as risk factors for these complications.

• With the achievement of prolonged survival for patients with ICGCTs, researchers became increasingly aware of long-term effects of cranial radiation on intellectual and endocrine functions.
  • These complications are correlated with the total dose and fraction sizes of irradiation and are correlated conversely to the patient's age at the time of treatment. Concomitant chemotherapy increases the risk of toxicity.
  • Verbal IQs and reading skills are affected to a lesser degree than performance IQs or mathematic ability. Personality changes include anxiety, depression, lability, belligerence, hypersexuality, reduced attention span, memory, and reasoning ability.
  • GH deficiency with growth retardation and hypothyroidism are much more common than gonadotropin and corticotropin deficiencies.
  • Leukoencephalopathy, hearing loss, and second malignancies (20-y cumulative probability of about 12% for the latter) are increased after cranial irradiation.

Prognosis:

• Analysis of available data on 5862 patients with GCTs resulted in development of a classification system by the International Germ Cell Collaborative Group (IGCCG). This system categorizes tumors on the basis of histologic type (seminomas have better prognosis than nonseminomas), localization of metastases (retroperitoneal and testicular portend better prognosis than mediastinal and intracranial GCTs), and initial levels of serum AFP, bhCG, and LDH (the higher the tumor markers the worse the effect on survival).

• Nonseminoma

• Good prognosis is indicated by all of the following:
  • Testis/retroperitoneal primary
  • No nonpulmonary visceral metastases
  • Good markers - AFP less than 1000 ng/mL, bhCG less than 1000 IU/L, and LDH less than 1.5 X upper limit of normal (N)
  • Includes 56% of nonseminomas, which have a 5-year progression-free survival rate (PFS) of 89% and 5-year survival rate of 92%

• Intermediate prognosis is indicated by all of the following:
  • Testis/retroperitoneal primary
  • No nonpulmonary visceral metastases
  • Any of AFP >1000 and less than 10,000 ng/mL, bhCG >5000 and less than 50,000 IU/L, or LDH >1.5 X N and less than 10 X N
  • Includes 28% of nonseminomas, which have a 5-year PFS of 75% and 5-year survival rate of 92%

• Poor prognosis is indicated by any of the following:
  • Mediastinal primary
  • Nonpulmonary visceral metastases
  • Poor markers - Any of AFP >10,000 ng/mL, bhCG >50,000 IU/L, or LDH >10 X N
  • Includes 16% of nonseminomas, which have a 5-year PFS of 41% and 5-year survival rate of 48%

• Seminoma

• Good prognosis is indicated by the following:
  • Any primary site
  • No nonpulmonary visceral metastases
  • Normal AFP, any bhCG, any LDH
  • Includes 90% of seminomas, which have a 5-year PFS of 92% and 5-year survival rate of 88%

• Intermediate prognosis is indicated by the following:
  • Any primary site
  • Nonpulmonary visceral metastases
  • Normal AFP, any bhCG, any LDH
  • Includes 10% of seminomas, which have a 5-year PFS of 67% and 5-year survival rate of 72%
• Poor prognosis: No patients are classified as having poor prognosis.

• Ganjoo analyzed the data from 75 patients treated at Indiana University for NS-MGCTs with chemotherapy followed by surgery. Tumor marker elevation prior to or after chemotherapy was not found to be an independent prognostic variable for survival. However, the presence of visceral metastases and especially postchemotherapy pathology were the most important predictors of survival.

• The Institut Gustave-Roussy prognostic model based on tumor marker levels was not able to accurately classify their group of 38 patients treated for NS-MGCT. The use of etoposide seemed not to make any difference in survival. Although patients who were able to receive dose-intensive chemotherapy fared better, this did not reach statistical significance. Extrapulmonary metastases remained the sole significant parameter in long-term survival.
• Patients with MGCT have a poor prognosis owing to at least the following 3 factors: MGCTs are not as sensitive as other GCT to chemotherapy, bulky disease increases the risk of poor outcome in the short term owing to respiratory failure, and hematologic malignancies are linked to a very unfavorable prognosis.

Patient Education:

• For excellent patient education resources, visit eMedicine's Back, Ribs, Neck, and Head Center. Also, see eMedicine's patient education article Tailbone (Coccyx) Injury.