January 17, 2007

Germ Cell Tumors

Synonyms and related keywords: germ cell tumors, GCT, testicular cancer, seminoma, embryonal carcinoma, teratoma, choriocarcinoma, yolk sac tumor


Background: Germ cell tumors (GCTs) are a morphologically distinct group of neoplasms with varied clinical presentation. Ninety-five percent of tumors arising in the testes are GCTs, indicating that they originate from the primordial germ cells. More than 90% of patients with GCT diagnosed early are cured. A delay in diagnosis correlates with a higher stage at presentation and, consequently, a lower cure rate. The success in treating GCTs in the past 2 decades is attributed largely to the effectiveness of cisplatin-containing combination chemotherapy in curing advanced disease.



Recent studies of GCTs have suggested that cyclin D2 is overexpressed in malignant germ cells and is oncogenic.

GCT differentiation may be influenced by several interacting pathways, such as regulators of germ-cell totipotentiality, embryonic development, and genomic imprinting. Sensitivity and resistance to chemotherapy may be based in part on a p53-dependent apoptotic pathway.

Mechanism of germ cell transformation

Almost 100% of tumors show increased copy numbers of 12p (i12p). This chromosomal marker has been noted in carcinoma in situ (CIS), suggesting that it is one of the early changes associated with the origin of GCT. CIS is considered to be a precursor of all GCTs. Two models have been proposed to explain the origin of CIS cells, as follows:

Model 1: Fetal gonocytes that escape normal development into spermatogonia undergo abnormal cell division and proliferation. These gonocytes are prone to invasive growth, mediated by postnatal and pubertal gonadotrophin stimulation.

Model 2: Increased 12p copy number, cyclin D2 expression, consistent near triploid-tetraploid chromosome numbers, and increased expression of wild-type p53 result in tumorigenesis. Abnormal chromatid exchanges during meiotic crossing over leads to increased 12p copy number and cyclin D2 overexpression. In cells containing unrepaired DNA strand breaks, cyclin D2 can block p53-dependent apoptosis and leads to re-initiation of cell cycle and genomic instability.

Recently, models involving other cyclins and inhibitory molecules have also been proposed.


Mortality/Morbidity: For all patients with GCT, the 5-year survival rate is about 95%. Cure rates are highest for early stage disease and lower for advanced disease.

Race: GCTs are seen predominantly in whites and rarely in African Americans. The incidence ratio of whites to African Americans is approximately 5:1.

Despite this, a sharp increase in the incidence of germ cell tumors in men of African descent has occurred. In the United States, the incidence increased by 100% from 1988 to 2001. Diagnoses of seminomas increased 124% in that time period and nonseminomas increased by 64%. No significant increase occurred in the incidence of early-stage disease in proportion to all diagnoses in this population, indicating that the significant increase was not due to an increased prevalence of screening or earlier detection.

Age: GCT is the most common solid tumor in men aged 15-35 years. However, the disease has 3 modal peaks: infancy, ages 25-40 years, and age 60 years.


History: Most patients present with a complaint of a painless testicular mass. Less common presenting symptoms, such as back pain, cough, and hemoptysis, arise from metastatic disease.

  • A painless testicular mass is the most common presentation in patients with testicular cancer. However, about 20-40% of patients with primary testicular cancer present with pain, swelling, hardness, or a combination of these symptoms. Treating patients who have no palpable mass using a trial of antibiotics is reasonable, as infectious epididymitis or orchitis is more common than tumor. A testicular ultrasound examination is indicated if symptoms and signs are not controlled or do not revert in 2 weeks. Tumor-bearing testicles may be more susceptible to bleeding and hematoma development; therefore, patients who experience a hematoma with minor trauma should undergo evaluation for an underlying tumor.
  • Testicular pain may be associated with epididymitis, torsion of the testes, tumor, or bleeding or infarction in the tumor. Flank pain, back pain, or abdominal pain can occur from metastatic disease.
  • Gynecomastia may occur in patients with tumors that produce human chorionic gonadotropin (HCG), such as choriocarcinoma.
  • Pulmonary symptoms such as shortness of breath, chest pain, and hemoptysis, although rare, can occur in patients with advanced pulmonary disease or primary mediastinal GCT.
  • Symptoms due to central nervous system metastasis or to bone metastases are rare.


  • Physical examination of the testicles is performed by fully palpating all areas of the testicle between thumb and fingers. Testicular mass with or without pain is a finding that requires immediate attention.
  • Other areas of emphasis include examination for the following:
    • Left supraclavicular lymphadenopathy
    • Hepatomegaly
    • Bone tenderness
    • Gynecomastia
    • Abdominal mass
    • GCTs should be distinguished by seminoma versus nonseminoma subtypes because they are treated differently.
  • Seminoma, a GCT subtype, has the following clinical features:
    • This usually presents in the fourth decade of life. Seminoma is confined to the testes in about 70% of cases and metastasizes to the lymph nodes in about 25% of cases. Metastatic disease is present in 5% of cases at presentation. These testicular primary tumors are usually homogenous and large.
    • Spermatocytic seminoma occurs in the sixth decade of life. It presents bilaterally more often than seminoma and is an indolent tumor that rarely metastasizes. Spermatocytic seminoma is not associated with CIS.
  • Nonseminomatous germ cell tumor (NSGCT) is often composed of several histologic forms (mixed) and may contain any of the following forms:
    • Embryonal carcinoma is characterized by rapid and bulky growth and by spread via lymphatic and hematogenous routes to distant viscera (eg, lungs, liver). More than 60% of patients have metastases at the time of presentation. Pain is a common feature in these patients.
    • Teratoma is found commonly in residual or recurrent masses. It is the least aggressive form, but approximately 30% of patients with clinical stage 1 disease have relapse after orchiectomy.
    • Choriocarcinoma is the most aggressive of the NSGCTs. It disseminates hematogenously to lungs, liver, brain, and other viscera very early in the disease process. Bleeding is common in patients with metastatic choriocarcinoma and may present as hemoptysis, gastrointestinal bleeding, or, rarely, intracerebral hemorrhage.
    • Yolk sac tumors typically present as a large primary tumor.

Causes: No environmental exposures have been proven to lead to GCTs. However, a few congenital developmental defects are related to the development of GCTs.

  • Cryptorchidism: Risk of developing GCT in the cryptorchid testis is 10- to- 40-fold higher than in the normally descended testis. About 5-20% of patients with a history of cryptorchid testis develop tumors in the normally descended testis. The risk of developing GCT when a cryptorchid testis is intraabdominal is about 5%. The risk falls to 1% if the testis is retained in the inguinal canal and decreases further if the undescended testis is surgically placed in the scrotum when the patient is younger than 6 years.
  • Diethylstilbestrol: No clear association is seen between diethylstilbestrol and development of GCT.
  • Klinefelter syndrome: Patients with Klinefelter syndrome have an increased incidence of mediastinal GCT.


Lymphoma, Non-Hodgkin
Testicular Torsion


Lab Studies:

Imaging Studies:


Histologic Findings: GCTs are classified on the basis of their histologic features into seminomas and nonseminomas. Seminomas account for about 40% of GCTs, of which classic and anaplastic cell types constitute the majority. The rest are classified as spermatocytic. Seminomas, both classic and anaplastic, occur in men aged 25-45 years, whereas spermatocytic seminoma occurs in men aged 65 years on average.



Medical Care: Virtually all germ cell tumors (GCTs) should be considered curable. Patients who undergo chemotherapy should be assessed according to the International Germ Cell Cancer Cooperative Group (IGCCCG) system of risk assessment. In this system, patients are classified as good, intermediate, or poor risk. Patients with a good-risk disease can receive 3 cycles of bleomycin, etoposide, and cisplatin (BEP) chemotherapy or 4 cycles of etoposide and cisplatin (EP). Patients with intermediate- and poor-risk disease should receive 4 cycles of BEP as initial therapy.

Surgical Care: Postchemotherapy surgery should be considered in all patients with NSGCTs who have residual masses. Postchemotherapy surgery for seminoma is more difficult and is generally restricted to large masses. PET scanning may be useful in patients with seminoma following chemotherapy (see Imaging Studies).

Consultations: Sperm banking should be offered to all patients prior to chemotherapy because therapy for GCTs results in sterility in approximately 35% of patients.


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

Drug Category: Antineoplastic agents -- Cancer chemotherapy is based on an understanding of tumor cell growth and of how drugs affect this growth. After cells divide, they enter a period of growth (phase G1), followed by DNA synthesis (phase S). The next phase is a premitotic phase (G2), and the final phase involves mitotic cell division (phase M).

The cell division rate varies for different tumors. The majority of common cancers increase very slowly in size compared to normal tissues, and the rate may decrease further in large tumors. This difference allows normal cells to recover more quickly from chemotherapy than malignant ones and is the rationale for current cyclic dosage schedules. Dosage cycles are determined by cancer stage and tolerance of adverse effects.

Antineoplastic agents interfere with cell reproduction. Some agents are cell-cycle specific, while others (eg, alkylating agents, anthracyclines, cisplatin) are not. Cellular apoptosis (ie, programmed cell death) is also a potential mechanism of many antineoplastic agents.
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 the 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 Dose20 mg/m2/d IV over 20-60 min for 5 d; repeat q21d for 4 cycles
Pediatric DoseNot established
ContraindicationsDocumented hypersensitivity; preexisting renal insufficiency; myelosuppression; hearing impairment
InteractionsIncreases toxicity of bleomycin and ethacrynic acid; other nephrotoxic drugs (eg, aminoglycosides, amphotericin B, cyclosporine) 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; paclitaxel-related peripheral neuropathy may be increased in patients previously treated with cisplatin
Pregnancy D - Unsafe in pregnancy
PrecautionsAdminister 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 a third of patients treated, but this 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, VP-16 (Toposar, VePesid) -- Inhibits topoisomerase II and causes DNA strand breakage, causing cell proliferation to arrest in late S or early G2 phase of cell cycle. Prodrug activated by dephosphorylation. Reduce dose in hepatic (increased total bilirubin [TB]) or renal (decreased CrCl) impairment.
Adult Dose100 mg/m2/d IV for 5 d; repeat q21d for 4 cycles; adjust dose in hepatic or renal dysfunction
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 DoseNot established
ContraindicationsDocumented hypersensitivity; IT administration (may cause death)
InteractionsMay 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
PrecautionsIT administration may cause death
Bleeding, severe myelosuppression, nausea, vomiting, hypotension, allergic reaction, and alopecia may occur; reduce dose in hepatic (increased TB) or renal (decreased CrCl) impairment
Note: small but real risk of secondary leukemia has been reported
Drug Name
Bleomycin (Blenoxane) -- Glycopeptide antibiotic that acts by intercalating and binding to guanosine and cytosine portions of DNA. May induce single-stranded or double-stranded DNA breaks by ability to form oxygen free radicals.
Adult DoseTest dose (optional): 1-2 U IV/IM prior to full dose
30 U IV bolus every wk on days 2, 9, and 16; repeat q21d for 4 cycles; 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 DoseNot established
ContraindicationsDocumented hypersensitivity; significant renal function impairment; compromised pulmonary function
InteractionsMay decrease plasma levels of digoxin and phenytoin; cisplatin may increase toxicity
Pregnancy D - Unsafe in pregnancy
PrecautionsCaution 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 activated in liver to phosphoramide mustard and acrolein. Phosphoramide mustard cross-links DNA strands and is responsible for therapeutic effect. Acrolein related to bladder toxicity.
Adult Dose1200 mg/m2/d IV continuous infusion on days 1-5; repeat q21d for 4 cycles
Pediatric DoseNot established
ContraindicationsDocumented hypersensitivity; depressed bone marrow function; uncontrolled infection
InteractionsPhenobarbital, phenytoin, chloral hydrate, and other drugs that induce CYP-450 activity may enhance metabolism of ifosfamide to its active metabolites
Pregnancy D - Unsafe in pregnancy
PrecautionsMay cause hemorrhagic cystitis (use with mesna to decrease risk) and severe myelosuppression; caution in renal function impairment or compromised bone marrow reserve; nausea, vomiting, diarrhea, and constipation may occur; CNS toxic effects include somnolence, confusion, depressive psychosis, and hallucinations; seizures and coma may occur
Drug Name
Vinblastine (Velban) -- Vinca alkaloid, inhibits microtubule formation, which disrupts formation of mitotic spindle, causing cell proliferation to arrest at metaphase.
Adult Dose0.11 mg/kg IV on days 1 and 2; repeat q21d for 4 cycles; adjust dose in hepatic impairment
TB >3 mg/dL: 50% dose reduction
Pediatric DoseNot established
ContraindicationsDocumented hypersensitivity; bone marrow suppression; IT administration (may cause death)
Careful administration in patients with underlying neurological disorders
InteractionsMay reduce plasma phenytoin levels; previous or concurrent use of mitomycin-C increases pulmonary toxicity; drugs that inhibit P-450 CYP3A isoform (eg, erythromycin) may decrease vinblastine metabolism, causing increased toxicity
Pregnancy D - Unsafe in pregnancy
PrecautionsIT administration may cause death
Careful administration in patients with underlying neurological disorders
Reduce dose in impaired liver function; mitomycin-C may cause shortness of breath and bronchospasm; extravasation precautions necessary due to vein irritation (is a vesicant and should be given exclusively via side port of freely flowing IV); if extravasation occurs, antidote is hyaluronidase, 150 mg SC around needle site, and apply warm compresses at site of extravasation; adverse effects include neurotoxicity, myelosuppression, alopecia, nausea, vomiting, anorexia, constipation, and paresthesia; dose reduction not required in impaired renal function
Drug Category: Uroprotective antidote -- Mesna is a prophylactic detoxifying agent used to inhibit hemorrhagic cystitis caused by ifosfamide and cyclophosphamide. In the kidney, mesna disulfide is reduced to free mesna. Free mesna has thiol groups that react with acrolein, the ifosfamide and cyclophosphamide metabolite considered responsible for urotoxicity.
Drug Name
Mesna (Mesnex) -- Inactivates acrolein and prevents urothelial toxicity without affecting cytostatic activity.
Adult Dose1200 mg/m2/d IV continuous infusion on days 1-6 of each cycle; IV dose of mesna equivalent to ifosfamide dose
Pediatric DoseNot established
ContraindicationsDocumented hypersensitivity
InteractionsMay increase warfarin effect, adjust dose according to INR target
Pregnancy B - Usually safe but benefits must outweigh the risks.
PrecautionsMonitor morning urine for hematuria prior to ifosfamide or cyclophosphamide dose; common adverse effects include hypotension, headache, GI toxicity, and limb pain


Further Outpatient Care:



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