Extragonadal germ cell tumors are rare and account for only a small percentage of all germ cell tumors. However, the true incidence of these tumors may conceivably be higher than originally thought because of failure to diagnose them properly.
Extragonadal germ cell tumors can be benign (teratoma) or malignant. The latter group can be divided into seminoma and nonseminoma germ cell tumors, which include:
Extragonadal germ cell tumors occur much more often in males than in females [1] and are usually seen in young adults. These aggressive neoplasms can arise virtually anywhere, but the site of origin is typically in the midline (mediastinum, retroperitoneum, or pineal gland). Gonadal origin should be excluded by careful testicular examination and ultrasound. The diagnosis can be difficult and should be considered in any patient with a poorly defined epithelial malignancy, particularly young individuals with midline masses.[2,3]
An international germ cell tumor prognostic classification has been developed based on a retrospective analysis of 5,202 patients with metastatic nonseminomatous germ cell tumors and 660 patients with metastatic seminomatous germ cell tumors.[4] All patients received treatment with cisplatin-containing or carboplatin-containing therapy as their first chemotherapy course. The prognostic classification, shown below, was agreed on in early 1997 by all major clinical trial groups worldwide and should be used for the reporting of clinical trial results of patients with extragonadal germ cell tumors.
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No patients are classified as poor prognosis.
Benign teratomas are treated with surgical excision only. These tumors are frequently very large, and the surgical procedure can be formidable.
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The diagnosis of seminoma requires that the serum alpha-fetoprotein be normal, with no other germ cells present. Management decisions in patients presenting with these tumors can be difficult.
As in testicular seminoma, these tumors are very radiosensitive. About 60% to 80% of patients will remain disease free after treatment with radiation therapy.[1] Craniospinal radiation therapy for intracranial germinomas (the intracranial counterpart of seminoma) is associated with relapse-free and overall survival rates of 90% to 95% at 5 years, respectively, as evidenced in the GER-GPO-MAKEI-86/89 trial, for example.[2][Level of evidence C1]
Initial chemotherapy with regimens used in nonseminoma testicular cancer is also efficacious. Practically speaking, patients with localized relatively small tumors are usually treated initially with radiation therapy, while those with very bulky tumors or nonlocalized tumors are treated with etoposide-based and cisplatin-based chemotherapy regimens.
As in testicular seminoma, many patients will be left with a residual mass posttreatment. If the residual mass is smaller than 3.0 cm, most experts agree that observation is appropriate. In those with larger residual masses, some experts favor surgical excision while others favor observation.[3,4]
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Patients with nonseminomas should receive chemotherapy at diagnosis. These patients tend to have a large tumor volume at diagnosis and are usually symptomatic. Initial debulking surgery is rarely useful. Many high-risk patients qualify for clinical trials. Standard therapy is generally four courses of BEP (bleomycin, etoposide, and cisplatin).[1,2]
A randomized study comparing four courses of BEP with four courses of VIP (etoposide, ifosfamide, and cisplatin) showed similar overall survival (OS) and time-to-treatment failure for the two regimens in patients with advanced disseminated germ cell tumors who had not received previous chemotherapy.[3,4][Level of evidence A1] Of the 304 patients in this study, 66 had extragonadal primary tumors. In this subset of patients, responses to the two regimens were similar. Hematologic toxic effects in OS were substantially worse with the VIP regimen than with the BEP regimen.
Patients with a residual mass after chemotherapy may achieve long-term disease-free survival after postchemotherapy surgery with resection of all residual disease.[5][Level of evidence C2] Patients with nonseminomatous extragonadal germ cell tumors who relapse after front-line chemotherapy generally have poor prognoses with poor responses to salvage chemotherapy regimens, including autologous bone marrow transplant, that have had success for recurrent testicular cancer.[6-8] Such patients are candidates for studies of new approaches.
Mediastinal nonseminomas have certain unique aspects. The tumors are more frequent in individuals with Klinefelter syndrome and are associated with a risk of subsequent development of hematologic neoplasia that is not treatment related.[9,10] Approximately 50% of patients with mediastinal nonseminomas will survive with appropriate management.[11] High risk is partially related to tumor bulk, chemotherapy resistance, and a predisposition to develop hematologic neoplasia and other nongerm cell malignancies. In an uncontrolled study, some patients with a postchemotherapy residual mediastinal mass achieved long-term disease-free survival after complete resection, even when serum tumor markers were elevated.[5][Level of evidence C2] Patient selection factors may play a role in these favorable outcomes.
The prognosis of retroperitoneal nonseminoma is reasonably good and, similar to the situation with nodal metastasis from a testicular primary tumor, is related to tumor volume.
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A randomized controlled trial compared conventional doses of salvage chemotherapy to high-dose chemotherapy with autologous marrow rescue in 263 patients with recurrent or refractory germ cell tumors. Of the 263 patients, 43 of whom had extragonadal primary tumors, more toxic effects and treatment-related deaths were seen in the high-dose arm, without any improvement in response rate or overall survival.[1][Level of evidence A1]
Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.
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This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the treatment of extragonadal germ cell tumors. It is intended as a resource to inform and assist clinicians in the care of their patients. It does not provide formal guidelines or recommendations for making health care decisions.
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PDQ® Adult Treatment Editorial Board. PDQ Extragonadal Germ Cell Tumors Treatment. Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at: https://www.cancer.gov/types/extragonadal-germ-cell/hp/extragonadal-treatment-pdq. Accessed <MM/DD/YYYY>. [PMID: 26389346]
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