Purpose of This PDQ Summary
General Information
Cellular Classification

Good Prognosis         Nonseminoma         Seminoma Intermediate Prognosis         Nonseminoma         Seminoma Poor Prognosis         Nonseminoma         Seminoma

Benign Teratoma

Current Clinical Trials

Seminoma

Current Clinical Trials

Nonseminoma

Mediastinal Nonseminoma Retroperitoneal Nonseminoma Current Clinical Trials

Recurrent or Refractory Extragonadal Germ Cell Tumors

Current Clinical Trials

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Changes to This Summary (05/16/2008)
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Purpose of This PDQ Summary

This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the treatment of extragonadal germ cell tumors. This summary is reviewed regularly and updated as necessary by the PDQ Adult Treatment Editorial Board ¹.

Information about the following is included in this summary:

• Cellular classification.
• Staging.
• Treatment options for different types of tumors.

This summary is intended as a resource to inform and assist clinicians who care for cancer patients. It does not provide formal guidelines or recommendations for making health care decisions.

Some of the reference citations in the summary are accompanied by a level-of-evidence designation. These designations are intended to help readers assess the strength of the evidence supporting the use of specific interventions or approaches. The PDQ Adult Treatment Editorial Board uses a formal evidence ranking system ² in developing its level-of-evidence designations. Based on the strength of the available evidence, treatment options are described as either “standard” or “under clinical evaluation.” These classifications should not be used as a basis for reimbursement determinations.

This summary is available in a patient version ³, written in less technical language, and in Spanish ⁴.

General Information

Note: Separate PDQ summaries on Ovarian Germ Cell Tumors Treatment ⁵ and Testicular Cancer Treatment ⁶ are also available.

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.

Cellular Classification

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 embryonal carcinomas, malignant teratomas, endodermal sinus tumors, choriocarcinomas, and mixed germ cell tumors.

Extragonadal germ cell tumors occur much more commonly in males than in females [1] and are usually seen in young adults. They are aggressive neoplasms and can arise virtually anywhere, but typically the site of origin is 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 trials' results of patients with extragonadal germ cell tumors.

• Testis/retroperitoneal primary

  and

• No nonpulmonary visceral metastases

  and

• Good markers - all of:
  • AFP less than 1,000 ng/mL

    and

  • hCG less than 5,000 iu/L (1,000 ng/mL)

    and

  • LDH less than 1.5 x upper limit of normal

56% of nonseminomas

5-year progression-free survival (PFS) rate of 89%

5-year survival rate of 92%

• Any primary site

  and

• No nonpulmonary visceral metastases

  and

• Normal AFP, any hCG, any LDH

90% of seminomas

5-year PFS rate of 82%

5-year survival rate of 86%

• Testis/retroperitoneal primary

  and

• No nonpulmonary visceral metastases

  and

• Intermediate markers - any of:
  • AFP 1,000 ng/mL or greater and 10,000 ng/mL or less

    or

  • hCG 5,000 iu/L or greater and 50,000 iu/L or less

    or

  • LDH 1.5 × N or greater and 10 × N or less

28% of nonseminomas

5-year PFS rate of 75%

5-year survival rate of 80%

• Any primary site

  and

• Nonpulmonary visceral metastases

  and

• Normal AFP, any hCG, any LDH

10% of seminomas

5-year PFS rate of 67%

5-year survival rate of 72%

• Mediastinal primary

  or

• Nonpulmonary visceral metastases

  or

• Poor markers - any of:
  • AFP greater than 10,000 ng/mL

    or

  • hCG greater than 50,000 iu/L (1,000 ng/mL)

    or

  • LDH greater than 10 × upper limit of normal

16% of nonseminomas

5-year PFS rate of 41%

5-year survival rate of 48%

No patients are classified as poor prognosis.

References

1. Mayordomo JI, Paz-Ares L, Rivera F, et al.: Ovarian and extragonadal malignant germ-cell tumors in females: a single-institution experience with 43 patients. Ann Oncol 5 (3): 225-31, 1994.  [PUBMED Abstract]
   
   
2. Greco FA, Vaughn WK, Hainsworth JD: Advanced poorly differentiated carcinoma of unknown primary site: recognition of a treatable syndrome. Ann Intern Med 104 (4): 547-53, 1986.  [PUBMED Abstract]
   
   
3. Hainsworth JD, Greco FA: Extragonadal germ cell tumors and unrecognized germ cell tumors. Semin Oncol 19 (2): 119-27, 1992.  [PUBMED Abstract]
   
   
4. International Germ Cell Consensus Classification: a prognostic factor-based staging system for metastatic germ cell cancers. International Germ Cell Cancer Collaborative Group. J Clin Oncol 15 (2): 594-603, 1997.  [PUBMED Abstract]
   
   

Benign Teratoma

Benign teratomas are treated with surgical excision only. These tumors are frequently very large, and the surgical procedure can be formidable.

Check for U.S. clinical trials from NCI's PDQ Cancer Clinical Trials Registry that are now accepting patients with benign teratoma ⁷. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI Web site ⁸.

Seminoma

Note: Some citations in the text of this section are followed by a level of evidence. The PDQ editorial boards use a formal ranking system to help the reader judge the strength of evidence linked to the reported results of a therapeutic strategy. (Refer to the PDQ summary on Levels of Evidence ² for more information.)

The diagnosis of seminoma requires that the serum alpha fetoprotein (AFP) be normal, and no other germ cells be present. Management decisions in patients presenting with these tumors can sometimes 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 as evidenced in the MAKEI-83/86/89 ⁹ trial, for example.[2][Level of evidence: 3iiiA]

Initial chemotherapy with regimens used in nonseminoma testicular cancer is also very efficacious. Practically speaking, patients with localized relatively small tumors are usually treated initially with radiation, 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, the majority of experts agree that observation is appropriate. In those with larger residual masses, some experts favor surgical excision while others favor observation.[3,4]

Check for U.S. clinical trials from NCI's PDQ Cancer Clinical Trials Registry that are now accepting patients with extragonadal seminoma ¹⁰. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI Web site ⁸.

References

1. Clamon GH: Management of primary mediastinal seminoma. Chest 83 (2): 263-7, 1983.  [PUBMED Abstract]
   
   
2. Bamberg M, Kortmann RD, Calaminus G, et al.: Radiation therapy for intracranial germinoma: results of the German cooperative prospective trials MAKEI 83/86/89. J Clin Oncol 17 (8): 2585-92, 1999.  [PUBMED Abstract]
   
   
3. Motzer R, Bosl G, Heelan R, et al.: Residual mass: an indication for further therapy in patients with advanced seminoma following systemic chemotherapy. J Clin Oncol 5 (7): 1064-70, 1987.  [PUBMED Abstract]
   
   
4. Schultz SM, Einhorn LH, Conces DJ Jr, et al.: Management of postchemotherapy residual mass in patients with advanced seminoma: Indiana University experience. J Clin Oncol 7 (10): 1497-503, 1989.  [PUBMED Abstract]
   
   

Nonseminoma

Note: Some citations in the text of this section are followed by a level of evidence. The PDQ editorial boards use a formal ranking system to help the reader judge the strength of evidence linked to the reported results of a therapeutic strategy. (Refer to the PDQ summary on Levels of Evidence ² for more information.)

Patients with nonseminomas should receive chemotherapy at diagnosis. These patients tend to have a very 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 would generally be considered to be 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 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: 1iiA] Of the 304 patients on this study, 66 patients had extragonadal primary tumors, and in this subset of patients, responses were similar on the two regimens. Hematologic toxic effects in the overall study 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: 3iiiDii] 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 transplantation, that have had success for recurrent testicular cancer.[6-8] Such patients, therefore, 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, to chemotherapy resistance, and to 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: 3iiiDii] 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, is related to tumor volume.

Check for U.S. clinical trials from NCI's PDQ Cancer Clinical Trials Registry that are now accepting patients with malignant extragonadal non-seminomatous germ cell tumor ¹¹. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI Web site ⁸.

References

1. Williams SD, Birch R, Einhorn LH, et al.: Treatment of disseminated germ-cell tumors with cisplatin, bleomycin, and either vinblastine or etoposide. N Engl J Med 316 (23): 1435-40, 1987.  [PUBMED Abstract]
   
   
2. Bosl GJ, Gluckman R, Geller NL, et al.: VAB-6: an effective chemotherapy regimen for patients with germ-cell tumors. J Clin Oncol 4 (10): 1493-9, 1986.  [PUBMED Abstract]
   
   
3. Nichols CR, Catalano PJ, Crawford ED, et al.: Randomized comparison of cisplatin and etoposide and either bleomycin or ifosfamide in treatment of advanced disseminated germ cell tumors: an Eastern Cooperative Oncology Group, Southwest Oncology Group, and Cancer and Leukemia Group B Study. J Clin Oncol 16 (4): 1287-93, 1998.  [PUBMED Abstract]
   
   
4. Hinton S, Catalano PJ, Einhorn LH, et al.: Cisplatin, etoposide and either bleomycin or ifosfamide in the treatment of disseminated germ cell tumors: final analysis of an intergroup trial. Cancer 97 (8): 1869-75, 2003.  [PUBMED Abstract]
   
   
5. Schneider BP, Kesler KA, Brooks JA, et al.: Outcome of patients with residual germ cell or non-germ cell malignancy after resection of primary mediastinal nonseminomatous germ cell cancer. J Clin Oncol 22 (7): 1195-200, 2004.  [PUBMED Abstract]
   
   
6. Saxman SB, Nichols CR, Einhorn LH: Salvage chemotherapy in patients with extragonadal nonseminomatous germ cell tumors: the Indiana University experience. J Clin Oncol 12 (7): 1390-3, 1994.  [PUBMED Abstract]
   
   
7. Beyer J, Kramar A, Mandanas R, et al.: High-dose chemotherapy as salvage treatment in germ cell tumors: a multivariate analysis of prognostic variables. J Clin Oncol 14 (10): 2638-45, 1996.  [PUBMED Abstract]
   
   
8. Loehrer PJ Sr, Gonin R, Nichols CR, et al.: Vinblastine plus ifosfamide plus cisplatin as initial salvage therapy in recurrent germ cell tumor. J Clin Oncol 16 (7): 2500-4, 1998.  [PUBMED Abstract]
   
   
9. Nichols CR, Heerema NA, Palmer C, et al.: Klinefelter's syndrome associated with mediastinal germ cell neoplasms. J Clin Oncol 5 (8): 1290-4, 1987.  [PUBMED Abstract]
   
   
10. Nichols CR, Roth BJ, Heerema N, et al.: Hematologic neoplasia associated with primary mediastinal germ-cell tumors. N Engl J Med 322 (20): 1425-9, 1990.  [PUBMED Abstract]
    
    
11. Nichols CR, Saxman S, Williams SD, et al.: Primary mediastinal nonseminomatous germ cell tumors. A modern single institution experience. Cancer 65 (7): 1641-6, 1990.  [PUBMED Abstract]
    
    

Recurrent or Refractory Extragonadal Germ Cell Tumors

Note: Some citations in the text of this section are followed by a level of evidence. The PDQ editorial boards use a formal ranking system to help the reader judge the strength of evidence linked to the reported results of a therapeutic strategy. (Refer to the PDQ summary on Levels of Evidence ² for more information.)

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: 1iiA]

Check for U.S. clinical trials from NCI's PDQ Cancer Clinical Trials Registry that are now accepting patients with recurrent extragonadal germ cell tumor ¹². The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI Web site ⁸.

References

1. Pico JL, Rosti G, Kramar A, et al.: A randomised trial of high-dose chemotherapy in the salvage treatment of patients failing first-line platinum chemotherapy for advanced germ cell tumours. Ann Oncol 16 (7): 1152-9, 2005.  [PUBMED Abstract]
   
   

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Changes to This Summary (05/16/2008)

The PDQ cancer information summaries are reviewed regularly and updated as new information becomes available. This section describes the latest changes made to this summary as of the date above.

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Glossary Terms

Randomized, controlled, nonblinded clinical trial with total mortality as an endpoint. See Levels of Evidence for Adult and Pediatric Cancer Treatment Studies (PDQ®) for more information.

Nonconsecutive case series with total mortality as an endpoint. See Levels of Evidence for Adult and Pediatric Cancer Treatment Studies (PDQ®) for more information.

Nonconsecutive case series with total disease-free survival as an endpoint. See Levels of Evidence for Adult and Pediatric Cancer Treatment Studies (PDQ®) for more information.