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Extragonadal germ cell tumor


Table of Contents

DISEASE DESCRIPTION

DISEASE DESCRIPTION

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 levels of evidence summary for more information.

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, which includes embryonal carcinoma, malignant teratoma, endodermal sinus tumor, choriocarcinoma, and mixed germ cell tumors. Although much more common in males, they also occur in females.[1] They are usually seen in young adults and are aggressive neoplasms. They can arise virtually anywhere, but typically the site of origin is in the mid-line (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 mid-line masses.[2,3]

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

The diagnosis of seminoma requires that the serum alpha fetoprotein (AFP) be normal and no other germ cells be present. Management decisions in these patients can sometimes be difficult. As in testicular seminoma, these tumors are very radiosensitive. About 60% to 80% will remain disease free after radiation.[4] However, initial chemotherapy with regimens used in nonseminoma testis 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- and cisplatin-based chemotherapy regimens.

As in testicular seminoma, many will be left with a residual mass after treatment. If the residual mass is smaller than 3.0 centimeters, nearly all would agree that observation is appropriate. In those with larger residual masses, some groups favor surgical excision while others favor observation.[5,6]

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 ongoing trials, such as randomized studies comparing high- dose chemotherapy plus hematopoietic rescue to "standard" therapy.[7] "Standard" therapy would generally be considered to be four courses of bleomycin, etoposide, and cisplatin (BEP).[8,9] A randomized study comparing four courses of BEP to four courses of VIP (etoposide + ifosfamide + cisplatin) showed equivalent overall survival and time-to-treatment failure for the two regimens in patients with advanced disseminated germ cell tumors who had not received prior chemotherapy.[10][Level of evidence: 1iiA] Of the 204 patients on this study, 66 had extragonadal primary tumors, and responses in this subset of patients were similar on the two regimens. Hematologic toxic effects in the overall study were substantially worse with the VIP regimen compared to the BEP regimen. Those patients with normal markers and a residual mass after chemotherapy should undergo postchemotherapy surgery with resection of all residual disease. Patients with nonseminomatous extragonadal germ cell tumors who relapse after front-line chemotherapy generally have a poor prognosis with a poor response to salvage chemotherapy regimens, including autologous bone marrow transplantation, that have had success for recurrent testicular cancer.[11-13] Therefore, such patients are candidates for studies of new approaches.

Mediastinal nonseminomas have certain unique aspects. They are more frequent in individuals with Klinefelter's syndrome and are associated with a risk of subsequent development of hematologic neoplasia that is not treatment related.[14,15] Approximately 50% will survive with appropriate management.[16] High risk is partially related to tumor bulk, to chemotherapy resistance, and to a predisposition to develop hematologic neoplasia and other non-germ cell malignancies.

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.

An international germ cell tumor prognostic classification has been developed based on a retrospective analysis of 5,202 patients with metastatic nonseminomatous and 660 patients with metastatic seminomatous germ cell tumors.[17] All patients received treatment with cisplatin- 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. It should be used for reporting of clinical trials results of patients with extragonadal germ cell tumors.


--Good Prognosis--
Nonseminoma:
   testis/retroperitoneal primary and
   no non-pulmonary visceral metastases and
   good markers - all of:
     AFP<1000 ng/ml and 
     hCG<5000 iu/l (1000 ng/ml) and 
     LDH<1.5 x upper limit of normal
56% of nonseminomas 
5 year progression-free survival (PFS) 89%
5 year survival 92%

Seminoma:
   Any primary site and
   no non-pulmonary visceral metastases and
   normal AFP, any hCG, any LDH
90% of seminomas
5 year PFS 82%
5 year survival 86%

--Intermediate Prognosis--
Nonseminoma:
   testis/retroperitoneal primary and
   no non-pulmonary visceral metastases and 
   intermediate markers - any of:
      AFP>/=1000 and </=10,000 ng/mL or
      hCG>/=5000 iu/l and </=50,000 iu/l or
      LDH>/=1.5 x N and </=10 x N
28% of nonseminomas
5 year PFS 75%
5 year survival 80%

Seminoma:
   any primary site and
   non-pulmonary visceral metastases and
   normal AFP, any hCG, any LDH
10% of seminomas
5 year PFS 67%
5 year survival 72%

--Poor Prognosis--
Nonseminoma:
   mediastinal primary or
   non-pulmonary visceral metastases or
   poor markers - any of:
      AFP>10,000 ng/ml or
      hCG>50,000 iu/l (1000 ng/ml) or
      LDH>10 x upper limit of normal
16% of nonseminomas
5 year PFS 41%
5 year survival 48%

Seminoma:
No patients 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. Annals of Oncology 5(3): 225-231, 1994.

  2. Greco FA, Vaughn WK, Hainsworth JD: Advanced poorly differentiated carcinoma of unknown primary site: recognition of a treatable syndrome. Annals of Internal Medicine 104(4): 547-553, 1986.

  3. Hainsworth JD, Greco FA: Extragonadal germ cell tumors and unrecognized germ cell tumors. Seminars in Oncology 19(2): 119-127, 1992.

  4. Clamon GH: Management of primary mediastinal seminoma. Chest 83(2): 263-267, 1983.

  5. Motzer R, Bosl G, Heelan R, et al.: Residual mass: an indication for further therapy in patients with advanced seminoma following systemic chemotherapy. Journal of Clinical Oncology 5(7): 1064-1070, 1987.

  6. Schultz SM, Einhorn LH, Conces DJ, et al.: Management of postchemotherapy residual mass in patients with advanced seminoma: Indiana University experience. Journal of Clinical Oncology 7(10): 1497-1503, 1989.

  7. Motzer RJ, Memorial Sloan-Kettering Cancer Center: Phase III Randomized Study of BEP (BLEO/VP-16/CDDP) Alone vs BEP Followed by High-Dose CBDCA/VP-16/CTX with Hematopoietic Rescue in Males with Previously Untreated Poor and Intermediate Risk Germ Cell Tumors (Summary Last Modified 05/1997), MSKCC-94076, clinical trial, active, 09/08/1994.

  8. Williams SD, Birch R, Einhorn LH, et al.: Treatment of disseminated germ-cell tumors with cisplatin, bleomycin, and either vinblastine or etoposide. New England Journal of Medicine 316(23): 1435-1440, 1987.

  9. Bosl GJ, Gluckman R, Geller NL, et al.: VAB-6: an effective chemotherapy regimen for patients with germ-cell tumors. Journal of Clinical Oncology 4(10): 1493-1499, 1986.

  10. 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. Journal of Clinical Oncology 16(4): 1287-1293, 1998.

  11. Saxman SB, Nichols CR, Einhorn LH: Salvage chemotherapy in patients with extragonadal nonseminomatous germ cell tumors: the Indiana University experience. Journal of Clinical Oncology 12(7): 1390-1393, 1994.

  12. Beyer J, Kramar A, Mandanas R, et al.: High-dose chemotherapy as salvage treatment in germ cell tumors: a multivariate analysis of prognostic variables. Journal of Clinical Oncology 14(10): 2638-2645, 1996.

  13. Loehrer PJ Sr, Gonin R, Nichols CR, et al.: Vinblastine plus ifosfamide plus cisplatin as initial salvage therapy in recurrent germ cell tumor. Journal of Clinical Oncology 16(7): 2500-2504, 1998.

  14. Nichols CR, Heerema NA, Palmer C, et al.: Klinefelter's syndrome associated with mediastinal germ cell neoplasms. Journal of Clinical Oncology 5(8): 1290-1294, 1987.

  15. Nichols CR, Roth BJ, Heerema N, et al.: Hematologic neoplasia associated with primary mediastinal germ-cell tumors. New England Journal of Medicine 322(20): 1425-1429, 1990.

  16. Nichols CR, Saxman S, Williams SD, et al.: Primary mediastinal nonseminomatous germ cell tumors: a modern single institution experience. Cancer 65(5): 1641-1646, 1990.

  17. International Germ Cell Cancer Collaborative Group: International Germ Cell Consensus Classification: a prognostic factor-based staging system for metastatic germ cell cancers. Journal of Clinical Oncology 15(2): 594-603, 1997.

Date Last Modified: 05/1999



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