Primary Mediastinal Non-Seminomatous Germ Cell Tumor
Related narrative: Primary Mediastinal Non-Seminomatous Germ Cell Tumor
This discussion will provide a concise overview of Primary Mediastinal Non-Seminomatous Germ Cell Tumors (PMNSGCT). A broad overview of testicular tumors is available in the testicular cancer discussion.
Extragonadal germ cell tumors arise in the anterior mediastinum or retroperitonuem and represent 15% of adult anterior mediastinal tumors. By definition, these tumors display no evidence by radiographic imaging or physical exam of testicular primary malignancy. Histological differentiation divides mediastinal GCTs into seminomas, non-seminomatous germ cell tumors (NSGCT), and teratomas, which are rare. Histologically, NSGCT include primary yolk sac tumor, embryonal carcinoma, choriocarcinoma, and nonteratomatous combined germ cell tumors. Extragonadal seminomas and non-seminomatous tumors carry substantially different prognoses, and thus differentiation by biopsy radically changes treatment and prognostic scenarios. Chemotherapy for patients with mediastinal and retroperitoneal seminomas results in a long-term disease-free survival of approximately 90%. By contrast, PMNSGCT carries a dismal long-term survival, ranging between 30%-60% and is classified as a poor-risk disease by the International Germ Cell Cancer Collaborative Group.
Epidemiology and Risk Factors
PMNSGCT are rare tumors and arise nearly exclusively in young males. In the context of germ cell tumors as a whole, 2% - 5% have been reported to originate extragonadally, with the majority in the anterior medistinum and retroperitoneum (although occurrence has been noted in pineal gland, presacral area and liver.) However, more recently this number may be closer to 5%-10% of all germ cell tumors, given increased availability of tumor markers and improved pathology. One international multicenter review of 142 patients with PMNSGCT noted a mean patient age of 29 years with a range from 17-67, all male.
Klinefelter's syndrome appears to be a risk factor for PMNSGCT. In one series 4 of 22 consecutive patients with NSGCT also met criteria for Klinefelter's syndrome. Klinefelter's syndrome carries a relative risk of 66.7 for the development of malignant mediastinal germ-cell tumors.
Clinical Manifestation and Diagnosis
The most common symptoms at presentation are chest pain and shortness of breath, followed by cough, weight loss, chills and fever, and superior vena cava syndrome. Chest wall mass and dysphagia are less frequently observed. In general, PMNSGCT are fast growing tumors and cause compression of mediastinal structures, with abdominal and back pain reported in 29% and 19% of patients in one study.
PMNSGCT are serologically and histologically similar to primary testicular tumors. An elevated AFP is expected in most patients, although a minority may display an elevated beta-hCG. Diagnostically, the presence of AFP precludes the diagnosis of mediastinal seminoma, and thus points to a poorer prognostic outcome.
Initial diagnosis is achieved by clinical history, imaging, and tumor markers (AFP, beta-HCG), and confirmed by biopsy and histologic classification. Tumor markers are useful in monitoring response and recurrence, especially in post-resection observation.
A multicenter analysis by Bokemeyer et al, noted 51% of patients with PMNSGCT presented with only mediastinal tumor, 34% with one metastatic site, and 16% with two or more.
Stage I: Well-circumscribed tumor with or without focal adhesions to the pleura or pericardium but without microscopic evidence of invasion into adjacent structures
Stage II: Tumor confined to the mediastinum with macroscopic and/or microscopic evidence of infiltration into adjacent structures (such as pleura, pericardium, and great vessels)
Stage III: Tumor with metastasis
Treatment and Prognosis
Treatment is focused on cisplatin-based combination chemotherapy regimens with additional aggressive postchemotherapy surgical resection in patients with radiographic evidence of residual disease. Standard treatment involves four cycles of BEP (Bleomycin, Etoposide, Cisplatin), or alternatively VIP (Vinblastine, Ifosfamide, Cisplatin). Resection has become an integral component of treatment, as salvage chemotherapy has proven futile. Saxman analyzed a series of 73 patients with mediastinal NSGCT with attempted salvage chemotherapy. Only 7% achieved a long-term disease-free survival.
Hartmann notes that there is evidence that patients with mediastinal NSGCT benefit from aggressive resections, "even when thoracic surgery has necessitated prosthetic replacement of the superior vena cava." Vuky et. al. also explicitly states that "patients may benefit from referral to specialized centers for surgical resection." The presence of extramediastinal metastases prechemotherapy adversely affects 5-year overall survival, although postchemotherapy/preoperative elevated tumor markers show no prognostic significance. Ganjoo et al reported 15 (24%) of 62 patients achieved complete remission with chemotherapy alone, with 14 of these continuously without evidence of disease; 47 (76%) of 62 achieved no evidence of disease with chemotherapy and resection. Overall, 41% treated at Indiana University and 55.5% referred for resection were continuously without evidence of disease.
Regarding patients undergoing postcehomotherapy resection, shorter survival rates were noted with the presence of viable tumor in a resected specimen and also in patients requiring more than one site resected during surgery. Overall survival in patients undergoing postchemotherapy resection varies, with Vuky et. al. noting a median survival of 10 months (32 patients, range 9-139 months). Seven (29%) were noted to be continuously disease free. Schneider, et. al. noted a median overall survival of 64 weeks (47 patients, range 3-576 weeks) with 16 of the 47 (34%) continually without evidence of disease.
PMNSGCT also carries with it an increased risk of hematologic disorders. Bokemeyer, et. al. note 17 of 287 patients with PMNSGCT developed hematologic disorders within 6 months of diagnosis, mainly acute megaloblastic leukemia and myelodysplasia with abnormal megakaryocytes. This represents a standardized incidental ratio of 250 among patients with PMNSGCT.
Discussion Author: Dennis White
Bokemeyer C, Nichols CR, Droz, JP, et al. Extragonadal germ cell tumors of the mediastinum and retroperitoneum. Journal Clinical Oncology 2002; 20:1864 - 1873.
Ganjoo K, Rieger K, Kesler K, Sharma M, Heilman D, Einhorn L. Results of Modern Therapy for Patients with Mediastinal Nonseminomatous Germ Cell Tumors. Cancer. 2000; 88: 1051-1056.
Hartmann J, et al. Second line chemotherapy in Patients with Relapsed Extragonadal Nonseminomatous Germ Cell tumors: Results of an international multicenter analysis. Journal Clin Onc 2001. Vol 19: 6. 1641-1648.
Hasle H, Mellemgaard A, Nielsen J, Hansen J. Cancer incidence in men with Klinefelter syndrome. Br J Cancer 1995;71:416-20.
Moran CA, Suster S. Primary germ cell tumors of the mediastinum. Analysis of 322 cases with special emphasis on teratomatous lesions and a proposal for histopathologic classification and clinical staging. Cancer. 1997;80:681-90.
Mullen B, Richardson JD. Primary anterior mediastinal tumor in children and adults. Annalof Thoracic Surgery. 1987; 42: 338-48.
Nichols CR, Heerema NA, Palmer C, Williams SD, Loehrer PJ, Einhorn LH. Klinfelter's syndrome associated with mediastinal germ cell neoplasms. Journal Clinical Oncology. 1987;5:1290-1294.
Saxman S, et al. Salvage chemotherapy in patients with extragonadal nonseminomatous germ cell tumors: The Indiana University Experience. Journal of Clin Onc 12: 1390-1393, 1994.
Schneider B, Kesler K, Brooks J, Yiannoutsos C, Einhorn L. Outcome of ptatients with residual germ cell tumor or non-germ cell malignancy after resection of primary mediastinal nonseminomatous germ cell cancer. Journal of Clinical Oncology 2004; 22: 1195-1200.
Vuky J, et al. Role of Postchemotherapy Adjunctive Surgery in the Management of Patients with Nonseminoma Arising From the Mediastinum. Journal of Clin Onc 2001, Vol 19: 3. 682-688.