Mediastinal Germ Cell Tumors

Continuing Education Activity

Mediastinal germ cell tumors can be classified as a teratoma, a seminomatous tumor, or a non-seminomatous tumor. They have similar histology and treatment regimens to their gonadal variants. This activity outlines the evaluation and management of mediastinal germ cell tumors and reviews the role of the interprofessional team in the care of patients with this condition.


  • Describe the etiology of mediastinal germ cell tumors.
  • Review the epidemiology of mediastinal germ cell tumors.
  • Outline the treatment guidelines for mediastinal germ cell tumors.
  • Summarize the importance of interprofessional team strategies for identifying and treating mediastinal germ cell tumors to improve outcomes.


The anterior mediastinum is the most common location of extragonadal germ cell tumors (GCTs). Only a small percent of GCTs have been found in the posterior mediastinum. The distant location from their traditional primary sites (gonads) is thought to be attributed to an abnormal migration during embryogenesis. Primary mediastinal and gonadal GCTs share histological and biochemical features with a common cytogenetic abnormality in isochromosome 12p. Mediastinal germ cell tumors (MGCTs) are unique for their association with Klinefelter syndrome and hematologic malignancies. They are histologically classified as teratomas, seminomas, or non-seminomatous tumors. Each classification carries important distinctions regarding their prognosis and treatment.

Most MGCTs are found incidentally on imaging studies. At the time of diagnosis, approximately 20% to 40% of patients are asymptomatic. Generally, initial symptoms are associated with the enlargement of the mediastinal cavity and protrusion into surrounding structures. Common clinical symptoms include chest pain, cough, dyspnea, fever, night sweats, and weight loss. Manifestations are dependent on the size of the tumor and its histological subtype. Treatment involves either surgical resection or cisplatin-based chemotherapy followed by surgical resection depending on the histological subtype.[1][2][3][4][5]


Germ cell tumors traditionally originate in the gonads, primarily in testicles and very rarely in ovaries. Outside of the gonads, GCTs can be found along with midline structures such as the mediastinum, the retroperitoneum, and less often in the pineal and suprasellar areas. The etiology of germ cell malignancy presence outside of the gonads is still unclear, although there are several theories.

Testicular formation during embryonic development relies on the migration of primordial germ cells from the proximal epiblast to the dorsally located urogenital ridge. The leading hypothesis suggests that there is a stop during their descent, which later leads to tumor formation in the mediastinum. The alternative hypothesis is the reverse migration of transformed germ cells in the gonads. This idea is supported by common genetic cell origin data; however, it does not explain some of the biological differences observed.[3][6][7]


Germ cell tumors of the mediastinum are a rare entity, making up only 15% of all tumors located in that area. They are the most common type of GCT outside of the gonads but only account for approximately 1% to 3% of all germ cell malignancies. MGCTs are predominantly seen in males (97%) and occur in younger patients with a mean age of 31 years old.[8] Teratomas are the most common histological subtype, making up approximately 44% of mediastinal germ cell cases. Seminomas make up approximately 16%-37% of cases.[3][9][10]

History and Physical

Mediastinal germ cell tumors are usually found incidentally on imaging studies and are often asymptomatic. Larger sized MGCTs cause symptoms when compressing or obstructing against nearby structures. A few cases have reported an infectious process within the tumor. The contents of the tumor can sometimes include proteolytic or digestive enzymes. This can lead to the rupture of the tumor itself and can induce inflammation in the surrounding structures. The most serious complications include rupture or erosion into the pleural or pericardial space.

Bronchial obstruction can present as pneumonia or hemoptysis if erosion is present. Non-seminomatous MGCTs have more propensity for symptoms with a greater chance of lymph node metastasis. Unlike seminomas and teratomas, non-seminomatous GCTs are more likely to cause symptoms. They can be associated with weight loss, fever, cough, dyspnea, chest pain and can lead to superior vena cava syndrome.[3][11][12][13]


A thorough physical examination is necessary to evaluate a patient with suspicion for MGCT, paying special attention to the gonads. Testicular ultrasound should be a part of the standard screening to identify co-existing GCTs. Further imaging, histological, and biochemical analysis is necessary to make a diagnosis and develop an accurate prognosis. Patients usually present after an incidental anterior mediastinal mass is found on a chest X-ray. Imaging with computed tomography (CT) or magnetic resonance imaging (MRI) can assist in better defining the tumor size, location, and borders. Biochemical markers, alpha-fetoprotein (AFP), beta-human chorionic gonadotropin (b-hCG), and lactate dehydrogenase (LDH) can be elevated and should be checked.


Mediastinal teratomas are usually located near or within the thymus gland in the anterior space of the mediastinum. Biochemical markers are typically not elevated in benign masses. The contents of a mediastinal mature teratoma include at least two out of the three embryonic cell layers (ectoderm, mesoderm, endoderm) developed into well-differentiated histologic elements. Mesodermal elements are represented by bone, cartilage, and muscle. Endodermal elements include gastrointestinal, respiratory, and endocrine gland tissue. Ectodermal tissue can exhibit skin, dermal appendages, and cystic structures lined by squamous epithelium.  

Mature teratoma tumors containing formed teeth or bone are not uncommon. Imaging studies show evidence of calcification in approximately 20%-40% of cases. Contents can include calcification in or within the tumor wall, ossification in mature bone, or calcification from actual teeth remnants. CT scans will often exhibit a well-demarcated mass with cystic components. Immature teratomas are defined when immature embryonic tissue is intermixed with mature elements from all three germ cell layers. Their clinical significance is that they can form cystic structures with areas of hemorrhage and necrosis. Unlike mature teratomas, chemotherapy is often initiated prior to surgical resection.[5][14][15][16][17]

Seminomatous Tumors 

The seminomatous variant is the most common MGCT. Their gross appearance is characterized by a lobulated surface with a homogenous appearance with areas of hemorrhage and necrosis. Histologically, cells have a distinct cell membrane exhibiting abundant clear eosinophilic cytoplasm containing glycogen. This characteristic can be easily demonstrated by a periodic acid-Schiff (PAS) reaction. B-hCG serum levels are elevated in approximately one-third of patients. The presence of elevated AFP is an indication that a pure seminoma GCT is not present. Metastasis in most of the cases has already occurred during the time of discovery, with the most common involvement in adjacent lymph nodes. CT scans will appear as large masses with sharply demarcated borders, often with homogeneous attenuation.[5][10][16][17][18] 

Non-seminomatous Tumors 

The non-seminomatous MGCT classification includes the remaining histological subtypes, including yolk sac tumors, choriocarcinoma, embryonal carcinoma, or mixed type. They make up the most malignant variants of MGCTs. The yolk sac tumor is the most common histological subtype, making up approximately 60% of the non-seminomatous MGCT cases. Yolk sac tumors are soft gray-white masses consisting of necrotic and hemorrhagic patches. They have distinctive glomeruloid perivascular structure, known as Schiller-Duval bodies, interlaced with various histological types, similar to those seen in the gonadal variants. Embryonal carcinomas have the gross appearance of poorly circumscribed invasive tumors. Their cells appear large with the primitive appearance and indistinct cell borders. Choriocarcinomas are larger tumors with extensive areas of hemorrhage. Histologically they are a mixture of different early blast cells that are typically only present during embryogenesis.[10][15][16][17][18][19]

Treatment / Management

The treatment guidelines for MGCTs are similar to those of gonadal GCTs. The rarity of the disease has not allowed for large prospective randomized controlled studies. According to the International Germ Cell Cancer Collaborative Group (IGCCCG), non-seminoma MGCT are considered to be “poor risk” tumors.[2] Teratomas and seminoma MGCT are classified as good or intermediate risk based on their tumor markers and evidence of metastasis. Benign mature teratomas do not respond to chemotherapy, and thus a surgical approach is recommended when symptomatic. Surgical resection involves a median sternotomy or posterolateral thoracotomy. Incomplete resection to avoid vital structure involvement does not require later chemoradiotherapy as these tumors typically do not have an extra-mediastinal invasion.  

For poor-risk tumors (non-seminomatous), first-line therapy usually involves chemotherapy followed by surgical resection of residual tissue. The chemotherapy regimen includes a combination of bleomycin, etoposide, and cisplatin (BEP) with the number of rounds dependent on the category of classification outlined by the IGCCCG.[2] Often, ifosfamide is substituted for bleomycin to avoid its known side effect of drug-induced lung injury. A 2003 study involving 28 patients showed better outcomes and survival rates with the replacement of bleomycin with high dose ifosfamide. Surgical resection followed by chemotherapy is crucial as residual germ cell tissue can lead to growing teratoma syndrome, a rare but documented sequelae of unresected tissue.[20][21] Repeated surgical resection is recommended in those who are good surgical candidates and leads to improved long-term survival. Radiation therapy is a viable option in patients with residual tissue near vital organs.[22]

Relapse, after completed therapy, can occur. A retrospective study of 79 cases of MGCTs found that only 11% of patients were found to be long-term disease-free. Thus, the second round of chemotherapy is warranted in these patients, although clear guidelines of an alternative chemotherapy regimen have not been outlined. Irrespective of the chemotherapy regimen used, studies show very poor cure rates (5%nto 10%) in the salvage therapy setting.[23][24]

Differential Diagnosis

  • Lymphoma
  • Thymoma
  • Thymic carcinoma
  • Sarcoma 
  • Tuberculosis
  • Myasthenia gravis


Prognostication factors include age, metastasis with the number of sites, the elevation of the tumor, and biochemical markers (AFP, b-hCG, LDH). Higher levels of AFP and b-hCG at the time of diagnosis are associated with poorer outcomes. Mediastinal seminoma GCTs had a 5-year survival of 72% to 100%, compared to 48% to 65% in non-seminomatous GCT patients. The most favorable outcomes for non-seminomatous malignancy is in young patients (<29 years old) with normal b-hCG levels. Nonpulmonary visceral metastasis is associated with poorer prognosis. In cases of seminomatous tumors without pulmonary involvement, the 5-year survival rate is more than 90%.[2][3][8][25][26]


During the course of the disease, MGCTs can metastasize into surrounding structures. Common sites of metastasis are adjacent bone, lungs, liver, and thoracic lymph nodes. During treatment, chemotherapy-associated complications can arise. In addition, post-surgical complications such as the development of pyothorax, phrenic nerve injury, and excessive blood loss can also cause complications.

Deterrence and Patient Education

Mediastinal germ cell tumors are thought to arise from abnormal migration of germ cells during embryogenesis. Younger males are most commonly affected. Biomarker screening (AFP, b-HCG, LDH) is necessary for patients who present with an anterior mediastinal mass even when symptoms are absent. Screening for Klinefelter symptoms is necessary with a cytogenetic analysis as it is a reported association. Early recognition and treatment can lead to more favorable outcomes.

Pearls and Other Issues

  • Masses found in the anterior mediastinum should warrant tumor factor studies (AFP, b-hCG, LDH)
  • Early recognition and treatment initiation can lead to better outcomes. 
  • Benign teratomas have a low propensity for malignant transformation and do not respond well to chemotherapy. Surgical resection is only recommended if they are symptomatic due to mass effect. 
  • Mediastinal non-seminomatous GCTs are less common than mediastinal seminomatous GCTs
  • Non-seminomatous variants have the worst prognosis and require chemotherapy, followed by surgical resection. 
  • Relapse can occur after therapy, and second-line chemotherapy results in very low cure rates.

Enhancing Healthcare Team Outcomes

Identification and management of MGCTs require an interprofessional team of primary care clinicians, pulmonologists, radiologists, medical/surgical oncologists, and thoracic surgeons. MGCTs have great malignant potential. Once an anterior mediastinal mass has been identified, the primary care clinician should begin screening with tumor markers. Referral to a pulmonologist is warranted if the mass is affecting pulmonary structures or there are respiratory complications. Discussion with radiologists is key to identify vital structures that may be affected or any other sites of metastasis. After a diagnosis is made, medical oncologists can develop treatment plans that may involve chemotherapy and surgical intervention. Prompt consultation and close communication between the interprofessional team is necessary to achieve the best patient outcomes. [Level 4]

Article Details

Article Author

James Kang

Article Author

Hyfaa Mashaal

Article Editor:

Fatima Anjum


12/4/2020 2:11:12 PM



Hailemariam S,Engeler DS,Bannwart F,Amin MB, Primary mediastinal germ cell tumor with intratubular germ cell neoplasia of the testis--further support for germ cell origin of these tumors: a case report. Cancer. 1997 Mar 1;     [PubMed PMID: 9041167]


International Germ Cell Consensus Classification: a prognostic factor-based staging system for metastatic germ cell cancers. International Germ Cell Cancer Collaborative Group. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 1997 Feb;     [PubMed PMID: 9053482]


Travis WD,Brambilla E,Nicholson AG,Yatabe Y,Austin JHM,Beasley MB,Chirieac LR,Dacic S,Duhig E,Flieder DB,Geisinger K,Hirsch FR,Ishikawa Y,Kerr KM,Noguchi M,Pelosi G,Powell CA,Tsao MS,Wistuba I, The 2015 World Health Organization Classification of Lung Tumors: Impact of Genetic, Clinical and Radiologic Advances Since the 2004 Classification. Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer. 2015 Sep;     [PubMed PMID: 26291008]


Völkl TM,Langer T,Aigner T,Greess H,Beck JD,Rauch AM,Dörr HG, Klinefelter syndrome and mediastinal germ cell tumors. American journal of medical genetics. Part A. 2006 Mar 1;     [PubMed PMID: 16470792]


Rosti G,Secondino S,Necchi A,Fornarini G,Pedrazzoli P, Primary mediastinal germ cell tumors. Seminars in oncology. 2019 Apr;     [PubMed PMID: 31076171]


Chaganti RS,Rodriguez E,Mathew S, Origin of adult male mediastinal germ-cell tumours. Lancet (London, England). 1994 May 7;     [PubMed PMID: 7910232]


Lee KC, Primary mediastinal germ cell tumor with intratubular germ cell neoplasia of the testis--further support for germ cell origin of these tumors: a case report. Cancer. 1997 Sep 1;     [PubMed PMID: 9307213]


Bokemeyer C,Nichols CR,Droz JP,Schmoll HJ,Horwich A,Gerl A,Fossa SD,Beyer J,Pont J,Kanz L,Einhorn L,Hartmann JT, Extragonadal germ cell tumors of the mediastinum and retroperitoneum: results from an international analysis. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2002 Apr 1;     [PubMed PMID: 11919246]


Dulmet EM,Macchiarini P,Suc B,Verley JM, Germ cell tumors of the mediastinum. A 30-year experience. Cancer. 1993 Sep 15;     [PubMed PMID: 7689921]


Moran CA,Suster S, Germ-cell tumors of the mediastinum. Advances in anatomic pathology. 1998 Jan;     [PubMed PMID: 9868508]


Goldstraw P, Spontaneous intrapleural rupture of mediastinal teratoma--Ashour M, Hawass el-Din, Adam KAR, Joharjy I. Respir Med 1993; 87: 69-72. Respiratory medicine. 1993 Jul;     [PubMed PMID: 8209064]


Hiraiwa T,Hayashi T,Kaneda M,Sakai T,Namikawa S,Kusagawa M,Kusano I, Rupture of a benign mediastinal teratoma into the right pleural cavity. The Annals of thoracic surgery. 1991 Jan;     [PubMed PMID: 1985547]


Sasaka K,Kurihara Y,Nakajima Y,Seto Y,Endo I,Ishikawa T,Takagi M, Spontaneous rupture: a complication of benign mature teratomas of the mediastinum. AJR. American journal of roentgenology. 1998 Feb;     [PubMed PMID: 9456938]


Ashour M,el-Din Hawass N,Adam KA,Joharjy I, Spontaneous intrapleural rupture of mediastinal teratoma. Respiratory medicine. 1993 Jan;     [PubMed PMID: 7679797]


Levitt RG,Husband JE,Glazer HS, CT of primary germ-cell tumors of the mediastinum. AJR. American journal of roentgenology. 1984 Jan;     [PubMed PMID: 6318540]


Drevelegas A,Palladas P,Scordalaki A, Mediastinal germ cell tumors: a radiologic-pathologic review. European radiology. 2001;     [PubMed PMID: 11702124]


Domínguez Malagón H,Pérez Montiel D, Mediastinal germ cell tumors. Seminars in diagnostic pathology. 2005 Aug;     [PubMed PMID: 16711404]


Moran CA,Suster S,Przygodzki RM,Koss MN, Primary germ cell tumors of the mediastinum: II. Mediastinal seminomas--a clinicopathologic and immunohistochemical study of 120 cases. Cancer. 1997 Aug 15;     [PubMed PMID: 9264352]


Moran CA,Suster S,Koss MN, Primary germ cell tumors of the mediastinum: III. Yolk sac tumor, embryonal carcinoma, choriocarcinoma, and combined nonteratomatous germ cell tumors of the mediastinum--a clinicopathologic and immunohistochemical study of 64 cases. Cancer. 1997 Aug 15;     [PubMed PMID: 9264353]


Bokemeyer C,Schleucher N,Metzner B,Thomas M,Rick O,Schmoll HJ,Kollmannsberger C,Boehlke I,Kanz L,Hartmann JT, First-line sequential high-dose VIP chemotherapy with autologous transplantation for patients with primary mediastinal nonseminomatous germ cell tumours: a prospective trial. British journal of cancer. 2003 Jul 7;     [PubMed PMID: 12838296]


Kataria SP,Varshney AN,Nagar M,Mandal AK,Jha V, Growing Teratoma Syndrome. Indian journal of surgical oncology. 2017 Mar;     [PubMed PMID: 28127182]


Vuky J,Bains M,Bacik J,Higgins G,Bajorin DF,Mazumdar M,Bosl GJ,Motzer RJ, Role of postchemotherapy adjunctive surgery in the management of patients with nonseminoma arising from the mediastinum. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2001 Feb 1;     [PubMed PMID: 11157018]


Hartmann JT,Einhorn L,Nichols CR,Droz JP,Horwich A,Gerl A,Fossa SD,Beyer J,Pont J,Schmoll HJ,Kanz L,Bokemeyer C, Second-line chemotherapy in patients with relapsed extragonadal nonseminomatous germ cell tumors: results of an international multicenter analysis. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2001 Mar 15;     [PubMed PMID: 11250992]


Voss MH,Feldman DR,Bosl GJ,Motzer RJ, A review of second-line chemotherapy and prognostic models for disseminated germ cell tumors. Hematology/oncology clinics of North America. 2011 Jun;     [PubMed PMID: 21570609]


Hartmann JT,Nichols CR,Droz JP,Horwich A,Gerl A,Fossa SD,Beyer J,Pont J,Kanz L,Einhorn L,Bokemeyer C, Prognostic variables for response and outcome in patients with extragonadal germ-cell tumors. Annals of oncology : official journal of the European Society for Medical Oncology. 2002 Jul;     [PubMed PMID: 12176779]


Rivera C,Arame A,Jougon J,Velly JF,Begueret H,Dahan M,Riquet M, Prognostic factors in patients with primary mediastinal germ cell tumors, a surgical multicenter retrospective study. Interactive cardiovascular and thoracic surgery. 2010 Nov;     [PubMed PMID: 20709694]