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.

Teratomas

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]

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]

• 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.

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.

• 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.

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]