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Mediastinal Germ Cell Tumors

Editor: Fatima Anjum Updated: 4/27/2023 11:32:56 PM

Introduction

The anterior mediastinum is the most common location of extragonadal germ cell tumors constituting approximately 50 to 70% of all cases.[1] Germ cell tumors of the posterior mediastinum are a rarity. Primary mediastinal germ cell tumors and gonadal germ cell tumors have biochemical and histologic resemblances with each other, including the detection of isochromosome 12p.[2] Mediastinal germ cell tumors have been noted to have an association with Klinefelter syndrome and various hematologic malignancies.[3] Similar to gonadal germ cell tumors, there are three main subtypes: teratomas, other non-seminomatous tumors, and seminomas. Each one of these carries important distinctions with regard to prognosis and treatments.

Most mediastinal germ cell tumors are found incidentally in 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.[4][5][6][7][2]

Etiology

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Etiology

Germ cell tumors arise from the gonads, most commonly noted from testicles in men and very rarely from ovaries in women. Non-gonadal origin is rare and can include midline structures such as the mediastinum, retroperitoneum, pineal, or suprasellar areas.[2][1] The etiology of germ cell malignancy noted outside the gonads is still unclear, although several hypotheses exist.

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 anterior mediastinum. The alternative hypothesis is the reverse migration of transformed germ cells in the gonads. Common genetic cell origin data support this idea; however, it does not explain some of the biological differences observed.[6][8][9]

Epidemiology

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 germ cell tumors outside the gonads but only account for approximately 1% to 3% of all germ cell malignancies. Mediastinal germ cell tumors are predominantly seen in men (97%) and occur in younger patients with a mean age of 31 years.[10] Mediastinal germ cell tumors have been associated with Klinefelter syndrome, especially for non-seminomatous variants.[1][3] 

Pathophysiology

Mediastinal germ cell tumors and gonadal germ cell tumors share features, including the gain of isochromosome 12p.[1] At the same time, there are several differences in various components, including higher incidences of TP53 mutations, yolk sac tumor types, and alpha-fetoprotein elevations.[11] 

Histopathology

Teratomas are the most common histological subtype, making up approximately 44% of mediastinal germ cell cases. In total, non-seminomatous germ cell tumors comprise approximately 70% of all mediastinal germ cell tumors. Seminomas make up approximately 30% of cases.[6][12][13]

History and Physical

Mediastinal germ cell tumors can be found incidentally on imaging studies and might be asymptomatic. However, larger-sized mediastinal germ cell tumors cause symptoms when compressing or obstructing nearby structures. A few cases have reported an infectious process within the tumor.[14][15] The contents of the tumor can sometimes include proteolytic or digestive enzymes. These tumors can rupture spontaneously and 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 post-obstructive pneumonia or hemoptysis if erosion is present. Non-seminomatous mediastinal germ cell tumors have more propensity for symptoms with a greater chance of lymph node metastasis, unlike seminomas and teratomas. They can be associated with weight loss, fever, cough, dyspnea, and chest pain and can also lead to superior vena cava syndrome.[6][16][17][18]

Evaluation

A thorough physical examination is necessary to evaluate a patient with suspicion of mediastinal germ cell tumors, paying particular attention to the gonads. Testicular ultrasound should be a part of the standard work-up to identify co-existing germ cell tumors. Further imaging, histological, and biochemical analysis are necessary to make a diagnosis. Patients usually present after an incidental anterior mediastinal mass is found on a chest X-ray or may present with symptoms related to a large anterior mediastinal mass. 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. Similar to germ cell tumor diagnostic pathways, a significant elevation in serum B-hCG of >1,000 U/L with or without elevation in AFP is supportive of diagnosing mediastinal germ cell tumors in the appropriate clinical setting.[1]

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 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% to 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.[2][19][20][21][22]

Seminomatous Tumors 

The seminomatous variant is the most common mediastinal germ cell tumor. 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 germ cell tumor 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.[2][13][21][22][23] 

Non-seminomatous Tumors 

The non-seminomatous mediastinal germ cell tumor classification includes the remaining histological subtypes, including yolk sac tumors, choriocarcinoma, embryonal carcinoma, or mixed type. They make up the most malignant variants of mediastinal germ cell tumors. The yolk sac tumor is the most common histological subtype, making up approximately 60% of the non-seminomatous mediastinal germ cell tumor cases. Yolk sac tumors are soft gray-white masses consisting of necrotic and hemorrhagic patches. They have distinctive glomeruloid perivascular structures, 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 a 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.[13][20][21][22][23][24]

Treatment / Management

The treatment guidelines for mediastinal germ cell tumors are similar to those of gonadal germ cell tumors. 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-seminomatous mediastinal germ cell tumors are considered “poor risk” tumors.[5] Teratomas and seminomatous mediastinal germ cell tumors are classified as good or intermediate risk based on tumor markers and evidence of metastasis at presentation. Benign mature teratomas do not respond to chemotherapy; 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 subsequent chemoradiotherapy as these tumors typically do not have an extra-mediastinal invasion.  (B2)

For seminomatous mediastinal germ cell tumors, treatment consists of 3 or 4 cycles of bleomycin, etoposide, and cisplatin chemotherapy (BEP), based on being in the good or intermediate risk category. 

For poor-risk tumors (non-seminomatous), first-line therapy usually involves chemotherapy followed by surgical resection of residual tissue. The original chemotherapy regimen that included four cycles of a combination of bleomycin, etoposide, and cisplatin (BEP) resulted in pulmonary complications, which were noted to be harmful in patients with mediastinal germ cell tumors, who may need extensive thoracic surgery after chemotherapy.[5] This was addressed by replacing bleomycin with ifosfamide.[11] A 2003 study involving 28 patients showed better outcomes and survival rates with the replacement of bleomycin with high-dose ifosfamide. In the case of residual disease post-chemotherapy, surgical resection is crucial as residual germ cell tissue can lead to growing teratoma syndrome, a rare but documented sequelae of unresected tissue.[25][26] Repeated surgical resection is recommended in good surgical candidates and leads to improved long-term survival. Radiation therapy is a viable option in patients with residual tissue near vital organs.[27](B2)

There is a lack of strong evidence to support the role of upfront high-dose chemotherapy followed by autologous stem cell rescue. However, this modality could be considered for high-risk disease subtypes and in cases of early relapse.[2]

Relapse after completing therapy can occur. A retrospective study of 79 cases of mediastinal germ cell tumors found that only 11% of patients were found to be disease-free in the long term. Thus, the second round of chemotherapy is warranted in most of these patients, although clear guidelines for an optimal second-line chemotherapy regimen have not been outlined. Irrespective of the chemotherapy regimen used, studies show very poor cure rates (5% to 10%) in the salvage therapy setting.[28][29](B2)

Differential Diagnosis

  • Lymphoma
  • Thymoma
  • Thymic carcinoma
  • Sarcoma 
  • Tuberculosis
  • Mediastinal goiter
  • Thymolipoma

Surgical Oncology

Upfront surgery is considered the best therapeutic approach for mature teratoma-type mediastinal germ cell tumors, without very high-risk features, including elevated tumor markers.[2][1] Seminomatous germ cell tumors are very sensitive to chemotherapy, and there is a limited role for surgical intervention in these tumor subtypes. 

Surgery for residual disease after chemotherapy is considered the standard of care and is timed based on the normalization of tumor markers and in those patients where the disease is limited to one site.[11] 

Prognosis

Negative prognostic factors include non-seminomatous germ cell tumors, increased age, lung metastasis, and elevated tumor markers(AFP, B-hCG, LDH). Mediastinal seminomatous germ cell tumors had a 5-year survival of 72% to 100%, compared to 48% to 65% in non-seminomatous germ cell tumor patients. The most favorable outcome for non-seminomatous malignancy was noted in young patients (under 29 years of age) with normal B-hCG levels. Nonpulmonary visceral metastasis is associated with a poorer prognosis. In seminomatous tumors without pulmonary involvement, the 5-year survival rate is more than 90%.[5][6][10][30][31]

According to the recent update from the International Germ Cell Cancer Collaborative Group, LDH greater than 1.5 times the upper limit of normal was associated with adverse prognosis in patients with seminomatous mediastinal germ cell tumors.[32]

Complications

During the course of the disease, mediastinal gem cell tumors can metastasize into surrounding structures. Common sites of metastasis are adjacent structures, including 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 be noted as possible complications in managing mediastinal germ cell tumors. 

Consultations

Management of mediastinal germ cell tumors requires a multi-disciplinary approach consisting of close collaboration between thoracic surgery, surgical oncology, medical oncology, pulmonology, radiology, pathology, and palliative care. 

Deterrence and Patient Education

Mediastinal germ cell tumors are thought to arise from the abnormal migration of germ cells during embryogenesis. Younger males are most commonly affected. Biomarker screening (AFP, B-hCG, LDH) is necessary for patients with an anterior mediastinal mass, even when symptoms are absent. Screening for Klinefelter symptoms is required 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 germ cell tumors are more common than mediastinal seminomatous germ cell tumors.
  • Non-teratoma non-seminomatous variants have the worst prognosis and require chemotherapy, followed by surgical resection. 
  • Relapses can occur after therapy, and second-line chemotherapy results in very low cure rates.

Enhancing Healthcare Team Outcomes

Identifying and managing mediastinal germ cell tumors requires an interprofessional team of primary care clinicians, pulmonologists, radiologists, medical/surgical oncologists, thoracic surgeons, and oncology-specialized nurses and pharmacists. Mediastinal gem cell tumors have high 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 affects pulmonary structures or creates respiratory complications. Discussion with radiologists is key to identifying 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. All clinicians must maintain accurate and updated patient records so everyone involved in the case has the most up-to-date patient data from which to make treatment decisions.

Nursing plays a crucial role in the interprofessional management of these patients. They will assist with patient assessment and during surgery, counsel patients, and often serve as the liaison point for the various specialties involved in the case. Pharmacists will assist in chemotherapy regimen selection, verify dosing and perform medication reconciliation, alerting the care team of any discrepancies or concerns they may encounter. Prompt consultation and close communication between the interprofessional team are necessary to achieve the best patient outcomes. [Level 2]

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