Introduction
Background
Germ cell tumors occur most frequently in the gonad, but in rare cases, they occur in extragonadal locations, usually in or near the midline. A variety of extragonadal germ cell tumors are known. The mediastinum is the most common extragonadal location. In adults, approximately 10-15% of mediastinal tumors are germ cell tumors; in children, 25% of mediastinal tumors are germ cell tumors. Germ cell tumors derive from germ cell rest remnants in the mediastinum.
Germ cell tumors may be benign or malignant. Benign varieties include benign teratoma and teratodermoids. Malignant tumors include seminomas and nonseminomatous tumors (malignant teratomas). Nonseminomatous tumors are further classified as teratocarcinomas, choriocarcinomas, embryonal carcinomas, and endodermal sinus or yolk-sac tumors. About 80% of mediastinal germ cell tumors are benign; these occur with equal frequency in males and females. Malignant tumors are predominant in men; the male-to-female ratio is 9:1. Benign germ cell tumors are termed teratomas or dermoids if they are primarily solid. Some tumors are predominantly cystic; these are referred to as epidermoid or dermoid cysts. Most patients are men 20-40 years of age.
About one third of patients are asymptomatic. Symptoms, when present, are related to the size of the lesion. Human chorionic gonadotropin (HCG) levels are elevated in 7-18% of patients, but alpha-fetoprotein (AFP) levels are usually normal. Metastatic spread involves the regional lymph nodes, lungs, and bone. The neoplasm is highly chemosensitive and radiosensitive, and 5-year survival rates greater than 75% are not uncommon.
Malignant germ cell tumors are subdivided into seminomas and malignant teratomas (nonseminomatous tumors). Seminoma is the second most common mediastinal GCT. The imaging features of seminomas are usually those of a large, well-marginated, homogeneous, anterior mediastinal mass with soft tissue opacity or attenuation that shows minimal contrast enhancement. Calcification is exceptional. Embryonal carcinoma, endodermal sinus tumor, choriocarcinoma, and combinations of these histologic types constitute nonseminomatous germ cell tumors. These lesions occur almost exclusively in men. Approximately 20% of nonseminomatous malignant mediastinal germ cell tumors are associated with Klinefelter syndrome (47,XXY). AFP levels are elevated in 80% of patients and are usually associated with endodermal sinus tumor or embryonal cell carcinoma. HCG levels are elevated in 30% of patients.
A combination of radiotherapy and chemotherapy is the treatment of choice; 5-year survival is about 50%. These patients are at risk for concurrent hematologic malignancy that is unrelated to chemotherapy. Imaging features include a large, anterior mediastinal mass that may contain large areas of hemorrhage and necrosis. The surrounding fat planes are typically obliterated.1,2,3,4,5,6,7,8,9,10
Smooth, well-defined anterior mediastinal tumor with heterogeneous attenuation associated with calcific intratumoral nodules suggests a mediastinal teratodermoid. Note also the curvilinear calcification.
Contrast-enhanced axial CT scan shows an ill-defined anterior mediastinal mass with irregular borders that is infiltrating the mediastinal fat. CT-guided needle biopsy revealed a mediastinal seminoma.
Patient with asymmetrically placed anterior mediastinal mass. Lateral linear tomogram shows a well-defined, uniformly attenuating mass (not shown), sonogram shows a mass with smooth, uniform echotexture. The patient had not undergone surgery, and findings on follow-up over several years showed little change.
Pathophysiology
Regarding germ cell tumor pathophysiology, several theories explaining the development of benign teratomas have been postulated. Some investigators suggest that teratomas are derived from cells of the third branchial cleft, whereas others believe they derive from totipotential cells, which are capable of forming tissues from at least 2 of the 3 primitive germ cell layers. One theory suggests that these tumors arise from germ cell nests located along the urogenital ridge that fail to migrate to the gonads during embryonic development.
The origin of seminomas and malignant teratomas is still debated. One theory postulates their development from extragonadal or extraembryonic yolk-sac germ cells whose normal migration along the urogenital ridge to the gonad is halted in the mediastinum. A second theory maintains that they originate from somatic cells from the branchial cleft that are associated with the developing thymus.
Tumors and cysts may have a local mediastinal mass effect and may produce compressive symptoms. These effects are more obvious in children than in adults. An enlarging tumor can compress parts of the airways, esophagus, or the right heart and great veins, which may produce symptoms. Some cystic tumors become infected; infection may also occur secondarily in nearby structures, such as the lungs, as a result of local compression or obstruction.
Malignant mediastinal tumors may also cause local compressive symptoms, but they most often produce symptoms by invading adjacent structures. Tumors may invade the major airways and lungs, esophagus, superior vena cava (SVC), pleura, and chest wall, as well as any adjacent intrathoracic nerve. Such invasion can cause obstructive pneumonia and hemoptysis, dysphagia, SVC syndrome, pleural effusion, vocal cord paralysis, Horner syndrome, paraplegia, diaphragmatic paralysis, and pain in the distribution of intercostal nerves.
Some mediastinal tumors produce bioactive substances that cause systemic symptoms. Nonseminomatous mediastinal germ cell tumors may produce alpha-fetoprotein (AFP) and/or beta-human chorionic gonadotropin (bHCG). Approximately 10% of seminomas produce bHCG, which may cause gynecomastia and precocious puberty. Serum lactate dehydrogenase levels are usually elevated in patients with seminoma.
Mediastinal seminomas share several characteristics with seminomas occurring in the gonads. Seminomas often produce cystic changes and cause reactive lymphoid follicular hyperplasia, granulomatous reaction, and fibrosis. The cellular component of the tumors consists of sheets or lobules of medium-sized round or polygonal cells with clear cytoplasm separated by fine septa. Lymphocytes often infiltrate cellular areas. Individual cells have hyperchromatic nucleoli. Mitoses are frequent.
Teratomas often are classified as mature, immature, or as having malignant components. Mature teratomas are commonly cystic and possess well-differentiated tissues from the 3 germ cell layers and often contain cartilage, fat, and glandular and squamous cell epithelium.
Mature teratomas are common. Immature teratomas comprise mature epithelial and connective tissues, as well as immature areas with neuroectodermal and mesenchymal elements. These tumors are generally well defined by a wall of fibrous tissue, which may become calcified. Cystic tumors may contain hair and sebaceous material.
Malignant teratomas are classified by the type of additional malignant components and include the germ cell tumor type, adenocarcinoma or squamous carcinoma, the mesenchymal or sarcomatous type, or a combination of a variety of malignant cells.
Choriocarcinomas often have large areas of hemorrhage and necrosis and consist of large pleomorphic, multinucleated cells with ample eosinophilic cytoplasm known as syncytiocytotrophoblasts and cytotrophoblasts, which are polygonal cells with a clear cytoplasm, round nuclei, and conspicuous nucleoli.
Embryonal carcinomas are composed of highly atypical cells that have a moderate amount of cytoplasm, large nuclei, conspicuous nucleoli, and numerous mitotic figures. Considerable variation is observed in the cell types in a single specimen; they vary from primitive, undifferentiated cells to an organized, glandular configuration. The tumor may be solid or trabecular.
Considerable histologic variation is noted in yolk-sac or endodermal sinus tumors. These may be the endodermal sinus type, comprising a labyrinthine or festoon pattern and Schiller-Duval bodies; the glandular-alveolar type; the microcystic type; the myxomatous type; the papillary type; the polyvesicular-vitelline type; the hepatoid type; the solid type; the clear cell type; the endometrioid type; the parietal type; the sarcomatoid type; the macrocystic type; and the intestinal type. Several of these histologic patterns may be found in the same tumor.
The incidence of hematologic malignancies is increased in patients with nonseminomatous mediastinal germ cell tumors, particularly those with serologic or histologic evidence of yolk-sac elements. The 2 most common hematologic neoplasms in this syndrome are acute megakaryoblastic leukemia and malignant histiocytosis. Cytogenetic abnormalities have not yet been identified, but the finding of the marker chromosome isochromosome (12p) in the mediastinal germ cell tumor and associated leukemic blasts in 1 patient suggest that these tumors may arise from a common progenitor cell.
Germ cell tumors are associated with Klinefelter syndrome (47,XXY). In patients with Klinefelter syndrome, the relative risk of having a malignant mediastinal germ cell tumor is 66.7. At least 8% of male patients with primary mediastinal tumors have Klinefelter syndrome (50 times the expected frequency).
No specific staging system has been established for primary mediastinal germ cell tumor, though a well-established staging system has been described for gonadal germ cell tumors. The staging system for gonadal germ cell tumors is determined by using the tumor, nodes, and metastases (TNM) classifications, as well as an additional category, S, which denotes the serum tumor-marker status. Well-established systems are also available for staging other mediastinal tumors, such as thymomas, lymphomas, and neuroblastomas. These staging systems can be applied to mediastinal germ cell tumors.
Frequency
United States
The mediastinum is the most common extragonadal site for germ cell tumors; germ cell tumors account for approximately 10-15% of mediastinal masses in adults and 25% of mediastinal masses in children. Germ cell tumors are the fourth most common tumors in the mediastinum, after nondermoid cysts, neurogenic tumors, and lymphomas. About 80% of mediastinal germ cell tumors are benign. Seminomas represent approximately 20% of primary mediastinal germ cell tumors and about 3% of all mediastinal tumors.
International
No data suggest that the frequency of germ cell tumors worldwide differs from that in the United States.
Mortality/Morbidity
Therapy for germ cell tumors varies according to cell type and may include surgery, radiation therapy, or chemotherapy. The prognosis is excellent for patients with mature teratoma, good for patients with pure seminoma, and poor for patients with nonseminomatous malignant or mixed germ cell tumors.
The prognosis after resection of a mediastinal tumor varies widely, depending on the type of lesion resected. After resection of mediastinal cysts and benign tumors, the prognosis is generally excellent. Germ cell tumors included in this group are benign teratomas and dermoid cysts. The prognosis after treatment of malignant mediastinal tumors depends on the type of lesion, its biologic behavior, and the extent of disease.
Primary treatment of seminoma is generally radiotherapy or chemotherapy. A number of series report cure rates of approximately 60-65% after primary radiation therapy; long-term survival rates are as high as 87% when chemotherapy is the primary treatment. Residual disease is radiographically present in 10-20% of patients after initial systemic treatment. The preferred way to manage this problem is somewhat debated. In some centers, close observation is advocated, because many residual masses simply represent fibrotic changes. However, in many centers, an aggressive approach involving surgical resection is taken in addressing radiologic evidence of residual disease.
For malignant teratomas, the long-term (>24 mo) disease-free survival rate after systemic chemotherapy is about 42%.
Race
No racial predilection is reported for mediastinal germ cell tumors.
Sex
Benign mediastinal germ cell tumors occur with equal frequency in males and females; malignant tumors occur predominantly in men, with a ratio of 9:1.
- Mature teratomas occur with equal frequency in men and women, though a slight female predominance may be observed.
- Mediastinal seminomas occur almost exclusively in men, but several histologically verified cases have been described in women.
Age
In children and infants, neurogenic tumors, dermoid cysts, and foregut cysts are the most common anterior mediastinal masses. Germ cell tumors rank third, followed by lymphomas; lymphangiomas and angiomas; tumors of the thymus; and pericardial cysts. Germ cell tumors account for about 25% of the mediastinal tumors found in children.
- In adults, germ cell tumors occur most commonly between the second and fourth decades of life; they occur in equal numbers in males and females.
- Most patients with mature mediastinal teratomas are younger than 40 years (mean age, 24 y).
- Most patients with mediastinal seminomas are 20-40 years of age.
Anatomy
The mediastinum is anatomically divided into superior, anterior, middle, and posterior compartments.
The classic subdivision of the mediastinum is not useful for cross-sectional imaging. Therefore, some investigators have altered the division so that the esophagus and all tissue posterior to it are included in the posterior mediastinum. This division is extremely useful in the clinical differential diagnosis of specific masses or neoplasms. For practical purposes, the anterior mediastinum extends from the posterior surface of the sternum to the anterior surface of the pericardium and great vessels. It is normally occupied by the thymus, fatty tissue, and lymph nodes. The vast majority of teratomas and other germ cell tumors (GCTs) arise in the anterior mediastinum. The second most common location for mediastinal GCTs is the posterior mediastinum.
Presentation
Physical examination
Most mediastinal solid tumors and cysts are asymptomatic and are incidentally found on a chest radiograph or other imaging study of the thorax performed for reasons unrelated to an investigation of germ cell tumors. Approximately one third of adults with a mediastinal tumor or cyst have symptoms; two thirds of children present with symptoms, which are usually related to the respiratory tract. In adults, asymptomatic masses are most likely to be benign.
In general, symptoms associated with the respiratory tract are predominant in children because, in children, the airway is malleable and the small thorax makes the effects of compression more obvious than is the case with adults. Respiratory symptoms include persistent cough, dyspnea, and stridor. If the location and size of the mass result in partial or complete obstruction, obstructive pneumonia can also occur.
In adults, benign lesions may produce symptoms associated with compression; this occurs less frequently in children. Compared with benign lesions, malignant tumors more commonly produce obstructive symptoms as a result of tumor invasion of normal mediastinal structures.
Mediastinal tumors that produce bioactive substances may be associated with gynecomastia and precocious puberty.
Systemic symptoms of malignant tumors, such as weight loss, fever, malaise, and vague chest discomfort, are more common in children than in adults, but they do occur in some adults.
Superior vena cava obstruction may cause more severe symptoms than those commonly associated with malignancy (eg, cough, dyspnea, stridor, dysphagia). Invasion of the chest wall and/or pleura by a malignant tumor may produce persistent pain and pleural effusions. Invasion of mediastinal and/or thoracic nerves may produce local and referred pain, as well as various other findings, such as hoarseness from recurrent nerve involvement, diaphragmatic paralysis from phrenic-nerve involvement, Horner syndrome from autonomic-nerve invasion, and even motor paralysis from direct spinal-cord involvement. Pain in the shoulder or upper extremity may occur as a result of invasion of the ipsilateral brachial plexus.
Various hematologic malignancies and other syndromes are occasionally observed with nonseminomatous germ cell tumors of the mediastinum. Of note, this association has not been described with gonadal germ cell tumors.
Laboratory studies
High levels of beta-human chorionic gonadotropin (bHCG) are commonly found in patients with nonseminomatous germ cell tumors. Serum levels of bHCG greater than 500 mg/mL are said to be diagnostic of a nonseminomatous germ cell tumor. Only 10% of patients with seminomas have elevated bHCG levels; such levels are usually lower in patients with germ cell tumors than in patients with nonseminomatous tumors.
The alpha-fetoprotein (AFP) level is also commonly elevated in individuals with nonseminomatous germ cell tumors, regardless of type. Serum levels greater that 500 mg/mL are virtually diagnostic of nonseminomatous germ cell tumors. The AFP level is usually normal in patients with a pure seminoma. AFP normalization may be used as a prognostic factor for embryonal carcinoma of mediastinal origin after chemotherapy, as an index of residual malignancy.
Tumor rejection antigen 1 (TRA-1-60) and CD30 are believed to be useful in the monitoring of patients with embryonal cell carcinoma.
Differential diagnosis and other problems to be considered
Anterior mediastinal cystic masses
Cystic mediastinal lesions are well-marginated, round, epithelium-lined masses that contain fluid. The relatively common anterior mediastinal cystic masses include congenital benign cysts. Examples are mature cystic teratomas; lymphangiomas; and bronchogenic, esophageal duplication, neurenteric, pericardial, and thymic cysts.
Many solid anterior mediastinal tumors undergo cystic degeneration. Examples are thymomas, Hodgkin disease, germ cell tumors, mediastinal carcinomas, lymph node metastases, and nerve root tumors. Cystic degeneration especially occurs after radiation therapy and chemotherapy.
Intrapericardial teratoma is a rare tumor that may mimic other mediastinal tumors. The tumor is generally benign and originates from the 3 germinal layers. About 60% of patients with this tumor present in the first 2 years of life. Severe cardiorespiratory distress, which results from mediastinal compression, and pericardial effusion are the main clinical symptoms. Echocardiographic and cineangiographic findings confirm the diagnosis, and early surgical removal is recommended.
Mediastinal carcinoid tumors are rare. They are frequently malignant. The course of disease is different from that of the more benign anterior mediastinal tumors. Imaging usually does not help in differentiating these tumors; tissue diagnosis is usually required.
Thymic neoplasms are a common type of anterior mediastinal mass; they may be benign or malignant. Thymoma and thymic carcinoma are epithelial malignancies with distinct clinicopathologic features. True thymic hyperplasia and thymic lymphoid hyperplasia may enlarge the thymus and simulate a neoplasm. Thymic carcinoid is a rare, aggressive neuroendocrine malignancy associated with multiple endocrine neoplasia type 1. Thymolipoma is a benign neoplasm. Hodgkin and non-Hodgkin lymphoma may primarily or secondarily involve the thymus.
Thyroid and parathyroid ectopic tissue and associated masses
Thyroid tissue masses in the anterior mediastinum may arise either from ectopic thyroid tissue or from retrosternal extension of a cervical thyroid gland into the mediastinum. Although rare, goiter, adenoma, carcinoma, and lymphoma may all arise in ectopic thyroid tissue. Ectopic parathyroid tissue is occasionally found in the superior and/or anterior mediastinum adjacent to the thymus; this is the most common location for ectopic parathyroid adenomas. Radionuclide scans provide a near–tissue-specific diagnosis, though cross-sectional imaging may be required to improve anatomic definition.
Cystic hygromas
Most mediastinal cystic hygromas are extensions of cervical lesions. It is rare for cystic hygromas to be confined solely to the mediastinum. The cyst may be unilocular or multilocular and of variable size. The cyst wall is of variable thickness; it may be fibromuscular and contain mural thrombi. These lesions are known to be associated with chromosomal and other congenital anomalies. Cystic hygromas grow with the child but may suddenly increase in size as a result of infection or hemorrhage. Spontaneous shrinkage may also occur. On clinical examination, hygromas appear as smooth soft tissue masses; they are usually found in patients younger than 2 years.
Pancreatic pseudocysts
Extension of the pancreatic pseudocyst into the mediastinum is a rare but serious complication of acute pancreatitis. The clinical presentation may be misleading, and a correct diagnosis is necessary for instituting appropriate management.
The most common site of a pseudocyst is the lesser sac. However, an enlarging pseudocyst dissects along the planes of least resistance and may extend through potential communication sites between the thorax and abdomen, such as the aortic and esophageal hiatus into the middle or posterior mediastinum or, more rarely, the foramen of Morgagni into the anterior mediastinum. The proteolytic pancreatic juices may also spread into the mediastinum as a result of the erosion of the diaphragm itself.
Paragangliomas
Paragangliomas (chemodectomas) arise from paraganglia tissue in the paravertebral sympathetic chain along the aorta, the aortopulmonary window, or the vagus nerve. These are rare, benign, nonfunctioning tumors. Approximately 10% of lesions behave aggressively and are typically locally invasive.
On CT scans, paragangliomas appear as well-marginated, homogeneous, soft tissue masses that are intensely enhancing after the administration of iodinated contrast material. These tumors are commonly para-aortic or paraspinous. However, the tumor may occur in the aortopulmonary window, along the recurrent laryngeal nerve, and near the proximal aspect of the subclavian arteries. The tumor may undergo extensive cystic degeneration or hemorrhage internally, which may result in areas of low attenuation.
On T1-weighted MRIs, the lesions are of heterogeneous signal intensity; areas of signal void are present as a result of flowing blood. These tumors have high signal intensity on T2-weighted images.
Hemangiomas
Hemangiomas should be considered in the differential diagnosis of well-marginated mediastinal masses that have heterogeneous attenuation on CT scans, central enhancement after the administration of contrast material, or punctate calcification. Centrally increased attenuation is observed more frequently after the administration of a bolus of contrast material than after slow infusion. Radiologically demonstrable calcification may be punctate or present in phleboliths.
Sternal tumors
Sternal tumors may mimic other mediastinal tumors. Most sternal tumors represent metastases from breast, lung, kidney, or thyroid. Primary sternal tumors are rare. Chondrosarcoma is the most common primary malignant sternal tumor; osteosarcoma is rare. Chondrosarcomas typically arise near the costochondral junction.
CT is superior to MRI in demonstrating foci of calcification in chondrosarcomas and osteosarcomas. However, because of its great ability to distinguish tumor from normal soft tissue, MRI is the modality of choice for assessing the extent of chest wall tumors and their relationship to adjacent structures.
Mediastinal lymphomas
Most histologic types of lymphoma may involve the mediastinum; however, some types of lymphomas have a predilection for the mediastinum; these include the following: (1) nodular sclerotic Hodgkin disease, which is classically seen in young women; (2) lymphoblastic lymphoma, which occurs in children and can grow rapidly; and (3) a diffuse large cell type of lymphoma that can occur in patients of any age.
Preferred Examination
Recent major developments have led to improvements in the diagnosis and management of primary mediastinal tumors. New diagnostic techniques and therapies have led to more objective preoperative diagnoses and better long-term results. The advent of techniques such as radioisotope scanning with monoclonal antibodies, hormonal assay, electron microscopy, fine-needle aspiration (FNA), CT, and MRI has had a major effect on patient care.
Conventional radiographs still have a major role in the initial diagnosis of a mediastinal mass.
Ultrasonography is advancing, particularly in the pediatric age group, and it is highly sensitive in differentiating cystic from solid mediastinal masses.
Echocardiography is an invaluable tool for differentiating tumors arising from the pericardium and/or myocardium from other tumors.
Image-guided preoperative biopsy allows for better planning of treatment options.
Radionuclide imaging may provide a near–tissue-specific diagnosis for functioning endocrine tumors, such as mediastinal carcinoid, aberrant thyroid and/or parathyroid tissue, and pheochromocytomas.
Angiography is occasionally needed to evaluate anterior mediastinal vascular malformations and/or aneurysms and to differentiate these from other mediastinal tumors.11,12,13,14,15,16,17,18,19,20
Limitations of Techniques
The appearances of an anterior mediastinal mass on chest radiographs are nonspecific, and the differential diagnosis is wide. Differentiation between benign lesions and malignant lesions may not be possible. Subtle calcification and bone erosions may be missed on radiographs. Underlying masses with pleural and pericardial effusions may not be detected. Fat may be obscured by tumoral hemorrhage or rupture, and a false diagnosis of a malignant lesion may be made. The vascularity of mediastinal tumors cannot be assessed on conventional radiographs. A standard posteroanterior (PA) chest radiograph may be difficult to obtain in ill patients, and in young children, anterior mediastinal masses may be obscured on anteroposterior (AP) radiographs with mediastinal magnification.
Although CT is the examination of choice for the assessment of anterior mediastinal masses, it has limitations. CT can be invasive, and sedation or general anesthesia may be required in young patients. In addition, CT delivers a radiation dose to the patient. Patients may be allergic to iodinated contrast medium, which should be used with caution in patients with renal failure.
Like other cross-sectional imaging studies, MRI is nonspecific in terms of tissue diagnosis of anterior mediastinal masses. The differential diagnosis of anterior mediastinal masses is wide, and false-positive diagnoses are possible. MRI is expensive and is not universally available. Patients with claustrophobia and young children may need sedation or general anesthesia. MRI cannot be used for patients in whom certain types of metallic implants, clips, cardiac pacemakers, or ferromagnetic foreign bodies are present. For image-guided biopsy, expensive MRI-compatible equipment may be needed.
Ultrasonography is operator dependent, and access to the anterior mediastinum may be difficult because of the thoracic bony cage and lungs.
Angiography is invasive and poses a minor morbidity risk.
Although radionuclide scanning is more tissue specific than other imaging modalities, false-positive results are possible, and uptake may occur in a variety of normal, inflammatory, and neoplastic tissues.
Differential Diagnoses
Other Problems to Be Considered
Thyroid and parathyroid ectopic tissue and associated masses
Cystic hygromas
Extralobar sequestration
Pancreatic pseudocysts
Mediastinal lipomatosis
Hernias
Neural tumors
Paragangliomas
Hemangiomas
Sternal tumors
Mediastinal lymphoma — thymoma, neuroblastoma, seminoma, metastatic small cell carcinoma
Anterior mediastinal cystic masses — Congenital benign cysts such as mature cystic teratomas; lymphangiomas; and bronchogenic, esophageal duplication, neurenteric, pericardial, and thymic cysts
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Keywords
germ cell tumors, germ cell neoplasm, mediastinal germ cell tumor, GCTs, Klinefelter syndrome, teratoma, seminoma, epidermoid cyst, dermoids, dermoid cyst, mediastinal dermoid
