Pulmonary Medicine

Mediastinal Tumors

What every physician needs to know

MEDIASTINAL COMPARTMENTS

The mediastinum is an anatomic space in the chest located between the two pleural spaces, behind the posterior sternal table, extending superiorly to the thoracic inlet, posteriorly to the anterior longitudinal ligament of the spine and paraspinal sulci, and inferiorly to the diaphragm.

The three-compartment model proposed by Shields (Figure 1) defines the anterior compartment, which lies between the posterior aspect of the sternal plate and the anterior aspect of the great vessels, and contains the thymus, the internal mammary vessels, the extra-pericardial aorta and its branches, the great veins, and lymphatic tissue (a summary of anterior mediastinal masses is found in Table II). The middle (visceral) compartment lies between the anterior aspect of the pericardium and the ventral aspect of the thoracic spine and is defined as the heart, the intrapericardial great vessels, the pericardium, and the trachea (a summary of the middle mediastinal masses if found in Table III). Finally, the posterior (paraventral sulcus) compartment, which includes the spine and the costovertebral sulci, is defined as the esophagus, the vagus nerves, the thoracic duct, the sympathetic chain, and the azygus venous system (a summary of the posterior mediastinum is found in Table IV.

Figure 1.

Mediastinal compartments

Table II.

Summary of anterior mediastinal masses

Table III.

Summary of Middle compartment tumors

Table IV.

Summary of Posterior compartment tumors

Classification:

THE ANTERIOR MEDIASTINUM

  1. Thymic Masses

  2. Lymphoma

  3. Germ Cell Tumor

  4. Esophageal Tumor

  5. Neuroendocrine Tumor

MIDDLE MEDIASTINUM

  1. Esophageal Tumor

  2. Parathyroid Adenoma

  3. Bronchogenic Cyst

  4. Esophageal Ductal Cyst

  5. Tracheal Tumor

POSTERIOR MEDIASTINUM

  1. Neurogenic tumors

  2. Thymic neuroendocrine tumor

Thymoma:

There are several clinical and pathologic classification systems for thymomas. The most widely used clinical classification scheme is the Masaoka classification (Table V), while histologic classification systems include the Muller-Hermelink (Table VI) and the World Health Organization (WHO) systems (Table VII).

Table V.

Masaoka: Clinical classification system

Table VI.

Muller-Hermelink subtypes: Pathologic classification

Table VII.

WHO classification: Pathologic classification system

Current staging of Hodgkin’s Lymphoma is done through the Ann Arbor Staging and Cotswolds modifications (Table VIII). This staging not only aids in classification of Hodgkin’s Lymphoma, but also guides treatment.

Table VIII.

Lugano Classifications for Non-Hodgkin's Lymphoma

Current non-Hodgkin’s Lymphoma staging is based on revised classifications of the 1988 Cotswolds Modifications, called the Lugano Classification (Table IX).

Table IX.

Ann Arbor Staging of Hodgkin's Lymphoma with Cotswolds Modification

Are you sure your patient has a mediastinal tumor? What should you expect to find?

The initial evaluation of a patient with a mediastinal mass includes a thorough history and physical examination. Most patients with mediastinal masses are asymptomatic, and masses are incidentally found on imaging. CT scan imaging is more definitive. Symptoms may result from local compression or invasion of adjacent mediastinal structures. A history of a cough, chest pain or pressure, head and arm swelling (superior vena cava syndrome), and shortness of breath (pleural or pericardial effusion, tracheal involvement) should be ascertained. Fevers, night sweats, and weight loss should also be documented.

Thymoma

A thymoma (Figure 2) is a slow growing thymic epithelial tumor in which the epithelial component exhibits no overt atypia and retains histologic features specific to the normal thymus. Most tumors contain a proportion of epithelial cells and lymphocytes, although the majority of thymomas are completely encapsulated. Thirty-four percent invade through the capsule and may extend into surrounding structures, including the thymus, pleura, pericardium, and lung. Distant spread can occur to the pleura, the diaphragm, and occasionally the mediastinal lymph nodes. The pleura is the most common site for distant spread and recurrence. Lymph node and hematogenous spread is rare.

Figure 2.

Thymoma seen on sagittal CT image

The majority of patients diagnosed with thymomas are asymptomatic at the time of presentation, although approximately a third present with a history of chest pain, cough, or dyspnea attributed to compression of adjacent structures.

Often thymomas present alongside other diseases such as myasthenia gravis, polymyositis, systemic lupus erythmatosis, rheumatoid arthritis, thyroiditis, Sjogren’s syndrome, SIADH, pre red cell aplasia, and hypogammaglobilinemia.

Myasthenia gravis (MG), the most common paraneoplastic syndrome, is reported in 30-50% of patients with thymomas. MG is an autoimmune neuromuscular disease caused by circulating autoantibodies that block acetylcholine receptors at the postsynaptic membrane. Complete remission of MG following thymectomy occurs in approximately 36% of cases. The presence of a thymoma does not affect the remission rate.

Pure red cell aplasia (PRCA) occurs due to a loss of reticulocytes, probably because of IgG antibody-inhibiting red blood cell synthesis that results in a normoblastic, normochromic anemia with an associated absence of reticulocytes. PRCA is found in 5 to 15% of people with thymomas. The spindle cell variant of thymoma is commonly seen in PRCA. It has recently been shown that thymoma associated PRCA responds very well to cyclosporin and cyclosporin-containing regimens. Most patients who present with PRCA secondary to thymoma do undergo thymectomy,

Hypogammaglobulinemia is an uncommon paraneoplastic syndrome that occurs in less than 5% of patients with thymoma. Good's syndrome (thymoma with hypogammaglobulinemia) is a rare cause of combined B and T cell immunodeficiency in adults. In patients with thymoma, the cause and pathogenesis of this syndrome is unknown. Typically, the hypogammaglobulinemia does not respond to thymectomy/thymoma resection, and the long-term prognosis is not favorable.

Thymic Carcinoma

Thymic carcinomas are aggressive epithelial tumors associated with a high incidence of local invasion and distant metastases (lung, liver, brain, and bone). Symptoms are more common than in thymomas, and patients frequently present with cough, chest pain, and shortness of breath.

The thymic carcinoma classification is based upon histologic characteristics that correlate with survival. The two categories of thymic carcinomas are low-grade (squamous, mucoepidermoid, and basaloid, with a median survival of twenty-nine months) and high-grade (sarcomatoid, clear cell with a median survival of eleven months).

Thymic carcinomas, which have a similar appearance to thymomas on CT scan and MRI, spread along pleural and pericardial surfaces, and subsequent loss of normal tissue planes is common with these tumors. Malignant cytologic features, including cell atypia, necrosis, and mitotic figures, distinguish this tumor from invasive thymomas.

Hodgkins Lymphoma

Hodgkins lymphoma represents approximately 50-70% of mediastinal lymphomas, with an incidence of 2-4 cases per 100,000 people per year. Hodgkins affects the anterior mediastinal compartment more often than non-Hodgkin's lymphoma does (46 vs. 13%), although it is rare for either to be localized to the mediastinum.

Approximately 20-30% of patients with Hodgkins lymphoma experience B symptoms (fevers, night sweats, and weight loss), and patients with mediastinal involvement may develop chest pain, cough, and shortness of breath. Involvement of local structures may result in SVC syndrome, resulting in head and upper extremity swelling. Supraclavicular or cervical adenopathy is common in these patients, so a careful head and neck exam is warranted in all patients with a mediastinal mass.

Thymolipoma

Thymolipomas are rare, slow-growing tumors seen in adults, with males and females affected equally. Histologically, these tumors contain mature adipocytes and normal thymic cells. The tumors have been associated with thymic paraneoplastic syndromes, including red cell aplasia, hypogammaglobulinemia, and aplastic anemia. Most often they are found incidentally on chest X-ray, although patient often times present with dyspnea, cough, and chest pain.

Thymic cyst

Two types of cysts can occur: 1) Congenital thymic cysts are derived from remnants of thymopharyngeal duct and tend to be unilocular. They can occur anywhere along the course of the embryonic thymic gland, from the angle of the mandible to the mediastinum; 2) Acquired thymic cysts are associated with inflammation or an inflammatory neoplasm (e.g., Hodgkins lymphoma) and tend to be multilocular.

Hodgkins Lymphoma

Hodgkin’s lymphoma is a lymphoma of B cell origin. The four subtypes of Hodgkins lymphoma (HL), based on the Reed-Sternberg cell morphology and the type of infiltrate on biopsy, are nodular sclerosing, lymphocyte-rich, mixed cellularity, and lymphocyte-depleted. Nodular sclerosing, the most common subtype, has a predilection for the thymus. The other subtypes typically spare the thymus and involve other lymph nodes in the mediastinum. HL affects the anterior mediastinal compartment more often than non-Hodgkin's lymphoma does (46% vs. 13%), although it is rare for either to be localized to the mediastinum.

Approximately 20-30% of patients with Hodgkins lymphoma experience B symptoms (fevers, night sweats, and weight loss), and patients with mediastinal involvement may develop chest pain, cough, and shortness of breath. Involvement of local structures may result in SVC syndrome. Supraclavicular or cervical adenopathy is common in these patients.

Non-Hodgkins Lymphoma

Non-Hodgkins lymphoma (NHL) represents 15 to 25% of mediastinal lymphomas. Two variants of NHL, lymphoblastic lymphoma and large B-cell lymphoma, have a predilection for the anterior mediastinum. Lymphoblastic lymphoma arises from thymic lymphocytes and is highly aggressive. Bone marrow involvement in this variant is common and may distinguish it from a primary mediastinal B-cell lymphoma.

Clinical presentation of patients with non-Hodgkins lymphoma varies according to the location of the tumor and its rate of growth in the mediastinum. Large, infiltrating tumors may lead to respiratory difficulties from tracheal invasion, SVC syndrome from vascular invasion/compression, and chest pain from chest wall involvement.

Germ cell tumors/Teratoma

Primary mediastinal germ cell tumors arise from primitive germ cells that failed to migrate during embryonic development. They represent 15% of anterior mediastinal masses. Histologically, they appear identical to primary gonadal tumors. Although they arise primarily in the mediastinum, a mediastinal mass in a young adult should prompt an evaluation for a primary gonadal tumor.

Mature teratomas are the most common primary mediastinal germ cell tumor (60-70% of mediastinal germ cell tumors). These tumors contain tissue from at least two of the three germ cell layers. Although they do not usually cause symptoms, they may occasionally compress local structures, resulting in chest pain, cough, or shortness of breath. Rupture of tumor precipitated by the presence of digestive enzymes have been reported. Mature teratomas are histologically well defined and benign, but rare cases of malignant transformation of mature teratomas have been reported. Immature teratomas contain fetal tissue, and although they have a good prognosis in children, they can recur or metastasize in adults.

Primary mediastinal seminomas represent 25-50% of malignant mediastinal germ cell tumors. Symptoms are common and often include dyspnea, cough, substernal pain, weakness, weight loss, and gynecomastia. Approximately 10% of patients present with SVC syndrome. Confirmation of the primary nature of these tumors requires that there be no retroperitoneal or testicular disease present.

Several types of non-seminoma mediastinal germ cell tumors (NSGCTs) have been identified, including embryonal cell carcinomas, endodermal sinus carcinomas, yolk sac tumors, choriocarcinomas, and mixed germ cell tumors. Symptoms, including chest pain, cough, fever, hemoptysis, and weight loss, are found at the time of presentation in 85% of patients primarily because of the large size of these tumors. NSGCTs are associated with a high rate of hematologic neoplasia not related to tumor treatment.

Thyroid/Substernal goiter

Mediastinal goiters represent 5-10% of all resected mediastinal masses. Although the majority of intrathoracic goiters are asymptomatic, some may cause symptoms related to airway or esophageal compression. In 80% of cases, the goiter extends into the prevascular space, while posterior extension along the trachea occurs in 20% of cases. Typically, the intrathoracic mass is contiguous with the thyroid tissue in the neck; however, it may appear discontinuous (connected by a thin stalk to the main thyroid); rarely, it contains no connection to the thyroid.

Esophageal Tumors

The two most common histologic types of esophageal cancers are squamous cell and adenocarcinoma. Historically, smoking has been associated with squamous cell cancer, often located in the proximal esophagus, while growing prevalence of gastroesophageal reflux disease has resulted in increased incidence of Barrett’s esophagus, which in turn is responsible for a higher incidence of adenocarcinoma. Squamous Cell carcinoma accounts for about 95% of esophageal cancers, with slowly growing numbers of adenocarcinoma.

Bronchogenic cyst

Bronchogenic cysts are foregut abnormalities that form during embryonic development. They are usually located adjacent to the trachea, bronchi, and the carina, although they are found in the lung parenchyma in approximately 15% of cases. Histologically, they are lined with ciliated, pseudostratified, columnar epithelium, and they frequently contain cartilage. Symptoms, which include cough, chest pain, and shortness of breath, occur in approximately 40% of patients. Bronchogenic cysts are more likely to produce symptoms in children than in adults, and they may be life-threatening in infants.

Parathyroid adenomas

Parathyroid adenomas may be found in ectopic locations in the neck and mediastinum. When located in the mediastinum, 80% are found in the anterior compartment and are encapsulated, round, and small (<3cm). Patients typically have an elevated blood parathyroid hormone level that normalizes after resection of the adenoma.

Esophageal Duplication Cyst

Esophageal duplication cysts are thought to develop during embryogenesis during vacuolization of the primitive muscle and submucosa of the esophagus. An aberrant vacuole that does not typically communicate with the new lumen may enlarge into an intramural or paraesophageal cyst.

Esophageal duplication cysts are often found in adults during evaluation for respiratory symptoms (cough, chest fullness, or discomfort) or upper GI complaints. Approximately 60% of these cysts occur in the distal esophagus, where swallowing difficulties are usually the presenting symptoms. Respiratory symptoms are more common in patients with proximal esophageal cysts (20% of cysts occur proximally) because of airway compression. Cyst rupture, infection, and hemorrhage have been reported. Malignant degeneration is rare.

Tracheal tumors

Tracheal tumors are an uncommon cause of a mediastinal mass, but most primary tracheal tumors in adults are malignant. The most common primary tumors of the trachea are squamous cell carcinomas (SCC) and adenoid cystic carcinoma. Primary SCC may be exophytic, ulcerative, or longitudinally infiltrating. As it grows, a tracheal tumor may invade local structures. The most common site of metastasis is local lymph nodes. Adenoid cystic carcinoma is the second most common tracheal tumor. Although these tumors tend to grow into the mediastinum, they tend to displace adjacent structures before invading them.

From half to two thirds of primary tracheal tumors are squamous cell carcinomas. Adenoid cystic carcinomas account for 10-15% of cases. Squamous cell carcinomas often present with hemoptysis due to ulceration and irritation of the mucosal surface. Adenoid cystic carcinomas often present with refractory wheezing.

Pericardial Cysts

Pericardial cysts are uncommon congenital mediastinal masses. They may also form as a result of pericarditis. The walls of the cyst are composed of connective tissue, and normally filled with fluid.

Neurogenic tumors

Neurogenic tumors are the most common posterior mediastinal tumors. They arise from peripheral nerves, lymph vessels, blood vessels, pericyte origin, adipose tissue, muscle, pluripotential mesenchyme, skeletal tissue, sympathetic ganglia (ganglioneuroma, ganglioneuroblastoma, and neuroblastoma), and (uncommonly) parasympathetic ganglia. Neuroblastomas are childhood tumors that are uncommon in adults.

The most common nerve sheath tumors are the schwannoma (Figure 3) and neurofibroma. These slow-growing tumors can arise anywhere along the thoracic nerves and are usually found incidentally on chest x-ray (Figure 4). Neurofibromas are often associated with type I neurofibromatosis or multiple plexiform neurofibromas. Malignant tumors of nerve sheath origin are spindle cell and are uncommon. They typically arise from a simple or plexiform neurofibroma or (rarely) from a pre-existing schwannoma.

Figure 3.

Schwannoma seen on CT

Figure 4.

Posterior mediastinal mass on CXR

Sympathetic ganglia tumors are rare tumors of nerve cell origin that range from being slow-growing to highly malignant. These tumors typically appear as well-circumscribed masses along the anterior spine in the region of the sympathetic ganglia. Ganglioneuromas are typically slow growing, encapsulated tumors that are found incidentally. Symptoms may occur because of mass effect or from local extension into the spinal canal.

Neuroendocrine tumors

Thymic neuroendocrine tumors include the thymic carcinoid tumor and small-cell carcinoma of the thymus. A distinguishing feature of thymic neuroendocrine tumors is the presence of APUD (amine precursor uptake and decarboxylation) cells.

Histologically, carcinoid tumors of the thymus appear similar to carcinoids found in other sites in the body. They may be associated with Cushing's syndrome (a third of cases) and multiple endocrine neoplasias. The classic carcinoid syndrome is rarely associated with thymic carcinoid tumors. Approximately half of thymic carcinoids are hormonally active, usually secreting ACTH with associated Cushing's syndrome. An elevated ACTH level is a poor prognostic indicator in these tumors. The small-cell variant is uncommon and has a poor prognosis.

Thymic carcinoid tumors typically present as a large, lobulated mass in the anterior mediastinum that may have areas of necrosis and hemorrhage. Regional lymph node and distant metastases occur in up to 73% of patients.

The differential diagnosis of a mediastinal mass is dictated by the particular compartment that is involved. Refer to Table I, Table II, Table III for a summary of tumors divided by their location in the anterior, middle and posterior mediastinum respectively.

Table I.

Summary of Mediastinal Tumors by compartment

Beware: there are other diseases that can mimic mediastinal tumors.

The radiographic differential diagnosis of a mediastinal mass includes mediastinal fat, aortic aneurysm, post-surgical changes from a gastric pull-up as well as rotation. A CT chest with contrast is often necessary to better identify the anatomy including the compartment affected.

How and/or why did the patient develop a mediastinal tumor?

Not applicable

Which individuals are at greatest risk for developing a mediastinal tumor?

There is no known genetic predisposition for the development of mediastinal masses. The epidemiology varies depending on the tumor and will be reviewed below.

Thymoma: With an incidence of 0.13 cases per 100,000, thymoma is the most common tumor of the anterior mediastinum. As a rare tumor, it accounts for 0.2 to 1.5% of all cancers. The median age at time of diagnosis is approximately fifty-four years, with the peak incidence between the ages of 40-60 years. While the incidence in men and women is equal, there is a higher association within Asians and Pacific Islanders and blacks, than Caucasians.

Thymic Carcinoma: Thymic carcinomas comprise 1% of thymic malignancies, and typically occur in middle-aged men (mean age of forty-six years).

Thymolipoma: Comprise approximately 5% of thymic masses without any gender predisposition. Mean age is approximately 22 years.

Thymic Cyst: Thymic cysts comprise of 1-3% of anterior mediastinal masses. They usually occur in those aged 20-50.

Hodgkin’s Lymphoma: There are approximately 8500 new cases of Hodgkin’s Lymphoma annually in the United States, with a bimodal distribution with a peak seen in young adults (mean age in the 20s) and in patients over age fifty (mean age of 65). HL represents approximately 50-70 % of mediastinal lymphomas, with an incidence of 2-4 cases per 100,000 people per year. There is a slight predominance in males, specifically in young adults. Additionally, there is a higher incidence in older patients of Hispanic origin than other races.

Non-Hodgkin’s Lymphoma: The overall incidence of non-Hodgkins Lymphoma is greatest in men over age fifty-five.

Germ Cell Tumors/Teratoma: Mature teratomas usually occur in children and young adults, and males and females are affected equally. Primary mediastinal seminomas usually occur in men 20-40 years of age. Mediastinal seminomas can occur, though rarely, in women with histologically normal ovaries. Non-seminoma germ cell tumors are six times more common in males than in females. NSGCTs are seen most often in patients with Klinefelter's syndrome.

Thyroid/Substernal goiter: Substernal goiter accounts for 5-10% of mediastinal masses. It is hard to specify the incidence of substernal goiters, given differences in classification.

Esophageal Tumors: There is an estimated incidence of 16,940 patients with esophageal cancer annually, affecting both men and women equally. There is a high rate of variability in incidence internationally, with the highest rates found in Southern and Eastern Africa and Eastern Asia, and the lowest rates found in Middle Africa and Central America.

Parathyroid Adenoma: 80-85% of hyperparathyroidism is caused by parathyroid adenomas. In a study conducted of 202 patients with parathyroid adenoma, 38% were found to be in the thymus, while 31% were found to be in the retroesophageal space; 18% were found to be intrathyroidal.

Bronchogenic Cyst: BC comprise 5-10 % of pediatric mediastinal masses.

Esophageal Duplication Cyst: Esophageal duplication cysts account for 5-10% of mediastinal cysts and are much less common than bronchogenic cysts.

Pericardial Cysts: Pericardial cysts are very rare, occurring in 1 in 100,000 persons.

Neurogenic Tumors: Neurogenic tumors comprise 19-39% of all mediastinal tumors.

Tracheal Tumors: Primary tracheal tumors are rare, with an incidence of 0.1 out of 100,000 per year, with a median age of 63.

Neuroendocrine tumors: Thymic neuroendocrine tumors usually occur during the fourth or fifth decade of life.

What laboratory studies should you order to help make the diagnosis, and how should you interpret the results?

The most appropriate laboratory investigations are dependent on the compartment in which the mass is identified as well as the most probable etiology.

Thymoma: Complete hemogram in addition to the following tumor markers are recommended when thymoma is considered: β HCG, AFP (to rule out Germ cell tumors), T3, T4, TSH, gamma globulins, ACTH, ADH (to rule out Neuroendocrine tumor). One must obtain serum anti-acetylcholine receptor antibody to assess for Myasthenia Gravis.

Hodgkin’s Lymphoma: In the case of HL, lab work is used in guiding treatment process. It can help in determining the most appropriate chemotherapy regimen. Once HL is confirmed, one should obtain CBC, ESR, biochemical tests of bone, liver, and renal function, LDH, lipid panel, and calcium concentrations, Beta HCG, and HIV testing.

Non-Hodgkin’s Lymphoma: Laboratory investigations for NHL include: CBC, BMP, LDH, SPEP.

Germ Cell Tumors/Teratomas: Serum beta HCG and AFP are essential for diagnosis.

Parathyroid adenomas: A patient’s evaluation should begin with assessing the cause of hyperparathyroidism. Repeat calcium should be drawn as well as serum PTH and 24 hour urinary calcium concentration. Serum 25-hydroxyvitamin D can be useful in distinguishing different forms of hyperparathyroidism.

What imaging studies will be helpful in making or excluding the diagnosis of a mediastinal tumor?

Imaging studies should include a posteroanterior and a lateral chest x-ray. Loss of the normal mediastinal contour is frequently present, and displacement of adjacent structures like the trachea may be apparent. CT scan of the chest is highly useful in characterizing the mass and determining whether there is associated lymphadenopathy, pleural/pericardial effusion, or evidence of associated pulmonary or pleural nodules. CT may also suggest invasion of the mass by loss of normal tissue planes. Although not routinely ordered, MRI may be a helpful study in further characterizing the mass as cystic or solid and in assessing vascular and spinal involvement. MRI is also the appropriate study with which to ascertain invasion of the diaphragm.

Thymoma: Chest X-ray, which is frequently the first study performed, often shows widening of the mediastinum on postero-anterior views with loss of the normal mediastinal contour. Lateral films may demonstrate an opacity in the space anterior to the heart, behind the posterior table of the sternum.

CT scan (Figure 2), the next most often recommended imaging study, typically shows an encapsulated, lobulated, or round-appearing mass extending into one side of the mediastinum. The mass usually appears homogeneous, but it may contain focal areas of calcification and/or cyst formation. CT is also helpful in finding adenopathy outside of the anterior mediastinum that may suggest lymphoma. Invasion of adjacent structures may be evident from loss of normal tissue planes between the mass and surrounding structures.

One study noted that FDG-PET was very useful in distinguishing thymomas from thymic hyperplasia. While it did not show a benefit in detecting ectopic thymic tissue, there was a clear benefit in detecting recurrent lesions after resection. MRI (Figure 5) is usually reserved for assessing vascular invasion, however it may further characterize the mass.

Figure 5.

Thymoma seen on T2 weighted MRI in anterior mediastinum.

Thymic Carcinoma: A CT scan typically demonstrates a heterogeneous, large, and infiltrative mass. Cystic changes may be present within the tumor. Metastases are common in the pleura and pericardium, and pleural and pericardial effusions occur differentiating them from thymoma.

Thymolipoma: CXR may show a large anterior mediastinal mass. CT may show heterogenous mass of fatty tissue interspersed with thymic tissue, while MRI demonstrates a fat density.

Thymic Cyst: On X-ray may appear as rounded, circumscribed mass, with a rim of calcification.

Hodgkin’s Lymphoma: An abnormal CXR is seen in 76% of patients with Hodgkins disease. Asymmetric mediastinal nodal disease may be apparent on plain films due to paratracheal and prevascular nodal enlargement (Figure 6 and Figure 7). CT scan may demonstrate a mediastinal mass with adjacent adenopathy or a cluster of enlarged mediastinal nodes. The mass, which may appear homogeneous or heterogeneous on CT scan, is often infiltrative, with loss of tissue planes between mediastinal structures.

Figure 6.

Anterior fullness seen on lateral Chest X-ray

Figure 7.

Mediastinal lymphadenopathy seen on Chest X-ray

PET CT of the chest, abdomen, and pelvis is critical for staging to determine the extent of disease or tumor burden. (Figure 8)

Figure 8.

FDG-PET avid mass of the anterior mediastinum.

Germ Cell Tumors/ Teratomas: Mature teratomas appear as multilocular cystic tumors that typically extend to one side of the midline. Calcifications are present in 2% of tumors. The presence of fluid, calcium, soft tissue and/or fat in an anterior mediastinal mass on CT is highly suggestive of a mature teratoma. Seminomas appear as bulky, homogeneous anterior mediastinal masses, and calcification is rare. A testicular exam and scrotal ultrasound is recommended when a mediastinal mass is found in a male patient.

Thyroid/Substernal Goiter: CT scan typically confirms the association of the mass with the thyroid gland (Figure 9). Long-standing goiters may have calcium deposits within the tissue. Radionucleotide imaging of the thyroid (Figure 10) typically shows some functioning thyroid tissue in the intrathoracic goiter.

Figure 9.

CT image of intrathoracic goiter

Figure 10.

Radionucleotide scan showing active thyroid tissue outside of the thyroid gland.

Esophageal Tumors: Symptoms usually lead to barium studies that may be suggestive of an esophageal cancer. Further evaluation inclusive of an endoscopic biopsy must be done to secure the diagnosis. Preoperatively, CT scan can be performed to screen for primary cancer, and look for any distant metastasis. Endoscopic ultrasound can be used to assess for locoregional disease extension.

Parathyroid Adenomas: Sestamibi scans are usually helpful in identifying the location of mediastinal parathyroid adenomas. MRI and CT have also been used if sestamibi is inconclusive.

CT scan shows a well-defined mass with homogeneous density similar to that of water. Viscous fluid within the cyst may give the appearance of the mass's being solid, and MRI may be helpful in further characterizing the mass. Bronchogenic cysts typically show an MRI signal intensity higher than that of muscle on T1 weighted images because of the high protein content in the cyst fluid. The signal intensity on the T2-weighted images is typically high suggesting a cystic lesion. Bronchogenic cysts typically remain stable in size except when complicated by hemorrhage or infection.

Bronchogenic Cyst: Bronchogenic cysts appear as rounded structures of soft-tissue on CXR. Typically CXR is followed by CT, which can show a spherical mass with variable fluid composition. Sometimes MRI is performed showing high signal intensity in T2 imaging due to the high fluid content.

Esophageal Ductal Cyst: Plain films often demonstrate a well-circumscribed central opacity that usually protrudes into the lower right chest. CT scan often shows them as well-demarcated, spherical lesions with variable enhancement. MRI may reveal variable signal intensity on T1 weighted images and high intensity on T2 weighted images.

Tracheal Tumors: Diagnosis of tracheal tumors is often delayed due to their non-specific presentation. Often, evaluation begins with a CXR. Rarely, CXR will show tracheal narrowing. The plain film is frequently followed by CT, which then can show a lesion or a growth. Depending on the history and imaging results a decision whether to proceed to PET-CT or bronchoscopy for direct visualization can be made. If cancer is highly suspected, a physician may recommend a PET-CT prior to bronchoscopy.

Pericardial Cysts: Typically a mass can be seen abutting the cardiac silhouette on pain CXR. CT and MRI imaging are done to assess the location and composition of the fluid.

Neurogenic Tumors: Radiologically, nerve sheath tumors appear well circumscribed and round or lobulated with homogeneous tissue density and attenuation density that is often lower than muscle because of areas of low cellularity. MRI may be helpful in characterizing neurogenic tumors. Schwannomas have a signal intensity similar to or higher than that of muscle with T1 weighted imaging and significantly higher than that of muscle on T2 imaging (Figure 11). Neurofibromas have characteristic high peripheral signal intensity and lower central signal intensity on T2 weighted images. MRI is essential when assessing intra-spinal involvement prior to surgical resection.

Figure 11.

Schwannoma seen on MRI

What non-invasive pulmonary diagnostic studies will be helpful in making or excluding the diagnosis of a mediastinal tumor?

Not applicable

What diagnostic procedures will be helpful in making or excluding the diagnosis of a mediastinal tumor?

Diagnosis of most mediastinal masses is made at the time the tumor is excised. Invasive procedures, including fine-needle aspiration, core-needle biopsy, and cervical or anterior mediastinoscopy, may be required to elucidate the nature of a more invasive mediastinal tumor prior to resection. A biopsy should also be performed in tumors that might not be treated surgically, such as lymphoma or a germ cell tumor to confirm the diagnosis.

Thymoma: Beyond the potential for possible tumor spillage or needle-track seeding, it is generally not helpful or necessary to obtain a preoperative biopsy in a suitable operative candidate, unless, an alternate diagnosis is possible or probable. Biopsies for a suspected thymoma should be done if nonoperative or neoadjuvant treatment is indicated because of dissemination of the disease, unresectability, or the patient's physical condition.

The success rate of fine-needle aspiration in making the diagnosis of a thymoma is approximately 60%. These tumors are typically located in a place favorable to percutaneous-needle biopsy, which may be performed using CT or ultrasound guidance. Therefore, when a mass appears resectable and is thought most likely to be a thymoma in a healthy patient, many thoracic surgeons favor proceeding directly to surgery without a needle biopsy.

Thymic carcinoma: Needle biopsy of the mass is usually diagnostic.

Hodgkins lymphoma: Ultrasound or CT-guided biopsy may be attempted to obtain tissue with which to diagnose Hodgkins lymphoma. The identification of Reed-Sternberg cells is pathognomonic of Hodgkins disease. Reed-Sternberg cells are characterized by bilobed eosinophilic nuclei, and immunohistochemistry demonstrates CD15 and CD30 positive cells. However, Reed-Sternberg cells may be difficult to identify on the small samples provided by needle aspiration, particularly with the nodular sclerosing variant of Hodgkins. A core-needle or surgical biopsy may be required if FNA is not feasible or if it is non-diagnostic.

Non-Hodgkins Lymphoma: The diagnosis of non-Hodgkins lymphoma requires adequate tissue, and sub-classification of lymphoma depends in part upon architectural pattern and immunophenotyping. Therefore, fine-needle aspiration is less useful for the initial diagnosis of lymphoma, but it may be helpful in the setting of a relapse. Core-needle biopsy has been reported to be successful in diagnosing lymphoma in 70% of cases. Open surgical biopsy using mediastinoscopy, mediastinotomy, or video-assisted thoracoscopic surgery (VATS) provides a large amount of tissue and remains the definitive means for diagnosing mediastinal lymphoma.

Germ cell tumors: Definitive diagnosis of teratomas requires surgical excision of the tumor. Subtotal resection for symptom relief, followed by adjuvant chemotherapy, may also be beneficial.

Fine-needle aspiration typically confirms the diagnosis of medistinal seminomas.

What pathology/cytology/genetic studies will be helpful in making or excluding the diagnosis of a mediastinal tumor?

See above

If you decide the patient has a mediastinal tumor, how should the patient be managed?

Thymoma: Surgical resection of the thymoma with complete thymectomy is the initial treatment of choice when there are no metastases or evidence of invasion. The most common surgical approach is via a median sternotomy. After opening the sternum, the thymus is dissected from the pericardium and innominate vein. The lateral extent of the dissection involves removing all thymic tissue from the left to the right phrenic nerves. Superiorly, the left and right cornu of the thymus are dissected into the neck and resected with the specimen. The thymus and thymoma are removed en bloc.

Less invasive methods include transcervical thymectomy, video-assisted thoracoscopic (VATS), thymectomy, and robotic thymectomy. Although cervical thymectomy is an accepted, perhaps optimal approach for thymectomy to treat myasthenia, it remains controversial for resection of thymic tumors. Robotic and VATS thymectomy, which allow more visualization, angles of attack, and preservation of oncologic principles compared to cervical thymectomy, are gaining acceptance.

Patients with thymomas and concurrent myasthenia gravis may require medical treatment and should be referred to a neurologist for an evaluation and recommendations for treatment prior to surgery. Surgeons must work in concert with neurologists for symptomatic patients, as surgery can precipitate a potentially fatal episode of myasthenic crisis.

Neoadjuvant chemotherapy, with or without radiation, may be used in patients with advanced thymomas prior to resection when CT scan demonstrates loss of tissue planes or evidence of local tumor invasion. Complete resection (negative surgical margins) is associated with significantly improved survival, so en bloc resection of invaded structures is warranted when feasible. Evidence of invasion of surrounding structures, either intraoperatively or on the pathology report, should point to the need for a radiation oncology consultation.

Thymic carcinoma: Complete surgical resection, the treatment of choice when it is feasible, can be curative. Induction therapy (chemotherapy and radiation or chemotherapy alone), followed by resection and postoperative radiation (if not given pre-operatively) in patients with no evidence of metastatic disease, has had some success. A variable response has been observed with chemotherapy in patients with unresectable disease, and studies are underway to determine the best regimen.

Thymolipoma: The recommended treatment for thymolipomas is surgical excision. There are no reports of recurrence.

Thymic Cyst: Histologically, thymic cysts appear identical to cystic thymic neoplasms, so complete resection is usually recommended.

Hodgkin’s Lymphoma: Treatment of HL depends upon the disease stage and whether the disease is bulky. Favorable stage I or stage II disease is typically treated with combined involved-field radiation and chemotherapy. Stage I or stage II bulky disease can be treated using chemotherapy, followed by radiation, while stage III or stage IV Hodgkins lymphoma is best treated using chemotherapy alone.

Non-Hodgkin’s Lymphoma: Treatment of non-Hodgkins lymphoma depends upon tumor stage, grade, type of lymphoma, and clinical factors (see Chapter NHL).

Germ Cell Tumors/ Teratoma: Definitive treatment of teratomas involves surgical excision of the tumor. Sub-total resection for symptom relief, followed by adjuvant chemotherapy may also be beneficial.

Patients with localized and relatively small mediastinal seminomas are usually treated with radiation. Bulky tumors or non-localized tumors are treated with systemic chemotherapy, including etoposide or cisplatinum-based regimens. The treatment of a residual mass depends upon size; tumors smaller than 3cm may be followed, while those larger than 3cm are typically resected.

Thyroid/Substernal Goiter: While there is some controversy in regards to the management of substernal goiters, most physicians will recommend resection if the goiter extends below the brachiocephalic vein. If above, some prefer to monitor with serial CT imaging. Substernal goiters are typically approached through a neck incision, with delivery of the substernal portion through this incision. Rarely, a partial or complete sternotomy is required to help remove the intrathoracic portion of the gland. For patients who are non-operative candidates, they can be treated with radioiodine therapy.

Esophageal Tumors: Treatment of esophageal cancer is highly dependent on the stage of cancer. Depending on the primary cancer, a patient may undergo radiation, chemotherapy, stenting, and esophagectomy.

Parathyroid Adenoma: Most commonly, parathyroid adenomas are resected, achieving a cure rate of 95%. Patients with mild disease are often treated with hormone replacement therapy to decrease bone loss.

Bronchogenic Cyst: Resection of bronchogenic cysts can be performed thoracoscopically or via a thoracotomy, depending upon the skill of the operator and the character of the cyst. Complete cyst excision prevents recurrence, while incomplete resection may result in infection, a chronic draining sinus, or (rarely) a fistula to the esophagus or the bronchus. The usual recommendation for bronchogenic cysts is to remove them to prevent complications and to avoid the very rare occurrence of malignant transformation.

Esophageal Duplication Cyst: Treatment of esophageal duplication cysts involves cyst resection; preoperative biopsy is not recommended. The procedure usually involves an operative approach through the right chest since most of the intrathoracic esophagus is accessible via this approach. The traditional thoracotomy approach is rapidly being replaced by less invasive methods, including VATs and robotic resection.

Tracheal Tumors: Treatment of primary tracheal neoplasms involves resection of the portion of trachea involved, followed by reconstruction of the remaining trachea. Tracheal tumors are often not amenable to resection because of the extent of tumor and are best treated with local therapies: thermal ablation, stenting, or external beam radiation for palliation.

Pericardial Cyst: Most often, cysts are clinically observed, given their benign nature. If very large, they may be drained through aspiration or resection.

Neurogenic Tumors: The majority of neurogenic tumors are treated by surgical resection. Biopsy is not usually necessary prior to resection because of the common location and radiographic appearance of these tumors. MRI is required prior to resection to assess intra-spinal involvement in paravertebral tumors.

Neuroendocrine Tumors: When surgical resection is feasible, it is the treatment of choice for thymic neuroendocrine tumors. The use of chemotherapy and/or radiation has been reported with limited benefit.

What is the prognosis for patients managed in the recommended ways?

Thymoma Prognosis: Features associated with a poor prognosis include large size (>10cm), age less than thirty years, epithelial or mixed cytology, and the presence of a hematologic paraneoplastic syndrome. The ten-year survival rates after surgical resection depend primarily upon the tumor stage. The best survival is seen in stage I (90% ten-year survival), while stage IVa patients have the worst prognosis (35% ten-year survival).

Thymic Carcinoma Prognosis: Prognosis is determined largely by morphologic features present within the tumor. Poor prognostic indicators include the presence of high-grade atypia and necrosis, greater than 10 mitoses/high powered field, absence of lobular growth, and infiltration of the tumor margins. Overall, five-year survival rates of 33% have been reported; survival correlates with histologic grade.

What other considerations exist for patients with mediastinal tumors?

None

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