The mediastinum is the region in the chest between the pleural cavities that contains the heart and other thoracic viscera, except the lungs. Interest in the mediastinum as a separate body region stems from the diversity and importance of the structures it contains and the multiplicity of disease processes by which it can be affected. The mass lesions that arise in the mediastinum represent a heterogenous group of benign and malignant processes that defy easy categorization. The nonspecific clinical manifestations of most of these disorders and the relative inaccessibility for tissue sampling result in considerable challenges to the clinician evaluating mediastinal disease. This chapter describes the normal anatomy and contents of the mediastinum, the clinical manifestations produced by mediastinal disease, and the means available for diagnostic investigation. It then describes the features of specific mediastinal tumors and cysts and outlines an overall clinical approach to the evaluation of mediastinal disease. The focus of the discussion of pathology is on lesions that arise primarily in the mediastinum; lung cancer is discussed as it pertains to findings in the mediastinum.
Normal Anatomy of the Mediastinum
The anatomy of the mediastinum is divided into anterior, middle, and posterior compartments. This three-compartment model is consistent with embryonic development of the region and with the characteristic distribution of individual disorders encountered clinically. The anatomic relationships of the mediastinal viscera and tissue planes are best appreciated on axial images such as are shown schematically on a lateral chest radiograph in Fig. 83-1 .
The anterior compartment consists of everything anterior and superior to the heart; its boundaries are the sternum, the first rib, and an imaginary curved line following the anterior heart border and brachiocephalic vessels from the thoracic inlet to the diaphragm. Within the anterior compartment lie the thymus gland, any substernal extensions of the thyroid and parathyroid glands, and lymphatic tissue ( Table 83-1 ).
|Substernal extensions of thyroid and parathyroid glands|
|Lymphatic vessels and lymph nodes|
|Aortic arch and great vessels|
|Innominate veins and superior vena cava|
|Trachea and main bronchi|
|Phrenic and upper vagus nerves|
|Azygos and hemiazygos veins|
|Paravertebral lymph nodes|
|Vagus nerves (lower portions)|
The middle compartment, dorsal to the anterior mediastinum, extends from the lower edge of the anterior heart border along the diaphragm and then cranial along the posterior heart border and posterior wall of the trachea. It contains the heart, the pericardium, the aortic arch and its major branches, the innominate veins and superior vena cava (SVC), the pulmonary arteries and hila, the trachea, and several groups of lymph nodes. In addition, the phrenic and upper vagus nerves course through the middle mediastinal compartment.
The posterior compartment occupies the space between the back of the heart and trachea and the front of the posterior ribs and paravertebral gutters. It extends from the diaphragm cranial to the first rib. In it are the esophagus, descending aorta, azygos and hemiazygos veins, paravertebral lymph nodes, and thoracic duct. The lower portions of the vagus nerve and sympathetic chains also lie within the posterior mediastinum.
Clinical Presentations of Mediastinal Disease
Mediastinum in Patients with Malignancy
The most common reason that clinicians evaluate the mediastinum is in the staging of patients with lung cancer, because the extent to which the mediastinum is involved is crucial to management. Staging of lung cancer is discussed in greater detail in Chapters 21 and 53 . Careful preoperative evaluation of the mediastinum is critical in determining a patient’s candidacy for surgical resection or other treatment modalities.
Nonthoracic malignancies also may metastasize to the mediastinum. This is particularly common in tumors originating in the head and neck, the esophagus, the genitourinary tract, the breasts, and the skin (malignant melanoma).
The majority of mediastinal masses are discovered incidentally—at least half of all mediastinal masses are asymptomatic and detected by chest radiography performed for unrelated reasons. About 80% of such asymptomatic masses are benign, whereas more than half of those that produce symptoms are malignant.
Compression or Invasion of Adjacent Tissues
Symptoms in patients with mediastinal mass lesions are usually caused by compression or invasion of adjacent intrathoracic structures. Chest pain, from traction on mediastinal tissues, tissue invasion, or bone erosion, is common. Cough may be due to extrinsic compression of the trachea or bronchi, erosion into the airway, and sometimes postobstructive pneumonia. Hemoptysis, hoarseness, or stridor also may be part of the clinical presentation. Invasion or inflammation of the pleural surface may produce a pleural effusion, and cause pain and dyspnea. Compression or direct invasion of the esophagus may lead to dysphagia. Rarely, anterior mediastinal tumors can cause pericarditis or pericardial tamponade, and masses in the middle mediastinum can produce right ventricular outflow obstruction and cor pulmonale.
The SVC is especially vulnerable to extrinsic compression and obstruction because it is thin-walled and has low intravascular pressure. The SVC syndrome results from increased venous pressure in the upper thorax, head, and neck and is characterized by dilation of collateral veins in the upper portion of the thorax and neck, edema and plethora of the face, neck, and upper torso, and suffusion and edema of the conjunctiva (see Fig. 53-5A and B ). Neurologic symptoms such as headache, disturbance of consciousness, and visual distortion, may be present. Symptoms are exacerbated in the supine position. Numerous benign causes of SVC syndrome are described, but bronchogenic carcinoma ( and eFig. 83-1 ) and lymphoma ( and eFig. 83-2 ) are now the most common etiologies.
The compression or invasion of nerves may result in hoarseness from involvement of the recurrent laryngeal nerve, Horner syndrome from involvement of sympathetic ganglia, dyspnea from involvement of the phrenic nerve causing diaphragmatic paralysis, tachycardia from involvement of the vagus nerve and clinical manifestations of spinal cord compression.
Systemic Symptoms and Syndromes
Fever, anorexia, weight loss, and other systemic symptoms are nonspecific features of malignancy and inflammation that may manifest in patients with mediastinal disease.
In addition, primary mediastinal tumors are associated with a wide array of distinctive systemic syndromes ( Table 83-2 ). Some typically have endocrine activity, such as intrathoracic goiter, which may present with thyrotoxicosis. Cushing syndrome is associated with thymomas and carcinoid tumors. Thymomas are classically associated with myasthenia gravis ( and eFig. 83-4 ), in addition to other systemic syndromes. Patients with human chorionic gonadotropin-secreting germ cell tumors may manifest with gynecomastia; patients with pheochromocytoma may present with hypertension. Hypercalcemia may be a presenting abnormality observed in patients with parathyroid adenoma and lymphoma. Hypoglycemia in patients with certain pleural tumors, teratomas, fibrosarcomas, and neurosarcomas is also believed to be the result of tumor products with endocrine activity.
|Hypothyroidism or hyperthyroidism |
|Mediastinal goiter |
Parathyroid adenoma, lymphoma
|Hypertension||Pheochromocytoma, ganglioneuroma, chemodectoma|
|Cushing syndrome||Carcinoid, thymoma|
|Gynecomastia||Germ cell tumor|
|Red cell aplasia||Thymoma|
|Multiple endocrine neoplasia||Parathyroid adenoma, pheochromocytoma|
|Alcohol-induced pain||Hodgkin lymphoma|
|Fever and night sweats||Lymphoma|
Imaging the Mediastinum
The mediastinum is relatively inaccessible for examination or exploration. Accordingly, imaging studies play an important role in the initial evaluation of mediastinal disease. These include conventional radiographic studies, computed tomography (CT), magnetic resonance imaging (MRI), transthoracic and endoscopic ultrasonography, PET, and other radionuclide studies.
Conventional Radiographic Techniques
Most mediastinal abnormalities are first detected by standard posteroanterior and lateral chest radiographs, and certain mediastinal mass lesions have characteristic findings ( Table 83-3 ). For example, teratomas are usually anterior and may contain areas of calcium (sometimes teeth or bone), fat, and soft tissue. Neural tumors lie posteriorly and have sharply delineated margins. Bronchogenic cysts tend to lie against the trachea, carina, or main bronchus. These findings give clues to the possible origin of a mediastinal mass, but further imaging evaluation is usually required.
|Bulky mass on initial presentation||Anterior: lymphoma, germ cell tumor, thymoma or thymic carcinoma|
|Posterior: neurogenic tumor|
|Teardrop-shaped mass within interlobar fissure||Pericardial or bronchogenic cyst|
|Fat density on CT scan||Mediastinal lipomatosis or lipoma|
|Calcification in mass||In rim of mass:|
|Cystic thymoma or thyroid adenoma|
|Silicosis (“eggshell” calcification)|
|In center of mass:|
|Teeth or bone||Teratoma|
|Air-fluid level in mass||Esophageal disease|
|Mass with associated parenchymal opacity||Granulomatous inflammation/infection|
|Metastatic bronchogenic carcinoma|
|Lymphoma with direct extension into lung|
|Esophageal abnormality with aspiration pneumonitis|
|Bronchial compression by primary mediastinal mass|
|Mass with associated pleural effusion||Metastatic malignancy with pleural involvement|
|Granulomatous inflammation of lymph nodes|
|Superior vena cava obstruction||Recent onset:|
|Erosion or destruction of bone||Arterial aneurysm|
|Tumors of peripheral nerves or sympathetic ganglia|
|Spine or rib deformity||Enteric cyst|
In the appropriate clinical settings, contrast studies remain important diagnostic tools in mediastinal disease. Barium esophagrams can demonstrate extrinsic compression, esophageal diverticulum, tumor invasion, or fistula formation. Angiography can identify vascular compression or invasion, can define the vascular supply of tumors, and can sample blood for hormonal localization of certain tumors. Myelography may help delineate intraspinal extension of posterior mediastinal tumors and differentiate neurogenic neoplasms from meningoceles. For the most part, these techniques have been supplanted by CT and MRI.
CT imaging is the mainstay of radiographic evaluation of the mediastinum, because this modality can firmly determine the anatomic location, morphology, and tissue density of a mass. The transaxial plane of CT is well suited for assessment of mediastinal structures, most of which are oriented perpendicularly to this plane. Administration of intravenous contrast helps delineate vascular structures as they relate to a mass and other mediastinal structures. Easily identified CT patterns include the high density of calcified tissue and contrast-enhanced blood vessels, and the characteristic low density of fat ( Fig. 83-2 ). Normal anatomic variations and fluid-filled cysts can be distinguished confidently from bulky solid masses, which may be irregularly bordered and possess necrotic areas. Additionally, the site of origin of mediastinal masses can be better identified. Characteristic CT findings in a variety of mediastinal disorders have been described (see Table 83-3 ). For example, the specificity of the CT appearance of teratomas ( , eFigs. 83-9 and 83-10 ), thymolipomas ( and eFig. 83-11 ), and omental fat herniation ( and eFig. 83-12 ) is 100%, but the overall accuracy of CT for predicting the diagnosis of all mediastinal masses is less than 50%.
Lymph nodes are readily identifiable on CT scan and can be categorized by size and morphology. Mediastinal lymph nodes greater than 1 cm in diameter in the short axis are considered to be abnormally enlarged and are suspicious for malignancy in the proper clinical context. Mediastinal lymph nodes greater than 2 cm in diameter are virtually always abnormal. In the most recent systematic review of studies on the use of CT in mediastinal staging of lung cancer, the median sensitivity and specificity for identifying metastatic lymph nodes using the greater than 1 cm criteria were 55% and 81%, respectively, similar to what was previously reported by Gould and coworkers. However, even in series of patients with proven bronchogenic carcinoma, benign findings were present in 10% to 37% of lymph nodes that were either larger than 2 cm in diameter or had evidence of central necrosis.
Even though CT cannot reliably distinguish between benign and malignant disease, it remains the initial imaging procedure of choice for the evaluation of the mediastinum in patients with a primary mediastinal mass or with suspected lung cancer. CT can precisely define the mediastinal anatomy and guide subsequent invasive diagnostic and staging procedures, or can confirm a clinical suspicion of extensive mediastinal involvement or visceral organ invasion that precludes curative resection.
Magnetic Resonance Imaging
Although much less frequently used than CT in evaluating mediastinal lesions, MRI offers several potential advantages over CT. MRI assesses tissues by measuring radiofrequency-induced nuclear resonance emissions, and the better contrast resolution over CT is advantageous in evaluating soft tissue structures and tissue boundaries ( Fig. 83-3 ). Blood vessels are identifiable without the need for contrast enhancement ( Fig. 83-4 ) ( and ), thus MRI can provide an alternative to patients who cannot be given iodinated contrast material required by CT. Ionizing radiation exposure is also eliminated.
MRI has utility in evaluating neurogenic tumors, and it may also be useful in evaluating thymoma and distinguishing it from congenital cyst or thymic carcinoma. MRI can be helpful for defining anatomy before surgical resection of superior sulcus tumors or those invading the mediastinum, chest wall, or diaphragm.
Whereas CT is more commonly used for routine staging of lung cancer, MRI may be useful for defining anatomy in special circumstances, such as before surgical resection of superior sulcus tumors or tumors invading the mediastinum, chest wall, or diaphragm. A large multicenter study comparing CT and MRI in patients with lung cancer found similar accuracy for the detection of mediastinal node involvement, but MRI was superior for detecting direct mediastinal tumor invasion ( and eFig. 83-15 ; see also Chapter 18 ). Diffusion-weighted MRI distinguished between malignant and benign mediastinal lesions based on apparent diffusion coefficient levels with a sensitivity of 95% and specificity of 87% in a study of 53 mediastinal lesions, with evidence of lower apparent diffusion coefficient values indicating a slower diffusion of water molecules in the malignant lesions. However, the use of MRI to establish malignancy or benignity requires further study.
Ultrasonography can confirm the cystic nature of mediastinal masses, but it cannot readily distinguish between benign and malignant cystic lesions. Both transthoracic and endoscopic ultrasound probes are useful in the evaluation of mediastinal disease in the context of guiding endoscopic biopsy procedures.
Nuclear imaging studies rely on the localization of markers based on specific metabolic or immunologic properties of the target tissue to provide a functional image of a lesion. The spatial resolution of radionuclide scans is relatively poor, but the overall diagnostic accuracy may be high if a sufficiently specific probe is available. Nuclear studies offer the potential to identify a primary malignancy and identify distant metastases with a single scan of the entire body.
PET is a widely used nuclear imaging technique that relies on high-energy photon–emitting probes, such as 18 F-fluorodeoxyglucose (FDG), which are chemically trapped within metabolically active neoplastic cells. The result is a high signal-to-background ratio and excellent spatial resolution for a functional image of a tumor ( Fig. 83-5 ). More recently, use of combined and co-registered PET and CT images has allowed for more accurate anatomic localization of the lesions in question but at the cost of lower specificity and increased false-positive results.
The use of PET in the evaluation of the mediastinum is largely focused on metastatic disease from thoracic malignancies, because it is useful in staging and preoperative planning for lung cancer. In the evaluation of suspected lung cancer, PET can identify metastatic foci in the mediastinum and extrathoracic sites and help determine the optimal biopsy approach that will make a histologic diagnosis as well as stage the disease. Despite widespread use of PET scanning, standardized quantitative criteria for defining an abnormal scan are lacking, and accuracy is far from perfect. False-positive results can be caused by granulomatous, inflammatory, or infectious conditions. FDG-PET has been shown to be more accurate than CT for mediastinal staging of lung cancer with a sensitivity of 80% and a specificity of 88% in an updated meta-analysis ; when lymph nodes are enlarged by CT criteria, sensitivity increases while specificity decreases. Mediastinal lymph node sampling is warranted in the setting of a positive PET scan if the findings of mediastinal involvement would alter the subsequent surgical approach (see Chapters 21 and 53 ).
The utility of PET for the evaluation of primary mediastinal lesions is not as well established as it is for metastatic disease. FDG-PET may differentiate between thymoma and thymic carcinoma, but has low sensitivity in differentiating between nonaggressive and aggressive subtypes of thymoma. It is not used routinely for staging of thymoma. However, PET is considered standard of care in the pretreatment workup and follow-up of mediastinal lymphoma ( Fig. 83-6 ). FDG-PET also plays a role in detecting residual post-chemotherapy malignant germ cell tumors, specifically seminomas, of the mediastinum. There is little role for PET in evaluating neurogenic tumors. Hypermetabolic lesions in the mediastinum may also represent sarcoidosis, mycobacterial and fungal infection, or brown fat.
Other nuclear medicine techniques for the evaluation of the mediastinum include radioiodine scanning for the detection of ectopic thyroid tissue; a positive result is pathognomonic for that condition. This approach must be planned carefully because iodinated contrast administered intravenously for a CT scan may prevent the uptake of radioiodine for several weeks or more.
Techniques for Obtaining Mediastinal Tissue
Definitive diagnosis of most mediastinal masses requires the evaluation of a tissue sample. However, biopsy of mediastinal tissue should be reserved for instances when diagnostic results will influence subsequent treatment. The decision to perform a biopsy rather than surgical resection is based on the presumptive diagnosis. If definitive surgical resection is the treatment choice regardless of the results of a biopsy, then a “diagnostic delay” should be avoided.
Available approaches for biopsy of mediastinal lesions include needle aspiration and biopsy via transbronchial, percutaneous, or transesophageal approaches. Surgical biopsies are obtained by more invasive procedures including mediastinoscopy and thoracoscopy.
Endobronchial Ultrasound-Guided Transbronchial Needle Aspiration
For evaluation of mediastinal adenopathy or other lesions in the middle mediastinum, transbronchial needle aspiration (TBNA) via the fiberoptic bronchoscope offers a less invasive option to surgical mediastinoscopy. Although few significant complications have been reported, the sensitivity of blind TBNA is low, ranging from 14% to 50%.
Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) is a recent technology that has significantly improved the ability of pulmonologists to diagnose and stage non–small cell lung cancer in a minimally invasive manner. With the advent of a curvilinear ultrasound probe integrated at the end of the bronchoscope, TBNA with a 22-gauge needle can be performed under real-time ultrasonographic guidance. The ability to visualize the area of interest as well as adjacent vascular structures has vastly improved diagnostic yields. Upper and lower paratracheal, subcarinal, and hilar lymph nodes are readily accessible by EBUS-TBNA, as is any mediastinal or hilar lesion that is adjacent to the large airways. EBUS-TBNA has the advantage over mediastinoscopy in accessing the posterior subcarinal lymph nodes as well as hilar nodes or masses, in addition to being an ambulatory procedure with lower associated health care costs.
While the efficacy of EBUS-TBNA is now firmly established in the evaluation of lung cancer, there is also an increasing role for the initial evaluation of isolated mediastinal adenopathy due to other conditions such as sarcoidosis. In a randomized controlled trial of 50 patients with clinically suspected sarcoidosis due to the presence of mediastinal and hilar adenopathy, the diagnostic yield of EBUS-TBNA was superior to blind TBNA, with a sensitivity of 83% and specificity of 100%. In a prospective trial of 77 patients with isolated mediastinal adenopathy, a specific diagnosis of sarcoidosis, tuberculosis, lymphoma, or other malignancy was made in 67 of them, thus obviating the need for a more invasive surgical mediastinoscopy. EBUS-TBNA can be useful in providing a definitive diagnosis of primary or recurrent lymphoma; however, its role in the initial diagnosis of mediastinal lymphoproliferative disorders is controversial because the amount of tissue provided may not be adequate for histologic subtyping.
Endoscopic Ultrasound-Guided Needle Aspiration and Biopsy
Endoscopic ultrasound (EUS)–guided sampling relies on the placement of biopsy needles that are passed through the working channel of a gastroscope. The proximity of the esophagus to mediastinal sites relatively inaccessible to mediastinoscopy, such as the posterior subcarinal lymph nodes, makes this approach particularly useful in selected cases. EUS-guided biopsy has similar sensitivity as PET for determining inoperability in lung cancer and, importantly, superior specificity (100% vs. 72%). In selected cases, it can confirm the presence of mediastinal metastases and thereby obviate the need for surgical staging procedures.
Percutaneous Needle Aspiration and Biopsy
Percutaneous needle aspiration and biopsy of mediastinal masses, usually in the anterior compartment, can be performed using ultrasound or, more often, CT guidance ( Fig. 83-7 ). Percutaneous needle aspiration of the mediastinum has acceptable morbidity and yields comparable to those from percutaneous biopsy of pulmonary lesions. As with TBNA, serious bleeding is seldom encountered, and accurate diagnosis of a wide variety of lesions has been reported.
Mediastinoscopy allows direct inspection and biopsy of lymph nodes or other masses in the superior portion of the anterior mediastinum. Cervical mediastinoscopy provides access to the paratracheal and subcarinal lymph nodes, whereas an anterior mediastinotomy (otherwise known as an anterior or parasternal mediastinoscopy) provides access to the lymph nodes in the aortopulmonary window. Although more invasive than a percutaneous or endobronchial approach, mediastinoscopy has the advantage of providing the entire lymph node for histologic examination, rather than the cellular aspirates or small tissue fragments produced by needle biopsy techniques. Mediastinoscopy is most frequently used in the staging of bronchogenic carcinoma, but has utility in evaluating mediastinal adenopathy or mass lesions of other etiologies. Either frozen section or imprint cytology methods can provide rapid, accurate results and facilitate immediate decisions about the feasibility of curative resection.
Mediastinal anatomy from the perspective of the surgeon performing a mediastinoscopy is different from that based on the lateral chest radiograph as described earlier. For mediastinoscopy, structures are considered according to whether they lie anterior, posterior, or immediately to the right or left of the trachea. Mediastinoscopy is performed using general anesthesia, but is typically an outpatient procedure when subsequent thoracotomy is not planned to follow immediately.
Mediastinoscopy is safe and well tolerated. Complications of mediastinoscopy include pneumothorax, hemorrhage, recurrent laryngeal nerve or phrenic nerve paralysis, injury to the trachea, esophageal perforation, thoracic duct laceration, air embolism, and mediastinitis.
Video-Assisted Thoracoscopic Surgery
Biopsies of mediastinal lymph nodes can also be performed by video-assisted thoracoscopic surgery (VATS). VATS provides access to the hilar nodes and inferior pulmonary ligament lymph nodes on both sides. Additionally, on the right side, VATS can provide access to the right paratracheal lymph nodes and subcarinal nodes. Left-sided VATS can provide access to the aortopulmonary nodes. VATS can also be a tool for the evaluation of pleural and lung abnormalities in the management of mediastinal diseases. After dissection through the mediastinal pleura, mediastinal lymph nodes can be sampled to aid in the staging of malignancies such as esophageal carcinoma and for the diagnosis and resection of primary mediastinal tumors and cysts. VATS requires a general anesthetic, chest tube placement at the conclusion of the procedure, and typically a limited stay in the hospital.
Mediastinal masses are considered primary, that is, arising solely from structures within the mediastinum, or secondary, usually as metastatic disease from intrathoracic or extrathoracic malignancy.
The most practical clinical classification of primary mediastinal masses groups together lesions that are characteristically found in the anterior, middle, or posterior mediastinal compartments ( Table 83-4 ), with the recognition that such a simplified scheme overlooks the fact that mediastinal masses will not necessarily respect anatomic borders. Masses found within any of the mediastinal compartments may be due to lesions more commonly found in another mediastinal compartment or due to those that have extended from another area in the mediastinum ( Fig. 83-8 ).
|Anterior Mediastinum||Middle Mediastinum||Posterior Mediastinum|
|Thymic neoplasms||Lymphadenopathy||Neurogenic tumors|
|Germ cell tumors||Reactive and granulomatous inflammation||Meningocele|
|Seminoma||Angiofollicular lymphoid hyperplasia (Castleman disease)||Carcinoma|
|Nonseminomatous germ cell tumors||Lymphoma||Diverticula|
|Embryonal cell carcinoma||Developmental cysts||Diaphragmatic hernia (Bochdalek)|
|Lymphoma||Foregut duplication cysts|
|Hodgkin lymphoma||Bronchogenic cyst|
|Non-Hodgkin lymphoma||Enteric cyst|
|Parathyroid neoplasms||Vascular enlargements|
|Mesenchymal tumors||Diaphragmatic hernia (hiatal)|
|Diaphragmatic hernia (Morgagni)|
|NUT midline carcinoma|
In a series of 400 consecutive patients with a primary mediastinal lesion, 25% had a primary cystic lesion and 42% had a malignant lesion. The anterior compartment was the most common compartment for a lesion, which was more likely to be malignant, followed by the posterior and then middle compartments. Although two thirds of mediastinal masses are benign, the likelihood of malignancy depends on the location, age of the patient, and presence or absence of symptoms. In a series of 38 patients with malignant mediastinal tumors, 31 had at least one sign or symptom.
The true incidence of primary mediastinal masses is difficult to ascertain. In a study of more than 9000 patients in a lung cancer CT screening trial, the prevalence of an incidentally detected mediastinal mass was 0.77%; on follow-up annual screening, the incidence was 0.01%. Historically, thymomas and developmental cysts were the most common masses found in adults, followed by neurogenic tumors and lymphoma, based on the collection by Silverman and Sabiston of nearly 2400 cases from the literature ( Table 83-5 ). More recent series suggest a similar pattern, although Cohen and associates have observed both a rising incidence of mediastinal masses in general and an increasing proportion of lymphoma and malignant neurogenic tumors over the course of their 45-year survey. Neurogenic tumors, thymomas, and developmental cysts account for about 60% of all mediastinal masses. Lymphomas and germ cell tumors such as teratoma and seminoma account for about 25%, and a large number of other lesions, both benign and malignant, constitute the remaining 15%.
|Lesion||Adults (%)||Children (%)|
|Germ cell tumors||11||11|
|Endocrine (thyroid, parathyroid, carcinoid)||6||—|
Specific Mediastinal Tumors and Cysts
Lesions of the Anterior Mediastinum
Thymoma is the most common neoplasm arising in the anterior mediastinum and is increasingly recognized in the course of thorough evaluations of patients with myasthenia gravis. It remains a rare tumor, with an overall incidence of 0.13 per 100,000 person-years in the United States. The peak incidence of thymomas is between the ages of 40 and 60 years and is higher in Asians and African Americans, with equal gender predilection.
Although most thymomas are not biologically aggressive, about one third of thymomas found have already invaded their capsules. Advanced disease involves extension into local structures and transdiaphragmatic extension into the abdomen and pericardial involvement, but lymphogenous and hematogenous metastases are rare. The histologic classification remains a subject of debate and revision. The current World Health Organization classification system, which is based on histologic features, does not accurately predict clinical outcome, thus treatment of patients has been based historically on the presence and degree of tumor invasion into microscopic and local structures. Most clinicians use the Masaoka clinical staging system, which is based on the degree of invasion of the tumor through the capsule into adjacent structures. Moran and colleagues recently proposed a new staging system in which the overall prognosis and recurrence is based on extent of tumor infiltration. Currently the International Thymic Malignancies Interest Group (ITMIG) and the International Association for the Study of Lung Cancer (IASLC) are collaborating on developing a new TNM-based classification system, which is expected in 2017.
Clinically, the majority of patients with thymoma are asymptomatic, while one-third of patients will present with nonspecific chest pain, cough, or dyspnea due to local tumor effects. Forty to 70% have at least laboratory evidence of one or more of the two dozen systemic “parathymic” syndromes that have been recognized. Thymomas are associated with numerous systemic syndromes, most of which appear to be autoimmune in origin. The most familiar of these is myasthenia gravis, reported in 10% to 50% of patients with thymoma and thought to be due to autoantibodies to the postsynaptic acetylcholine receptor. Other associated syndromes include pure red blood cell aplasia, myocarditis, and hypogammaglobulinemia. Patients with thymoma also have an increased incidence of collagen vascular disease, Whipple disease, and malignancy elsewhere in the body.
On chest radiography, thymomas appear as an ovoid, smooth or lobulated unilateral mass near the junction of the heart and great vessels ( Fig. 83-9 ). Compared with thymic hyperplasia, which is typically symmetrical, thymoma usually distorts the gland’s normal shape and extends to one side. On CT scan, most thymomas present as a solid 5- to 10-cm anterior mediastinal mass outlined by fat; up to one third of thymomas contain cystic, necrotic, or hemorrhagic areas that enhance heterogeneously. Contrast CT is necessary for the staging of thymoma, specifically for discerning vascular involvement. MRI can help distinguish benign cysts from a cystic thymoma or thymic carcinoma. At this time, nuclear medicine has little role in the evaluation of thymoma. Due to their relatively indolent nature, most thymomas have low FDG uptake, which limits the utility of PET imaging to discern a benign from a malignant thymic mass.
The mainstay of therapy for thymomas is surgical resection, which provides the best chance for an optimal prognosis. Adjunctive treatment with postoperative radiotherapy is typically provided, and the addition of preoperative or adjuvant chemotherapy appears promising for more advanced stages.
Patients whose tumors are fully encapsulated with no evidence of invasion can expect postoperative survival equal to that of the general population. Invasive tumors have a poorer prognosis, with 50% to 77% 5-year and 30% to 55% 10-year survival. Thymoma recurs after resection in nearly a third of patients. The largest and most recent retrospective survey of thymic tumors from the European Society of Thoracic Surgeons database showed that higher Masaoka stage (with evidence of invasion), incomplete resection, and nonthymoma histology were factors in recurrence and worsening survival.
Thymic carcinoma is an aggressive epithelial malignancy that invades locally and frequently metastasizes. This rare cancer develops predominantly in middle-aged men, who present with symptoms of cough, dyspnea, and chest pain as well as nonspecific systemic symptoms. On imaging, thymic carcinomas are heterogenous masses with areas of necrosis and calcifications. They are highly FDG-avid on PET scan. The prognosis, which depends on the histologic grade and the anatomic stage, is generally poor. Surgical resection is the treatment of choice; chemotherapy and radiation therapy are advocated for unresectable disease.
Carcinoid tumors occasionally arise in the thymus. They may cause Cushing syndrome and be associated with multiple endocrine adenomatosis. Locally invasive carcinoids may be difficult to resect completely, but characteristically have a prolonged clinical course. Interestingly, the thymus is also a common site for mediastinal Hodgkin lymphoma, and normal thymic tissue may enlarge following chemotherapy for lymphoma (a process termed thymic rebound ) ( eFig. 83-25 ), mimicking recurrence of the primary disease. Other thymic mass lesions include benign conditions such as thymic hyperplasia ( eFig. 83-26 ), thymic cysts, and lipothymomas (see and eFig. 83-11 ).
Germ Cell Tumors
Approximately 10% to 12% of primary mediastinal masses are derived from multipotent germ cells that migrated abnormally during early embryonic development. These neoplasms are classified into three groups: benign teratoma, seminoma, and nonseminomatous germ cell tumors.
Teratomas, the most common germ cell tumors, are by definition made up of tissues foreign to the area in which they arise. Ectodermal derivatives predominate, but structures originating in all three primary germ cell layers may be found. Dermoid cyst refers to a lesion that contains only the epidermis and its derivatives. Teratomas arise most often in young adults, but have been reported in all age groups; men and women are affected with equal frequency. Most patients with teratomas have symptoms caused by the tumor; only about a third are asymptomatic. Usual symptoms are pain, cough, and dyspnea. Teratomas can rupture into the pleural space or into the pericardium. If the tumor erodes into a bronchus, the patient may have hemoptysis or even expectorate differentiated tissue such as hair (trichoptysis) or sebaceous material.
On chest radiographs, teratomas appear smooth, rounded, and circumscribed if they are cystic. Solid lesions can appear lobulated and asymmetric. On CT scans (see and eFig. 83-10 ), soft tissue, fat, and calcification (occasionally, fully formed teeth and bone) can be identified, rendering this one of few mediastinal tumors that can be diagnosed confidently before operation ( Fig. 83-10 ). All teratomas should be resected due to malignant potential and effects of impingement on adjacent vital structures. In malignant teratoma, adjuvant combination chemotherapy may result in improved survival.
Seminomas and nonseminomatous germ cell tumors are malignant and nearly always cause symptoms. These lesions appear as a large anterior mediastinal mass on chest imaging ( and eFig. 83-29 ). Seminomas are seen almost exclusively in men, usually in the third decade of life. Most patients seek medical attention because of chest pain, dyspnea, cough, hoarseness, or dysphagia. Seminomas are aggressive malignant tumors that extend locally and metastasize distantly, usually to skeletal structures. The tumor can obstruct the SVC. They may secrete human chorionic gonadotropin, but not alpha-fetoprotein. Factors associated with a poor prognosis include age older than 35 years, SVC obstruction, supraclavicular, cervical, or hilar adenopathy, and fever. Seminomas are extremely radiosensitive and may respond dramatically to chemotherapy, even in cases with dissemination. With aggressive cisplatin-based regimens, long-term survival for all mediastinal seminomas is approximately 80%.
Nonseminomatous mediastinal germ cell tumors include embryonal cell carcinoma and choriocarcinoma. Like seminoma, these tumors develop mainly in men in the third and fourth decades and are usually symptomatic. These malignancies carry a poorer prognosis relative to cancers arising from the gonads. Embryonal cell carcinoma is also called endodermal sinus or yolk sac tumor ( and eFig. 83-30 ). These highly aggressive tumors often secrete human chorionic gonadotropin, alpha-fetoprotein, or carcinoembryonic antigen. Human chorionic gonadotropin may also produce clinical manifestations, such as gynecomastia, in 50% of patients. Associations have been noted with Klinefelter syndrome and with hematologic malignancy. Most patients present with disseminated disease, and the prognosis has been less favorable than in seminoma. Cisplatin-based treatment regimens have markedly improved the outcome, with more than 50% of patients achieving long-term survival. Long-term survival may also be possible in those who undergo a complete surgical resection following chemotherapy. Even disseminated and refractory malignant germ cell tumors may respond to aggressive chemotherapy and salvage regimens involving bone marrow transplantation.
Lymphoma is an important cause of mediastinal mass, and is distinguished from other mediastinal lesions in that management is primarily medical, not surgical. In most series, lymphoma represents between 10% and 20% of mediastinal masses in both adults and children. Lymphomas are the most common anterior and middle mediastinal masses in children; a majority of pediatric patients with Hodgkin lymphoma (HL) and half of those with non-Hodgkin lymphoma (NHL) present with a mediastinal mass. HL has a bimodal distribution, arising in adolescents and young adults as well as in those older than 50, whereas NHL arises most commonly in older adults.
Primary mediastinal B-cell lymphoma (PMBL) is a distinct subset of NHL that has a similar clinical presentation as classic HL of the nodular sclerosing subtype. Both present in the third or fourth decade of life and tend to affect females. These tumors present as a bulky anterior mediastinal mass involving the thymus (see Fig. 83-6 ). SVC syndrome is a common presentation of PMBL, less so for HL (see and eFig. 83-2 ), which can involve the hilar nodes and lung parenchyma. However, there are distinct and nonoverlapping histologic features. HL is characterized by the Hodgkin/Reed Sternberg cell in a nodular growth pattern with a specific immunophenotype of CD30+, CD45−, and CD15+ in 85% of cases. PMBL is histologically characterized by an infiltrate of large cells in a diffuse pattern with an immunophenotype of a mature B lymphocyte expressing CD20. A B-cell lymphoma that exhibits histologic features of both PMBL and HL has been named “gray zone lymphoma.”
Distinguishing HL from PMBL is important for guiding therapy, thus tissue biopsy is indicated. The current standard of treatment for early stage, bulky mediastinal disease is combined modality therapy, consisting of ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine) and radiation. Optimal therapy for nonbulky mediastinal HL is controversial; recent clinical trials suggest no difference in overall survival but an increase in risk for disease progression with chemotherapy alone. The benefits of radiation therapy must be balanced with the risk for serious late complications, including pulmonary fibrosis, cardiovascular disease, and secondary malignancies such as breast and lung cancer.
PMBL is treated with immunochemotherapy, which includes rituximab with CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone)-based regimens, followed by radiation. Whereas these standard dose regimens have a cure rate of up to 75%, more recent evidence has shown that dose intensity may improve outcomes in PMBL. DA-EPOCH (dose-adjusted etoposide, vincristine, doxorubicin, cyclophosphamide, prednisone, rituximab) has been shown to confer an overall survival of 97% without the need for radiation treatment in the majority of patients. The prognosis of HL and NHL has improved strikingly in the past 2 decades as staging of the disease has been refined and as more effective and less toxic combinations of radiotherapy and chemotherapy have evolved. With new chemotherapy regimens, radiotherapy may not be a necessary part of the treatment plan for PMBL. PET scan, which is often used to restage aggressive lymphomas, appears to have a high negative predictive value and may be helpful for clinicians in deciding when to omit radiotherapy after primary chemotherapy; this is being investigated in an ongoing clinical trial. Effective salvage regimens including bone marrow transplantation have been developed to treat relapsed disease. HL is curable in approximately 75% of patients, although late toxicities of treatment contribute significantly to mortality.
In surgical series, ectopic thyroid glands account for fewer than 10% of mediastinal masses but, in clinical practice, these are probably more common. Thyroid tissue within the mediastinum is of two distinct origins. Most commonly, a cervical goiter extends substernally into the anterior mediastinum. Primary intrathoracic goiter, presumably originating from an embryonic nest of heterotopic thyroid tissue, is rare. Most such goiters are in the anterior mediastinum, but they may arise in the middle or posterior mediastinum as well. Intrathoracic goiter presents predominantly in middle aged or older women. Although it is usually asymptomatic, goiter may cause hoarseness, cough, or swelling of the face and arms. Intrathoracic thyroid tissue is easily recognized by radioactive iodine scanning, as long as the scan is completed before intravenous iodinated contrast injection, which may block iodine uptake for weeks. It may be suspected on the basis of high radiodensity on CT scans, particularly after iodinated contrast injection. Treatment is surgical resection.
Mediastinal parathyroid tissue accounts for up to 10% of cases of hyperparathyroidism, and the mediastinum is the most common site for ectopic parathyroid adenomas in surgically resistant hyperparathyroidism. Half of ectopic parathyroid adenomas lie in the anterior mediastinum, usually near the thymus. Parathyroid cysts may enlarge sufficiently to appear as a mass on the chest radiograph and to produce symptoms, but ectopic tissue may be difficult to locate. Evaluation of the lesion is typically conducted using CT angiography, ultrasound, MRI, and the sensitive technetium-99m sestamibi scanning. Selective arteriography and venous sampling for parathormone levels have largely been supplanted by sestamibi radionuclide scanning. Parathyroid adenomas are cured by complete resection, and resection via VATS is increasingly advocated. Parathyroid carcinoma may be functional, resulting in varying degrees of hyperparathyroidism, but is also locally invasive and may metastasize. Cure is possible with aggressive surgical management that may be guided by imaging and functional localization studies.
Included in this group of unusual mediastinal masses are lipomas, fibromas, mesotheliomas, and lymphangiomas (see Table 83-4 ). They arise from connective tissue, fat, smooth muscle, striated muscle, blood vessels, or lymphatic channels and can be found in any region of the mediastinum. Histologically and clinically, they are not substantially different from their counterparts elsewhere in the body. Unless the lesion is very large, the presence of symptoms usually indicates that the lesion is malignant.
Lipoma is the most common mesenchymal tumor of the mediastinum and is most often located in the anterior mediastinum. It may be encapsulated or unencapsulated, appearing as a smooth and rounded lesion with well-defined margins. The characteristic low density of lipomas on CT images ( Fig. 83-11 ) permits a confident diagnosis unless there is associated heterogeneity, invasion of surrounding tissues, or poor demarcation of the mass’s perimeter, in which case malignancy (liposarcoma or lipoblastoma) or teratoma must be excluded. Considerably more common than lipoma is mediastinal lipomatosis, or generalized overabundance of histologically normal unencapsulated fat (see Fig. 83-2 ). Mediastinal lipomatosis appears on the conventional radiograph as a smooth widening or bulging of normal mediastinal contours, and its low homogeneous CT density confirms the diagnosis. Mediastinal lipomatosis does not compress or displace other mediastinal structures.