AUTHOR AND EDITOR INFORMATION

Section 1 of 13  

• Authors and Editors
• Introduction
• Indications
• Relevant Anatomy
• Contraindications
• Workup
• Treatment
• Complications
• Outcome and Prognosis
• Future and Controversies
• Acknowledgments
• Multimedia
• References

INTRODUCTION

Section 2 of 13  

• Authors and Editors
• Introduction
• Indications
• Relevant Anatomy
• Contraindications
• Workup
• Treatment
• Complications
• Outcome and Prognosis
• Future and Controversies
• Acknowledgments
• Multimedia
• References

The thymus gland is located in the anterior portion of the mediastinum. Various tumors, cysts, and other abnormalities related to the thymus can develop. An understanding of the embryology of this area, and of the anatomic relationships of the normal structures within the mediastinum, is essential for the proper diagnosis of a mass or tumor located in this area.

History of the Procedure

A few surgeons in the late 1800s and early 1900s attempted and described surgical approaches to the mediastinum. In 1888, Nassiloff first showed that the esophagus was accessible using a posterior approach. In this time frame, with no ability to safely manage the airway or ventilation, such a surgical approach had to remain completely extrapleural because perforation of the pleura would result in a fatal pneumothorax.

Not long afterward, other surgeons began to approach abnormalities of the anterior mediastinum, specifically tumors and infections of the thymus and anterior mediastinal lymph nodes. In 1893, Bastinelli described the removal of an anterior mediastinal dermoid cyst. The procedure required resection of the manubrium, but the patient recovered.

In 1897, Milton wrote extensively on mediastinal surgery using the median sternotomy approach. He first tried this approach on human cadavers, finding that median sternotomy gave him excellent access to the mediastinum. He then used the same approach to explore the mediastinum of a live goat. Although he entered the pleural cavities of the animal, he was able to perform a tracheostomy and give artificial respiration through the opening. This support enabled him to explore the mediastinum successfully and allowed the animal to have an uneventful recovery. Milton then described a human case in which he resected most of a tuberculous sternum and 2 large tuberculous lymph nodes from the mediastinum, successfully avoiding the pleural spaces. This patient did well.

In 1940, Heuer published a monograph on mediastinal tumors. Most of the cases he referenced were from the 1920s and 1930s and, in spite of Milton's previously described work, no reference was made to the use of median sternotomy as an acceptable surgical approach to the mediastinum.

Heuer noted that at that time, dermoid cysts and teratomas were the most commonly found tumors of the mediastinum. He also described successful removal of neurogenic tumors from the posterior mediastinum and described a number of types of thymic tumors.

In 1939, Alfred Blalock reported the first case in which symptoms of myasthenia gravis were completely relieved by removal of a thymic tumor, thus initiating a surgical option in the treatment of that disease.

Problem

Any discussion of masses and tumors of the mediastinum requires delineation of the boundaries of that area. The portion of the thorax defined as the mediastinum extends from the posterior aspect of the sternum to the anterior surface of the vertebral bodies and includes the paravertebral sulci. The mediastinum is limited bilaterally by the mediastinal parietal pleura and extends from the diaphragm inferiorly to the level of the thoracic inlet superiorly.

Because a number of mediastinal tumors and other masses are found most commonly in particular mediastinal locations, many authors have artificially subdivided the area for better descriptive localization of specific lesions. Usually, the mediastinum is subdivided into 3 spaces or compartments (ie, anterior, middle, posterior) when discussing the location or origin of specific masses or neoplasms. The anterior compartment extends from the posterior surface of the sternum to the anterior surface of the pericardium and great vessels. The middle compartment, or middle mediastinum, is located between the posterior limit of the anterior compartment and the anterior longitudinal spinal ligament. The posterior mediastinum comprises the area posterior to the heart and trachea and includes the paravertebral sulci.

The most common tumors and masses in the anterior compartment are of thymic, lymphatic, or germ cell origin; thymic is the most common. Less commonly, masses associated with aberrant parathyroid or thyroid tissue are found. Neoplasms and other masses originating from vascular or mesenchymal tissues also occur in this area.

While neoplasms of the middle mediastinum are most commonly of lymphatic origin, neurogenic tumors also may occasionally occur in this area. Another significant group of masses identified in this compartment are cystic structures associated with developmental abnormalities of the primitive foregut or the precursors of the pericardium or pleura. They include bronchogenic, esophageal, gastric, and pleuropericardial cysts. In addition, more complex cysts related to embryologic abnormalities, such as neurenteric or gastroenteric cysts, can develop. Isolated cystic abnormalities of lymphatic origin, such as hygromas or lymphangiomas, can develop within the middle mediastinal compartment; however, more commonly they are extensions of these abnormalities from the cervical lymphatics.

Neurogenic tumors are, by far, the most common neoplasm of the posterior mediastinum. Tumors originating from lymphatic, vascular, or mesenchymal tissues can also be found in this compartment.

Frequency

A review of collected series reveals that many mediastinal neoplasms and masses vary in incidence and presentation depending on patient age. Also, as noted previously, a number of mediastinal tumors characteristically occur in specific areas within the mediastinum.

In adults, historically, thymic tumors have been described as the second most common type of mediastinal tumor or cyst found, following neurogenic tumors in frequency of occurrence. Lymphomas and germ cell tumors are next in frequency in adults, followed by foregut and pericardial cysts. More recent data seem to indicate that thymomas occur with greater frequency compared to neurogenic tumors.

In children and infants, neurogenic tumors are also the most commonly occurring tumor or cyst, followed by foregut cysts, germ cell tumors, lymphomas, lymphangiomas and angiomas, tumors of the thymus, and pericardial cysts.

In patients younger than 20 years or older than 40 years, approximately one third of mediastinal tumors are malignant, while in patients aged 20-40 years, roughly half are malignant.

Approximately two thirds of mediastinal tumors and cysts are symptomatic in the pediatric population, while only approximately one third produce symptoms in adults. The higher incidence of symptoms in the pediatric population is most likely related to the fact that a mediastinal mass, even a small one, is more likely to have a compressive effect on the small, flexible airway structures of a child.

When considering all age groups, nearly 55% of patients with benign mediastinal masses are asymptomatic at presentation, compared to only approximately 15% of those in whom masses are found to be malignant.

Thymoma is the most common anterior mediastinal tumor in adults, accounting for almost 50% of the neoplasms occurring in this compartment. Thymoma is rare in children and teenagers.

Etiology

Thymic neoplasms and cysts

The tumors and cysts found in the mediastinum result from several causes. Several different lesions originate from the thymus, including thymomas, thymic carcinomas, thymic neuroendocrine tumors, thymic hyperplasia, thymic cysts, and thymolipomas.

Thymomas originate from either the cortical or medullary epithelial cells of the thymus. They are considered histologically benign tumors even though they may exhibit clinically invasive behavior.

Thymic carcinomas are, for the most part, of epithelial origin, although a few other unusual cell types can be found. All these lesions are very uncommon, and several are rare. They include some with low malignant potential (eg, well-differentiated squamous cell carcinoma, basaloid carcinoma, mucoepidermoid carcinoma) and those with features of a more aggressive malignancy (eg, sarcomatoid carcinoma, clear cell carcinoma, neuroendocrine carcinoma, lymphoepitheliomalike tumors, anaplastic undifferentiated tumors).

Primary neuroendocrine carcinomas of the thymus, previously termed thymic carcinoids, are extremely rare. They are believed to have their origins from endodermal or foregut cellular precursors, similar to neuroendocrine tumors in other anatomic locations. In addition, as with other neuroendocrine tumors, a spectrum of differentiation exists for these tumors, ranging from the more indolent well-differentiated type to the very aggressive, poorly differentiated neuroendocrine carcinoma.

Thymic hyperplasia, while not a distinct neoplasm, is described here because it represents abnormal growth of the thymus. Follicular or lymphoid hyperplasia of the thymus is frequently found in association with autoimmune disorders, especially in patients with myasthenia gravis. Massive or idiopathic hyperplasia is a rare benign condition identified in children and characterized by extensive uniform thymic enlargement secondary to benign cellular proliferation. Thymic hyperplasia may also occur in children as a response to the cessation of chemotherapeutic treatment of Hodgkin disease or other malignancies. This condition is termed thymic rebound.

Thymic cysts may be congenital or acquired. Congenital cysts are thin-walled and characteristically have thymic tissue in their lining. They are thought to be remnants of the thymopharyngeal duct and can be found at any point along the course of the thymus as it migrates from the neck into the mediastinum during embryologic development. Other cysts can occur within the thymus in association with thymomas or other neoplastic or inflammatory processes of the anterior mediastinum.

Thymolipomas are benign thymic neoplasms made up of well-differentiated adipose and thymic tissue. Because of the large proportion of adipose tissue within these tumors, they are sometimes categorized as mesenchymal tumors.

Ectopic tumors of thymic origin can be found in the neck, pericardium, pleura, and lung. Three additional tumors are found outside the mediastinum with presumed thymic origin. These tumors are ectopic hamartomatous thymoma (benign), spindle epithelial tumor with thymus-like differentiation (malignant), and carcinoma showing thymic-like differentiation (malignant).

Pathophysiology

Tumors and cysts of the mediastinum can produce abnormal effects at both systemic and local levels.

Local Pathophysiology

Because of the malleable nature and small size of the pediatric airway and other normal mediastinal structures, benign tumors and cysts can produce local effects. This is more evident in children than in adults. Compression or obstruction of portions of the airway, the esophagus, or the right heart and great veins by an enlarging tumor or cyst can occur easily and result in a number of symptoms. Infection can occur primarily within some of these mediastinal lesions, particularly those of a cystic nature, or can result secondarily in nearby structures (eg, lungs) as a result of local compression or obstruction.

Malignant mediastinal tumors can cause all of the same local effects as those associated with benign lesions but, in addition, can produce abnormalities by invasion of local structures. Local structures most commonly subjected to invasion by malignant tumors include the tracheobronchial tree and lungs, esophagus, superior vena cava, pleura, chest wall, and any adjacent intrathoracic nerves. Pathophysiologic changes that can be produced by invasion of specific structures are obstructive pneumonia and hemoptysis, dysphagia, superior vena cava syndrome, and pleural effusion. Changes can also include various neurologic abnormalities, such as vocal cord paralysis, Horner syndrome, paraplegia, diaphragmatic paralysis, and pain in the distribution of specific sensory nerves.

Systemic Pathophysiology

Certain mediastinal tumors can produce systemic abnormalities. Many of these manifestations are related to bioactive substances produced by specific neoplasms.

Thymic neoplasms

The most common systemic manifestation associated with thymoma is myasthenia gravis. This occurs in 10-50% of patients with thymoma and is thought by many to be an autoimmune phenomenon because a high titer of antiacetylcholine receptor antibodies is present in these patients. Only approximately 10-15% of patients presenting with myasthenia gravis are found to have a thymoma. The vast majority of patients with myasthenia who do not have a thymoma are found to have thymic hyperplasia, and only approximately 10-20% have no identifiable abnormality of the thymus gland.

Other, less common, syndromes can be associated with thymoma. These include other neuromuscular syndromes, hematologic syndromes, immune deficiency syndromes, bone disorders, collagen diseases and autoimmune disorders, endocrine disorders, renal disease, and dermatologic diseases. Neuromuscular syndromes besides myasthenia gravis include myotonic dystrophy, Eaton-Lambert syndrome, and myositis. Hematologic syndromes include red blood cell aplasia, erythrocytosis, pancytopenia, megakaryocytopenia, T-cell lymphocytosis, acute leukemia, and multiple myeloma. Immune deficiency syndromes include hypogammaglobulinemia and T-cell deficiency syndrome.

The only reported bone abnormality is hypertrophic osteoarthropathy. Collagen diseases and autoimmune disorders include systemic lupus erythematosus, rheumatoid arthritis, polymyositis, myocarditis, Sjögren syndrome, and scleroderma. Endocrine disorders include hyperparathyroidism, Hashimoto thyroiditis, Addison disease, and chemodectoma. Renal disorders include nephrotic syndrome and minimal change nephropathy. Dermatologic diseases include pemphigus and chronic mucocutaneous candidiasis. The mechanisms that produce these systemic manifestations are not entirely understood but are believed to be autoimmune in nature.

Thymic carcinoid tumors are able to produce vasoactive substances similar to pulmonary carcinoid tumors. These tumors can produce excess adrenocorticotropic hormone (ACTH) or antidiuretic hormone. The clinical manifestations of these high levels of circulating hormone would be evident.

Clinical

Many mediastinal tumors and cysts produce no symptoms and are found incidentally after chest radiography or other imaging studies of the thorax. Symptoms are present in approximately one third of adult patients with any type of mediastinal tumor or cyst but are observed more commonly in the pediatric population, in which nearly two thirds present with some symptoms. In adults, asymptomatic masses are more likely to be benign.

Approximately 50% of individuals presenting with thymomas are clinically asymptomatic. When symptoms are present with these neoplasms, they may be manifested as local or systemic symptoms or a combination of both. Ill-defined chest pain, cough, and shortness of breath are the most commonly identified associated symptoms. More severe symptoms, such as superior vena cava syndrome, phrenic nerve paralysis, or recurrent laryngeal nerve involvement resulting in hoarseness, are less common but are often indications of malignant disease. Invasion of the chest wall or pleura can also occur with a malignant neoplasm. This can produce persistent pleural effusions and a significant amount of local pain. Other constitutional symptoms associated with thymoma in almost 20% of patients include weight loss, fever, fatigue, and night sweats.

Mediastinal tumors that produce bioactive substances are associated with symptoms produced by those substances (see Systemic pathophysiology).

INDICATIONS

Section 3 of 13  

• Authors and Editors
• Introduction
• Indications
• Relevant Anatomy
• Contraindications
• Workup
• Treatment
• Complications
• Outcome and Prognosis
• Future and Controversies
• Acknowledgments
• Multimedia
• References

Treatment selection for a given mediastinal tumor or cyst depends on the diagnosis of the lesion being investigated. Surgical resection is indicated in a large percentage of cases.

Thymic lesions

Because complete surgical resection is the most critical factor in long-term patient survival, all neoplasms of the thymus gland (except widely metastatic thymoma) should be completely resected. This includes thymoma, thymic carcinomas, thymolipomas, and neuroendocrine tumors of the thymus. Thymic cysts are also generally treated with surgical resection because most manifest as cystic anterior mediastinal masses of an undefined etiology.

Resection of the thymus is also indicated in persons with myasthenia gravis, although a thymic neoplasm is identified in only approximately 15-20% of these patients. The abnormality that is found is known as lymphoid or follicular thymic hyperplasia and is identified in more than 60% of patients with myasthenia. No thymic abnormality is identified in the remainder of these patients.

RELEVANT ANATOMY

Section 4 of 13  

• Authors and Editors
• Introduction
• Indications
• Relevant Anatomy
• Contraindications
• Workup
• Treatment
• Complications
• Outcome and Prognosis
• Future and Controversies
• Acknowledgments
• Multimedia
• References

The portion of the thorax defined as the mediastinum extends from the posterior aspect of the sternum to the anterior surface of the vertebral bodies and includes the paravertebral sulci when defining the location of specific mediastinal masses. It is limited bilaterally by the mediastinal parietal pleura and extends from the diaphragm inferiorly to the level of the thoracic inlet superiorly.

Traditionally, the mediastinum is artificially subdivided into 3 compartments for better descriptive localization of specific lesions. Most commonly, the compartments or spaces are defined as anterior, middle, and posterior with regard to the location or origin of specific masses or neoplasms.

The anterior compartment extends from the posterior surface of the sternum to the anterior surface of the pericardium and great vessels. It normally contains the thymus gland, adipose tissue, and lymph nodes. Neoplasms, cysts, and other abnormalities of thymic origin are found in this space.

CONTRAINDICATIONS

Section 5 of 13  

• Authors and Editors
• Introduction
• Indications
• Relevant Anatomy
• Contraindications
• Workup
• Treatment
• Complications
• Outcome and Prognosis
• Future and Controversies
• Acknowledgments
• Multimedia
• References

Contraindications to surgical correction of thymic tumors are based on the patient's comorbidities and his or her ability to tolerate surgery. Widely metastatic thymoma is also a contraindication to surgical resection.

WORKUP

Section 6 of 13  

• Authors and Editors
• Introduction
• Indications
• Relevant Anatomy
• Contraindications
• Workup
• Treatment
• Complications
• Outcome and Prognosis
• Future and Controversies
• Acknowledgments
• Multimedia
• References

Lab Studies

• Hemoglobin, hematocrit, and white blood cell count
• • Red blood cell aplasia is found in approximately 5% of patients with thymoma and manifests as a normochromic-normocytic anemia. These studies are not routinely performed for evaluation of a mediastinal mass, but red blood cell aplasia may be an abnormality found in association with a mediastinal mass.
  • Although rare, neutropenia can be found in association with thymomas. These studies are also not part of the routine evaluation of a mediastinal mass, but neutropenia may be an associated abnormality.
• Gamma globulin levels: Hypogammaglobulinemia is associated with some cases of thymoma.
• Adrenocorticotropic hormone (ACTH) levels
• • The thorax should always be investigated for the source of ectopic ACTH production.
  • If the workup of a patient with Cushing syndrome calls for investigation for an extra-adrenal source, a neuroendocrine or carcinoid tumor of the thorax should be excluded. These tumors occur in the mediastinum, particularly in the thymus gland, and in the lung.
• Antidiuretic hormone levels: These may be elevated with some neuroendocrine tumors of the thymus.

Imaging Studies

• Chest radiography
• • Posteroanterior and lateral radiographs of the chest taken for an unrelated cause are the usual ways an asymptomatic mediastinal mass is identified. Chest radiography is obviously the first radiologic study that would be performed in an individual with symptoms referable to the thorax. Most thymic neoplasms are visualized on standard chest radiograph.
  • The lateral chest radiograph is very helpful in the determination of the involved compartment of the mediastinum. This information, combined with the age, sex, and associated clinical findings, aids the physician in the proper choice of subsequent diagnostic studies.
• CT scan of the chest and mediastinum
• • CT is a routine part of the diagnostic evaluation of mediastinal tumors, cysts, and other masses.
  • CT scans can greatly assist in determining the exact location of the mediastinal tumor and its relationship to adjacent structures. These images are also useful in differentiating masses that originate in the mediastinum from those that encroach on the mediastinum from the lung or other structures.
  • CT is very useful for helping differentiate tissue densities. This greatly assists in distinguishing structures that are cystic or vascular from those that are solid.
  • CT is the preferred imaging modality to visualize a thymoma. However, thymomas have no absolute diagnostic features; they are usually homogeneous and enhance with contrast. CT scan images can reveal evidence of local invasion of adjacent structures by a mass or the presence of intrathoracic metastases.
• Magnetic resonance imaging
• • MRI is useful in both the initial diagnosis of a mediastinal mass and in the follow-up evaluation after treatment. MRI can help differentiate between a possible mediastinal mass and a vascular abnormality such as an aortic aneurysm.
  • MRI offers direct multiplanar imaging. It can be used when iodinated contrast cannot be given. MRI provides increased detail in the subcarinal and aortopulmonary window areas and in the inferior aspects of the mediastinum at the level of the diaphragm.
  • MRI adds little that CT does not provide and should not be performed except under special circumstances.
• Radionuclide scanning
• • The origin of a mass located at the thoracic inlet can occasionally be difficult to identify. Additional testing, at times, may be required to better identify such a mass and help differentiate whether it is of thymic, thyroid, or other origin.
  • While the iodine I 131 or iodine I 123 scans are specific for thyroid tissue, they are mentioned here because they are very helpful in distinguishing thyroid tissue from other masses. They are often used in identifying an anterior mediastinal mass located at the level of the thoracic inlet as the substernal extension of a cervical thyroid goiter. A radioactive iodine scan may also help identify ectopic thyroid tissue within the mediastinum. These studies must be performed before any tests requiring the administration of iodinated contrast because this material may interfere with thyroid uptake and scanning.
  • The octreotide scan, using indium In 111–labeled pentetreotide, is useful for localizing various neuroendocrine neoplasms, including carcinoid tumors, pheochromocytomas, and paragangliomas. Carcinoid tumors, although uncommon, can occur in the thymus.
• Echocardiography and ultrasonography
• • Ultrasonographic methods have been used to differentiate solid from cystic mediastinal masses and to assist in determining if a connection is present between a mass and adjacent structures. These studies are more useful in the evaluation of cardiac abnormalities than in the evaluation of mediastinal tumors.
  • Given the accuracy and detail provided by CT scan images, MRI, and selected radionuclide scan images, ultrasound techniques are generally not used as primary tools in the evaluation of mediastinal tumors and cysts.
• Positron emission tomography (PET) scan (Click here to complete a Medscape CME activity on PET scanning.)
• • PET scans have been studied extensively for the evaluation of a number of neoplasms, such as lung, colorectal, breast, lymphoma, and melanoma. Its usefulness in the evaluation of mediastinal tumors is unknown.
  • Some results of using PET scan for thymomas suggest that a high 18-fluorodeoxyglucose (FDG) uptake on PET scan reflects the invasiveness of malignant nature of thymic tumors and can be used to differentiate these from benign thymomas.¹ A preliminary report suggests that PET scanning is a sensitive test for thymomas.²

Diagnostic Procedures

• Transthoracic needle biopsy
• • In the past, percutaneous biopsy methods were believed to be too dangerous to use in the evaluation of mediastinal masses, and open surgical biopsy was the diagnostic procedure of choice.
  • Although still controversial, CT-guided fine-needle aspiration and core-needle biopsy techniques are being used with increasing success at several centers.^{3, 4} Differentiation between thymomas, lymphomas, and germ cell tumors can be achieved in a number of cases when tissue obtained from a core-needle biopsy is subjected to special histologic staining methods, including immunohistochemical techniques. In some cases, lymphoma subtypes can also be identified.
  • Importantly, expert clinical judgment is necessary when selecting appropriate cases for this diagnostic method. In addition, considerable expertise in tissue processing and analysis is necessary for diagnostic accuracy. Many consider tumor size an important factor when deciding to proceed with needle biopsy. Tumors larger than 5 cm can be considered for biopsy because preoperative chemotherapy may be considered for invasive thymoma and thymic carcinoma.
• Cervical mediastinoscopy and substernal extended mediastinotomy
• • Cervical mediastinoscopy is a commonly used surgical diagnostic procedure for the evaluation of the retrovascular pretracheal area of the mediastinum. It is used most often for staging of bronchogenic carcinoma and for evaluation of hilar and paratracheal lymphadenopathy, but it can be modified into what has been termed a substernal extended mediastinoscopy to evaluate the prevascular area of the mediastinum.
  • The thymus and any tumors or cysts found in this area, as well as lymph nodes of the aortopulmonary window, are accessible for biopsy using this approach.
• Anterior mediastinotomy
• • This parasternal approach to the mediastinum has been used most commonly in situations in which standard cervical mediastinoscopy was believed or found to be inadequate.
  • The classic approach is to the upper left parasternal area in order to obtain access to the aortopulmonary window and areas of the anterior mediastinum inferior to the aortic arch.
  • Anterior mediastinotomy is being replaced in many centers, either by extended cervical mediastinoscopy or video-assisted thoracic surgical (VATS) techniques.⁵
• Video-assisted thoracoscopy
• • VATS techniques have been used successfully for biopsy of various masses in all areas of the mediastinum.⁶ VATS is commonly used for the sampling of perihilar lymph nodes or masses that are accessible via either thoracic cavity.
  • VATS is superior to the various indirect biopsy techniques because it allows direct visualization of the mass or lesion from where the biopsy sample will be taken and a view of nearby structures and organs. This gives the surgeon an excellent idea of tumor extent and resectability.
• Sternotomy and thoracotomy
• • In spite of the numerous minimally invasive options available for histologic diagnosis of mediastinal tumors and cysts, open surgical access is needed at times.
  • In some cases, standard sternotomy or thoracotomy may be the safest method available to obtain an adequate tissue diagnosis.
  • Ministernotomy can also be used for complete resection of a localized thymoma.

Histologic Findings

Thymoma

Thymomas arise from thymic epithelial cells. They are generally composed of 2 cell types, epithelial and lymphocytic. The morphology of the epithelial cells can be round, oval, or spindle-shaped. The cells are rather large and tend to organize into clusters. They have vesicular nuclei with small nucleoli and cytoplasm that is eosinophilic or amphophilic. The spindle-shaped variety of epithelial cell is often arranged in a whorl-type pattern. Individual cells have an appearance similar to that of fibroblasts. The lymphocytic component of thymomas is made up of mature lymphocytes with no significant atypia.

Thymomas are generally classified as predominantly epithelial, predominantly lymphocytic, mixed lymphoepithelial, and spindle cell type, which is a variant of the epithelial type and is composed mostly of the spindle-shaped epithelial cells. Other microscopic features that have been noted include Hassall corpuscles, keratinizing squamous epithelium, rosettes, glands and pseudoglands, cysts, papillary structures, and germinal centers. These features do not appear to have any significance in predicting the activity of the tumor.

Cellular makeup is not the prime consideration in the determination of a thymoma's malignant or indolent potential. The most important features are the gross pathologic characteristics. These include encapsulation of the tumor and fixation or invasion of adjacent structures. While no thymoma is truly benign, well-encapsulated thymomas with no evidence of invasion of the capsule are considered much less aggressive. Any evidence of invasion of the capsule or adjacent structures suggests a much more malignant level of activity.

Immunohistochemical staining methods with antikeratin antibodies can be helpful in the histologic identification of a thymoma. A number of thymic epithelial markers, such as cytokeratin, thymosin beta-3, thymosin alpha-1, and epithelial membrane antigen, have also been used.

Thymic carcinomas

The various types of carcinoma that occur in the thymus are quite rare. Squamous cell carcinoma of the thymus resembles typical squamous cell carcinoma. Well-differentiated tumors display prominent lobulation and are composed of large polygonal cells in groups or cords connected by intercellular bridges. The nuclei are vesicular or densely pigmented and have distinct nucleoli. The cytoplasm is eosinophilic, and keratin "pearls" are common. These tumors may be only locally invasive.

Poorly differentiated squamous cell tumors are more aggressive locally, have little of the lobular architecture found in the well-differentiated form, and may metastasize to distant sites. These tumors have a more disarrayed architecture and cellular atypia. Distinct fibrous septae or bridges within the tumor often are lacking. Cytoplasm is sparse and amphophilic. Keratin pearls are not seen.

Lymphoepitheliomalike carcinoma of the thymus is made up of dense sheets of polygonal epithelial cells with indistinct cytoplasmic membranes. These cells have round vesicular nuclei, large eosinophilic nucleoli, and amphophilic cytoplasm. The tumors always have groups of lymphocytes interspersed throughout. These tumors are virtually identical to lymphoepitheliomas located in the nasopharynx.

Neuroendocrine tumors of the thymus

These tumors have features virtually identical to neuroendocrine tumors identified in other parts of the body. A spectrum of disease exists for this type of tumor, ranging from the well-differentiated or typical carcinoid tumor to the highly aggressive small cell carcinoma.

In the more well-differentiated or typical carcinoid type, cells are arranged in nests surrounded by fibrovascular septae or are situated in cords or ribbons with minimal septation. Cells are small and have a regular shape with round nuclei that have clumped chromatin within them. The cytoplasm is abundant and acidophilic.

More poorly differentiated neuroendocrine tumors have more pronounced atypia. Nuclei are larger and have nucleoli that are more prominent. Mitotic figures are more frequent. The general architecture of these tumors takes on a more monotonous sheetlike appearance. Areas of necrosis are common.

Poorly differentiated tumors equivalent to small cell carcinoma have sheets or cords of remarkably atypical cells, large areas of necrosis, and high mitotic activity. Immunohistochemical staining, particularly using chromogranin, can be very helpful in identifying neuroendocrine tumors.

Staging

A great deal of controversy has been raised about the staging of thymomas. Two staging systems are used for thymomas, based on the specific feature of the tumor. In the most commonly used system, thymomas are staged based on gross and microscopic features of the encapsulation or invasiveness of the tumor. This staging system is referred to as the Masaoka system, and several other authorities have modified it further.

The other staging method, put forth by Marino and Muller-Hermelink, is based on the cell type found within a given thymoma. Thymomas are classified as cortical, medullary, or mixed. The most accurate method of staging is likely some combination of these systems.

• Masaoka postsurgical staging of thymomas
• • Stage I: Grossly, the tumor is completely encapsulated. Microscopically, no invasion of the capsule is seen.
  • Stage II
  • • IIA: Grossly, invasion is seen into the surrounding fatty tissues or mediastinal pleura.
    • IIB: Microscopically, tumor invasion is seen extending into the capsule.
  • Stage III: Gross evidence of invasion into an adjacent organ or structure (eg, pericardium, lung, great vessels, including vena cava) is seen.
  • Stage IV
  • • IVA: Tumor dissemination is seen in the pleura or pericardium.
    • IVB: Evidence of hematogenous or lymphogenous metastases is present.

TREATMENT

Section 7 of 13  

• Authors and Editors
• Introduction
• Indications
• Relevant Anatomy
• Contraindications
• Workup
• Treatment
• Complications
• Outcome and Prognosis
• Future and Controversies
• Acknowledgments
• Multimedia
• References

Medical Therapy

While most tumors and cysts of the mediastinum are treated surgically, medical therapy is the primary form of treatment in several diseases. Thymic neoplasms are discussed as follows:

Thymoma

Although surgical resection is the preferred treatment for thymoma, patients with clinically unresectable extrathoracic disease require radiation therapy, chemotherapy, or both. Radiation therapy is an essential part of the treatment of any thymoma with invasive characteristics. Controversy exists regarding the use of radiation therapy for patients with stage I tumors; however, it is recommended unanimously for those with tumors in more advanced stages. Radiation therapy has also been used preoperatively to facilitate the resection of bulky tumors; however, this role is usually played by chemotherapy.

Cisplatin-based chemotherapy regimens are often recommended for patients with unresectable stage III disease or with disseminated stage IV disease. Chemotherapy is also a useful induction agent for locally advanced thymomas to facilitate resection of these bulky tumors. Cisplatin-based regimens have shown promise for improving both resectability and long-term patient survival.

Thymic carcinoma

Because the number of these cases is limited, limited data are available regarding specific modes of treatment. Radiotherapy may be indicated for thymic carcinoma, as some long-term patient survival has been achieved even with radiation as a primary modality of treatment.

Cisplatin-based chemotherapy protocols have been used in some cases of undifferentiated mediastinal carcinoma and may be applicable to cases of recurrent or metastatic disease. Because cases are limited, the effectiveness of treatment regimens is difficult to evaluate. Several cases describe some long-term survivors.

Neuroendocrine tumors of the thymus

Radiation and chemotherapy have not been found beneficial in the treatment of thymic neuroendocrine malignancies. Radiation therapy has been reported to provide local control and help limit symptoms due to paraneoplastic syndromes.

Surgical Therapy

Surgical resection is the treatment of choice for most neoplasms that occur in the mediastinum.

In cases of benign neoplasms, complete excision of the lesion itself is generally sufficient. Thymoma is one exception to this principle because, in addition to removal of the tumor, total thymectomy is indicated for all thymomas. All benign neoplasms that are encapsulated should be resected without violating the capsule.

In cases of malignant neoplasms, complete resection including local extension should be included as indicated. Pericardium, brachiocephalic vein, superior vena cava, lung, pleura, sternum, ribs, phrenic nerve, and diaphragm have all been resected with extensive malignant thymomas.

Preoperative Details

Standard preoperative management applicable to all thoracic surgical cases applies to the preoperative treatment of individuals undergoing resection of mediastinal tumors. Airway management is of paramount importance when dealing with tumors that can produce a mass effect on these structures. Safe management of the airway distorted or narrowed by a mediastinal mass involves (1) performing a detailed preoperative assessment of the airway, (2) achieving adequate visualization, and (3) having supplementary equipment (eg, flexible bronchoscope) readily available. Placement of a double-lumen endotracheal tube to provide single-lung ventilation is usually preferred for any procedure in which a thoracotomy approach is used.

Some mediastinal tumors may require extensive resection of adjacent tissues, and blood loss may be substantial in these cases. Provide for adequate intravenous access, appropriate monitoring capability, and necessary blood products, all extremely important, before surgery is begun.

Involvement of associated intrathoracic structures by tumor may mandate their resection. Pulmonary resection, excision of nervous system structures (eg, phrenic, vagus, sympathetic chain), sternum, rib, or even resection of major vascular structures (eg, superior vena cava, brachiocephalic vein) may be required. The surgeon must be prepared for this, and the patient must be informed preoperatively that such resection may be required because this may have additional impact on recovery and perioperative risk.

Several mediastinal tumors can produce important effects that should be taken into account preoperatively.

Superior vena cava syndrome

Superior vena cava syndrome (SVCS) can occur in association with a variety of thoracic neoplasms. While bronchial carcinoma represents the most common cause of this problem, lymphoma, germ cell malignancies, thymic neoplasms, and a host of the less common mediastinal malignancies can produce the syndrome.

If SVCS is noted to be acute in a preoperative patient, treatment with bedrest, elevation of the head, and oxygen administration can be helpful. Salt restriction and diuretics are generally not indicated. Corticosteroids can be useful for treatment of associated laryngeal edema or in the presence of brain metastases producing increased intracranial pressure. High-dose corticosteroids can result in a transient reduction in size of some mediastinal neoplasms, such as lymphomas, and may be useful as immediate treatment.

Care must be used in the placement of intravenous lines because venous inflow to the heart from the supracardiac great veins will be greatly altered. Many clinicians place intravenous lines in sites below the level of the heart to assure direct, rapid flow of medications and fluids to the heart. Try to not place intravenous lines in the neck because jugular venous pressure may be markedly elevated and accidental extravasation of blood from these sites may lead to airway compromise.

Intubation must be performed with care in individuals with SVCS because trauma to the airway may lead to disruption of small venous structures in the wall of the trachea. Normally, bleeding from these tiny vessels is self-limiting; however, in patients with SVCS, venous pressure is elevated and bleeding may be more pronounced. Individuals with SVCS may not be able to lie comfortably in a supine position for an extended period because this produces increased intracerebral venous pressure. Take this factor into account during transport and positioning of the patient.

Myasthenia gravis

Approximately 30-50% of individuals with thymomas have some clinical evidence of myasthenia gravis. Attempts to stabilize neuromuscular symptoms associated with this disease with medical treatment prior to surgery are important. Medications used include pyridostigmine bromide (Mestinon), corticosteroids, and various immunosuppressive agents. If symptoms cannot be stabilized with medication, plasmapheresis is indicated. This preoperative management should be performed in conjunction with neurologist consultation.

Anesthetic considerations are directed at avoidance of perioperative myasthenic crisis and management of medications so that respiratory function and muscle strength are maximal at the completion of surgery. Usually, only a mild sedative and atropine are given preoperatively. Anticholinergic medications are avoided, as are muscle relaxants. Appropriate levels of anesthesia are obtained using inhalation agents and short-acting narcotics. Airway management with single-lumen endotracheal intubation is performed and presents no problem. Some centers use perioperative short courses of high-dose corticosteroids.

Intraoperative Details

As with all thoracic surgery, the position of the patient is of paramount importance. Tumors or cysts located in the anterior mediastinum are generally approached through a median sternotomy. This approach is used for tumors of the thymus, although many incisions are appropriate. Tumors and cysts located in the posterior or middle mediastinum and paravertebral sulci, such as most neurogenic tumors and foregut cysts, are approached through a posterolateral thoracotomy incision. Lateral thoracotomy and bilateral subcostal incision with transverse sternotomy (clamshell) have also been used in the treatment of thymomas. These incisions may be prudent for a small number of cases, including recurrent disease or tumor extension into the posterior mediastinum. Partial sternotomy and a transcervical approach have also been used; these approaches offer a cosmetic advantage. The da Vinci Surgical System (Intuitive Surgical, Inc., Sunnyvale, Calif) has been reported to be used for thymectomy.⁷

Standard single-lumen endotracheal intubation is appropriate for resections performed via the median sternotomy approach. Use of a double-lumen endotracheal tube for single-lung ventilation is preferable for those procedures performed through a thoracotomy incision, clamshell, and VATS.

VATS has been used for resection of selected tumors of the mediastinum. Thymectomy for encapsulated thymomas that range from small to moderate in size has been performed using this method, as has resection of various neurogenic tumors and foregut cysts. Regardless of the method chosen to accomplish thymectomy, this operation requires complete removal of all thymic tissue, which generally includes a large adipose component in the adult. When this is performed, certain mediastinal structures are virtually skeletonized. Care must be taken during these procedures to avoid damage to the phrenic nerves and to the brachiocephalic veins.

Extensive thymic tumors may be found to invade the superior vena cava or the brachiocephalic veins. Some of these structures may be resected with the tumor. Should this be necessary, a number of options are available for replacement of the superior vena cava or the innominate vein. Autologous venous, pericardial, and prosthetic grafts have been used.

Postoperative Details

Care of patients after resection or biopsy of mediastinal tumors is similar to that for any noncardiac surgery of the chest.

Extubation can be performed at the completion of the case or shortly thereafter in the postanesthesia recovery area. Patients who require ventilatory support for a longer period should be treated accordingly.

Pulmonary toilet is an essential part of the postoperative management after any kind of chest surgery to prevent atelectasis and mobilize and clear any bronchial secretions. Various methods are available to assist with pulmonary toilet, including chest physiotherapy, incentive spirometry, and respiratory treatments with inhaled bronchodilators.

Pain control is also a critical factor in postoperative management after thoracic surgery. Adequate cough effort and ventilatory excursion cannot be maintained without satisfactory pain control. Administration of analgesic agents via a thoracic epidural catheter is an excellent and highly effective method of pain management. Lumbar epidural catheters can also be used and, with proper choice of analgesic agents, can provide good pain relief. A continuous infusion of 0.25% bupivacaine at 4 mL/h through the ON-Q elastomeric infusion pump is also a safe and effective adjunct in postoperative pain management after thoracotomy. The use of the ON-Q Post-Op Pain Relief System (I-Flow Corporation, Lake Forest, Calif) results in decreased narcotic use and lower pain scores compared with continuous epidural infusion.

Patient-controlled analgesia is another widely used method and is preferred to traditional intramuscular or intravenous administration of narcotics and other agents. It is not as efficient for pain control compared to epidural analgesia. At some point after oral intake has begun, pain medication can be converted to oral analgesic agents.

Wound management is straightforward. In most cases, operative dressings are removed after 24 hours. Thoracic surgical incisions heal well and have an extremely low rate of dehiscence and infection.

Chest tubes are managed in the same way as those used in other forms of thoracic surgery. Most cases of mediastinal tumor or cyst resection or biopsy do not involve pulmonary or esophageal resection. Chest tubes are maintained on minus 20 cm of water-seal suction, and drainage from the tubes is measured daily. Patients are monitored with daily chest radiographs that are evaluated for residual, undrained collections; complete pulmonary expansion; lobar atelectasis and infiltrates; and other abnormalities. When drainage from the chest tubes is less than 50-100 mL in a 24-hour period, when no air leak is present, and when the chest radiograph shows full pulmonary expansion with no collections on the operated side, the chest tubes may be removed.

Follow-up

Patients who undergo resection of benign neoplasms or mediastinal cysts can be followed for a short time (ie, 3-6 mo) postoperatively while wound healing and progression of patient activity are being monitored.

After resection of a thymoma, patients may be monitored using CBC count, chest radiography, and chest CT studies at appropriate intervals. One published recommendation suggests monitoring postoperative patients with malignant thymoma every 6 months for the first 5 years and annually thereafter. According to this follow-up protocol, a CBC count and chest radiograph are performed every 6 months in the first year, and then these studies, along with chest CT scan, are performed annually.

COMPLICATIONS

Section 8 of 13  

• Authors and Editors
• Introduction
• Indications
• Relevant Anatomy
• Contraindications
• Workup
• Treatment
• Complications
• Outcome and Prognosis
• Future and Controversies
• Acknowledgments
• Multimedia
• References

Appropriate preoperative, intraoperative, and postoperative antibiotic coverage is warranted. Sternal dehiscence occurs very rarely after sternotomy performed for noncardiac procedures. If dehiscence occurs in the absence of infection, the sternum can be debrided and rewired primarily. If infection is present, aggressive debridement of devascularized bone and cartilage is needed, as is vigorous irrigation of the area. Cases in which significant infection is present are best treated with rotation of muscle flaps, such as the pectoralis major and rectus abdominus muscles, to cover the wound. Omentum can also be used in these cases.

Wound infections after thoracotomy are rare. The chest wall has an excellent blood supply, and, with few exceptions, healing occurs readily. Also, existing intrathoracic infection is generally not a factor during resection of any of the noted mediastinal tumors, and these operations are considered clean procedures. The exception to this may be in cases of resection of some foregut cysts that may already have secondary infection.

In infected cases, appropriate preoperative, intraoperative, and postoperative antibiotic coverage is warranted, usually with a third-generation cephalosporin unless a particular organism is isolated. In that case, antibiotic coverage is tailored to the sensitivities reported.

Injury to the phrenic nerve can occur, resulting in temporary or permanent diaphragmatic paralysis. This can cause the patient to have symptomatic dyspnea and atelectasis on the affected side.

Individuals with marginal pulmonary status from underlying pulmonary disease or those with neuromuscular abnormalities causing weakness of the muscles of respiration, such as those with myasthenia gravis, can experience significant respiratory difficulties from this complication.

Injury to a vagus nerve can also occur during surgery of the mediastinum. Usually, only one vagus nerve is injured and the remaining intact nerve maintains parasympathetic input to the gut without symptoms. If both vagus nerves are injured, difficulties with gastric emptying may occur because the innervation to the pylorus is disrupted.

OUTCOME AND PROGNOSIS

Section 9 of 13  

• Authors and Editors
• Introduction
• Indications
• Relevant Anatomy
• Contraindications
• Workup
• Treatment
• Complications
• Outcome and Prognosis
• Future and Controversies
• Acknowledgments
• Multimedia
• References

Prognosis after resection of a mediastinal tumor varies widely depending on the type of lesion resected. After resection of mediastinal cysts and benign tumors, prognosis is generally excellent. Thymic neoplasms included in this group are thymolipomas. Prognosis after treatment of malignant mediastinal tumors depends on the type of lesion, its biological behavior, and the extent of the disease present.

Thymoma

Thymomas are not considered benign neoplasms. Survival rates associated with tumors that are encapsulated or stage I is 95-97% at 5 years and 80-95% at 10 years.

Invasive or stage II tumors are associated with a reduced 5-year survival rate of 60-70% and a 10-year survival rate of 40-50%.

Survival rates for stage III tumors are reported to be less than 60% at 5 years and 14% at 10 years.

Survival rates for stage IVA tumors have been reported at 40% for 5 years and 0% at 10 years.

Other thymic malignancies

Squamous cell carcinoma of the thymus is quite rare, with fewer than 200 cases reported in the literature. Prognosis is considered excellent in cases of well-differentiated squamous cell tumors found and resected early. Poorly differentiated tumors have a uniformly poor prognosis.

The overall cure rate for neuroendocrine tumors of the thymus is low. One series reports a 13% 5-year survival rate.

The survival rate for patients with thymic epithelial neoplasms is 77% at 5 years. Risk factors with prognostic significance included staging and histologic type.

FUTURE AND CONTROVERSIES

Section 10 of 13  

• Authors and Editors
• Introduction
• Indications
• Relevant Anatomy
• Contraindications
• Workup
• Treatment
• Complications
• Outcome and Prognosis
• Future and Controversies
• Acknowledgments
• Multimedia
• References

A number of exciting advances have been made in areas of diagnostic imaging, biologic analysis, and therapy.

Emerging diagnostic modalities such as PET scanning and other radionuclide studies may assist in the diagnosis of specific neoplasms and in posttherapy surveillance for recurrent disease. PET scanning has preliminarily demonstrated the ability to differentiate benign thymomas and malignant thymomas.

Numerous biological markers have been identified for many tumors and will play a vital role in better identifying individual neoplasms so that treatment can be optimized.

Use of VATS and robotic technology has entered the armamentarium of the thoracic surgeon with respect to the treatment of a number of mediastinal diseases. This modality is already commonly used for biopsy of masses and lymph nodes. It has also been described for resection of various mediastinal cysts, mediastinal parathyroid adenomas, and localized benign tumors of the posterior mediastinum, such as ganglioneuromas. The success of these modalities will be determined by data obtained in the long-term follow-up of cases. Because these neoplasms grow slowly, these data are not yet available.

ACKNOWLEDGMENTS

Section 11 of 13  

• Authors and Editors
• Introduction
• Indications
• Relevant Anatomy
• Contraindications
• Workup
• Treatment
• Complications
• Outcome and Prognosis
• Future and Controversies
• Acknowledgments
• Multimedia
• References

The authors and editors of eMedicine gratefully acknowledge the contributions of previous author Jane M Eggerstedt, MD to the development and writing of this article.

MULTIMEDIA

Section 12 of 13  

• Authors and Editors
• Introduction
• Indications
• Relevant Anatomy
• Contraindications
• Workup
• Treatment
• Complications
• Outcome and Prognosis
• Future and Controversies
• Acknowledgments
• Multimedia
• References

Media file 1:  Posteroanterior chest film of a 34-year-old woman with large anterior mediastinal mass. Pathology results indicated malignant thymoma.
	View Full Size Image
Media type:  X-RAY

Media file 2:  Lateral view of tumor in Image 1, ie, a 34-year-old woman with anterior mediastinal mass found to be a malignant thymoma. Note the fullness and haziness above the heart shadow.
	View Full Size Image
Media type:  X-RAY

Media file 3:  CT scan view of tumor in images 1 and 2, ie, a 34-year-old woman with large anterior mediastinal mass found to be a malignant thymoma. Arrow indicates the area in which the tumor (malignant thymoma) is invading the anterior chest wall.
	View Full Size Image
Media type:  CT

REFERENCES

Section 13 of 13

• Authors and Editors
• Introduction
• Indications
• Relevant Anatomy
• Contraindications
• Workup
• Treatment
• Complications
• Outcome and Prognosis
• Future and Controversies
• Acknowledgments
• Multimedia
• References

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Article Last Updated: Sep 3, 2008