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Thymic Tumors

  • Author: Dale K Mueller, MD; Chief Editor: Mary C Mancini, MD, PhD, MMM  more...
 
Updated: Nov 02, 2015
 

Background

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.

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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.

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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.

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Epidemiology

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.

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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).

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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.

System pathophysiology - 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.

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Presentation

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).

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Indications

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.

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Relevant Anatomy

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.

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Contraindications

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.

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Contributor Information and Disclosures
Author

Dale K Mueller, MD Co-Medical Director of Thoracic Center of Excellence, Chairman, Department of Cardiovascular Medicine and Surgery, OSF Saint Francis Medical Center; Cardiovascular and Thoracic Surgeon, HeartCare Midwest, Ltd, A Subsidiary of OSF Saint Francis Medical Center; Section Chief, Department of Surgery, University of Illinois at Peoria College of Medicine

Dale K Mueller, MD is a member of the following medical societies: American College of Chest Physicians, American College of Surgeons, American Medical Association, Chicago Medical Society, Illinois State Medical Society, International Society for Heart and Lung Transplantation, Society of Thoracic Surgeons, Rush Surgical Society

Disclosure: Received consulting fee from Provation Medical for writing.

Specialty Editor Board

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Received salary from Medscape for employment. for: Medscape.

Daniel S Schwartz, MD, FACS Medical Director of Thoracic Oncology, St Catherine of Siena Medical Center, Catholic Health Services

Daniel S Schwartz, MD, FACS is a member of the following medical societies: Society of Thoracic Surgeons, Western Thoracic Surgical Association, American College of Chest Physicians, American College of Surgeons

Disclosure: Nothing to disclose.

Chief Editor

Mary C Mancini, MD, PhD, MMM Professor and Chief of Cardiothoracic Surgery, Department of Surgery, Louisiana State University School of Medicine in Shreveport

Mary C Mancini, MD, PhD, MMM is a member of the following medical societies: American Association for Thoracic Surgery, American College of Surgeons, American Surgical Association, Society of Thoracic Surgeons, Phi Beta Kappa

Disclosure: Nothing to disclose.

Additional Contributors

Richard Thurer, MD B and Donald Carlin Professor of Thoracic Surgical Oncology, University of Miami, Leonard M Miller School of Medicine

Richard Thurer, MD is a member of the following medical societies: American Association for Thoracic Surgery, American College of Chest Physicians, American College of Surgeons, American Medical Association, American Thoracic Society, Florida Medical Association, Society of Surgical Oncology, Society of Thoracic Surgeons

Disclosure: Nothing to disclose.

Acknowledgements

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

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Posteroanterior chest film of a 34-year-old woman with large anterior mediastinal mass. Pathology results indicated malignant thymoma.
Lateral view of tumor in the image above (a 34-year-old woman with anterior mediastinal mass found to be a malignant thymoma). Note the fullness and haziness above the heart shadow.
CT scan view of tumor in the images above (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.
 
 
 
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