Lymphomas, Endocrine, Mesenchymal, and Other Rare Tumors of the Mediastinum

Updated: Nov 06, 2015
  • Author: Mary C Mancini, MD, PhD, MMM; Chief Editor: John Geibel, MD, DSc, MSc, AGAF  more...
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Overview

Background

Because a great many organ systems and varieties of tissues are represented within the mediastinum, tumors that occur in this area can represent many different clinical entities and pathologic processes. Lymphomas, primary or ectopic endocrine tumors, and a wide variety of mesenchymal tumors can occur in the mediastinum. An understanding of the embryology and of the anatomic relations of the normal structures of the mediastinum is essential in the proper determination of the exact nature of a mass or tumor located in this area.

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History of the Procedure

Although the entire field of surgery is an ancient one, successful surgical procedures of the thorax are a relatively recent advancement. Until the era when the airway and ventilation could be controlled artificially, the mediastinum, like other parts of the thorax, was deemed a dangerous area to approach.

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 manage the airway or to ventilate safely, such a surgical approach had to remain completely extrapleural because perforation of the pleura would result in a fatal pneumothorax.

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 tried this approach first on human cadavers, finding that a 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 did enter the pleural cavity of the animal, Milton was able to perform a tracheostomy and give artificial respiration through it. 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 plus 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 referenced in the monograph 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 several 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.

Wakeley and Mulvany described intrathoracic goiters in 1940. [1] The authors divided these lesions into 3 subtypes. These were (1) the "small substernal extension" of a goiter primarily located in the neck; (2) the "partial" intrathoracic goiter for which a large portion, although not all of the goiter, is in the thorax; and (3) the "complete" intrathoracic goiter, for which the entire goiter appears to be within the thorax. Their report indicated that 8-9% of goiters had some intrathoracic component. Of these, more than 80% were of the first type, and only approximately 3% were of the third type.

The first described removal of a parathyroid adenoma from the mediastinum occurred in 1932. This was performed on a patient who had undergone 6 previously unsuccessful surgeries for hyperparathyroidism.

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Problem

Any discussion of neoplasms or other masses found within the mediastinum requires delineation of the boundaries of that area. When defining the location of specific mediastinal masses, 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 most commonly found 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 is 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. More rarely, the masses found are associated with aberrant parathyroid or thyroid tissue. Neoplasms and other masses originating from vascular or mesenchymal tissues also may be found.

A relatively common mass identified as an anterior mediastinal mass is a substernal extension of a thyroid goiter. This is not, by definition, a tumor that originates within the mediastinum, but is often first identified as a mass lesion within the mediastinum that must be differentiated from other sources and, when symptomatic, must be treated. Even though not a primary tumor of the mediastinum, substernal extension of the cervical thyroid gland is discussed in this article because it is a relatively common problem and is traditionally considered one of the differential diagnoses of an anterior mediastinal mass.

While neoplasms of the middle mediastinum are most commonly of lymphatic origin, neurogenic tumors also occasionally occur in this area. Another significant group of masses identified in this compartment is 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. Isolated cystic abnormalities of lymphatic origin, such as hygromas or lymphangiomas, can develop within the middle mediastinal compartment but are more often extensions of these abnormalities from 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. [2]

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Epidemiology

A review of collected series reveals that many mediastinal neoplasms and masses vary in incidence and presentation depending on patient age. Also, a number of mediastinal tumors characteristically occur in specific areas within the mediastinum. [3, 4]

Historically, in adults the most common type of mediastinal tumor or cyst found is the neurogenic tumor, followed by thymic tumors, lymphomas, and germ cell tumors. Foregut and pericardial cysts are the next most frequently occurring abnormality within this group. However, more recent data from several large series indicate that thymomas have become the most common mediastinal tumor. Some series also indicate that mediastinal lymphoma has also passed neurogenic tumors in frequency.

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

Although lymphomas can be found in any of the mediastinal compartments, many of them manifest in the anterior compartment. As many as 45% of masses found in the anterior mediastinum of children are lymphomas, and, in adults, they are the second most common anterior mediastinal mass. [5]

True ectopic thyroid tissue, entirely detached from the cervical thyroid gland and having its own (albeit anomalous) blood supply in the mediastinum, is extremely rare. Only a few case reports exist. Most thyroid tissue found in the mediastinum results from an extension of the cervical thyroid gland, usually as a goiter. More than 80% of these extensions lie beneath the manubrium and in a position superior to the arch vessels. The remainder can lie within the middle mediastinum, some in a retrotracheal or even retroesophageal position. [6]

According to various reports, occult malignancy, usually papillary thyroid carcinoma, can be found in resected intrathoracic thyroid tissue. This has been reported in approximately 5% of cases.

Of all parathyroid tumors, only 1-3% are truly mediastinal in location, defined as those inaccessible by standard cervical exploration and requiring median sternotomy for excision. [7]

Mesenchymal tumors represent approximately 6% of all masses found in the mediastinum. [8, 9] More than 50% of these are malignant.

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Etiology

Tumors and cysts found in the mediastinum have various causes.

Lymphatic tumors

Several types of lymphomas can be found in the mediastinum. [10, 11] They may be found in the mediastinum as a primary process or as one of a number of involved locations in a systemic process. All forms of lymphoma originate from abnormalities of specific types of lymphocytes. They are generally divided into Hodgkin and non-Hodgkin lymphomas.

The many forms of non-Hodgkin lymphoma are categorized by cell type. [12, 13] The most common types of lymphoma found in the mediastinum include immunoblastic T-cell, immunoblastic B-cell, follicular center cell, and lymphoblastic. The most common form of Hodgkin lymphoma found in the mediastinum is the nodular sclerosing type. So-called mediastinal gray-zone lymphomas occur but are rare. [14, 15]

Mesenchymal tumors

Mediastinal neoplasms can arise from several cell types. They may be benign or malignant in activity, although a little more than half are malignant. The most common types of tissues from which they originate include vascular, lymphatic, muscular, fibrous, and adipose tissues. Very uncommon mediastinal tumors from a mesenchymal source include those originating from bony, cartilaginous, synovial, and meningeal tissues. [16, 17, 9]

Cystic hygroma is a form of lymphangioma that most commonly extends into the mediastinum from the neck. It is most often discovered at (or shortly after) birth and is believed to result from a developmental lymphatic abnormality within the neck.

Ectopic endocrine tumors

Approximately 20% of normal parathyroid glands are located inside the capsule of the thymus or in the anterior mediastinum. Parathyroid adenomas can develop within these ectopic glands in the mediastinum, and approximately 80% are identified within the anterior compartment. Parathyroid carcinoma can occur in an ectopic mediastinal parathyroid gland, but this is very unusual. [18, 7]

Aberrant thyroid tissue or thyroid completely separated from the cervical gland (rarely) can be found in the mediastinum. A distinguishing feature of this tissue is that its blood supply originates within the mediastinum. This feature is unlike the more commonly found substernal thyroid, which is simply an extension of the cervical thyroid gland into the mediastinum and receives its blood supply from the normal thyroid vessels within the neck. Thyroid tumors, benign or malignant, can arise in aberrant mediastinal thyroid tissue.

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Pathophysiology

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

Local

Because of the malleable nature and small size of the pediatric airway and other normal mediastinal structures, benign tumors and cysts can produce abnormal local effects. These effects are usually more evident in children than in adults. Compression or obstruction of portions of the airway, esophagus, or right heart and great veins by an enlarging tumor or cyst can easily occur and can 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.

Because of the close proximity to the trachea and the limited space of the thoracic inlet, patients with intrathoracic extension of a cervical goiter commonly present with symptoms of upper airway compression and can also present with esophageal compression.

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. Structures most commonly subject to invasion by malignant tumors include the tracheobronchial tree and lungs, esophagus, superior vena cava, pleura and 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 (SVCS); pleural effusion; and various neurologic abnormalities such as vocal cord paralysis, Horner syndrome, paraplegia, diaphragmatic paralysis, and pain in the distribution of specific sensory nerves.

Systemic

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

Lymphatic tumors

In some cases, Hodgkin lymphoma has been associated with hypercalcemia. The elaboration of other specific bioactive substances has not been associated with Hodgkin and non-Hodgkin lymphoma of the mediastinum. However, many individuals with these diseases have various systemic findings such as weight loss, night sweats, fever, and malaise.

Mesenchymal tumors

Rarely, fibrosarcomas can produce an insulinlike substance.

Ectopic endocrine tissue

Thyroid tumors developing within the mediastinum can produce excess thyroid hormone and associated systemic manifestations.

Mediastinal parathyroid adenomas or carcinomas commonly produce excess parathyroid hormone (PTH).

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Presentation

A large percentage of mediastinal tumors and cysts produce no symptoms and are found incidentally during chest radiograph or imaging studies of the thorax performed for other reasons. [19] Symptoms are present in approximately one third of adult patients with a mediastinal tumor or cyst but are more commonly observed in the pediatric population, nearly two thirds of which presents with some symptoms. In adults, asymptomatic masses are more likely to be benign.

Symptoms associated with the respiratory tract predominate in pediatric patients because airway compression is more likely. This occurs because of the significant amount of malleability of the airway structures and the small size of the chest cavity in infants and children. Symptoms observed most commonly include persistent cough, dyspnea, and stridor. If the location and size of the mass produce partial or complete obstruction, obstructive pneumonia can also occur. Infectious symptomatology, and even signs of sepsis, can also occur if a mediastinal cyst becomes infected.

Constitutional symptoms such as weight loss, fever, malaise, and vague chest pain occur commonly with malignant tumors in pediatric patients.

Symptoms associated with compression of some portion of the respiratory tract can also be produced by benign lesions in adults, but this is much less likely than in children. Intrathoracic extension of a cervical goiter is one noted largely benign abnormality that commonly manifests with upper respiratory symptoms. At least 70% of individuals with intrathoracic goiters have some symptoms of airway compression. Cough, wheezing, stridor, dyspnea, and dysphagia are among the common complaints.

Infectious symptoms or sepsis from infection of a mediastinal cyst can also occur in adults, although, again, this is very unlikely in this age group.

Malignant lesions are more likely to produce signs and symptoms of obstruction and/or compression than benign lesions because they invade or transfix normal mediastinal structures. Clinical findings associated with these malignant properties include cough, dyspnea, stridor, dysphagia, and more dramatic findings (eg, SVCS).

Invasion of the chest wall or pleura by a malignant neoplasm can produce persistent pleural effusions and significant local pain. Invasion of nearby nerves within the thorax can also produce local and referred pain and various other findings such as hoarseness from recurrent nerve paralysis, diaphragmatic paralysis from phrenic nerve paralysis, Horner syndrome from autonomic nerve invasion, and even motor paralysis from direct spinal cord involvement. Pain in the shoulder or upper extremity can occur from invasion of the ipsilateral brachial plexus. Systemic findings, such as weight loss, fever, and malaise, also occur.

Mediastinal tumors that produce bioactive substances are associated with symptoms produced by those substances, as discussed in Systemic pathophysiology above.

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Indications

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

Lymphatic tumors

Surgical resection is not indicated as primary treatment for any of the lymphomas involving the mediastinum. However, various surgical procedures, including staging laparotomy, may be required for the sampling of lymph nodes or other tissues so that accurate diagnosis and staging of the lymphatic tumor is achieved.

Specific complications of mediastinal lymphoma, such as pericardial effusion and tamponade or persistent pleural effusion, may require surgical treatment. Occasionally, surgical resection of a residual mediastinal mass is indicated after the completion of chemotherapy and radiotherapy in order to establish the presence or absence of residual tumor and to determine if further chemotherapy is indicated.

Mesenchymal tumors

Surgical excision is indicated for almost all tumors of mesenchymal origin. One noted exception is that of rhabdomyosarcoma, for which a combination for radiation and chemotherapy offers the best survival results.

Some mesenchymal tumors of the mediastinum are so rare that only anecdotal reports of their diagnosis and treatment exist; thus, recommendations for treatment of these tumors cannot be made.

Ectopic endocrine tissue

Surgical excision is indicated for ectopic endocrine tissue within the mediastinum. Nonfunctioning thyroid or parathyroid tissue may not have been identified previously and is often removed incidentally during surgery for another reason. Functioning or malignant endocrine tissues require removal.

Substernal goiter is not true ectopic endocrine tissue, but rather, the direct extension of an abnormal cervical thyroid into the mediastinum. Surgical resection may be indicated, even in asymptomatic cases, because of the risk of sudden airway obstruction and because of the somewhat increased chance of malignancy. Resection can be performed via the standard cervical thyroidectomy incision in almost all cases. On rare occasions, sternotomy is required.

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Relevant Anatomy

When determining the location of specific mediastinal masses, 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.

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

The anterior compartment extends from the posterior surface of the sternum to the anterior surface of the pericardium and great vessels. The anterior compartment normally contains the thymus gland, adipose tissue, and lymph nodes. The blood supply of almost all intrathoracic thyroid goiters is derived from the inferior thyroid arteries.

The middle compartment, or middle mediastinum, is located between the posterior limit of the anterior compartment and the anterior longitudinal spinal ligament. This area contains the heart, pericardium, ascending and transverse portions of the aorta, brachiocephalic vessels, main pulmonary arteries and veins, superior and inferior vena cavae, trachea and mainstem bronchi, and numerous lymph nodes.

The posterior mediastinum comprises the area posterior to the heart and trachea and includes the paravertebral sulci. The posterior mediastinum contains the descending thoracic aorta and ligamentum arteriosum; esophagus; thoracic duct; azygos vein; and numerous neural structures, including autonomic ganglion and nerves, lymph nodes, and adipose tissue.

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Contraindications

Surgical removal is not indicated as primary treatment for lymphomas and rhabdomyosarcomas.

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