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

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.

Any discussion of neoplasms or other masses found within the mediastinum requires delineation of the boundaries of that area. Because a number of mediastinal tumors and other masses are most commonly found in particular mediastinal locations, many authors have artificially subdivided the area into the following three spaces or compartments for better descriptive localization of specific lesions (see Anatomy):

• Anterior
• Middle
• Posterior

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.

Advances continue to be made in the areas of diagnostic imaging, biologic analysis, and therapy. For example, modalities such as positron emission tomoggraphy (PET) and radionuclide studies may be able to assist in the diagnosis of specific neoplasms and in posttherapy surveillance for recurrent disease. ^[1]

Angiographic techniques using localized intra-arterial injection of hypertonic contrast and embolization techniques have been used in several centers to obliterate mediastinal parathyroid adenomas. At present, this technology is used in patients who are considered a poor risk for surgery; however, with increased experience and skill, these methods may become useful in the treatment of many such lesions.

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

Video-assisted thoracoscopic surgery (VATS) is part of the armamentarium of the thoracic surgeon for treatment of a number of mediastinal diseases. It is already used commonly for biopsy of masses and lymph nodes and has also been described for resection of various mediastinal cysts, mediastinal parathyroid adenomas, and localized benign tumors of the posterior mediastinum, such as ganglioneuromas. At several centers, VATS thymectomy has been performed. The completeness of thymic resection remains to be seen.

In 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.

For better descriptive localization of specific lesions, the mediastinum has traditionally been artificially subdivided into three spaces or compartments as follows:

• The anterior compartment, or anterior mediastinum, 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; 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; it contains the heart, pericardium, ascending and transverse portions of the aorta, brachiocephalic vessels, main pulmonary arteries and veins, superior cvena cava (SVC), inferior vena cava (IVC), trachea and mainstem bronchi, and numerous lymph nodes
• The posterior compartment, or posterior mediastinum, comprises the area posterior to the heart and trachea and includes the paravertebral sulci; it contains the descending thoracic aorta and ligamentum arteriosum, esophagus, thoracic duct, azygos vein, and numerous neural structures (eg, autonomic ganglion and nerves, lymph nodes, and adipose tissue)

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, SVC, 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; SVC 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).

Lymphatic tumors

Several types of lymphomas can be found in the mediastinum. ^{[2, 3]} 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. ^{[4, 5]} The most common types of lymphoma found in the mediastinum include immunoblastic T-cell, immunoblastic B-cell, follicular center cell, and lymphoblastic. ^[6] 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. ^{[7, 8]}

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. ^{[9, 10, 11]}

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. ^{[12, 13]}

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.

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. ^{[14, 15]}

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, whereas 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 all age groups are considered, nearly 55% of patients with benign mediastinal masses are asymptomatic at presentation, compared with 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. ^[16] 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. ^[17]

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. ^[18]

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. ^[13]

Mesenchymal tumors represent approximately 6% of all masses found in the mediastinum. ^{[19, 11]} More than 50% of these are malignant.

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. This group of tumors includes such neoplasms as thymolipomas; benign mesenchymal tumors such as fibromas, angiomas, and lymphangiomas; ectopic benign thyroid tissue, including intrathoracic extension of a cervical goiter; and parathyroid adenomas.

Prognosis after treatment of malignant mediastinal tumors depends on the type of lesion, its biologic behavior, and the extent of the disease present.

Mediastinal lymphomas

Excellent survival rates are reported with appropriate chemotherapeutic treatment of Hodgkin disease. According to some reports, even patients with stage IV disease can have disease-free survival for more than 10 years in as many as 70% of cases.

Large cell lymphomas, including anaplastic varieties, are reported to have a more than 50% 3-year survival rate after chemotherapy, radiation therapy, or both.

MALTomas are rare indolent tumors for which long-term survival is good, even in the absence of chemotherapy.

Mantle cell tumors are rare but usually manifest with widespread disease. Median survival is approximately 4 years.

Malignant mesenchymal tumors

The prognosis for liposarcoma depends on several factors. Completely resected pseudoencapsulated tumors have a better prognosis compared to those that are nonencapsulated and invasive. Cell type and cell differentiation also play a role. Myxoid liposarcoma has a poorer prognosis. In one small series, approximately 30% of patients died of their disease after a mean period of less than 3 years.

Angiosarcomas of the mediastinum are rare but have a very poor prognosis, especially when they originate in the heart or great vessels.

Fibrosarcomas have a uniformly poor prognosis, and most patients die from their disease within a few years.

Primary leiomyosarcoma of the mediastinum has been described. In one reported series of 10 patients who underwent resection, two were alive and well at 4 and 6 years. Four of the others died of their disease or developed recurrence.

Rhabdomyosarcoma has the best long-term survival of all mesenchymal tumors because effective chemotherapeutic regimens have been identified. According to one report, 10-year actuarial survival rates range from 52% to 83%, depending on the stage of disease at presentation and the existence of hematogenous metastases. Survival is much worse if the latter is present.

Mediastinal parathyroid carcinoma

Prognosis is generally good if complete resection can be accomplished.

Intrathoracic goiter with occult malignancy

Prognosis is generally good if complete resection of the gland can be accomplished.