Neurogenic Tumors of the Mediastinum 

Updated: Aug 02, 2021
Author: Dale K Mueller, MD; Chief Editor: Mary C Mancini, MD, PhD, MMM 

Overview

Practice Essentials

Several tumors of neurogenic origin can occur in the mediastinum. Tumors that occur in this area of the chest can present in many different ways clinically and can produce many different pathologic processes. An understanding of the embryology of this area and of the anatomic relations of the normal structures within the mediastinum is essential in the proper determination of the exact nature of a mass or tumor located in this area.

Although the entire field of surgery is an ancient one, successful surgical procedures within the thorax are a relatively recent advance.[1]  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.

Treatment selection depends on the diagnosis of the lesion being investigated. Surgical resection is the treatment of choice for tumors originating from nerve sheath tissue. Primary resection is the treatment of choice for neurogenic tumors of paraganglionic origin. Peripheral neuroectodermal tumors (PNETs), otherwise known as Askin tumors are generally treated with en-bloc resection. Treatment varies for neurogenic tumors originating from autonomic nervous tissues; whereas ganglioneuroma, neuroblastoma, and ganglioneuroblastoma identified at an early stage may be treated with primary resection, advanced stages are treated primarily with chemotherapy, and surgical resection is rarely indicated.

Video-assisted thoracoscopic surgery (VATS) has entered the armamentarium of the thoracic surgeon with respect to the treatment of numerous mediastinal diseases.[2, 3, 4]  This modality has been commonly used for biopsy of masses and lymph nodes. It has also been commonly used for resection of various mediastinal cysts, mediastinal parathyroid adenomas, and localized benign tumors of the posterior mediastinum such as ganglioneuromas.

Robotic resection has also been used for general thoracic surgical procedures, including thymectomy and extirpations of benign mediastinal masses. Its use may be limited by lack of appropriate instrumentation.[5]

Advances have been made in the areas of diagnostic imaging and biologic analysis. Diagnostic modalities such as positron emission tomography (PET) and various radionuclide studies may be able to assist in the diagnosis of specific neoplasms and in posttherapy surveillance for recurrent disease. 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.

Anatomy

Any discussion of masses and tumors of the mediastinum requires delineation of the boundaries of that area. In 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. It is limited bilaterally by the mediastinal parietal pleura and extends from the diaphragm inferiorly to the level of the thoracic inlet superiorly.[6]

Because some mediastinal tumors and other masses are most often found in particular mediastinal locations, many authors have artificially subdivided the area for better descriptive localization of specific lesions. Most commonly, the mediastinum is subdivided into three spaces or compartments for this purpose, 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 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 vena cava (SVC) and inferior vena cava (IVC), trachea and mainstem bronchi, numerous lymph nodes, and various neural structures (eg, phrenic nerves)
  • The posterior compartment, or posterior mediastinum, is 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 (including autonomic ganglion and nerves, lymph nodes, and adipose tissue)

Common anterior mediastinal tumors include thymomas, lymphomas, germ cell tumors, and mesenchymal tumors. Benign conditions include goiters and lymphangiomas. Most anterior mediastinal tumors are thymomas.

Whereas 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 consists of cystic structures associated with a developmental abnormality of the primitive foregut or the precursors of the pericardium or pleura.[7]

Almost all tumors of neurogenic origin occupy the posterior portion of the mediastinum. Although 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.

Pathophysiology

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 abnormal local effects. These effects are 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 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 occur secondarily in nearby structures, such as the 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 subject to invasion by malignant tumors include the following:

  • Tracheobronchial tree and lungs
  • Esophagus
  • SVC
  • Pleura and chest wall
  • Adjacent intrathoracic nerves

Pathophysiologic changes that can be produced by invasion of specific structures include the following:

Systemic pathophysiology

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

Tumors developing from autonomic nerve cells can produce several vasoactive substances. The most common of these is neuroblastoma, which produces excess amounts of the catecholamines, epinephrine, and norepinephrine. Ganglioneuroma and ganglioneuroblastoma can produce these substances but do so less often. Autonomic nerve tumors are also capable of producing excess amounts of vasoactive intestinal peptide. Neuroblastomas are thought to produce abnormal antibodies that are responsible for some unusual neurologic manifestations in some children with the tumor.

Some neurosarcomas have been associated with the production of an insulinlike substance that, in turn, can produce hypoglycemia.

Etiology

Neurogenic tumors of the mediastinum arise from cells of the nerve sheath, paraganglionic tissue, and autonomic ganglia, all of which originate embryonically from the neural crest. Several tissues, including neural tissue, neural sheath tissue, and associated fibrous connective tissue of mesodermal origin, can be the source of these neoplasms.

Epidemiology

A review of collected series revealed that many mediastinal neoplasms and masses vary in incidence and presentation depending on patient age.[8] Specific types of mediastinal tumors characteristically occur in specific areas within the mediastinum.

Historically, in adults, the most common type of mediastinal tumor or cyst found was the neurogenic tumor (21%), followed by thymic tumors (19%), lymphomas (13%), and germ cell tumors (10%). Foregut and pericardial cysts were the next most frequently occurring abnormality within this group. Subsequent data from several large series indicated that thymomas have become the most common mediastinal tumor. Some series also indicated that mediastinal lymphoma has passed neurogenic tumors in frequency.

In children and infants, neurogenic tumors are 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 adults, only approximately 1-2% of neurogenic tumors are malignant. 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. Benign lesions generally occur in individuals aged 20-50 years and occur slightly more frequently in women than in men.

Approximately two thirds of mediastinal tumors and cysts are symptomatic in the pediatric population, whereas 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 to only approximately 15% of those in whom masses are found to be malignant.

Neurogenic tumors make up approximately 21% of all adult mediastinal tumors and 35% of all pediatric mediastinal tumors. Neurogenic tumors are the most common posterior mediastinal mass. Neurogenic tumors make up roughly 20% of all mediastinal tumors.

Almost all neurogenic tumors in adult patients are of nerve sheath origin, these being neurilemomas and neurofibromas.

Approximately 90% of pheochromocytomas occur in the adrenal medulla, and only approximately 2% of pheochromocytomas occur in the chest.

Roughly 10% of pheochromocytomas are associated with one of a variety of familial syndromes, the most noted of which are the multiple endocrine neoplasia syndromes. One interesting syndrome specifically associated with multiple extraadrenal pheochromocytomas is the Carney triad, in which these neoplasms occur in association with pulmonary hamartomas and gastric leiomyosarcomas. However, this syndrome does not appear to be familial.

Prognosis

Prognosis after resection of a mediastinal tumor varies widely, depending on the type of lesion resected.

After resection of mediastinal cysts and benign tumors, the prognosis is generally excellent. This group of tumors includes such neoplasms as thymolipomas, benign teratomas,[9] benign neurilemomas and neurofibromas, ganglioneuromas, benign paragangliomas, benign mesenchymal tumors (eg, fibromas, angiomas, lymphangiomas), ectopic benign thyroid tissue and tumors, and parathyroid adenomas.

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

Neuroblastoma

Survival numbers in pediatric patients with neuroblastoma have been studied in depth and analyzed with reference to a number of clinical and biologic prognostic factors. This analysis is beyond the scope of this text. However, intrathoracic neuroblastomas generally have a more favorable outcome than extrathoracic types. The overall survival rate for thoracic neuroblastomas is greater than 70% at 5 years and greater than 60% at 10 years.

Ganglioneuroblastoma

These tumors are generally less aggressive than neuroblastomas. They are evaluated using the same prognostic and staging criteria as neuroblastoma. Ganglioneuroblastomas have a better prognosis because a large percentage of them manifest as an asymptomatic solitary mass and can be completely resected in many cases.

Neuroblastomas and ganglioneuroblastomas are extremely rare but much more aggressive in adults. Neuroblastoma exhibits wide local and distant spread and is rapidly fatal, while ganglioneuroblastoma may, in some cases, be treated with surgical resection.

Askin or peripheral neuroectodermal tumor

These are very rare but very aggressive tumors. Survival is commonly less than 1 year, and long-term survival, even with aggressive therapy, is rare.

Malignant nerve sheath tumors

Malignant schwannomas occurring in patients with von Recklinghausen disease have a poorer prognosis than do those that occur in the absence of that disease.

The long-term survival rate after resection approaches 50% for this neoplasm; however, individuals with associated von Recklinghausen disease have a high incidence of local or distant recurrence within 2 years.

Malignant mediastinal paragangliomas and pheochromocytomas

Extraadrenal pheochromocytomas are rare but have a higher malignant potential than their adrenal counterparts. Malignancy can occur in as many as 10% of these tumors. These tumors are commonly aggressive locally, and metastases may occur even after a long disease-free period following resection.

 

Presentation

History and Physical Examination

Many mediastinal tumors and cysts produce no symptoms and are found incidentally during chest radiography or other imaging studies of the thorax performed for another reason. Symptoms are present in approximately one third of adult patients with a mediastinal tumor or cyst but are seen 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.

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

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

Symptoms associated with compression of some portion of the respiratory tract can be produced by benign lesions in adults, but this occurs much less commonly than in children. Infectious symptoms or sepsis from infection of a mediastinal cyst can occur in adults, though this is also very unlikely in persons in this age group. However, malignant lesions are more likely to produce signs and symptoms of obstruction, compression, or both because they invade or transfix normal mediastinal structures.

Clinical findings associated with these malignant properties include cough, dyspnea, stridor, dysphagia, and even more dramatic findings such as superior vena cava syndrome.

Invasion of the chest wall or pleura by a malignant neoplasm can produce persistent pleural effusions and a significant amount of local pain. Invasion of nearby nerves within the thorax can produce local and referred pain and a variety of 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.

In von Recklinghausen disease or neurofibromatosis, an inheritable disease, the individual may develop multiple tumors, generally neurofibromas.

Functioning mediastinal pheochromocytomas produce an excess of circulating catecholamines. The hallmark clinical finding in individuals with these neoplasms is hypertension. The hypertension may be persistent, paroxysmal, or persistent with paroxysmal episodes.

Hypertensive crises may occur and may be triggered or exacerbated by anesthesia, trauma, and the onset of labor. The hypertension found in these individuals may be termed malignant and most often is resistant to any standard antihypertensive therapy. It certainly may lead to the usual complications of long-standing or severe hypertension such as stroke, cardiac failure, or renal function abnormalities.

In some patients, paroxysmal episodes can be accompanied by other symptoms, which include headaches, diaphoresis, anxiety, chest pain, palpitations, and pallor. Some patients also have an associated tachycardia.

Marked vasoconstriction from the excessive catecholamine discharge associated with these neoplasms creates a severely volume-contracted state in these individuals. This, in turn, produces the appearance of an elevated hematocrit value.

 

Workup

Laboratory Studies

Serum assays can be performed to obtain total or fractionated levels of catecholamines. Individual fractionated values can be obtained for epinephrine, norepinephrine, and dopamine.

Several authors note that for these levels to be accurate, the patient must be supine, euvolemic, and in a fasting state at the time the blood sample is taken. Also, blood must be drawn from an intravenous (IV) access site that has been in place for at least 30 minutes. Falsely positive vanillylmandelic acid (VMA) levels are possible in patients who consume products with high vanilla content, such as coffee and tea.

Because numerous medications can interfere with assaying techniques and with endogenous catecholamine release, those that interfere must be carefully screened for and stopped, if necessary, to obtain an accurate result.

Serum and 24-hour urinary catecholamine levels should be measured in all infants and children who present with a posterior mediastinal or paravertebral mass. These levels are frequently elevated in patients with neuroblastoma and ganglioneuroblastoma.

In addition, appropriate clinical signs and symptoms and elevated levels of serum catecholamines and urinary VMA mandate studies to identify the presence of a pheochromocytoma. Approximately 1-2% of pheochromocytomas are located in the thorax. Elevated levels of serum and urinary catecholamines are present in approximately 90% of individuals with a functioning pheochromocytoma.

Serum metanephrine levels also may be measured.

Urinary VMA, homovanillic acid, and metanephrine levels can be assayed in 24-hour, 12-hour, or 2- to 3-hour urine collections. Levels may be elevated in patients undergoing an evaluation for neuroblastoma, ganglioneuroblastoma, and pheochromocytoma. These levels have been found to be elevated in 85-95% of children with neuroblastoma and in approximately 50% of those with ganglioneuroblastoma.

Again, urinary excretion of these substances can be altered by medications or by increased intake of foods with high levels of phenolic acids and vanillin, such as coffee and tea. Attention should be paid to these factors prior to testing to avoid invalid results.

Note that assays of baseline serum and urinary free catecholamine levels and urinary metanephrines and VMA levels should all be obtained when these studies are undertaken. This is advised because a small percentage of patients with pheochromocytoma may have a positive result in only one of these measured assays.

Serum glucose and insulin levels may be suppressed by the production of an insulinlike substance by certain tumors (eg, some fibrosarcomas and neurosarcomas and occasional carcinoid tumors).

Chest Radiography

Posteroanterior (PA) and lateral radiography of the chest for an unrelated cause is the usual means by which an asymptomatic mediastinal mass in identified. Chest radiography is obviously the first study that would be performed in an individual with symptoms referable to the thorax.[10, 11, 12]  (See the image below.)

Asymptomatic mediastinal mass found during a routi Asymptomatic mediastinal mass found during a routine chest radiograph evaluation of a 34-year-old woman. At surgery, this was found to be a benign neurofibroma.

Lateral chest radiograph findings are very helpful for determining the compartment of the mediastinum involved. This information, combined with the age, sex, and associated clinical findings, aids the physician in the proper choice of subsequent diagnostic studies. (See the image below.)

Lateral chest radiograph of a mediastinal mass fou Lateral chest radiograph of a mediastinal mass found during a routine chest radiograph evaluation of a 34-year-old woman. At surgery, this was found to be a benign neurofibroma (same patient as in the image above).

Computed Tomography of Chest and Mediastinum

Computed tomography (CT) is a routine part of the diagnostic evaluation of mediastinal tumors, cysts, and other masses.[10, 11]

CT scans can greatly assist in determining the exact location of the mediastinal tumor and in determining its relationship to adjacent structures. CT is also useful in differentiating masses that originate in the mediastinum from those that encroach on the mediastinum from the lung or other structures.

Though not infallible, CT is very useful in helping differentiate tissue densities. This greatly assists in distinguishing structures that are cystic or vascular from those that are solid.

CT scans can reveal evidence of local invasion of adjacent structures by a mass or the presence of intrathoracic metastases. In the past, CT was recommended in the evaluation of all paravertebral masses to help determine the presence of intraspinal extension or invasion. Magnetic resonance imaging (MRI) has since come to be considered better for this purpose.

Magnetic Resonance Imaging

MRI is useful both in the initial diagnosis of a mediastinal mass and in follow-up evaluations after treatment.[13, 10, 11, 14]  It provides superior vascular imaging and can help better delineate the relationship of an identified mediastinal mass to nearby intrathoracic vascular structures. MRI can help differentiate between a possible mediastinal mass and a vascular abnormality such as an aortic aneurysm.

MRI offers direct multiplanar images. It can be used when iodinated contrast is contraindicated. It 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 is especially superior to CT for the evaluation of neurogenic tumors of the mediastinum and can eliminate the need for additional studies such as myelography. It can be augmented with magnetic resonance angiography if more extensive evaluation of associated vascular structures is needed, eliminating the need for separate conventional angiography studies.

MRI is more useful than the CT in the evaluation of invasion or extension of tumors, especially neurogenic tumors extending into the spinal canal or tumors closely associated with the heart.

MRI is superior to CT for the evaluation of masses located at the thoracic inlet or at the thoracoabdominal level. It is increasingly being used for the evaluation of residual or recurrent disease after treatment of lymphoma. Although histologic analysis of any residual mass after chemotherapy and radiotherapy remains the standard, MRI evaluation findings from questionable areas have been found to correlate well with histologic findings when attempting to differentiate residual tumor from fibrosis.

Radionuclide Scanning

Findings from scans using iodine I-131 iodine metaiodobenzylguanidine (MIBG) have been shown to be useful for the identification of pheochromocytomas and neuroblastomas.

The octreotide scan using indium In-111–labeled pentetreotide is useful for localizing various neuroendocrine neoplasms, including carcinoid tumors, pheochromocytomas, and paragangliomas. It has been used at some centers for the evaluation of certain lymphomas.

Ultrasonography and Echocardiography

Ultrasonographic methods have been used to help differentiate solid from cystic mediastinal masses and to assist in determining a connection between a mass and adjacent structures.

The results from these studies are more useful in evaluating masses associated with the heart and in vascular abnormalities.

In view of the accuracy and detail provided by CT, MRI, and selected radionuclide studies, ultrasound techniques are not generally used as primary tools in the evaluation of mediastinal tumors and cysts.

Positron Emission Tomography

Positron emission tomography (PET) has proved to be a useful test in for helping identify some pheochromocytomas.

Agents used in these PET studies include 11C-hydroxyephedrine, 11C-epinephrine, and 18F-fluorodeoxyglucose. The results from these tests may be positive even when other test results, such as from MIBG scans, are negative.

Arteriography

Conventional angiography has been used to help differentiate mediastinal masses from vascular abnormalities and to help determine the relationship between known masses and adjacent vascular structures. This is usually unnecessary, given that CT is able to distinguish mediastinal masses from vascular structures and abnormalities.

In most cases, it has been replaced by MRI and magnetic resonance angiography (MRA).

Other Tests

In the past, suppressive or provocative tests were used to assist in the diagnosis of pheochromocytoma. They include the use of phentolamine to elicit a hypotensive response and the use of glucagon, histamine, or tyramine to elicit a hypertensive response. These studies are considered obsolete and are no longer used. Currently, the only study used is the clonidine suppression test, which should be used only in individuals whose plasma and urinary catecholamine assay results are borderline.

Procedures

Transthoracic needle biopsy

In the past, percutaneous biopsy methods were believed 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 (FNA) biopsy (FNAB) and core needle biopsy (CNB) techniques have been increasingly used with success at several centers.[10, 15, 16]  Note that expert clinical judgment is necessary for selecting appropriate cases for this diagnostic method. In addition, considerable expertise in tissue processing and analysis is necessary for diagnostic accuracy.

FNAB has been described for use with neurogenic tumors, although because surgical resection is the treatment for these lesions after adequate workup, needle biopsy may be deemed an unnecessary step.

Cervical mediastinoscopy

Cervical mediastinoscopy is a commonly used surgical diagnostic procedure in the evaluation of the retrovascular, pretracheal area of the middle mediastinum.[16]

Cervical mediastinoscopy is most commonly used for the staging of bronchogenic carcinoma and for the 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.

This diagnostic test is best used for evaluation or biopsy of masses of the anterior mediastinal compartment. Using this approach, the thymus, any tumors or cysts found in the thymic area, and lymph nodes of the aortopulmonary window are accessible for biopsy. Tumors located in the posterior mediastinum, where most neurogenic tumors are found, are not approachable using this method. Some lesions of neurogenic origin, when located high in the mediastinum in the region of the thoracic inlet, may be approached and resected through a cervical 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.[16]  The classic approach is the upper left parasternal area, in order to gain access to the aortopulmonary window and areas of the anterior mediastinum inferior to the aortic arch.

This procedure can afford access to areas of the anterior and middle mediastinum, but it is ill-suited as an approach to masses or structures of the posterior mediastinum.

Posterior mediastinotomy

This is a rarely used procedure for biopsy of some of the posteriorly situated lymph nodes or a mass in the paravertebral sulcus. Posterior mediastinotomy is most often performed on the right side in a paravertebral location immediately lateral to the paravertebral muscles. Similar to the anterior mediastinotomy, small segments of several ribs in the area can be excised for extrapleural access to the ipsilateral paravertebral sulcus. The mediastinoscope also may be used for lymph node biopsy with this approach.

This approach is rarely used for mediastinal tumors and cysts because these are more appropriately managed by either standard thoracotomy or video-assisted thoracoscopic surgery (VATS) techniques.

Video-assisted thoracoscopic surgery

VATS techniques have been used successfully for biopsy of various mediastinal masses and are often used for the sampling of perihilar lymph nodes.[3]  VATS can also be used to resect benign posterior mediastinal tumors.[17]  Shorter hospital stay and faster return to work have been demonstrated with this technique.[18, 19]

VATS is one of the commonly used methods for the evaluation of mediastinal lymphoma.

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. Posterior mediastinal tumors are typically approached through a thoracotomy, if not with VATS.[18]

In some cases, standard sternotomy or thoracotomy may be the safest method available to obtain adequate tissue for diagnosis.

Another option for some thoracic surgeries is the da Vinci Surgical System (Intuitive Surgical, Sunnyvale, Calif), a robotic surgical system. Advanced general thoracic procedures have been performed with the use of the robot. A major limitation is the lack of more appropriate instrumentation.[5]

Histologic Findings

Various benign and malignant neurogenic tumors occur in the mediastinum, essentially the posterior mediastinum.

Schwannomas (neurilemmoma, neurinoma)

Schwannomas are of nerve sheath origin.[20] They are often found in individuals with neurofibromatosis or von Recklinghausen disease. These well-encapsulated, soft, yellowish tumors are attached to peripheral nerves.

Microscopically, schwannomas are composed of spindle cells with twisted nuclei and amphophilic cytoplasm. Densely cellular areas of the tumor are given the designation Antoni A areas, while less-cellular areas with a myxoid stroma are called Antoni B areas. Mitoses are rare in schwannomas. Patients with neurofibromatosis are likely to display a variant form of this tumor called plexiform schwannoma. Melanocytic schwannoma is a variant form, which has a pronounced brownish cytoplasmic pigment. Some authorities consider this variant potentially malignant.

Neurofibroma

Neurofibromas are of peripheral nerve origin.[20] A variant form, called plexiform neurofibroma, is commonly associated with neurofibromatosis. Grossly, these tumors are pseudoencapsulated. They are soft, grayish-white tumors that appear to be part of the nerve of origin rather than attached to it.

Microscopically, neurofibromas are composed of spindle cells and fibroblasts, which can often be seen to extend through the epineurium and infiltrate adjacent tissues. Tumor cells are often arranged in loose whorls and can be accompanied by various inflammatory cells. Atypia and frequent mitotic figures are not characteristic. While neurofibromas are benign neoplasms, some can have a very cellular appearance and exhibit atypia. However, they do not display the frequent mitoses of neurosarcomas.

Ganglioneuroma

Ganglioneuromas are benign tumors arising from the sympathetic or parasympathetic paraganglia.[20] These are firm, well-defined, encapsulated neoplasms that are gray or tan. On cut surface, they resemble leiomyomas. Ganglioneuromas are composed of a combination of mature ganglion cells, spindle cells, and nerve fibers. Ganglion cells have a large nucleus with distinct nucleoli and granular, basophilic cytoplasm.

Granular cell tumors

These benign tumors are believed to be of Schwann cell origin.[20] They are soft in consistency, nonencapsulated, and have a grayish or yellowish color. Granular cell tumors consist of polygonal cells with round central nuclei and granular eosinophilic cytoplasm. Cells are arranged in nests or ribbons and are mixed with a fibrous stroma.

Malignant schwannoma

These tumors are the malignant version of schwannomas and neurofibromas. Grossly, malignant schwannomas are large, oval, or fusiform masses. In many cases, the nerve from which they originate can be easily identified. They are soft tumors with a gray-to-pinkish color and commonly have areas of necrosis or hemorrhage within.

Microscopically, malignant schwannomas consist of sheets or bundles of pleomorphic spindle cells. The cells are aligned in a manner that closely resembles the architecture of leiomyosarcomas or other spindle cell sarcomas. They have numerous mitotic figures and areas of necrosis. A characteristic feature of malignant schwannomas is their ability to exhibit other cellular components such as clusters of epithelial cells; mucin-secreting glands; and even mesenchymal features such as bone, cartilage, or skeletal muscle.

Neuroblastoma

Neuroblastomas of the mediastinum originate from ganglion cells. Grossly, they are large, soft, lobulated, pseudoencapsulated tumors ranging from white to pink in color and displaying significant hemorrhage, necrosis, and calcifications.

At a cellular level, they consist of small cells with round nuclei and sparse cytoplasm. Chromatin within the nuclei has a characteristic dusty appearance. An eosinophilic fibrillary stroma is present in varying amounts. Mitoses are frequent, as are regions of extensive necrosis and calcification. Pseudorosettes are a characteristic feature of well-differentiated tumors.

Neuroblastomas exhibit a range of differentiation that is directly related to prognosis. Tumors exhibiting large amounts of stroma are often better differentiated and are associated with a better prognosis, while stroma-poor tumors are more poorly differentiated.

Ganglioneuroblastoma

These tumors are neuroblastomas that display distinct differentiation of the ganglion cells and often have neurons with various levels of differentiation present. Additionally, ganglioneuroblastomas have plentiful extracellular neurofibrillary material.

Melanotic progonoma

These darkly pigmented malignant tumors usually occur in the jaw but can occur in the mediastinum. They are composed of neuroepithelial cells mixed with irregular spaces lined by cuboidal cells that contain melanin.

Askin tumor

These highly malignant tumors are believed to be of neuroectodermal origin, possibly arising from a peripheral nerve such as an intercostal nerve. Askin tumors contain numerous small cell neurosecretory granules.

Mediastinal paragangliomas and pheochromocytomas

Paragangliomas are usually soft vascular tumors. While they histologically resemble adrenal pheochromocytomas, they do not functionally mimic them and produce no catecholamines. They display nests of small oval cells separated by reticulin. Mitoses are uncommon. A mediastinal paraganglioma that is found to secrete catecholamines is termed an extraadrenal pheochromocytoma or a functioning paraganglioma.

Staging

Well-established staging systems exist for several tumors that occur within the mediastinum. Most noted are those for thymoma, lymphoma, and neuroblastoma.

No specific staging systems are described for the many other types of tumors that occur, most likely because of their infrequent occurrence.

The International Neuroblastoma Staging System (INSS) is widely used for the staging of neuroblastoma and has essentially replaced other staging systems.

The staging system for neuroblastomas is as follows:

  • Stage I - Tumor localized and confined to area of origin; complete gross excision possible (residual microscopic disease may or may not be present); negative findings upon microscopy of ipsilateral and contralateral lymph nodes removed at surgery
  • Stage 2A - Incomplete gross excision of unilateral tumor; negative findings upon microscopy of ipsilateral and contralateral lymph nodes removed at surgery
  • Stage 2B - Complete or incomplete gross excision of a unilateral tumor with positive findings from ipsilateral lymph nodes; negative findings upon microscopy of identifiable contralateral lymph nodes
  • Stage 3 - Tumor found to infiltrate across the midline, with or without regional lymph node involvement, tumor is unilateral but contralateral lymph node involvement is found, or, tumor is midline with bilateral lymph node involvement
  • Stage 4 - Tumor dissemination to bone, bone marrow, distant lymph nodes, liver, and other organs, except as defined for stage 4S
  • Stage 4S - Localized primary tumor as defined by stage 1 or 2 but with disseminated disease to liver, less than 10% of bone marrow, skin, or all, diagnosed in patients ranging in age from newborn to younger than 1 year
 

Treatment

Approach Considerations

Treatment selection for a given mediastinal tumor or cyst depends on the diagnosis of the lesion being investigated.[21]  Surgical resection is the primary treatment of choice in a large percentage of cases of neurogenic tumors.

Surgical resection is the treatment of choice for tumors originating from nerve sheath tissue, including neurilemoma, neurofibroma, and neurogenic sarcoma. Complete resection of the more malignant forms of these tumors may not be possible, and additional treatment modalities may be required.

Primary resection is the treatment of choice for neurogenic tumors of paraganglionic origin, which include paraganglionoma, chemodectomas, and mediastinal pheochromocytoma. Approximately 10% of pheochromocytomas are malignant and may not be entirely resectable. Some, even though benign, may be incompletely resected because of their location and increased vascularity. Preoperative treatment including alpha and beta blockade to prevent malignant hypertension during dissection is critical to excision of these tumors.

Peripheral neuroectodermal tumors (PNETs), otherwise known as Askin tumors, are rare tumors occurring in the posterior sulcus or chest wall of adolescent and young adult patients. They are believed to develop from intercostal nerve tissue. Standard therapy includes en-bloc resection, with accompanying radiotherapy and chemotherapy if complete resection is not possible.

Treatment varies for neurogenic tumors originating from autonomic nervous tissues. Ganglioneuroma, the most mature and benign form of autonomic nerve tumor, is treated by surgical resection. Neuroblastoma and ganglioneuroblastoma identified at an early stage of disease also may be treated with primary resection. Advanced stages of these diseases are treated primarily with chemotherapy, and surgical resection is rarely indicated.

Surgical removal is not indicated as primary treatment for some specific mediastinal tumors and cysts. Advanced stages of neuroblastoma and ganglioneuroblastoma are the tumors of neurogenic origin for which surgical resection is not considered as primary treatment.

Medical Therapy

Whereas most tumors and cysts of the mediastinum are treated surgically, medical therapy is the primary form of treatment in several diseases.

Benign schwannomas and neurofibromas

Treatment for these lesions is surgical resection.[22] This includes the plexiform varieties and melanotic schwannoma.

Granular cell tumors

Treatment for this rare lesion is surgical in nature.

Malignant schwannoma and neurofibrosarcoma

Surgical resection is the primary mode of therapy. Radiation therapy may be used postoperatively to control residual disease, but the benefit of this is unknown. No known chemotherapeutic regimens are effective against these tumors.

Ganglioneuroma

Treatment is surgical in nature.

Neuroblastoma

Treatment of mediastinal neuroblastoma is based on the evaluation of a number of risk factors that are used to assign a stage to the disease according the International Neuroblastoma Staging System (INSS; see Staging). This is identical to the staging system used for neuroblastoma occurring elsewhere in the body.

Patients at INSS stages 1 and 2 are considered candidates for resection. For patients with more advanced disease (INSS stage 3, 4, or 4S), a combination of surgery and chemotherapy is recommended. High-risk patients rarely benefit from surgery. Intense chemotherapy with whole-body irradiation or myeloablative chemotherapy is administered, followed by autologous bone marrow transplant.

Neuroblastoma occurs much less frequently in adults than in children and infants but is a much more aggressive disease. Stage 1 disease is treated surgically, while irradiation is recommended for stage 2 disease. Chemotherapy has been tried for disseminated disease in adults, although no proven benefit has been observed.

Ganglioneuroblastoma

These tumors are also graded using the INSS. Surgical resection is indicated in those with early disease, and chemotherapeutic therapy is added for those with more advanced disease.

Melanotic progonoma

Surgical resection is the only recommended treatment.

Askin tumor

Surgical resection followed by irradiation and chemotherapy is recommended in all cases. Some studies have used myeloablative chemotherapy or whole-body irradiation followed by autologous bone marrow transplant, but, to date, benefits of this aggressive therapy have not been identified.

Chemodectomas are primarily treated with surgical resection. Preoperative embolization may be indicated because of the excessive vascularity of these tumors. Radiation therapy has also been used and is an acceptable alternative to surgical resection.

Surgical Therapy

In cases of benign neoplasms, complete excision of the lesion itself is generally sufficient.[23] Benign neurofibroma requires some resection in addition to the lesion itself, that being resection of the associated nerve. All benign neoplasms that are encapsulated should be resected without violation of the capsule. Resection via video-assisted thoracoscopic surgery (VATS) is now commonplace for these benign tumors. Shorter hospital stay and more rapid return to work have been demonstrated with this method. Robotic approaches have been described as well.[24]

When surgical resection of malignant neoplasms of the mediastinum is the primary treatment, en-bloc resection of the tumor should be performed whenever possible. Regional lymphadenectomy should accompany surgical resection of operable neuroblastomas.

Preparation for surgery

Standard preoperative management applicable to all chest surgical cases applies to the preoperative management 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. For safe management of the airway distorted or narrowed by a mediastinal mass, consider detailed preoperative assessment of the airway and ensure adequate visualization and readily available supplementary equipment (eg, flexible bronchoscope). 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. Adequate intravenous (IV) access, appropriate monitoring capability, and easy availability of necessary blood products (all of paramount importance) should be provided before surgery is begun.

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

Several mediastinal tumors can produce important effects that should be taken into account preoperatively. Neurogenic tumors that secrete catecholamines require special consideration.

Pheochromocytoma

Perform preoperative treatment on individuals with pheochromocytoma in order to prevent a catecholamine surge and an intraoperative hypertensive crisis.

Most authors recommend the administration of the alpha-blocker phenoxybenzamine. This medication is initiated approximately 2 weeks preoperatively, beginning at doses of 10 mg twice a day and increasing the dose every other day until a normotensive or near-normotensive state, with minimization or elimination of paroxysmal episodes, is achieved. Most patients require 40-120 mg/day to achieve this effect. Because of the prolonged half-life of this agent, reduction of the dose 24-48 hours before surgery is recommended; otherwise, postoperative hypotension may occur after the source of excess catecholamine production is removed.

Other drugs that may be used instead are prazosin (a selective alpha blocker) or labetalol (an alpha and beta blocker). Alpha-methylparatyrosine has been used successfully in a few patients who cannot tolerate alpha blockade with other agents.

Preoperative beta blockade can also be performed but is indicated only if persistent tachycardia or supraventricular arrhythmias are present. Beta blockade should be started only after alpha blockade is stabilized to prevent unopposed beta blockade.

Atropine should not be given with preoperative medication. Anesthetic induction with good oxygenation should be rapid and unimpaired. Most commonly, thiopentone is used for induction; however, fentanyl and alfentanil can also be used because they do not result in histamine release, as do other agents. The choice of muscle relaxant is important because some (eg, tubocurarine, atracurium) can cause histamine release and others (eg, pancuronium) can release catecholamine stores. Vecuronium is the drug of choice because it produces none of these effects.

Pheochromocytomas are highly vascular tumors. Adequate availability of blood products is a key feature in the treatment of these patients.

Operative details

As with all thoracic surgery, the patient must be properly positioned for the indicated procedure. Tumors or cysts located in the anterior mediastinum are generally approached through a median sternotomy. This approach is used for tumors of the thymus. Those located in the posterior or middle mediastinum and paravertebral sulci, such as most neurogenic tumors and foregut cysts, are approached through a VATS incision or a posterolateral thoracotomy.[25, 26]

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

Specific management of neurogenic tumors with intraspinal extension should be mentioned. Evaluation of all patients with tumors of the posterior mediastinum preoperatively is essential to rule out intraspinal extension. Combined management by neurosurgical and thoracic surgical teams is warranted when intraspinal extension is suggested.

If intraspinal extension is first identified at the time of thoracotomy and was not considered beforehand, the outcome could prove disastrous. The approach to these tumors usually requires laminectomy for resection of the intraspinal portion of the tumor and thoracotomy for the intrathoracic portion. In cases where laminectomy must be performed at multiple levels, some form of stabilization of the vertebral column is undertaken. Laminectomy combined with VATS and thoracoscopy has also been reported for neurogenic tumors involving the spinal column.

A consideration for the resection of pheochromocytomas is that manipulation of a pheochromocytoma during surgical resection may result in a sudden introduction of catecholamines into the circulation. This can occur even in the presence of preoperative preparation with alpha and beta blockers. Early in the dissection, care must be taken during surgery to manipulate these tumors as little as possible and to control venous outflow.

Postoperative Care

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. Some patients require ventilatory support for a longer time and should be managed accordingly.

Pulmonary toilet is an essential part of postoperative management after any kind of chest surgery to prevent atelectasis and to mobilize and clear any bronchial secretions. Various methods to assist with pulmonary toilet are available.

Pain control is a critical factor in postoperative management after thoracic surgery. Adequate cough effort and ventilatory excursion cannot be maintained without satisfactory pain control. The administration of analgesic agents via a thoracic epidural catheter is an excellent and highly effective method of pain management. Lumbar or thoracic epidural catheters can also be used and, with proper choice of analgesic agents, can provide good pain relief.

Patient-controlled analgesia (PCA) is another widely used method and is preferred to traditional intramuscular or IV administration of narcotics and other agents. PCA is not as efficient for pain control as epidural analgesia.

Continuous infusion of 0.25% bupivacaine at 4 mL/hr through the ON-Q elastomeric infusion pump is a safe and effective adjunct to pain management after thoracotomy.[27] The use of the ON-Q Pain Relief System results in decreased narcotic use and lower pain scores compared with continuous epidural infusion. At some point after oral intake has begun, pain medication can be converted to oral analgesic agents.

Wound management is straightforward. Operative dressings are removed after 24 hours in most cases. 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 –20 cm of water-seal suction, and drainage from the tubes is measured daily. Intermittent chest radiographs are obtained and evaluated for findings of residual undrained collections, complete pulmonary expansion, lobar atelectasis and infiltrates, and other abnormalities.

When drainage from the chest tubes is less than 400 mL in 24 hours, no air leak is present, and the chest radiograph shows full pulmonary expansion with no collections on the operated side, the chest tubes may be removed.

Complications

Complications that occur after resection of mediastinal tumors are similar to those that can occur after any thoracic surgical procedure.

As with any thoracic surgical procedure, postoperative pulmonary complications are most common. Atelectasis is a common postoperative complication and can develop into pneumonia if not treated aggressively. Aggressive pulmonary toilet and pain management are the key factors in the prevention of these complications.

Wound infections after sternotomy or thoracotomy are rare. The chest wall has an excellent blood supply and, with few exceptions, healing occurs readily. In addition, 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 have secondary infection present.

Appropriate preoperative, intraoperative, and postoperative antibiotic coverage is warranted. Sternal dehiscence occurs very rarely after sternotomy performed for noncardiac procedures. If it occurs without the presence of infection, simple washout, debridement, and rewiring can be performed. If infection is present, aggressive debridement of devascularized bone and cartilage should be performed along with a vigorous washout. Cases where significant infection is present are best treated with rotation of muscle flaps (eg, pectoralis major and rectus abdominis) to cover the wound.

Injury to the phrenic nerve can occur, resulting in temporary or permanent diaphragmatic paresis. 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 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.

Long-Term Monitoring

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

Because of the heterogeneity and small numbers of malignant tumors found in the mediastinum, no single specific method has been described for the follow-up of patients who undergo intended curative resection of a malignant neoplasm. Optimal follow-up treatment for patients with thoracic malignancy has not been demonstrated in randomized controlled trials.[28]  Computed tomography (CT) of the chest has been suggested as a surveillance tool for children with high-risk neuroblastoma.[29]