Thymic Tumors 

Updated: Feb 22, 2021
Author: Dale K Mueller, MD; Chief Editor: Mary C Mancini, MD, PhD, MMM 



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

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 via a posterior approach. In this time frame, with no ability to safely manage the airway or ventilation, such a surgical approach had to remain completely extrapleural because perforation of the pleura would result in a fatal pneumothorax.

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

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

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

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

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


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

Because a number of mediastinal tumors and other masses are found most commonly in particular mediastinal locations, many authors have artificially subdivided the area for better descriptive localization of specific lesions. Usually, the mediastinum is subdivided into three spaces or compartments (ie, anterior, middle, and posterior) when the location or origin of specific masses or neoplasms is being discussed. These three spaces are defined as follows:

  • The anterior compartment extends from the posterior surface of the sternum to the anterior surface of the pericardium and great vessels; it normally contains the thymus gland, adipose tissue, and lymph nodes
  • The middle compartment, or middle mediastinum, is located between the posterior limit of the anterior compartment and the anterior longitudinal spinal ligament
  • The posterior mediastinum comprises the area posterior to the heart and trachea and includes the paravertebral sulci

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

Although neoplasms of the middle mediastinum are most commonly of lymphatic origin, neurogenic tumors also may occasionally occur in this area. Another significant group of masses identified in this compartment are cystic structures associated with developmental abnormalities of the primitive foregut or the precursors of the pericardium or pleura. They include bronchogenic, esophageal, gastric, and pleuropericardial cysts.

In addition, more complex cysts related to embryologic abnormalities, such as neurenteric or gastroenteric cysts, can develop. Isolated cystic abnormalities of lymphatic origin, such as hygromas or lymphangiomas, can develop within the middle mediastinal compartment; however, more commonly they are extensions of these abnormalities from the cervical lymphatics.

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


Local effects

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

Malignant mediastinal tumors can cause all of the same local effects as those associated with benign lesions but, in addition, can produce abnormalities by invasion of local structures. Local structures most commonly subjected to invasion by malignant tumors include the following:

  • Tracheobronchial tree and lungs
  • Esophagus
  • Superior vena cava
  • Pleura
  • Chest wall
  • 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), and pleural effusion. Changes can also include various neurologic abnormalities, such as vocal cord paralysis, Horner syndrome, paraplegia, diaphragmatic paralysis, and pain in the distribution of specific sensory nerves.


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

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

Other, less common syndromes can be associated with thymoma, including the following:

  • Other neuromuscular syndromes
  • Hematologic syndromes
  • Immune deficiency syndromes
  • Bone disorders
  • Collagen diseases and autoimmune disorders
  • Endocrine disorders
  • Renal diseases
  • Dermatologic diseases

Neuromuscular syndromes besides MG include myotonic dystrophy, Eaton-Lambert syndrome, and myositis.

Hematologic syndromes include red blood cell aplasia, erythrocytosis, pancytopenia, megakaryocytopenia, T-cell lymphocytosis, acute leukemia, and multiple myeloma.

Immune deficiency syndromes include hypogammaglobulinemia and T-cell deficiency syndrome.

The only reported bone abnormality is hypertrophic osteoarthropathy.

Collagen diseases and autoimmune disorders include systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), polymyositis, myocarditis, Sjögren syndrome, and scleroderma.

Endocrine disorders include hyperparathyroidism, Hashimoto thyroiditis, Addison disease, and chemodectoma.

Renal disorders include nephrotic syndrome and minimal-change nephropathy.

Dermatologic diseases include pemphigus and chronic mucocutaneous candidiasis.

The mechanisms that produce these systemic manifestations are not entirely understood but are believed to be autoimmune in nature.

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


The tumors and cysts found in the mediastinum result from several causes. Several different lesions originate from the thymus, including the following:

  • Thymomas
  • Thymic carcinomas
  • Thymic neuroendocrine tumors (NETs)
  • Thymic hyperplasia
  • Thymic cysts
  • Thymolipomas

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

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

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

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

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

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

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


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

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

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

In patients younger than 20 years or older than 40 years, approximately one third of mediastinal tumors are malignant, 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, whereas only about 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 about 15% of those in whom masses are found to be malignant.

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


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


Thymomas are not considered benign neoplasms. Survival rates associated with tumors that are encapsulated or stage I is 95-97% at 5 years and 80-95% at 10 years. Invasive or stage II tumors are associated with a reduced 5-year survival rate of 60-70% and a 10-year survival rate of 40-50%. Survival rates for stage III tumors are reported to be less than 60% at 5 years and 14% at 10 years. Survival rates for stage IVA tumors have been reported at 40% for 5 years and 0% at 10 years.

Surgical resection should be considered for patients with recurrent thymoma.[1]

Other thymic malignancies

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

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

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



History and Physical Examination

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

Approximately 50% of individuals presenting with thymomas are clinically asymptomatic. When symptoms are present with these neoplasms, they may be manifested as local or systemic symptoms or a combination of both. Ill-defined chest pain, cough, and shortness of breath are the most commonly identified associated symptoms.

More severe symptoms (eg, superior vena cava syndrome [SVCS], phrenic nerve paralysis, or recurrent laryngeal nerve involvement resulting in hoarseness) are less common but are often indications of malignant disease. Invasion of the chest wall or pleura can also occur with a malignant neoplasm. This can produce persistent pleural effusions and a significant amount of local pain. Other constitutional symptoms associated with thymoma in almost 20% of patients include weight loss, fever, fatigue, and night sweats.

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



Approach Considerations

Various advances have been made in rthe areas of diagnostic imaging and biologic analysis.

Diagnostic modalities such as positron emission tomography (PET) and other radionuclide studies may assist in the diagnosis of specific neoplasms and in posttherapy surveillance for recurrent disease. In preliminary studies, PET demonstrated the ability to differentiate benign thymomas from malignant thymomas.

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.

Laboratory Studies

Red blood cell (RBC) aplasia is found in approximately 5% of patients with thymoma and manifests as a normochromic-normocytic anemia. These studies are not routinely performed for evaluation of a mediastinal mass, but RBC aplasia may be an abnormality found in association with a mediastinal mass. Neutropenia, though rare, can be found in association with thymomas. These studies are also not part of the routine evaluation of a mediastinal mass, but neutropenia may be an associated abnormality.

Hypogammaglobulinemia is associated with some cases of thymoma.

The thorax should always be investigated for the source of ectopic adrenocorticotropic (ACTH) production. If the workup of a patient with Cushing syndrome calls for investigation for an extra-adrenal source, a neuroendocrine tumor (NET) or carcinoid tumor of the thorax should be excluded. These tumors occur in the mediastinum, particularly in the thymus gland, and in the lung.

Antidiuretic hormone (ADH) levels may be elevated with some NETs of the thymus.

Imaging Studies

Chest radiography

Posteroanterior and lateral radiographs of the chest taken for an unrelated cause are the usual means by which an asymptomatic mediastinal mass is identified (see the image below). Chest radiography is obviously the first radiologic study that would be performed in an individual with symptoms referable to the thorax. Most thymic neoplasms are visualized on standard chest radiography.

Posteroanterior chest film of a 34-year-old woman Posteroanterior chest film of a 34-year-old woman with large anterior mediastinal mass. Pathology results indicated malignant thymoma.

The lateral chest radiograph is very helpful in the determination of the involved compartment of the mediastinum (see the image below). This information, combined with the age, sex, and associated clinical findings, aids the physician in the proper choice of subsequent diagnostic studies.

Lateral view of tumor in the image above (a 34-yea Lateral view of tumor in the image above (a 34-year-old woman with anterior mediastinal mass found to be a malignant thymoma). Note the fullness and haziness above the heart shadow.

Computed tomography

Computed tomography (CT) of the chest and mediastinum is a routine part of the diagnostic evaluation of mediastinal tumors, cysts, and other masses (see the image below).

CT scan view of tumor in the images above (a 34-ye CT scan view of tumor in the images above (a 34-year-old woman with large anterior mediastinal mass found to be a malignant thymoma). Arrow indicates the area in which the tumor (malignant thymoma) is invading the anterior chest wall.

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

CT is very useful for helping differentiate tissue densities. This greatly assists in distinguishing structures that are cystic or vascular from those that are solid.

CT is the preferred imaging modality for visualizing a thymoma. However, thymomas have no absolute diagnostic features; they are usually homogeneous and enhance with contrast. CT scans can reveal evidence of local invasion of adjacent structures by a mass or the presence of intrathoracic metastases. CT has been found to be capable of differentiating stage I/II from stage III/IV and may be useful for predicting the need for neoadjunctive therapy.[2]

Magnetic resonance imaging

Magnetic resonance imaging (MRI) is useful both for initial diagnosis of a mediastinal mass and for follow-up evaluation after treatment. MRI can help differentiate between a possible mediastinal mass and a vascular abnormality such as an aortic aneurysm.

MRI offers direct multiplanar imaging. It can be used when iodinated contrast cannot be given. MRI provides increased detail in the subcarinal and aortopulmonary window areas and in the inferior aspects of the mediastinum at the level of the diaphragm.

MRI adds little that CT does not provide and should not be performed except under special circumstances.

Radionuclide scanning

The origin of a mass located at the thoracic inlet can occasionally be difficult to identify. At times, additional testing may be required to better identify such a mass and help differentiate whether it is of thymic, thyroid, or other origin.

Although the iodine 131 or iodine 123 scans are specific for thyroid tissue, they are worth mentioning in the context of thymic tumors because they are very helpful in distinguishing thyroid tissue from other masses. These scans are often used in identifying an anterior mediastinal mass located at the level of the thoracic inlet as the substernal extension of a cervical thyroid goiter. A radioactive iodine scan may also help identify ectopic thyroid tissue within the mediastinum. These studies must be performed before any tests requiring the administration of iodinated contrast because this material may interfere with thyroid uptake and scanning.

The octreotide scan, using indium 111In-labeled pentetreotide, is useful for localizing various neuroendocrine neoplasms, including carcinoid tumors, pheochromocytomas, and paragangliomas. Carcinoid tumors, though uncommon, can occur in the thymus.

Echocardiography and ultrasonography

Ultrasonographic methods have been used to differentiate solid from cystic mediastinal masses and to assist in determining whether a connection is present between a mass and adjacent structures. These studies are more useful in the evaluation of cardiac abnormalities than in the evaluation of mediastinal tumors.

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

Positron emission tomography

PET has been studied extensively for the evaluation of a number of neoplasms (eg, lung cancer, colorectal cancer, breast cancer, lymphoma, and melanoma). Its usefulness in the evaluation of mediastinal tumors has not been definitively established.

Some results of using PET for thymomas suggest that a high 18-fluorodeoxyglucose (FDG) uptake on PET reflects the invasiveness of malignant nature of thymic tumors and can be used to differentiate these from benign thymomas.[3] A preliminary report suggested that PET is a sensitive test for thymomas.[4]


Transthoracic needle biopsy

In the past, percutaneous biopsy methods were believed to be too dangerous to use in the evaluation of mediastinal masses, and open surgical biopsy was the diagnostic procedure of choice.

Despite some degree of controversy, CT-guided fine-needle aspiration biopsy (FNAB) and core needle biopsy (CNB) techniques have been used with increasing success at several centers.[5, 6]  Differentiation between thymomas, lymphomas, and germ cell tumors can be achieved in a number of cases when tissue obtained from a CNB is subjected to special histologic staining methods, including immunohistochemical techniques. In some cases, lymphoma subtypes can also be identified.

Expert clinical judgment is necessary in the selection of appropriate cases for this diagnostic method. In addition, considerable expertise in tissue processing and analysis is necessary for diagnostic accuracy. Many consider tumor size an important factor when deciding to proceed with needle biopsy. Tumors larger than 5 cm can be considered for biopsy because preoperative chemotherapy may be considered for invasive thymoma and thymic carcinoma.

Cervical mediastinoscopy and substernal extended mediastinotomy

Cervical mediastinoscopy is a commonly used surgical diagnostic procedure for the evaluation of the retrovascular pretracheal area of the mediastinum. It is used most often for staging of bronchogenic carcinoma and for evaluation of hilar and paratracheal lymphadenopathy, but it can be modified into what has been termed a substernal extended mediastinoscopy to evaluate the prevascular area of the mediastinum.

The thymus and any tumors or cysts found in this area, as well as lymph nodes of the aortopulmonary window, are accessible for biopsy via this approach.

Anterior mediastinotomy

This parasternal approach to the mediastinum has been used most commonly in situations in which standard cervical mediastinoscopy was believed or found to be inadequate. The classic approach is to the upper left parasternal area in order to obtain access to the aortopulmonary window and areas of the anterior mediastinum inferior to the aortic arch. Anterior mediastinotomy is being replaced in many centers, either by extended cervical mediastinoscopy or by video-assisted thoracoscopic surgery (VATS).[7]

Video-assisted thoracoscopy

VATS techniques have been used successfully for biopsy of various masses in all areas of the mediastinum.[8]  VATS is commonly used for the sampling of perihilar lymph nodes or masses that are accessible via either thoracic cavity. VATS is superior to the various indirect biopsy techniques because it allows direct visualization of the mass or lesion from where the biopsy sample will be taken and a view of nearby structures and organs. This gives the surgeon an excellent idea of tumor extent and resectability.

Sternotomy and thoracotomy

In spite of the numerous minimally invasive options available for histologic diagnosis of mediastinal tumors and cysts, situations still arise for which open surgical access is needed. In some cases, standard sternotomy or thoracotomy may be the safest method available for obtaining an adequate tissue diagnosis. Ministernotomy can also be used for complete resection of a localized thymoma.

Histologic Findings


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

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

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

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

Thymic carcinomas

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

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

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

Neuroendocrine tumors of thymus

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

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

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

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


A great deal of controversy has been raised about the staging of thymomas. More than one staging system has been used for these lesions, based on the specific feature of the tumor. In the most commonly used system, thymomas are staged according to gross and microscopic features of the encapsulation or invasiveness of the tumor. This staging system is referred to as the Masaoka system, and several other authorities (eg, Koga) have modified it further.

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

In the Masaoka system, thymomas are staged as follows:

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

A staging system based on TNM (tumor-node-metastasis) classification has been developed by the American Joint Committee on Cancer (AJCC).[9]



Approach Considerations

The National Comprehensive Cancer Network (NCCN) has published guidelines on the treatment of thymoma and thymic carcinoma,[10]  as well as on neuroendocrine tumors of the thymus.[11]

Treatment selection for a given mediastinal tumor or cyst depends on the diagnosis of the lesion being investigated. Surgical resection is indicated in a large percentage of cases. Radiation therapy appears to be playing an expanding role in the treatment of thymic malignancies.[12]

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

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

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

Significant advances have been made in therapy. Video-assisted thoracoscopic surgery (VATS) and robotic technology have entered the armamentarium of the thoracic surgeon for the treatment of a number of mediastinal diseases. Minimally invasive techniques are commonly used for biopsy of masses and lymph nodes, as well as for resection of various mediastinal cysts, mediastinal parathyroid adenomas, and localized benign tumors of the posterior mediastinum (eg, ganglioneuromas). The success of these modalities will be determined by data obtained in the long-term follow-up of cases. Because these neoplasms grow slowly, these data become available slowly.

Medical Therapy

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


Although surgical resection is the preferred treatment for thymoma, patients with clinically unresectable extrathoracic disease require radiation therapy, chemotherapy, or both. Radiation therapy is an essential part of the treatment of any thymoma with invasive characteristics. Radiation therapy for patients with stage I tumors is controversial; however, it is recommended for those with tumors in more advanced stages, though a study by Berman et al demonstrated no advantage for stage II thymic tumors.[13] Radiation therapy has also been used preoperatively to facilitate the resection of bulky tumors; however, this role is usually played by chemotherapy.

Cisplatin-based chemotherapy regimens are often recommended for patients with unresectable stage III disease or with disseminated stage IV disease. Chemotherapy is also a useful induction agent for locally advanced thymomas to facilitate resection of these bulky tumors.[14] Cisplatin-based regimens have shown promise for improving both resectability and long-term patient survival.

Thymic carcinoma

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

Cisplatin-based chemotherapy protocols have been used in some cases of undifferentiated mediastinal carcinoma and may be applicable to cases of recurrent or metastatic disease.[14] Because cases are limited, the effectiveness of treatment regimens is difficult to evaluate. Several cases describe some long-term survivors.

Neuroendocrine tumors of thymus

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

Surgical Therapy

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

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

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

In an analysis using data from the National Cancer Data Base to investigate the impact of postoperative radiation therapy (PORT) on overall survival (OS) in 2001 patients who had undergone surgical treatment of thymoma and thymic carcinoma, Jackson et al found that PORT was associated with longer OS.[15]  The greatest relative benefits were noted for stage IIB/III disease and positive margins.

Preparation for surgery

Standard preoperative management applicable to all thoracic surgical cases applies to the preoperative treatment of individuals undergoing resection of mediastinal tumors. Airway management is of paramount importance in dealing with tumors that can produce a mass effect on these structures. Safe management of the airway distorted or narrowed by a mediastinal mass involves the following:

  • Performing a detailed preoperative assessment of the airway
  • Achieving adequate visualization
  • Having supplementary equipment (eg, flexible bronchoscope) readily available

Placement of a double-lumen endotracheal tube to provide single-lung ventilation is usually preferred for any procedure in which a thoracotomy approach is used.

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

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

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

Indications for and results of salvage surgery in mediastinal tumors are yet to be clearly established. Mediastinal salvage surgery is defined as surgical resection of persistent or recurrent primary mediastinal tumors after previous local treatments with curative intent or exclusive chemotherapy in case of bulky tumors. One study concluded that mediastinal salvage surgery can offer a chance of curative treatment in selected patients with an acceptable morbidity and mortality.[16]  Thymic tumors obtain the best results in term of long-term survival.

Superior vena cava syndrome

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

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

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

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

Myasthenia gravis

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

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

Operative details

As with all thoracic surgery, the position of the patient is of paramount importance. Tumors or cysts located in the anterior mediastinum are generally approached through a median sternotomy. This approach is used for tumors of the thymus, though many incisions are appropriate.

Tumors and cysts located in the posterior or middle mediastinum and paravertebral sulci, such as most neurogenic tumors and foregut cysts, are approached through a posterolateral thoracotomy incision.

Lateral thoracotomy and bilateral subcostal incision with transverse sternotomy (clamshell) have also been used in the treatment of thymomas. These incisions may be prudent for a small number of cases, including recurrent disease or tumor extension into the posterior mediastinum. Partial sternotomy and a transcervical approach have also been used; these approaches offer a cosmetic advantage. The da Vinci Surgical System (Intuitive Surgical, Sunnyvale, CA) has been used for thymectomy.[17]

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

VATS has been used for resection of selected tumors of the mediastinum. Thymectomy for encapsulated thymomas that range from small to moderate in size has been performed using this method, as has resection of various neurogenic tumors and foregut cysts.

Regardless of the method chosen to accomplish thymectomy, this operation requires complete removal of all thymic tissue, which generally includes a large adipose component in the adult. When this is performed, certain mediastinal structures are virtually skeletonized. Care must be taken during these procedures to avoid damage to the phrenic nerves and to the brachiocephalic veins.

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

Postoperative Care

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

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

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

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

A continuous infusion of 0.25% bupivacaine at 4 mL/hr through the ON-Q elastomeric infusion pump is also a safe and effective adjunct in postoperative pain management after thoracotomy. The use of the ON-Q Post-Op Pain Relief System (I-Flow Corporation, Lake Forest, CA) results in decreased narcotic use and lower pain scores compared with continuous epidural infusion.

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

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

Chest tubes are managed in the same way as those used in other forms of thoracic surgery. Most cases of mediastinal tumor or cyst resection or biopsy do not involve pulmonary or esophageal resection. Chest tubes are maintained on –20 cm of water-seal suction, and drainage from the tubes is measured daily.

Patients are monitored with daily chest radiographs that are evaluated for residual, undrained collections; complete pulmonary expansion; lobar atelectasis and infiltrates; and other abnormalities. When drainage from the chest tubes is less than 50-100 mL in a 24-hour period, when no air leak is present, and when the chest radiograph shows full pulmonary expansion with no collections on the operated side, the chest tubes may be removed.


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

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

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

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

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

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

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 are being monitored.

After resection of a thymoma, patients may be monitored by means of complete blood count (CBC) , chest radiography, and computed tomography (CT) of the chest at appropriate intervals. One published recommendation suggested monitoring postoperative patients with malignant thymoma every 6 months for the first 5 years and annually thereafter. According to this follow-up protocol, a CBC and a chest radiograph are obtained every 6 months in the first year, after which these studies, along with chest CT, are performed annually.



Guidelines for Thymic Neuroendocrine Tumors

The following organizations have released guidelines for the management of thymic neuroendocrine tumors (NETs):

  • National Comprehensive Cancer Network (NCCN) [11]
  • North American Neuroendocrine Tumor Society (NANETS) [18]
  • European Society of Medical Oncology (ESMO) [19]

Grading and staging

Grading schemes for gastroenteropancreatic NETs use mitotic count; the level of the nuclear protein Ki-67, which is associated with cellular proliferation; and assessment of necrosis. However, for NETs of the lungs and thymus, the WHO includes only mitotic count and assessment of necrosis.[20]  

Under the 2015 WHO grading scheme, tumors fall into one of the following three grades[20] :

  • Low-grade tumors, < 2 mitoses per 10 high power fields (HPFs; or 2 mm 2) and no necrosis
  • Intermediate tumors, 2-10 mitoses per 10 HPFs/2 mm 2 and/or foci of necrosis
  • High-grade tumors, >10 mitoses per 10 HPFs/2 mm 2

Whereas NCCN recommends use of the WHO scheme for grading, it also recommends that tumor differentiation, mitotic rate, and Ki-67 rate be included in the pathology report and that the specific classification and grading scheme be noted to avoid confusion.[11] Clinicians are advised to view histologic grade as a general guide and use clinical judgment to make treatment decisions, particularly in cases of discordance between differentiation and Ki-67 proliferation results.

ESMO uses only mitotic count in determining tumor grade, as follows[19] :

  • Low-grade tumors, < 10 mitoses/10 HPFs
  • Intermediate tumors, 10-20 mitoses/10 HPFs
  • High-grade tumors, >20 mitoses/10 HPFs

The ESMO guidelines recommend staging according to the seventh edition of the American Joint Committee on Cancer's AJCC Cancer Staging Manual[19] ; the NCCN guidelines follow the eighth edition.[11]  TNM staging of thymic NETs follows the general rules for tumors of the thymus.[9]

NANETS concluded that while the criteria differ among the various classification systems, the underlying data are similar and pathology reports should include notation of the systems and parameters used to assign the grade and stage. For NETs of the thorax (including the lungs and thymus) resection margins should be indicated, measuring the distance from the tumor edge to guarantee radical excision on surgical specimens.[18]

NCCN recommendations include the following[11] :

  • Localized disease (stage I/II) - Surgical resection
  • Locoregional disease (stage IIIA/B) - If the lesion is resectable, surgical resection with clean margins; if resection is incomplete or margins are positive, follow with radiation therapy (RT) and/or chemotherapy; if the lesion is locally unresectable, consider observation or RT with or without cytotoxic chemotherapy

The NANETS guidelines include the following recommendations[18] :

  • Locoregional disease - Surgical resection including mediastinal lymphadenectomy
  • Recurrent localized disease - Surgical resection of localized disease
  • Metastatic or unresectable disease - Options include RT (for unresectable disease), everolimus, interferon alfa, or temozolomide

The ESMO guidelines note that a protracted follow-up should always be performed after surgical resection because of the high rates of recurrence. For metastatic disease, although the available chemotherapy regimens have not demonstrated good effects, cisplatin-based regimens have been of value and temozolomide-based treatment gives some benefit.[19]

Guidelines for Thymoma and Thymic Carcinoma

NCCN guidelines have been developed for management of thymoma and thymic carcinoma.[10]

Initial management

Recommendations for initial management include the following[10] :

  • Surgically resectable lesion - Total thymectomy with complete excision of tumor
  • Locally advanced disease, unresectable lesion - Core needle biopsy (CNB) or open biopsy

Locally advanced, advanced, or recurrent disease

Recommendations for locally advanced, advanced, or recurrent disease include the following[10] :

  • Locally advanced disease - If unresectable, concurrent chemoradiation; if potentially resectable, chemotherapy, with computed tomography (CT) of the chest with contrast or fluorodeoxyglucose (FDG) positron emission tomography (PET)/CT to assess resectability; if resectable, surgical resection of primary tumor and isolated metastases, with consideration of postoperative RT; if unresectable, RT ± chemotherapy
  • Solitary metastasis or ipsilateral pleural metastasis - If potentially resectable, chemotherapy, followed by chest CT or PET/CT and subsequent therapeutic approach as for locally advanced disease; alternatively, surgery, with consideration or postoperative chemotherapy or RT
  • Evidence of extrathoracic metastases - Chemotherapy

Surgical resection

Principles of surgical resection include the following[10] :

  • Surgical resection should be performed on carefully evaluated by board-certified thoracic surgeons; locally advanced (unresectable) and resectable stage ≥II cases should be evaluated by a multidisciplinary team
  • Surgical biopsy should be avoided if a resectable thymoma is strongly suspected
  • Biopsy of a possible thymoma should not be done transpleurally
  • Before surgical resection, patients should be evaluated for myasthenia gravis (MG) and should be medically controlled
  • Goals - Complete excision of the lesion with total thymectomy and complete resection of contiguous and noncontiguous disease
  • Complete excision may require resection of adjacent structures; bilateral phrenic nerve resection should be avoided
  • Surgical clips should be placed at the time of resection to help guide RT (when indicated)
  • During thymectomy, pleural surfaces should be examined for metastases, which should be resected if possible to achieve complete gross resection
  • Minimally invasive procedures currently are not routinely recommended but may be considered for stage I/II lesions if (1) all oncologic goals can be met and (2) they are performed in specialized centers by surgeons with relevant experience

Radiation therapy

General principles of RT include the following[10] :

  • RT recommendations should be made by a radiation oncologist with experience in managing thymomas and thymic carcinomas
  • Definitive RT should be provided to (1) patients with unresectable disease that progresses on induction chemotherapy, (2) patients with incompletely resected thymoma or thymic carcinoma, or (3) to patients with locally advanced disease as adjuvant therapy after chemotherapy and surgery
  • Radiation oncologists must communicate (1) with surgeons, to review operative findings and help determine target volume at risk; and (2) with pathologists, to assess detailed pathology, disease extent, and surgical margins
  • Definition of treatment volumes is facilitated by review of preoperative imaging and coregistration of preoperative imaging into the planning system


First-line combination chemotherapy regimens include the following[10] :

  • CAP (cisplatin-doxorubicin-cyclophosphamide; preferred for thymoma)
  • Carboplatin-paclitaxel (preferred for thymic carcinoma)
  • CAP + prednisone
  • ADOC (cisplatin-doxorubicin-vincristine-cyclophosphamide)
  • PE (cisplatin-etoposide)
  • Etoposide-ifosfamide-cisplatin

Second-line systemic therapies include the following[10] :

  • Sunitinib (thymic carcinoma only)
  • Pembrolizumab (thymic carcinoma only)
  • Lenvatinib (thymic carcinoma only)
  • Pemetrexed
  • Everolimus
  • Paclitaxel
  • Octreotide (including LAR) ± prednisone
  • Gemcitabine ± capecitabine
  • 5-Fluorouracil (5-FU) + leucovorin
  • Etoposide
  • Ifosfamide