Introduction

Neoplasms of the mediastinum are a diverse group of benign and malignant pathologic entities that include both primary and secondary malignancies. Most neoplasms of the mediastinum are metastases, typically from lung cancer, although extrathoracic neoplasms such as breast cancer and melanoma have a predilection for spread to the mediastinum. Primary neoplasms of the mediastinum are uncommon, and whereas the majority in adults are benign, those in children are malignant.¹ In terms of primary neoplasms, the most common anterior mediastinal neoplasms include thymomas, teratomas, and lymphomas. Neoplasms of the middle mediastinum are typically congenital cysts, including foregut and pericardial cysts, whereas those that arise in the posterior mediastinum are often neurogenic neoplasms.

This chapter discusses mediastinal neoplasms according to their anatomic location with an emphasis on those primary neoplasms that are more likely to be encountered clinically in an oncologic medical practice. Specifically, thymic, germ cell, and neurogenic neoplasms are reviewed. Imaging findings that are important in establishing the diagnosis are discussed, and computed tomography (CT), magnetic resonance imaging (MRI), and positron-emission tomography (PET)/CT findings that need to be emphasized or clarified so that oncologists and surgeons can deliver appropriate care are addressed.

Epidemiology and Risk Factors

Thymic, germ cell, and neurogenic neoplasms are a heterogeneous group of primary mediastinal neoplasms. Thymic neoplasms account for 17%, lymphomas 16%, and neurogenic neoplasms 14% of all cases of primary mediastinal neoplasms.² Germ cell tumors (teratomas, seminomas, embryonal carcinomas, endodermal sinus tumors, and choriocarcinomas) account for approximately 15% of all mediastinal tumors in adults and 24% in children.³ The remainder of the neoplasms in the mediastinum represents a large group of miscellaneous entities that includes mediastinal cysts (bronchogenic, esophageal, pericardial, thymic, and neurenteric) that account for 15% to 20% of all mediastinal masses.

Thymomas are the most common of the thymic neoplasms and characteristically are located in the anterior mediastinum. Thymomas typically occur in patients older than 40 years, are rare in children, and affect men and women equally.^4–6 Thymic neuroendocrine tumors (carcinoid, small cell carcinoma, and large cell carcinoma) are uncommon. Thymic carcinoid tumor is the most common of this group of tumors. Affected patients are typically in the fourth and fifth decades of life and there is a male predominance.

Germ cell tumors usually occur in young adults (mean age 27 yr).⁷ Most malignant germ cell neoplasms (>90%) occur in men, whereas benign neoplasms (mature teratomas) occur with equal incidence in men and women.⁷ Teratomas are the most common germ cell neoplasm, representing 70% of all germ cell neoplasms in childhood and 60% in adults.⁷ Men and woman are equally affected. Malignant germ cell neoplasms are divided into seminomas and nonseminomatous neoplasms. Seminomas are the most common pure histologic type, accounting for 40% of such neoplasms, and usually occur in men between the third and fourth decades of life.⁷ The nonseminomatous germ cell tumors of the mediastinum include embryonal cell carcinoma, endodermal sinus tumor, choriocarcinoma, and mixed germ cell tumors. Teratoma with embryonal cell carcinoma (teratocarcinoma) is the most common subtype, whereas pure endodermal sinus tumors, choriocarcinomas, and embryonal carcinomas are much less common.

Neurogenic neoplasms represent 75% of all primary posterior mediastinal masses.⁸ These neoplasms are classified as tumors of peripheral nerves (neurofibromas, schwannomas, and malignant tumors of nerve sheath origin), sympathetic ganglia (ganglioneuromas, ganglioneuroblastomas, and neuroblastomas), or parasympathetic ganglia (paraganglioma and pheochromocytoma). Peripheral nerves are more commonly involved in adults and schwannomas constitute 75% of this group, whereas sympathetic ganglia neoplasms are more common in children. Schwannomas and neurofibromas typically occur with equal frequency in men and women, most commonly in the third and fourth decades of life. Thirty percent to 45% of neurofibromas⁹ occur in patients with neurofibromatosis (NF), and multiple neurogenic tumors or a single plexiform neurofibroma is considered pathognomonic of the disease.¹⁰ Malignant tumors of nerve sheath origin (also termed malignant neurofibromas, malignant schwannomas, or neurofibrosarcomas) are rare and typically develop from solitary or plexiform neurofibromas in the third to fifth decades of life. Up to 50% occur in patients with NF-1, and in these patients, tumors occur at an earlier age (typically adolescents) and with a higher incidence than in the general population.^4,11 Neuroblastomas are the most common extracranial solid neoplasms in children, accounting for 10% of all childhood neoplasms. Neuroblastomas are typically diagnosed at a median age of younger than 2 years, ganglioneuroblastomas at 5.5 years of age, and ganglioneuromas at 10 years.¹²

Anatomy and Pathology

The mediastinum is located in the central portion of the thorax between the two pleural cavities, extending from the diaphragm to the thoracic inlet. Historically, the mediastinum has been divided into anatomic regions or compartments. Although there are no fascial planes that separate these compartments, this division facilitates tumor localization and is useful in limiting the differential diagnosis. However, this traditional division into anterior, middle, and posterior compartments is less important today because CT and MRI are able to accurately localize and, in many instances, characterize masses.

The anterior mediastinum is bounded anteriorly by the sternum; posteriorly by the pericardium, aorta, and brachiocephalic vessels; superiorly by the thoracic inlet; and inferiorly by the diaphragm. Its contents include the thymus, lymph nodes, and fat. The middle mediastinum is bounded by the pericardium, and its contents include the heart and pericardium, aorta, vena cava, brachiocephalic vessels, pulmonary vessels, trachea and main bronchi, lymph nodes, and phrenic, vagus, and left recurrent laryngeal nerves. The posterior mediastinum is bounded anteriorly by the trachea and pericardium, anteroinferiorly by the diaphragm, posteriorly by the vertebral column, and superiorly by the thoracic inlet. Although the true anatomic posterior boundary is the vertebral column, with respect to mediastinal disease, masses in the paravertebral regions are usually included in the posterior mediastinum. The contents of the posterior mediastinum include the esophagus, descending aorta, azygos and hemiazygos veins, thoracic duct, vagus and splanchnic nerves, lymph nodes, and fat.¹³

In the anterior mediastinum, significant proportions of the neoplasms arise from the thymus. Accordingly, an understanding of the normal appearance and location of the thymus is important in the detection and diagnosis of these neoplasms. The thymus consists of two lobes placed in close contact along the midline extending from the fourth costal cartilage upward, as high as the lower border of the thyroid gland. However, ectopic thymic tissue can occur at any level in the pathway of normal thymic descent, from the angle of the mandible to the upper anterior mediastinum. The two lobes generally differ in size; the left lobe is larger than the right and extends more inferiorly. Thymic hyperplasia, an increase in weight and size, has two distinct histologic forms: true and lymphoid hyperplasia. True hyperplasia occurs in children and young adults recovering from severe illness or trauma or after chemotherapy (Figure 7-1). Lymphoid hyperplasia occurs most commonly in patients with myasthenia gravis but also in association with other diseases such as hyperthyroidism, Graves’ disease, rheumatoid arthritis, and scleroderma.¹⁴

Figure 7-1 Thymic hyperplasia in a 15-year-old girl with a right femoral osteosarcoma. A, Axial computed tomography (CT) image shows decrease in thymic volume during chemotherapy. B, Axial CT image shows increase in thymic size 6 months after completion of chemotherapy. Note diffuse, symmetrical enlargement with preservation of the normal shape of the thymus.

Thymic neoplasms are usually epithelial in origin and include thymomas and carcinomas. Most thymomas are solid neoplasms that are encapsulated and localized to the thymus. However, one third have necrosis, hemorrhage, or cystic components; invasion of the capsule and involvement of the surrounding structures occurs in approximately one third of cases.¹⁵ Thymomas have a wide variety of histologic features, and there is a strong association between the histologic findings and invasiveness as well as prognosis.¹⁶ Thymic carcinomas usually manifest histologically as large, solid, and infiltrating masses with cystic and necrotic areas. They are histologically classified as low or high grade, with squamous cell–like or lymphoepithelioma-like variants being the most common cell types.⁴ Thymic neuroendocrine neoplasms are uncommon. These tumors typically manifest as a large, lobulated, and usually invasive anterior mediastinal mass that can exhibit areas of hemorrhage and necrosis.^4,17 Malignant potential ranges from relatively benign (thymic carcinoid) to highly malignant (small cell/large cell carcinoma of the thymus). Typical carcinoid has low mitotic activity (<2 mitoses/2 mm²) without necrosis, whereas atypical carcinoid has a higher degree of mitotic rate (2-10 mitoses/2 mm²) and/or necrosis. Small cell and large cell neuroendocrine carcinomas have a higher rate of mitotic activity (>10 mitosis/2 mm²) and associated necrosis.

Germ cell tumors are thought to arise from mediastinal remnants of embryonal cell migration. The mediastinum is the most common extragonadal primary site of these neoplasms and accounts for 60% of all germ cell tumors in adults. Teratomas, the most common mediastinal germ cell tumors, are composed of elements that arise from one or more of the three primitive germ cell layers (ectoderm, mesoderm, and endoderm). Mediastinal teratomas are classified as mature, immature, or malignant; most teratomas are composed of well-differentiated or mature tissue and are benign. Mature or benign teratomas are composed of ectoderm, endoderm, or mesoderm, with ectodermal derivatives predominating. Teratomas are spherical, lobulated, and encapsulated neoplasms that are frequently cystic and multiloculated. These neoplasms can contain sebaceous material as well as hair and teeth. Respiratory and intestinal epithelium may also be present. Nonteratomatous tumors include seminomas and nonseminomatous types. Seminomas, also known as germinomas or dysgerminomas, are the second most common mediastinal germ cell tumor. They typically manifest as solid masses with lobulated contours. Nonseminomatous neoplasms are divided into embryonal carcinoma, endodermal sinus tumor, choriocarcinoma, and mixed types, which include any combination of these histologic types.

In the posterior mediastinum, most of the neoplasms are neurogenic in origin. Nerve sheath tumors are either schwannomas, neurofibromas, or malignant tumors of nerve sheath origin (malignant neurofibroma, malignant schwannoma, and neurogenic fibrosarcoma). Histologically, schwannomas are encapsulated tumors which arise from Schwann cells located in the nerve sheath and grow along the nerve, causing extrinsic compression.¹¹ They are heterogeneous in composition and can have low cellularity, areas of cystic degeneration, hemorrhage, and small calcifications. Neurofibromas differ from schwannomas in that they are unencapsulated and result from proliferation of all nerve elements, including Schwann cells, nerve fibers, and fibroblasts. They grow by diffusely expanding the nerve. Plexiform neurofibromas are variants of neurofibromas that infiltrate along nerve trunks or plexuses.¹⁸ Ganglion cell tumors arise from the autonomic nervous system rather than nerve sheaths and range from benign encapsulated neoplasms (ganglioneuromas) to moderately aggressive neoplasms (ganglioneuroblastomas) to malignant unencapsulated masses (neuroblastomas). They are derived from cells of embryologic origin or sympathetic ganglia. After the abdomen, the thorax is the second most common location of neuroblastomas,¹⁹ whereas ganglioneuromas and ganglioneuroblastomas are more common in the sympathetic chain of the posterior mediastinum. Ganglioneuromas are benign tumors composed of one or more mature ganglionic cells. Ganglioneuroblastomas have histologic features of both ganglioneuromas and neuroblastomas. They are the least common type of neurogenic tumors. Neuroblastomas are the most aggressive type and are composed of small round cells arranged in sheets or pseudorosettes.^20,21

Clinical Presentation

Most patients with mediastinal neoplasms are asymptomatic at the time of the diagnosis. Symptoms are usually related to local effects of the neoplasm, including compression and invasion, and can manifest as respiratory distress, dysphagia, diaphragm paralysis, or superior vena cava (SVC) syndrome. Systemic symptoms and paraneoplastic syndromes occur occasionally and are typically due to secretion of hormones, antibodies, or cytokines by the tumor.

Thymomas usually are an incidental finding, but they can manifest as chest pain, cough, or dyspnea in up to one third of patients.²² Myasthenia gravis, characteristically associated with thymomas, occurs most frequently in women. Thirty percent to 50% of patients with thymomas have myasthenia gravis, whereas 10% to 15% of patients with myasthenia gravis have a thymoma.²³ Patients with myasthenia gravis usually have diplopia, ptosis, dysphagia, and fatigue. Ten percent of patients with a thymoma have hypogammaglobulinemia and 5% of patients have pure red cell aplasia. Thymomas are also associated with various autoimmune disorders such as systemic lupus erythematosus, polymyositis, or myocarditis.² Thymic carcinomas are frequently symptomatic at presentation owing to marked local invasion and involvement of mediastinal structures. Symptoms include chest pain, dyspnea, cough, SVC syndrome, usually due to compression or invasion of the SVC; unlike thymomas, paraneoplastic syndromes are rare. Thymic neuroendocrine tumors are also associated with ectopic secretion of hormones. Up to 50% of affected patients with thymic carcinoid tumors have hormonal abnormalities and up to 35% have Cushing’s syndrome due to tumoral production of adrenocorticotropic hormone (ACTH). Nonfunctioning thymic carcinoids may be seen in association with the multiple endocrine neoplasia syndrome type 1.

Patients with germ cell tumors are often asymptomatic. Large tumors can manifest clinically as cough, dyspnea, chest pain, or pulmonary infection. Rarely, teratomas may erode and rupture into adjacent airway, resulting in expectoration of oily material or hair (tricophtysis). Seminomas can manifest as SVC syndrome in 10% of cases. Beta-human chorionic gonadotropin (β-hCG) and alpha-fetoprotein (AFP) levels are usually normal. However, 7% to 8% of patients with pure seminomas are reported to have elevated serum levels of β-hCG and elevation of serum lactate dehydrogenase (LDH) levels occurs in 80% of patients with advanced seminomas. Importantly, elevation of AFP indicates a nonseminomatous component of the tumor. Most (90%) of patients with nonseminomatous germ cell tumors of the mediastinum are symptomatic at presentation with chest pain, cough, dyspnea, weight loss, and fever. Serologic tumor markers are important in the diagnostic evaluation and 71% of affected patients have elevated levels of AFP and 54% have elevated levels of β-hCG.²⁴ There is an association between malignant nonseminomatous germ cell tumors of the mediastinum and hematologic malignancies. In addition, approximately 20% of cases are associated with Klinefelter’s syndrome (gynecomastia, testicular atrophy, and 47 XXY karyotype).

Nerve sheath tumors are usually asymptomatic. Because most patients with a benign neurogenic tumor are asymptomatic, the development of pain often indicates malignant transformation (malignant neurofibromas, malignant schwannomas, or neurofibrosarcomas). Mediastinal neuroblastomas can manifest clinically due to local mass effect leading to respiratory distress or spinal cord compression. Neuroblastomas and, less frequently, ganglioneuroblastoma and ganglioneuroma can produce metabolically active catecholamines responsible for hypertension, flushing, and watery diarrhea syndrome.^25,26 Catecholamine derivatives, such as vanilmandelic acid and homovanilic acid, can be secreted and associated with elevated catecholamine plasma levels and are helpful in establishing the diagnosis.

Staging

Several classification schemes and staging systems for thymic epithelial tumors have been proposed over the last few decades that reflect to various degrees the clinical and functional behavior of thymic epithelial tumors and their histology. However, because thymomas are composed of a mixture of neoplastic epithelial cells and non-neoplastic lymphocytes, there is a marked variability in the histology of these tumors, both in the same tumor and between different thymomas. Accordingly, the histologic classification of thymomas is difficult.

In 1999, the World Health Organization (WHO) Consensus Committee published a histologic classification of tumors of the thymus. In this scheme, thymomas are classified on the combined basis of the morphology of the neoplastic epithelial cells and the lymphocyte–to–epithelial cell ratio. This classification has resulted in six separate histologic subtypes of thymomas (types A, AB, B1, B2, B3, and C) (Table 7-1). An update on the WHO classification was published in 2004.²⁷ It retained its classifications of A through B3 thymomas but relegated type C to a separate category of thymic carcinoma and acknowledged that certain types of thymoma do not fall into these categories. The applicability and clinical significance of the WHO histologic classification of thymomas is still being evaluated. It appears that most thymomas can be classified using the WHO criteria, although the clinical and prognostic relevance of this classification has not been conclusively determined. Most thymomas of types A and AB tend to have no local invasion, are completely resectable, and have no recurrence or tumor-related deaths. There is an increasing tendency to local invasion, incomplete resection, and recurrence after resection in the order of types of B1 and B2, type B3, and type C thymomas. In this regard, most type C thymomas are locally invasive, many are incompletely resected and there is a high early relapse rate and poor prognosis. The WHO histologic subtype classification of thymomas has been reported to correlate with the staging classification devised by Masaoka and coworkers. The Masaoka staging system is a pathologic staging system that is based on the presence of capsular invasion and is currently the most widely used to determine therapy.²⁸ In this staging system, the stages are defined as stage I, macroscopically encapsulated and microscopically no capsular invasion; stage II, macroscopic invasion into surrounding fatty tissue of mediastinal pleura or microscopic invasion into capsule; stage III, macroscopic invasion into a neighboring organ; stage IVa, pleural or pericardial dissemination; and stage IVb, lymphogenous or hematogenous metastasis.

Table 7-1 World Health Organization Classification Scheme for Thymic Epithelial Tumors

Neuroblastomas are currently staged according to the International Neuroblastoma Staging System (INSS), which is based on surgical findings as well as lymph node and metastatic involvement. However, new guidelines for a pretreatment staging system have been developed by the International Neuroblastoma Risk Group (INRG); this staging system is being implemented clinically.²⁹ This staging model is based on clinical and imaging features rather than surgical findings. Currently, both of these staging systems have an important role in the determination of appropriate treatment and prediction of outcome in patients with neuroblastoma (Table 7-2).

Table 7-2 Comparison between International Neuroblastoma Staging System and International Neuroblastoma Risk Group Staging System

IDRFs, image-defined risk factors; INRGSS, International Neuroblastoma Risk Group Staging System; INSS, International Neuroblastoma Staging System; MIBG, iodine-123-metaiodobenzylguanidine.

Adapted from Monclair T, Brodeur GM, Ambros PF, et al. The International Neuroblastoma Risk Group (INRG) staging system: an INRG Task Force report. J Clin Oncol. 2009;27:298-303.

Patterns of Spread

Thymomas can remain localized or spread through the mediastinum in a contiguous fashion. Characteristically, if invasion of the adjacent pleura occurs, dissemination in the pleural space can result in solitary, multiple, or diffuse metastases distant to the primary mass. Historically, this dissemination of metastases in the pleural space has been referred to as drop metastases (Figure 7-2). Pleural effusion is uncommon, despite often extensive pleural metastatic disease. Transdiaphragmatic spread has been reported in up to one third of patients.³⁰ Pericardial involvement due to contiguous spread is common and can manifest as nodular or diffuse thickening and a pericardial effusion. Systemic dissemination is rare, although lung metastases can occur. Thymic carcinomas are aggressive malignancies that often exhibit marked local invasion and early dissemination. In 40% of cases, there is invasion of adjacent organs, 40% present with nodal metastatic disease, and 10% have pleural or pericardial involvement. Distant metastases to lung, liver, adrenal glands, brain, and bone occur in 40% of patients.

Figure 7-2 Thymoma in a 52-year-old man with chest pain. Axial CT image shows an anterior mediastinal mass (arrow) and focal pleural thickening (arrowheads). Biopsy revealed metastatic pleural disease. Note that dissemination of metastases in the pleural space has been referred to as drop metastases.

Although mature teratomas are benign, rare cases of tumor rupture into the lung, pleural space, and pericardium have been reported. Seminomas usually have lymphatic or systemic dissemination, and local invasion of adjacent structures is rare. Metastases to regional nodes as well as metastatic involvement of cervical (25%) and abdominal lymph nodes (8%) are reported.³¹ In cases of nonseminomatous tumors, invasion of the adjacent structures such as lung and mediastinal pleural is frequent.³² Pleural and pericardial effusion are common owing to local and direct invasion. Chest wall invasion is more frequently associated with larger masses. Hematogenous disseminated metastases to lungs, liver, brain, and bones are common and occur in up to 50% of patients. Metastatic spread to lymph nodes is less frequent.

Because neurogenic tumors usually arise in a paravertebral location, intraspinal extension is common. Ten percent of paravertebral neurofibromas and schwannomas extend into the neural foramina and spinal canal.¹¹ Compression and destruction of adjacent structures can occur as a result of aggressive local tumor invasion. Ganglioneuromas are encapsulated benign tumors without evidence of local or distant dissemination. Ganglioneuroblastomas and neuroblastomas are more aggressive, with evidence of local and intraspinal invasion. Neuroblastomas have a tendency to grow across the midline and lymph node involvement can occur. Lymphatic and hematogenous dissemination are common and sites of metastatic involvement include bone (60%), regional lymph nodes (45%), orbit (20%), liver (15%), brain (14%), and lung (10%).

Imaging

Imaging has an important role in the evaluation of a mediastinal neoplasm and establishes a diagnosis or relevant differential in most patients. Specifically, the location of a neoplasm in the mediastinum together with its morphologic features is often helpful in differentiating a benign from a malignant neoplasm. One of the most common clinical indications for radiologic evaluation is a known or suspected mediastinal mass. Although conventional radiography may allow detection or suggest the presence of a mediastinal mass, in most cases, CT, MRI, and/or integrated PET/CT are required for further evaluation. CT is frequently performed to evaluate the mediastinum if, on chest radiography, there is an abnormality suspicious for a mediastinal mass. MRI is usually reserved for clarifying problems encountered on CT or to examine patients who cannot tolerate intravenous administration of iodinated contrast material. PET/CT not only can be used to detect disease but also can be useful in differentiating benign from malignant masses and diagnosing disease recurrence.

Importantly, in the assessment of thymic neoplasms, the normal thymus in young children and thymic hyperplasia can mimic a mediastinal mass on chest radiographic assessment. CT and MRI are useful in differentiating normal thymic tissue and the hyperplastic thymus from tumors. Thymic hyperplasia manifesting as a mass on CT or MRI is differentiated from a primary mediastinal neoplasm based on diffuse, symmetrical enlargement with preservation of normal shape of the thymus (see Figure 7-1). Similar findings distinguish rebound hyperplasia, which occurs 3 to 8 months after cessation of chemotherapy in approximately 25% of patients, from recurrence of the initial neoplasm.³³ When CT and conventional MRI sequences are not able to differentiate between a normal thymus or thymic hyperplasia and a thymoma, chemical shift MRI sequences (in-phase and out-of-phase gradient echo sequences) can be helpful in the diagnosis—that is, homogeneous signal decrease occurs in normal and hyperplastic tissue compared with absence of signal decrease in tumors. PET/CT imaging is being increasing performed in oncologic patients. The normal thymus can have mildly increased fluoro-2-deoxy-d-glucose (FDG), especially in children. In addition, increased FDG uptake in the thymus, mainly related to hyperplasia after chemotherapy, has been reported to occur in 28% of patients and is higher in younger patients (in 80% of patients < 10 yr of age, compared with 8% of patients in the 31- to 40-yr age group).³⁴

Thymic Neoplasms

Thymomas are usually located anterior to the aortic arch but can occur in the cardiophrenic recesses.^4,35 They typically manifest as a 1- to 10-cm (mean 5 cm) smooth or lobulated well-marginated mass that characteristically arises from one lobe of the thymus. Although thymomas typically manifest as a unilateral mass, bilateral mediastinal involvement can occur.³⁶ On CT, thymomas are usually of homogeneous soft tissue attenuation (see Figure 7-2). Calcification, seen in up to 7% of cases, is usually thin, linear, and located in the capsule. Enhancement after intravenous administration of contrast is usually homogeneous except in the one third of thymomas that are necrotic or cystic or contain hemorrhage. Tomiyama and colleagues³⁷ suggested that a combination of lobulated or irregular contour, cystic or necrotic portion within the tumor and multifocal calcification is more suggestive of invasive thymoma (Figure 7-3). On MRI, thymomas manifest with low to intermediate signal intensity (similar to skeletal muscle) on T1-weighted images and high signal intensity on T2-weighted images. Heterogeneous signal intensity is present in those tumors that have focal areas of necrosis, hemorrhage, and cystic change. MRI can occasionally reveal fibrous septa within the masses. Pleural metastases manifest on CT and MRI as an isolated pleural nodule, multifocal masses, or contiguous pleural involvement, which can be smooth, nodular, or diffuse, mimicking malignant pleural mesothelioma. Pleural effusion is uncommon, despite often extensive pleural metastatic disease.^4,38 Pericardial thickening and/or effusion typically are associated with invasive thymomas. The differentiation of benign from invasive thymomas is usually not possible on CT and MRI.

Figure 7-3 Invasive thymoma in a 66-year-old man with an incidentally detected mediastinal mass at the time of coronary artery bypass graft surgery. A, Axial CT image shows an anterior mediastinal mass (large arrow) with irregular contours and punctate calcification. There is focal pleural thickening (small arrows). B, Axial positron-emission tomography (PET)/CT image shows increased fluoro-2-deoxy-d-glucose (FDG) uptake in the mass and pleura suspicious for pleural metastasis. Biopsy confirmed pleural metastasis.

The precise role of PET/CT in the evaluation of thymomas is unclear. One difficulty is that FDG uptake in the normal thymus is variable and increased FDG uptake by the thymus is common, especially in young patients.³⁴ Although it has been reported that PET/CT can be useful in distinguishing thymic epithelial tumors according to the WHO classification as well as for staging the extent of the disease,^39–41 in our experience, PET/CT is unreliable in distinguishing noninvasive from invasive thymomas or thymic carcinomas. Thymic carcinomas commonly manifest as large, poorly marginated anterior mediastinal masses that are calcified in 10% to 40% of cases.^37,42,43 Intrathoracic lymphadenopathy is common. On CT, thymic carcinomas are usually of heterogeneous attenuation and have poorly defined margins. On MRI, they typically have intermediate signal intensity (slightly higher than skeletal muscle) on T1-weighted images and high signal intensity on T2-weighted images. Signal intensity can be heterogeneous because of hemorrhage and necrosis within the mass. MRI can be helpful for revealing local soft tissue and vascular invasion. Similar to the evaluation of thymomas, the role of PET/CT in the diagnosis and staging of thymic carcinomas has not been clearly established. It has been reported that thymic carcinomas typically exhibit increased FDG uptake on PET/CT that is usually higher and more homogeneous than in thymomas and thymic hyperplasia.^39,41,44 However, clinically, the role of FDG-PET imaging in differentiating thymomas from thymic carcinomas is limited, although the detection of unexpected nodal and distant metastases is useful in patient management.

Thymic neuroendocrine tumors usually manifest as a large anterior mediastinal mass, with a propensity for local invasion and metastasis (Figures 7-4 and 7-5). Focal areas of necrosis or punctuate and dystrophic calcification may be present.¹⁷ On CT or MRI, the masses are usually of heterogeneous attenuation or signal intensity, respectively. Differentiation between thymic neuroendocrine tumors and invasive thymic epithelial tumors may be difficult on the basis of imaging findings alone. Thymic neuroendocrine tumors have a poor prognosis owing to a high prevalence of recurrence and metastasis.

Figure 7-4 Neuroendocrine thymic tumor in a 60-year-old asymptomatic man with a mediastinal mass detected during routine chest radiograph evaluation. A, Chest CT image shows an anterior mediastinal mass (M) with lobulated contours and obliteration of the fat plane with the ascending aorta (Ao), suspicious for locoregional invasion. B, Axial PET/CT image shows increased FDG uptake in the mass.

Figure 7-5 Small cell neuroendocrine thymic tumor in a 31-year-old man presenting with hip pain due to metastatic disease. A, Posteroanterior chest radiograph shows a large anterior mediastinal mass extending into both hemithoraces (arrows). B, Axial CT image confirms a large anterior mediastinal mass and shows necrosis and prominent vasculature (arrow). C, Coronal PET/CT image shows FDG uptake in the periphery of the mass (white arrows) and low FDG activity centrally due to necrosis. Note focal increased FDG uptake in a humeral metastasis (black arrow) due to metastatic bone disease.

Germ Cell Tumors

These neoplasms have a range of manifestations in the mediastinum. Mature teratomas manifest on CT or MRI as smooth or lobulated mediastinal masses that typically have cystic and solid components, whereas malignant teratomas are usually poorly marginated masses containing areas of necrosis. The combination of fluid, soft tissue, calcium, and/or fat is diagnostic of teratomas (Figure 7-6). The finding of a fat-fluid level within a mass on CT or MRI is also diagnostic of a teratoma. Fat occurs in up to 75% of mature teratomas and up to 40% of malignant teratomas. However, only 17% to 39% of mature teratomas will have all tissue components and approximately 15% of mature teratomas manifest only a unilocular or multilocular cystic component. In this regard, these masses can mimic mediastinal cysts. In terms of differentiation, benign mediastinal cysts manifest as well-defined thin-walled masses with low attenuation (0-20 HU) on CT and no enhancement after contrast administration⁴⁵ whereas teratomas show rim enhancement and enhancement of tissue septa. Because simple cysts can contain proteinaceous fluid and have high attenuation on CT, MRI can be useful in differentiating these lesions. Simple cysts characteristically have low signal intensity on T1-weighted image sequences and high signal intensity on T2-weighted sequences (high signal intensity occurs on T1-weighted image sequences when proteinaceous material or hemorrhage is present). Teratomas containing fat typically manifest as high signal intensity on T1-weighted images. A fat-saturation MRI technique can be used to detect and distinguish fat from hemorrhage. Importantly, if a cystic neoplasm is suspected because the CT or MRI findings are atypical or because the mass has increased in size, aspiration may be required for diagnosis. Mature teratomas can rupture into lung, pleural space, and pericardium, and CT or MRI can be useful in detecting fat within these regions. In addition, ancillary changes such as adjacent parenchymal consolidation or atelectasis, pleural effusion, and pericardial effusion are associated with rupture into the pleural or pericardial space. PET/CT is not useful in the evaluation of mature teratomas owing to the lack of FDG avidity. Seminomas manifest as large/bulky, well-marginated masses with lobulated contours and typically have homogeneous attenuation or signal intensity on CT and MRI, respectively. However, cysts or areas of necrosis can occur and calcification is rare. Seminomas enhance only slightly after administration of intravenous contrast material. Compression of adjacent mediastinal structures is common but invasion is uncommon (Figure 7-7). Extension into the middle and posterior compartments and obliteration of fat planes can occur. In contradistinction, nonseminomatous tumors are usually large, unencapsulated, heterogeneous soft tissue masses that tend to invade and infiltrate adjacent structures, including the lung and chest wall. Fat planes are typically obliterated, and the interface between the tumor and the adjacent lung may be irregular and spiculated owing to lung invasion. These tumors can contain large areas of hemorrhage, necrosis, and cyst formation (Figure 7-8). Associated pleural and pericardial effusions can occur. Metastases to the regional lymph nodes and distant sites are common. Multiple pulmonary nodules representing metastases can be present. The role of PET/CT has not been clearly elucidated in patients with primary mediastinal seminomas and nonseminomatous tumors.

Figure 7-6 Teratoma in a 29-year-old man presenting with chest discomfort. Axial CT image shows a mediastinal mass that contains adipose tissue (*) and focal calcification. Note that fat occurs in up to 75% of teratomas.

Case courtesy of S. Rossi, Centro de Diagnostico Dr. Enrique Rossi, Buenos Aires, Argentina.

Figure 7-7 Seminomatous germ cell tumor in a 37-year-old man presenting with superior vena cava (SVC) syndrome (facial swelling, enlargement of the neck veins). Axial CT image shows homogeneous anterior mediastinal mass and SVC compression (arrow). Note that compression of adjacent mediastinal structures is common.

Figure 7-8 Nonseminomatous germ cell tumor in a 21-year-old man presenting with shortness of breath and chest pain. Axial CT image shows large heterogeneous anterior mediastinal mass with SVC (*) compression and paravertebral collateral circulation (arrow). Mild right pleural effusion is also noted. Note that nonseminomatous tumors tend to present necrosis and most patients are symptomatic at presentation.

Neurogenic Tumors

The benign peripheral nerve tumors (schwannomas and neurofibromas) are slowly growing neoplasms that often are radiologically indistinguishable. Schwannomas and neurofibromas are usually sharply marginated, spherical, and lobulated paravertebral masses. On CT imaging, punctate calcification and low-attenuation areas caused by the presence of fat, cystic change, or hemorrhage can be seen. Enhancement after intravenous contrast administration is variable and can be homogeneous, heterogeneous,⁴⁶ or peripheral.¹⁸ Enlargement of neural foramina with or without extension into the spinal canal and osseous abnormalities, such as rib erosion and splaying of the ribs, can occur. MRI is the preferred modality for demonstrating the intraspinal extension of the tumor or the presence of an associated spinal cord abnormality (Figure 7-9). On MRI, neurofibromas and schwannomas have variable signal intensity on T1-weighted images but typically have similar signal intensity to the spinal cord. On T2-weighted images, these neoplasms characteristically have high signal intensity peripherally and low signal intensity centrally (target sign) due to collagen deposition (Figure 7-10). This feature, when present, helps distinguish neurofibromas from other mediastinal tumors. Also, areas of cystic degeneration within the mass can result in foci of increased signal intensity on T2-weighted images. Although the high signal intensity of schwannomas and neurofibromas on T2-weighted images can facilitate differentiation of tumors from spinal cord, the tumors can be obscured by the high signal intensity of cerebrospinal fluid. Schwannomas and neurofibromas, however, enhance with gadolinium; this feature can be useful in detecting and determining intradural extension of these tumors. Paravertebral neurofibromas and schwannomas that extend into the spinal canal manifest as dumbbell-shaped masses with widening of the affected neural foramen. In several small series, neurofibromas and schwannomas have been reported to be FDG-avid on PET/CT. On CT, plexiform neurofibromas manifest as low-attenuation, poorly marginated masses located along the mediastinal nerves and sympathetic chains. MRI of plexiform neurofibromas shows the infiltrative nature of the tumors, and the masses have low signal on both T1-weighted and T2-weighted images owing to the fibrous nature of the tumors.

Figure 7-9 Neurofibroma in a 44-year-old asymptomatic woman with a mediastinal mass detected on chest radiography. Gadolinium-enhanced T1-weighted axial magnetic resonance imaging (MRI) demonstrates large right paraspinal mass (M) that extends to the neural foramina (arrows). Note that MRI is the preferred modality for demonstrating intraspinal extension of the tumor.

Case courtesy of L. Ginsberg, The University of Texas M. D. Anderson Cancer Center, Houston, Texas.

Figure 7-10 Neurofibroma in a 35-year-old woman with a history of neurofibromatosis type 1. A, Posteroanterior chest radiograph shows a lobulated well-defined posterior mediastinal mass (arrows). B, Coronal T2-weighted image shows a heterogeneous posterior mediastinal mass (*) with peripheral high signal intensity. Note that neurofibromas characteristically have high signal intensity peripherally and low signal intensity centrally (target sign) on T2-weighted images.

Malignant tumors of nerve sheath origin are rare but typically develop from solitary or plexiform neurofibromas. On CT or MRI, malignant tumors of nerve sheath origin typically manifest as posterior mediastinal masses larger than 5 cm in diameter. Although benign and malignant neurogenic tumors cannot be differentiated with certainty, findings that suggest malignancy include a sudden change in size of a preexisting mass or development of heterogeneous signal intensity on MRI (caused by necrosis and hemorrhage). The presence of multiple target signs throughout the lesion on MRI favors the diagnosis of a plexiform neurofibroma rather than a malignant tumor of nerve sheath origin. Neurofibrosarcomas are often FDG-avid and when the standardized uptake value (SUV) is greater than 3, aggressive behavior has been reported. The sympathetic ganglia tumors, ganglioneuromas and ganglioneuroblastomas, usually manifest as well-marginated, elliptical, posterior mediastinal masses that extend vertically over three to five vertebral bodies (Figure 7-11). They are usually located lateral to the spine and can cause pressure erosion on adjacent vertebral bodies. On CT, they are typically heterogeneous and contain stippled or punctate calcification in up to 30% of masses.⁴⁷ On T1- and T2-weighted MRI, they are usually homogeneous and of intermediate signal intensity. Occasionally, these lesions are heterogeneous and of high signal intensity on T2-weighted images.⁴⁸ Ganglioneuroblastomas are typically larger and more aggressive with evidence of local and intraspinal invasion than ganglioneuromas. Neuroblastomas manifest as a paraspinal mass of heterogeneous, predominantly soft tissue attenuation (Figure 7-12). The masses usually contain areas of hemorrhage, necrosis, and cystic generation. Calcification occurs in up to 80% of cases and can be coarse, mottled, solid, or ring-shaped.⁴⁹ Neuroblastomas often show widespread local invasion and have irregular margins, although many of these lesions are well-marginated on CT or MRI. The primary tumor can also spread through the neural foramina, resulting in a classic dumbbell-shaped tumor.¹² On CT, discrete lytic or mixed lytic and sclerotic areas or metaphyseal lucencies are typical of metastatic osseous involvement. On MRI, neuroblastomas show homogeneous or heterogeneous signal intensity on all sequences and variable enhancement after contrast administration.⁴⁸ Iodine-123-metaiodobenzylguanidine (¹²³I-MIBG) is an essential part of the evaluation for patients with neuroblastomas and improves the detection of the primary malignancy as well as metastases and is also useful in the assessment of response to therapy. The role of PET/CT in evaluation of patients with neuroblastoma is unclear. PET/CT can be useful in ¹²³I-MIBG-negative neuroblastoma patients and is better in the evaluation of disease extent in the chest, abdomen, and pelvis. PET/CT is superior in depicting stage 1 and 2 neuroblastoma, although ¹²³I-MIBG is overall superior in the evaluation of stage 4 neuroblastoma, mainly because of the better detection of bone or marrow metastases.⁵⁰

Figure 7-11 Ganglioneuroma in a 10-year-old girl. A, Posteroanterior chest radiograph shows a large posterior mediastinal mass. B, Coronal T2-weighted image shows a high–signal intensity well-marginated large right paravertebral mass (M). Note that the elongated elliptical shape that extends vertically over five to six vertebrae is typical of sympathetic ganglia tumors.

Figure 7-12 Neuroblastoma in a 1-year-old girl with respiratory distress. Axial CT image shows a poorly marginated posterior mediastinal mass (M) that compresses the left atrium (arrowheads) and displaces the descending aorta (Ao). Note that neuroblastomas are the most common posterior mediastinal mass in infants.

Key Points Imaging

• Thymic neoplasms. Thymoma, a lobulated mass within the anterior mediastinum. Mediastinal fat, great vessel invasion as well as pleural seeding are findings suggestive of local invasion. Thymic carcinoma, a large anterior mediastinal mass with local and distant metastasis.

• Germ cell tumors: Teratoma, a multiloculated cystic mass, can contain adipose tissue. Seminoma is a homogeneous and well-marginated mass. Nonseminomatous germ cell tumor is a large and irregular mass due to hemorrhage, necrosis, or cystic change.

• Neurogenic tumors: Neurofibroma and schwannoma are posterior mediastinal with enlargement of neural foramina. The MRI target appearance is high signal intensity in the periphery and intermediate signal intensity in the central zone. Ganglion cell is a paraspinal soft tissue mass with elongated vertical direction. Neuroblastomas are heterogeneous, predominantly soft tissue attenuation paraspinal masses, with calcification in up to 80%.

Treatment

Treatment of primary mediastinal tumors is complex and this section provides only a brief general outline of the more standard therapeutic options for thymic, germ cell, and neurogenic neoplasms.

Thymic Tumors

Surgery resection is the cornerstone of treatment for patients with thymomas.⁵¹ Generally, postoperative radiotherapy is recommended in patients with incompletely resected thymomas and chemoradiation should be considered in nonsurgical patients. Treatment recommendations are dependent on stage. In this regard, patients with stage I tumors are treated with surgical resection alone. In patients with Masaoka stage II who undergo complete resection, adjuvant radiation therapy is controversial. However, in Masaoka stage II tumors of a high-risk WHO category such as B2 or B3, adjuvant radiotherapy should be considered. Adjuvant radiotherapy is generally considered an effective treatment in patients with advanced thymomas (Masaoka stages III and IVa). Chemotherapy is not considered as a treatment of choice in localized, surgically resectable thymomas. However, cisplatin-based chemotherapy is advocated in patients with inoperable or gross residual disease after resection, mainly for Masaoka stage III or IV thymomas.⁵² Multimodality therapy has been used to manage patients with unresectable tumors (usually Masaoka III, IVa, and IVb thymomas). In this regard, induction chemoradiotherapy can be used to downstage thymomas to improve surgical respectability.^53–55 In addition, Lucchi and associates have reported reasonable long-term survival in Masaoka stage III and IVa thymomas using neoadjuvant chemotherapy, surgery, and postoperative radiotherapy or primary surgical resection followed by adjuvant chemotherapy or radiation therapy or both.⁵⁶ In view of the complexity of management of thymic tumors, a schematic approach as outlined by the National Comprehensive Cancer Network (NCCN) is included to clarify the management of resectable and advanced disease (Figures 7-13 and 7-14).

Figure 7-13 Treatment of thymic tumors—postoperative management of resectable disease. RT, radiotherapy.

Figure 7-14 Treatment of thymic tumors—advanced disease.

Surveillance

Each specific neoplasm discussed has a different approach for evaluation after definitive treatment. A complete explanation is beyond the scope of this chapter and the reader is referred to the NCCN. However, in all cases, patients should be managed by an experienced multidisciplinary team. In patients with thymic tumors, annual chest CT is performed to evaluate for disease recurrence. CT of the abdomen and pelvis, brain MRI, and PET/CT scans are performed based on sites of metastases and symptomatology. Surveillance for germ cell tumors depends on the type and stage of the tumor. Usually, patients with seminoma are followed after treatment with serum markers (AFP, β-hCG, and LDH) and chest CT. In cases of nonseminomatous tumors, surveillance is also done with serum markers (LDH, β-hCG, and AFP) and chest and abdominal/pelvic CT. PET/CT, brain MRI, and bone scan are obtained when clinically indicated. Although the incidence is higher in patients with NF-1, malignant nerve sheath tumors occur in patients with or without NF, and evaluation with CT or MRI is required if the patient presents with chest pain or other symptomatology suspicious for malignant degeneration of a preexisting neurogenic tumor. Evaluation by chest CT is done routinely and MRI can also be useful in cases with neural foramina or spinal cord invasion. In cases of neuroblastoma, CT is performed routinely to detect the relapse that occurs in a substantial portion of patients. The most reliable test to detect disease progression or recurrence is ¹²³I-MIBG imaging.

New Therapies

The increasing understanding of tumor-associated genes/cancer immunotherapy and molecular-targeted therapeutic options has clinical potential in the future treatment of patients with thymic, germ cell, and neurogenic tumors of the mediastinum. Because the response rates of currently used standard therapy for advanced stage thymomas and thymic carcinomas are not optimal, there has been an interest in new therapeutic targets. A novel target that has the potential to optimize the response rate in thymomas and thymic carcinomas is cyclooxygenase-2 (COX-2), which is overexpressed in several thymomas and thymic carcinomas.⁵⁸ Another promising target is the epidermal growth factor receptor (EGFR), which has a high frequency of overexpression in thymomas and, to a lesser extent, in thymic carcinomas. In a phase II study of gefitinib treatment in 26 patients with advanced thymic malignancies, 1 patient had a partial response and 14 patients (54%) had stable disease.⁵⁸ Furthermore, cetuximab, a monoclonal antibody with EGFR inhibitor activity, given with traditional chemotherapy regimens in patients with advanced-stage thymoma (stages III and IVA) before surgery, is being evaluated in a phase II trial. In addition, experimental drugs that block the insulin-like growth factor-1 receptor (IGF-1R) and sunitinib, a multitargeted receptor tyrosine kinase (RTK) inhibitor with antiangiogenic effect, are being evaluated in patients with invasive thymomas. In patients with germ cell tumors, new antitumoral agents such as bevacizumab combined with oxaliplatin are being assessed in patients with refractory or relapsed germ cell tumors. Pegfilgrastim, an immunostimulator that functions as a granulocyte colony–stimulating factor, in combination with chemotherapy is being studied in patients with untreated germ cell tumors.

Patients with NF-1 and multiple neurofibromas and large plexiform neurofibromas have provided the impetus for the development of new agents for targeted molecular therapy in patients with neurogenic neoplasms. In this regard, the principal therapeutic option, surgical resection, may not be feasible in patients with multiple neurofibromas or plexiform neurofibromas. In addition, there is a high recurrence rate after resection and a risk of malignant transformation in patients with large plexiform neurofibromas.^59–61 Accordingly, innovative therapeutic options are being investigated in preclinical and clinical trials. Proposed treatments that target mast cell functioning, the Ras signaling pathways, the downstream effector of the Ras signaling pathway, and inhibition of PI3K and KIT all have the potential to be effective in the management of patients with neurofibromas.^59,62–65 An additional therapeutic option is to target the mTOR pathway with the mTOR inhibitor rapamycin.^66–68 Some of these studies have shown encouraging preclinical results in the treatment of malignant peripheral nerve sheath tumors.^59,69

The development of new therapeutic strategies is important in patients with neuroblastoma and advanced tumor stages because the prognosis with current therapy is poor. Monoclonal antibody therapy may have a role in the future treatment of patients with advanced neuroblastoma. Currently, the Children Oncologic Group is studying the use of monoclonal antibody therapy with granulocyte-macrophage colony–stimulating factor and interleukin-2 combined with cis-retinoic acid after chemotherapy.^70,71 In addition, the New Approaches to Neuroblastoma Therapy consortium is evaluating the inclusion of myeloablative doses of ¹³¹I-MIBG with chemotherapy prior to stem cell transplantation in patients with an incomplete response to induction chemotherapy. The use of new therapies is evolving and beyond the scope of this article. The interested reader is referred to a recent article by Wagner and coworkers⁷² that reviews the new treatment options for high-risk neuroblastoma.

The Radiology Report

Conclusion

Thymic, germ cell, and neurogenic neoplasms of the mediastinum are uncommon. However, an understanding of their clinical and radiologic manifestations is useful in distinguishing these tumors from one another and from the more commonly encountered benign mediastinal neoplasms. Once a definitive diagnosis has been established, imaging is important in determining the local extent of disease and the detection of metastases. Awareness of the patterns of spread and knowledge of the current staging of these neoplasms are essential in the evaluation and treatment of patients with mediastinal neoplasms.