Primary Mediastinal Neoplasms

Introduction

The mediastinum can be the site of a variety of neoplastic conditions that can include both benign and malignant entities. 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 tend to be malignant. In terms of primary neoplasms, the most common prevascular or anterior compartment neoplasms include thymomas, teratomas, and lymphomas. Neoplasms of the visceral or middle compartment are typically congenital cysts, including foregut and pericardial cysts, whereas those that arise in the posterior or paravertebral compartment are often tumors of neurogenic origin.

This chapter discusses mediastinal neoplasms, with particular emphasis on those primary neoplasms that are frequently encountered in an oncologic medical practice. Computed tomography (CT), magnetic resonance imaging (MRI), and positron emission tomography (PET)/CT will be emphasized as the tools of choice in the characterization of these neoplastic entities to help referring physicians, oncologists, and surgeons deliver proper care and follow-up of afflicted patients.

Epidemiology And Risk Factors

Thymic neoplasms account for 17%, lymphomas 16%, and neurogenic neoplasms 14% of all cases of primary mediastinal neoplasms. 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. The remainder of the neoplasms in the mediastinum represent a substantial group of miscellaneous entities, including mediastinal cysts (bronchogenic, esophageal, pericardial, thymic, and neurenteric), which account for 15% to 20% of all mediastinal masses.

Thymomas are the most common thymic epithelial neoplasms, and characteristically are located in the prevascular or anterior compartment. Thymomas typically occur in patients older than 40 years, are rare in children, and affect men and women with equal frequency. Thymic neuroendocrine tumors (carcinoid, small cell carcinoma, and large cell carcinoma) are uncommon. Thymic carcinoid tumors represents the most common of this group of tumors. Affected patients are typically in the fourth and fifth decades of life, with a male predominance.

Germ cell tumors usually occur in young adults (mean age 27 years). Most malignant germ cell neoplasms (>90%) occur in men. Teratomas are the most common germ cell neoplasm, representing 70% of all germ cell tumors in children and 60% in adults. Men and women are affected with equal frequency. 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, usually occurring in men in the third and fourth decades of life. 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 less common.

Neurogenic neoplasms represent 75% of primary paravertebral or posterior compartment masses. 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. Some 30% to 45% of neurofibromas occur in patients with neurofibromatosis (NF), and multiple neurogenic tumors or a single plexiform neurofibroma are considered pathognomonic for the disease. 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 type 1 NF (NF-1), and in these patients tumors occur at an earlier age (typically adolescents) and with a higher incidence than in the general population. 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.

Anatomy And Pathology

The mediastinum is located in the central portion of the thorax, sandwiched between the two pleural cavities and extending from the diaphragm to the thoracic inlet in the longitudinal axis. The mediastinum is generally divided into three anatomic regions or compartments: prevascular (anterior), visceral (middle), and paravertebral (posterior). Although there are no fascial planes that separate these compartments from each other, this division facilitates tumor localization and is useful in limiting the differential diagnosis.

The prevascular compartment is bounded anteriorly by the sternum, posteriorly by the anterior portion of the pericardium, superiorly by the thoracic inlet, and inferiorly by the diaphragm. Its contents include the thymus, lymph nodes, and fat. The visceral compartment is bounded anteriorly by the pericardium and posteriorly by a vertical line through the vertebral bodies 1 cm posterior to their anterior margin, and its contents include the heart, aorta, vena cava, brachiocephalic vessels, pulmonary vessels, trachea and main bronchi, esophagus, lymph nodes, and phrenic, vagus, and left recurrent laryngeal nerves. The paravertebral compartment is bounded anteriorly by the visceral compartment, inferiorly by the diaphragm, posteriorly by the vertebral transverse processes, and superiorly by the thoracic inlet. The contents of the paravertebral compartment include the paravertebral soft tissues and the thoracic spine.

A significant proportion of the neoplasms that occur in the prevascular compartment arise from the thymus. An understanding of the normal size, appearance, and location of the thymus at different ages is important. Anatomically, the thymus consists of two lobes in close contact with each other along the midline extending from the fourth costal cartilage superiorly, 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, which extends from the angle of the mandible to the upper prevascular compartment more inferiorly. The two lobes generally differ in size; the left lobe is usually 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 ( Fig. 8.1 ). 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.

Thymic epithelial neoplasms include thymomas and carcinomas. Most thymomas are solid neoplasms that are encapsulated and anatomically limited 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. Thymomas have a wide variety of histologic features, and there is a strong association between the histologic findings and prognosis. 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. Thymic neuroendocrine neoplasms are uncommon. These tumors typically present as a large, lobulated, and usually invasive prevascular mediastinal mass that can exhibit areas of hemorrhage and necrosis. Malignant potential ranges from relatively benign (thymic carcinoid) to highly malignant (small cell/large cell carcinoma of the thymus). The typical carcinoid has low mitotic activity (<2 mitoses/2 mm ² ) without necrosis, whereas atypical carcinoids have a higher rate of mitosis (2–10 mitoses/2 mm ² ) and/or necrosis. Small cell and large cell neuroendocrine carcinomas have a higher rate of mitotic activity (>10 mitoses/2 mm ² ) and associated necrosis.

Germ cell tumors arise from mediastinal remnants of embryonal cell migration. The mediastinum is the most common extragonadal primary site of these neoplasms and can account 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 usually 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. These tumors typically present 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 paravertebral or posterior compartment, most of the neoplasms are of neurogenic origin. Nerve sheath tumors are schwannomas, neurofibromas, or malignant tumors of nerve sheath origin (malignant neurofibroma, malignant schwannoma, and neurogenic fibrosarcoma). From a histologic perspective, schwannomas are encapsulated tumors that arise from Schwann cells located in the nerve sheath and extend along the nerve, causing extrinsic compression. They are heterogeneous in composition and can have low cellularity, areas of cystic degeneration, and hemorrhage, as well as 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. Neurofibromas grow by diffusely expanding the nerve, whereas plexiform neurofibromas, variants of neurofibromas, infiltrate along nerve trunks or plexuses. 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). These tumors derive from cells of embryologic origin or from sympathetic ganglia. After the abdomen, the thorax is the second most common location of neuroblastomas, whereas ganglioneuromas and ganglioneuroblastomas are more common in the sympathetic chain of the paravertebral compartment. Ganglioneuromas are benign tumors composed of one or more mature ganglionic cells. Ganglioneuroblastomas, the least common type of neurogenic tumors, have histologic features of both ganglioneuromas and neuroblastomas. Neuroblastomas are the most aggressive type and are composed of small round cells arranged in sheets or pseudorosettes.

Clinical Presentation

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

Thymomas usually are an incidental finding, but patients can present with chest pain, cough, or dyspnea in up to one-third of cases. Myasthenia gravis, which is characteristically associated with thymomas, occurs most frequently in women. Some 30% to 50% of patients with thymomas have myasthenia gravis, whereas 10% to 15% of patients with myasthenia gravis have a hymoma. Some 10% 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. Thymic carcinomas are frequently symptomatic at presentation owing to marked local invasion of mediastinal structures. Symptoms include SVC syndrome, usually are attributed to compression or invasion of the SVC; 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 syndrome as a result of tumoral production of adrenocorticotropic hormone. Nonfunctioning thymic carcinoids may be seen in association with multiple endocrine neoplasia syndrome type 1.

Patients with germ cell tumors are often asymptomatic. Large tumors, however, can lead to the development of clinical symptoms depending on the location and the adjacent structures. Seminomas can manifest as SVC syndrome in 10% of cases. β-human chorionic gonadotropin (β-hCG) and α-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 can occur in up to 80% of patients with advanced seminomas. Importantly, elevation of AFP indicates a nonseminomatous component of the tumor. Most (90%) patients with nonseminomatous germ cell tumors of the mediastinum exhibit symptoms at the time of diagnosis including weight loss and fever, 71% of affected patients have elevated AFP levels, and 54% have elevated β-hCG levels. There is an association between malignant nonseminomatous germ cell tumors of the mediastinum and hematologic malignancies, and approximately 20% of cases are associated with Klinefelter syndrome.

Nerve sheath tumors are usually asymptomatic. The development of pain often indicates malignant transformation (malignant neurofibromas, schwannomas, or neurofibrosarcomas). Mediastinal neuroblastomas can cause symptoms caused by local mass effect or spinal cord compression. Neuroblastomas and, less frequently, ganglioneuroblastoma and ganglioneuroma can produce metabolically active catecholamines that can be responsible for hypertension, flushing, and watery diarrhea syndrome. Catecholamine derivatives, such as vanilmandelic acid and homovanilic acid, can be secreted.

Staging

Several classification schemes and staging systems for thymic epithelial tumors have been proposed; however, because thymomas are composed of a mixture of neoplastic epithelial cells and nonneoplastic lymphocytes, there is a marked variability in the histology of these tumors, both within the same tumor and between different thymomas.

In 1999, the World Health Organization (WHO) Consensus Committee published a histologic classification of tumors of the thymus. In this scheme, thymomas are classified the morphology of the neoplastic epithelial cells and the lymphocyte to epithelial cell ratio. Updates to the WHO classification were published in 2004 and 2015. This classification outlines six separate histologic subtypes of thymomas (types A, AB, B1, B2, and B3) ( Table 8.1 ). The type C term is no longer used. The neuroendocrine thymic carcinomas are included in the thymic carcinomas, except for thymic paraganglioma. A new addition in the 2015 classification is the “atypical type A thymoma variant,” which can show increased cellularity and mitotic activity. Immunohistochemical features are included as criteria for diagnosis of thymomas with ambiguous histology. Most type A and type AB thymomas 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 from types B1 and B2 to type B3. In this regard, most thymic carcinomas are locally invasive, many are incompletely resected, and there is a high early relapse rate and poor prognosis. The WHO histologic subtype classification and the Masaoka staging system provide the clinician and surgeon the information needed to provide a prognosis. The Masaoka staging system is a pathologic staging system that is based on the presence of capsular invasion and is currently the system that is most widely used to determine therapy. In this staging system, the stages are defined as follows: 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.

Neuroblastomas are currently staged according to the International Neuroblastoma Risk Group (INRG) (pretreatment) and International Neuroblastoma Staging System (INSS) (postsurgical). INRG classification is based on clinical and imaging features, whereas INSS classification is based on surgical findings, as well as lymph node and metastatic involvement. Both of these staging systems have an important role in the determination of appropriate treatment and prediction of outcome in patients with neuroblastoma ( Table 8.2 ).

Patterns Of Spread

Thymomas can remain localized or can spread through the mediastinum in a contiguous fashion. Dissemination into the pleural space can result in solitary, multiple, or diffuse metastases distant to the primary mass, an occurrence referred to as drop metastases ( Fig. 8.2 ). Pleural effusions are not common. Transdiaphragmatic spread has been reported in up to one-third of patients. Pericardial involvement is common and can manifest as nodular or diffuse thickening, as well as 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.

Mature teratomas are benign, although rare cases of tumor rupture into adjacent structures 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%), has been reported. In cases of nonseminomatous tumors, invasion of the adjacent structures such as lung and mediastinal pleura is frequent. Pleural and pericardial effusions are common as a result of 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 can occur in up to 50% of patients. Metastatic spread to the lymph nodes is less frequent.

Intraspinal extension in neurogenic tumors is common. Some 10% of paravertebral neurofibromas and schwannomas extend into the neural foramina and spinal canal. 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%).