The mediastinum is centrally located in the thoracic cavity. It extends from the thoracic inlet to the diaphragm and from the sternum to thoracic spine, and it is demarcated by the pleural cavities laterally. Clinically, the mediastinum is divided into anterior, middle, and posterior compartments.

The anterior compartment is defined as the space posterior to the sternum and anterior to the heart and brachiocephalic vessels. It extends from the thoracic inlet to the diaphragm and it contains the thymus, fat, loose connective tissue, and lymph nodes. The boundary of the middle, or visceral, compartment extends from the anterior border of pericardium to the anterior border of the vertebral bodies. Contained within this space are the transverse aorta, the brachiocephalic vessels, the vena cavae, the hilar pulmonary vessels, the trachea and main bronchi, the esophagus, and the lymph nodes. The posterior compartment is not truly a mediastinal space. It is between the anterior border of the vertebral bodies and the posterior curvature of the ribs. The azygos vein, sympathetic chain, vagus nerve, thoracic duct, descending aorta, and the lymph nodes are located within the posterior compartment.

Primary mediastinal tumors represent a heterogenous group of neoplastic, congenital, and inflammatory conditions. Although the heart, trachea, and esophagus lie within the mediastinum, tumors that originate in these structures are outside the scope of this chapter. Table 65-1 summarizes the common neoplasms broken down into the different compartments within the mediastinum. Generally, the most common causes of an anterior mediastinal mass are thymomas, teratomas, thyroid disease, and lymphomas (so called “3T+1L”). Masses of the middle mediastinum include bronchogenic, foregut or pericardial cysts, lymphadenopathy, and inflammatory granulomas. Tumors that are located in the posterior mediastinum are often neurogenic tumors.

The likelihood of malignancy is influenced by the tumor location, patient’s age, and the presence or absence of symptoms.¹ By tumor location, the anterior mediastinum is associated with the highest incidence of malignancy (54%), followed by the posterior mediastinum (26%), and finally the middle mediastinum (20%).² With regards to the patient’s age, neurogenic tumors present most commonly during the first decade of life, lymphomas and germ cell tumors (GCTs) during the second through fourth decades, and thymomas, thyroid masses, and lymphomas during the fifth decade and beyond.³ Finally, approximately 80% of asymptomatic patients with mediastinal tumors have benign lesions, whereas 60% of the lesions present in symptomatic patients are malignant.²

The most common symptoms at presentation are cough, chest pain, sensation of chest heaviness, and dyspnea. Compression or invasion of mediastinal structures by a mediastinal mass can lead to signs and symptoms of superior vena cava (SVC) syndrome, Horner syndrome, and vocal cord paralysis. Several mediastinal lesions contribute to paraneoplastic syndromes, such as, myasthenia gravis, hypogammaglobulinemia or red cell aplasia with thymoma, recurrence fevers (B symptoms) with mediastinal lymphoma, and von Recklinghausen disease with neurofibromas.

Although conventional chest radiography can identify the presence of a mediastinal mass, computed tomography (CT) has become the most common imaging modality used to evaluate a patient with a mediastinal tumor. Contrast-enhanced CT scans provide information on the tumor’s location and heterogeneous components (i.e., air, fluid, fat, soft tissue, and calcification). In addition, CT is the most common modality used to assist fine needle aspiration (FNA) or core needle biopsies when tissue sample is required. Magnetic resonance imaging (MRI) is the ideal tool for the assessment of tumor invasion into adjacent neural or vascular structures. For posterior mediastinal tumors or those close to the thoracic inlet, MRI is useful in identifying invasion of the vertebral foramina and brachial plexus. In addition, MRI can distinguish between thymic hyperplasias, thymic neoplasms, and lymphomas.⁴

In addition to the morphological features gained from CT and MRI, fluorine-18-fluorodeoxyglucose positron emission tomography (FDG-PET) allows the identification of intratumoral increased metabolic activity by measuring FDG and several authors reported the utility of FDG-PET in diagnosis or treatment management of mediastinal tumors.^5–7 Single-photon emission computed tomography (SPECT) technology has been used to assess the malignant nature of primary lesions and identify residual or recurrence tumors. Octreotide or m-iodobenzylguanidine (MIBG) scans are helpful in the diagnosis and localization of pheochromocytomas and neuroblastomas.^8,9

Serological assessments of beta-human chorionic gonadotropin (β-HCG) or alpha-fetoprotein (AFP) are helpful in the differential diagnosis of suspected mediastinal GCTs. For nonseminomatous GCTs, over 90% of cases will significantly increase either serum AFP or β-HCG. In contrast, the AFP and β-HCG levels are usually normal in patients with mediastinal seminomas. If a thymoma is suspected in patients with symptoms of myasthenia gravis, a preoperative measurement of anti-acetylcholine antibodies in serum is helpful in order to confirm the diagnosis and increase awareness of a potential postoperative myasthenic crisis. In patients with a history of significant hypertension and suspected pheochromocytoma or catecholamine-secreting tumors (i.e., a neuroblastoma and other neural crest tumors), serum catecholamine levels and 24-hour urine levels of homovanillic acid and vanillylmandelic acid (catecholamine metabolites) should be preoperatively checked. If these levels are elevated, preoperative α-adrenergic blockers and intraoperative β-blocker need to be administered in order to avoid perioperative complications from episodic catecholamine release during tumor manipulation.

The decision to proceed with tissue biopsy procedure depends on the necessity of pretreatment pathologic or histologic diagnosis. In most asymptomatic cases with well-encapsulated or resectable mediastinal tumors, direct surgical resection achieves both a diagnostic and therapeutic purpose. In tumors with invasion into neighboring structures or with bulky lymphadenopathy, a tissue biopsy should be obtained to make a histopathologic diagnosis and to determine the appropriate neoadjuvant therapy. CT-guided FNA biopsies may be effective and safe in diagnosing mediastinal tumors.¹⁰ However, if a lymphoma is suspected, a core biopsy is preferable to an FNA because it provides more tissue sample for flow cytometric and phenotypic characterization. Surgical approaches to obtain the adequate tissue sample from the mediastinal tumors are also required. Anterior mediastinotomy (Chamberlain procedure), cervical mediastinoscopy, and video-assisted thoracic surgery (VATS) all offered good access for incision biopsy of most mediastinal masses with less operative time and less morbidity. Surgical approach to biopsy is often the preferred approach to rule out residual or recurrent lymphoma following treatment. While performing surgical biopsy for mediastinal tumors, care should be taken not only to avoid disseminating the tumor with drop metastases of chest wall implants, but also to avoid damage to surrounding vessels and nerves to avoid traction injury.

Surgical resection is the gold standard of treatment for most mediastinal tumors, except for lymphomas and GCTs due to their high chemoradiation sensitivity. Generally, median sternotomy is the optimal approach to remove anterior mediastinal tumors. Even in the presence of pulmonary involvement, upper lobe lobectomy and main pulmonary artery resection can be done using this approach. Alternatively, an axillary anterolateral thoracotomy, a lateral thoracotomy with sternal extension (hemiclamshell), and clamshell thoracotomy can also be used. A posterolateral thoracotomy is usually used for posterior mediastinal tumor resection.¹¹

Absolute contraindications to resection of mediastinal masses are invasion of the myocardium, aorta, or a long tracheal segment. If a tumor is invading the pericardium, a partial pericardiectomy should be done to achieve complete resection. To prevent cardiac herniation, reconstruction of pericardial defect by synthetic mesh is necessary. This is especially true if a pneumonectomy or lobectomy has also been performed, or when the pericardial defect is small. Reconstruction of the anterior pericardium is helpful when reresection is anticipated. The phrenic nerve can easily be encased by a mediastinal tumor, especially in the anterior compartment. Sacrifice of the phrenic nerve is reasonable to achieve a complete tumor resection. However, the phrenic nerve should be preserved on at least one side to preserve normal diaphragmatic motion, especially if pulmonary resection is planned.¹² If the mediastinal tumor invades the SVC, resection of the SVC and replacement by a ringed vascular graft may be required. After intraoperative systemic heparinization, the patient should be administered oral warfarin sodium during the postoperative period followed by a shift to aspirin, 6 months postoperation.

Minimally invasive surgery, such as VATS or robotic-aided thoracoscopic surgery, has been determined to have a therapeutic purpose in mediastinal tumors.^13–15 In general, early-stage thymomas with myasthenia gravis, simple mediastinal cysts, and benign posterior mediastinal neurogenic tumors are the best candidates for resection with minimal invasive surgery.

Thymic Tumor

THYMOMA

While thymomas are rare epithelial tumors, they represent the most common type of neoplasm in the mediastinum and they account for 45% of anterior mediastinal tumors. These tumors occur with equal frequency in men and women, and are often detected during the fourth to seventh decade of life.^16,17

Although most patients are asymptomatic, approximately one-third of them experience chest pain, coughing, dyspnea, and chest tightness. If the tumor invades the phrenic nerve, patients may present with shortness of breath either because of a paralyzed hemidiaphragm or a pleural effusion.¹⁸ Approximately 60% of thymomas are associated with various systemic or paraneoplastic disorders, such as myasthenia gravis, hypogammaglobulinemia, and red cell aplasia. Myasthenia gravis exhibits in 30% to 60% of patients with thymomas, whereas only 5% to 15% of patients with myasthenia gravis have thymomas. The presence or absence of myasthenia gravis has no impact on the clinical outcome of thymomas patients. However, thymectomies can alleviate the myasthenia gravis symptoms in most of cases.^19–23 On CT imaging, thymomas typically appear as homogenously encapsulated masses with smooth contours. Certain findings, such as encasement of mediastinal structures, infiltration of fat planes, irregular interface between the mass and lung parenchyma, and vascular involvement are referred to as “advanced-stage of thymomas.” On occasion, pleural and multiple lung metastases could be found by initial imaging presentation.²⁴

To date, Masaoka schema and the subsequent Koga-modified Masaoka staging system (Table 65-2) remains the most commonly used classification.^20,25 This staging system takes into account the gross presence or absence of invasion into adjacent structures as identified at the time of surgery. This schema is able to show a stepwise decline of survival curves in association with the advance of clinical stages. The World Health Organization (WHO) devised a classification system in 1999 and 2004 to categorize thymomas based on cytologic differences.²⁶ Two major types of thymomas were identified and they were separated based on whether the epithelial cells showed a spindle/oval shape (designated type A) or if they showed a round and epithelioid appearance (designated type B). Tumors showing a combination of these two cell types are designated as type AB. In general, the type A thymomas are referred as medullary thymomas and have the best clinical outcome. Type AB thymomas are mixed foci showing both features of type A and B, and an intermediate prognosis. Type B thymomas are referred to as the cortical type of thymomas and they are associated with poor prognosis. Type B thymomas can be further divided into three subtypes: B1, B2, and B3 based on the lymphocyte infiltration and presence of atypical epithelial cells. Type C thymomas are regarded as thymic carcinomas. After comparison of the proportions of thymoma histologic types by Masaoka stage, it showed that type A, AB, and B1 thymomas were significantly more frequent in stage I and II. Conversely, type B2 and B3 thymomas were significantly more frequent in stages III and IV, and they are expected to show a “high risk” for early recurrence and poor prognosis.^27–30 The WHO histologic systems can be used in combination with a Masaoka-type staging system to provide more precise prognostic information.

Currently, surgery is the mainstay of thymoma treatment and a complete resection leads to the best prognosis. Complete resection rates are achieved in 47% and 26% of stage III and IV cases, respectively, compared to 100% and 85% in stage I and II cases, respectively.³¹ With regards to resectability, if advanced thymomas did not invade adjacent structures, surgery should be initially undertaken with the aim of complete removal of the tumor with free resection margins. However, if a tumor had invaded into great vessels or other vital organs, patients should be reassessed for surgery after neoadjuvant chemoradiation therapy.³² There are several surgical approaches developed to remove the thymic thymoma. In general, a median sternotomy provides excellent exposure to the tumor as well as the great vessels. Minimally invasive surgery is recommended for small size and early stage thymomas, with or without myasthenia gravis.^33–35 Regardless of the surgical approaches chosen, the major goal is the removal of the entire tumor and thymus without spillage.

Operative mortality rates ranges from 0% to 5% and mostly due to myasthenic crises. Preoperative adjustment of medication and plasmapheresis are indicated for the patient who presents with severe myasthenia gravis symptoms. The 5-year survival rate is 89% to 100%, 59% to 75%, 34% to 71%, and 0% to 53% in stage I, II, III, and IV, respectively. The Masaoka stage and completeness of resection are the most commonly cited prognostic factors in thymoma. In stage III thymomas, involvement of great vessels and the WHO classification (type A vs. B2 or B3) are also independent prognostic factors.^29,36,37

Until now, the role of debulking surgery in advanced thymoma was controversial. However, debulking surgery can protect the adjacent organs from irradiation toxicity by reducing the adjuvant radiotherapy field. Therefore, debulking surgery should be considered for patients with advanced stage thymomas who require extensive radiotherapy.^32,38 Currently, routine adjuvant radiotherapy is not recommended for stage I and II thymomas because of their low (5%) local recurrence rate. Adjuvant radiotherapy is indicated for patients with macroscopic capsular invasion, WHO type B thymomas, and tumor adherent to the pericardium. For patients whose tumors were incompletely resected and had gross residual disease, postoperative radiotherapy may achieve a local control effect. Adjuvant chemotherapy is also necessary to eradicate the microscopic metastasis in the distant sites. A combination of adjuvant chemotherapy and radiotherapy is recommended for stage III and IV thymoma patients after surgery. If patients who are medically unfit for surgery or with a technically unresectable tumor, definitive chemotherapy concurrent with, or sequential to, radiation therapy would be an option of treatment. Local recurrence or limited pleural metastasis can occur after primary surgery. A redo operation is recommended or there is data to support a survival advantage. Otherwise, definitive chemoradiation therapy may be a better option for patients with systemic and distant metastatic recurrence.