The mediastinum is a complicated space associated with a variety of malignant and nonmalignant processes. Due in part to the confinement by the taut mediastinal pleurae, disease of this space may progress rapidly, compress vital structures, or be associated with fulminant inflammatory processes in need of surgical intervention. In this regard, “benign” processes such as infection or traumatic injuries of the mediastinum can be significant threats to the patient.

The mediastinum is the space between the thoracic inlet superiorly, vertebral column posteriorly, sternum anteriorly, and diaphragm inferiorly. The lateral borders of the mediastinum are the mediastinal pleurae. With the exception of the lungs, which lie in the pleural space, all contents of the thorax lie within the mediastinum.

It is useful to consider the mediastinum in terms of three compartments that also serve to organize disease processes, which tend to be localized to one compartment or another (Table 17-1).

The anterior–superior mediastinum contains blood vessels (the transverse aortic arch, innominate artery, origin of the left common carotid artery, innominate veins, and the upper portion of the superior vena cava), peripheral nerves (the vagus, phrenic, and left recurrent laryngeal nerves), as well as the trachea, esophagus, thoracic duct, thymus, and some lymph nodes.

The middle mediastinum contains the pericardium and heart, the ascending aorta, junction of the superior vena cava with the right atrium, junction of the superior vena cava and the azygos vein, tracheal bifurcation, mainstem bronchi, proximal pulmonary artery and bifurcation, confluences of the left and right pulmonary veins, phrenic nerves adjacent to the pericardium, and the peritracheal and subcarinal lymph nodes. The middle mediastinum is bordered posteriorly by the pericardium.

The posterior mediastinum runs parallel to the vertebral column behind and is bounded anteriorly by the pericardium, inferiorly by the diaphragm, and laterally by the mediastinal pleurae. It contains the descending aorta, azygos and hemiazygos veins, esophagus, thoracic duct, splanchnic nerves, and lymph nodes.

Surgical approaches to the mediastinum differ based on compartment, and the differential diagnosis for clinical phenomena in this irregularly shaped space is often organized based on location (Fig. 17-1).

The risk of malignancy is about two-thirds for anterior mediastinal masses, compared to 15 to 20 percent for posterior mediastinal lesions.¹

Embryologically, the space arises from the combination of the ventral and dorsal mesenteries of the esophagus. During embryonic life, the dorsal mesoesophagus supports the esophagus, dorsal primitive aortas, and the cardinal veins in addition to lymphatics and both sympathetic trunks. The ventral mesoesophagus contains the lungs, pericardium, and the heart. The penetrating vessels to the esophagus that arise with the mesoesophagus and the direct lymphatic drainage to the thoracic duct (perhaps contributing to the early systemic spread of esophageal cancer) are clinically relevant anatomic findings that relate directly to the embryogenesis of the mediastinum.

Mediastinal Infections

Pneumomediastinum

Pneumomediastinum may derive from injury or perforation of the proximal tracheobronchial tree or the esophagus. It is an emergent condition given the risk of rapid progression to life-threatening mediastinitis with contamination of the confined space lying between the pleurae.

Limited, spontaneous pneumomediastinum (SPM) in the absence of symptoms of systemic infection is generally managed conservatively with bedrest, analgesics, and cough suppressants, as well as prophylactic antibiotics to reduce the possibility of secondary mediastinitis. In general, spontaneous pneumomediastinum does not require surgical intervention. Complications, such as tension pneumomediastinum, delayed pneumothorax, or airway compromise, are rare. The challenge is to differentiate cases of benign spontaneous pneumomediastinum from those associated with more ominous diagnoses such as transmural tears of the esophagus or tracheal injury. The key differentiator lies in the absence of symptoms referable to a finding that is effectively an incidental radiologic observation.²

Outcomes.

Comparisons of patients with different etiologies of SPM have not been published, nor are there studies analyzing risk factors in patients with SPM. Patients developing pneumomediastinum secondary to barotrauma in the ICU have been noted to have 27 times higher mortality risk compared with other underlying conditions. Ventilator-induced barotrauma is an independent prognostic factor for hospital mortality. Secondary pneumomediastinum resulting from blunt force thoracic trauma has a more favorable outcome in comparison with pneumomediastinum associated with prolonged ventilation, poorly compliant lungs, and subsequent barotrauma.³

Prognosis.

Mortality rates of 10 and 13 percent have been noted among trauma patients with pneumomediastinum.² In ventilator-induced barotraumas, mortality rates of 55 and 65 percent have been noted in patients with mediastinal emphysema and pneumothorax, respectively.³

Acute Mediastinitis

Treatment.

Acute mediastinitis is a surgical emergency for which medical therapies serve an adjunctive role only. Surgical correction of the source of the mediastinal contamination, debridement of infected tissues, and, in certain cases, diversion of the esophagus are the keys to a successful outcome. Antibiotic administration, fluid resuscitation, invasive monitoring, and hemodynamic support are principal nonsurgical measures.

Outcomes.

Outcomes are dependent on host risk factors that might contribute to the development of deep surgical site infections, including obesity, diabetes mellitus, ischemia (following the use of bilateral internal thoracic artery grafts, for example), advanced age, female sex, chronic lung disease, active smoking, prolonged mechanical ventilation, the use of steroids, and preoperative hospital stay longer than 5 days.¹

Prognosis.

Postoperative mediastinitis occurs in 1 to 3 percent of patients undergoing median sternotomy, and its associated mortality has been reported to be as high as 40 percent.²

Chronic Mediastinitis

Once symptoms for both granulomatous and fibrosing (also known as sclerosing) mediastinitis have ensued as a result of obstruction and compression of mediastinal structures, no medical therapy has been shown to be of uniform benefit, nor have surgical corrections been met with much success. Antifungal agents, steroids, and immunosuppressive agents are used for both etiologies, while studies have shown that tamoxifen can be effective in the medical treatment of fibrosing mediastinitis. The effectiveness of steroid therapy has been controversial.⁴

Superior Vena Cava Obstruction

Treatment.

Treatment is directed at either symptomatic alleviation or the underlying cause. First-line therapy is classically surgery or stenting procedures. Traditional medical treatment has included systemic steroids (prednisolone or dexamethasone) and diuretics. For patients with SVC obstruction due to malignancy, chemoradiotherapy is used. Steroids are generally given in conjunction with radiotherapy because of the concern for radiation-induced edema. Radiotherapy can take two to four weeks to show effect and has significant rates of complications, including radiation-induced esophagitis and pneumonitis. A systematic review by Rowell et al. found complete relief of the symptoms of SVC obstruction in 77 percent of patients with small-cell lung cancer and 60 percent with non–small-cell lung cancer at two weeks.⁵ For patients with SVC obstruction due to intravascular thrombus associated with an indwelling catheter, removal of the catheter and anticoagulation is standard. However, the efficacy of short- or long-term anticoagulation therapy is unclear. Although thrombolytic agents have been used effectively in patients with vena caval thrombosis, most experts recommend anticoagulation after thrombolysis (to prevent disease progression and recurrence) and aspirin after stent placement in the absence of thrombosis.

Outcomes.

Outcomes are dependent on the underlying cause. Despite treatment with radiotherapy or chemotherapy, some patients fail to respond and symptoms persist. Systematic analysis noted a 17 percent recurrence rate.⁵

Prognosis.

Reported recurrence rates are 18 to 20 percent. Recurrence can be due to either persisting tumor mass or SVC thrombosis.⁶ In some patients, SVC obstruction may relapse after a period of time despite a good initial response.

Castleman Disease

Castleman disease or benign B-cell hyperproliferation, often associated with HIV infection, involves lymphadenopathy within the mediastinum.

Treatment.

Surgery is the mainstay of treatment for both multicentric and unicentric disease. For multicentric Castleman disease, variable treatment modalities have been used, including lymphoma-based chemotherapeutic regimens such as cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP), immunotherapies such as interferon alpha, and monoclonal antibodies such as rituximab. For unicentric Castleman disease, chemotherapy is usually unnecessary.^7,8 For locally advanced, unresectable, unicentric Castleman disease, neoadjuvant radiotherapy of 40 to 50 Gy is used to facilitate radical resection. No randomized controlled trials have been conducted to definitively characterize optimal treatment because of the infrequency of the diagnosis; case reports are predominant in the literature.^7,8

Outcomes.

For unicentric disease, complete resection has been reported to be curative and recurrence is rare. For multicentric disease, outcomes are significantly worse, but the true difference is unclear because treatment strategies vary.⁹

Prognosis.

For patients with resectable unicentric disease, treatment is curative. For patients with multicentric disease, the median survival is two to three years.⁹

Anterior Mediastinal Masses

The anterior–superior compartment is the most common site for mediastinal masses, and the majority of these masses are malignant. Lymphomas, thymomas, and germ cell tumors are the leading diagnoses in this compartment. Less frequently, masses may be of endocrine origin, lipomas, infections, vascular malformations, or other rare neoplasms.

Characteristics of the masses on imaging may suggest a diagnosis, but a complete history and physical examination add valuable information. Symptomatic patients are more likely to have a malignant mass than asymptomatic patients. Constitutional symptoms suggest lymphoma or an endocrine tumor. Weakness with repetitive muscle use suggests myasthenia gravis (MG) with associated thymoma. Cardiothoracic symptoms such as chest pain, cough, dysphagia, or hoarseness suggest compression by the tumor. On physical examination, findings of neck masses, lymphadenopathy, evidence of SVC syndrome, or testicular masses all add valuable information to the working diagnosis. Laboratory evaluation for endocrine disease, paraneoplastic syndromes, or tumor markers such as beta human chorionic gonadotropin (β-hCG) and alpha-fetoprotein (AFP) may have a role. The standard imaging of a chest x-ray and CT scan may be supplemented with nuclear imaging by SESTAMIBI or positron emission tomography (PET) scanning for endocrinologically active tumors such as thyroid masses, parathyroid adenomas, and thymic carcinoid.

The role of biopsy for anterior mediastinal masses, particularly thymomas, is controversial because of the possibility of tumor seeding. In addition, even with CT or ultrasound guidance, the fine-needle aspiration (FNA) may produce a false-negative biopsy. Finally, the pathologist may not be able to differentiate thymoma from lymphoma on the basis of an FNA sample. Core biopsy allows more tissue for evaluation, and despite earlier concerns about the use of cutting needles for mediastinal biopsies, it is now generally accepted as safe. Surgical biopsy, which can often be obtained through a small anterior mediastinotomy (Chamberlain incision), permits accurate diagnosis when clinical history, radiographs, and percutaneous biopsy are not determinant.

Lymphoma

Lymphomas are the most common neoplasm of the mediastinum, although primary mediastinal lymphomas are rare and account for less than 10 percent of lymphomas. The most common types of lymphomas found in the mediastinum include Hodgkin, non-Hodgkin, and lymphoblastic lymphomas. B-cell lymphomas arise when errors occur during critical processes of B-cell development, such as V(D)J recombination, somatic hypermutation, and class switch recombination, which are involved in light- and heavy-chain formation and DNA modification. Largely curable, Hodgkin lymphoma (HL) is most common in the third decade of life but has a bimodal peak at 15 to 34 years and over 60 years. Hodgkin lymphoma outcomes are predicted according to the International Prognostic Score. The most common histologic types in order of incidence are classical Hodgkin lymphoma (nodular sclerosis, mixed cellularity, lymphocyte-predominant, and lymphocyte-depleted types) and nonclassical Hodgkin lymphoma (nodular lymphocyte-predominant). Non-Hodgkin lymphoma (NHL) is a heterogeneous group of malignancies seen at all ages but is most concentrated in patients greater than 50 years of age. In addition, patients with HIV/AIDS are at increased risk for NHL. Lymphoblastic lymphoma is a rare and aggressive neoplasm of immature B-cells committed to the B-cell or T-cell lineage that primarily affects children but can also be seen in adults with a median age of 39 years (Fig. 17-2).

Treatment.

Patients with early-stage Hodgkin lymphoma are treated with two to four cycles of doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) followed by involved-field radiotherapy (IF-RT) with 30 Gy.^2–5 In advanced HL, administration of six to eight cycles of chemotherapy optionally followed by radiotherapy of residual disease is the treatment of choice. Recently bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone (BEACOPP) are being used, particularly for high-risk patients. An optimal treatment regimen for Hodgkin lymphoma has not been determined; at this time, chemotherapy alone or various combinations of chemotherapy and radiotherapy are associated with high overall survival rates. Meta-analysis has suggested chemotherapy plus radiotherapy is superior to chemotherapy alone, although side effects and the development of secondary malignancies in younger patients continue to be a concern.^4–5 Currently, ABVD remains the gold standard of chemotherapy although increasing data note that using the aggressive BEACOPP regimen has improved survival in advanced stages. Mustargen, oncovin, procarbazine, and prenisone (MOPP) and MOPP/ABVD have been replaced due to concerns for toxicity, while European groups are increasingly using BEACOPP.¹⁰

NHL treatment strategies are based on histology and World Health Organization staging criteria. The current standard of care for first-line chemotherapy is cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP). For patients with follicular NHL or diffuse large B-cell lymphoma, the addition of anti-CD20 rituximab is considered standard therapy. Monoclonal antibodies and integration of radioimmunotherapy as part of initial therapy are being investigated at this time.

Outcomes.

The five-year survival rate for patients with early-stage Hodgkin lymphoma has consistently been greater than 90 percent, with complete remission occurring in more than 70 percent.¹¹ABVD-based treatments have noted five-year recurrence rates of 61 to 66 percent and five-year overall survival rates of 73 to 83 percent. Unfortunately, 30 to 40 percent of patients with advanced stage Hodgkin lymphoma experience treatment failure requiring salvage high-dose chemotherapy or autologous stem cell transplantation.¹² Patients presenting with mediastinal manifestations, despite the lack of a unified system of categorization, are defined as high risk according to most standards. For patients older than 60 years, treatment options have been limited due to increased susceptibility to the toxic effects of intensive therapy and often comorbid conditions.¹³

Patients with low-grade NHL are likely to respond to standard treatment regimens with subsequent relapse, although the duration of relapse decreases with each subsequent treatment. For patients with low-grade NHL, autologous bone marrow transplantation can lead to complete remission although long-term follow-up is required for determination of cure rate. For patients with intermediate- to high-grade NHL that does not go into remission or relapse, the prognosis is poor.¹⁵

Prognosis.

In accounting for all stages of HL, the five-year survival rate is greater than 90 percent. However, more patients die from treatment-related complications than from progressive or recurrent lymphoma. Secondary malignancies occur at roughly one percent per year for 30 years after treatment and are particularly high among young women (age <30 years) who received thoracic radiation. Between 30 and 40 percent of these women will develop breast cancer in the 25 years posttreatment.¹⁴ In addition, cardiac disease due to radiotherapy and chemotherapy has been noted to be significantly increased for more than 25 years posttreatment, with increased rates of coronary artery disease, myocardial injury, valvular disease, and pericardial fibrosis.