Anterior Mediastinal Masses

Pathology

Thymomas are derived from thymic epithelial cells, but most contain varying mixes of epithelial cells and lymphocytes. Traditional histologic classifications have therefore grouped thymomas according to cytologic make-up: (1) predominantly lymphocytic, (2) predominantly epithelial, and (3) mixed. There is also a recognized spindle-cell variant of the epithelial subtype. Approximately 50% of the tumors are of the mixed variety, with the remainder split between the epithelial and lymphocytic subtypes. Unfortunately, these subtypes have little prognostic significance aside from the generally better prognosis of the spindle-cell variant, and thus more recent investigators have proposed alternative histologic classification schemes (discussed later).

Of clinical significance is the fact that it may be more difficult to establish the diagnosis of thymoma from a small sample (e.g., by needle biopsy) of a lymphocyte-predominant thymoma versus the other subtypes because of its microscopic similarity to lymphoma. Immunohistochemical staining for cytokeratin often aids in making the diagnosis, because antibodies to this protein are present in 95% to 100% of thymomas. Chromogranin staining allows for differentiation between thymoma and thymic carcinoid (the former being negative and the latter being positive for chromogranin).

Classification

No tumor-nodes-metastasis (TNM) classification has been found to be of value for staging thymomas.

The most widely used clinical classification scheme is that proposed by Masaoka and colleagues in 1981 ( Table 41-2 ). This scheme takes into account the gross presence or absence of encapsulation, and fixation or invasion, into adjacent structures as identified at the time of surgery. It also recognizes that a grossly well-encapsulated tumor may be found to have invasion through the capsule at microscopic examination. In the years since it was originally proposed, the Masaoka system, or later variations of it, have been found by numerous authors to have prognostic significance.

In 1985, Marino and Müller-Hermelink proposed a histologic classification that has come to be known as the Müller-Hermelink (MH) classification. This scheme divides thymomas into cortical, medullary, and mixed types. The cortical type contains medium to large epithelial cells of characteristic appearance, and usually abundant lymphocytes. The medullary type contains small to medium cells with different features and fewer lymphocytes. The former tend to be of higher clinical stage, whereas the latter tend to be of lower invasiveness. Many investigators have generated data in support of the prognostic significance of the MH classification, showing that the medullary type has the best and the cortical type the least favorable prognosis. The World Health Organization (WHO) has adopted a classification system based on the MH criteria (see Table 41-2 ). Currently the state of the art is to use a combination of the WHO histologic systems in combination with the Masaoka staging system to provide the most precise prognostic information.

Presentation

Most patients with thymomas present at an age older than 40 years. There is no major predominance in men or women. Approximately 50% of patients are asymptomatic; the remaining patients have either local symptoms (e.g., pain, dyspnea, cough, hoarseness) resulting from locally invasive tumors or systemic symptoms of one of the associated systemic diseases.

Association with Myasthenia Gravis

Patients with thymomas may present with a number of associated diseases, largely autoimmune in etiology, but the most common associated illness is MG. Accumulated experience suggests that 5% to 15% of patients with MG are found to have thymomas, and that 30% to 50% of thymomas are associated with clinical MG. Notably, the disease may develop later, even after thymoma resection, if it is not present at the time of discovery of the thymic tumor. For this reason, it is essential that a complete thymectomy be performed as part of the resection of any anterior mediastinal tumor that may be a thymoma. Because MG is an autoimmune disease caused by anti-acetylcholine receptor (anti-AChR) antibodies, its relationship to thymoma and treatment by thymectomy appears to be related to the role of the thymus in the creation of these antibodies.

This association has a long and very interesting history that is beyond the scope of this chapter. Highlights, however, include the first description by Schumacher and Roth in 1912 of improvement in MG after thymectomy, the more systematic evaluation of this concept by Blalock and coworkers in the late 1930s, and the subsequent controversy over whether the morbidity and rare mortality rates associated with the procedure justified the chances of a remission from MG. Only in the late 1960s and 1970s did thymectomy for MG in the absence of thymoma gain wide acceptance, because improvements in perioperative care reduced the morbidity of the procedure and the benefits became clearer. Convincing data suggest that patients with MG who are treated with thymectomy have a higher remission rate than historical controls treated by medication alone. A multinational randomized study sponsored by the National Institute of Neurological Disorders and Stroke to definitively establish this concept is currently ongoing. Results are eagerly awaited in the coming years.

Association with Other Diseases

Box 41-3 lists MG and the other systemic, autoimmune disorders most commonly associated with thymoma. Two percent to 15% of patients with thymoma have some type of cytopenia. The most common type is pure red-cell aplasia thought to result from an abnormal IgG antibody that inhibits red-cell synthesis. Most patients with this disease have the favorable, spindle-cell type of thymoma. Approximately one-third of patients with aplasia demonstrate improvement after thymectomy. Hypogammaglobulinemia occurs in less than 5% of patients with thymoma, those being principally older patients. This disease generally does not respond to thymectomy and the prognosis is poor. Of the other autoimmune disorders that occur in association with thymoma in lower frequencies, lupus appears to be the most common; again, resection does not appear to have an impact on the clinical course.

The Anterior Mediastinal Mass That Might Be Thymoma

Imaging

Radiologic studies play a central role in the evaluation of thymoma. Because many patients are asymptomatic at presentation, a widened mediastinum or loss of the normal anterior clear space on the lateral film of a routine chest radiograph may be the first sign of disease. In such a patient, a computed tomography (CT) scan of the chest with intravenous contrast medium should be obtained as the next step. Patients who present with MG or another of the disorders that may be associated with thymoma should also have a chest CT scan.

Although no appearance on CT scan is definitively diagnostic of thymoma, a well-circumscribed, solid anterior mediastinal mass in an adult older than 40 years, without low-density areas that suggest the cystic and fatty components of a teratoma, is very likely to be a thymoma ( Figs. 41-2 and 41-3 ). The presence of calcification is not particularly helpful, because both thymomas and teratomas may contain calcium. In some cases, lymphoma will be the obvious diagnosis on the basis of adenopathy outside of the anterior mediastinum or “B” symptoms, but in the absence of these findings, differentiating a thymoma from a lymphoma may be difficult. It is often possible to suspect one over the other only on the basis of the thymoma patient's typically more advanced age. Magnetic resonance imaging (MRI) provides useful additional information only when the fluid or fatty nature of a component of the tumor is not clearly defined by CT scan or when a vascular structure (e.g., an aneurysm) is suspected and has not been clearly ruled out by the contrast CT study.

The chest CT scan also provides information about a putative thymoma's local and regional spread. Loss of planes between the tumor and normal structures may suggest direct invasion, and visceral or parietal pleural deposits may be visible as well. The presence of such signs of local aggressiveness should steer the surgeon toward biopsy rather than primary resection, given the recent data suggesting improved results with neoadjuvant chemoradiotherapy before operation in aggressive thymoma and thymic carcinoma. The role of positron emission tomography (PET) in thymic tumors is not well-defined. It has been shown that PET may be useful for predicting the grade of malignancy according to histologic subtype.