Thymoma: Update for the New Millenium

Thymomas are relatively common tumors of the anterior superior mediastinum. They are usually relatively slowly growing tumors and their prognosis depends on the macroscopic and microscopic invasion of surrounding tissues. Surgery is the mainstay treatment of thymomas, and complete resection represents one of the most important prognostic factors in this disease. Other important prognostic indicators include the tumor stage and size and the presence of symptoms. Postoperative radiotherapy is indicated in tumors with invasion of surrounding tissues, even if resection was radical, since it improves local control and survival. Cytotoxic chemotherapy has been employed in several relatively small phase II studies and in advanced disease has been demonstrated to produce a 50%-80% objective response rate. Neoadjuvant cytotoxic chemotherapy and/or external beam radiotherapy has been used with some success in patients with tumors which are not readily resectable. Novel antiproliferative systemic agents, with both cytotoxic and cytostatic mechanisms of action, are being tested in ongoing prospective clinical trials. The Oncologist 2001;6:239-246 The Oncologist 2001;6:239-246 www.TheOncologist.com Correspondence: Charles Thomas, Jr., M.D., Department of Radiation Oncology, UTHSCSA, Mail Code 7800, 7703 Floyd Curl Drive, San Antonio, Texas 78229-3900, USA. Telephone: 210-616-5648; Fax: 210-949-5085; e-mail: [email protected] www: cancerdata.com Received October 11, 2000; accepted for publication May 11, 2001. ©AlphaMed Press 1083-7159/2001/$5.00/0 INTRODUCTION Thymic tumors are common among anterior mediastinal tumors in adults. The vast majority of thymic lesions are thymoma [1]. Thymoma is relatively unique among tumors in that the prognosis appears to be more closely related to the invasive characteristics seen at operation rather than histological appearance. Indeed, the degree of encapsulation and invasion of adjacent tissues define malignancy for these tumors rather than the histologic appearance of the tumor cells [2]. Current treatment of thymoma is often multidisciplinary in nature, and has evolved based upon a growing number of studies to date. These studies have looked at various outcomes based upon associated patient syndromes, tumor histology, and tumor staging, as well as various surgical, radiotherapeutic, chemotherapeutic, and multimodality trials. These studies form the basis of this review. CLINICAL PRESENTATION Anatomically, the mediastinum is divided into three compartments: anterior, visceral (or middle), and paravertebral (or posterior) [3]. The anterior compartment is bounded by the undersurface of the sternum anteriorly and the pericardium/great vessels posteriorly. Space occupying lesions occurring in this compartment include thymoma, lymphoma, germ cell neoplasms, and others. Although lymphomas are the most common tumors in the mediastinum overall, for primary tumors, thymomas are more common in the anterior mediastinum [3, 4]. Clinical symptoms presenting in patients with thymoma are varied. Most patients are asymptomatic; however, when symptoms are present they most often consist of cough, dyspnea, and other upper respiratory complaints [4]. Approximately 15% of patients with myasthenia gravis (MG) have thymoma, either benign or malignant, while approximately 35% of patients with thymoma have MG [5]. In patients with MG, presenting symptoms typically involve neurologic findings consisting of both systemic and ocular abnormalities. Patients with thymoma and MG may have an increased operative mortality since most surgical deaths can be attributed to MG crisis [6]. For this reason the surgeon should carefully search for signs and symptoms of MG preoperatively in patients with thymoma that offer no previous history of MG. Interestingly, recurrence of thymoma may be higher in those without than in those with MG [7]. In one study, death in patients with thymoma and MG was most commonly due to complications of MG, whereas in patients without MG, death was most frequently due to local progression of tumor [6]. While MG may influence the operative mortality of patients with thymoma and MG, the overall long-term prognosis does not appear to be adversely affected by the presence of MG [6, 8]. Other systemic syndromes may occur in 5%-10% of patients with thymoma [1, 4, 9]. These syndromes include erythroid and neutrophil hypoplasia, pancytopenia, Cushing’s syndrome, DiGeorge syndrome, carcinoid syndrome, Lambert-Eaton syndrome, nephrotic syndrome, syndrome of inappropriate secretion of antidiuretic hormone, Whipple’s disease, lupus erythematosus, pemphigus, scleroderma, polymyositis, polyneuritis, polyarthropathy, myotonic dystrophy, Sjogren’s syndrome, Addison’s disease, hypogammaglobulinemia, and thyroid carcinoma [2, 5, 9]. Diagnostic work-up of a patient with an anterior mediastinal mass begins with a thorough history and physical exam. Particular focus should be given to detect subtle physical findings that may suggest the presence of MG. Routine blood work and serum chemistries should be obtained as they may give clues to the presence of associated syndromes. Serum alpha-feto-protein and beta-human chorionic gonadotropin levels should be obtained in young adult males, as these are most certainly elevated in the presence of nonseminomatous germ cell tumors [10]. Imaging studies such as computerized tomography (CT) are helpful in clinically staging mediastinal tumors and defining their local extent. Although a preoperative biopsy of an anterior mediastinal mass may aid in its diagnosis, a planned resection of an anterior mediastinal mass may be appropriate without a preoperative biopsy in some cases when a thorough clinical and radiographical evaluation of peripheral lymph nodes is negative [4]. PATHOLOGY Although there have been various attempts to classify the various histological subtypes of thymoma [11-13], it is generally agreed that tumors with true malignant cytologic characteristics are considered thymic carcinomas rather than thymoma. Malignant thymoma, on the other hand, refers to invasive thymoma (as defined either macroscopically or microscopically) that continues to retain typically “bland” cytologic characteristics [12]. Although the various histological subtypes of thymoma may be associated with different degrees of metastatic and invasive potential and, even in some cases, with various systemic syndromes, it is generally agreed that the cell of origin is epithelial and not lymphocytic [12, 14]. In addition, overall prognosis of patients with thymoma has more to do with the degree of tumor invasiveness than the tumor’s cytologic or histologic classification [13, 15, 16]. The most widely accepted histologic classification is that proposed by Marino and Muller-Hermelink that classifies thymoma into cortical, mixed (common versus predominately cortical versus predominately medullary), and medullary types [13]. Using this classification, tumors of the cortical type tend to be more aggressive and are associated with a less favorable prognosis than the medullary type, which, in most cases, tend to be less aggressive. Likewise, those tumors that are mixed tend to show an intermediate behavior and have an intermediate prognosis [17]. Although degree of tumor invasiveness is directly related to stage and prognosis of thymoma, histologic classification of thymoma may be an independent predictor of overall recurrence. In one study, none of the medullary or mixed-type tumors recurred, even though 30% were invasive [18]. STAGING The most widely accepted staging system in use today is that which was proposed by Masaoka and colleagues (Table 1). In this staging system, stage I tumors are completely encapsulated, both macroscopically and microscopically. Stage II tumors violate the capsule, either grossly or histologically. Stage III tumors have obvious invasion into contiguous structures, oftentimes necessitating resection of additional tissue to obtain negative surgical margins. Stage IV tumors have either pleural or pericardial implants, which oftentimes can only be confirmed at the time of surgical exploration. It is for this reason that both pleural cavities should be widely opened and explored at the time of operation. Stage IV also includes patients with distant metastases. Although tumor histology may influence overall prognosis, tumor stage is a more important overall survival indicator, as confirmed by a number of published studies (Table 2). SURGERY Successful treatment of thymoma (both invasive and noninvasive) largely depends on complete surgical resection [19], if possible. Operation for thymoma carries a low morbidity 240 Thymoma: Update for the New Millenium Table 1. Masaoka staging system [51] Stage I Macroscopically encapsulated with no microscopically detectable capsular invasion Stage II Macroscopic invasion of mediastinal fatty tissue or mediastinal pleura, or microscopic invasion into the capsule Stage III Macroscopic invasion into surrounding structures (pericardium, great vessels, lung) Stage IV A) Pleural or pericardial dissemination B) Lymphogenous or hematogenous metastases