Thymic malignancies have often been poorly understood,

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1 MALIGNANCIES OF THE THYMUS Evaluation and Treatment of Stage I and II Thymoma Frank C. Detterbeck, MD Abstract: Thymomas are relatively uncommon. Nevertheless, an accumulation of studies (mostly retrospective, single-institution series) have made it important to approach this disease in a knowledgeable, evidence-based fashion. This begins with the approach to evaluation of a patient with an anterior mediastinal mass, in whom a reliable clinical diagnosis is usually possible in experienced centers. Surgical resection is the mainstay of treatment, and every effort must be made to achieve a complete resection. Key Words: Thymoma, Myasthenia gravis (MG), Surgical resection, Adjuvant radiotherapy. (J Thorac Oncol. 2010;5: S318 S322) Thymic malignancies have often been poorly understood, partly because of their relative infrequency. However, other factors have contributed to a lack of appreciation for the data that has been accumulated about this disease. The familiarity of the normal thymus to cardiac surgeons contributes to a sense of complacency when approaching a patient with a thymic malignancy. The misleading and inappropriate term benign thymoma has also perpetuated a lack of diligence in reviewing and understanding the available literature. This article reviews data that pertains to defining a clinical approach to patients and to treatment, with a focus on earlystage thymic tumors. CLINICAL PRESENTATION AND DIAGNOSIS Thymomas occur in patients of all ages, ranging from 8 months 1 to 94 years. 2,3 The age distribution of patients with a thymoma shows a broad peak between approximately 35 and 70 years. 4 The reported median age is approximately 54 years among studies of 100 patients. 3,5 10,11 As a group, patients with myasthenia gravis (MG) tend to present at a slightly younger age than patients without MG, but there is broad overlap in the age distributions between these two groups. 4 The ratio of men to women in series of thymomas is approximately equal. There are slightly more women than men in the older age groups. 4 This appears to be primarily Thoracic Surgery, Department of Surgery, Yale University, New Haven, Connecticut. Disclosure: The author declares no conflicts of interest. Address for correspondence: Frank C. Dettterbeck, MD, 330 Cedar Street BB205, Yale University, New Haven, CT frank. detterbeck@yale.edu Copyright 2010 by the International Association for the Study of Lung Cancer ISSN: /10/ the result of a slight increase in the proportion of women without MG who are found to have a thymoma among the older age groups. 4 Approximately 40 to 45% of patients present with MG, which is the most common parathymic condition. 12,13 These also include hypogammaglobunlinemia and red cell aplasia. Approximately 1/3 of patients are asymptomatic, whereas about 1/3 have symptoms typical of a mass in the chest (cough, dyspnea, chest pain). 4 Thymoma accounts for 50% of anterior mediastinal masses in patients older than 50, and 70% if substernal goiters are excluded, which are usually easy to recognize. However, for women between the age of 20 to 40, lymphoma accounts for approximately 50% of anterior mediastinal masses, with an increasing minor proportion of thymoma from about 15% at age 20 to 40% at age 40. A similar proportion of men aged 20 to 40 have thymomas; the diagnoses are mixed in the rest with no dominant etiology of the anterior mediastinal mass. Thymomas are relatively uncommon below age 20. These proportions can be used to guide the approach to a patient with an anterior mediastinal mass. In many instances, a clinical diagnosis of thymoma is sufficient. The presence of a parathymic condition and an anterior mediastinal mass reliably establishes a clinical diagnosis of thymoma. 4 Furthermore, it is not necessary to establish a preoperative diagnosis of a small, resectable tumor in the anterior mediastinum with radiographic imaging typical of a thymoma. A definitive diagnosis is needed primarily when a presumed thymoma is so extensive that it is thought best treated with a nonoperative approach or with preoperative chemoradiotherapy, or in instances where lymphoma is considered to be a strong possibility. Pathologic confirmation of the diagnosis of thymoma can be achieved from a needle aspiration (FNA) or via an open surgical biopsy. The success rate of FNA in establishing the diagnosis is reported to be approximately 60%. 10,14 16 It appears that in many of these cases, a core biopsy or multiple passes were performed to have an adequate sample of tissue. In one of the more detailed studies, an FNA had a sensitivity of 71%, a specificity of 94%, a false positive rate of 23%, and a false negative rate of 8%. 14 The success rate of an open surgical biopsy in establishing the diagnosis is reported to be approximately 90%. 10,16 The reliability of establishing the histologic subtype of thymoma from a limited biopsy may be difficult, because of the characteristic variability in morphologic appearance within a thymoma. 17 However, the histologic subtype is of questionable value in determining optimal therapy. 18 S318 Journal of Thoracic Oncology Volume 5, Number 10, Supplement 4, October 2010

2 Journal of Thoracic Oncology Volume 5, Number 10, Supplement 4, October 2010 Evaluation and Treatment of Stage I and II Thymoma TABLE 1. Overall Survival after Resection of a Thymoma Overall Survival References n Years Included Treatment (%) 5-Yr Survival (%) 10-Yr Survival (%) R 0 Ch RT I II III IVa I II III IVa Regnard et al Maggi et al de Jong et al a 33 a Verley and Hollmann Few Most Chen et al Ströbel et al a Park et al Nakahara et al. 1 b Few c c Wilkins et al Blumberg et al d Quintanilla-Martinez et al (70) e (0) e Pan et al. 51 b Ogawa 11 b Elert et al e Kondo et al c Average f Inclusion criteria: results of 100 patients, with results by Masaoka stage. a Estimated from data provided. b Thymic carcinoma excluded. c Stage IVa, b. d 9-yr survival data. e 5 patients. f Excluding values in parentheses. Ch, chemotherapy; R 0, complete resection; RT, radiotherapy. There exists a widespread dogma that biopsy of a presumed thymoma should not be undertaken because it risks spreading the tumor into the pleural space or the needle tract or biopsy site. 19 However, there is little data to substantiate this. No case of seeding of a needle tract or incisional biopsy site has ever been reported. Three instances of a recurrence at the thoracotomy site used for resection have been mentioned. 16,20 A large series of 136 patients found that there was a trend to better survival in those patients who underwent a preresection biopsy by multivariate analysis (p 0.056). 8 Furthermore, it is standard policy to obtain a biopsy in cases of larger tumors suspected to be a thymoma in many centers with extensive experience in thymoma. 10,15,16,21 24 TREATMENT Natural History and Clinical Behavior The prognosis without treatment (i.e., natural history) of patients with a thymoma has not been well studied. The clinical progression of disease appears to be rather indolent in most cases. In 31 patients in whom prior films were available, 77% demonstrated a thymoma 1 to 26 years previously (mean, 6 years). 25 A case has been reported documenting slow growth of a thymoma over 21 years. 26 The indolent course is also corroborated by the long interval to recurrence (1 32 years, average 5 years) among treated patients who develop further manifestations of disease. Although thymomas are generally indolent tumors, they do have the ability to metastasize to the pleura and pericardium and to distant sites. A study of metastases revealed that 4% of 207 patients referred to a surgery clinic had lymph node or distant metastases at the time of presentation, and another 16% developed lymph node or distant metastases during the course of their disease. 27 Of those who developed metastases, nodes were involved in 14% of patients, pleural or pericardial metastases in 56%, and distant sites in 31%. 27 The distant sites involved 1/3 lung, 1/3 liver, 1/6 bone, and 1/6 kidney, brain, or bone marrow. 27 Among each stage at presentation (including stage I), some patients subsequently developed distant metastases in a classic study of 200 patients by Verley and Hollmann, 28 and this has been confirmed by others. 29 In every large series with long-term follow-up, metastases have been reported for each stage or histologic appearance of thymoma. This data demonstrates that all thymomas are malignant tumors (i.e., have the ability to metastasize) despite a generally protracted course. 4,30 The misleading term benign thymoma is no longer appropriate given the available data. 30 Surgical Resection Survival after Surgical Resection Overall survival of surgical series of 100 patients with thymoma is shown in Table 1. The 5-year survival rates are quite good, even for patients with stage III and IV disease. The 10-year survival rates are approximately 90% and 70% for stage I and II, and 55% and 35% for stage III and IVa. Overall survival rates at 15 years for stage I, II, III, and IV disease are reported as 78%, 73%, 30%, and 8%, respectively. 31 Representative survival curves from one of the largest S319

3 Detterbeck Journal of Thoracic Oncology Volume 5, Number 10, Supplement 4, October 2010 completely resected on average. However, there is wide variation in the reported resectability rates between studies in patients with higher stage thymomas (from 43 to 100% for stage II, 0 to 89% for stage III, and 0 to 78% for stage IV). The most likely explanation appears to be differences in philosophy about the role of subtotal resection between different centers, and the willingness of surgeons to undertake more extensive operations (such as resection of the superior vena cava). FIGURE 1. Overall survival according to Masaoka Stage. Reproduced with permission from J Thorac Cardiovasc Surg. 31 TABLE 2. by Stage Rate of Complete Resection of a Thymoma References n I II III IVa IVb Regnard et al Fang et al Okumura et al. 5 a Nakahara et al. 1 a Blumberg et al Kondo et al Curran et al. 7 a Masaoka et al. 43 a (0) b Gamondès et al. 55 a Kaiser and Martini Average c Inclusion criteria: studies of 50 patients reporting stage specific resectability rates in patients undergoing primary surgery. a Thymic carcinoma excluded. b 5 patients. c Excluding values in parentheses. studies are shown in Figure 1. These survival rates include patients undergoing a partial resection (among the stage III or IV thymomas). Significantly better survival has been noted in patients who underwent complete resection by every large study examining this issue. 1,2,5,8 10,21,31 34 It is remarkable that the long-term survival of patients with a stage III thymoma is similar to that of those with a stage I thymoma, provided a complete resection is performed. 31,35 These findings imply that a complete resection may be the most important prognostic factor, and that every effort must be made at the time of surgery to accomplish this. Resectability The ability to perform a grossly and microscopically complete resection, varies with the stage of the thymoma. It is uniformly high in patients with stage I thymomas, and high in most reports in patients with stage II thymomas as well (Table 2). Approximately half of patients with stage III and only about a quarter of patients with stage IV tumors can be Cause of Death Overall, approximately 50% of the deaths are due to thymoma or due to the treatment. 4,36 Approximately 20% of deaths have been due to MG, and 10% to autoimmune disorders associated with thymomas. The rest of the deaths have been attributed to unrelated conditions, including other malignancies. 4 Whether deaths due to second primary malignancies should be viewed as unrelated is debatable, however, because many studies have noted a higher than expected incidence of second primary malignancies in patients with a thymoma (average 15%, range, 9 27% of patients with thymoma). 8,10,12,37 41 Studies reporting death rates by stage have fairly consistently shown death rates from thymoma of 1% (range, 0 2%) for patients with stage I, 8% (range, 3 12%) for those with stage II, 23% (range, 10 36%) for those with stage III, and 50% (range, 36 67%) for those with stage IV tumors. 1,19,28,31,42 The percentage of all deaths that are due to thymoma is 1% (range, 0 3%) of deaths in patients with stage I disease, 32% (range, 20 50%) of deaths in patients with stage II, 57% (range, 50 71%) of deaths in patients with stage III, and 77% (range, %) of deaths in patients with stage IV disease. 19,31,42 In addition, the rate of death from thymoma is 5% (range, 5 6%) for patients who underwent a complete resection (R 0 ), 38% (range, 31 44%) for subtotal resection (R 1,2 ), and 67% (range, 50 83%) of patients who underwent only a biopsy. 1,43 Recurrence Rates and Patterns Local recurrence is by far more common than a distant recurrence. Approximately half of the local recurrences involve the pleural space or the lung, with the typical appearance being a nodule under the parietal pleura. 4 Half of the local recurrences involve the mediastinum (which includes the pericardium, where pericardial nodules are also common). Liver and bone are the two most common sites of distant metastases. 4 The rate of recurrence is a better measure of outcome after treatment of thymoma than overall survival, given the indolent behavior of many of these tumors. 36 Recurrence rates taken from a comprehensive review 4 are shown in Figure 2. 4 Average recurrence rates are low for Masaoka stage I tumors (3%), but increase progressively to 11 and 30% for stage II and III tumors. The indolent behavior of thymic tumors is demonstrated by the average time to recurrence of approximately 5 years. 2,8,10,21,29,31 The mean time to recurrence was 10 years in patients with a stage I thymoma, compared with 3 S320

4 Journal of Thoracic Oncology Volume 5, Number 10, Supplement 4, October 2010 Evaluation and Treatment of Stage I and II Thymoma FIGURE 2. Recurrence rates after resection. Data taken from a comprehensive review. 4 FIGURE 3. Recurrence rates after complete resection with or without adjuvant radiotherapy (RT). Data taken from a comprehensive review of studies reporting 50 patients and specific data by stage and complete resection. 4 years in patients with a stage II to IV thymoma. 28 However, because recurrences can be seen 10 to 20 years later, and because surgical resection of a local recurrence affords good survival, 4,10,29 surveillance of a patient with a resected thymoma should probably extend at least 20 years. 36 Adjuvant Radiotherapy In the past, adjuvant radiotherapy (RT) was given frequently to patients with thymoma. Over time, however, data has emerged that this is of limited (if any) benefit in patients who have been completely resected Data taken from series that reported results by stage and for completely resected patients is shown in Figure 3. Several meta-analyses have also suggested no benefit in completely resected patients However, these are not randomized series, and selection of patients at higher risk for recurrence may have been more likely in the RT treatment cohorts. Although the propensity to local recurrence provides a rationale for adjuvant RT, it must be remembered that most of these local recurrences involve pleural or pericardial implants, which are not necessarily contiguous with the original tumor location. 9 Given the nonrandomized data suggesting little benefit, it is probably best to omit RT for a completely resected stage I or II thymoma. CONCLUSIONS The clinical presentation, radiographic appearance, and knowledge of the proportions of diagnoses of anterior mediastinal masses allow a very reliable clinical diagnosis of thymoma to be made in the majority of patients. Although a preoperative biopsy can sometimes be useful, it is generally not needed. Despite a generally indolent behavior, all thymomas are malignant in nature and in general should be treated. Surgical resection is the mainstay of treatment, particularly for stage I and II thymomas. Long-term survival and freedom-from-recurrence rates are excellent when the tumor is completely resected, and adjuvant RT has little role for completely resected, early stage thymomas. REFERENCES 1. Nakahara K, Ohno K, Hashimoto J, et al. Thymoma: results with complete resection and adjuvant postoperative irradiation in 141 consecutive patients. J Thorac Cardiovasc Surg 1988;95: Lewis JE, Wick MR, Scheithauer BW, et al. Thymoma: a clinicopathologic review. 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