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Journal of Thoracic Oncology:
doi: 10.1097/JTO.0b013e31828cb3c2
Original Articles

Is Thymectomy Necessary in Nonmyasthenic Patients with Early Thymoma?

Tseng, Yen-Chiang MD*; Hsieh, Chih-Cheng MD*; Huang, Hsin-Yi MS; Huang, Chien-Sheng MD*; Hsu, Wen-Hu MD*; Huang, Biing-Shiun MD, PhD*; Huang, Min-Hsiung MD*; Hsu, Han-Shui MD, PhD*†‡

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Author Information

*Department of Surgery, Division of Thoracic Surgery, Taipei Veterans General Hospital, National Yang-Ming University School; Division of Biostatistics, Institute of Public Health, and Institute of Emergency and Critical Care Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan.

Disclosure: The authors declare no conflict of interest.

Address for correspondence: Han-Shui Hsu, MD, PhD, Institute of Emergency and Critical Care Medicine, National Yang-Ming University School of Medicine, No 201, Sec 2, Shih-Pai Road, Taipei, Taiwan, 11217. E-mail: hsuhs@vghtpe.gov.tw

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Abstract

Background:

In thymoma patients without myasthenia gravis, it is debatable whether thymectomy should be performed in addition to thymomectomy, the procedure in which the thymoma alone is resected. In this study, we proposed to compare the surgical results in early-stage nonmyasthenic thymoma patients who underwent thymomectomy with and without extended thymectomy.

Methods:

A total of 95 patients without clinical evidence of preoperative myasthenia gravis, who underwent surgery for early-stage thymoma (stages I and II), were selected for the study. Thymomectomy with extended thymectomy was performed through median sternotomy on 42 patients, whereas thymomectomy without thymectomy was carried out through video-assisted thoracoscopic surgery (VATS) or thoracotomy in 53 patients. Outcomes and surgical complications were compared between the two patient groups.

Results:

The median duration of the follow-up was 57 months (6–121 months). Three patients, one in the thymomectomy group (1.9%) and two in the thymomectomy with thymectomy group (4.5%), developed tumor recurrences. Tumor recurrence rates between the two groups were not significantly different. During the follow-up period, we did not document the development of postoperative myasthenia gravis in any of the patients enrolled. Postoperative opioid use, the number of days of drainage, and hospitalization length were lower in patients undergoing thymomectomy through thoracotomy or VATS.

Conclusions:

In early-stage nonmyasthenic thymoma patients, thymomectomy without thymectomy through thoracotomy or VATS was associated with lower morbidity and shorter hospitalization, than thymomectomy with extended thymectomy. Postoperative myasthenia gravis did not develop in any of the patients enrolled in our study during the 57-month median follow-up period. Overall tumor recurrence rates were not significantly different between these two patient groups. On the basis of our results, we conclude that thymomectomy without thymectomy through thoracotomy or VATS is justified for early-stage nonmyasthenic thymoma patients, and longer follow-up is needed to investigate the necessity of thymectomy in this group.

Thymoma, the most common anterior mediastinal tumor in the adult population, has an indolent growth pattern, but presents the potential for malignant transformation with local invasion and pleural dissemination.1,2 In the United States, the overall incidence of thymoma is 0.13 in 100,000 persons.3 It was reported that, at the time of diagnosis approximately 50% of the thymomas were encapsulated without invading adjacent organs, which may correspond to Masaoka stages I and II.4,5 The mainstay treatment for thymoma is surgery.6,7 Generally, as Toker et al.6 recommended, median sternotomy, with an en bloc removal of the entire thymus and mediastinal fat bilaterally between the phrenic nerves and from the diaphragm to the innominate vein, should be performed to decrease tumor recurrences. Median sternotomy for thymectomy, even though not common, accounts for serious complications, including mediastinitis and osteomyelitis.8 Recently, video-assisted thoracoscopic surgery (VATS), with all the technological advances, or robotic-assisted resection of thymoma and thymectomy have been advocated at certain institutes.9–12 Myasthenia gravis is present in a significant proportion of patients with thymoma. In these patients, thymectomy in addition to the complete resection of thymoma is always indicated. However, in cases of thymoma without myasthenia gravis, whether thymectomy should be performed in addition to thymoma resection remains debatable.13,14 Only a few cases of postoperative myasthenia gravis, after thymoma removal in previously nonmyasthenic patients, were reported in the literature.15–17 The aim of this study was to compare the surgical results of thymomectomy through thoracotomy or VATS with thymomectomy with extended thymectomy through median sternotomy in nonmyasthenic patients with stage I and II thymomas, and to discuss the efficacy of thymectomy in these patients.

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PATIENTS AND METHODS

Patient Characteristics

A total of 95 patients without clinical evidence of preoperative myasthenia gravis, who underwent surgery for early-stage thymoma (stages I and II) in Taipei Veterans General Hospital (Taiwan) between January 2002 and August 2011, were selected for the study. Our Institutional Review Board approved this study and granted an exemption from informed consent (201208010BC). The process of patient selection is shown in Figure 1. Only patients with stage I or II thymoma were selected for analysis. Patients having incomplete resection were inevitably stage III or IV after surgery, and were thus, excluded from the study. From 16 nonmyasthenic patients with stage III or IV thymoma, 10 patients underwent median sternotomy for thymomectomy (thymomectomy and thymectomy) and six patients underwent thoracotomy for thymomectomy. In these 16 patients, four patients had incomplete resection (R1 or R2 resection), including two patients receiving thymectomy, and two patients thymomectomy only. In our institution, biopsy was not routinely performed preoperatively for anterior mediastinal tumors, unless they were considered to be nonresectable. All patients in our study underwent imaging studies, including chest computed tomography or magnetic resonance scans, before surgery. In our institution, positron emission tomography scans were not routinely performed on patients with thymomas. The imaging findings for early thymomas usually showed sharply demarcated, elongated, round, or lobulated tumors. Most often, tumor growth occurs asymmetrically to one side of the mediastinum and they appear homogeneous in attenuation with or without contrast injection. Calcification may occur in the capsule or within the tumors. The clinical data for these 95 patients, including sex, age, surgical procedures, tumor size, pathological diagnosis, adjuvant therapy, tumor recurrence, postoperative development of myasthenia gravis, surgical complications, and outcome were retrospectively reviewed. For patients with tumors located superiorly in the mediastinum near the innominate vein, median sternotomy was usually performed. For patients with well-defined tumors located laterally and inferiorly in the mediastinum, thoracotomy or VATS was usually preferred. Among these 95 patients, tumor removal (thymomectomy), in addition to extended thymectomy through median sternotomy, was performed on 42 patients, whereas thymomectomy without thymectomy was carried out through VATS or thoracotomy on 53 patients. VATS was performed through a thoracoscopically guided anterior minithoracotomy with a 2- to 3-cm working port. For patients with thoracotomy or VATS, some thymic tissue and perithymic fat were dissected to avoid injury from the tumor capsule. All study participants had complete resection of the tumors (R0 resection). In patients with thymectomy, surgery was performed through median sternotomy. After the mediastinum was entered, the pleura was opened on both sides. The thymus, along with the tumor and the adjacent pericardial fat, was freed from the pericardium and the mediastinal pleura. The cervical extension of each lobe was easily removed with the body of the gland by gentle traction. The phrenic nerves were carefully identified and preserved throughout the procedure. For tumor removal by thoracotomy or VATS without thymectomy, patients were placed in right or left lateral position. Tumors, along with some thymic tissue or perithymic fat, were carefully removed with a safe margin. The phrenic nerve was properly identified and protected during the procedure. The performance status of these patients was good. All patients in the study were Eastern Cooperative Oncology Group grade 0, which means that they were fully active and able to carry on with all activities that they performed before, without any restrictions. Four surgeons, who are among the authors, performed the operations during the study period. Chest tubes were usually removed when the pleural effusions became serosanguinous, and the drainage volume was less than 150 ml per day, without air leaks. Follow-up was performed for all patients at outpatient clinics on a regular basis, every 6 months for the first 5 years postsurgery, and annually after that. Chest computed scans were used to evaluate tumor recurrences. Adjuvant radiotherapy was given to some patients when tumors were of more aggressive World Health Organization (WHO) histological types, including B2 and B3. Surgical complications and outcomes were compared between these two patient groups.

FIGURE 1.
FIGURE 1.
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Statistical Analysis

SPSS version 13.0 statistical software was used for data analysis (SPSS Inc., Chicago, IL). Continuous data were expressed as mean ± SD. Continuous variables were analyzed by the independent t test or the Mann–Witney U test. To compare the frequencies between the two groups, the χ2 tests were applied for the univariate analysis. Disease-free survival curves were estimated by the Kaplan–Meier method and compared by the log-rank test. A p value of less than 0.05 was considered statistically significant.

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RESULTS

Patient characteristics are summarized in Table 1. All 95 patients underwent complete resection of the thymoma. Of these, 34 had Masaoka stage I, and 61 had stage II thymoma, including 17 patients with stage IIA and 44 patients with stage IIB. Postoperative adjuvant therapy was administered to 18 of 53 patients undergoing thymomectomy, and to 16 of 42 patients undergoing thymomectomy with thymectomy. Lymph node dissection was not performed routinely on these patients. In the thymomectomy group, lymph node sampling was performed for five patients only. Of these, one lymph node was removed in three patients, and four and seven lymph nodes were removed in one patient each, respectively. In the thymomectomy with thymectomy group, seven patients had lymph nodes sampled during operation. The number of lymph nodes removed was one in four patients, and two, three, and nine in one patient each, respectively. No tumor involvement was found in the lymph nodes removed in these patients. Between groups, the study variables, including sex, tumor behavior, and tumor size, were not statistically different. The only difference between the groups was age. Patients undergoing thymomectomy without thymectomy were older than those who underwent only thymectomy. An analysis of age and tumor characteristics was further performed and showed no statistical differences in these patients (Table 2). Surgical outcomes are shown in Table 3. The duration of surgery was significantly shorter in patients undergoing thymomectomy than in patients undergoing thymomectomy with thymectomy. Blood loss during surgery was also lower in patients undergoing thymomectomy. In addition, postoperative opioid use, the number of days of drainage, and the length of hospital stay were lower in patients undergoing thymomectomy. One patient had major bleeding because of innominate vein injury during surgery. The approach taken for this patient was performing VATS from the left side. The procedure was then converted to lateral thoracotomy to check the bleeding. In the 31 patients with thoracotomy, surgical approach was from the right side in 14 patients and from the left side in 17 patients. In the 22 patients with VATS, the approach was from the right side in 13 patients and from the left side in nine patients. Postoperative complications occurred in two patients in the thymomectomy group, and included phrenic-nerve injury and chylothorax. Sternal osteomyelitis occurred in one patient undergoing thymomectomy with thymectomy through sternotomy. No surgery-related mortality occurred in any of the patients. The case number of patients undergoing thymoma removal, with and without thymectomy before and after 2007, is shown in Figure 2. The percentage of patients without thymectomy increased after 2007. The median duration of the follow-up was 57 months (6–121 months) for all patients, 62 months for patients with thymectomy, and 55 months for patients without thymectomy. No patients were lost during follow-up in the study. No myasthenia gravis development was seen during the postoperative follow-up in any of the patients included. Three patients, one in the thymomectomy group (1.9%) and two in the thymomectomy with thymectomy group (4.5%), developed tumor recurrences. Their relapse patterns are listed in Table 4. In the group that underwent thymomectomy, the tumor recurred in one patient. The relapse pattern in this patient was pleural seeding, indicating regional recurrence within the intrathorax and not contiguous with the thymus or the thymoma. In the group that underwent thymectomy, two patients had tumor recurrences. Their relapse patterns were pleural seeding and lung metastasis, indicating distant metastasis to the lung parenchyma. All these three patients received adjuvant radiotherapy or chemotherapy and were still alive, despite the tumor recurrences. The freedom-from-recurrence curve with error bars for the 5-year timepoint is shown in Figure 3. The vertical bars indicate 95% confidence intervals for the thymectomy (0.88,1) and thymomectomy (0.79,1) groups. The 5-year freedom-from-recurrence rate was 96.8%. Surgical approach, age, sex, tumor stage, tumor size, and WHO classification were not statistically different between patients with and without tumor recurrence. The age of the three patients with tumor recurrences was 42, 45, and 48 years, respectively. All these three patients were Masaoka stage IIB and WHO histological types B1 to B3, respectively. The tumor recurrence rate was 4.9% in patients with stage II disease. The time from surgery to recurrences in these three patients was 7, 23, and 60 months, respectively. Two of the three patients received postoperative adjuvant radiation therapy after the initial thymoma resection. After the tumor recurrences occurred, all three patients underwent surgery and further chemoirradiation. All patients in this study are still alive, including the patients with disease recurrences. The overall survival rate is 100%.

TABLE 1.
TABLE 1.
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TABLE 2.
TABLE 2.
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TABLE 3.
TABLE 3.
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TABLE 4.
TABLE 4.
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FIGURE 2.
FIGURE 2.
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FIGURE 3.
FIGURE 3.
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DISCUSSION

Surgery remains the mainstay treatment for thymoma. Most surgeons recommend additional thymectomy, irrespective of the presence of myasthenia gravis.1–6,13,14 Murakawa et al.13 reported their experience on the surgical treatment of thymomas. In their series, the authors mentioned that before 1976, patients with thymoma underwent thymomectomy without extended thymectomy. In these patients with stage I thymoma, tumor recurrence rates were 14.8% (4 of 27 patients). The authors concluded that stage I thymoma can be completely cured by extended thymectomy with thymomectomy through median sternotomy. The article did not mention the incidence of postoperative myasthenia gravis. Our study represents the largest series in the literature to present the surgical outcomes in early-stage nonmyasthenic thymoma patients. In contrast to the findings of Murakawa et al., tumor recurrences in our series occurred in only one of 53 patients (1.9%) undergoing thymomectomy without thymectomy. We also found that tumor removal without extended thymectomy, through thoracotomy or VATS, presents several advantages, including decreased blood loss, earlier extubation and chest tube removal, shorter stay in the intensive care unit, and shorter postoperative hospitalization.

The incidence of postoperative myasthenia gravis developing in nonmyasthenic thymoma patients after resection is not clear, and it is currently not known whether thymectomy plays a role in preventing postoperative myasthenia gravis development. Only sporadic cases of postoperative myasthenia gravis have been reported in the literature.15–18 Terauchi et al.15 reported an asymptomatic thymoma patient who developed myasthenia gravis and lung metastasis 12 years after undergoing thymoma resection. This patient had WHO B1 and stage I thymoma. In 2005, Kondo et al.14 examined 1089 thymoma patients from 115 institutes in Japan, and found that myasthenia gravis developed postoperatively in eight of 827 participants (0.9%) who did not have preoperative myasthenia gravis. All these eight patients underwent extended thymectomy in addition to tumor resection, and no tumor recurrences were noted in them. In their series, none of the patients undergoing tumor resection alone developed postoperative myasthenia gravis. The authors concluded that thymus resection does not prevent postoperative myasthenia gravis. In 2008, Nakajima and colleagues19 presented their results about post-thymectomy myasthenia gravis. Fifty-five asymptomatic patients with thymoma undergoing thymectomy were enrolled. Five of them developed post-thymectomy myasthenia gravis 3 to 46 months after thymectomy, and only one patient presented a tumor recurrence during the follow-up period. Recently, Sun et al.17 reported that six of 125 thymoma patients without preoperative myasthenia gravis developed postoperative myasthenia gravis. All these six patients underwent thymectomy, including resection of the thymoma and of the thymus gland. None of the patients undergoing thymoma resection alone developed postoperative myasthenia gravis. It is of interest that all patients who developed postoperative myasthenia gravis in these reports underwent thymectomy in addition to thymomectomy. In our series, none of the 95 patients selected in the study had myasthenia gravis preoperatively, and none of them developed it postoperatively. The reason why certain asymptomatic patients undergoing thymectomy for thymomas still developed myasthenia gravis postoperatively is unknown. Further investigations are mandatory to elucidate whether thymectomy is necessary in early-stage nonmyasthenic thymoma patients.

Tumor recurrence after surgery in thymoma patients is related to the tumor stage and WHO histological type, the completeness of its surgical removal, and the type of treatment.20–22 Kondo et al.23 reported tumor recurrence rates of 0.9%, 4.1%, 28.4%, 34.3%, and 51% for stage I, II, III, and IV tumors and thymic carcinoma, respectively.14 Haniuda et al.21 found recurrence rates ranging between 5% and 50%, depending on the initial staging of the disease. Strobel and colleagues20 concluded in their study on 228 thymoma patients that the long-term outcome is related to tumor stage, WHO histology, and the type of treatment. Chang et al.20 reviewed 76 patients with stage II or III thymomas and found that Masaoka staging and adjuvant radiation were related to disease-free survival in completely resected tumors. Recently, Sakamoto et al.24 reported the results of extended thymectomy through median sternotomy for 162 thymoma patients, and found that type B3 is a poor prognostic factor for survival. In our study, three patients developed tumor recurrences. Two recurrences occurred in patients with extended thymectomy and one in a patient with thymomectomy through thoracotomy. No tumor recurrences were recorded in patients undergoing thymomectomy with VATS. These three patients were at Masaoka stage IIB and had tumors with WHO histological types of B1 to B3, respectively. The overall tumor recurrence rate in the study was only 3.16%. Two of these three patients received postoperative adjuvant radiotherapy after the initial surgical intervention. In the study, the percentage of patients without thymectomy increased after 2007. Even though some temporal bias existed regarding surgical approaches, only one patient had tumor recurrence in a 21-patient series undergoing thymomectomy without thymectomy before 2007, and none of them developed myasthenia gravis. The mean follow-up duration in these patients was 82.9 months.

There are several limitations to this study. First, this is a nonrandomized retrospective study with a 57-month median follow-up, and with the longest follow-up duration of 121 months. Because thymoma is an indolent tumor, a longer follow-up may be needed. Second, the surgical procedures were performed according to the tumor location and the surgeon’s preferences, and some selection bias could exist. Third, because this study consisted of only early-stage nonmyasthenic thymoma patients from a single institute, the analysis may not be sufficient to reach an appropriate conclusion. A larger patient cohort and case-match study, or a prospective controlled study may be needed to solve this controversial issue.

In summary, for early-stage nonmyasthenic thymoma patients, thymomectomy without thymectomy, through thoracotomy or VATS, was associated with less morbidity and shorter hospitalization than thymomectomy with extended thymectomy. We did not notice postoperative myasthenia gravis in any of the study patients during the 57-month median follow-up. The overall tumor recurrence rate, which was only 3.16%, was not significantly different between the two patient groups. We conclude that thymomectomy without thymectomy, through thoracotomy or VATS, is justified in early-stage nonmyasthenic thymoma patients. Longer follow-up is required to investigate the necessity of thymectomy in early-stage nonmyasthenic thymoma patients.

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ACKNOWLEDGMENTS

This work was supported in part by the Lung Cancer Foundation in Memory of Doctor K.S. Lu. We thank Ling-Chen Tai and Hui-Chen Lee from Biostatistics Task Force, Taipei Veterans General Hospital, for their statistical assistance.

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19. Nakajima J, Murakawa T, Fukami T, Sano A, Takamoto S, Ohtsu H. Postthymectomy myasthenia gravis: relationship with thymoma and antiacetylcholine receptor antibody. Ann Thorac Surg. 2008; 86:941–945

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Keywords:

Thymoma; Thymomectomy; Extended thymectomy; Video-assisted thoracoscopic surgery.

Copyright © 2013 by the International Association for the Study of Lung Cancer

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