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Ann Thorac Surg 2005;79:219-224
© 2005 The Society of Thoracic Surgeons

Original article: General thoracic

Thymoma and Myasthenia Gravis: A Clinical Study of 1,089 Patients From Japan

Kazuya Kondo, MD, PhD*, Yasumasa Monden, MD, PhD

Department of Oncological and Regenerative Surgery, Institute of Health Biosciences, University of Tokushima Graduate School, Tokushima, Japan

Accepted for publication June 25, 2004.

* Address reprint requests to Dr Kondo, Department of Oncological and Regenerative Surgery, Institute of Health Biosciences, University of Tokushima Graduate School, Kuramoto-cho, Tokushima 770-8503, Japan (E-mail: kondo{at}clin.med.tokushima-u.ac.jp).


   Abstract
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 Abstract
Introduction
 Material and Methods
 Results
 Comment
 References
 
BACKGROUND: The thymus or thymoma plays a role in the pathogenesis of myasthenia gravis (MG). Although previous studies have reported that the presence of MG in thymoma patients is an indicator of poor prognosis, recent reports have shown that the presence of MG no longer influences the prognosis or indicates a more favorable prognosis in thymoma patients.

METHODS: To clarify the difference in tumor behavior between thymoma with MG and that without MG, we compiled 1,089 thymomas treated between 1990 and 1994 from 115 institutes in Japan and analyzed the clinical characteristics of thymoma with MG compared with thymoma without MG.

RESULTS: MG was associated with 270 cases (24.8%) of thymoma. The total resection cases comprised 94.6% and 91.4%, and the recurrent cases comprised 6.4% and 8.3% in the groups with and without MG, respectively. The 5-year survival rates for thymoma with and without MG in stage III were 85.7% and 89.3%, respectively; and those in stage IV were 85.1% and 63.9%, respectively. The prognosis of thymoma with MG in stage IV tended to be better than that of thymoma without MG (p = 0.0523). The thymoma with MG group had fewer stage IVb thymomas than did the thymoma without MG group (15% vs 34%). The resectability rate in the thymoma with MG group was higher than that in the thymoma without MG group (60% vs 38%).

CONCLUSIONS: Thymoma with MG is equally or less malignant than that without MG. The infrequency of stage IVb thymomas and the high respectability rate had an influence on the favorable prognosis of stage IV thymoma with MG.


   Introduction
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 Abstract
 Introduction
Material and Methods
 Results
 Comment
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Thymoma is an uncommon neoplasm that is derived from the epithelial cells of the thymus. It is well known for several interesting features, including an association with myasthenia gravis (MG) and other autoimmune diseases, histologic variability, and heterogeneity of malignant behavior [1, 2]. MG is an autoimmune disease in which the clinical features—muscular weakness and fatigability of skeletal muscles—are known to be caused by an autoimmune antibody against the acetylcholine receptor at the neuromuscular junction [3].

Thymoma occurs in approximately 10% of patients with MG and, in turn, MG occurs in approximately 33% of patients with thymoma [4]. It has long been suspected that the thymus or thymoma plays a role in the pathogenesis of MG. Most series in the literature have analyzed predictors of outcome and clinical features in patients with MG with and without associated thymoma [5–7]. However, there has been little recent information regarding differences in the clinical features and prognosis of thymoma patients with and without MG [8–10].

Several studies have reported that the presence of MG in thymoma patients is an indicator of poor prognosis [11–13]; however, recent reports have showed that MG no longer influences the prognosis of thymoma. This is due to the development of techniques for the long-term management of patients with MG [14, 15]. In addition, more recent reports have demonstrated that the presence of MG indicates a more favorable prognosis in thymoma patients [8–10].

It is controversial whether a favorable prognosis for thymoma with MG is due to the earlier detection of the thymoma by the careful surveillance of MG, or to the tumor behavior of thymoma with MG. In this study, to clarify the difference in tumor behavior between thymoma with MG and that without MG, we compiled 1,089 patients with thymomas treated between 1990 and 1994 from 115 institutes in Japan. We analyzed the clinical characteristics of thymoma with MG and compared them to thymoma in patients without MG.


   Material and Methods
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 Abstract
 Introduction
 Material and Methods
Results
 Comment
 References
 
Patients
We sent a questionnaire on thymic epithelial tumors to 185 institutes certified as special institutes by the Japanese Association for Chest Surgery and received replies from 115 institutes (62%). We compiled 1,093 thymoma patients that were treated between 1990 and 1994. The thymoma patients included 495 males and 590 females. The patients' ages ranged from 8 to 94 years, with a mean age of 53.7 ± 14.0 (standard deviation). The thymomas were subclassified according to a modification of Bernatz's classification into the following types: predominantly lymphocytic thymoma (PL-thymoma, n = 344), predominantly epithelial thymoma (PE-thymoma, n = 226), mixed thymoma (n = 428), and spindle cell thymoma (n = 41) [16].

In this study, pathologists certified by the Japanese Society of Pathology in each institute made the diagnoses of thymoma, thymic carcinoma, or thymic carcinoid. The final pathologic staging was based on Masaoka's staging system [17]. The surgical procedures for thymoma was classified into three groups according to resectability: total resection (no tumor remained macroscopically), subtotal resection (almost all of the tumor was resected macroscopically), and inoperable (including partial resection, exploratory thoracotomy, and simple biopsy). The surgical method for thymoma was classified into three groups: extended thymectomy (resection of the thymoma, thymus, and the anterior mediastinal adipose tissue around the thymus), thymothymectomy (resection of the thymoma and thymus), and tumor resection (resection of the tumor and a portion of the thymus) [18].

Statistical Analysis
Statistical analysis was performed by using the {chi}2 test, Fisher's exact probability test, and the unpaired t test with the SPSS for Windows (Version 11.0.1; Chicago, IL). Prognostic factors were analyzed by the Kaplan-Meier method with respect to survival. Deaths that were due to complications such as MG and pure red cell aplasia (PRCA), or unrelated diseases, were excluded from the analysis. Comparisons between survival curves were made by using the log-rank test. Significance was defined as a p value of less than 0.05.


   Results
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 Abstract
 Introduction
 Material and Methods
 Results
Comment
 References
 
Complication Rate of Thymic Epithelial Tumors
There were no statements regarding MG in 4 thymoma patients. MG was associated with 270 patients (24.8%) out of the 1089 patients with thymomas, including 8 postoperative MG. PRCA, including 4 postoperative PRCA, hyperglobulinemia or hypoglobulinemia, and Sjögren's syndrome were associated with 28 cases (2.6%), 7 cases (0.65%), and 5 cases (0.46%) of thymoma, respectively.

Clinical Findings of Thymoma With or Without MG
The 8 patients with postoperative MG and 3 patients without adequate clinical data were excluded from the thymoma with MG group. Excluded from the thymoma without MG group were 40 patients with other complications such as PRCA, hyperglobulinemia or hypoglobulinemia, and Sjögren's syndrome, and 9 patients without adequate clinical data.

The clinical data of the thymoma with and without MG groups are listed in Table 1. Both groups showed a slight female dominance. The patients with MG were significantly younger than those without MG (49.2 vs 54.9, p < 0.0001). The frequency of mixed-type thymoma in the thymoma with MG group was higher than in the group without MG. On the other hand, the frequency of PE and spindle-type thymoma in the group with MG was lower than in the group without MG. The distribution according to Bernatz's histologic classification was significantly different between the two groups (p = 0.014).


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  		Table 1. Clinical Data of the Thymoma With and Without Myasthenia Gravis Groups
 
Masaoka Clinical Stage of Thymoma With or Without MG
The distribution of Masaoka clinical stages in the group with MG was 124 (48.2%) in stage I, 70 (27.2%) in stage II, 43 (16.7%) in stage III, 17 (6.6%) in stage IVa, and 3 (1.2%) in stage IVb. On the other hand, the distribution in the group without MG was 372 (48.8%) in stage I, 159 (20.9%) in stage II, 154 (20.2%) in stage III, 51 (6.7%) in stage IVa, and 26 (3.4%) in stage IVb. There was tendency toward different stage distribution between the two groups (p = 0.088). There tended to be more thymomas with MG than those without MG in stages I and II (75.4% vs 69.7%, p = 0.076). In stage IV, the frequency of stage IVb thymomas in the thymoma without MG group was higher than in the thymoma with MG group (26/77 [33.8%] vs 3/20 [15.0%]).

Treatment for Thymoma With or Without MG
Treatments for thymoma with or without MG were divided into three groups: surgery only, surgery plus adjuvant therapy including radiotherapy, chemotherapy, or both, and nonsurgery including exploratory thoracotomy and simple biopsy (Table 2). In stage I, most of the patients in both the thymoma with MG and the thymoma without MG groups underwent surgery only. In stage II, one third of the thymoma patients with MG and half of the patients without MG underwent surgery with adjuvant therapy (p = 0.07). In stages III and IV, more than 70% of the patients underwent surgery with adjuvant therapy in both groups. Most of the adjuvant therapy for stage I, II, and III thymomas consisted of radiotherapy. More than half of the adjuvant therapy for stage IV thymomas included chemotherapy. The therapeutic modalities between thymoma patients with MG and those without MG were not significantly different.


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  		Table 2. Therapeutic Modalities of Thymoma With or Without Myasthenia Gravis
 
Surgical Methods for Thymoma With or Without MG
All thymomas were completely resected in stages I and II. In stage IV, the resectability rate of stage IV thymoma in the thymoma without MG group was lower than that in the thymoma with MG group (38% vs 60%). Moreover, in stages III and IV, the frequency of inoperable cases in the thymoma without MG group was higher than that in the thymoma with MG group (stage III: 6.8% vs 0%, p = 0.079; stage IV: 22.1% vs 5.0%, p = 0.082).

The surgical methods in the group with MG included 190 (74.8%) extended thymectomies, 59 (23.2%) thymothymectomies, and 5 (2.0%) tumor resections. On the other hand, the methods in the group without MG included 273 (37.7%) extended thymectomies, 315 (43.4%) thymothymectomies, and 137 (18.9%) tumor resections. The frequency of extended thymectomy in the group with MG was significantly higher than that in the group without MG (p < 0.0001). The total resection cases comprised 94.6% in the group with MG and 91.4% in the group without MG.

Recurrence and Prognosis of Thymoma With or Without MG
In the group with MG, there were 13 (6.4%) recurrent cases out of the 202 patients with total resection of the tumor, and the number of recurrences of stages I, II, III, and IV was 0, 3 (5.3%), 8 (25.8%), and 2 (22.2%), respectively. In the group without MG, 51 (8.3%) of the 612 patients with total resection experienced recurrence, and the number of recurrences of stages I, II, III, IVa, and IVb was 4 (1.2%), 6 (4.2%), 31 (27.4%), and 10 (45.5%), respectively (Table 3). All 4 patients with recurrent tumors in stage I belonged to the group without MG. In stage IV, the frequency of recurrence in the group without MG was higher than that in the group with MG.


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  		Table 3. Recurrence Rate According to Clinical Stage in the Groups With and Without Myasthenia Gravis
 
Figure 1 shows the survival curves for thymoma with and without MG in stages III and IV. The 5-year survival rates for thymoma with MG and thymoma without MG in stage III were 85.7% and 89.3%, respectively. No significant differences in survival rate were noted between thymoma with and without MG. The 5-year survival rates for thymoma with and without MG in stage IV were 85.1% and 63.9%, respectively. The prognosis of thymoma with MG tended to be better than that of thymoma without MG (p = 0.0523).



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  		Fig 1. (A) Survival curves for thymoma with myasthenia gravis (MG) (solid line) and thymoma without MG (n = 141) (dashed line) in stage III thymoma with MG (n = 33). (B) Survival curves for thymoma with MG (n = 17) (solid line) and thymoma without MG (n = 77) (dashed line) in stage IV.

 

   Comment
Top
 Abstract
 Introduction
 Material and Methods
 Results
 Comment
References
 
MG occurred in 25% of the patients with thymoma in this study, as was shown in previous studies [4]. The association of MG with thymoma was reported to be an indicator of poor prognosis by reviews until the 1970s [11–13, 19–22]. However, some reports after the 1980s demonstrated that the presence of MG was no longer an adverse factor in patients with thymoma [14, 15, 17]; and moreover, that thymoma patients with MG had a better survival rate than those without MG [8–10].

It is said that the improved survival rate of patients with thymoma and MG is a reflection of improved postoperative respiratory support as well as improved long-term medical care of MG patients [9, 10]. Maggi and colleagues reported that the 5-year and 10-year survival rates of thymoma patients with MG (85% and 82%, respectively) were significantly higher than those without MG (78% and 67%, respectively) [9]. Monden and colleagues reported that the survival curve, excluding MG death of thymoma patients with MG, was significantly better than that of those without MG [8]. Okumura and colleagues demonstrated that patients with thymoma and MG had a more favorable prognosis than thymoma patients without MG (p = 0.07) but that the association with MG was no longer an independent prognostic factor in multivariate analysis [10].

Previous studies have reported that thymoma with MG has a lower rate of tumor recurrence than does thymoma without MG (the MG–without MG ratios were 13%:29%, 9%:12%, 12%:16%) [8, 9, 14]. This study also demonstrated that in totally resected cases, thymoma with MG had a lower frequency of occurrence than did thymoma without MG (6.4% vs 8.6%).

The Maggi and Okumura researchers suggested that the improved survival of thymoma patients with MG might be due to the early discovery of associated thymoma [9, 10]. The present study demonstrated that thymomas with MG were at earlier stages (stage I and II) than those without MG (75.4% vs 69.7%, p = 0.076). Previous reports showing a favorable prognosis of thymoma with MG support our findings (the ratio of rate of stages I and II in thymoma with MG–in thymoma without MG was 71%:55%) [8–10, 15].

To remove the influence of the clinical stage of disease on the survival rate, we drew survival curves of thymoma patients with or without MG according to each clinical stage of the disease. To evaluate the prognosis in both groups only by the malignant behavior of the tumor, MG-related deaths in the MG group were excluded from these survival analyses. In stage III, no significant difference was noted in 5-year survival between thymoma with MG and that without MG. This result is in accordance with that of the Okumura group's study. However, stage IV thymoma patients with MG had better prognoses than those without MG (5-year survival: 85.1% vs 63.9%, p = 0.0523).

The present study revealed that thymoma with MG in stage III has an equal prognosis to that without MG, as treatment modalities for thymoma with MG in stage III are similar to those for thymoma without MG. This study also showed that some factors have an influence on the better prognosis for stage IV thymoma patients with MG.

First, there were more stage IVb thymomas in the thymoma without MG group than in the thymoma with MG group (34% vs 15%). All 3 patients in the MG group had only lymph node metastasis. On the other hand, in the thymoma without MG group, 12 patients had only lymph node metastasis, 10 had distant metastasis, and 3 had both metastases. Some studies have shown a worse prognosis for stage IVb thymoma than with stage IVa thymoma [24, 25]. Okumura and associates also showed that there was less stage IVb thymoma in thymoma with MG than in thymoma without MG (0 vs 6 cases) [10].

Second, the resectability rate in the thymoma without MG group was lower than that in the thymoma with MG group (38% vs 60%). Moreover, the thymoma without MG group had more inoperable cases than did the thymoma with MG group (22% vs 5%). Most studies have demonstrated that total resection of the tumor is the most important factor in the survival rate in invasive thymoma [9, 17, 26]. This study demonstrated that there was more thymoma with the potential of lymphogenous or hematogenous metastases, or both, in thymoma without MG than in thymoma with MG. However, it is unknown whether the clinical behavior of thymoma with MG is due to a tumor feature or to the earlier discovery of the tumor by MG.

In conclusion, thymomas with MG were at earlier stages and showed a lower recurrence rate than those without MG. They showed the same prognosis as those without MG in stages I, II, and III, and a better prognosis in stage IV. This study suggests that thymoma with MG is equally or less malignant than that without MG.[23]


   References
Top
 Abstract
 Introduction
 Material and Methods
 Results
 Comment
 References
 

  1. Rosai J, Levine GD. Tumor of the thymusIn: Firminger HI, editor. Atlas of Tumor Pathology. 2nd series, fascicle 13. Washington, DC: Armed Forces Institute of Pathology; 1976.
  2. Shimosato Y, Mukai K. Tumor of the mediastinumIn: Rosai J, Sobin LH, editors. Atlas of Tumor Pathology. 3rd series, fascicle 21. Washington, DC: Armed Forces Institute of Pathology; 1997.
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  4. Thomas CR, Wright CD, Loehrer PJ. Thymoma: state of the art J Clin Oncol 1999;17:2280-2289.[Abstract/Free Full Text]
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  6. Bril V, Kojic J, Dhanani A. The long-term clinical outcome of myasthenia gravis in patients with thymoma Neurology 1998;51:1198-1200.[Abstract/Free Full Text]
  7. de Perrot M, Liu J, Bril V, McRae K, Bezjak A, Keshavjee SH. Prognostic significance of thymomas in patients with myasthenia gravis Ann Thorac Surg 2002;74:1658-1662.[Abstract/Free Full Text]
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  18. Masaoka A, Yamakawa Y, Niwa H, et al. Extended thymectomy for myasthenia gravis patients: a 20-year review Ann Thorac Surg 1996;62:853-859.[Abstract/Free Full Text]
  19. Leg MA, Brady WJ. Pathology and clinical behavior of thymomas: a survey of 51 cases Cancer 1965;18:1131-1144.[Medline]
  20. Weissberg D, Goldberg M, Pearson FG. Thymoma Ann Thorac Surg 1973;16:141-147.[Medline]
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  23. Monden Y, Nakahara K, Fujii Y, et al. Myasthenia gravis in elderly patients Ann Thorac Surg 1985;39:433-436.[Abstract]
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