Ann Thorac Surg 2008;86:941-945. doi:10.1016/j.athoracsur.2008.04.070
© 2008 The Society of Thoracic Surgeons
Original Articles: General Thoracic
Postthymectomy Myasthenia Gravis: Relationship With Thymoma and Antiacetylcholine Receptor Antibody
Jun Nakajima, MD, DMedSc*,
Tomohiro Murakawa, MD, DMedSc,
Takeshi Fukami, MD, DMedSc,
Atsushi Sano, MD, DMedSc,
Shinichi Takamoto, MD, DMedSc,
Hiroshi Ohtsu, MS
Department of Cardiothoracic Surgery and Department of Clinical Trial Data Management, The University of Tokyo Graduate School of Medicine, Tokyo, Japan
Accepted for publication April 23, 2008.
* Address correspondence to Dr Nakajima, Department of Cardiothoracic Surgery, The University of Tokyo Graduate School of Medicine, 7-3-1, Hongo, Bunkyo-ku, Tokyo 113-8655, Japan (Email: nakajima-tho{at}h.u-tokyo.ac.jp).
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Abstract
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Background: Myasthenia gravis occasionally develops in a postthymectomy patient with no preoperative history of this disease.
Methods: We retrospectively assessed the clinical course, history, and findings of myasthenia gravis, and examined the serum titers of antiacetylcholine receptor-binding antibody in patients who had undergone thymectomy.
Results: We enrolled 67 patients with thymoma and 11 with other thymic tumors, all of whom underwent thymectomy. Twelve thymoma patients had had myasthenia gravis preoperatively, and their serum titers were all positive for antiacetylcholine receptor-binding antibody. Thirteen of 55 patients (24%) who had had no preoperative myasthenia gravis, but none with other thymic tumors (p < 0.0001), had a similar positive reaction. Five of the 55 thymoma patients without preoperative myasthenia gravis presented with the disease 3 to 46 months after thymectomy. These 5 patients showed no significant clinical or pathologic features, and in only 1 did the tumor recur. However, they all, including 2 patients who had shown negative antiacetylcholine receptor-binding antibody titers preoperatively, showed the presence of antiacetylcholine receptor antibody after onset. No postoperative elevation of the antiacetylcholine receptor binding antibody titer was observed in any postthymectomy patient who had no myasthenia gravis.
Conclusions: We found that patients in whom postthymectomy myasthenia gravis developed showed high titers of antiacetylcholine receptor-binding antibody at the onset of the myasthenia gravis. We suggest that a positive preoperative antiacetylcholine receptor antibody level may be a risk factor for postthymectomy myasthenia gravis.
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Introduction
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Myasthenia gravis is an autoimmune disease manifested by general muscle weakness and fatigability fluctuating with the circadian rhythm. It is caused by antibodies to acetylcholine receptors on the neuromuscular junctions and is closely associated with thymoma. Thymoma is present in 10% to 12% of patients with myasthenia gravis [1], and the proportion of patients with thymoma who have myasthenia gravis is 15% [2]. Thymectomy is recommended for patients with either disease, but myasthenia gravis occasionally develops postoperatively in a patient in who had thymoma, although there was no sign of myasthenia gravis before the operation. The mechanisms of this type of myasthenia gravis are obscure. We hypothesized that the serum titer of the antiacetylcholine receptor-binding antibody (ARAb), which is indicative of progression of myasthenia gravis, would be predictive of this postthymectomy disease.
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Patients and Methods
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Before the study, the Research Review Board at our institution examined and approved our research protocol in light of the Declaration of Helsinki. All patients gave their informed consent before surgical intervention.
We retrospectively enrolled patients who had undergone thymectomy because of thymoma and other thymic tumors between 1994 and 2007. The preoperative serum titer of ARAb was assessed, and the diagnosis of myasthenia gravis was evaluated in all patients at the same time by using Masaoka's clinicopathologic staging [3] and application of the World Health Organization (WHO) pathologic subtype classification of thymoma [4]. ARAb was determined by radioimmunoassay (reference range, 0.3 nmol/L or less), and the diagnosis of myasthenia gravis was made from the clinical signs and symptoms, the edrophonium test, and electromyograms.
The surgical procedure for thymoma and thymic cancer has been described elsewhere [5]. Briefly, extended en bloc thymectomy encompassing the thymoma, the thymus gland, and the surrounding tissues of the anterior mediastinum was performed through a median sternotomy. Concomitant resection of the neighboring tissues and organs involved by the invasive thymoma was performed for complete resection. For the pleural dissemination in patients with stage IVa thymoma, either pleuropneumonectomy or pleurectomy with thymectomy was performed. Patients with thymic cysts underwent extirpation of the cyst through a median sternotomy or a thoracoscopy.
Follow-up examinations were performed every 3 to 6 months postoperatively to observe whether onset of myasthenia gravis occurred postoperatively and to monitor the changes in the serum titer of ARAb. The mean ± standard deviation follow-up interval was 70 ± 59 months in patients with thymoma. We performed a 
2 test for the bivariate analysis of categoric data. Differences were considered significant at p < 0.05.
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Results
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We enrolled 67 patients with thymoma who underwent extended thymectomy, 3 patients with thymic cancer, and 8 patients with thymic cysts. Myasthenia gravis coexisted with thymoma in 12 of 67 patients (18%). All them had the generalized type of myasthenia gravis. According to Masaoka's clinicopathologic staging, 41 thymomas were at stage I, 14 were at stage II, 8 at stage III, and 4 at stage IVa. The WHO pathologic subtypes of the thymomas were type A in 6 patients, type AB in 20, type B1 in 16, type B2 in 20, and type B3 in 5. No characteristic distributions of Masaoka's staging or the WHO subtypes of thymomas were observed in the patients with myasthenia gravis (Table 1).
All patients with thymomas or thymic cancer underwent extended thymectomy. Two of the 4 patients with stage IVa thymomas with pleural tumor dissemination had undergone pleuropneumonectomy and thymectomy for complete resection. The other 2 patients underwent thymectomy and subtotal resection of the pleural dissemination. Thus, 65 of the 67 patients underwent macroscopically complete tumor resection. No operative mortality occurred. One patient died of malignant lymphoma 16 months after thymectomy.
The preoperative serum titer of ARAb was high in all patients with myasthenia gravis (range, 0.7 to 142), and in 13 of 55 patients (24%) without preoperative myasthenia gravis (range, 0.6 to 76.2); however, no patients with thymic cysts or thymic cancer showed high titers of ARAb (Table 2). We found significant differences in the incidence of positive serum titers of ARAb among the three groups (p < 0.0001, 2 test).
In 5 of the patients with thymoma, myasthenia gravis developed postoperatively without having appeared preoperatively. The interval between the thymectomy and the onset of myasthenia gravis was 3 to 46 months. The thymomas of these patients showed no unusual characteristics in Masaoka's staging or in WHO pathologic thymoma subtyping. One patient, who had undergone subtotal resection of the pleural dissemination for stage IVa thymoma, presented recurrence of thymoma at the time of overt myasthenia gravis. However, the others had no recurrence of thymoma. The preoperative serum titer of ARAb was high in 3 of the 5 patients, but all 5 showed high serum titers of ARAb at the onset of postoperative myasthenia gravis (Table 3).
The positive-predictive value of the preoperative serum titer of ARAb in postthymectomy myasthenia gravis was 23%, the negative-predictive value was 95%, sensitivity was 60%, and the specificity was 80% (Table 4). No patients with thymic cysts or thymic cancer presented with myasthenia gravis postoperatively.
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Table 4 Relationship Between Occurrence of Postoperative Myasthenia Gravis and Preoperative Serum Titer of Antiacetylcholine Receptor Antibody
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Medical treatment, including the administration of anticholinesterase drugs and corticosteroids, was started after the onset of myasthenia gravis. Remission of the myasthenia gravis occurred in 1 patient, but the other 4 patients have shown no amelioration of the myasthenia gravis to date. No consistent pattern of postoperative ARAb levels was observed in the 5 patients, except that positive ARAb levels were maintained in all patients after the onset of myasthenia gravis.
The postoperative serum titer of ARAb was assayed in 11 of the patients with thymoma but without myasthenia gravis, and they showed high preoperative ARAb, which remained high in all of them. On the other hand, 21 of the patients without positive preoperative ARAb were assayed postoperatively, and the ARAb turned positive in 2 patients who had postthymectomy myasthenia gravis and remained negative in the other 19 patients without postoperative myasthenia gravis (Fig 1).
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Fig 1. Diagram shows preoperative and postoperative myasthenia gravis (MG) and preoperative and postoperative acetylcholine receptor-binding antibody (ARAb) serum titer levels in each patient.
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Comment
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In our study, we found no characteristic tendencies in the staging or the pathologic subtypes of the thymomas or in the preoperative serum titer of ARAb among the patients with postthymectomy myasthenia gravis. However, the serum titer of ARAb was positive in all patients at the onset of myasthenia gravis.
Postthymectomy myasthenia gravis had been hypothesized to occur in patients having a recurrence of thymoma [6, 7]. However, Namba and colleagues [8] reported that postthymectomy myasthenia gravis could occur in patients without tumor recurrence.
Some investigators state that patients with postthymectomy myasthenia gravis of early onset may have harbored subclinical myasthenia gravis preoperatively. Li and colleagues [9] suggested that usage of non-depolarizing muscle relaxants may cause the postoperative onset of myasthenia gravis in patients with thymoma who have undergone thymectomy. Incidences of postthymectomy myasthenia gravis from 0.9% to 20% [8–12] have been reported (Table 5).
ARAb is thought to be pathognomonic in myasthenia gravis. On the other hand, 15% to 20% of patients with myasthenia gravis are found to be negative for ARAb. Antimuscle-specific receptor tyrosine kinase (MuSK) antibody is often positive in ARAb-negative patients with myasthenia gravis [13]; however, almost all patients with both thymoma and myasthenia gravis have high serum titers of ARAb. Thymoma seems to be closely related to the production of ARAb. Patients with thymoma-associated myasthenia gravis were reported to have unfavorable prognoses due to nonremission of myasthenia gravis after thymectomy [14]. Some investigators even concluded that the long-term benefits attributable to thymectomy could not be demonstrated in patients with both thymoma and myasthenia gravis [15].
The serum titer of ARAb is occasionally high in patients with thymoma but without myasthenia gravis [16]. Ohta and colleagues [10] reported that 33% of these thymoma patients had high titers of ARAb, and 39% had high antiskeletal muscle antibody titers. They observed that 9 of the 15 patients with high ARAb titers had contracted myasthenia gravis after thymectomy [10]. Sakuraba and colleagues [17] reported that 8 of 31 patients (26%) with thymoma showed high serum titers of ARAb preoperatively, even though they had not preoperatively had myasthenia gravis. They observed no postthymectomy myasthenia gravis in these 8 patients but noticed that in one patient, who had not had an elevated level of ARAb preoperatively, myasthenia gravis developed with the recurrence of the thymoma [17].
In our study, postthymectomy myasthenia gravis was found in 3 of 13 patients (23%) with high preoperative levels of ARAb and in 2 of 42 patients (4.8%) without high ARAb levels. A high preoperative serum titer of ARAb was statistically related to postthymectomy myasthenia gravis (p = 0.045, 2 test). We suggest that a positive preoperative ARAb level might be a predictor for postthymectomy myasthenia gravis. In the 2 postthymectomy myasthenia gravis patients with negative preoperative ARAb, no recurrence of the thymoma was observed at the onset of the myasthenia gravis.
Kondo and colleagues [13] reported 8 patients with postthymectomy myasthenia gravis. Some of these patients underwent total resection of the residual thymus gland after the onset of myasthenia gravis, but no amelioration or remission of myasthenia gravis was observed afterwards [13]. In our study, 4 of 5 patients with postthymectomy myasthenia gravis had undergone extended thymectomy without postoperative recurrence of the thymoma. These findings suggested that an extrathymic mechanism of continuous production of ARAb might be active in these patients.
It should be stressed in relation to our study that myasthenia gravis was not manifested in 10 patients with thymomas who showed high serum titers of ARAb in both the preoperative and postoperative periods. These findings indicate that ARAb and some other factors can probably cause the onset of myasthenia gravis in those undergoing thymectomy for thymoma, although possibly, the test result of ARAb might be false-positive in some patients with thymoma.
In conclusion, this study found no relationship between the Masaoka stage of the thymoma or the WHO microscopic type of thymoma and the appearance of myasthenia gravis before or after thymectomy; or between the appearance of myasthenia gravis after thymectomy and the recurrence of the thymoma. All patients with myasthenia gravis before or after thymectomy had high levels of ARAb at the onset of myasthenia gravis. Among patients without preoperative myasthenia gravis and with elevated preoperative levels of ARAb, the incidence of myasthenia gravis after thymectomy was 23% (3 of 13), whereas among patients without preoperative myasthenia gravis and normal levels of ARAb, the incidence was 4.7% (2 of 42). We suggest that a positive preoperative ARAb level might be a predictive indicator for postthymectomy myasthenia gravis.
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Acknowledgments
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We are grateful to Chris W. P. Reynolds for his careful linguistic assistance with this article.
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References
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Abstract
Introduction
