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Ann Thorac Surg 2003;76:1643-1649
© 2003 The Society of Thoracic Surgeons

Original article: general thoracic

Clinical and pathologic predictors of outcome in Thymoma-Associated myasthenia gravis

Manuel López-Cano, MD, PhDa*, José M. Ponseti-Bosch, MD, PhDa, Eloi Espin-Basany, MD, PhDa, José L. Sánchez-García, MD, PhDa, Manuel Armengol-Carrasco, MD, PhDa

a Department of General Surgery, Hospital Universitari Vall d'Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain

Accepted for publication May 12, 2003.

* Address reprint requests to Dr López-Cano, Department of General Surgery, Hospital Universitari Vall d'Hebron, Passeig Vall d'Hebron 119-129, E-08035 Barcelona, Spain.
e-mail: lopezc{at}hg.vhebron.es


   Abstract
Top
 Abstract
Introduction
 Patients and methods
 Results
 Comment
 Acknowledgments
 References
 
BACKGROUND: Myasthenia gravis is by far the most common paraneoplastic syndrome of thymomas. There is little information regarding the influence of clinical variables and thymoma-associated factors on biologic development of myasthenia gravis. The aim of the study was to determine independent predictors of clinical outcome in thymoma with myasthenia gravis.

METHODS: We studied 108 patients with thymoma-associated myasthenia gravis undergoing removal of the mediastinal mass between 1967 and 2000. Clinical and pathologic variables associated with clinical outcome of myasthenia were assessed by multivariate Cox regression analysis.

RESULTS: Patients were followed for a mean period of 10 years (9 months to 33 years). A total of 38 patients died (35.2%), in 14 cases (37%) because of myasthenia gravis and in 6 (16%) because of recurrence of thymoma. With respect to clinical outcome of myasthenia gravis, at the end of the follow-up period, the rate of remission was 16% (n = 17). Of the 91 patients in whom remission was not achieved, 55 had no symptoms with immunosuppressive medication and 36 had symptoms with medication.

CONCLUSIONS: In patients with thymoma-associated myasthenia gravis, well-differentiated thymic carcinoma (Müller-Hermelink system), age more than 55 years, and interval from the onset of symptoms to thymectomy of less than 1 year were found to be independent predictors of nonremission of myasthenia gravis after thymectomy.


   Introduction
Top
 Abstract
 Introduction
Patients and methods
 Results
 Comment
 Acknowledgments
 References
 
Myasthenia gravis is an autoimmune disease in which clinical features—muscular weakness and fatigability of skeletal muscles are the hallmarks of the disease—are known to be caused by an antibody-mediated autoimmune attack directed against acetylcholine receptors at neuromuscular junctions [1]. Patients with myasthenia gravis have an increased incidence of associated conditions, including disorders of the thymus gland (thymoma, hyperplasia, atrophy).

The relationship between myasthenia gravis and the thymus has been recognized for a number of years. Myasthenia gravis is by far the most common paraneoplastic syndrome of thymomas. Thymic tumors occur in approximately 10% of patients with myasthenia gravis and, in turn, myasthenia gravis occurs in approximately 15% of patients with thymoma [2]. On the other hand, thymomas account for about 15% of all mediastinal masses. Several studies have indicated the importance of histologic classification, initial tumor invasion, and extent of surgical resection as predictors of recurrence and survival after resection of a thymoma [3–7]. However, there is little information regarding the influence of clinical variables and thymoma-associated factors on biologic development of myasthenia gravis. Moreover, because of the low incidence of thymoma-associated myasthenia gravis, most series in the literature [8–10] have analyzed predictors of outcome in patients with myasthenia gravis with and without associated thymoma as well as in patients with myasthenia gravis and other abnormalities of the thymus gland.

This study was therefore conducted to determine independent predictors of clinical outcome in thymoma with myasthenia gravis. We evaluated our experience with 108 patients with myasthenia gravis and a histologic diagnosis of primary thymoma during the past 33 years.


   Patients and methods
Top
 Abstract
 Introduction
 Patients and methods
Results
 Comment
 Acknowledgments
 References
 
A retrospective review of the surgery and pathology files of patients evaluated at Hospital Universitari Vall d'Hebron between January 1, 1967, and March 31, 2000, revealed 108 patients with a clinical diagnosis of myasthenia gravis and a histologic diagnosis of primary thymoma. No patients were included for whom medical records and pathologic slides were unavailable.

The system of Osserman [11] was used for the clinical classification of myasthenia gravis (type I, myasthenia limited to ocular region only; type IIA, mild generalized myasthenia gravis with ocular involvement; type IIB, moderately severe generalized myasthenia gravis with ocular involvement and mild bulbar symptoms; type III, acute severe myasthenia with severe bulbar symptoms gravis; type 0, thymoma and myasthenia gravis without myasthenic symptoms at the time of operation, past history of myasthenia gravis). In all patients, the diagnosis of myasthenia was made on clinical grounds and confirmed by positive anticholinesterase test (edrophonium chloride, Tensilon, Roche Laboratories, Hoffmann-La Roche Inc, Nutley, NJ), assay for anti–acetylcholine receptor antibody, anti–striated muscle antibody, and electromyography tests (motor and single fiber). Concomitant neuromuscular pathologic processes and autoimmune diseases were excluded by muscle biopsy, thyroid function tests, or other electrophysiologic and immunocytochemical tests. The preoperative diagnosis of thymoma was based on clinical symptoms, conventional radiographs, and computed tomographic scans. Because of the retrospective nature of the study, the same confirmatory diagnostic testing was not available in all patients. Indication for surgery included coexistent thymoma based on radioimaging evidence in a patient with myasthenia gravis.

Preoperative preparation for thymectomy included the use of anticholinesterase agents, corticosteroids, and short-term immunotherapies (intravenous immune globulin and plasma exchange) depending on individual patients' characteristics. Two methods of thymectomy for thymoma with myasthenia gravis were used in our hospital. One was transsternal total thymectomy (up to the 1980s), in which only the thymus and tumor were resected, and the other was extended thymectomy, in which not only the thymus and tumor but also the anterior mediastinal adipose tissue was resected by median sternotomy. The mediastinum was thoroughly explored up to the cervical thymic extensions and laterally down to the phrenic nerves. In all instances, every effort was made to remove all thymic tissue as completely as feasible by clearing the innominate vein and anterior pericardium from all resident mediastinal fat. Radicality of the resection of the thymoma was accomplished in all cases.

Microscopic sections of all 108 tumors fulfilling the diagnostic criteria of thymoma were reviewed by an independent pathologist blinded to clinical data and were classified according to the traditional classification proposed by Bernatz and colleagues [3] and a modification of the Marino and Müller-Hermelink system [4] as medullary, mixed, predominantly cortical, cortical, or well-differentiated thymic carcinoma type. Pathologic staging was done according to Masaoka and colleagues [5]. Stage I was defined as patients with encapsulated thymomas; stage II, invasion into surrounding fatty tissue or mediastinal pleura or microscopic invasion of the thymic capsule; stage III, invasion into mediastinal structures (ie, lung, pericardium, or great vessels); and stage IV, pleural or pericardial dissemination (IVa) and lymphogenous or hematogenous metastasis (IVb). In addition to operation, patients were treated with adjuvant radiation therapy (stage III) or both adjuvant radiation therapy and chemotherapy (stage IV), with the most common agents being cisplatin, cyclophosphamide, and doxorubicin.

The postoperative prognosis of patients with myasthenia gravis was estimated at 1 week after discharge from the hospital, at monthly intervals during the first 3 months, and at 3-month intervals during the first year after thymectomy. Thereafter, the frequency of follow-up assessments was established depending on the status of patients. To evaluate postoperative long-term outcome, the following categories were defined: (1) remission, no symptoms without medication, full working life; (2) improved or asymptomatic with medication, full activity with the same or less medication, any attempts to discontinue medication is followed by reappearance of symptoms; and (3) symptomatic with medication, increased activity with high doses of anticholinesterase agents, steroids, or immunosuppressant drugs, or no clinical change despite more medication. Nonremission included categories 2 and 3. Postoperative Osserman classes [11] were recorded at the most recent follow-up available. The remission rate is the ratio of the number of patients in remission to the total number of patients. Death was defined as related to the thymic tumor (local, distance recurrence, or both); to complications of myasthenia gravis; or as a result of other causes (unrelated to thymoma with myasthenia gravis).

Statistical analysis
The Student's t test was used for the comparison of continuous variables and the {chi}2 test for the comparison of categorical variables. Statistical significance was set at p less than 0.05. The cumulative probability of survival for the clinical outcome variable remission of myasthenia gravis versus nonremission was analyzed by the Kaplan-Meier method. Survival by groupings of different variables was compared using the log-rank test. Multivariate analysis was performed by use of the Cox proportional hazards model. Adjusted hazard ratios (risk ratios) and associated 95% confidence intervals were calculated for each covariate. The statistical analysis was done with the {chi}2 test. Significance was defined as p values less than 0.05. Statistical significance of each variable in the regression model was assessed using the Wald {chi}2 test.


   Results
Top
 Abstract
 Introduction
 Patients and methods
 Results
Comment
 Acknowledgments
 References
 
We treated 108 patients with myasthenia gravis and thymoma between 1967 and 2000. Complete follow-up until March 31, 2000, or until death was obtained in all patients, with a mean follow-up of 10 years (range, 9 months to 33 years).

The mean age at diagnosis was 49.6 years (range, 14 to 76 years). Overall, 59 (55%) were female and 108 (100%) were white. Clinical presentation with regard to classification of myasthenia gravis and thymoma-related symptoms, diagnosis, intraoperative data, and postoperative complications are shown in Table 1. The clinical type of myasthenia gravis was IIB or III in 87 (80.5%) patients. With regard to thymoma-related symptoms, 94 (87%) patients were asymptomatic when thymoma was discovered during chest radiographs or computed tomographic scans. Operative approach was median sternotomy in 100% of patients. Total thymectomy was performed in 40 (37%) patients and extended thymectomy in the remaining 68 (63%). Intraoperative and postoperative complications during hospital stay occurred in 43.5% and 25% of patients, respectively, and were more common in patients with postoperative myasthenic crisis (44 patients, 40.7%). No surgical deaths occurred in this series. Postoperatively, 27 (25%) patients were treated with adjuvant mediastinal radiation therapy (stage III, n = 21) and both adjuvant radiation therapy and chemotherapy (stage IV, n = 6).


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  		Table 1. Clinical, Diagnostic, and Surgery Data in 108 Patients With Thymoma and Myasthenia Gravis

 
Pathologic classification and clinical stage are shown in Table 2. During the follow-up period (Fig 1), 38 (35.2%) patients died. Causes included a myasthenic crisis in 14 patients, recurrence of thymoma in 6 patients, and other conditions unrelated to thymoma and myasthenia in the remaining 18 patients (dysrhythmia or sudden electrical cardiac arrest 9, bladder carcinoma 2, renal failure 2, cancer of the colon 1, malignant melanoma 1, septic shock 1, pulmonary thromboembolism 1, and traffic accident 1). Therefore, the mortality rate attributable to thymoma-associated myasthenia was 18.5% (20 of 108 patients). With respect to clinical outcome of myasthenia gravis, at the end of the follow-up period, the rate of remission was 16%. In the 17 patients in whom remission was achieved total thymectomy had been performed in 9 and extended thymectomy in 8. Of the 91 patients in whom remission was not achieved, 55 had no symptoms with immunosuppressive medication and 36 had symptoms with medication. Total thymectomy had been performed in 31 patients and an extended thymectomy in 60.


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  		Table 2. Pathologic Classification and Clinical Stage

 


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  		Fig 1. Outcome of myasthenia in 108 patients with thymoma-associated myasthenia gravis.

 
The analysis of three different time periods (Table 3) showed a significant trend throughout the study period for an increase in the tumor size, use of computed tomographic scanning for preoperative assessment, preparation with short-term immunotherapy, substitution of total thymectomy by extended thymectomy, and occurrence of invasive thymomas and well-differentiated thymic carcinoma, as well as a better outcome, with a decrease in the occurrence of postoperative myasthenic crisis and in the number of deaths. Myasthenia gravis was the most frequent cause of death during the first two decades (11 of 14 patients). On the other hand, 4 of the 6 patients in whom the cause of death was recurrence of thymoma died in the last decade.


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  		Table 3. Time Course of Thymoma With Myasthenia Gravis in 108 Patients at Three Different Time Periods

 
Table 4 shows differences in the cumulative probability of survival for the clinical outcome remission versus nonremission of myasthenia gravis analyzed by the Kaplan-Meier method. Thymoma-related symptoms, Müller-Hermelink pathologic grade, age more than 55 years, tumor size, time elapsed from the onset of symptoms to thymectomy, and type of surgical technique were significantly associated with poor clinical outcome of myasthenia gravis. In the multivariate analysis, well-differentiated thymic carcinoma (Müller-Hermelink system), age more than 55 years, and interval from the onset of symptoms to thymectomy of less than 1 year were found to be independent predictors of nonremission of myasthenia gravis after thymectomy (Table 5).


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  		Table 4. Effect of Different Variables on the Probability of Remission of Myasthenia Gravis

 

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  		Table 5. Multivariate Analysis of Factors Associated With Nonremission of Myasthenia at Follow-Up in Patients With Thymoma With Myasthenia Gravis

 

   Comment
Top
 Abstract
 Introduction
 Patients and methods
 Results
 Comment
Acknowledgments
 References
 
Epidemiologic features of the present series are similar to those found in other studies [1, 12] in which thymoma and myasthenia gravis were not significantly associated with demographic characteristics (age, sex), although it occurred more frequently between the fourth and sixth decades of life. Most of the patients presented with severe myasthenic symptoms, which confirms that myasthenia gravis associated with thymoma is more severe than myasthenia without thymoma [13]. Symptoms attributable to compression or invasion of adjacent mediastinal structures, such as chest pain, cough, and dyspnea, are uncommon as initial presenting manifestations of thymomas (13% in our study) [14].

Some diagnostic testing, such as edrophonium chloride test or motor nerve electromyography, were used in all patients, but other diagnostic procedures including assay for anti–acetylcholine receptor antibody and single-fiber electromyography have been added to the diagnostic protocol of myasthenia gravis more recently as soon as these tests have become widely available in routine clinical practice. All these tests showed a high diagnostic reliability. It should be noted that serum positivity for anti–striated muscle antibodies has been related to thymoma with myasthenia gravis [15]. In the present study, in the 56 patients in which this assay was performed, the percentage of positivity was 100%. In our study, like others [16], thymomas are best assessed by computed tomography rather than by chest radiograph. Computed tomographic scan not only presents a high rate of positivity (91.4% of cases in the present series) but also can suggest whether the tumor is invasive or not.

Preoperative medication using anticholinesterase agents, corticosteroids, and intravenous immune globulin has the effect of minimizing myasthenic crisis in the early postoperative period. Immune globulin treatment was introduced in the 1980s on the basis of a mechanism of action on anti–acetylcholine receptor antibodies [17, 18]. Surgical removal of the mediastinal mass was performed through a median sternotomy. Two surgical techniques were used in this series: (1) total thymectomy (up to the 1980s) and (2) extended thymectomy in which the anterior mediastinal lympho-adipose tissue was also resected [19]. Both procedures involved radicality of the resection of the thymus and tumor. In reference to maximal thymectomy for myasthenia gravis described by Jarezki and coworkers [20, 21], this technique was not used. Maximal thymectomy includes resection of the thymus and tumor, mediastinal pleura down to the phrenic nerves, pericardium and pericardial fat down to the diaphragm, aortopulmonary window adipose tissue, and cervical pretracheal adipose tissue up to the thyroid gland. The greater efficacy of maximal thymectomy versus extended thymectomy is still a matter of debate. Extended thymectomy seems to offer the same advantages in relation to the myasthenic disease with a lower morbidity. In fact, the remission rate obtained by Jarezki and associates [20] in 15 patients with myasthenia gravis and thymoma was 13.3%, which is lower than 16% in our study. However, type of operation was not a significant predictor of outcome in the logistic regression analysis in our series probably because we studied thymoma-associated myasthenia gravis and no patient with myasthenia and hyperplasia of the thymus was included. In the postoperative period, 40.7% of patients developed a myasthenic crisis. However, no case of myasthenic crisis occurred in patients treated with intravenous immune globulin preoperatively. These findings support the use of immune globulin for the treatment and preparation of myasthenic patients. However, the high percentage of crisis contributes to the poor clinical prognosis in the immediate postoperative period of thymoma-associated myasthenia gravis.

With respect to pathologic classification of thymomas, cortical and well-differentiated thymic carcinoma accounted for 50.9% of cases, a distribution similar to that reported by Müller-Hermelink and colleagues [22] in patients with thymoma and myasthenia gravis. The overall survival was similar to that found in other studies [23, 24]. During the follow-up period, 38 patients died, but in only 15.8% of cases was the cause of death related to recurrence of thymoma. This finding indicates that thymomas are notably indolent tumors. In the analysis of outcome during the 33-year study period, deaths related to recurrence of thymoma were more frequent in the subset of 45 patients operated on between 1990 and 2000, the time at which invasive tumors occurred in 64% (29 of 45) of cases and well-differentiated thymic carcinomas in 13% (6 of 45). In fact, 6 of the 7 cases of thymic carcinomas were diagnosed in these 45 patients. Although myasthenia gravis was the most common cause of death in our series (36.8% of cases), 11 of the 14 deaths had occurred before 1990. Moreover, in the group of patients who died as a result of causes unrelated to thymoma or myasthenia gravis, in 23.6% of cases, heart disease was the cause of death. At the end of the follow-up period, 84.3% of patients had symptoms of myasthenia. The remission rate was only 15.7%. However, 50.9% of patients in the group of nonremission were asymptomatic on immunosuppressive treatment. This may be explained by three circumstances: a change in the surgical approach of thymoma with current use of extended thymectomy, progress in the medical management of myasthenia gravis, and specialized treatment of myasthenia gravis in a specialized unit for the integral care of patients with myasthenia gravis.

With regard to predictors of clinical outcome in thymoma with myasthenia, we found that age more than 55 years was significantly associated with nonremission of myasthenia gravis. The prognostic effect of the patient's age on outcome of thymoma with myasthenia gravis has not been previously reported. On the other hand, initial thymoma-related symptoms (probably in relation to a large size of the tumor and invasiveness) were significantly associated with nonremission of myasthenia. In fact, tumor size more than 6 cm was also significantly associated with nonremission of myasthenia gravis. It should be noted, however, that the underlying mechanisms (probably of immunologic substrate) [25] responsible for the appearance of myasthenia gravis associated with a thymoma are unclear [26]. The effect of the size of the thymic tumor on autoimmune behavior in patients with myasthenia gravis is unknown. In agreement with these two variables, thymoma-related symptoms and size, a short time interval from the onset of symptoms to thymectomy (<1 year) was also significantly associated with poor clinical outcome of myasthenia gravis.

An interesting finding of this study was the prognostic value of the Müller-Hermelink pathologic classification system with respect to clinical outcome of myasthenia gravis. Although the effect of Müller-Hermelink pathologic grade on overall survival in patients with thymoma has been confirmed by others [26–29], the favorable or unfavorable effect of this variable on the long-term outcome of myasthenia gravis after thymectomy (remission versus nonremission) has not been previously studied. In this respect, this pathologic classification system of thymoma appeared to be useful for predicting clinical prognosis of myasthenia gravis on initial thymectomy. Finally, well-differentiated thymic carcinoma (Müller-Hermelink system), age more than 55 years, and interval from the onset of symptoms to thymectomy of less than 1 year were found to be independent predictors of nonremission of myasthenia gravis after thymectomy in the Cox regression analysis.

It should be noted that the new World Health Organization classification scheme proposed in 1999 [30] for categorization of thymic epithelial tumors was not used nor did we use a cytomorphologic classification based on cytokeratin profiles [31]. Although the World Health Organization scheme should facilitate interobserver reproducibility to make clinical studies comparable in the future, consistency and validity of the present results are not compromised by the use of the Müller-Hermelink system.

We conclude that the effectiveness of thymectomy in the long-term control of myasthenic symptoms in thymoma with myasthenia gravis seen in a series of 108 patients followed for a mean of 10 years was adversely affected by age older than 55 years, interval of less than 1 year between thymoma-related symptoms and surgical resection, and Müller-Hermelink pathologic grade (well-differentiated thymic carcinoma). Clinicians should have heightened awareness regarding the low rate of remission in thymoma-associated myasthenia gravis, particularly in the presence of such demographic, preoperative, and pathologic features.


   Acknowledgments
Top
 Abstract
 Introduction
 Patients and methods
 Results
 Comment
 Acknowledgments
References
 
We thank Carmen Ruiz-Marcellan, MD, for pathologic review of the cases and Marta Pulido, MD, for editing the manuscript and editorial assistance.


   References
Top
 Abstract
 Introduction
 Patients and methods
 Results
 Comment
 Acknowledgments
 References
 

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C. Zisis, D. Rontogianni, C. Tzavara, K. Stefanaki, A. Chatzimichalis, A. Loutsidis, K. Iliadis, A. Kontaxis, T. Dosios, and I. Bellenis
Prognostic Factors in Thymic Epithelial Tumors Undergoing Complete Resection
Ann. Thorac. Surg., September 1, 2005; 80(3): 1056 - 1062.
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