Myasthenia Gravis with Thymoma: Analysis of and Postoperative Prognosis for 65 Patients with Thymomatous Myasthenia Gravis

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1 Myasthenia Gravis with Thymoma: Analysis of and Postoperative Prognosis for 65 Patients with Thymomatous Myasthenia Gravis Yasumasa Monden, M.D., Kazuya Nakahara, M.D., Katsumi Kagotani, M.D., Yoshitaka Fujii, M.D., Akira Masaoka, M.D., and Yasunaru Kawashima, M.D. ABSTRACT Sixty-five patients with thymomatous myasthenia gravis were investigated. Thymomas were present in 44 of the male patients and 9 of the female patients with myasthenia gravis. The incidence of thymomatous disease in male patients was higher than in female patients in all age groups. Eighty percent of men more than 50 years old and women more than 60 years old had myasthenia gravis with thymoma. Germinal center formation in the thymus of patients with thymomatous myasthenia gravis was positive in 9 and was high grade. The prognosis for patients undergoing extended thymectomy of thymomatous myasthenia gravis was significantly better than in those having transsternal simple thymectomy, but it was worse than the prognosis for patients with nonthymomatous myasthenia gravis. No increase in the rate of remission or palliation was seen one year after thymectomy. It is concluded that early thymectomy is effective in control of myasthenia gravis in thymomatous myasthenia gravis. Surgical removal of the thymus is an effective therapy for myasthenia gravis (MG). In spite of the fact that the effectiveness of thymectomy for MG was pointed out in 939 by Blalock and colleagues [l] in relation to a girl with thymomatous MG, thymectomy is less effective in thymomatous than in nonthymomatous MG. In this study, we analyzed the clinical characteristics of and the prognosis after thymectomy for patients with thymomatous MG. Material and Methods As a rule, all patients in these two groups were operated on: adults with generalized MG and patients with thymomatous MG. In our clinic, we performed thymectomy on 65 patients with thymomatous MG and 70 with nonthymomatous MG. The system of Osserman and Genkins [2] was used with minor modifications for the clinical classification of From the First Department of Surgery, Osaka University Medical School, Osaka, Japan. Accepted for publication Oct 28, 983. Address reprint requests to Dr. Monden, First Department of Surgery, Osaka University Medical School, --50, Fukushima, Fukushima-ku, Osaka 553, Japan. MG. We categorized patients with type IV MG in the Osserman and Genkins classification as type IIA or type IIB according to the severity of symptoms at the time of operation. In addition, patients with no myasthenic symptoms at the time of operation, but who had past histories of myasthenic symptoms and had been treated with anticholinesterase drugs, were classified as type 0 in our modified system. Classification of Myasthenia Gravis Juvenile type Development of MG at any time from birth to puberty; no myasthenia in the mothers of the affected children Adult type I-Myasthenia gravis limited to ocular region only IIA-Mild generalized MG IIB-Severe generalized MG -Acute fulminating MG 0-Thymomatous MG without myasthenic symptoms at time of operation; past history of MG Thymomas were classified according to our criteria for clinical staging of these entities [3]. In brief, the criteria are as follows: stage I-macroscopically, completely encapsulated and microscopically, no capsular invasion; stage -macroscopic invasion into surrounding fatty tissue or mediastinal pleura, or microscopic invasion into capsule; stage -macroscopic invasion into neighboring organ (i.e., pericardium, great vessels, or lung); stage IVa-pleural or pericardial dissemination; stage IVb-lymphogenous or hematogenous metastasis. In this paper, invasive thymoma was defined as clinical stage or IV, and noninvasive thymoma as stage I or. Germinal center formation in the thymus was classified into five categories according to the following criteria: grade 0-normal; grade -germinal center absent but accumulation of lymphocytes in the distended medulla; grade 2-one or two germinal centers in one histological section; grade 3-number of centers between those for grade 2 and grade 4; grade 4-numerous germinal centers (one or more in one lobulus). Two methods of thymectomy for thymomatous MG were employed in our clinic. One was transsternal simple thymectomy, 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 were resected by the transsternal approach. The postoperative prognosis for 46

2 47 Monden et al: Myasthenia Gravis with Thymoma patients with MG was analyzed according to the method of thymectomy and the preoperative duration of symptoms. Evaluation of the effect of the thymectomy on MG was conducted at 3 months, 6 months, year, 3 years, and 5 years after the operation, in accordance with the protocol of Papatestas's group [4]. The remission rate is the ratio of the number of patients in remission to the total number of patients, while the palliation rate is the ratio of the number of patients in remission and improved patients to the total number. The patients with MG of type 0 were excluded from the analysis of postoperative prognosis. Results The group of patients with thymomatous MG who underwent thymectomy consisted of 35 men and 30 women; in the group with nonthymomatous MG were 45 male and 25 female patients (Table ). Thus, thy- momas were present in 44 (35430) of the male and 9 (30/55) of the female patients with MG. The distribution of patients with thymomatous MG according to clinical classification was quite similar to that of patients with nonthymomatous MG. Eighty percent of the patients with thymomatous MG were type I (IIA, 22; IIB, 58). Thymomas were not found in any male or female patients less than 20 years old. The incidence of thymomas in the male patients with MG was higher than in the female patients in all age groups. More than 80 of the male patients older than 50 years and the female patients older than 60 years had thymomas. Thymomas were noninvasive in 42 instances and invasive in 23 (35). Germinal Center Formation The grade of germinal center formation in the thymus was investigated in 45 patients with thymomatous MG Table. Clinical Characteristics of Patients Undergoing Thymectomy for Treatment of Thymomatous and Nonthymomatous Myasthenia Gravis (N = 235) Type of MGb Variable Thy momatous Nonthymomatous Total Sex M F Classification of MG" Juvenile 0 7 (4) 7 I 4 (6) 4 (8) 8 IIA 4 (22) 38 (22) 52 IIB 38 (58) 0 (65) 48 I 5 (8) () (6) 0 4 Age (yr) 59 M F (0)' M (24) F (5) M (38) F (23) M (35) F (22) M (83) F ' (25) 260 M (00) F 4 5 (80) "See text for details. bnumbers in parentheses are percentages. 'Numbers in parentheses are association rates for thymomas in patients with MG. Association rates were obtained by dividing the number of.patients with thymomatous MG by the total number with MG and multiplying the result by 00. MG = myasthenia gravis.

3 48 The Annals of Thoracic Surgery Vol 38 No July 984 Table 2. Germinal Center Formation in Thymus Grade of Germinal CenteP Type of Disease Thymomatous MG (N = 45) Lymphocytic thymoma Mixed thymoma Epithelial thymoma Nonthymomatous MG (N = 98) "See text for details. MG = myasthenia gravis and 98 with nonthymomatous MG (Table 2). Patients with nonthymomatous MG were distributed evenly in all grades of germinal center formation except grade 3. On the other hand, patients with thymomatous MG tended to have a higher grade of germinal center formation. There were significant differences in the grade of germinal center formation between patients with thymomatous MG and those with nonthymomatous MG. However, the relationship between the histological type of thymoma and the grade of germinal center formation was not clear (chi-square analysis; p < 0.00). Prognosis after Thymectomy METHOD OF THYMECTOMY AND PROGNOSIS. Out of the 65 patients with thymomatous MG, 9 underwent thymectomy by the simple transsternal method (Group ) and 46 had extended thymectomy (Group 2). The clinical data for these groups were almost identical (Table 3). The palliation rates after operation for Group and Group 2 were 35 and 7, respectively, at 3 months after thymectomy, 53 and 73 at 6 months, 56 and 8 at year, 56 and 74 at 3 years, and 56 and 84 at 5 years. The remission rates for Group and Group 2 were 2 and lo, respectively, at 3 months, 2 and 5 at 6 months, 3 and 27 at year, 6 and 30 at 3 years, and and 26 at 5 years. The prognosis for patients with MG after thymectomy was thus significantly better in Group 2 than in Group, according to analysis of variables relative to an identified distribution. No increase in the rate of remission or palliation following thymectomy was seen after the first postoperative year in either group (Fig ). PREOPERATIVE DURATION AND PROGNOSIS. The postoperative prognosis was affected by the method of thymectomy as described. Therefore, we investigated the effect of the duration of symptoms preoperatively on the postoperative prognosis for patients who were operated on using the same method of thymectomy. The relationship between the preoperative duration and prognosis after thymectomy was investigated in Group 2 (extended thymectomy) (Fig 2). The patients were subdivided into two groups, a "short group" and a "long group." The duration of symptoms preoperatively of the patients in the "short Table 3. Clinical Data on Patients Undergoing Thyrnectomy for Thymomatous Myasthenia Gravis (N = 65) Variable Classification of MG" I I I 0 Stage of thymomaa I I IV Preop. duration < yr 2 yr Unknown Sex M F Age (yr) Mean SD SST f 9 Type of Thymectomy ET "See text for details. MG = myasthenia gravis; SST = transsternal simple thymectomy; ET = extended thymectomy. group" was less than year, while that of the "long group" was year or more. The palliation rates for these subgroups ranged from 70 to 80, and there was no significant difference between them. The remission rates for the "short group" and the "long group" were 4 and 5, respectively, at 3 months after operation, 23 and 6 at 6 months, 38 and 3 at year, 46 and 4 at 3 years, and 45 and 0 at 5 years. The difference in the remission rates between the two groups is clear. The postoperative prognosis for the "short group" in Groups and 2 was compared (Fig 3). The prognosis for

4 49 Monden et al: Myasthenia Gravis with Thymoma loor Palliation Rate PALLIATION RATE 40 lo 20 Fig I. Prognosis after thymectomy for patients with thymomatous myasthenia gravis undergoing extended thymectomy (-) and transsternal simple thymectomy (6-4). (M = months.) I /' Palliation Rate _--- _-.. Fig 3. Prognosis after thymectomy in the "short group" of patients undergoing extended thymectomy (-) and transsternal simple thymectomy (&-A). (M = months.) 04 to- 20 I Remission Rate Fig 2. Relationship between prognosis after extended thymectomy and preoperative duration of symptoms. (- = duration of less than I year; = duration of I year or more; M = months.) Group 2 was better than that for Group. Almost the same result was obtained in the "long group." POSTOPERATIVE PROGNOSIS FOR THYMOMATOUS AND NONTHYMOMATOUS MG. The postoperative prognosis for patients undergoing extended thymectomy of thymomatous MG was compared with that for patients with nonthymomatous MG who were also operated on by this method (Fig 4). The palliation rate for patients with thymomatous MG was 7 at 3 months after operation, 75 at 6 months, 8 at year, 74 at 3 years, and 84 at 5 years. On the other hand, the palliation rate for patients with nonthymomatous MG was about 0 higher at each time compared with the results for thymomatous MG patients. Fig 4. Prognosis for patients with thymomatous and nonthymomatous myasthenia gravis after extended thymectomy. ( ) = with thymoma; = without thymoma; M = months.) The remission rates for patients with thymomatous MG and nonthymomatous MG were 0 and 3, respectively, at 3 months, 5 and 5 at 6 months, 27 and 2 at year, 30 and 43 at 3 years, and 26 and 53 at 5 years. The difference between the effect of thymectomy on thymomatous MG and nonthymomatous MG was not significant at 3 months, 6 months, or year after operation by analysis of variables relative to an identified distribution, but it was significant at 3 years and 5 years ( p < 0.05).

5 50 The Annals of Thoracic Surgery Vol 38 No July 984 Table 4. Myasthenia Gravis with Thymoma According to Sex: Review of the Literature Patients with MG" Reference Male Female Total GROUP lb Eaton and Clagett 3524 (6.4) 42/258 (6.3) 77/472 (6.3) (955) [22] Simpson (958) [23] 8/34 (3.4) (0.7) 47/404 (.6) Kornfeld et a /,557 (0.5) (978) [lo] GROUP 2' Simpson (958) [23] /294 (2.2) 88/276 (3.9) Papatestas et aid 32/57 (56.) 4228 (32.8) 7485 (40.0)e (97) [4 Paletto and Maggi 36/04 (34.6) 44/26 (20.4) (25.0) (982) [6 LeBrigand (982) [25] 3/77 (40.3) 42/7 (24.6) 73/248 (29.4) Monden et a 35/80 (43.8) 30/55 (9.4) 65/235 (27.7) [present study] "Ratios are number of patients with thymomatous MG to total number of patients with MG, with or without thymoma. bgroup reports include patients undergoing operation as well as those who did not. 'All patients in these series were operated on. dreports from the same institution. 'This figure was not included in the total number, because the reports from Perlo and Papatestas and their colleagues are from the same institution. MG = myasthenia gravis. Comment It is well known that thymoma is often found in patients with MG, but the reported incidence of thymomas in patients with MG ranges from 0 to 42. The reported rates of association for thymomas with MG are shown in Table 4. The association rates for thymomas ranged from 0.5 to 6.3 and the mean was.8 in 287 out of 2,433 patients, including patients not having operation. On the other hand, the association rates for patients undergoing operation ranged from 2.2 to 3.9 and the mean was 24.9 in 342 out of,373 patients. One reason why the association rate for thymoma in the patients having operation was almost twice that in the group including patients not operated on is that thymectomy is usually performed in all patients with thymomatous MG but not in all patients with nonthymomatous MG. Another reason is that a thymoma can be found during the operation in some patients who had been diagnosed as having nonthymomatous MG. Thymomatous MG was diagnosed in 35 male and 30 female patients in our series and in 52 male and 99 female patients in the other reports listed in Table 4. The association rate for thymomas in male patients with MG was almost twice that in female patients in our series. In the reports listed in Table 4, the mean rate for male patients was about.8 times that for female patients undergoing operation. This means that the number of patients of both sexes with thymomatous MG was almost the same, but the association rates for thymomas in patients with MG were quite different for male and female patients. There are few previous reports giving detailed analysis of the relationship between age, sex, and association rates for thymomas in MG. Schwab and Leland [5] reported that thymomas were present in 29 of male patients less than 30 years old and 36 of men older than 30 years, but in only 5 of female patients less than 30 years old and 78 of the older women. Paletto and Maggi [6] noted that the association rate for thymomas in MG was 5 in patients less than 40 years old and 42 in those older than 40 years. In our series, the association rate for thymomas in male patients with MG was higher than that in the female patients in each age group. The association rates for men more than 50 years old and women more than 60 years old were extremely high compared with those for younger patients. Therefore, older patients should be examined with special care for the presence of thymomas. Thirty-five percent of patients with thymomatous MG had invasive thymomas in our series. In previous reports, the incidence of invasive thymomas ranged from 29 to 43 [6-9. Kornfeld and colleagues [ 0 reported that germinal centers were found in the thymus in 6 (46) of 35 patients with thymomatous MG. In our series, germinal

6 ~ 5 Monden et al: Myasthenia Gravis with Thymoma Table 5. Prognosis after Thymectorny for Patients with Thymomatous Myasthenia Gravis ~~~~~ Remission Palliation No. of Rate Rate Reference Patients () () Eaton and Clagett (955) (22 Simpson (958) [23] Buckberg et a (967) [26] Papatestas et a (97) [4 Cohn et a (974) [27] Emeryk and Strugalska (976) [28] Paletto and Maggi (982) [ LeBrigand (982) [25] centers were present in 4 (9) of 45 patients with thymomatous MG and in 63 (64) of 98 patients with nonthymomatous MG. The positive rate for thymomatous MG was significantly higher than that for nonthymomatous MG (p < 0.005). The grade of germinal center formation in the thymus of patients with thymomatous MG was higher than that in those with nonthymomatous MG. We could not find previous reports concerning the grade of germinal center formation in thymomatous MG. Our group [ll] elucidated that the anterior mediastinal adipose tissue included thymic tissue and proposed extended thymectomy as a new method of operation. It was previously reported that extended thymectomy was the most effective among several methods of thymectomy, including transsternal simple thymectomy and transcervical simple thymectomy, in treatment of nonthymomatous MG [2]. In this study, the extended thymectomy group also showed significantly better results than the group having transsternal simple thymectomy. Results reported by various groups concerning the prognosis after thymectomy for patients with thymomatous MG are compiled in Table 5. These authors performed thymectomy by the transsternal or transcervical simple thymectomy approach or by lateral thoracotomy. Our results for patients having extended thymectomy are remarkably better than those given in Table 5, although the times at which the authors estimated the effects of the operation were not clear. Thus, it has been proven that the extended thymectomy method we have proposed is a better method for treating both thymomatous and nonthymomatous MG. The antiacetylcholine receptor antibody (Anti-AchR Ab) in serum is important in the pathogenesis of MG. Vincent and associates [3] and Mittag and co-workers (4 reported that the thymus of patients with MG pro- duced Anti-AchR Ab. Olanow [5], Scadding [6], and their colleagues noted that the serum level of Anti-AchR Ab decreased in patients with MG who underwent thymectomy. Joceph and Johns [7] and Rosenberg and associates [8] reported the postoperative recurrence of hyperplastic thymus, which might be a cause of the failure of surgical treatment. Thymectomy by the extended method seems to leave no abnormal thymus to participate in the production of Anti-AchR Ab and also seems to reduce the possibility of recurrence of abnormal thymus. However, further investigations must be carried out to resolve these issues. The effect of thymectomy on nonthymomatous MG was poorer in patients with a high degree of thymic germinal center formation than in those with a low degree [9]. The germinal center formation in the thymus of patients with thymomatous MG was of a high degree. If transsternal simple thymectomy is performed for thymomatous MG, highly abnormal thymic tissue can be left. This seems to be one of the reasons why the results in the extended thymectomy group were better than in the group having transsternal simple thymectomy in our series. Early thymectomy is effective in patients with nonthymomatous MG [9-2. Although early thymectomy in thymomatous MG had been recommended for the control of thymomas, the effect of early thymectomy for MG had not been analyzed previously. It is concluded from the results of this study that early thymectomy in patients with thymomatous Mg is effective for MG. 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