Role of T h y m e c t o m y in the Surgical T r e a t m e n t o f M y a s t h e n i a Gravis Kohki KONOMI, Seiichi TOYODA, Fujihiko NISHIKATA, Shoichiro SAITO, Hiroshi YAMAMOTO~Motomichi ToRISU and Sachiko KAWANAMI* A B S T R A C T : O f the 26 patients with myasthenia gravis undergone thymectomy, 11 cases had either benign or malignant thymoma as judged not only by hitologieal examination but also by their clinical and operative findings. Age of initial onset ranged from 13 to 64 years old. Fifteen out of 26 (58 per cent) benefited from thymectomy. Duration of the symptom from the onset to the operation and the presence or absence of the thymoma are not related to their outcome. Benign or malignant nature of thymoma should not be determined by histological examination alone but by combined evaluation of clinical and operative findings. Serial studies of serum immunoglobulin levels before and after thymectomy suggested that this disorder could be associated with humoral antibody (IgG). H L A typing of the patients with myasthenia gravis did not indicate the presence of any specific antigens. K E Y W O R D S : myasthenia gravis, thymoma, thymectomy, immunoglobulin, H L A typing. INTRODUCTION
T h e cause of myasthenia gravis remains obscure and definte therapeutic methods have not been established. Myasthenia gravis are often accompanied by abnormal thymus and thyroid gland and their etiological role has been suggested.l,a, 21 Since the first thymectomy for myastbenia gravis by Blalock 4 in 1939, this operation has been adovocated with some favorable result. However, efficacy of thymectomy in myasthenia gravis so far reported varies considerably. In the present communication, 26 consecutive cases undergone thymectomy have been presented. Immunological and genetic aspects of the disease have been discussed based on the study of immunoglobulin level before and after thymectomy and HLA typing.
MATERIAL AND METHOD
Patients Twenty six patients with confirmed myasthenia gravis seen at Kyushu University Hospital, Fukuoka, Japan, underwent thymectomy from 1971 to 1975. O f the 26 patients, 10 were males and 16 were females. Their ages ranged from 14 to 67 years. In 15 patients, the symptoms started before 20 years of age and after 50 in one case. The onset From the Department of Surgery I, Kyushu University Faculty of Medicine, and * the Department of Neurology, Fukuoka University Hospital, Fukuoka, Japan. JAPANESEJOURNAL OF SURGERY,VOL. 9, No. 1, pp. 24-31, 1979
Volume 9 Number 1
Thymectomy for Myasthenia Gravis
25
of the first symptom in patients with myasthenia gravis was most common between the ages of 20 and 30 years. Eight patients had mild generalized myasthenia (Osserman II-A) 17, 14 moderately severe generalized disease (II-B), one acute fulminating form (III) and three late severe stage of the disease (IV). There were no cases of atrophic form (V). U p o n exploration, thymomas were found in 11 patients, six males and five females. The tumors were invasive to thorax wall, pericardium, lung and phrenic nerve in six cases. T h e y were followed up from seven months to five years and three months after thymectomy. Clinical evaluation of the result of thymectomy was based on the following criteria: A Remission: Complete remission of the symptom without further necessitate of anticholinesterase drugs for three months or more. B I m p r o v e m e n t : Symptoms improved, reduced dose of drugs and fluctuation of the symptoms by day difference, infection and stress. C Slight improvement: Reduced dose of drugs, slight improvement of tile symptoms, reduced fluctuation of the symptoms by various factors. D No change. E Deterioration. Operative Procedure T h y m e c t o m y was performed as an elective procedure. Patients were selected for operation if satisfactory medical control of the symptoms could not be achieved. The demonstration of the thymoma was an absolute indication for operative intervention. Those with mild symptoms that were readily controlled by anticholinesterase drug or those with long-standing end stage myasthenia did not receive surgical treatment. U p p e r median sternotomy was used to prove optimal exposure of anterior mediastinum which lessen the operative scar feature especially important in young females. Either posterolateral thoracotomy or median sternotomy was used for thymoma or for the removal of fat pad from the anterior mediastinum. Transcervical technic was not used because of inherent failure of complete removal. Pericardial or pleural involvement was removed en-bloc. Postoperatively all patients were transferred to intensive care unit for at least two to three days for control of respiratory function. Use of nasotracheal intubation with respirator, obviated tracheotomy. Anticholinesterase drug was started for three to four days postoperatively after the removal of nasotracheal tube after Tensilon test to determine proper dose. Determination of Immunoglobulin Levels T e n sera collected preoperatively and days 1, 3, 7, 14 and 21 after thymectomy were subjected to immunoglobulin level (IgG, I g M and IgA) determination by Mancini's method 18 using immunodifusion plates. HLA Typing H L A typing by the microcytotoxicity method15, ~3 was done on five ml ofsera obtained from 45 patients with myasthenia gravis either before or after thymectomy. RESULTS
Clinical Results O f the 26 patients including t h y m o m a cases, 15 patients (58 per cent) benefited from the operation (B: eight cases , C: seven cases). However, as indicated in Table 1, the symptoms fluctuated after the operation. The general condition improved after two to three years postoperatively despite the poor results in the early postoperative period
26
Jpn. J. Surg.
Konomi et aL T a b l e 1.
March 1979
Postoperative course of 26 patients with m y a s t h e n i a gravis POSTOPERATIVE 10
20
30
MONTHS 40
50
EFFECT 60
B-~D B D ---~B D ~-~ B --. E - , B B C-~
D--~ C C D~C D D--~ B C~B C~B D C--~D B
C -~ D --~
E--,C D-*C D-+C D~? E-~ E D D-+E D D
T H Y : T h y m o m a , T : Patient with t h y m o m a . Dotted-area indicates unfavorable postoperative period.
C
?
Volume 9 Number 1
Thymectomy for Myasthenia Gravis
27
indicating that postoperative results m a y be expected to improve with longer follow up. However, there was no case of complete remission (A). The condition deteriorated postoperatively in two patients (E) and unchanged (D) in seven patients. Even with more severe forms of the disease (Osserman I I I and IV), occasional good response was experienced. O f the eight patients who received thymectomy within one year after the onset of the symptom, four (50 per cent) benefited from the operation (B and C groups). O f the 12 patients with one to five years interval after the onset, seven (58.3 per cent) benefited. Out of six patients who received operation with over five years interval, four (66.6 per cent) improved. O f the 10 patients with thymoma, seven (70 per cent) benefited from the operation. On the other hand, out of 14 without thymoma, eight (57 per cent) improved (Table 2). Five out of I1 thymoma were well encapsulated. Remaining six were invasive to the contiguous thorax wall, pericardium, pleura and phrenic nerve being excised widely along with those pericardium or pleura. Histological findings of these tumors were either lymphoid cell type, epithelial cell type or mixed type of those. In a 50 years old female, the tumor invaded pericardium to myocardium. Fluid in the pericardium cavity was turbid (Fig. 1). In this case, despite these findings, histological survey did not show definite evidence of malignancy (Fig. 2). Concomitant tracheotomy
Table 2. Effect of operative intervention with and without thymoma Thymoma (+)
Thymoma (--)
Effective (A--C)
7/10
(70%)
8/14
(57%)
Ineffective (D--E)
3/10
(30%)
6/14
(43%)
One case unknown with the effect of operative intervention was omitted from each group with and without thymoma.
Fig. 1. Thymoma in 50 years old female--the tumor invaded pericardium to myocardium.
Konomi et al.
28
Fig. 2.
Jpn. J. Surg. March 1979
Photomicrograph of the thymoma removed from the case presented in Fig. 6 (H.E. x 480).
O
0
o
,, A C
2500
oDE
2000
A
.
1000
PREOR
1
,
3
,
7
J7
1~4
S'
--
2'1
POSTOPERATIVE DAYS Fig.
3.
Changes of serum IgG levels before and after thymectomy.
was not performed. Control of respiratory system inserting nasotracheal tube in the intensive care unit did not necessitate tracheotomy.
Serum Immunoglobulin Level before and after Thymectomy In the group benefited from the operation (B and C groups), preoperative I g G level was in normal range with transient dip immediately after the operation and then returned to the initial high level. In contrast, patients with unfavorable course (D and E groups)
Volume 9 Number 1
Thymectomy for Myasthenia Gravis T a b l e 3.
H L A typing in 45 patients with myasthenia gravis Myasthenia gravis (N=45)
Locus A
Aw
Locus B
Bw
29
Normal ( N = 397)
+
--
P.F.
+
--
P.F.
1 2 3 9 10 11 19
0 17 0 32 7 6 4
45 28 45 13 38 39 41
0 37.8 0 71.7 15.6 13.3 8.9
1 167 2 240 73 81 29
396 230 395 157 324 316 368
0.2 42.1 0.5 60.5 18.4 20.4 7.3
X 2
0 0.31 0 1.94 0.22 1.28 0.15
5 7 8 12 13 14 15 17 18 27 16 21 22 35 40
16 3 0 9 1 0 2 0 0 0 2 0 7 7 15
29 42 45 36 44 45 43 45 45 45 43 45 38 38 30
35.6 6.7 0 20.0 2.2 0 4.4 0 0 0 4.4 0 15.6 15.6 33.3
153 65 0 65 6 0 32 4 1 3 23 0 86 50 128
244 332 397 332 391 397 365 393 396 394 374 397 311 347 269
38.5 16.4 0 16.4 1.5 0 8.1 1.0 0 0.8 5.8 0 21.7 12.6 32.2
0.15 2.93 0 0.38 0.13 0 0.74 0.46 0.11 0.34 0.14 0 0.91 0.32 0.02
P.F. : per cent frequency showed high I g G level before a n d after the operation. I n some cases transient d i p i m m e diate p o s t o p e r a t i v e l y was not noticed. T h e s e changes were not d e p e n d i n g on the presence o f t h y m o m a (Fig. 3). O n the o t h e r h a n d , s e r u m I g A a n d I g M level before a n d after the o p e r a t i o n did n o t show definite changes as to indicate the prognosis.
HLA Typing F o r t y five cases o f m y a s t h e n i a gravis were subjected to typing. X 2 v a l u e from b o t h H L A - 1 a n d 8 was zero in contrast to h i g h v a l u e observed in m y a s t h e n i a gravis a m o n g Caucasians. T h e highest X 2 value was 2.93 for B-7 a n d not significant ( T a b l e 3).
DISCUSSlON T h y m e c t o m y has long been a d o v o c a t e d for the t r e a t m e n t o f m y a s t h e n i a gravis. T h e relationship b e t w e e n clinical s y m p t o m s a n d the presence o f t h y m o m a has been d e b a t e d . 16 But definite e v a l u a t i o n o f the efficacy of t h y m e c t o m y in the m a n a g e m e n t o f m y a s t h e n i a gravis has not b e e n done. I n the present studies, 58 p e r cent o f the cases i m p r o v e d from the o p e r a t i o n showing c o n s i d e r a b l e efficacy o f t h y m e c t o m y in patients w i t h m y a s t h e n i a gravis. H o w e v e r , the s y m p t o m s f l u c t u a t e d p o s t o p e r a t i v e l y w h e n followed for l o n g e r p e r i o d of time suggesting t h a t the e v a l u a t i o n should be done after long t e r m observation. T h y m e c t o m y is said to p r o d u c e the greatest benefit in m y a s t h e n i a gravis o f short d u r a t i o n . 20 O u r present result does n o t c o r r e s p o n d with this. Those u n d e r g o n e t h y m e c t o m y m o r e t h a n five years after the onset benefited from the o p e r a t i o n in two t h i r d of the cases. O n the o t h e r h a n d , 50 p e r cent o f the patients with t h y m e c t o m y p e r f o r m e d w i t h i n one y e a r after the onset h a d beneficial result. T h e incidence o f m y a s -
30
Konomi et al.
Jpn. jr. Surg. March 1979
thenia gravis in patients with thymoma has been reported to be from 10 to 50 per cent, n whereas the reported incidence of thymoma in patients with myasthenia gravis ranged from eight to 15 per cent.ll,ls, 2a I n the present series the presence or absence o f t h y m o m a did not make any difference in their clinical postoperative course. Seventy per cent of the patients with thymoma improved after thymectomy, while 57 per cent without thymoma benefited from the operation. These findings suggest that indication of thymectomy for myasthenia gravis could be expanded more to include those without apFarent evidence of the presence of thymoma. The histological classification of thymoma is still controversial and the many conflicting reports served only to confuse the issue. Minkowitz 14 suggested that thymoma which shows malignant epithelial proliferation should be described as thymocarcinoma and not as thymoma. In recent years, hitherto exceedingly complex classifications have been largely replaced by more simple one. Bernatz ~ and Shields 22 classified thymic tumors simply as invasive or non-invasive. Thymic tumor presents further difficulties in determining its nature. Despite a microscopic appearance of an orderly cellular pattern suggesting benign nature of the tumor, their behavior can apparently be malignant with the direct local extension into lung, pericardium, heart, the great vessels or with lymph node involvement either locally in the mediastinum or more distantly into supraclavicular lymph nodes. 5 Consequently the nature of thymoma should be determined not only by the histological examination, but also by clinical and or operative findings. Myasthenia gravis is said to be of autoimmune etiologyg,~4 and related to the cellmediated immunity.2,12 The present study on the changes of serum immunoglobulin levels before and after thymectomy suggests that postoperative improvement is associated with normal or lower IgG level. On the other hand, elevated I g G level is associated with no change of symptoms or even deterioration. The humoral immunity could be associated with the etiology of the myasthenia gravis. HLA-1 and 8 are associated closely with myasthenia gravisfi -s especially in HLA-8 with high X 2 value of 103.19 No close association was found between H L A type and myasthenia gravis in our ")resent series. X 2 value for both HLA-1 and 8 are zero and quite different from those reported in Caucasoid population (Table 3).
ACKNOWLEDGEMENT The authors wishes to express their most sincere thanks to Professors Masaya Nishimura and Fumio Nakayama, Department of Surgery I, Kyushu University, Fukuoka, Japan, for their encouragement and advice during the investigation. (Received for publication on February 10, 1978) References 1. Alpert, L.I., Papatestas, A., Kark, A., Osserman, R.S. and Osserman, K. : A histologic reappraisal of the thymus in myasthenia gravis. A correlative study of thymic pathology and response to thymectom$, Arch. Path. 91: 55-61, 1971. 2. Armstrong, R.M., Nowak, R.M. and Falk, R.E. : Thymic lymphocytefunction in myasthenia gravis, Neurology23 : 1078-1083, 1973.
3. Bernatz, P.E., Harrison, E.G. and Clagett, O. T.: Thymoma: A clinicopathologic study, J. Thorac. & Cardiovas. Surg. 42: 424-444, 1961. 4. Blalock, A., Mason, M.F., Morgan, H.J. and Riven, S.S.: Myasthenia gravls and tumors of the thymic region, Ann. Surg. 110: 544561, 1939. 5. Castleman, B. : Tumor of the thymus gland, in
Volume 9 Number 1
6.
7. 8.
9.
10. 11.
12.
13.
14.
Thymectomy for Myasthenia Grads
Armed Forces Institute of Pathology, Atlas of tumor pathology, Sect. 5, Fasc. 19, Washington, D.C.: National Research Council, 1955. Feltkamp, T.E.W., Van den Berg-Loonen, P.M., Nijenhuis, L.E., Engelfriet, C.P., Van Rossum, A.L., Van Loghem, J.J. and Oosterhuis, H.J.G.H.: Myasthenla gravis, Autoantlbodies, and HLA antigens, Bri. Med. dr. 1 : 131-133, 1974. Fritze, D., Herrmann, C., Smith, G.S. and Walford, R.L. : HLA types in myasthenia gravls, Lancet 2 : 211, 1973. Frltze, D., Herrmann, C., Naeim, F., Smith, G.S. and Walford, R.L. : HLA antigens in myasthenia gravis, Lancet 1 : 240-242, 1974. Fudenberg, H.H., Good, R.A., Goodman, H.C., Hitzlg, W., Kunkel, H.G., Roitt, I.M., Rosen, F.S., Rowe, D.S., Sellgmann, M. and Soothill, J.R. : Primary immunodeficlencies. Reports of World Health Organization Committee, Pediatrics 47: 927-946, 1971. Iverson, L. : Thymoma. A review and reclassification, Amer. J. Pathol. 32: 695-719, 1956. Keynes, G. : Investigaton into thymle disease and tumor formation, Bri. J. Surg. 42 : 449462, 1955. Kott, E. and Rule, A.H.: Myasthenia gravls: Cellular response to basic myelin protein compared with cellular and humoral immunity to muscle antigens, Neurology 23: 745748, 1973. Mancinl, J., Carbonara, A.O. and Heremans, J.D.: Immunoehemical quantitation ofantlgens by single radical immunodiffusion, Immunoehemistry 2 : 235-254, 1965. Minkowitz, S., Solomon, L. and Nigastri, A.D. : Cytologically malignant thymoma with distant metastasis, Cancer 21 : 426-433, 1968.
31
15. Miyyal, K.K., Mickey, M.R., Singal, D.P. and Terasaki, P.I.: Serotyping for homotransplantation. X V l l l . Refinemer~t of microdroplet lymphocyte cytotoxieity test, Transplantation 6: 913-927, 1968. 16. Mulder, D.G., Herrmann, C. and Buckberg, G.D. : Effect of thymectomy in patients with myasthenia gravis. A sixteen year experience, Amer. J. Surg. 128: 202-206, 1974. 17. Osserman, K.E.: Myasthenia gravis, Grune and Strutton, New York, 1958. 18. Papatestas, A.E., Alpert, L.I., Osserman, K.E., Osserman, R.S. and Kark, A.E.: Studies in myasthenia gravis: Effect of thymectomy, Results on 185 patients with nonthymomatous and thymomatous myasthenia gravis, 1941-1969, Amer. J. Med. 50: 465-474, 1971. 19. Ryder, L.P., Nielsen, L.S. and Svejgaard, A.: Associations between HLA histocompatibility antigens and non-mallgnant disease, Humangenetik 25: 251-264, 1974. 20. Sabiston, D.C. and Oldham, H.N.: The mediastlnum, in Gibbon's surgery of the chest, W.B. Saunders, Philadelphia, 1976. 21. Seybold, W.D., McDonald, J.R., Clagett, O.T. and Good, C.A. : Tumor of thymus, J. Thorac. Surg. 20: 195-215, 1950. 22. Shield, T.W., Fox, R.T. and Lees, W.M.: Thymlc tumors: Classification and treatment, Arch. Surg. 92: 617-622, 1966. 23. Terasaki, P.I. and McClleland, J.D.: Microdroplet assay for human serum cytotoxins, Nature 204: 998-1000, 1964. 24. White, R.G. and Marshall, A.H.E.: The autoimmune response in myasthenla gravis, Lancet 2" 120-123, 1962. 25. Wilkins, E.W., Edmunds, L.H. and Castleman, B.: Case of thymoma at the Massachusetts General Hospital, J. Thorac. & Cardiovas. Surg. 52: 322-330, 1966.
T h e cause of myasthenia gravis remains obscure and definte therapeutic methods have not been established. Myasthenia gravis are often accompanied by abnormal thymus and thyroid gland and their etiological role has been suggested.l,a, 21 Since the first thymectomy for myastbenia gravis by Blalock 4 in 1939, this operation has been adovocated with some favorable result. However, efficacy of thymectomy in myasthenia gravis so far reported varies considerably. In the present communication, 26 consecutive cases undergone thymectomy have been presented. Immunological and genetic aspects of the disease have been discussed based on the study of immunoglobulin level before and after thymectomy and HLA typing.
MATERIAL AND METHOD
Patients Twenty six patients with confirmed myasthenia gravis seen at Kyushu University Hospital, Fukuoka, Japan, underwent thymectomy from 1971 to 1975. O f the 26 patients, 10 were males and 16 were females. Their ages ranged from 14 to 67 years. In 15 patients, the symptoms started before 20 years of age and after 50 in one case. The onset From the Department of Surgery I, Kyushu University Faculty of Medicine, and * the Department of Neurology, Fukuoka University Hospital, Fukuoka, Japan. JAPANESEJOURNAL OF SURGERY,VOL. 9, No. 1, pp. 24-31, 1979
Volume 9 Number 1
Thymectomy for Myasthenia Gravis
25
of the first symptom in patients with myasthenia gravis was most common between the ages of 20 and 30 years. Eight patients had mild generalized myasthenia (Osserman II-A) 17, 14 moderately severe generalized disease (II-B), one acute fulminating form (III) and three late severe stage of the disease (IV). There were no cases of atrophic form (V). U p o n exploration, thymomas were found in 11 patients, six males and five females. The tumors were invasive to thorax wall, pericardium, lung and phrenic nerve in six cases. T h e y were followed up from seven months to five years and three months after thymectomy. Clinical evaluation of the result of thymectomy was based on the following criteria: A Remission: Complete remission of the symptom without further necessitate of anticholinesterase drugs for three months or more. B I m p r o v e m e n t : Symptoms improved, reduced dose of drugs and fluctuation of the symptoms by day difference, infection and stress. C Slight improvement: Reduced dose of drugs, slight improvement of tile symptoms, reduced fluctuation of the symptoms by various factors. D No change. E Deterioration. Operative Procedure T h y m e c t o m y was performed as an elective procedure. Patients were selected for operation if satisfactory medical control of the symptoms could not be achieved. The demonstration of the thymoma was an absolute indication for operative intervention. Those with mild symptoms that were readily controlled by anticholinesterase drug or those with long-standing end stage myasthenia did not receive surgical treatment. U p p e r median sternotomy was used to prove optimal exposure of anterior mediastinum which lessen the operative scar feature especially important in young females. Either posterolateral thoracotomy or median sternotomy was used for thymoma or for the removal of fat pad from the anterior mediastinum. Transcervical technic was not used because of inherent failure of complete removal. Pericardial or pleural involvement was removed en-bloc. Postoperatively all patients were transferred to intensive care unit for at least two to three days for control of respiratory function. Use of nasotracheal intubation with respirator, obviated tracheotomy. Anticholinesterase drug was started for three to four days postoperatively after the removal of nasotracheal tube after Tensilon test to determine proper dose. Determination of Immunoglobulin Levels T e n sera collected preoperatively and days 1, 3, 7, 14 and 21 after thymectomy were subjected to immunoglobulin level (IgG, I g M and IgA) determination by Mancini's method 18 using immunodifusion plates. HLA Typing H L A typing by the microcytotoxicity method15, ~3 was done on five ml ofsera obtained from 45 patients with myasthenia gravis either before or after thymectomy. RESULTS
Clinical Results O f the 26 patients including t h y m o m a cases, 15 patients (58 per cent) benefited from the operation (B: eight cases , C: seven cases). However, as indicated in Table 1, the symptoms fluctuated after the operation. The general condition improved after two to three years postoperatively despite the poor results in the early postoperative period
26
Jpn. J. Surg.
Konomi et aL T a b l e 1.
March 1979
Postoperative course of 26 patients with m y a s t h e n i a gravis POSTOPERATIVE 10
20
30
MONTHS 40
50
EFFECT 60
B-~D B D ---~B D ~-~ B --. E - , B B C-~
D--~ C C D~C D D--~ B C~B C~B D C--~D B
C -~ D --~
E--,C D-*C D-+C D~? E-~ E D D-+E D D
T H Y : T h y m o m a , T : Patient with t h y m o m a . Dotted-area indicates unfavorable postoperative period.
C
?
Volume 9 Number 1
Thymectomy for Myasthenia Gravis
27
indicating that postoperative results m a y be expected to improve with longer follow up. However, there was no case of complete remission (A). The condition deteriorated postoperatively in two patients (E) and unchanged (D) in seven patients. Even with more severe forms of the disease (Osserman I I I and IV), occasional good response was experienced. O f the eight patients who received thymectomy within one year after the onset of the symptom, four (50 per cent) benefited from the operation (B and C groups). O f the 12 patients with one to five years interval after the onset, seven (58.3 per cent) benefited. Out of six patients who received operation with over five years interval, four (66.6 per cent) improved. O f the 10 patients with thymoma, seven (70 per cent) benefited from the operation. On the other hand, out of 14 without thymoma, eight (57 per cent) improved (Table 2). Five out of I1 thymoma were well encapsulated. Remaining six were invasive to the contiguous thorax wall, pericardium, pleura and phrenic nerve being excised widely along with those pericardium or pleura. Histological findings of these tumors were either lymphoid cell type, epithelial cell type or mixed type of those. In a 50 years old female, the tumor invaded pericardium to myocardium. Fluid in the pericardium cavity was turbid (Fig. 1). In this case, despite these findings, histological survey did not show definite evidence of malignancy (Fig. 2). Concomitant tracheotomy
Table 2. Effect of operative intervention with and without thymoma Thymoma (+)
Thymoma (--)
Effective (A--C)
7/10
(70%)
8/14
(57%)
Ineffective (D--E)
3/10
(30%)
6/14
(43%)
One case unknown with the effect of operative intervention was omitted from each group with and without thymoma.
Fig. 1. Thymoma in 50 years old female--the tumor invaded pericardium to myocardium.
Konomi et al.
28
Fig. 2.
Jpn. J. Surg. March 1979
Photomicrograph of the thymoma removed from the case presented in Fig. 6 (H.E. x 480).
O
0
o
,, A C
2500
oDE
2000
A
.
1000
PREOR
1
,
3
,
7
J7
1~4
S'
--
2'1
POSTOPERATIVE DAYS Fig.
3.
Changes of serum IgG levels before and after thymectomy.
was not performed. Control of respiratory system inserting nasotracheal tube in the intensive care unit did not necessitate tracheotomy.
Serum Immunoglobulin Level before and after Thymectomy In the group benefited from the operation (B and C groups), preoperative I g G level was in normal range with transient dip immediately after the operation and then returned to the initial high level. In contrast, patients with unfavorable course (D and E groups)
Volume 9 Number 1
Thymectomy for Myasthenia Gravis T a b l e 3.
H L A typing in 45 patients with myasthenia gravis Myasthenia gravis (N=45)
Locus A
Aw
Locus B
Bw
29
Normal ( N = 397)
+
--
P.F.
+
--
P.F.
1 2 3 9 10 11 19
0 17 0 32 7 6 4
45 28 45 13 38 39 41
0 37.8 0 71.7 15.6 13.3 8.9
1 167 2 240 73 81 29
396 230 395 157 324 316 368
0.2 42.1 0.5 60.5 18.4 20.4 7.3
X 2
0 0.31 0 1.94 0.22 1.28 0.15
5 7 8 12 13 14 15 17 18 27 16 21 22 35 40
16 3 0 9 1 0 2 0 0 0 2 0 7 7 15
29 42 45 36 44 45 43 45 45 45 43 45 38 38 30
35.6 6.7 0 20.0 2.2 0 4.4 0 0 0 4.4 0 15.6 15.6 33.3
153 65 0 65 6 0 32 4 1 3 23 0 86 50 128
244 332 397 332 391 397 365 393 396 394 374 397 311 347 269
38.5 16.4 0 16.4 1.5 0 8.1 1.0 0 0.8 5.8 0 21.7 12.6 32.2
0.15 2.93 0 0.38 0.13 0 0.74 0.46 0.11 0.34 0.14 0 0.91 0.32 0.02
P.F. : per cent frequency showed high I g G level before a n d after the operation. I n some cases transient d i p i m m e diate p o s t o p e r a t i v e l y was not noticed. T h e s e changes were not d e p e n d i n g on the presence o f t h y m o m a (Fig. 3). O n the o t h e r h a n d , s e r u m I g A a n d I g M level before a n d after the o p e r a t i o n did n o t show definite changes as to indicate the prognosis.
HLA Typing F o r t y five cases o f m y a s t h e n i a gravis were subjected to typing. X 2 v a l u e from b o t h H L A - 1 a n d 8 was zero in contrast to h i g h v a l u e observed in m y a s t h e n i a gravis a m o n g Caucasians. T h e highest X 2 value was 2.93 for B-7 a n d not significant ( T a b l e 3).
DISCUSSlON T h y m e c t o m y has long been a d o v o c a t e d for the t r e a t m e n t o f m y a s t h e n i a gravis. T h e relationship b e t w e e n clinical s y m p t o m s a n d the presence o f t h y m o m a has been d e b a t e d . 16 But definite e v a l u a t i o n o f the efficacy of t h y m e c t o m y in the m a n a g e m e n t o f m y a s t h e n i a gravis has not b e e n done. I n the present studies, 58 p e r cent o f the cases i m p r o v e d from the o p e r a t i o n showing c o n s i d e r a b l e efficacy o f t h y m e c t o m y in patients w i t h m y a s t h e n i a gravis. H o w e v e r , the s y m p t o m s f l u c t u a t e d p o s t o p e r a t i v e l y w h e n followed for l o n g e r p e r i o d of time suggesting t h a t the e v a l u a t i o n should be done after long t e r m observation. T h y m e c t o m y is said to p r o d u c e the greatest benefit in m y a s t h e n i a gravis o f short d u r a t i o n . 20 O u r present result does n o t c o r r e s p o n d with this. Those u n d e r g o n e t h y m e c t o m y m o r e t h a n five years after the onset benefited from the o p e r a t i o n in two t h i r d of the cases. O n the o t h e r h a n d , 50 p e r cent o f the patients with t h y m e c t o m y p e r f o r m e d w i t h i n one y e a r after the onset h a d beneficial result. T h e incidence o f m y a s -
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Konomi et al.
Jpn. jr. Surg. March 1979
thenia gravis in patients with thymoma has been reported to be from 10 to 50 per cent, n whereas the reported incidence of thymoma in patients with myasthenia gravis ranged from eight to 15 per cent.ll,ls, 2a I n the present series the presence or absence o f t h y m o m a did not make any difference in their clinical postoperative course. Seventy per cent of the patients with thymoma improved after thymectomy, while 57 per cent without thymoma benefited from the operation. These findings suggest that indication of thymectomy for myasthenia gravis could be expanded more to include those without apFarent evidence of the presence of thymoma. The histological classification of thymoma is still controversial and the many conflicting reports served only to confuse the issue. Minkowitz 14 suggested that thymoma which shows malignant epithelial proliferation should be described as thymocarcinoma and not as thymoma. In recent years, hitherto exceedingly complex classifications have been largely replaced by more simple one. Bernatz ~ and Shields 22 classified thymic tumors simply as invasive or non-invasive. Thymic tumor presents further difficulties in determining its nature. Despite a microscopic appearance of an orderly cellular pattern suggesting benign nature of the tumor, their behavior can apparently be malignant with the direct local extension into lung, pericardium, heart, the great vessels or with lymph node involvement either locally in the mediastinum or more distantly into supraclavicular lymph nodes. 5 Consequently the nature of thymoma should be determined not only by the histological examination, but also by clinical and or operative findings. Myasthenia gravis is said to be of autoimmune etiologyg,~4 and related to the cellmediated immunity.2,12 The present study on the changes of serum immunoglobulin levels before and after thymectomy suggests that postoperative improvement is associated with normal or lower IgG level. On the other hand, elevated I g G level is associated with no change of symptoms or even deterioration. The humoral immunity could be associated with the etiology of the myasthenia gravis. HLA-1 and 8 are associated closely with myasthenia gravisfi -s especially in HLA-8 with high X 2 value of 103.19 No close association was found between H L A type and myasthenia gravis in our ")resent series. X 2 value for both HLA-1 and 8 are zero and quite different from those reported in Caucasoid population (Table 3).
ACKNOWLEDGEMENT The authors wishes to express their most sincere thanks to Professors Masaya Nishimura and Fumio Nakayama, Department of Surgery I, Kyushu University, Fukuoka, Japan, for their encouragement and advice during the investigation. (Received for publication on February 10, 1978) References 1. Alpert, L.I., Papatestas, A., Kark, A., Osserman, R.S. and Osserman, K. : A histologic reappraisal of the thymus in myasthenia gravis. A correlative study of thymic pathology and response to thymectom$, Arch. Path. 91: 55-61, 1971. 2. Armstrong, R.M., Nowak, R.M. and Falk, R.E. : Thymic lymphocytefunction in myasthenia gravis, Neurology23 : 1078-1083, 1973.
3. Bernatz, P.E., Harrison, E.G. and Clagett, O. T.: Thymoma: A clinicopathologic study, J. Thorac. & Cardiovas. Surg. 42: 424-444, 1961. 4. Blalock, A., Mason, M.F., Morgan, H.J. and Riven, S.S.: Myasthenia gravls and tumors of the thymic region, Ann. Surg. 110: 544561, 1939. 5. Castleman, B. : Tumor of the thymus gland, in
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7. 8.
9.
10. 11.
12.
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14.
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Armed Forces Institute of Pathology, Atlas of tumor pathology, Sect. 5, Fasc. 19, Washington, D.C.: National Research Council, 1955. Feltkamp, T.E.W., Van den Berg-Loonen, P.M., Nijenhuis, L.E., Engelfriet, C.P., Van Rossum, A.L., Van Loghem, J.J. and Oosterhuis, H.J.G.H.: Myasthenla gravis, Autoantlbodies, and HLA antigens, Bri. Med. dr. 1 : 131-133, 1974. Fritze, D., Herrmann, C., Smith, G.S. and Walford, R.L. : HLA types in myasthenia gravls, Lancet 2 : 211, 1973. Frltze, D., Herrmann, C., Naeim, F., Smith, G.S. and Walford, R.L. : HLA antigens in myasthenia gravis, Lancet 1 : 240-242, 1974. Fudenberg, H.H., Good, R.A., Goodman, H.C., Hitzlg, W., Kunkel, H.G., Roitt, I.M., Rosen, F.S., Rowe, D.S., Sellgmann, M. and Soothill, J.R. : Primary immunodeficlencies. Reports of World Health Organization Committee, Pediatrics 47: 927-946, 1971. Iverson, L. : Thymoma. A review and reclassification, Amer. J. Pathol. 32: 695-719, 1956. Keynes, G. : Investigaton into thymle disease and tumor formation, Bri. J. Surg. 42 : 449462, 1955. Kott, E. and Rule, A.H.: Myasthenia gravls: Cellular response to basic myelin protein compared with cellular and humoral immunity to muscle antigens, Neurology 23: 745748, 1973. Mancinl, J., Carbonara, A.O. and Heremans, J.D.: Immunoehemical quantitation ofantlgens by single radical immunodiffusion, Immunoehemistry 2 : 235-254, 1965. Minkowitz, S., Solomon, L. and Nigastri, A.D. : Cytologically malignant thymoma with distant metastasis, Cancer 21 : 426-433, 1968.
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15. Miyyal, K.K., Mickey, M.R., Singal, D.P. and Terasaki, P.I.: Serotyping for homotransplantation. X V l l l . Refinemer~t of microdroplet lymphocyte cytotoxieity test, Transplantation 6: 913-927, 1968. 16. Mulder, D.G., Herrmann, C. and Buckberg, G.D. : Effect of thymectomy in patients with myasthenia gravis. A sixteen year experience, Amer. J. Surg. 128: 202-206, 1974. 17. Osserman, K.E.: Myasthenia gravis, Grune and Strutton, New York, 1958. 18. Papatestas, A.E., Alpert, L.I., Osserman, K.E., Osserman, R.S. and Kark, A.E.: Studies in myasthenia gravis: Effect of thymectomy, Results on 185 patients with nonthymomatous and thymomatous myasthenia gravis, 1941-1969, Amer. J. Med. 50: 465-474, 1971. 19. Ryder, L.P., Nielsen, L.S. and Svejgaard, A.: Associations between HLA histocompatibility antigens and non-mallgnant disease, Humangenetik 25: 251-264, 1974. 20. Sabiston, D.C. and Oldham, H.N.: The mediastlnum, in Gibbon's surgery of the chest, W.B. Saunders, Philadelphia, 1976. 21. Seybold, W.D., McDonald, J.R., Clagett, O.T. and Good, C.A. : Tumor of thymus, J. Thorac. Surg. 20: 195-215, 1950. 22. Shield, T.W., Fox, R.T. and Lees, W.M.: Thymlc tumors: Classification and treatment, Arch. Surg. 92: 617-622, 1966. 23. Terasaki, P.I. and McClleland, J.D.: Microdroplet assay for human serum cytotoxins, Nature 204: 998-1000, 1964. 24. White, R.G. and Marshall, A.H.E.: The autoimmune response in myasthenla gravis, Lancet 2" 120-123, 1962. 25. Wilkins, E.W., Edmunds, L.H. and Castleman, B.: Case of thymoma at the Massachusetts General Hospital, J. Thorac. & Cardiovas. Surg. 52: 322-330, 1966.
