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J Thorac Cardiovasc Surg 1999;117:605-611
© 1999 Mosby, Inc.
GENERAL THORACIC SURGERY |
From First Department of Surgery, Osaka University Medical School,a Osaka; The Department of Surgery, Osaka Chuo Hospital,b Osaka; The Second Department of Surgery, Nagoya City University, Medical School,c Aichi; and the Department of Surgery, Ohtemae Hospital,d Osaka, Japan.
Received for publication April 21, 1998. Rrevisions requested June 17, 1998. Revisions received Oct 16, 1998. Accepted for publication Oct 19, 1998. Address for reprints: Shinichiro Miyoshi, MD, First Department of Surgery, E-1, Osaka University Medical School, 2-2 Yamada-Oka, Suita-City, Osaka 565-0871, Japan.
| Abstract |
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| Introduction |
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The main therapeutic strategy in the treatment of thymoma is surgical resection,
3-8 and the outcome of surgical treatment for this disease has been shown to depend on the local invasiveness of the tumor.
9-14 The clinical staging system by Masaoka, which is based on the local extension of the tumor,
15 has been shown to reflect the prognosis of thymoma, and the significance of this staging system as a prognostic factor has been confirmed by several other institutes.
7,8,16,17 According to this staging system, however, cases that have involvement of the pericardium, the lung, the great vessels, or other surrounding organs are all classified as stage III disease if pleural dissemination or distant metastases are not associated. Thus which organ is involved by the tumor is left out of consideration in this staging system. There have not been, however, any reports concerning the importance of the particular involved organ as a prognostic factor, except for several studies focusing on the reconstruction of the great veins in thymoma
18,19 and a study on thymic carcinoma.
20 The significance of each involved organ as a prognostic factor and its relationship with other prognostic factors remain to be elucidated. To clarify this issue, we analyzed the long-term results of surgical treatment for thymoma with special reference to the involved organs with other previously reported prognostic factors, based on the retrospective review of 194 consecutive patients who underwent surgical treatment at our institute.
| Patients and methods |
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The extent of the tumor was evaluated before the operation by routine chest radiographic examination, conventional chest computed tomography, and recently by magnetic resonance imaging. A total of 208 patients with thymoma were treated at Osaka University Hospital from January 1957 to June 1996. Four patients who had received their initial surgical treatment at other institutes and another 10 patients who underwent a biopsy only were excluded from this study. Accordingly, the study group consisted of 194 patients who underwent complete or subtotal resection at our institute.
There were 107 male and 87 female patients. The age of the patients ranged from 10 to 74 years, and the median age was 45 years (mean ± standard deviation: 45.5 ± 13.0 years). Myasthenia gravis was associated in 109 patients (56.2%). Other associated diseases were pure red cell aplasia (7 patients), rheumatoid arthritis (2 patients), systemic lupus erythematosus (1 patient), Graves' disease (1 patient), Hashimoto's disease (1 patient), Sjögren syndrome (1 patient), and pemphigus vulgaris (1 patient).
The thymomas were classified histologically on the basis of the predominance of epithelial cells or lymphocytes according to the proposal of Bernatz and associates,
23 and 53, 38, and 102 thymomas were classified into the predominantly lymphocytic type, the predominantly epithelial type, and the mixed lymphoepithelial type, respectively. The histologic subtype in 1 patient with stage III disease was not determined because of extensive necrosis induced by preoperative chemotherapy.
The involved organs in each patient were confirmed by critical review of the records of operation. The great vessels refer to the brachiocephalic veins, the superior vena cava, or the aorta in this study.
Association of myasthenia gravis, completeness of resection, and the involved organs according to the Masaoka staging system are presented in Table I. In the patients with stage IV disease, resection was judged as subtotal even when all the lesions appeared to be removed.
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The outcome of patients was confirmed by the physicians' records and direct contact with patients by telephone. Postoperative follow-up study was performed by annual chest radiographic examination; when tumor recurrence was suspected, chest computed tomography was added. In recent cases, magnetic resonance imaging was also used for further evaluation. Seven patients in the study group required a second surgical treatment for recurrent tumors afterward. The follow-up period ranged from 2 months (death from myasthenia gravis) to 38 years, and the median follow-up period was 10.3 years (mean ± SD; 11.3 ± 7.8 years). Sixty-six patients died during the follow-up period. Although 32 patients died of a tumor, 34 patients died of accidents or other diseases including crisis of myasthenia gravis (12 patients). One hundred patients, including 4 with tumor recurrence, were alive in January 1998. Nineteen patients were alive at some point between 1991 and 1997. The remaining 9 patients were lost to follow-up before 1991 at 23, 23, 15, 13, 10, 8, 7, and 7 years, and 3 months after operation, respectively.
Statistical analysis
To focus on the oncologic behavior of thymoma, the patients who died of other diseases or accidents were dealt with as drop-out cases at the time of the event. In this study therefore survival refers to freedom from tumor death. The actuarial survivals were calculated with the method of Kaplan and Meier. The statistical difference of survival was examined with the log rank test. The relative importance of various prognostic factors for postoperative survival as identified by multivariable analysis was analyzed with Cox's proportional hazards model with the forward stepwise method. Association between categoric variables was examined by the
2 test or Fisher's exact test. The statistical difference of the mean value was examined by the Student t test. Statistical analyses were performed with the commercially available personal computer program SPSS (SPSS, Inc, Chicago, Ill).
| Results |
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Table V denotes 10- and 20-year survivals and the mean survival time of patients with stage III disease, according to the prognostic factors examined. By univariate analysis, there was a significant difference in the survival of patients with stage III disease according to completeness of resection and involvement of the great vessels. There was no statistical difference, however, in survival of patients with stage III disease according to involvement of the pleura, the pericardium, or the lung or association of myasthenia gravis, unlike the results obtained by univariate analyses from all patients (Table III
). The survival curves of patients with stage III disease according to presence or absence of involvement of the great vessels are shown in Fig 4.
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Table VI denotes the relation of involvement of the great vessels to other factors. Although there was no significant relation between involvement of the great vessels and of each age, sex, association of myasthenia gravis, histologic subtype, or involvement of other organs, there was a significant relation between the involvement of the great vessels and completeness of resection (P = .001).
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| Discussion |
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Another important issue in the research of thymomas is the confusion between thymoma and thymic carcinoma. Levine and Rosai
2 first classified invasive thymomas into 2 categories: category I malignant thymoma, which have no or minimal cytologic atypia, and category II malignant thymoma, which are obviously malignant cytologically. Category II malignant thymoma was later defined as thymic carcinoma by this group.
2,21,22 More recently, Müller-Hermelink and associates
25,26 proposed a new classification of thymoma based on the origin of the neoplastic epithelial cell, that is, the cortical type or the medullary type. This group later added another category and named well-differentiated thymic carcinoma.
27 Thymic tumors of this category are characterized by a predominance of epithelial cells, an epidermoid differentiation with slight to moderate cytologic atypia, the constant presence of interepithelial immature cortical thymocytes, lobular growth, and formation of epithelial palisades around perivascular spaces. On the other hand, the most recent classification of thymic epithelial tumors proposed by Shimosato and Mukai
28 takes into consideration whether the neoplastic epithelial cells still hold the thymic epithelial function to induce immature T cells from bone marrowderived T-cell precursors; the tumors that retain this function are defined as thymoma although thymic carcinomas do not hold it any more. The fact that Müller-Hermelink and associates' well-differentiated thymic carcinoma contains immature cortical thymocytes suggests that this tumor still holds the thymic epithelial function. In this sense, Shimosato and Mukai included Müller-Hermelink and associates' well-differentiated thymic carcinoma in a group of atypical thymomas. The high incidence of association with myasthenia gravis in these tumors also suggests the biologic analogy to benign thymomas. In this study, thymic carcinomas were defined according to the definition of Rosai and associates
21,22 and were excluded from the study group. On the other hand, Müller-Hermelink and associates' well-differentiated thymic carcinoma were included in the study group, following Shimosato and Mukai's definition.
Under these conditions, the univariate analyses in this study demonstrated that the Masaoka staging system and completeness of resection are significant prognostic factors, consistent with previous reports.
5-8,14-17 According to the Masaoka staging system, the prognosis of patients with stage I and II diseases was extremely good with a 30-year survival of 90% (Fig 1
). On the contrary, the survival of patients with stage III, IVa, or IVb disease deteriorates as the stage progresses. The multivariate analysis also revealed that the Masaoka staging system is a significant factor. Thus the Masaoka staging system is demonstrated to be highly valuable as a prognostic factor of thymoma when survival was evaluated in terms of freedom from tumor death. Although completeness of resection was also shown to be a significant prognostic factor by univariate analysis (Fig 2
), as reported by other investigators,
6,16 it no longer appeared as an independent factor by multivariate analysis. In place of it, involvement of the great vessels was chosen as an independent prognostic factor along with Masaoka staging system (Table IV
). Furthermore, although univariate analyses showed that survival depends on involvement of each surrounding organ such as the pleura, the pericardium, the lungs, or the great vessels (Table III
), none of these factors were considered as an independent prognostic factor by multivariate analysis. These results are presumed to come from the situation in which the Masaoka staging system or involvement of the great vessels are related to each of the remaining factors.
Association of myasthenia gravis was also reported to be one of the prognostic factors. This was derived from perioperative deaths from myasthenia gravis in the earlier days.
29 However, association of myasthenia gravis is no longer considered an adverse factor in survival.
24 Conversely, Maggi and associates
7 reported that association of myasthenia gravis contributes to early discovery of associated thymoma, thus allowing a better survival for patients with thymoma associated with myasthenia gravis compared with those not associated with it. Because our institute is one of the centers for surgical treatment of myasthenia gravis in Japan, this seems to result in the high incidence of association with myasthenia gravis in this series and is presumed to have presented the result similar to Maggi and associates. By multivariate analysis, however, association of myasthenia gravis was no longer an independent prognostic factor. This might come from the higher proportion of patients with earlier stages when associated with myasthenia gravis. Actually, in this series, the proportion of patients with stage I or II disease was 71.6% in cases associated with myasthenia gravis and 51.7% in cases not associated with it (Table I
).
Because the category of stage III according to the Masaoka staging system seems to be highly heterogeneous in terms of the involved organs and the completeness of resection, as pointed out by Rea and associates,
30 univariate and multivariate analyses were again performed according to those prognostic factors in patients with stage III disease. Although both completeness of resection and involvement of the great vessels were considered to be the prognostic factors by univariate analysis, the multivariate analysis demonstrated that involvement of the great vessels is the single independent prognostic factor. The significant relation between completeness of resection and involvement of the great vessels shown in Table VI
explains that these 2 factors are well linked. Actually, 6 of 20 patients with involvement of the great vessels underwent subtotal resection. Even in the remaining 14 patients who underwent complete resection, tumor recurrence occurred in 7 patients (50%), and the relapsed sites included distant organs in 5 patients. Thus involvement of the great vessels seems to have a greater adverse effect on survival than completeness of resection. Postoperative radiation with or without chemotherapy was the main strategy for adjuvant therapy to those patients with involvement of the great vessels in our series. Rea and associates
30 and Macchiarini and associates
31 attempted a prospective, single-arm treatment study investigating induction chemotherapy with surgical intervention. Considering the effectiveness in reduction of tumor by induction chemotherapy, this approach seems to be recommended for cases of highly invasive stage III thymoma, especially with involvement of the great vessels.
Blumberg and associates
20 reported the prognosis of thymic carcinomas and determined that involvement of the great vessels is an independent prognostic factor. This was quite similar to our result. On the other hand, the Masaoka staging system had no impact on survival in the series of Blumberg and associates. The inconsistency between the results from our series and Blumberg and associates might be derived from the difference between our patient group and Blumberg and associates patient group, which is composed mostly of thymic carcinomas as described by Rosai and associates.
21,22 The difference of clinical implication of the Masaoka staging system between these 2 studies might reflect the oncologic distinction between thymomas and thymic carcinomas.
In conclusion, the Masaoka staging system and involvement of the great vessels were independent prognostic factors in our series of thymomas. Involvement of the great vessels was also an independent prognostic factor in patients with stage III disease. Thus the category of stage III disease in the Masaoka staging system is a heterogeneous group, consisting of 2 subgroups with distinct prognosis depending on involvement of the great vessels. Involvement of the great vessels was suggested to be an essential factor in determining the therapeutic modality for stage III thymoma.
| Acknowledgments |
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| References |
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