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Kazuya Kondo, MD, PhD, Kiyoshi Yoshizawa, MD, PhD, Masaru Tsuyuguchi, MD, PhD, Suguru Kimura, MD, PhD, Masayuki Sumitomo, MD, Junji Morita, MD, PhD, Takanori Miyoshi, MD, PhD, Shoji Sakiyama, MD, PhD, Kiyoshi Mukai, MD, PhD, and Yasumasa Monden, MD, PhD
Department of Oncological and Regenerative Surgery, School of Medicine, University of Tokushima, Department of Surgery, Tokushima Municipal Hospital, Department of Surgery, Tokushima Red Cross Hospital, and Department of Surgery, Tokushima Prefectural Central Hospital, Tokushima; Department of Surgery, Takamatsu Red Cross Hospital, Takamatsu; and First Department of Pathology, Tokyo Medical University, Tokyo, Japan
Background. The histologic classication of thymoma has remained a subject of controversy for many years. In 1999, the World Health Organization Consensus Committee published a histologic typing system for tumors of the thymus. Methods. We reclassied a series of 100 thymomas resected at Tokushima University Hospital and four afliated hospitals in Japan between 1973 and 2001 according to the World Health Organization histologic classication and reported its clinicopathologic relationship and prognostic relevance. Results. There were 8 type A, 17 type AB, 27 type B1, 8 type B2, 12 type B3, and 28 type C thymomas. The frequency of invasion to neighboring organs increased according to tumor subtype in the order A (0%), AB (6%), B1 (19%), B2 (25%), B3 (42%), and C (89%). There was no recurrence in patients with type A, AB, or B2 thymoma. The recurrence rates of patients with B1, B3, or C thy-
moma were 15%, 36%, and 47%, respectively. The disease-free survival rates were 100% for types A and AB, 83% for types B1 and B2, 36% for type B3, and 28% for type C thymoma at 10 years. There were signicant differences in disease-free survival between types A and AB and types B1 and B2 (p 0.0436), and between type B3 and type C (p 0.042). By multivariate analysis, only Masaoka clinical stage (p 0.002) showed signicant independent effects on disease-free survival. The 10-year survival rates of types A and AB, types B1 and B2, type B3, and type C thymoma were 100%, 94%, 92%, and 58%, respectively. Conclusions. The current study conrmed the World Health Organization histologic classication as a good prognostic factor. (Ann Thorac Surg 2004;77:1183 8) 2004 by The Society of Thoracic Surgeons
hymoma is an uncommon neoplasm that is derived from the epithelial cells of the thymus. It is well known for several interesting features: association with myasthenia gravis (MG) or other autoimmune disease, histologic variability, and heterogeneity of malignant behavior [1, 2]. Surgery remains the mainstay of treatment, and radiation and chemotherapy also have been applied widely as adjuvant and palliative procedures [35]. The histologic classication of thymoma has remained a subject of controversy for many years [6]. In 1976, Rosai and Levine [1] proposed that thymoma is restricted to neoplasms of thymic epithelial cells and divided into benign encapsulated (noninvasive) and malignant invasive thymoma. Two years later, they divided malignant thymoma into invasive but cytologically bland thyAccepted for publication July 17, 2003. Address reprint requests to Dr Kondo, Dept of Oncological and Regenerative Surgery, School of Medicine, University of Tokushima, Kuramotocho, Tokushima 770-8503, Japan; e-mail: kondo@clin.med.tokushimau.ac.jp.
moma (malignant thymoma, category I) and cytologically malignant epithelial tumors, which correspond to thymic carcinoma (malignant thymoma, category II) [7]. In 1989, Muller-Hermelink and associates [8] divided the thymic epithelial tumors into medullary, mixed medullary and cortical, predominantly cortical, and cortical thymoma; well-differentiated thymic carcinoma (WDTC); and high-grade carcinoma. This classication was reported to be useful for predicting the outcomes of patients with these tumors [9, 10]. In 1999, the World Health Organization (WHO) Consensus Committee published a histologic typing system of tumors of the thymus [11]. Thymomas are now stratied into six entities (types A, AB, B1, B2, B3, and C) on the basis of the morphology of epithelial cells and the lymphocyte-to epithelial cell ratio (Table 1). In this retrospective study, we report on the WHO histologic classication and its clinicopathologic relationship and prognostic relevance in a series of 100 thymomas resected at Tokushima University Hospital and four afliated hospitals in Japan between 1973 and 2001.
0003-4975/04/$30.00 doi:10.1016/j.authoracsur.2003.07.042
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B2
B3
decided to use the major component of the tumor for the histologic diagnosis. These cases were 2 type B2, 2 type B3, and 1 type C thymomas. Final pathologic staging was decided by the Masaoka staging system (Table 2) [12].
Statistical Analysis
The method of Kaplan-Meier was used for the analysis of overall survival and freedom from relapse (disease-free survival), and the log-rank test for comparisons of survival. Cox regression analysis was used to investigate the effects of multiple predictors (age: 58 years, 58 years; sex; Masaoka staging system: I and II versus III and IV; WHO histologic classication: A, AB, B1, and B2 versus B3 and C; completeness of resection; and presence of MG) by SPSS for Windows (version 11.0.1; SPSS Japan Inc, Tokyo, Japan). Signicance was dened as a p value less than 0.05. Deaths as a result of MG or unrelated disease were excluded.
Results World Health Organization Histologic Subtypes and Masaoka Clinical Stage in Thymoma
All 100 thymic epithelial tumors were classied according to the WHO histologic classication. No patient underwent preoperative steroid therapy. There were 8 patients with type A (8%), 17 patients with type AB (17%), 27 patients with type B1 (27%), 8 patients with type B2 (8%), 12 patients with type B3 (12%), and 28 patients with type C (28%). The relationship between the WHO histologic subtypes and the Masaoka clinical staging system is
Macroscopically completely encapsulated and microscopically no capsular invasion 1. Macroscopic invasion into surrounding fatty tissue or mediastinal pleura, or 2. Microscopic invasion into capsule. Macroscopic invasion into neighboring organs, ie, pericardium, great vessels, or lung Pleural or pericardial dissemination Lymphogenous or hematogenous metastasis
Table 3. World Health Organization Histologic Subtypes and Masaoka Clinical Stagea
Histologic Subtype A AB B1 B2 B3 C Total
a
I 4 11 11 3 5 2 36
II 4 5 11 3 2 1 26
III 0 1 1 2 2 11 17
IVa 0 0 2 0 2 2 6
IVb 0 0 2 0 1 12 15
Total 8 17 27 8 12 28 100
Cases of Invasion to Neighboring 0 1 5 2 5 25 38 0.0% 5.9% 18.5% 25.0% 41.7% 89.3% 38.0% 0 1 9 4 6 0 20
MG myasthenia gravis.
shown in Table 3. The frequency of invasion to neighboring organs (rate of cases with stage III or IV tumor) was none in type A, 1 (5.9%) in type AB, 5 (18.5%) in type B1, 2 (25.0%) in type B2, 5 (41.7%) in type B3, and 25 (89.3%) in type C. The rate of invasion to neighboring organs in the individual subtypes increased according to tumor type in the order A, AB, B1, B2, B3, and C. Of 100 thymic epithelial tumor patients, 20 patients (20%) had MG. The frequency of MG was 1 (6%) in type AB, 9 (33%) in type B1, 4 (50%) in type B2, and 6 (50%) in type B3. There were no patients with MG in type A or C. Therefore, patients with type B1, B2, or B3 thymoma most frequently had MG (Table 3).
Table 4. Therapeutic Modalities and Recurrence in World Health Organization Histologic Subtypes
Histologic Subtype A AB B1 B2 B3 C total
a
Resection Total 8 17 27 8 11 13 84 100% 100% 100% 100% 92% 46% 84% Subtotal 0 0 0 0 0 4 4 Inope 0 0 0 0 1 11 12
It was the recurrence rate from patients with total or subtotal resection of the tumor. Inope inoperable; Rad radiotherapy.
Chemo chemotherapy;
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moma to be worse than that of patients with stage III (p 0.0574; Fig 3).
Disease-free survival of patients with thymoma was dependent on only Masaoka clinical stage (p 0.002). Sex, age, association with MG, completeness of resection (p 0.051), and WHO histologic classication (p 0.117) were not factors predictive of survival. Survival of patients with thymoma was dependent on Masaoka clinical stage (p 0.040) and completeness of resection (p 0.049). Sex, age, association with MG, and WHO histologic classication (p 0.687) were not factors predictive of survival.
Comment
A few reports have investigated the applicability and clinical signicance of the WHO histologic classication of thymoma since its publication in 1999 [13, 14]. We reclassied 100 successive cases of thymic epithelial tumors excepting 5 thymic carcinoids treated between 1973 and 2001 at Tokushima University Hospital and four afliated hospitals according to the WHO criteria, evaluated its relation with clinical stage, and examined survival and disease-free survival with reference to the WHO criteria. The present study showed that 95% of thymomas could be classied using the WHO criteria. The remaining ve
Fig 2. Survival curve of thymoma according to World Health Organization histologic classication.
Total 36 26 12 3 7 84
Subtotal 0 0 2 0 2 4
Inope 0 0 3 3 6 12
It was the recurrence rate from patients with total or subtotal resection of the tumor. Inope inoperable; Rad radiotherapy.
Chemo chemotherapy;
cases were combined thymomas, which consisted of 4 B2 and B3 type thymomas and 1 B3 and C type thymoma. There were also some cases in which it was very difcult to distinguish type B2 from type B3 thymoma. Shimosato [6] reported that distinction between cortical thymoma (type B2 thymoma) and well-differentiated thymic carcinoma (type B3 thymoma) appears difcult and that definitions of the two categories vary among authors, whereas Kirchner and associates [10] and QuintanillaMartinez and colleagues [15] described the presence of borderline areas and borderline cases of them. The proportions of WHO thymoma subtypes, ie, types A, AB, B1, B2, B3, and C thymoma in this study were 8%, 17%, 27%, 8%, 12%, and 28%, respectively. The proportions of WHO thymoma subtypes among patients from Asia were 4.0% to 10.3% in type A, 19.5% to 34% in type AB, 8.5% to 13.8% in type B1, 16.1% to 33% in type B2, 13.5% to 23% in type B3, and 8% to 18% in type C [14, 16, 17]. The WHO histologic subtype showed good correlations to the state of invasion to neighboring organs, the frequency of recurrence, and disease-free survival. There were differences in disease-free survival between types A and AB and types B1 and B2, between types B1 and B2 and type B3, and between type B3 and type C. However, in the overall survival rate, there was no signicant
difference between types A and AB and types B1 and B2, between types B1 and B2 and type B3, or between type B3 and type C, although there was a tendency for the prognosis to become worse in the order of types A and AB, types B1 and B2, type B3, and type C thymoma, because patients with recurrent thymoma frequently survived for a long time. We believe that the malignant behavior of thymoma should be evaluated by diseasefree survival rate as well as overall survival rate, although the previous study evaluated the malignancy of thymoma using only the overall survival rate [13, 14]. Most of types A and AB thymomas did not invade to neighboring organs, and they were totally resected and showed no recurrence or tumor-related death. We conrmed previous observations that these two subtypes are benign tumors with an excellent prognosis [10, 13, 14]. One fth of types B1 and B2 thymomas had invasion to organs. Although all tumors were totally resected, they showed recurrence or tumor-related death in some patients. These types thymomas (organoid thymoma) showed moderate invasiveness and had a small risk of relapse. About half of type B3 thymomas showed invasion to organs. Although most of them were totally resected, one third of cases had late relapse after more than 5 years. However, tumor-related death was low. Most of type C thymomas had invasion to organs at
Fig 3. Disease-free survival curve of thymic epithelial tumor according to Masaoka staging system.
Fig 4. Survival curve of thymic epithelial tumor according to Masaoka staging system.
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diagnosis. Although half of them were totally resected, half of the cases with total resection showed early relapse from 4 months to 4 years, and half of them were dead because of tumor at an early time after relapse. Type C thymoma should be considered to be a cancer. The current study conrmed the previous investigations that WHO histologic classication was a good prognostic factor compared with the previous histologic classication of thymoma [13, 14]. Several previous studies showed that clinical stage is one of the most important prognostic factors in thymoma [2, 3, 10, 12, 18]. Our previous study of 1,320 patients with thymic epithelial tumors from Japan demonstrated that the Masaoka clinical stage is an excellent indicator predicting the prognosis not only of thymoma but also of thymic carcinoma [19]. The present study conrmed that a clear-cut distinction is not always feasible in overall survival rate and disease-free survival between stage I and stage II thymomas, but that there is a signicant difference between stage II and stage III thymomas. In conclusion, we conrmed that the WHO histologic classication reects the oncologic behavior of thymoma. Types A and AB thymomas may be treated as benign tumors, and types B1 and B2 thymomas are the borderline between benign and malignant tumors. On the other hand, type B3 thymoma has a malignant behavior, and type C thymoma has more aggressive behavior as a cancer. This classication is useful for predicting the prognosis and selecting suitable treatment for patients with thymoma. In the future, by considering WHO histologic classication and Masaoka clinical stage, we can divide thymoma into some subpopulations and select the best treatment for each subpopulation.
We thank Doctor Takafumi Katayama, Medical Informatics, Tokushima University Hospital, for advice regarding the statistical analysis of this paper.
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5. 6. 7. 8. 9.
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References
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