WHO Histologic Classification is a Prognostic Indicator in Thymoma

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1 WHO Histologic Classification is a Prognostic Indicator in Thymoma 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 classification 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 reclassified a series of 100 thymomas resected at Tokushima University Hospital and four affiliated hospitals in Japan between 1973 and 2001 according to the World Health Organization histologic classification 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 thymoma 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 significant differences in disease-free survival between types A and AB and types B1 and B2 (p ), and between type B3 and type C (p 0.042). By multivariate analysis, only Masaoka clinical stage (p 0.002) showed significant 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 confirmed the World Health Organization histologic classification as a good prognostic factor. (Ann Thorac Surg 2004;77:1183 8) 2004 by The Society of Thoracic Surgeons Accepted for publication July 17, Address reprint requests to Dr Kondo, Dept of Oncological and Regenerative Surgery, School of Medicine, University of Tokushima, Kuramotocho, Tokushima , Japan; kondo@clin.med.tokushimau.ac.jp. Thymoma 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 [3 5]. The histologic classification 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 thymoma (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 classification 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 stratified 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 classification and its clinicopathologic relationship and prognostic relevance in a series of 100 thymomas resected at Tokushima University Hospital and four affiliated hospitals in Japan between 1973 and by The Society of Thoracic Surgeons /04/$30.00 Published by Elsevier Inc doi: /j.authoracsur

2 1184 KONDO ET AL Ann Thorac Surg WHO HISTOLOGIC CLASSIFICATION OF THYMOMA 2004;77: Table 1. World Health Organization Histologic Classification A AB B1 B2 B3 C A tumor composed of a population of neoplastic thymic epithelial cells having spindle/oval shape, lacking nuclear atypia, and accompanied by few or no nonneoplastic lymphocytes. A tumor in which foci having the features of type A thymoma are admixed with foci rich in lymphocytes. A tumor that resembles the normal functional thymus in that it combines large expanses having an appearance practically indistinguishable from normal thymic cortex with areas resembling thymic medulla. A tumor in which the neoplastic epithelial component appears as scattered plump cells with vesicular nuclei and distinct nucleoli among a heavy population of lymphocytes. Perivascular spaces are common and sometimes very prominent. A perivascular arrangement of tumor cells resulting in a palisading effect may be seen. A type of thymoma predominantly composed of epithelial cells having a round or polygonal shape and exhibiting no or mild atypia. They are admixed with a minor component of lymphocytes, resulting in a sheetlike growth of the neoplastic epithelial cells. A thymic tumor exhibiting clear-cut cytologic stypia and a set of cytoarchitectural features no longer specific to the thymus, but rather analogous to those seen in carcinomas of other organs. Type C thymomas lack immature lymphocytes; whatever lymphocytes may be present are mature and usually admixed with plasma cells. Material and Methods Patients During a 28-year period from 1973 to 2001, 127 successive cases of thymic epithelial tumors were treated at Tokushima University Hospital and four affiliated hospitals. We excluded thymic carcinoid from this study. One hundred cases, consisting of 57 women and 43 men, had sufficient files of exact clinical and pathologic data for the current study. The median age of all patients was 57.8 years, with a range of 15 to 81 years. Myasthenia gravis was related to disease in 20 patients (20%). Eighty-four patients (84%) underwent total resection macroscopically, 4 patients (4%) underwent subtotal resection, and 12 patients (12%) were inoperable including partial resection and biopsy in thoracotomy. Radiochemotherapy was performed in 19 patients, radiotherapy in 18 patients, and chemotherapy in 9 patients. Follow-up information with respect to survival was available for 98 patients. Histology and Staging Thymic epithelial tumor was classified according to the WHO criteria [11]. The definitions for the WHO histologic classification system are summarized in Table 1. Routine histologic sections, stained with hematoxylin and eosin, were reviewed without information on the clinical data. All cases (n 100) were referred to one of us (K.M.), who was one of the collaborators on Histologic Typing of Tumours of the Thymus by Rosai [11], for histologic consultation. Five cases were combined thymoma, which consisted of 4 type B2 plus type B3 thymomas and 1 type B3 plus type C thymoma. We 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 classification: A, AB, B1, and B2 versus B3 and C; completeness of resection; and presence of MG) by SPSS for Windows (version ; SPSS Japan Inc, Tokyo, Japan). Significance was defined as a p value less than Deaths as a result of MG or unrelated disease were excluded. Results Masaoka Clinical Stage in Thymoma All 100 thymic epithelial tumors were classified according to the WHO histologic classification. 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 Table 2. Masaoka Clinical Staging System I II III IVa IVb 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

3 Ann Thorac Surg KONDO ET AL 2004;77: WHO HISTOLOGIC CLASSIFICATION OF THYMOMA Table 3. Masaoka Clinical Stage a Histologic Subtype I II III IVa IVb Total Cases of Invasion to Neighboring MG 1185 A % 0 0.0% AB % 1 5.9% B % % B % % B % % C % 0 0.0% Total % % a Cases with stage III or IV tumor in individual subtype. 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). Therapeutic Modalities in Thymoma All patients with type A, AB, B1, or B2 thymoma underwent total resection. Patients with type A thymoma had no adjuvant therapy. Most patients of types AB and B1 thymomas with adjuvant therapy had prophylactic radiotherapy (Table 4). All patients with type B3 except one underwent total resection. Of 28 patients with type C thymoma, 13 patients (46%) underwent total resection, 4 (14%) had subtotal resection, and 11 (39%) were inoperable. Seven of the 11 inoperable patients underwent radiochemotherapy. The frequency of chemotherapy as additional therapy increased in types B2, B3, and C thymomas (50% to 100%). Recurrence in Thymoma The recurrence rate of patients with total or subtotal resection of the tumor is shown in Table 4. There was no recurrence in patients with types A, AB, and B2 thymoma. The recurrence rates of patients with types B1, B3, and C thymoma were 15%, 36%, and 47%, respectively. For statistical analysis, thymoma was divided into four categories: thymoma including neoplastic epithelial cells having spindle or oval shape (types A and AB), thymoma showing organoid pattern (types B1 and B2), atypical thymoma (type B3), and carcinoma (type C). None of the patients with types A and AB thymoma developed recurrence. Disease-free survival was 83.1% for types B1 and B2, 83.3% for type B3, and 33.7% for type C thymoma at 5 years and 83.1% for types B1 and B2, 35.7% for type B3, and 27.1% for type C thymoma at 10 years (Fig 1). There was a significant difference in disease-free survival between types A and AB and types B1 and B2 (p ), and between type B3 and type C (p 0.042). There was a tendency for disease-free survival of patients with type B3 thymoma to be worse than that of patients with types B1 and B2 thymoma (p 0.061). Patients with type B3 thymoma were at risk for late relapse between 5 and 8 years. On the other hand, patients with type C thymoma were at risk for early relapse between 4 months and 4 years. Table 4. Therapeutic Modalities and Recurrence in World Health Organization Histologic Subtypes Histologic Subtype Resection Total Subtotal Inope Adjuvant Therapy Rad and Rad Recurrence a A 8 100% % % AB % % 0% 100% 0% 0 0% B % % 8% 67% 25% 4 15% B % % 50% 0% 50% 0 0% B % % 50% 50% 0% 4 36% C 13 46% % 64% 18% 18% 8 47% total 84 84% % 41% 41% 18% 16 19% a It was the recurrence rate from patients with total or subtotal resection of the tumor. chemotherapy; Inope inoperable; Rad radiotherapy.

4 1186 KONDO ET AL Ann Thorac Surg WHO HISTOLOGIC CLASSIFICATION OF THYMOMA 2004;77: Clinical Stage and Recurrence in Thymic Epithelial Tumor The recurrence rate of patients with total or subtotal resection of the tumor according to clinical stage is shown in Table 5. The recurrence rates of patients with stages I, II, III, and IV thymoma were 2.8%, 7.7%, 50%, and 50%, respectively. Disease-free survival was 100% for stage I, 94.4% for stage II, 56.3% for stage III, and 20.8% for stage IV at 5 years, and 93.8% for stage I, 84.0% for stage II, and 43.8% for stage III at 10 years. There was a significant difference in disease-free survival between stage II and stage III (p ). There was a tendency for disease-free survival of patients with stage IV thymoma to be worse than that of patients with stage III (p ; Fig 3). Clinical Stage and Survival in Thymic Epithelial Tumor The survival curve of patients with thymic epithelial tumors according to clinical stage is shown in Figure 4. The 5-year survival rates of stages I, II, III, IVa, and IVb thymoma were 100%, 100%, 68.8%, and 57.2%, respectively. A significant difference in survival rate was observed between stages II and III (p ). There was no significant difference in survival rate between stages I and II, or stages III and IV. Fig 1. Disease-free survival curve of thymoma according to World Health Organization histologic classification. Survival in Thymoma The survival curve of patients with thymoma according to WHO histologic subtypes is shown in Figure 2. The 5- or 10-year survival rates of types A and AB, types B1 and B2, type B3, and type C thymoma were 100%, 94.4%, 91.7%, and 57.8%, respectively. Significant differences in survival rate were observed between types A and AB and type B3 (p ), and between types B1 and B2 and type C (p ). There was a tendency for survival rate of patients with type C thymoma to be worse than that of patients with type B3 (p ). Masaoka Clinical Stage and Therapeutic Modalities in Thymic Epithelial Tumor All patients with stage I or II thymoma underwent total resection. Most of the patients with stage I thymoma (noninvasive thymoma) had no adjuvant therapy (Table 5). One third of patients with stage II thymoma had adjuvant therapy, most of which was prophylactic radiotherapy. In stage III or IV thymomas, the rate of total resection decreased with increasing stage (stage III, 72%; stage IVa, 50%; stage IVb, 47%). Most of the patients with stage III or IV thymomas (82% to 100%) had adjuvant therapy, most of which included chemotherapy (61% to 100%). Multivariate Analysis of Disease-Free Survival and Overall Survival in Thymoma 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 classification (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 classification (p 0.687) were not factors predictive of survival. Comment A few reports have investigated the applicability and clinical significance of the WHO histologic classification of thymoma since its publication in 1999 [13, 14]. We reclassified 100 successive cases of thymic epithelial tumors excepting 5 thymic carcinoids treated between 1973 and 2001 at Tokushima University Hospital and four affiliated 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 classified using the WHO criteria. The remaining five Fig 2. Survival curve of thymoma according to World Health Organization histologic classification.

5 Ann Thorac Surg KONDO ET AL 2004;77: WHO HISTOLOGIC CLASSIFICATION OF THYMOMA Table 5. Therapeutic Modalities and Recurrence in Masaoka Staging System Stage Resection Total Subtotal Inope Total Resection Ajduvant Therapy Rad and Rad 1187 Recurrence a I % 1 3% 0% 100% 0% 1 3% II % 10 38% 0% 90% 10% 2 8% III % 14 82% 50% 21% 29% 7 50% IVa % 6 100% 83% 0% 17% 2 67% IVb % 13 87% 46% 39% 15% 4 44% Total % 44 44% 41% 41% 18% 16 18% a It was the recurrence rate from patients with total or subtotal resection of the tumor. chemotherapy; Inope inoperable; Rad radiotherapy. 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 difficult 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 difficult and that definitions of the two categories vary among authors, whereas Kirchner and associates [10] and Quintanilla- Martinez 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 significant 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 confirmed previous observations that these two subtypes are benign tumors with an excellent prognosis [10, 13, 14]. One fifth 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.

6 1188 KONDO ET AL Ann Thorac Surg WHO HISTOLOGIC CLASSIFICATION OF THYMOMA 2004;77: 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 confirmed the previous investigations that WHO histologic classification was a good prognostic factor compared with the previous histologic classification 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 confirmed 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 significant difference between stage II and stage III thymomas. In conclusion, we confirmed that the WHO histologic classification reflects 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 classification is useful for predicting the prognosis and selecting suitable treatment for patients with thymoma. In the future, by considering WHO histologic classification 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. References 1. Rosai J, Levine GD. Tumor of the thymus. In: Atlas of tumor pathology, 2nd series, fascicle 13. Washington, DC: Armed Forces Institute of Pathology, Shimosato Y, Mukai K. Tumors of the mediastinum. In: Atlas of tumor pathology, 3rd series, fascicle 21. Washington, DC: Armed Forces Institute of Pathology, Shields TW. Thymic tumors. In: Mediastinal surgery. Shields TW. Philadelphia: Lea & Febiger, 1991: Cowen D, Richaud P, Mornex F, et al. Thymoma. Results of a multicentric retrospective series of 149 non-metastatic irradiated patients and review of the literature. FNCLCC trialists. Federation Nationale des Centres de Lutte Contre le Cancer. Radiother Oncol 1995;34: Hejna M, Haberl I, Raderer M. Nonsurgical management of malignant thymoma. Cancer 1999;85: Shimosato Y. Controversies surrounding the subclassification of thymoma. Cancer 1994;74: Levine GD, Rosai J. Thymic hyperplasia and neoplasia: a review of current concepts. Hum Pathol 1978;9: Kirchner T, Muller-Hermelink HK. New approaches to the diagnosis of thymic epithelial tumors. Prog Surg Pathol 1989;10: Pescarmona E, Rendina EA, Venuta F, Ricci C, Ruco LP, Baroni CD. The prognostic implication of thymoma histologic subtyping. A study of 80 consecutive cases. Am J Clin Pathol 1990;93: Quintanilla-Martinez L, Wilkins EW Jr, Choi N, Efird J, Hug E, Harris NL. Thymoma histologic subclassification is an independent prognostic factor. Cancer 1994;74: Rosai J. Histological typing of tumours of the thymus. In: WHO International histological classification of tumours, 2nd ed. New York: Springer-Verlag, 1999: Masaoka A, Monden Y, Nakahara K, Tanioka T. Follow-up study of thymomas with special reference to their clinical stages. Cancer 1981;48: Okumura M, Ohta M, Tateyama H, et al. The World Health Organization histologic classification system reflects the oncologic behavior of thymoma. A clinical study of 273 patients. Cancer 2002;94: Chen G, Marx A, Wen-Hu C, et al. New WHO histologic classification predicts prognosis of thymic epithelial tumors. A clinicopathologic study of 200 thymoma cases from China. Cancer 2002;95: Kirchner T, Schalke B, Buchwald J, Ritter M, Marx A, Muller-Hermelink HK. Well-differentiated thymic carcinoma. Am J Surg Pathol 1992;16: Ho FC, Fu KH, Lam SY, Chiu SW, Chan AC, Muller- Hermelink HK. Evaluation of a histogenetic classification for thymic epithelial tumours. Histopathology 1994;25: Tan PH, Sng IT. Thymoma a study of 60 cases in Singapore. Histopathology 1995;26: Yamakawa Y, Masaoka A, Hashimoto T, et al. A tentative tumor-node-metastasis classification of thymoma. Cancer 1991;68: Kondo K, Monden Y. Therapy for thymic epithelial tumors: a clinical study of 1,320 patients from Japan. Ann Thorac Surg 2003;76: