HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Add to Personal Folders Download to citation manager Author home page(s): Kil Dong Kim Young Sam Kim Permission Requests Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Suk Park, M. Articles by Kyu Kim, S. Search for Related Content PubMed PubMed Citation Articles by Suk Park, M. Articles by Kyu Kim, S. Related Collections Mediastinum Related Article

Ann Thorac Surg 2004;78:992-997
© 2004 The Society of Thoracic Surgeons

---

Original article: general thoracic

Prognosis of thymic epithelial tumors according to the new World Health Organization histologic classification

^a Department of Internal Medicine, Yonsei University College of Medicine, Seoul, South Korea
^b Department of Thoracic and Cardiovascular Surgery, Yonsei University College of Medicine, Seoul, South Korea
^c Department of Pathology, Yonsei University College of Medicine, Seoul, South Korea
^d The Institute of Chest DiseasesYonsei University College of Medicine, Seoul, South Korea
^e Brain Korea 21 Project for Medical Sciences, Yonsei University College of Medicine, Seoul, South Korea
^f Cancer Metastasis Research Center, Yonsei University College of Medicine, Seoul, South Korea

Accepted for publication March 30, 2004.

^* Address reprint requests to Dr Se Kyu Kim, Department of Internal Medicine, Yonsei University College of Medicine, CPO Box 8044, Seoul, South Korea
sekyukim{at}yumc.yonsei.ac.kr

	Abstract

Top Abstract Introduction Patients and methods Results Comment Acknowledgments References

 
BACKGROUND: The aim of this study was to document the prognosis of thymic epithelial tumors (TETs) according to new the World Health Organization (WHO) classification.

METHODS: We retrospectively reviewed 150 patients with TETs that were confirmed pathologically during 11 years (from 1992 to 2002) in Severance Hospital, Seoul, Korea.

RESULTS: TETs were classified as type A, AB, B1, B2, B3, or C, tumors and these represented 7 (4.7%), 26 (17.3%), 13 (8.7%), 45 (30.0%), 26 (17.3%), and 33 (22.0%) cases, and the 5-year survival rates were 100%, 93%, 89%, 82%, 71%, and 23%, respectively. Their Masaoka stages were I, II, III, IVa, and IVb, with 53 (35.3%), 39 (26.0%), 20 (13.3%), 22 (14.7%), and 16 (10.7%) cases. Tumor invasiveness, recurrence, completeness of resection, and tumor-related death were more frequent in types AB, B2, B3, and C than in types A and B1. Multivariate analysis showed that Masaoka stage (p < 0.001) and the WHO classification (p = 0.019) were significant independent prognostic factors.

CONCLUSIONS: The WHO classification is associated with tumor invasiveness, recurrence, completeness of resection, and tumor-related death, and has good correlation with Masaoka stage. The WHO histologic subtypes are an independently significant prognostic factor with respect to survival in our multivariate analysis. Types AB, B2, B3, and C showed invasive behaviors and R1 or R2 resections were frequently performed. Postoperative adjuvant radiotherapy was effective, but long-term follow-up is recommended because of decreased survival after 5 years following operation. The WHO classification may be helpful in clinical practice for the assessment and treatment of TET patients.

	Introduction

Top Abstract Introduction Patients and methods Results Comment Acknowledgments References

 
Thymic epithelial tumors (TETs) are usually defined as thymoma and thymic carcinoma. They exhibit a wide spectrum of morphologic features and oncologic behavior and are associated with autoimmune diseases, as represented by myasthenia gravis (MG) [1]. High levels of difficulty and controversy are associated with the histologic classification of TETs [2–8] and any clinicians have studied the prognostic factors for TETs. In general, staging according to the Masaoka classification [9] and complete respectability [10] are considered to be the most important independent prognostic factors. Association with MG and survival in patients with thymoma is controversial [11]. Nevertheless, debate continues on the role of the histologic classification of TETs.

In 1999 the World Health Organization (WHO) published histologic criteria of TETs that was based on the morphology of epithelial cells and on the lymphocyte-to-epithelial cell ratio. TETs are now stratified into five thymoma entities: type A, AB, B1, B2, and B3 thymomas, and all thymic carcinomas, called type C thymomas [12].

In this paper we report on our study of the WHO histologic classification and clinicopathologic correlations in a series of 150 patients with TETs at the Severance Hospital, Seoul, Korea, during the period 1992 to 2002. We evaluated the WHO histologic classification, the Masaoka stage, and clinical factors with respect to prognosis.

	Patients and methods

Top Abstract Introduction Patients and methods Results Comment Acknowledgments References

 
Patients
One hundred and fifty-one consecutive cases of TETs were pathologically confirmed at the Severance Hospital, Seoul, Korea, during the period from 1992 to 2002. This study protocol was approved by the Institutional Review Board of Ethics Committee, and informed written consent was obtained from each study patient. One case was of thymoma with pseudosarcomatous stroma [13], which is not included in the WHO criteria, and therefore excluded.

Diagnosis was by surgical resection in 125 patients, mediastinoscopic biopsy in 15 patients, and by cutting needle biopsy in 10 patients. Complete medical follow-up data were obtained for all included patients.

Histology
A pathologic review was performed and confirmed according to the WHO histologic classification by a pathologist who was blinded as to stage and clinical information. One well-experienced pathologist (Yang WI) reviewed all 150 cases, compared the original histologic types produced by colleagues, and then made the final decision on the histologic type.

TETs were classified according to the WHO criteria (Table 1) [12]. Five of 150 cases (3.3%) were combinations of two thymoma subtypes. The combined thymomas in our series were B2 plus B3 thymomas. In one case the type B3 areas were less than 30%, so it was classified as a type B2 thymoma; the others were predominantly type B3 [14]. Of 33 cases (22.0%) of type C TETs, we observed 23 cases (69.7%) of squamous cell carcinomas, 5 cases (15.2%) of undifferentiated carcinoma, 2 cases (6.1%) of lymphoepithelioma-like carcinoma, and 1 (3.0%) case each of mixed small cell carcinoma, basaloid carcinoma, and papillary carcinoma. Of the 18 cases in which TETs recurred after complete resection (R0), an initial type B2 was replaced in 2 cases with recurred type B3.

Clinical information and Masaoka stage
Clinical information and recurrence were adapted and followed up by using regular medical records from the Cancer Registration Center and the Cancer Metastasis Research Center at Yonsei University. Patients with completely resected thymomas were followed up with computed tomography at least every 3 months after 1 year, every 6 months after the next 2 years, and yearly after next 3 years. These patients comprised types A (7 cases), AB (24), B1 (13), B2 (36), B3 (15), and C (8). Stages were I (53 cases), II (33), III (9), and IV (8). Lost cases were contacted by telephone and postcard. They were only included in survival analysis, but not in analysis regarding recurrence.

The stage of tumor was determined according to the clinicopathologic classification proposed by Masaoka [9]. Stage was based on surgical and pathologic reports. Radiation therapy was administered postoperatively as a general rule in patients with resected tumors that were considered invasive. Chemotherapy also was administered in patients with stage IV disease, unresectable disease, or when resection was considered incomplete. When resection of the recurrent tumor was feasible, surgical treatment was adopted. Otherwise, chemotherapy or radiation therapy was chosen.

Statistical analysis
Statistical analyses were performed with SPSS 11.0 (SPSS, Inc, Chicago, IL).

Prognostic factors such as age, sex, Masaoka stage, the WHO histologic classification, and the presence of MG were analyzed by the Kaplan-Meier method, comparisons were made with the log-rank test, and the Cox proportional hazards ratio model was used to investigate the simultaneous effect of multiple predictors on survival. Two-by-two associations between prognostic factors were analyzed using ² tests. Statistical tests resulting in p values of less than 0.05 were considered to be significant. Overall survival time was calculated from the date of surgery or initial pathologic diagnosis to death. That discrepancy was less than 1 month because surgery or other treatments were performed as soon as the diagnosis was made. The last follow-up was done on May 1, 2003.

	Results

Top Abstract Introduction Patients and methods Results Comment Acknowledgments References

 
Comparison of clinical data and Masaoka stage according to WHO subtypes
There were 88 male and 62 female patients. Patient age at the time of surgery and at initial diagnosis ranged from 4 years to 83 years, and averaged 48 ± 14 years. The concordance rate was 95% (14 of 150). Discrepancy was developed in the B2 and B3 combined type and in the differentiation between types AB and B2.

Paralysis from MG, found in 45 cases (30%), was the most frequent presenting symptom. It was related to disease in 48 patients (32.0%) and was most common in types B2 and B3, but was not seen in types A or C. The sex ratios were similar. Asymptomatic patients accounted for 39 cases (26.0%), and 66 cases (44.0%) had local pulmonary symptoms. Superior vena cava syndrome was observed in 13 cases among types B2, B3, and C, suggesting the invasiveness of these types. Tumor invasiveness, recurrence, completeness of resection, and tumor-related death were more frequent in types AB, B2, B3, and C than in types A and B1 (Table 2).

Surgical resection was not performed in 25 patients (10 female, 15 male) because of patient refusal, poor general condition, or an advanced stage (IVb). The WHO subtypes were B2, B3, and C in 5, 3, and 17 cases, respectively. The Masaoka stages were III, IVa, and IVb in 5, 12, and 8 cases, respectively.

Tumor recurrences (18 cases) after complete surgical resection (103 cases) were more frequent in types AB, B2, B3, or C than in types A or B1 (² test, p < 0.0001).

Prognostic factors analysis for survival
The mean follow-up duration of 150 patients was 47 months, ranging from 1 month to 10 years. Fifty-one patients died; 44 due to tumor. The causes of the other deaths were cardiovascular disease (3 patients), accident (2 patients), stroke (1 patient), and liver cirrhosis (1 patient). Tumor-related deaths were more frequent in types AB, B2, B3, or C than in types A or B1 (² test p < 0.0001).

Univariate analysis showed that age, WHO subtype, Masaoka stage, MG, and complete resectability (log-rank test, p < 0.05) were statistically significant in relation to survival. The overall 5-year survival of 150 patients was 69.9%. Survival curves according to Masaoka stage are shown in Figure 1. The 5-year survival rates were 100%, 88.2%, 63.0%, 22.5%, and 17.2% for patients with stages I, II, III, IVa, and IVb, respectively. In particular, a tumor of stage III or IV at the time of diagnosis was a significant predictor of a poor outcome (log-rank test, p < 0.0001).

View larger version (28K): [in this window] [in a new window]   Fig 1. Survival curves according to the Masaoka staging system (I, II, III, IVa, IVb) for patients with thymic epithelial tumors (TETs). Numbers in parentheses refer to number of patients with TET. TET patients with stage I and II disease had a better prognosis (log-rank test, p = 0.001).

View larger version (25K): [in this window] [in a new window]   Fig 2. Survival curves according to the World Health Organization histologic classification system (A, B1, B2, B3, AB, C) for patients with thymic epithelial tumors (TETs). Numbers in parentheses refer to number of patients with TET. Patients with a type C tumor had the worst prognosis (log-rank test, p < 0.0001).

View larger version (26K): [in this window] [in a new window]   Fig 3. Survival curves according to respectability for patients with thymic epithelial tumors (TETs). Numbers in parentheses refer to number of patients with TET. Patients with an R2 resection, or unresectable and biopsy-only cases, had the worst prognosis (log-rank test, p < 0.0001). (R0 = complete gross resection, negative microscopic margins; R1 = complete gross resection, positive microscopic margins; R2 = incomplete gross resection with gross residual tumor)

	Comment

Top Abstract Introduction Patients and methods Results Comment Acknowledgments References

We undertook a retrospective study of 150 TET cases that were reclassified according to the recent WHO histologic classification. This was then compared with clinical characteristics and prognosis. The most frequent histologic type was B TETs (56.0%), as described in recent studies [14, 17, 18]. TETs developed in all ages, and others have reported similar ranges [14, 15, 19]. Eighty-eight patients were male, and 62 were female, though Regnard and colleagues [19] reported a female predominance.

Univariate analysis showed an association between all factors, except sex, and survival. Multivariate analysis using the Cox proportional hazards model showed that Masaoka stage (p < 0.0001) and the WHO histologic classification (p = 0.019) were significant independent prognostic factors in all patients with TETs (Table 4). However, in surgically resected patients, excluding unresectable and biopsy-only cases, the WHO classification was marginal (p = 0.054). As the unresectable and biopsy-only patients only consisted of types B2, B3 and C, the significance of the WHO classification decreased compared with that of all patients in multivariate analysis.

Chen and colleagues [14] reported that the WHO histologic subtype is an independent prognostic factor in stage I and II TETs. Because they compared the sum of types A, AB, and B1 with that of types B2, B3, and C, a greater effect on survival was found. Okumura and colleagues [18] also reported that the WHO histologic subtype is an independent significant prognostic factor (p = 0.05). Their study was larger in scale (N = 273) but did not include frankly malignant type C TETs. Their results were based on surgically resected patients, not on all TET patients.

We found that type A and B1 TETs have a very low risk of recurrence or tumor-related death (Table 2), although some showed invasion into the mediastinal fat (stage II) or adjacent organs (stage III; Table 3). In contrast in type B2, B3, or C TETs, superior vena cave syndrome, which can be interpreted as the invasiveness of these WHO subtypes, was more frequently observed. The behavior of type A and B1 tumors differed from that of type AB, B2, B3 and C tumors, which supported the recommendation that clinical stage and the WHO histologic subtype should both be considered as independent prognostic factors when predicting survival.

The prognostic value of MG as a presenting symptom is controversial. In our study survival was statistically better for TETs with MG versus TETs without MG by univariate analysis (log-rank test, p = 0.0023), but not by multivariate analysis (log-rank test, p = 0.274). Maggi and colleagues [20] demonstrated a better prognosis for patients with MG, and Monden and colleagues [21] also found a lower recurrence rate among patients with MG. They reported that this better prognosis for patients with MG is probably linked to the earlier diagnosis of TET in these patients [21]; however, other studies have shown no survival differences in patients with or without MG [15, 19]. In our study, MG was more frequently observed in patients with lower stage cancers, suggesting earlier detection of cancer in the patients with MG.

Quintanilla-Martinez and colleagues [15] suggested that adjuvant therapy may be unnecessary in patients with medullary type (WHO type A) or mixed type (WHO type AB) thymomas in stage II, because recurrence was zero in 12 cases. This contrasts with our study, in which 4 cases of recurrence (3 cases were stage I and II) occurred after complete resection some 1 to 10 years later, and 3 cases of tumor-related death occurred. Because few patients in our series received combined radiochemotherapy, we cannot comment on the benefits of combination therapy over radiation therapy or chemotherapy alone. A recent study [22] of multimodality treatment with induction chemotherapy and adjuvant chemotherapy offered encouraging results for stage III thymic tumors.

Incomplete resection rates were 7% to 50% in invasive subtypes such as AB, B2, B3, and C. Since a strong correlation exists between the WHO histologic type and tumor stage and also the chance of incomplete resection, we can try to minimize incomplete resection by the preoperative identification of subtype. According to Greif and colleagues [23], a core needle biopsy identified specific histologic type in 83% of patients. We recommend routine preoperative tissue typing.

In conclusion, the WHO histologic subtype is an independently significant prognostic factor with respect to survival in our multivariate analysis. The WHO subtype can predict prognosis, perhaps not as good as surgical stage, but earlier. It can also predict the result of surgery. Compared with type A and B1, R1 or R2 resections were more frequent in AB, B2, B3, and C. Thus, the WHO classification may be helpful in clinical practice for the preoperative assessment and treatment of TET patients.

	Acknowledgments

Top Abstract Introduction Patients and methods Results Comment Acknowledgments References

 
We thank Dr Woo Ick Yang for the pathologic review and for reclassifying the TET cases. This work was supported by the Korea Science and Engineering Fund through the Cancer Metastasis Research Center at Yonsei University.

	References

Top Abstract Introduction Patients and methods Results Comment Acknowledgments References

 

1. Muller-Hermelink HK, Marx A. Thymoma. Curr Opin Oncol. 2000;12:426–433[Medline]
2. Bernatz PE, Harrison EG Jr, Glagett O. Thymoma: a clinico-pathological study. J Thorac Cardiovasc Surg. 1961;42:424–444[Medline]
3. Lattes R. Thymoma and other tumors of the thymus. An analysis of 107 cases. Cancer. 1962;15:1224–1260
4. Levine GD, Rosai J. Thymic hyperplasia and neoplasia: a review of current concepts. Hum Pathol. 1978;9:495–515[Medline]
5. Lewis JE, Wick MR, Scheithauer BW, Bernatz PE, Taylor WF. Thymoma. A clinicopathologic review. Cancer. 1987;60:2727–2743[Medline]
6. Marino M, Muller-Hermelink HK. Thymoma and thymic carcinoma. Relation of thymoma epithelial cells to the cortical and medullary differentiation of thymus. Virchows Arch A Pathol Anat Histopathol. 1985;407:119–149[Medline]
7. Kirchner T, Muller-Hermelink HK. New approaches to the diagnosis of thymic epithelial tumors. Prog Surg Pathol. 1989;10:167–189
8. Suster S, Moran CA. Thymoma, atypical thymoma, and thymic carcinoma. A novel conceptual approach to the classification of thymic epithelial neoplasms. Am J Clin Pathol. 1999;111:826–833[Medline]
9. Masaoka A, Monden Y, Nakahara K, et al. Follow-up study of thymomas with special reference to their clinical stages. Cancer. 1981;48:2485–2492[Medline]
10. Wilkins KB, Sheikh E, Green R, et al. Clinical and pathologic predictors of survival in patients with thymoma. Ann Surg. 1999;230:562–574[Medline]
11. Monden Y, Nakahara K, Kagotani K, Fujii Y, Masaoka A, Kawashima Y. Myasthenia gravis with thymoma: analysis of and postoperative prognosis for 65 patients with thymomatous myasthenia gravis. Ann Thorac Surg. 1984;38:46–52[Abstract/Free Full Text]
12. Rosai J, Sobin LH. Histological typing of tumors of the thymus. International Histological Classification of Tumors. 2^nd ed. New York, Berlin: Springer; 1999.
13. Suster S, Moran CA, Chan JK. Thymoma with pseudosarcomatous stroma: report of an unusual histologic variant of thymic epithelial neoplasm that may simulate carcinosarcoma. Am J Surg Pathol. 1997;21:1316–1323[Medline]
14. 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;95:420–429[Medline]
15. Quintanilla-Martinez L, Wilkins EW Jr, Choi N, Efird J, Hug E, Harris NL. Thymoma. Histologic subclassification is an independent prognostic factor. Cancer. 1994;74:606–617[Medline]
16. Lardinois D, Rechsteiner R, Lang RH, et al. Prognostic relevance of Masaoka and Muller-Hermelink classification in patients with thymic tumors. Ann Thorac Surg. 2000;69:1550–1555[Abstract/Free Full Text]
17. Okumura M, Miyoshi S, Fujii Y, et al. Clinical and functional significance of WHO classification on human thymic epithelial neoplasms: a study of 146 consecutive tumors. Am J Surg Pathol. 2001;25:103–110[Medline]
18. 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;94:624–632[Medline]
19. Regnard JF, Magdeleinat P, Dromer C, et al. Prognostic factors and long-term results after thymoma resection: a series of 307 patients. J Thorac Cardiovasc Surg. 1996;112:376–384[Abstract/Free Full Text]
20. Maggi G, Casadio C, Cavallo A, Cianci R, Molinatti M, Ruffini E. Thymoma: results of 241 operated cases. Ann Thorac Surg. 1991;51:152–156[Abstract/Free Full Text]
21. Monden Y, Nakahara K, Iioka S, et al. Recurrence of thymoma: clinicopathological features, therapy, and prognosis. Ann Thorac Surg. 1985;39:165–169[Abstract/Free Full Text]
22. Venuta F, Rendina EA, Longo F, et al. Long-term outcome after multimodality treatment for stage III thymic tumors. Ann Thorac Surg. 2003;76:1866–1872[Abstract/Free Full Text]
23. Greif J, Staroselsky AN, Gernjac M, et al. Percutaneous core needle biopsy in the diagnosis of mediastinal tumors. Lung Cancer. 1999;25:169–173[Medline]

This article has been cited by other articles:

				F. Venuta, M. Anile, D. Diso, D. Vitolo, E. A. Rendina, T. De Giacomo, F. Francioni, and G. F. Coloni Thymoma and thymic carcinoma Eur J Cardiothorac Surg, January 1, 2010; 37(1): 13 - 25. [Abstract] [Full Text] [PDF]

				Y. Inoue, L. D. True, and R. G. Martins Thymic Carcinoma Associated With Paraneoplastic Polymyositis J. Clin. Oncol., August 1, 2009; 27(22): e33 - e34. [Full Text] [PDF]

				Honglin Yin, Jun Du, Zhenfeng Lu, Xia Jiao, Jiandong Wang, and Xiaojun Zhou The Correlation of the World Health Organization Histologic Classification of Thymic Epithelial Tumors and Its Prognosis: A Clinicopathologic Study of 108 Patients From China International Journal of Surgical Pathology, June 1, 2009; 17(3): 255 - 261. [Abstract] [PDF]

				T. Utsumi, H. Shiono, A. Matsumura, H. Maeda, M. Ohta, H. Tada, A. Akashi, and M. Okumura Stage III thymoma: relationship of local invasion to recurrence. J. Thorac. Cardiovasc. Surg., December 1, 2008; 136(6): 1481 - 1485. [Abstract] [Full Text] [PDF]

				E. O. Gamboa, V. Sawhney, R. S. Lanoy, N. A. Haller, A. T. Powell, and S. V. Hazra Widespread Metastases After Resection of Noninvasive Thymoma J. Clin. Oncol., April 1, 2008; 26(10): 1752 - 1755. [Full Text] [PDF]

				S Suster Diagnosis of thymoma J. Clin. Pathol., December 1, 2006; 59(12): 1238 - 1244. [Abstract] [Full Text] [PDF]

				R. F. Riedel and W. R. Burfeind Jr Thymoma: Benign Appearance, Malignant Potential Oncologist, September 1, 2006; 11(8): 887 - 894. [Abstract] [Full Text] [PDF]

				F. C. Detterbeck Clinical Value of the WHO Classification System of Thymoma Ann. Thorac. Surg., June 1, 2006; 81(6): 2328 - 2334. [Abstract] [Full Text] [PDF]

				C. D. Wright, J. C. Wain, D. R. Wong, D. M. Donahue, H. A. Gaissert, H. C. Grillo, and D. J. Mathisen Predictors of recurrence in thymic tumors: Importance of invasion, World Health Organization histology, and size J. Thorac. Cardiovasc. Surg., November 1, 2005; 130(5): 1413 - 1421. [Abstract] [Full Text] [PDF]

This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Add to Personal Folders Download to citation manager Author home page(s): Kil Dong Kim Young Sam Kim Permission Requests Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Suk Park, M. Articles by Kyu Kim, S. Search for Related Content PubMed PubMed Citation Articles by Suk Park, M. Articles by Kyu Kim, S. Related Collections Mediastinum Related Article