2004;77:1183-1188 Ann Thorac SurgYasumasa Monden

Sumitomo, Junji Morita, Takanori Miyoshi, Shoji Sakiyama, Kiyoshi Mukai and Kazuya Kondo, Kiyoshi Yoshizawa, Masaru Tsuyuguchi, Suguru Kimura, Masayuki

WHO histologic classification is a prognostic indicator in thymoma

http://ats.ctsnetjournals.org/cgi/content/full/77/4/1183located on the World Wide Web at:

The online version of this article, along with updated information and services, is

Print ISSN: 0003-4975; eISSN: 1552-6259. Southern Thoracic Surgical Association. Copyright © 2004 by The Society of Thoracic Surgeons.

is the official journal of The Society of Thoracic Surgeons and theThe Annals of Thoracic Surgery

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HO Histologic Classification is a Prognosticndicator in Thymomaazuya Kondo, MD, PhD, Kiyoshi Yoshizawa, MD, PhD, Masaru Tsuyuguchi, MD, PhD,uguru Kimura, MD, PhD, Masayuki Sumitomo, MD, Junji Morita, MD, PhD,akanori Miyoshi, MD, PhD, Shoji Sakiyama, MD, PhD, Kiyoshi Mukai, MD, PhD, andasumasa Monden, MD, PhDepartment of Oncological and Regenerative Surgery, School of Medicine, University of Tokushima, Department of Surgery,okushima Municipal Hospital, Department of Surgery, Tokushima Red Cross Hospital, and Department of Surgery, Tokushimarefectural Central Hospital, Tokushima; Department of Surgery, Takamatsu Red Cross Hospital, Takamatsu; and First

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Background. The histologic classification of thymomaas remained a subject of controversy for many years. In999, the World Health Organization Consensus Com-ittee published a histologic typing system for tumors of

he thymus.Methods. We reclassified a series of 100 thymomas

esected at Tokushima University Hospital and fourffiliated hospitals in Japan between 1973 and 2001 ac-ording to the World Health Organization histologiclassification and reported its clinicopathologic relation-hip and prognostic relevance.

Results. There were 8 type A, 17 type AB, 27 type B1, 8ype B2, 12 type B3, and 28 type C thymomas. Therequency of invasion to neighboring organs increasedccording to tumor subtype in the order A (0%), AB (6%),1 (19%), B2 (25%), B3 (42%), and C (89%). There was no

ecurrence in patients with type A, AB, or B2 thymoma.

he recurrence rates of patients with B1, B3, or C thy-

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oma were 15%, 36%, and 47%, respectively. The dis-ase-free survival rates were 100% for types A and AB,3% for types B1 and B2, 36% for type B3, and 28% forype C thymoma at 10 years. There were significantifferences in disease-free survival between types A andB and types B1 and B2 (p � 0.0436), and between type3 and type C (p � 0.042). By multivariate analysis, onlyasaoka clinical stage (p � 0.002) showed significant

ndependent effects on disease-free survival. The 10-yearurvival rates of types A and AB, types B1 and B2, type3, and type C thymoma were 100%, 94%, 92%, and 58%,

espectively.Conclusions. The current study confirmed the Worldealth Organization histologic classification as a goodrognostic factor.

(Ann Thorac Surg 2004;77:1183–8)

© 2004 by The Society of Thoracic Surgeons

hymoma is an uncommon neoplasm that is derivedfrom the epithelial cells of the thymus. It is well

nown for several interesting features: association withyasthenia gravis (MG) or other autoimmune disease,

istologic variability, and heterogeneity of malignantehavior [1, 2]. Surgery remains the mainstay of treat-ent, and radiation and chemotherapy also have been

pplied widely as adjuvant and palliative procedures3–5].

The histologic classification of thymoma has remainedsubject of controversy for many years [6]. In 1976, Rosai

nd Levine [1] proposed that thymoma is restricted toeoplasms of thymic epithelial cells and divided intoenign encapsulated (noninvasive) and malignant in-asive thymoma. Two years later, they divided malig-ant thymoma into invasive but cytologically bland thy-

ccepted for publication July 17, 2003.

ddress reprint requests to Dr Kondo, Dept of Oncological and Regen-rative Surgery, School of Medicine, University of Tokushima, Kuramoto-ho, Tokushima 770-8503, Japan; e-mail: kondo@clin.med.tokushima-

oma (malignant thymoma, category I) and cytologicallyalignant epithelial tumors, which correspond to thymic

arcinoma (malignant thymoma, category II) [7]. In 1989,uller-Hermelink and associates [8] divided the thymic

pithelial tumors into medullary, mixed medullary andortical, predominantly cortical, and cortical thymoma;ell-differentiated thymic carcinoma (WDTC); andigh-grade carcinoma. This classification was reported toe useful for predicting the outcomes of patients with

hese tumors [9, 10]. In 1999, the World Health Organi-ation (WHO) Consensus Committee published a histo-ogic typing system of tumors of the thymus [11]. Thy-

omas are now stratified into six entities (types A, AB,1, B2, B3, and C) on the basis of the morphology ofpithelial cells and the lymphocyte-to epithelial cell ratioTable 1).

In this retrospective study, we report on the WHOistologic classification and its clinicopathologic re-

ationship and prognostic relevance in a series of 100hymomas resected at Tokushima University Hospitalnd four affiliated hospitals in Japan between 1973 and

001.

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1184 KONDO ET AL Ann Thorac SurgWHO HISTOLOGIC CLASSIFICATION OF THYMOMA 2004;77:1183–8

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aterial and Methods

atientsuring a 28-year period from 1973 to 2001, 127 successive

ases of thymic epithelial tumors were treated at To-ushima University Hospital and four affiliated hospitals.e excluded thymic carcinoid from this study. One

undred cases, consisting of 57 women and 43 men, hadufficient files of exact clinical and pathologic data for theurrent study. The median age of all patients was 57.8ears, with a range of 15 to 81 years. Myasthenia gravisas related to disease in 20 patients (20%). Eighty-fouratients (84%) underwent total resection macroscopi-ally, 4 patients (4%) underwent subtotal resection, and2 patients (12%) were inoperable including partial re-ection and biopsy in thoracotomy. Radiochemotherapyas performed in 19 patients, radiotherapy in 18 patients,

nd chemotherapy in 9 patients. Follow-up informationith respect to survival was available for 98 patients.

istology and Staginghymic epithelial tumor was classified according to theHO criteria [11]. The definitions for the WHO histo-

ogic classification system are summarized in Table 1.outine histologic sections, stained with hematoxylinnd eosin, were reviewed without information on thelinical data. All cases (n � 100) were referred to one of usK.M.), who was one of the collaborators on “Histologicyping of Tumours of the Thymus” by Rosai [11], foristologic consultation. Five cases were “combined thy-oma,” which consisted of 4 type B2 plus type B3

hymomas and 1 type B3 plus type C thymoma. We

able 1. World Health Organization Histologic Classification

A tumor composed of a population oflacking nuclear atypia, and accompa

B A tumor in which foci having the featu1 A tumor that resembles the normal fu

appearance practically indistinguishmedulla.

2 A tumor in which the neoplastic epithnuclei and distinct nucleoli among acommon and sometimes very promipalisading effect may be seen.

3 A type of thymoma predominantly comexhibiting no or mild atypia. They asheetlike growth of the neoplastic ep

A thymic tumor exhibiting clear-cut cyspecific to the thymus, but rather anthymomas lack immature lymphocytadmixed with plasma cells.

able 2. Masaoka Clinical Staging System

Macroscopically coI 1. Macroscopic i

2. Microscopic iII Macroscopic invasVa Pleural or pericardVb Lymphogenous or

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ecided to use the major component of the tumor for theistologic diagnosis. These cases were 2 type B2, 2 type3, and 1 type C thymomas. Final pathologic staging wasecided by the Masaoka staging system (Table 2) [12].

tatistical Analysishe method of Kaplan-Meier was used for the analysis ofverall survival and freedom from relapse (disease-freeurvival), and the log-rank test for comparisons of sur-ival. Cox regression analysis was used to investigate theffects of multiple predictors (age: � 58 years, �58 years;ex; Masaoka staging system: I and II versus III and IV;

HO histologic classification: A, AB, B1, and B2 versus3 and C; completeness of resection; and presence ofG) by SPSS for Windows (version 11.0.1; SPSS Japan

nc, Tokyo, Japan). Significance was defined as a p valueess than 0.05. Deaths as a result of MG or unrelatedisease were excluded.

esults

orld Health Organization Histologic Subtypes andasaoka Clinical Stage in Thymoma

ll 100 thymic epithelial tumors were classified accord-ng to the WHO histologic classification. No patientnderwent preoperative steroid therapy. There were 8atients with type A (8%), 17 patients with type AB (17%),7 patients with type B1 (27%), 8 patients with type B28%), 12 patients with type B3 (12%), and 28 patients withype C (28%). The relationship between the WHO histo-ogic subtypes and the Masaoka clinical staging system is

lastic thymic epithelial cells having spindle/oval shape,by few or no nonneoplastic lymphocytes.f type A thymoma are admixed with foci rich in lymphocytes.

nal thymus in that it combines large expanses having anfrom normal thymic cortex with areas resembling thymic

component appears as scattered plump cells with vesiculary population of lymphocytes. Perivascular spaces areA perivascular arrangement of tumor cells resulting in a

ed of epithelial cells having a round or polygonal shape andmixed with a minor component of lymphocytes, resulting in aial cells.ic stypia and a set of cytoarchitectural features no longerus to those seen in carcinomas of other organs. Type Chatever lymphocytes may be present are mature and usually

etely encapsulated and microscopically no capsular invasionion into surrounding fatty tissue or mediastinal pleura, oron into capsule.nto neighboring organs, ie, pericardium, great vessels, or lungisseminationatogenous metastasis

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1185Ann Thorac Surg KONDO ET AL2004;77:1183–8 WHO HISTOLOGIC CLASSIFICATION OF THYMOMA

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hown in Table 3. The frequency of invasion to neighbor-ng organs (rate of cases with stage III or IV tumor) wasone in type A, 1 (5.9%) in type AB, 5 (18.5%) in type B1,(25.0%) in type B2, 5 (41.7%) in type B3, and 25 (89.3%)

n type C. The rate of invasion to neighboring organs inhe individual subtypes increased according to tumorype in the order A, AB, B1, B2, B3, and C. Of 100 thymicpithelial tumor patients, 20 patients (20%) had MG. Therequency of MG was 1 (6%) in type AB, 9 (33%) in type1, 4 (50%) in type B2, and 6 (50%) in type B3. There wereo patients with MG in type A or C. Therefore, patientsith type B1, B2, or B3 thymoma most frequently had MG

Table 3).

orld Health Organization Histologic Subtypes andherapeutic Modalities in Thymomall patients with type A, AB, B1, or B2 thymoma under-ent total resection. Patients with type A thymoma hado adjuvant therapy. Most patients of types AB and B1

hymomas with adjuvant therapy had prophylactic radio-herapy (Table 4). All patients with type B3 except onenderwent total resection. Of 28 patients with type C

hymoma, 13 patients (46%) underwent total resection, 414%) had subtotal resection, and 11 (39%) were inoper-ble. Seven of the 11 inoperable patients underwentadiochemotherapy. The frequency of chemotherapy asdditional therapy increased in types B2, B3, and Chymomas (50% to 100%).

able 3. World Health Organization Histologic Subtypes and

istologicubtype I II III IVa I

4 4 0 0B 11 5 1 01 11 11 1 22 3 3 2 03 5 2 2 2

2 1 11 2otal 36 26 17 6

Cases with stage III or IV tumor in individual subtype.

G � myasthenia gravis.

able 4. Therapeutic Modalities and Recurrence in World Hea

istologicubtype

Resection

Total Subtotal Inope

8 100% 0 0 0B 17 100% 0 0 41 27 100% 0 0 122 8 100% 0 0 23 11 92% 0 1 4

13 46% 4 11 22otal 84 84% 4 12 44

It was the recurrence rate from patients with total or subtotal resection

hemo � chemotherapy; Inope � inoperable; Rad � radiotherapy.

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orld Health Organization Histologic Subtypes andecurrence in Thymomahe recurrence rate of patients with total or subtotalesection of the tumor is shown in Table 4. There was noecurrence in patients with types A, AB, and B2 thy-oma. The recurrence rates of patients with types B1, B3,

nd C thymoma were 15%, 36%, and 47%, respectively.or statistical analysis, thymoma was divided into fourategories: thymoma including neoplastic epithelial cellsaving spindle or oval shape (types A and AB), thymomahowing organoid pattern (types B1 and B2), atypicalhymoma (type B3), and carcinoma (type C). None of theatients with types A and AB thymoma developed recur-ence. Disease-free survival was 83.1% for types B1 and2, 83.3% for type B3, and 33.7% for type C thymoma at 5ears and 83.1% for types B1 and B2, 35.7% for type B3,nd 27.1% for type C thymoma at 10 years (Fig 1). Thereas a significant difference in disease-free survival be-

ween types A and AB and types B1 and B2 (p � 0.0436),nd between type B3 and type C (p � 0.042). There was aendency for disease-free survival of patients with type3 thymoma to be worse than that of patients with types1 and B2 thymoma (p � 0.061). Patients with type B3

hymoma were at risk for late relapse between 5 and 8ears. On the other hand, patients with type C thymomaere at risk for early relapse between 4 months and 4 years.

aoka Clinical Stagea

Total

Cases ofInvasion to

Neighboring MG

8 0 0.0% 0 0.0%17 1 5.9% 1 5.9%27 5 18.5% 9 33.3%8 2 25.0% 4 50.0%

12 5 41.7% 6 50.0%28 25 89.3% 0 0.0%

100 38 38.0% 20 20.0%

rganization Histologic Subtypes

vantapy

Rad andChemo

OnlyRad

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0% . . . . . . . . . 0 0%24% 0% 100% 0% 0 0%44% 8% 67% 25% 4 15%25% 50% 0% 50% 0 0%33% 50% 50% 0% 4 36%79% 64% 18% 18% 8 47%43% 41% 41% 18% 16 19%

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orld Health Organization Histologic Subtypes andurvival in Thymomahe survival curve of patients with thymoma according

o WHO histologic subtypes is shown in Figure 2. The 5-r 10-year survival rates of types A and AB, types B1 and2, type B3, and type C thymoma were 100%, 94.4%,1.7%, and 57.8%, respectively. Significant differences inurvival rate were observed between types A and AB andype B3 (p � 0.0357), and between types B1 and B2 andype C (p � 0.0004). There was a tendency for survivalate of patients with type C thymoma to be worse thanhat of patients with type B3 (p � 0.0962).

asaoka Clinical Stage and Therapeutic Modalities inhymic Epithelial Tumorll patients with stage I or II thymoma underwent total

esection. Most of the patients with stage I thymomanoninvasive thymoma) had no adjuvant therapy (Table). One third of patients with stage II thymoma haddjuvant therapy, most of which was prophylactic radio-herapy. In stage III or IV thymomas, the rate of totalesection decreased with increasing stage (stage III, 72%;tage IVa, 50%; stage IVb, 47%). Most of the patients withtage III or IV thymomas (82% to 100%) had adjuvantherapy, most of which included chemotherapy (61% to00%).

linical Stage and Recurrence in Thymic Epithelialumorhe recurrence rate of patients with total or subtotalesection of the tumor according to clinical stage ishown in Table 5. The recurrence rates of patients withtages I, II, III, and IV thymoma were 2.8%, 7.7%, 50%,nd 50%, respectively. Disease-free survival was 100% fortage I, 94.4% for stage II, 56.3% for stage III, and 20.8%or stage IV at 5 years, and 93.8% for stage I, 84.0% fortage II, and 43.8% for stage III at 10 years. There was aignificant difference in disease-free survival betweentage II and stage III (p � 0.0018). There was a tendency

ig 1. Disease-free survival curve of thymoma according to Worldealth Organization histologic classification.

or disease-free survival of patients with stage IV thy- n

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oma to be worse than that of patients with stage IIIp � 0.0574; Fig 3).

linical Stage and Survival in Thymic Epithelialumorhe survival curve of patients with thymic epithelial

umors according to clinical stage is shown in Figure 4.he 5-year survival rates of stages I, II, III, IVa, and IVb

hymoma were 100%, 100%, 68.8%, and 57.2%, respec-ively. A significant difference in survival rate was ob-erved between stages II and III (p � 0.0017). There waso significant difference in survival rate between stages Ind II, or stages III and IV.

ultivariate Analysis of Disease-Free Survival andverall Survival in Thymomaisease-free survival of patients with thymoma wasependent on only Masaoka clinical stage (p � 0.002).ex, age, association with MG, completeness of resection

p � 0.051), and WHO histologic classification (p � 0.117)ere not factors predictive of survival. Survival of pa-

ients with thymoma was dependent on Masaoka clinicaltage (p � 0.040) and completeness of resection (p �.049). Sex, age, association with MG, and WHO histo-ogic classification (p � 0.687) were not factors predictivef survival.

omment

few reports have investigated the applicability andlinical significance of the WHO histologic classificationf thymoma since its publication in 1999 [13, 14]. Weeclassified 100 successive cases of thymic epithelialumors excepting 5 thymic carcinoids treated between973 and 2001 at Tokushima University Hospital and fourffiliated hospitals according to the WHO criteria, evalu-ted its relation with clinical stage, and examined sur-ival and disease-free survival with reference to theHO criteria.The present study showed that 95% of thymomas could

e classified using the WHO criteria. The remaining five

ig 2. Survival curve of thymoma according to World Health Orga-

ization histologic classification.

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ases were “combined thymomas,” which consisted of 42 and B3 type thymomas and 1 B3 and C type thymoma.here were also some cases in which it was very difficult

o distinguish type B2 from type B3 thymoma. Shimosato6] reported that distinction between cortical thymomatype B2 thymoma) and well-differentiated thymic carci-oma (type B3 thymoma) appears difficult and that def-

nitions of the two categories vary among authors,hereas Kirchner and associates [10] and Quintanilla-artinez and colleagues [15] described the presence of

orderline areas and borderline cases of them.The proportions of WHO thymoma subtypes, ie, types, AB, B1, B2, B3, and C thymoma in this study were

%, 17%, 27%, 8%, 12%, and 28%, respectively. Theroportions of WHO thymoma subtypes among pa-

ients from Asia were 4.0% to 10.3% in type A, 19.5% to4% in type AB, 8.5% to 13.8% in type B1, 16.1% to 33%n type B2, 13.5% to 23% in type B3, and 8% to 18% in type

[14, 16, 17].The WHO histologic subtype showed good correla-

ions to the state of invasion to neighboring organs, therequency of recurrence, and disease-free survival. Thereere differences in disease-free survival between types A

nd AB and types B1 and B2, between types B1 and B2nd type B3, and between type B3 and type C. However,n the overall survival rate, there was no significant

able 5. Therapeutic Modalities and Recurrence in Masaoka S

tage

ResectionTotal

ResectionTotal Subtotal Inope

36 0 0 100%I 26 0 0 100% 1II 12 2 3 72% 1Va 3 0 3 50%Vb 7 2 6 47% 1otal 84 4 12 84% 4

It was the recurrence rate from patients with total or subtotal resection

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ig 3. Disease-free survival curve of thymic epithelial tumor accord-

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ifference between types A and AB and types B1 and B2,etween types B1 and B2 and type B3, or between type B3nd type C, although there was a tendency for therognosis to become worse in the order of types A andB, types B1 and B2, type B3, and type C thymoma,ecause patients with recurrent thymoma frequentlyurvived for a long time. We believe that the malignantehavior of thymoma should be evaluated by disease-

ree survival rate as well as overall survival rate, althoughhe previous study evaluated the malignancy of thy-

oma using only the overall survival rate [13, 14].Most of types A and AB thymomas did not invade to

eighboring organs, and they were totally resected andhowed no recurrence or tumor-related death. We con-rmed previous observations that these two subtypes areenign tumors with an excellent prognosis [10, 13, 14].ne fifth of types B1 and B2 thymomas had invasion to

rgans. Although all tumors were totally resected, theyhowed recurrence or tumor-related death in some pa-ients. These types thymomas (organoid thymoma)howed moderate invasiveness and had a small risk ofelapse. About half of type B3 thymomas showed inva-ion to organs. Although most of them were totallyesected, one third of cases had late relapse after morehan 5 years. However, tumor-related death was low.

ost of type C thymomas had invasion to organs at

ng System

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3% 0% 100% 0% 1 3%38% 0% 90% 10% 2 8%82% 50% 21% 29% 7 50%

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1188 KONDO ET AL Ann Thorac SurgWHO HISTOLOGIC CLASSIFICATION OF THYMOMA 2004;77:1183–8

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iagnosis. Although half of them were totally resected,alf of the cases with total resection showed early relapse

rom 4 months to 4 years, and half of them were deadecause of tumor at an early time after relapse. Type C

hymoma should be considered to be a cancer. Theurrent study confirmed the previous investigations that

HO histologic classification was a good prognosticactor compared with the previous histologic classifica-ion of thymoma [13, 14].

Several previous studies showed that clinical stage isne of the most important prognostic factors in thymoma2, 3, 10, 12, 18]. Our previous study of 1,320 patients withhymic epithelial tumors from Japan demonstrated thathe Masaoka clinical stage is an excellent indicator pre-icting the prognosis not only of thymoma but also of

hymic carcinoma [19]. The present study confirmed thatclear-cut distinction is not always feasible in overall

urvival rate and disease-free survival between stage Ind stage II thymomas, but that there is a significantifference between stage II and stage III thymomas.In conclusion, we confirmed that the WHO histologic

lassification reflects the oncologic behavior of thymoma.ypes A and AB thymomas may be treated as benign

umors, and types B1 and B2 thymomas are the border-ine between benign and malignant tumors. On the otherand, type B3 thymoma has a malignant behavior, and

ype C thymoma has more aggressive behavior as aancer. This classification is useful for predicting therognosis and selecting suitable treatment for patientsith thymoma. In the future, by considering WHO his-

ologic classification and Masaoka clinical stage, we canivide thymoma into some subpopulations and select theest treatment for each subpopulation.

e thank Doctor Takafumi Katayama, Medical Informatics,okushima University Hospital, for advice regarding the statis-

ical analysis of this paper.

eferences

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2. Shimosato Y, Mukai K. Tumors of the mediastinum. In: Atlas

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4. Cowen D, Richaud P, Mornex F, et al. Thymoma. Results ofa multicentric retrospective series of 149 non-metastaticirradiated patients and review of the literature. FNCLCCtrialists. Federation Nationale des Centres de Lutte Contre leCancer. Radiother Oncol 1995;34:9–16.

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9. Pescarmona E, Rendina EA, Venuta F, Ricci C, Ruco LP,Baroni CD. The prognostic implication of thymoma histo-logic subtyping. A study of 80 consecutive cases. Am J ClinPathol 1990;93:190–5.

0. Quintanilla-Martinez L, Wilkins EW Jr, Choi N, Efird J, HugE, Harris NL. Thymoma histologic subclassification is anindependent prognostic factor. Cancer 1994;74:606–17.

1. Rosai J. Histological typing of tumours of the thymus. In:WHO International histological classification of tumours,2nd ed. New York: Springer-Verlag, 1999:5–15.

2. Masaoka A, Monden Y, Nakahara K, Tanioka T. Follow-upstudy of thymomas with special reference to their clinicalstages. Cancer 1981;48:2485–92.

3. Okumura M, Ohta M, Tateyama H, et al. The World HealthOrganization histologic classification system reflects the on-cologic behavior of thymoma. A clinical study of 273 pa-tients. Cancer 2002;94:624–32.

4. Chen G, Marx A, Wen-Hu C, et al. New WHO histologicclassification predicts prognosis of thymic epithelial tumors.A clinicopathologic study of 200 thymoma cases from China.Cancer 2002;95:420–9.

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8. Yamakawa Y, Masaoka A, Hashimoto T, et al. A tentativetumor-node-metastasis classification of thymoma. Cancer1991;68:1984–7.

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2004;77:1183-1188 Ann Thorac SurgYasumasa Monden

Sumitomo, Junji Morita, Takanori Miyoshi, Shoji Sakiyama, Kiyoshi Mukai and Kazuya Kondo, Kiyoshi Yoshizawa, Masaru Tsuyuguchi, Suguru Kimura, Masayuki

WHO histologic classification is a prognostic indicator in thymoma

& ServicesUpdated Information

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