Lung Cancer (2005) 50, 59—66

World Health Organization histologicclassification: An independent prognostic factorin resected thymomas

Ottavio Renaa,∗, Esther Papaliaa, Giuliano Maggib, Alberto Oliarob,Enrico Ruffinib, PierLuigi Filossob, Maurizio Mancusob,Domenico Noveroc, Caterina Casadioa

a Thoracic Surgery Department, University of Eastern Piedmont, ‘‘Maggiore della Carita’’ General

Hospital, via Mazzini 18, Novara 28100, Italyb Thoracic Surgery Department, University of Torino, Torino, Italyc Pathology Department, University of Torino, Torino, Italy

Received 14 February 2005; received in revised form 13 May 2005; accepted 19 May 2005

KEYWORDSThymus;Thymoma;Tumour;Surgery;Histology;Survival

Summary The histologic classification of thymoma remained controversial since1999, when the World Health Organization (WHO) Consensus Committee publisheda histologic typing system for tumours of thymus. Clinical features, postoperativerelapsing rates, and survival of patients with thymoma were evaluated with ref-erence to the WHO histologic classification, based on a series of 178 patients,submitted to surgery between 1988 and 2000.There were 21 type A, 49 type AB,45 type B1, 50 type B2 and 13 type B3 tumours. The invasiveness of tumours was23.8%, 51%, 73.3%, 82% and 100% for types A, AB, B1, B2 and B3 tumours, respec-tively. The frequency of invasion of the great vessels increased according to thetumour type in the order A (0%), AB (4%), B1 (6.6%), B2 (22%), and B3 (23%). The10-year disease-free survival was 95%, 90%, 85%, 71% and 40% for types A, AB, B1,B2 and B3, respectively. According to the Masaoka staging system, the disease-freesurvival rates were 94%, 88% and 66% for stages I, II and III, respectively, at 10years. No stage IVA thymomas reached 10 years follow-up. Overall survival at 10years were 88% and 25% when complete and incomplete resection were considered.By multivariate analysis, Masaoka staging system, WHO histologic classification andcomplete resection were significant independent prognostic factors, whereas age-and sex-associated myasthenia gravis were not. The present study demonstrated theWorld Health Organization histologic classification a good prognostic factor, such ascompleteness of surgical resection and Masaoka staging system.© 2005 Elsevier Ireland Ltd. All rights reserved.

∗ Corresponding author. Tel.: +39 0321 3733363; fax: +39 0321 3733578.E-mail address: ottaviorena@libero.it (O. Rena).

0169-5002/$ — see front matter © 2005 Elsevier Ireland Ltd. All rights reserved.doi:10.1016/j.lungcan.2005.05.009

60 O. Rena et al.

1. Introduction

Thymomas are uncommon neoplasms that arederived from the epithelial cells of the thymus. Sev-eral classifications have been proposed in the pastto correlate histology and clinical course.

Previous study have demonstrated that thepropensity of invasion to neighbouring tissues asreflected by the staging system of Masaoka andcolleagues negatively affects prognosis in thesepatients [1]. Surgery remains the mainstay of treat-ment, and radiation or chemotherapy also havebeen applied widely as adjuvant, palliative andrecently reported neoadjuvant procedures [2—5].

The reported results regarding the benefit ofadjuvant treatment after resection are still con-troversial, indicating that the Masaoka classifica-tion might not be sufficient to clarify the roleof combined treatment modalities in patientswith advanced disease [6—8]. Therefore, not onlystaging the extent but also grading the tumourcould be required to predict prognosis, recur-rence pattern in thymomas and might help todefine more precisely the role of adjuvant andneoadjuvant treatments. Histological classification

Surgery Department of the University of Torinoand Novara. Nineteen tumours were diagnosedas thymic carcinoma or thymic carcinoids. Theremaining 178 tumours had the diagnosis of thy-moma and were the focus of the present study.There were 90 male and 88 female patients.Patients age at the time of surgery ranged between16 and 84 years, and the average age was 52 years.

Seventy patients (39.3%) manifested myastheniagravis (n = 66; 37%) or other autoimmune disorders(n = 10; 5.6%) related to the disease.

One-hundred and fifty patients (84%) underwentcomplete resection macroscopically, 26 patients(14%) underwent incomplete resection, and 2patients (2%) resulted to be inoperable and weresubmitted to incisional biopsy only.

Adjuvant therapy has been administered in 87patients (48%): radiotherapy alone in 63 patients(35%), chemotherapy alone in 9 patients (5%), andradio-chemotherapy in 14 patients (8%).

2.2. Histology and clinical—pathologicalstaging

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of thymomas remained a controversial subject formany years. In 1989, Marino and Muller-Hermelinkclassified thymic tumours in medullary, mixed,predominantly cortical, cortical thymoma, well-differentiated thymic carcinoma, and high-gradethymic carcinoma [9].Their classification has beenreported to be useful in predicting outcomes ofpatients affected by thymic tumours [10—12]. In1999, a new histologic subtyping system of thymictumours has been published by the World HealthOrganization (WHO) Consensus Committee [13].Thymomas are now stratified into five entities(types A, AB, B1, B2, and B3) on the basis of the mor-phology of the epithelial cells and the lymphocyte-to-epithelial cell ratio.

In this retrospective research, we report on theWHO histologic classification, its clinicopathologi-cal relationship and relevance in the prognosis of178 cases of thymoma operated at the ThoracicSurgery Department of the University of Torino andNovara in Italy between 1988 and 2000.

2. Material and methods

2.1. Patients

During a 13-year period, from January 1988 toDecember 2000, 197 consecutive cases of thymicepithelial tumours were operated at the Thoracic

hymomas were classified according to the WHOriteria [13] and divided into five subtypes (types, AB, B1, B2, and B3). Type A thymomas areumours composed of a population of neoplastichymic epithelial cells having spindle/oval shapeithout nuclear atypia, and accompanied by fewr no non-neoplastic lymphocytes. Type AB thymo-as are tumours in which foci with type A thymoma

eatures are admixed with foci rich in lymphocytes.ype B1 thymomas are tumours resembling the nor-al functional thymus in that they combined large

xpanses having an appearance pratically indistin-uishable from normal thymic cortex with areasesembling thymic medulla. Type B2 thymomas areumour in which the neoplastic epithelial compo-ent appears as scattered plump cells with vesci-ular nuclei and distinct nuclei among a heavyopulation of lymphocytes. Perivascular spaces areommon and sometimes very prominent. A perivas-ular arrangement of tumour cells resulting in aalisading effect may be seen. Type B3 thymomas predominantly composed of epithelial cells hav-ng a round or polygonal shape and exhibiting nor mild atypia. They are admixed with a minoromponent of lymphocytes, resulting in a sheet-ike growth of the neoplastic epithelial cells. Allamples were diagnosed and re-classified by theame pathologist (N.D.) on the basis of routineistologic sections, stained with hematoxylin andosin. Six cases out of 178 were represented by‘combined thymoma’’ consisting of type B2 plus

World Health Organization histologic classifications 61

B3 thymomas; they were all classified as B2 thy-momas because the B2 component resulted thepredominant one.

Pathological staging was decided on the basis ofthe Masaoka staging system [1]. Stage I thymoma isa tumour macroscopically completely encapsulatedand without microscopic capsular invasion. StageII thymoma demonstrates a macroscopic invasioninto surrounding fatty tissue or mediastinal pleuraor a microscopic invasion of the capsule. StageIII thymoma is a tumour with macroscopic inva-sion into neighbouring organs, such as pericardium,great vessels or lung. Stage IVA thymoma demon-strates pleural or pericardial dissemination. StageIVB thymoma is characterized by lymphogenous orhematogenous metastasis.

2.3. Follow-up of patients and statisticalanalysis

Analyses of survival and tumour-recurrence rateswere performed based on the outcome of patients,who underwent surgery before 31 December 2000.Follow-up data were obtained for 174 patients untildpp

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gated by the method of the Cox regression analysis.Significant values were considered when p < 0.05.

3. Results

All 178 patients were operated on sternotomy,anterolateral thoracotomy and posterolateral tho-racotomy performed in 84.5%, 6.5% and 9% cases,respectively. One-hundred sixty-seven patients(96.5%) had uneventful postoperative period. Therewas no perioperative mortality. Six patients (3.5%)had complications requiring medical or surgi-cal treatment: supraventricular arrhythmias (1),bleeding (4), and deep venous thrombosis (1). Nomyasthenia gravis patients required postoperativemechanical ventilation and morbidity was not influ-enced by the autoimmune disorder.

WHO histologic type was determined in all 178tumours, and there were 21 (12%) patients withtype A tumour, 49 (27%) patients with type ABtumour, 45 (25%) patients with type B1 tumour, 50(28%) patients with type B2 tumour and 13 (7%)patients with type B3 tumour. There was no sig-nificant difference in the distribution of genderamtmt1hC

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eath or completion of the study (June 2004). Fouratients were missed at follow-up. Mean follow-uperiod was 7 years (range 1—15 years).

The outcome of patients was confirmed by thehysicians’ records and postoperative follow-uponsisted of an annual chest X-ray examination.hen tumour recurrence was suspected, chest-

omputed tomography scans were used for furthervaluation. When resection of the recurrent tumouras feasible, surgical treatment was adopted. Oth-rwise, chemotherapy or radiation therapy washosen. To focus on the oncologic behaviour ofhymoma, the patients who died of myastheniaravis or other autoimmune-associated diseases,ther diseases or accidents were considered drop-ut patients at the time of the event. In this study,isease-free survival refers to freedom from tumourelapse and overall survival refers to freedom fromumour death.

Associations between categoric variables wereetermined by using the Chi-square test. The statis-ical difference of the average value was examinedith a Student’s t-test or an analysis of variance

ollowed by the Bonferroni test.The Kaplan—Meier method was used for the anal-

sis of disease-free and overall survival, and log-ank test was utilized to compare the survival data.ultiple predictors (age <52 years, age >52 years,

ex, presence of associated autoimmune diseases,asaoka staging system, completeness of resec-

ion, WHO histologic classification) were investi-

nd in the average age between the types of thy-oma, according to the WHO histologic classifica-

ion. Patients who had type B1, B2 or B3 tumoursore frequently had disease associated with myas-

henia gravis or other autoimmune disorders (62 of06 patients; 36.9%) compared with patients whoad type A or AB tumours (10 of 70 patients; 14.3%;hi-square test 14.504; p = 0.0001).

When the Masaoka staging system was consid-red, 62 patients resulted to be affected by stage, 58 by stage II, 36 by stage III and 23 by stage IVAumours.

At the time of the surgical procedure, thymomaas non-invasive in 34.8% of cases. When inva-

ive, the tumour involved pleura (84%), pericardium45.7%), lung (28%), phrenic nerve (7.7%) or supe-ior vena cava system (11.6%). In 23 patients, thy-oma was initially metastatic; all metastases were

ntrathoracic (pleuropulmonary). Thymoma resec-ion was enlarged to the pleura, pericardium oroth in 80 cases, to the lung in 37 cases (all wedgeesections), to one phrenic nerve in 13 cases, to theuperior vena cava system in 19 cases (15 innomi-ate vein resections and four vena cava tangentialesections without parietal reconstruction), to theiaphragm in one case.

The relationship between the WHO histologicypes and the Masaoka clinical staging system ishown in Table 1. The average number of casesy stage increased according to the tumour typerom type A to B3. At the analysis of variance, the

62 O. Rena et al.

Table 1 WHO histologic subtypes and Masaoka clini-cal staging system

WHO histo-logic sub-type

Masaoka clinical staging

I II III IVA Total Average

A 16 4 1 0 21 1.29AB 24 21 4 0 49 1.59B1 13 20 9 4 45 2.13B2 9 12 18 11 50 2.62B3 0 1 4 8 13 3.54

Total 62 58 36 23 178

WHO: World Health Organization.

average for stage resulted to be significantly differ-ent (p = 0.0001). Significant differences (p < 0.05)were noted between types A and B2 or B3, betweentypes AB and B2 or B3, and between types B1 andB2 or B3. No significant differences were notedbetween types A and AB, and between types ABand B1.

A correlation was demonstrated betweenMasaoka stages I and II, and WHO types A, AB andB1, and between Masaoka stages III and IVA andWHO types B2 and B3.

Completeness of surgical resection and thera-peutic modalities with reference to the Masaokastaging system resulted as follows: Stage I thymo-mas have been submitted to a complete resec-tion and no one received adjuvant therapies. StageII thymomas were ever submitted to a completeresection too and 28 (48.3%) received adjuvantradiation therapy. Stage III thymomas were sub-mitted to complete resection in 25 cases (69.4%)and 9 were incompletely resected; 35 out of 36patients (97%) were submitted to adjuvant ther-apies (34 patients underwent postoperative radi-ation therapy and one underwent postoperative

chemotherapy). Stage IVA thymomas were com-pletely resected in only five cases (21%) (onepatient did not receive adjuvant therapy, anotherone was submitted to radiotherapy, eight under-went chemotherapy and 14 received an associa-tion of radio- and chemotherapy). According tothe new WHO histologic classification of thymo-mas, the proportion of patients undergoing com-plete resection resulted to be significantly higherin patients affected by A, AB or B1 tumours (106of 115 patients, 92%) than in patients affected byB2 or B3 thymomas (44 of 63 patients, 71.4%; Chi-square test, 13.676; p = 0.0001). Most patients oftypes AB, B1, B2 and B3 (n = 87, 55%) had adjuvanttherapies. All type AB thymomas requiring adjuvanttherapy underwent radiation therapy only. TypesB1, B2 and B3 thymomas received radiation only,chemotherapy only or radiation-chemotherapy indifferent proportion.

3.1. Recurrence according to the WHOhistologic classification and Masaoka clinicalstaging

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Table 2 Completeness of resection and recurrence ratein thymoma

Com. Res. % R

WHO subtypesA 21 100 0AB 45 92 2B1 40 89 4B2 39 78 7B3 5 39 2

Masaoka stageI 62 100 1II 58 100 5III 25 69.4 7IVA 5 21.7 2

WHO: World health Organization; Com. Res.: Complete resecti

t the end of the study, 25 patients mani-ested tumours recurrence. The recurrence rate ofatients with particular regard to the complete-ess of surgical resection according to the WHOistologic classification and Masaoka clinical stag-ng is shown in Table 2. There was only one recur-ence in patients with type A thymoma. Recurrenceate increases from patients affected by type ABo those affected by type B3 thymomas and B2p > 0.05). Patients affected by AB thymoma were atisk for late relapse after a mean of 6 years (range—8), whereas in patients with recurrent types B1nd B2, the mean time of relapse is 5 years (range—10). In patients affected by type B3 thymoma,

cording to the WHO and Masaoka clinical staging system

rrence % Local %

0 0 04.4 2 100

10 4 10018 6 8640 1 50

19 1 1007.4 5 100

28 6 8640 1 50

World Health Organization histologic classifications 63

recurrence can occur after a mean of 3 years (range1—4).

The proportion of patients manifesting tumourrecurrence after a complete resection was signif-icantly lower in patients affected by A, AB or B1tumours (6 of 106 patients, 5.6%) than in patientsaffected by B2 or B3 thymomas (9 of 44 patients,20.4%; Chi-square test, 6.639; p = 0.010). WhenMasaoka clinical staging is considered, the propor-tion of patients manifesting recurrence after com-plete resection is significantly higher in patientsaffected by stage III or IVA tumours (9 of 30, 30%)than in patients affected by stage I or II tumour (6of 120, 5%; Chi-square test, 14.005; p = 0.0001).

3.2. Long-term disease-free survival andoverall survival according to the WHOhistologic classification, Masaoka staging,completeness of resection

At the end of the study, 25 patients manifestedtumour recurrence and 33 patients had died. Seven(21%) died of progressive tumour, 11 (33%) died ofprogressive autoimmune disease, and 15 (45%) diedof miscellaneous diseases.

Survival curves according to the WHO histologicclassification system are shown in Figs. 1 and 2. Thedisease-free survival was 100% for type A, 95% fortype AB, 92% for type B1, 90% for type B2 and 40%for type B3 at 5 years, and 95% for type A, 90% fortype AB, 85% for type B1, 71% for type B2 and 40%for type B3 at 10 years (Fig. 1). There was a sig-nificant difference in disease-free survival between

Fig. 1 Disease-free survival curve according to the WHOhistologic classification of thymoma. (Patients at risk at 5years: type A, n = 18; type AB, n = 32; type B1, n = 26; typeB2, n = 34; type B3, n = 10. Patients at risk at 10 years:type A, n = 9; type AB, n = 13; type B1, n = 9; type B2,n = 11; type B3, n = 3. Patients at risk at 15 years: type A,n = 1; type AB, n = 0; type B1, n = 0; type B2, n = 1; typeB3, n = 0.)

Fig. 2 Overall survival curve according to the WHO his-tologic classification of thymoma. (Patients at risk at 5years: type A, n = 18; type AB, n = 32; type B1, n = 26; typeB2, n = 34; type B3, n = 10. Patients at risk at 10 years:type A, n = 9; type AB, n = 13; type B1, n = 12; type B2,n = 17; type B3, n = 3. Patients at risk at 15 years: type A,n = 1; type AB, n = 0; type B1, n = 0; type B2, n = 1; typeB3, n = 0.)

types A and B2 (p = 0.0085), between types A and B3(p = 0.00016), between types AB and B2 (p = 0.024),between types AB and B3 (p = 0.00002), betweentypes B1 and B3 (p = 0.00027), and between typesB2 and B3 (p = 0.048). No significant difference indisease-free survival was obtained between typesA and AB, between types AB and B1, and betweentypes B1 and B2.

Overall survival was 100% for type A, 100% fortype AB, 100% for type B1, 100% for type B2 and65% for type B3 at 5 years and 100% for type A, 100%for type AB, 94% for type B1, 77% for type B2 at 10years (Fig. 2). There was a significant difference inoverall survival between types A and B3 (p = 0.013),between types AB and B3 (p = 0.0069), betweentypes B1 and B3 (p = 0.019) and between types B2and B3 (p = 0.012). No significant difference in over-all survival was obtained between patients witheach combination of types A, AB and B1 tumours.

Survival curves according to the staging systemof Masaoka et al. are shown in Figs. 3 and 4. Thedisease-free survival was 100% for stage I, 95% forstage II, 81% for stage III, 61% for stage IVA at 5years, and 94% for stage I, 88% for stage II, 66% forstage III at 10 years (Fig. 3). There was a significantdI(bsesIs

ifference in disease-free survival between stagesand III (p = 0.00112), between stages I and IVA

p = 0.00001), between stages II and III (p = 0.012),etween stages II and IVA (p = 0.00004), betweentages III and IVA (p = 0.047). No significant differ-nce in disease-free survival was obtained betweentages I and II. Overall survival was 100% for stage, 100% for stage II, 100% for stage III, 100% fortage IVA at 5 years, and 100% for stage I, 100%

64 O. Rena et al.

Fig. 3 Disease-free survival curve according to theMasaoka staging system of thymoma. (Patients at risk at5 years: stage I, n = 36; stage II, n = 50; stage III, n = 21;stage IVA, n = 9. Patients at risk at 10 years: stage I, n = 14;stage II, n = 21; stage III, n = 9; stage IVA, n = 0. Patientsat risk at 15 years: stage I, n = 1; stage II, n = 0; stage III,n = 1; stage IVA, n = 0.)

for stage II, 85% for stage III at 10 years (Fig. 4).There was a significant difference in overall survivalbetween stages I and III (p = 0.036), between stagesI and IVA (p = 0.00372), between stages II and III(p = 0.041), between stages II and IVA (p = 0.0076),between stages III and IVA (p = 0.047). No significantdifference in overall survival was obtained betweenpatients with stages I and II tumours.

Regarding the completeness of tumour surgicalresection, the disease-free survival was 96.5% forpatients undergoing complete resection and 47% forpatients with incomplete one or incisional biopsy

only at 5 years, and 88% for patients undergo-ing complete resection and 25% for patients withincomplete one or incisional biopsy only at 10 years(p = 0.00001). Overall survival was 92% for patientsundergoing complete resection and 64% for patientswith incomplete one or incisional biopsy only at 10years (p = 0.00198).

3.3. Multivariate analysis of disease-freeand overall survival in thymoma

Multivariate analysis was carried out to deter-mine the prognostic significance of parameterdemonstrated to be significant at the univariateone. Only patients submitted to complete resec-tion of their thymoma were considered whenMasaoka clinical—pathological staging and WHOhistological classification were analyzed. Disease-free survival of patients with thymoma wasdependent on WHO histologic classification sys-tem (p = 0.014) on Masaoka clinical—pathologicalstaging system (p = 0.012) and on completenessof resection (p = 0.0001). Gender, age, associa-tion with myasthenia gravis or other autoim-mune disorders were not factors predictive ofdwWM((nf

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Fig. 4 Overall survival curve according to the Masaokastaging system of thymoma. (Patients at risk at 5 years:stage I, n = 36; stage II, n = 52; stage III, n = 27; stage IVA,n = 8. Patients at risk at 10 years: stage I, n = 15; stageII, n = 25; stage III, n = 1; stage IVA, n = 0. Patients at riskat 15 years: stage I, n = 1; stage II, n = 0; stage III, n = 0;stage IVA, n = 0.)

isease-free survival. Overall survival of patientsith thymoma resulted to be dependent onHO histologic classification system (p = 0.028), onasaoka clinical—pathological classification system

p = 0.036) and completeness of surgical resectionp = 0.018). Gender, age, association with myasthe-ia gravis or other autoimmune disorders were notactors predictive of overall survival.

. Discussion

nly few reports investigated the applicability andrognostic significance of the WHO histologic clas-ification of thymoma since its publication in 1999nd successive re-edition, which doesn’t differrom the first, in 2004 [14—17]. We reported about78 successive cases of thymoma classified accord-ng to the WHO criteria [13], treated between988 and 2000 at the Torino and Eastern Pied-ont University Hospital in Italy. Thymoma sub-

ypes according to the WHO criteria were corre-ated with the clinical and follow-up data of theespective patients.

The histologic features of thymomas are greatlyifferent from one case to another: the most impor-ant characteristic of thymoma is the coesistencef non-neoplastic lymphoid cells associated witheoplastic epithelial cells. The neoplastic epithe-ial cells have a great variability in their morphology

World Health Organization histologic classifications 65

(from spindle cells to ones with polygonal shape) aswell in the atypia grading.

Taking into consideration all the morphologiccharacteristics of the neoplastic cells, the WHOclassification system divided thymomas into fivegroups: type A, AB, B1, B2, and B3. The mentionedclassification system resulted to be effective incategorizing the quite totality of thymomas. Onlysix cases resulted to be out of categorization onthe basis of the WHO criteria and were defined as‘‘combined thymomas’’ consisting of tot B2- andtot B3-type thymomas on the basis of the prepon-derant component of the tumour. In some cases,type B2 from B3 thymomas also were very diffi-cult to be distinguished. Some authors in the pastyears referred that the clear distinction betweentypes B2 and B3 thymomas appears not easily per-formed and the definition of the two subtypes varyamong series; other authors described borderlineareas and borderline cases of both the histologicsubtypes [11,18,19].

The present study demonstrated the WHO histo-logic classification to be an independent prognosticfactor in resected thymomas. The new histologicclassification has a correlation to the Masaoka clin-irv

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positive influence of myasthenia gravis on survivaldid not reach a significant value [6,22]. Accordingto other recent reports considering the WHO his-tologic classification, the presence of myastheniagravis has been demonstrated not to be a prog-nostic factor in resected thymoma at multivariateanalysis [14,17]. The erroneous interpretation ofthe presence of myasthenia gravis as a prognos-tic factors could be related to the different his-tologic classification system adopted in the previ-ous reports [6,20,22,23]. Previous histology classi-fications divided thymomas taking into considera-tion only one or few morphologic characteristicsof the tumours (the prevalence of non-neoplasticlymphoid cells or neoplastic epithelial ones, thegrading of atypia, the morphologic variability ofthe neoplastic cells—–from spindle to polygonal)[24—28]. Consequently, some reports in the pastused the predominance of epithelial or lymphoidcells population as an histologic classification cri-teria; both type A and B3 tumours of the presentWHO classification were cathegorized as predom-inantly epithelial tumours in the past includingthe least invasive tumour with the most aggres-sive ones. This resulted in a misleading evalua-tf

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copathological staging (Table 2), the frequency ofecurrence and the disease-free and overall sur-ival.

In particular, we demonstrate that type B2 and3 thymomas have more malignant behaviour inerms of prognosis and tumour recurrence com-ared with types A, AB and B1 thymomas. Thebove conclusion is not allowing to consider as‘benign thymomas’’ those tumours exhibiting noross evidence of invasion: recurrences and metas-ases after resection have been reported in all largeeries [6,14,16,17,20,21]. This is true for stage Ihymomas (1.9% of recurrence rate with 94% 10-ear disease-free survival in the present study), andt is true for each histologic subtype of thymomas94%, 91% and 85% 10-year disease-free survival inhe present study for types A, AB, and B1 thymo-as, respectively) [6,17,20,21]. Thus, non-invasive

hymomas, such as the subtypes A and AB tumours,ave the fundamental characteristics of a malig-ant tumour despite a relatively indolent course,nd in our opinion, the term ‘‘benign thymoma’’hould be discarded from the daily use.

Some reports in the international literature inhe past showed the Masaoka staging system anndependent prognostic factor in resected thy-oma [22].Similarly, during the past decade, the pres-

nce of myasthenia gravis has been described aspositive factor significantly influencing survival inatients with thymoma [20,23]; in other series, the

ion of the histologic classification as a prognosticactor.

According to other recent reports of the interna-ional literature, in our series, the Masaoka stagingystem was strongly associated with the WHO clas-ification [14]. The presence of myasthenia gravisesulted to be associated to the WHO classificationubtypes too.

Regarding to the use of adjuvant or neoadjuvantherapies, the current study did not discuss theirfficacy because no randomized trial of treatmentas been followed during the complete duration ofhe considered period. Even if not randomized, theresent series confirmed data previously reportedrom our institution that the use of adjuvant ther-pies in invasive thymomas did not affect signifi-antly the disease-free and long-term overall sur-ival when complete or incomplete resection areonsidered [20,21].

In conclusion, the results suggest that the com-leteness of resection, Masaoka clinical stagingystem and the WHO histologic classification arendependent prognostic factors in resected thy-oma. The histology appearance reflects the clin-

cal behaviour of thymoma when new WHO classi-cation system is adopted. Types B2 and B3 thy-oma have more aggressive behaviour compared to

ypes A, AB and B1 when local invasiveness, tumourelapse or postoperative survival are considered.ven if less aggressive than types B2 or B3, types A,B and B1 can manifest neighbouring tissues inva-

66 O. Rena et al.

sion at diagnosis and local recurrence after com-plete resection; the definition ‘‘benign thymoma’’to indicate these subtypes of tumour should beavoided because this could inappropriately influ-ence postoperative treatments and surveillance.Randomized trials are needed in the future todemonstrate the best treatment for each sub-population of WHO histologic classification thymictumours.

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