RECURRENCE OF THYMOMA: ANALYSIS OF CLINICOPATHOLOGIC FEATURES, TREATMENT, AND OUTCOME

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1 RCURRNC F THYMMA: ANALYSIS F CLINICPATHLGIC FATURS, TRATMNT, AND UTCM nric Ruffini, MD a Maurizi Mancus, MD a Albert liar, MD a Caterina Casadi, MD a Antni Cavall, MD a Rbert Cianci, MD a Pier Luigi Filss, MD a Massim Mlinatti, MD a Calger Prrell, MD a Nazari Cappell, PhD b Giulian Maggi, MD a bjective and methds: This study reprts clinicpathlgic features, treatment, and utcme f 30 recurrent thymmas ut f 266 ttally resected thymmas. Results: The mean disease-free interval t recurrence was 86 mnths. Recurrence ccurred less frequently and after a lnger disease-free interval after resectin f encapsulated versus invasive thymmas. The presence f assciated myasthenia gravis did nt affect recurrence prprtin, disease-free interval, r survival after recurrence. A lcal recurrence ccurred in 11 patients, 17 patients had a distant recurrence, and the extent f the recurrence culd nt be determined in 2 cases. Surgical treatment f the recurrent tumr was attempted in 16 cases, and a ttal resectin was pssible in 10 cases; exclusive raditherapy was dne in 11 cases. verall 5- and 10-year survivals were 48% and 24%, respectively. In a univariate analysis, survival was significantly better in the presence f a lcal recurrence and in case f a ttal resectin f the recurrent tumr. The use f adjuvant therapy after the resectin f the initial thymma had n effect n reducing the incidence f recurrence, in prlnging the disease-free interval, r in imprving survival after the develpment f the recurrence. In a multivariate survival analysis, significant prgnstic factrs were the presence f a lcal recurrence and ttal resectin f the recurrent tumr. Cnclusins: Surgical resectin is recmmended in patients with recurrent thymma. Lcal recurrence and ttal resectin f the recurrent tumr are assciated with excellent prgnsis. A pr prgnsis may be anticipated in the presence f distant recurrence and when radical surgical treatment is nt dne. (J Thrac Cardivasc Surg 1997;113:55-,63) S urgical resectin represents the main therapeutic mdality in the treatment f patients with thymma and has remarkable effects n lng-term survival. Many authrs have emphasized the beneficial impact n prgnsis f pstperative raditherapy, 1-4 which in several studies was fund t imprve survival after resectin f invasive thymmas. thers have advcated the use f preperative chemtherapy in advanced invasive thymmas, and Frm the Department f Thracic Surgery a and the Department f Genetics, Sectin f Bistatistics, b University f Trin, Trin, Italy. Received fr publicatin ct. 10, 1995; revisins requested Jan. 4, 1996; revisins received August 7, 1996; accepted fr publicatin August 7, Address fr reprints: Giulian Maggi, MD, Department f Thracic Surgery, University f Trin, 39/1, Via Millefnti, Trin, Italy. Cpyright 1997 by Msby-Year Bk, Inc /97 $ /1/77141 in ne series this was fund t yield encuraging results n survival, s Unfrtunately, the natural histry f thymma remains unpredictable because f the pssibility f recurrence f the tumr at fllw-up. Mst authrs agree that a prlnged fllw-up is necessary in patients wh underg resectin f thymma because recurrence may ccur up t several years after peratin?' 6-8 The recurrence is generally cnfined t the mediastinum, and smetimes intrathracic pleural disseminatin may ccur, whereas distant metastases are rare. Recurrence is nt infrequent after resectin f either encapsulated thymma r invasive tumrs. The pssibility that a thymma may recur after ttal resectin f the initial thymma has been frequently reprted in the literature. ó' s, 9 Cntrversy exists cncerning ptimal treatment f the recurrent tumr. Bth prpnents f peratin and prpnents f raditherapy have reprted interesting, althugh cnflicting, results. 55

2 56 Ruffini et al The Jurnal f Thracic and January 1997 Table I. Pstsurgical staging f thymma Stage I II III IVA IVB Definitin Macrscpically, cmpletely encapsulated; micrscpically, n capsular invasin Macrscpic invasin in surrunding fatty tissne r mediastinal pleura; micrscpic invasin int the capsule Macrscpic invasin int a neighbring rgan, such as pericardium, great vessels, r lung Plenral r pericardial disseminatin Hematgenus r lymphgenus metastases Table II. Recurrence prprtins by surgical-pathlgic staging and by use f adjuvant raditherapy after resectin f initial thymma Recurrence prprtin Recurrence prprtin Resectin Recurrence prprtin after initial resectin after adjuvant therapy and resectin with n adjuvant therapy after resectin ncapsulated (stage I) 7/152 (5%) 0/7 (0%) 7/145 (5%) Stage II 6/58 (10%) 4/13 (31%)* 2/45 (4%) Stage III 15/50 (30%) 9/14 (64%)* 6/36 (16%) Stage IVa 2/6 (33%) 1/2 (50%) 1/4 (25%) Invasive (ttal) 23/114 (20%)t 14/29 (48%)~ 9/85 (10%) *p = 0.02 versus crrespnding stage/n adjuvant therapy. tp = versus encapsulated thymmas. ~p = versus invasive/n adjuvant therapy. Table III. Recurrence prprtins by surgicalpathlgic staging in patient ppulatin and separately in MG and nn-mg recurrent thymmas Myasthenic Nnmyasthenic Stage Ttal thymmas thymmas I 7/152 (5%) 5/99 (5%) 2/53 (4%) I1 6/58 (10%) 5/45 (11%) 1/13 (8%) III 15/50 (30%) 11/35 (31%) 4/15 (26%) IVa 2/6 (33%) 1/2 (50%) 1/4 (25%) Ttal 30/266 (11%) 22/171 (13%)* 8/95 (8%) *p = 0.2 versus nnmyasthenic thymmas. The aim f the present study was t analyze cases f recurrent thymma after a ttal resectin f the tumr in the patient ppulatin seen at UT department t evaluate the frequency f recurrence, disease-free interval t recurrence, treatment mdalities, and utcme f these patients in relatin t clinicpathlgic features f the initial thymma, assciated myasthenia gravis (MG), and the ttal ppulatin f patients with nnrecurrent thymma. Patients and methds This study was undertaken under ur Investigatinal Review Bard's guidelines fr retrspective chart review. Between 1974 and 1993 a ttal f 310 thymmas were perated n at the Department f Thracic Surgery f the University f Trin. Amng the patients, 266 received a ttal resectin f the tumr. Thirty patients ut f these 266 had a recurrence f the initial thymma, and they represent the ppulatin f the present study. There were 16 men and 14 wmen with a mean age at the time f the riginal peratin f 42 years (range 20 t 71 years). Surgical-pathlgic staging f the initial thymma accrding t Masaka and clleagues 1 was dne (Table I) and revealed 7 encapsulated (stage I) and 23 invasive (6 stage II, 15 stage III, and 2 stage IVa) thymmas. MG was present in 22 patients. Surgical interventin fr all patients with and withut MG included resectin f the thymma and thymectmy. Histlgic study revealed 22 mixed lymphepithelial, 4 predminantly epithelial, and 3 predminantly lymphcytic thymmas and 1 thymic carcinma. The surgical apprach was sterntmy in 22 cases, psterlateral thractmy in 3 cases, and cervictmy with sternal split in 5 cases. Pstperative radiatin therapy was ffered t patients with invasive thymma. Raditherapy was administered with 6 C r 18 MeV phtns frm a linear acceleratr. Dses ranged between 38 and 44 Gy in fractins f 1.8 t 2 Gy ver 4 t 5 weeks. verall, 14 patients with recurrent thymma received adjuvant raditherapy after resectin f the initial thymma, including 4 with stage II, 9 with stage lii, and 1 with stage IVa disease. In 16 patients n adjuvant therapy was used after peratin because f the tumr staging (encapsulated thymmas in 7 cases), patient refusal, transfer f patient t anther institutin, r ther reasns. The interval frm thymectmy t the recurrence (disease-free interval) was defined as the perid frm the peratin fr the initial thymma t the diagnsis f recurrence. The extent f the recurrence was evaluated by the classificatin f Masaka and assciaties TM (Table I). ne patient had a stage I recurrence, and 1, 9, 13, and 4 patients had stage II, stage III, stage IVa, and stage IVb recurrences, respectively. In 2 patients the extent f the

3 The Jurnal f Thracic and Vlume 113, Number 1 Ruffini et al. 57 1,0 C 0,7 9 ~2 8.,. 0,6 %, Fig. 1. verall survival in the 30 cases f recurrent thymma frm the time f recurrence t death r mst recent fllw-up. recurrence was uncertain and thus was nt defined. Stage I thrugh III recurrences were cnsidered as lcal recurrences, whereas stages IVa and IVb were cnsidered distant recurrences. By this classificatin, 11 patients had a lcal recurrence and 17 a distant recurrence. The treatment f the recurrent tumr varied accrding t the extent f the recurrence, the cntrl f MG, and the general cnditin f the patient. peratin was dne in 16 cases; raditherapy was used in 11 cases and f these, 7 had adjuvant raditherapy after the riginal peratin. In 3 patients infrmatin regarding recurrence therapy was lacking. Almst always, recurrent thymmas were apprached by a ttal lngitudinal sterntmy. In nly a minrity f cases, when the recurrence was in the frm f unilateral pleural disseminatin withut mediastinal invlvement, a psterlateral thractmy was preferred. ccasinally, an additinal thractmic access dne ne r tw intercstal spaces belw the first ne (using the same skin incisin) was necessary t prperly resect recurrent lesins n the diaphragm, with a technique similar t that used in pleural mesthelima. A presumably ttal resectin f the recurrent tumr was btained in 10 cases. f these, 8 had a lcal recurrence and 2 a distant recurrence. A subttal resectin with debulking intent was undertaken in 6 patients because f the extent f the recurrence. Raditherapy was used as definitive treatment f the recurrence in 11 cases. f these, 2 had a lcal recurrence and 9 a distant recurrence. The statistical significance f recurrence prprtins was tested with 2 2 cntingency tables. Student's t test (with Fisher's exact test when apprpriate) was used t assess significance levels fr variables measured n an interval scale. A prbability value less than 5% (p < 0.05) was regarded as significant. Survival rates were cmputed by the Kaplan-Meier methd; the lg-rank test was used t cmpare survival curves. A multivariate analysis was dne by the stepwise prprtinal-hazards methd f Cx. 11 Data were analyzed with the use f STATISTICA release 5.0 sftware (StatSft, Tulsa, kla.). Results Recurrence prprtins. Amng 266 radically resected thymmas at ur institutin, 30 recurred (11%, 30/266). Recurrence after initial resectin f encapsulated thymmas ccurred less frequently than recurrence after initial resectin f invasive thymmas (Table II). The use f adjuvant therapy after cmplete resectin f ~nvasive thymmas was nt assciated with a decrease f the incidence f recurrence, either verall r by stage (a statistical analysis by stage was pssible nly fr stage II and stage III thymmas); in fact, adjuvant raditheräpy was assciated with an increase f recurrences (Table II). The recurrence prprtin f patients with

4 58 Ruffini et al. The Jurnal f Thracic and January ,0 Cr~ t"- 9 : > D 0,7 0,6 Im,,ùùù,ù. mù-,,, I l! i m... g... ~ DFI < œ'"" DFI > 60 Fig. 2. Survival by the disease-free interval. DFI <60, Disease-free interval shrter than 60 mnths; DFI >60, disease-free interval lnger than 60 mnths; p = 0.7. and withut assciated MG did nt shw statistically significant differences (Table III) either verall r by stage. Disease-free interval. Analysis f disease-free interval was dne n the ppulatin f 30 patients with recurrent thymmas. Disease-free interval ranged frm 4 t 192 mnths (mean 86, standard deviatin 45 mnths; the variable fllws a nrmallike distributin). A lnger mean disease-free interval was fund in encapsulated thymmas than in invasive thymmas (132 vs 71 mnths, p = 0.002). The use f adjuvant therapy had n effect n prlnging the disease-free interval in invasive thymmas. In fact, mean disease-free interval was lnger in patients wh did nt receive adjuvant therapy than in thse wh did (110 vs 57 mnths, p = 0.04). xtent f reeurrenee. The extent f recurrence was analyzed with regard t the stage f the initial thymma and separately fr MG and nn-mg recurrent thymmas. We fund that the incidence f recurrence in patients with MG was the same as that in the verall grup f patients. Bth lcal and distant recurrences were bserved after initial thymmas in every stage, althugh a lcal recurrence was slightly mre frequent in earlier stages f the initial thymma and in MG thymmas. The small number f cases, hwever, did nt allw statistical analysis. verall, a lcal recurrence ccurred in 2 (33%) f 6 cases f nn-mg recurrent thymmas (in 2 cases the extent f the recurrence was nt determined) and in 9 (41%) f 22 cases f MG recurrent thymmas. Survival. Survival curves were calculated frm the time f recurrence t the event f interest (death r the mst recent fllw-up in censred bservatins). The time frm the initial peratin t recurrence was cnsidered as a cvariate in the analysis. verall 5- and 10-year survivals fr the 30 recurrent thymmas were 48% and 24% (Fig. 1). We perfrmed a survival analysis by the Kaplan- Meier methd, adjusting fr each f five independent variables (Figs. 2 t 6): (1) disease-free interval (>60 r <60 mnths); (2) MG; (3) adjuvant therapy after resectin f the initial thymma; (4) treatment f the recurrent tumr (cmplete resectin, subttal resectin, nnsurgical therapy); and (5) extent f the recurrence (lcal r distant). We cmpared the survival curves with use f the lg-rank test. Survival was significantly better in patients wh did nt

5 The Jurnal f Thracic and Vlume 113, Number 1 1! Ruffini et al. 59 C -s - :..2.-s 0,7 i 0,6 i 0 m... ~m... m,,ù,ù,ù~... i....um Fig. 3. Survival by the presence f assciated MG; p = c-- MG u-,ù, N MG receive adjuvant therapy (p = 0.04), in patients in whm the recurrent tumr culd be ttally resected (p = 0.008), and in patients with a lcal recurrence (p = 0.004). By cntrast, the presence r absence f assciated MG and a disease-free interval shrter r lnger than 60 mnths had n influence n survival. A Cx regressin mdel was used adjusting fr all the afrementined independent variables (diseasefree interval was cnsidered in the multivariate analysis as a cntinuus rather than a categrical variable) and adjusting fr age cnsidering tw grups f patients, yunger and lder than 40 years, which apprximates the mean age f the patient ppulatin (the variable fllws a nrmal-like distributin). A final mdel was selected that included nly thse variables that were significant. Significant independent prgnstic factrs were the extent f the recurrence (/3 = 1.84; S* 0.88;p = 0.03), ttal resectin f the recurrent tumr (/3 = 1.85; S = 0.84; p = 0.03), and absence f adjuvant therapy after the initial resectin (/3 = -1.44; S = 0.69; p = 0.04). *Standard errr. Discussin peratin represents the main therapeutic mdality in patients with thymma, with the pssible use f adjuvant raditherapy r chemtherapy. Cmplete resectin f the thymma has been fund t have a remarkable effect n the lng-term survival f these patients. Unfrtunately, the pssibility f recurrence after ttal resectin f the tumr exists and has been extensively reprted in the literature. A number f reprts indicate recurrence rates after ttal resectin f thymma variably ranging frm 8% t 18%. 3, 6, 90ur prprtin f 11% f 226 ttal resectins cmpares favrably with the results in the literature. Recurrence rates are crrelated with the clinical stage. After resectin f encapsulated thymmas a mdest recurrence rate may be anticipated, which has been variably reprted in the literature between 0% and 10%.3, 6, 7, 12 The crrespnding figure in the present series was 5% (7/152). The recurrence prprtin after resectin f invasive thymmas in the present series was 20% (23/114), and cmparable figures ranging frm 11% t 36% have been reprted by several investigatrs. 3' 7, 12, 13 The assciatin f thymma and MG has been

6 60 Ruffini et al. The Jurnal f Thracic and January ,0, 0,7 C.- :. 0,6 I,. ù,ùù.ù,ùù,ùù,ùæù. ù, ù, ù,, ù.ll """"''"""''`,'""` '''"''"'`"'"""""' "'''''''"'"" 1 D-,ùùù,--ù-,ù,III N AD J-TH D,, AD&TH Fig. 4. Survival in cases f recurrent thymma by the use f adjuvant raditherapy (ADJ-TH) after the resectin f initial thymma; p = extensively investigated. Sme authrs fund that myasthenic thymmas recurred less frequently than nnmyasthenic thymmas. 2'3 By cntrast, ther studies reprted a mdest and nt significant difference in the recurrence rates between the tw grups. 6 In the present study we did nt find any significant difference in the incidence f recurrence, extent f the recurrence, r survival between MG and nn-mg recurrent thymma s. The disease-free interval frm the initial resectin t recurrence has been reprted t be as lng as 10 years 6, 7 and lnger after resectin f encapsulated thymmas. ur results cnfirm these findings. We agree, therefre, that lifetime surveillance and careful fllw-up f patients wh underg resectin f thymma (either encapsulated r invasive) are strngly advcated. In additin, we did nt find an assciatin between a lnger disease-free interval and a better survival rate either by univariate r multivariate analysis. Recurrence after resectin f the initial thymma may be lcal r distant. In ut ppulatin, a lcal recurrence cnfined t the mediastinum withut pleural disseminatin ccurred in 39% (11/28) f the cases, whereas intrathracic r extrathracic disseminatin (bth cnsidered as distant recurrence) were present in the remaining 61% (17/28). We, in accrdance with findings f ther authrs, 9 bserved that lcal and distant recurrences ccur with similar frequencies fr each stage f the initial thymma, irrespective f the presence f assciated MG disease. A significantly better survival is expected in the presence f lcal recurrence with a 5-year survival apprximating that f the ppulatin f patients with resected nnrecurrent thymmas. Imprtantly, the extent f the recurrence was a significant prgnstic factr in a multivariate survival analysis. ptimal treatment f the recurrent tumr may be exceedingly ditticult because f the general technical difficulties f secnd peratin, the frequent invlvement f intrathracic rgans, the pssibility f intrathracic disseminatin f the recurrence, and the presence f assciated severe myasthenic cnditins. The tw main therapeutic ptins, raditherapy and peratin, present advantages and disadvantages and have been widely used by a number f authrs bth separately and cmbined with cnflicting results. Unfrtunately, nly a few series are available in the literature that cmpare patients receiving peratin with patients receiving raditherapy fr treatment f the recurrent tumr. 14 In a previus reprt, we indicated that better survival

7 The Jurnal f Thracic and Vlume 113, Number 1 Ruffini et al 61 1,0 c ~ 9 fit. t~ 3 0,7 0,6 i"... : --.c 7 i : i :... i~.. Jl,,ll... I... i... : i J i. i Z ~ TTAL u,ù- RAD-TH Ib '«'- SUBTTAL Fig. 5. Survival by the treatment f the recurrence. Ttal, Ttal resectin; RAD-TH, exclusive raditherapy; Subttal, subttal resectin; p = ttal versus subttal plus exclusive raditherapy. 1,0. Il ù--g t,-,b.~- 0,7 ;œ... I!I 0,6 "" i ]~ùùù,,«e... ~ 0. r~! i11, LCAL l,,-distant Fig. 6. Survival by the extent f recurrence. Lcal, Lcal recurrence; Distant, distant recurrence; p =

8 6 2 Ruffini et al. The Jurnal f Thracic and January 1997 was expected when tumr recurrence was surgically treated than when nnsurgical therapies (raditherapy with r withut chemtherapy) were used, but at that time the difference was nt significant. 8 An additinal study frm ur department n 21 patients with intrathracic recurrence shwed a 7-year survival f 74% when peratin was used and f 65% when nly raditherapy was used; again, the difference was nt significant. 15 The results f the present study n a larger number f patients suggest that ttal resectin f the recurrent tumr ffers the best chance f lng-term survival. A subttal resectin, rten expressin f mre extensive disease, is usually assciated with a pr prgnsis, even with the additin f radiatin therapy. It shuld be nted, hwever, that the patients were nt randmly recruited fr the treatment f the recurrence; after a careful preperative and radilgic study thse patients with a presumably resectable recurrent tumr were ffered surgical peratin, whereas thse patients with a suppsedly mre advanced recurrence were given radiatin therapy. This ethically unavidable clinical bias implies that the difference f survival curves may result frm a different cnditin f the recurrent tumr rather than frm an actual effect f therapy. Despite the limits f a retrspective analysis, hwever, we recmmend peratin whenever feasible in recurrent thymmas, and similar cnclusins have been reached by ther authrs. 16 Cmplete resectin f the recurrent tumr is a frmidable task fr the surgen, because f the presence f psactinic fibrus tissue, neplastic invasin f mediastinal structures, and scar tissue frm the initial peratin. In the present series, a ttal resectin f the recurrent tumr was pssible in 62% (10/16) f the cases in which peratin was dne (10/30, 33% f the entire series), and 5-year survival in this grup was excellent (72%). The inability t perfrm a radical resectin ften results frm invlvement f the heart, ascending arta, r main pulmnary artery. In mst cases, this may nly be ascertained at the time f peratin. Adjuvant raditherapy after resectin f thymma has been fund in several studies t reduce recurrence rates, t increase the disease-free interval t recurrence, and t imprve lng-term survival after the develpment f the recurrence. 3' 17, 18 By cntrast, sme authrs have reached the ppsite cnclusin.19, 2 In the present study, adjuvant raditherapy after the initial resectin was nt assciated with a reductin f the incidence f recurrence; it had n effect n prlnging the recurrence inter- val and did nt increase survival after the develpment f the recurrence. ur results are in accrdance with thse f ther investigatrs wh fund that verall recurrence rates f invasive thymmas were nt significantly decreased by pstperative mediastinal irradiatin. 9'2 '21 The results f the effect f adjuvant raditherapy n recurrence must be interpreted with great cautin because, at least in the present study, the allcatin f patients with invasive thymmas t the radiatin r n-radiatin grup after the initial resectin was nt randm. f 114 patients with invasive thymmas, 29 received raditherapy after peratin and 85 did nt. The selectin f patients might well have been biased, and it is pssible that patients wh received raditherapy were selected because f a mre clinically advanced stage, even if they had received a ttal resectin. This selectin bias can accunt fr the surprising survival advantage in the n-radiatin grup, which was evident in bth univariate and multivariate analysis. Nnetheless, even when this cnsideratin is taken int accunt, ne might hypthesize that the beneficial effect f pstperative raditherapy n recurrence is questinable and deserves further investigatin. In cnclusin, the majr message f the present study n 30 recurrent thymmas ut f 266 ttal resectins is that patients with lcal recurrence in whm a ttal resectin f the recurrent tumr may be accmplished have an excellent prgnsis. Survival f these patients is similar t that f patients with cmplete resectin in whm recurrence did nt develp. RFRNCS 1. Chen DJ, Rnnigen LD, Graeber GM, et al. Management f patients with malignant thymma. J Thrac Cardivasc Surg 1984;87: Nakahara K, hn K, Hashimt J, et al. Thymma: results with cmplete resectin and adjuvant pstperative irradiatin in 141 cnsecutive patients. J Thrac Cardivasc Surg 1988;95: Mnden Y, Nakahara K, Iika S, et al. Recurrence f thymma: clinicpathlgical features, therapy and prgnsis. Ann Thrac Surg 1985;39: Marks RD Jr, Wallace KM, Pettit HS. Radiatin therapy cntrl f nine patients with malignant thymma. Cancer 1978;41: Rea F, Sartri F, Ly M, et al. Chemtherapy and peratin fr invasive thymma. J Thrac Cardivasc Surg 1993;106: Lewis J, Wick MR, Scheithauer BW, Bernatz P, Taylr WF. Thymma: a clinicpathlgic review. Cancer 1987;60: Verley JM, Hllmann KH. Thymma: a cmparative study f

9 The Jurnal f Thracic and Vlume 113, Number 1 Ruffini et al. 63 clinical stages, histlgic features, and survival in 200 cases. Cancer 1985;55: Maggi G, Casadi C, Cavall A, Cianci R, Mlinatti M, Ruffini. Thymma: results f 241 perated cases. Ann Thrac Surg 1991;51: Haniuda M, Mrimt M, Nishimura H, Kbayashi, Yamanda T, Iida F. Adjuvant raditherapy after cmplete resectin f thymma. Ann Thrac Surg 1992;54: Masaka A, Mnden Y, Nakahara K, Tanika T. Fllw-up study f thymmas with special reference t their clinical stages. Cancer 1981;48: Lee T. Statistical methds fr survival data analysis. 2nd ed. New Yrk: Jhn Wiley, 1992: Shamji F, Pearsn FG, Tdd TRJ, Ginsberg RJ, Ilves R, Cper JD. Results f surgical treatment fr thymma. J Thrac Cardivasc Surg 1984;87: Fujimura S, Knd T, Handa M, Shiraishi Y, Tamahashi N, Nakada T. Results f surgical treatment fr thymma based n 66 patients. J Thrac Cardivasc Surg 1987;93: Ribet M, Visin C, Pruvt FR, Ramn P, Dambrn P. Lymphepithelial thymmas: a retrspective study f 88 resectins. ur J Cardithrac Surg 1988;2: Urgesi A, Mnetti U, Rssi G, Ricardi U, Maggi G, Sannazzari GL. Aggressive treatment f intrathracic recurrences f thymma. Radither ncl 1992;24: Kirschner PA. Reperatin fr thymma: reprt f 23 cases. Ann Thrac Surg 1990;49: Batata MA, Martini N, Huvs AG, Aguilar RI, Beattie J Jr. Thymmas: clinicpathlgic features, therapy and prgnsis. Cancer 1974;34:38% Simpsn WL Raditherapy f thymic tumrs. In: Givel J-C, ed. Surgery f the thymus: pathlgy, assciated disrders and surgical technique. Berlin: Springer-Verlag, 1990: Slater G, Papatestas A, Genkins G, Krnfeld P, Hrwitz SH, Bender A. Thymmas in patients with myasthenia gravis. Ann Surg 1978;188: Blumberg D, Prt JL, Weksler B, et al. Thymma: a multivariate analysis f factrs predicting survival. Ann Thrac Surg 1995;60: Crucitti F, Dgliett GB, Bellantne R, Perri V, Tmmasini, Tnali P. ffects f surgical treatment in thymma with myasthenia gravis: ut experience in 103 patients. I Surg ncl 1992;50:43-6.