Impact of Positive Nodal Metastases in Patients with Thymic Carcinoma and Thymic Neuroendocrine Tumors

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1 Originl Article Impct of Positive Nodl Metstses in Ptients with Thymic Crcinom nd Thymic Neuroendocrine Tumors Benny Weksler, MD, Anthony Holden, MD, nd Jennifer L. Sullivn, MD Introduction: Thymic crcinoms nd thymic neuroendocrine tumors re rre diseses often treted with surgicl resection. Currently, there re no guidelines regrding nodl dissection t the time of tumor resection. Moreover, the prognostic significnce of nodl metstses is uncler. The gol of this study ws to define the incidence nd prognostic relevnce of nodl metstses in ptients with thymic crcinom nd thymic neuroendocrine tumors. Methods: The Surveillnce, Epidemiology nd End Results dtbse ws queried for ptients who underwent surgicl resection of thymic crcinom or thymic neuroendocrine tumor with documented pthologicl exmintion of lymph nodes. The incidence of nodl metstses nd the impct on survivl were exmined. Results: We identified 176 ptients with thymic crcinom nd 53 with thymic neuroendocrine tumors. A medin of three lymph nodes ws smpled per ptient. Positive metstsis to t lest one lymph node ws identified in 92 ptients (40.2%). Nodl metstsis ws more common in ptients with thymic neuroendocrine tumors thn in ptients with thymic crcinom (62.3% versus 33.5%). In multivrite nlysis, nodl metstsis ws more likely in ptients with thymic neuroendocrine tumors nd with more dvnced tumors. The presence of nodl metstses hd significnt, independent, dverse impct on survivl (hzrd rtio, 2.933, 95% confidence intervl, , p = 0.001). Medin survivl ws 47 months in ptients with nodl metstsis nd 124 months in ptients without nodl metstses (p < 0.001). Conclusions: Nodl sttus seems to be n importnt prognostic fctor in ptients with thymic crcinom nd thymic neuroendocrine tumors. Nodl smpling should be performed during resection of these thymic mlignncies. Key Words: Thymic tumors, Thymic crcinom, Thymic neuroendocrine tumors, Lymph node metstses, SEER registry. (J Thorc Oncol. 2015;10: ) Thymic crcinoms used to be defined by World Helth Orgniztion (WHO) clssifictions s heterogeneous Division of Thorcic Surgery, Deprtment of Surgery, University of Tennessee Helth Science Center, Memphis, Tennessee. Disclosure: The uthors declre no conflict of interest. Address for correspondence: Benny Weksler, MBA, MD, Division of Thorcic Surgery, University of Tennessee Helth Science Center, 1325 Estmorelnd Ave, Suite #410, Memphis, TN E-mil: bweksler@ uthsc.edu. DOI: /JTO Copyright 2015 by the Interntionl Assocition for the Study of Lung Cncer ISSN: /15/ group of tumors tht include denocrcinom of the thymus, squmous cell crcinom of the thymus, nd neuroendocrine tumors, mong others. 1 The recent WHO clssifiction 2 clerly distinguishes thymic crcinoms from thymic neuroendocrine tumors. Thymic crcinoms re very rre tumors, nd historiclly, they hve not been well studied becuse of the difficulty in cquiring sufficient cses for nlysis. 3 We nd others hve retrospectively nlyzed lrge dtbses to circumvent this limittion. We previously used the Surveillnce, Epidemiology, nd End Results (SEER) dtbse to nlyze prognostic vribles in cohort of 290 ptients with thymic crcinom. 4 In erly 2015, two lrge retrospective dtbse studies were published tht ssessed stge t presenttion, survivl, nd recurrence in ptients with thymic crcinom nd thymic neuroendocrine tumors. 5,6 Although most previous studies on thymic epithelil tumors esily defined the tumor nd metstses, very few studies hve ddressed the incidence nd prognostic significnce of the lymph nodl sttus in ptients with thymic crcinom or thymic neuroendocrine tumors. Our knowledge of nodl sttus in ptients with thymic epithelil tumors comes mostly from study by Kondo et l., 7 who compiled dtbse of 1320 ptients with thymic epithelil tumors including 183 ptients with thymic crcinom nd 40 ptients with thymic crcinoid tumors. The incidence of nodl metstses in these ptients ws 26.8% nd 27.5%, respectively. A smller study by Prk et l. 8 nlyzed nodl metstses in 29 ptients with thymic crcinom who underwent nodl dissection nd found tht 20.8% of ptients hd pthologiclly confirmed nodl metstses. This study ws designed to further define the incidence of nodl metstses in ptients with thymic crcinom nd thymic neuroendocrine tumors nd ssess the prognostic significnce of nodl metstses. MATERIALS AND METHODS Dtbse nd Query Criteri The SEER dtbse is sponsored by the Ntionl Cncer Institute nd hs been used to trck cncer incidence nd ptient survivl since The SEER dtbse currently covers pproximtely 28% of the U.S. popultion nd cptures 98% of ll cncer cses within the surveyed geogrphic res. We used the SEER 18 Registry including the Hurricne Ktrin Impcted Louisin Cses for this nlysis (SEER Progrm [ SEER*Stt Dtbse: Incidence SEER 18 Regs Reserch Dt + Hurricne Ktrin 1642 Journl of Thorcic Oncology Volume 10, Number 11, November 2015

2 Journl of Thorcic Oncology Volume 10, Number 11, November 2015 Impct of Nodl Metstses in Ptients with TC nd NETT Impcted Louisin Cses, November 2010 Sub [ vrying], Ntionl Cncer Institute, Surveillnce Reserch Progrm, Cncer Sttistics Brnch, relesed April 2014 bsed on the November 2013 submission). Specific fields for number of lymph nodes exmined nd number of positive nodes were creted in SEER*Stt softwre (seer.cncer.gov/ seerstt) version ws used for dt mining. The SEER 18 dtbse ws queried for ll cses of thymic crcinom nd thymic neuroendocrine tumors from Jnury 1, 1988 to December 31, 2011 using the ICD-03 codes 8002, 8010, 8012, 8013, 8020, 8021, , 8074, 8140, 8240, 8243, 8246, 8586, 8588, nd We included ptients with the primry site lbeled s C37.9 (thymus). We further refined the ptient cohort to include only ptients who hd resection or debulking of the thymus, hd t lest one lymph node nlyzed pthologiclly, nd who survived for more thn 30 dys fter resection. Ptients with thymom were not included in the nlysis. Using vilble dt, ptients were stged ccording to the Msok-Kog clssifiction. 9 Stge I (no trnscpsulr invsion) nd stge II (microscopic trnscpsulr invsion) could not be differentited from one nother using the vilble dt nd were nlyzed together. The University of Tennessee Helth Science Center Institutionl Review Bord pproved this study, nd the requirement for informed consent ws wived. Sttisticl Anlysis Continuous dt vribles were nlyzed using Student s t test. Nominl dt were nlyzed using crosstbs nd Person s χ 2 test. To identify vribles tht could predict the presence of nodl metstses, univrite binry logistic regression ws performed, followed by multivrite nlysis including only vribles tht hd p vlue less thn 0.10 in the univrite nlysis. Kpln Meier survivl curves were constructed nd compred using the log-rnk test. To ssess vribles tht impcted overll survivl, univrite nlysis ws performed using the Cox univrite model nd clculting the hzrd rtio nd 95% confidence intervl. Multivrite nlysis ws performed using Cox proportionl hzrd model, gin including only vribles tht hd p vlue less thn 0.10 in univrite nlysis. The proportionlity of hzrds ws evluted using Cox regression nlysis with time-dependent covribles. The ssumption of proportionlity of hzrds ws tested nd ws not broken in ny of the Cox regression models. Sttisticl nlysis ws performed with SPSS sttisticl softwre pckge version 21.0 (SPSS inc., Chicgo, IL). Significnce ws set t p vlue less thn RESULTS We identified 229 ptients in the SEER dtbse eligible for this nlysis (Tble 1). The mjority of ptients were mle (56.8%) nd white (79.0%) with medin ge of 59 yers (rnge yers). There were 176 ptients (76.9%) with thymic crcinom nd 53 (23.1%) with thymic neuroendocrine tumors. Excluding the upstging from nodl smpling, there were 62 (27.1%) clssified s Msok-Kog stge I/ IIA; 25 (10.9%) clssified s stge IIB; 120 (52.4%) s stge III; nd 20 (8.8%) s stge IV. There were two (0.8%) ptients TABLE 1. Ptient Demogrphics Full Cohort Node Negtive Node Positive n (%) 229 (100) 137 (59.8) 92 (40.2) Sex, n (%) Mle 130 (56.8) 73 (53.3) 57 (62.0) Femle 99 (43.2) 64 (46.7) 35 (38.0) Medin ge, yr (IQR) 59 (48, 69) 58 (49, 68) 59 (47, 70) White, n (%) 181 (79.0) 102 (75.0) 79 (85.9) Tumor type, n (%) <0.001 Thymic crcinom 176 (76.9) 117 (85.4) 59 (64.1) Neuroendocrine tumor 53 (23.1) 20 (14.6) 33 (35.9) Tumor size, mm (IQR) 67 (48, 90) 65 (48, 86) 70 (49, 100) Msok-Kog stge, n (%) <0.001 Stge I/IIA 46 (20.1) 46 (33.6) 0 Stge IIB 16 (7.0) 16 (11.7) 0 Stge III 68 (29.7) 68 (49.6) 0 Stge IV 98 (42.8) 6 (4.4) 92 (100) Stge unknown 1 (0.4) 1 (0.7) Lymph nodes nlyzed, 3 (1, 6) 2 (1, 6) 4 (1, 7) medin (IQR) Surgery, n (%) Resection 213 (93.0) 129 (94.2) 84 (91.3) Debulking 16 (7.0) 8 (5.8) 8 (8.3) Rdition therpy, n (%) Preopertive 14 (6.1) 8 (5.8) 6 (6.5) Postopertive 126 (55.0) 69 (50.4) 57 (62.0) None 86 (37.6) 57 (41.6) 29 (31.5) Unknown 3 (1.3) 3 (2.2) 0 (0) By definition the presence of positive lymph nodes dicttes clssifiction s stge IV. IQR, interqurtile rnge. who could not be stged without the nodl smpling. The medin number of lymph nodes smpled per ptient ws three (medin, 6; interqurtile rnge [IQR], 1 43) nd did not differ between ptients with nodl metstsis (node positive) nd ptients without nodl metstsis (node negtive). There were lso no difference in number of smpled nodes between ptients with thymic crcinom nd thymic neuroendocrine tumors (p = 0.590). Positive metstsis in t lest one lymph node ws identified in 92 ptients (40.2%), nd node-positive ptients hd medin of one positive node (IQR, 1 26). There were higher proportion of node-positive ptients with thymic neuroendocrine tumors thn with thymic crcinom. Nodl metstsis ws present in 33 of 53 ptients (62.3%) with thymic neuroendocrine tumors when compred with only 59 of 176 ptients (33.5%) with thymic crcinom (p < 0.001). Similrly, ptients with thymic neuroendocrine tumors hd significntly more positive nodes per ptient (medin, 2; IQR, 1 26) thn ptients with thymic crcinom (medin, 1; IQR, 1 9, p = 0.031). There were no significnt differences in surgicl tretment or rdition therpy between node-positive nd node-negtive ptients (Tble 1). Identifiction of positive nodes resulted in significnt chnges to Msok-Kog stging tht could be evluted in P Copyright 2015 by the Interntionl Assocition for the Study of Lung Cncer 1643

3 Weksler et l. Journl of Thorcic Oncology Volume 10, Number 11, November 2015 TABLE 2. Univrite Anlysis of Fctors Affecting Nodl Metstses Vrible HR (95% CI) P Sex (mle vs. femle) ( ) Age t dignosis ( ) Rce (white vs. others) ( ) Histology (thymic crcinom vs. NETT) ( ) <0.001 Tumor grde b ( ) Tumor size ( ) Number of lymph nodes exmined ( ) Msok-Kog c ( ) Anlyzed s continuous vrible. b Tumor grde defined by SEER s well differentited, modertely differentited, poorly differentited, nd nplstic. c Excluding the presence of nodl metstses. CI, confidence intervl; HR, hzrd rtio; NETT, thymic neuroendocrine tumors/ neuroendocrine thymic tumors; SEER, Surveillnce, Epidemiology, nd End Results. TABLE 3. Multivrite Anlysis of Fctors Affecting Nodl Metstses Vrible HR (95% CI) P Rce (white vs. others) ( ) Histology (thymic crcinom vs. NETT) ( ) Tumor size ( ) Msok-Kog stge b Stge IIB vs. I/IIA ( ) Stge III vs. I/IIA ( ) Stge IV vs. I/IIA ( ) Anlyzed s continuous vrible. b Msok-Kog stge s determined without exmintion of nodl sttus. CI, confidence intervl; HR, hzrd rtio; NETT, thymic neuroendocrine tumors/ neuroendocrine thymic tumors. 91 ptients. The smpling of lymph nodes nd the presence of positive nodes effectively upstged 77 of 91 ptients (84.6%) previously stged s I to III to stge IV. Discounting the positive nodes, 16 of 91 ptients (17.6%) would hve been clssified s Msok-Kog stge I/IIA, 9 of 91 (9.9%) s IIB, nd 52 of 91 (57.1%) would hve been clssified s stge III. Fourteen ptients (14/91, 15.4%) were lredy clssified s stge IV nd were not upstged s result of finding positive lymph node. Prognostic Fctors for Lymph Node Metstsis In univrite nlysis, the presence of nodl metstses ws more likely in non-whites (p = 0.049), in ptients with thymic neuroendocrine tumors (p < 0.001), nd in ptients with more dvnced locl tumor bsed on Msok-Kog clssifiction tht ws determined without knowledge of the presence of nodl metstses (p = 0.001; Tble 2). Multivrite nlysis reveled tht ptients with thymic neuroendocrine tumors (p = 0.001) nd ptients with more loclly dvnced tumors (p = 0.001) hd significntly higher likelihood of developing nodl metstses (Tble 3). Ptients with thymic neuroendocrine tumors were 3.5 times more likely to develop nodl metstses thn ptients with thymic crcinom. Ptients with tumors invding djcent orgns were 2.6 times more likely to hve nodl metstses when compred with ptients with stge I/IIA tumors, nd ptients with tumors clssified s stge IV bsed on criteri other thn nodl sttus were 6.7 times more likely to hve nodl metstses (Tble 3). Survivl Overll medin survivl in the entire cohort ws 103 months (95% confidence intervl, ). There ws no significnt difference in survivl between ptients with thymic crcinom nd ptients with thymic neuroendocrine tumors (117 versus 85 months, p = 0.794; Fig. 1A). Surgicl debulking ws performed in 16 of 229 ptients (7.0%), nd resection of the thymus nd the tumor ws performed in 213 of 229 ptients (93.0%). Survivl ws significntly worst in ptients who underwent debulking when compred with ptients who underwent resection (41 versus 109 months, p = 0.017). Node-negtive ptients hd better survivl thn node-positive ptients (124 versus 47 months, p < 0.001; Fig. 1B). Dt on neodjuvnt nd djuvnt rdition therpy were vilble for ll node-positive ptients. Rdition therpy ws dministered before surgery in 6 of 92 node-positive ptients (6.5%) nd fter surgery in 57 of 92 (62.0%). Rdition ws not dministered to 29 of 92 node-positive ptients (31.5%). Medin survivl in ptients who received preopertive rdition ws 60 months, 42 months in ptients who received postopertive rdition, nd 68 months in ptients who did not receive rdition (p = 0.618). In univrite nlysis, type of surgery (resection versus debulking, p = 0.020), Msok-Kog stge (p < 0.001), nd the presence of positive lymph nodes (p < 0.001) were significnt fctors ffecting survivl (Tble 4). Becuse Msok- Kog stge nd positive lymph nodes re strong covribles (ll ptients with positive lymph nodes re by definition Msok-Kog stge IV), we constructed two Cox models for multivrite nlysis (Tble 5). The first model included Msok-Kog stge, nd the second model included nodl sttus. In the first model, type of surgery nd Msok-Kog stge significntly ffected survivl. In the second model, type of surgery nd the presence of positive nodes significntly ffected survivl. DISCUSSION This nlysis of lymph node metstses in 229 ptients with thymic crcinom or thymic neuroendocrine tumors yielded severl relevnt findings. First, the presence of nodl metstses is n importnt prognostic fctor in these ptients, incresing the risk of deth by pproximtely threefold. Second, nodl metstses re more likely in ptients with thymic neuroendocrine tumors or more dvnced tumors. Third, the presence of nodl metstses, identified by nodl smpling, chnged the Msok-Kog stging of 84% of ptients who would not hve been clssified s stge IV otherwise. Finlly, type of surgery performed is significnt fctor ffecting survivl nd ptients who underwent debulking rther thn resection fre worse Copyright 2015 by the Interntionl Assocition for the Study of Lung Cncer

4 Journl of Thorcic Oncology Volume 10, Number 11, November 2015 Impct of Nodl Metstses in Ptients with TC nd NETT FIGURE 1. A, Kpln Meier survivl curve of ptients with thymic crcinom nd thymic neuroendocrine tumors. NETT, thymic neuroendocrine tumors/neuroendocrine thymic tumors. B, Kpln Meier survivl curve of ptients without nd with nodl metstses. TABLE 4. Univrite Anlysis of Fctors Affecting Survivl Vrible HR (95% CI) P Sex (mle vs. femle) ( ) Age t dignosis ( ) Rce (White vs. others) ( ) Tumor (Thymic crcinom vs. NETT) ( ) Tumor grde b ( ) Tumor size ( ) Number of lymph nodes exmined ( ) Surgery (resection vs. debulking) ( ) Msok-Kog stge I/IIA vs. IV ( ) <0.001 IIB vs. IV ( ) III vs. IV ( ) Positive lymph nodes (yes vs. no) ( ) <0.001 Rdition therpy (yes vs. no) ( ) Anlyzed s continuous vrible. b Tumor grde defined by SEER s well differentited, modertely differentited, poorly differentited, nd nplstic. CI, confidence intervl; HR, hzrd rtio; NETT, thymic neuroendocrine tumors/ neuroendocrine thymic tumors; SEER, Surveillnce, Epidemiology, nd End Results. Although the Interntionl Thymic Mlignncy Group (ITMIG) nd the Interntionl Assocition for the Study of Lung Cncer hve proposed new tumor, node, metstsis (TNM) clssifiction for thymic mlignncy tht incorportes nodl sttus, dt on nodl metstses in ptients with thymic mlignncies re sprse. 10,11 Only two previous publictions hve ddressed nodl sttus in ptients with thymic mlignncies, nd two recent, lrge dtbse studies did not ddress the nodl sttus of ptients with thymic crcinom or thymic neuroendocrine tumors. 5 8 Kondo et l. 7 sent questionnire to 185 Jpnese centers nd compiled dtbse of 1320 ptients with thymic mlignncies. 7 There were 183 cses of thymic crcinom nd 40 cses of thymic crcinoid TABLE 5. Multivrite Anlysis of Fctors Affecting Survivl Vrible HR (95% CI) P Model 1 Surgery (resection vs. debulking) ( ) Msok-Kog stge Msok-Kog stge I/IIA vs. IV ( ) <0.001 Msok-Kog stge IIB vs. IV ( ) Msok-Kog stge III vs. IV ( ) Model 2 Surgery (resection vs. debulking) ( ) Positive lymph nodes (yes vs. no) ( ) <0.001 CI, confidence intervl; HR, hzrd rtio. tumors. The incidence of nodl metstses in ptients with thymic crcinom ws 26.8%, nd it ws 27.5% in ptients with thymic crcinoid tumors. Prk et l., 8 in retrospective review of 37 ptients with thymic crcinom (29 underwent nodl dissection), found 20% incidence of nodl metstses. The incidence of metstses is lower in these studies thn in our study 33% incidence of nodl metstses in ptients with thymic crcinom nd 62.5% in ptients with thymic neuroendocrine tumors. There re severl possible resons for this difference. We included ptients with ll types of neuroendocrine thymic tumors including ptients with lrge-cell neuroendocrine crcinom, neuroendocrine crcinom, nd mlignnt crcinoid tumors, which my be more prone to metstses. It is uncler whether the whole spectr of thymic neuroendocrine tumors were included in Kondo et l. s study. 7 In ddition, we included ptients who underwent debulking, which my ccount for the higher incidence of nodl metstses. Prk et l. 8 excluded ptients who underwent incomplete resection. The 2004 WHO publiction on tumors of the lung, pleur, thymus, nd hert clssified thymic crcinom nd Copyright 2015 by the Interntionl Assocition for the Study of Lung Cncer 1645

5 Weksler et l. Journl of Thorcic Oncology Volume 10, Number 11, November 2015 thymic neuroendocrine tumors in single ctegory, differentiting both from thymom. 1 It is uncler if both diseses should be clssified together or if the nturl history of thymic crcinom nd thymic neuroendocrine tumors is similr. The ltest nd recent WHO clssifiction 2 clerly distinguishes thymic crcinom from thymic neuroendocrine tumors recognizing the significnt differences between the two pthologies. Although our study did not revel difference in survivl between these two thymic tumor types, it did show significnt difference in the risk of nodl metstses. Ptients with thymic neuroendocrine tumors hd n pproximtely three times higher risk of nodl metstses when compred with ptients with thymic crcinom. Another importnt finding in our study is the potentil for nodl metsttic disese even in tumors clssified s reltively erly stge by other criteri. We found tht without nodl smpling, 25 of 91 ptients (27.5%) would hve been stged s Msok-Kog stge I or II, nd 52 of 91 (57.1%) would hve been clssified s stge III. In totl, 84.6% of ptients were upstged from lower stges s result of node-positive sttus. This is very similr to our findings in ptients with thymom in whom the finding of nodl metstses upstged 80% of ptients with nodl metstses. Although ours is selected popultion tht my overestimte the incidence of metstses, our findings underscore the need for some nodl smpling s n integrl prt of surgicl tretment of thymic crcinoms nd thymic neuroendocrine tumors. This my require chnge in prctice for mny surgeons. The dvent of minimlly invsive techniques hs populrized unilterl thymectomies, which do not llow smpling of both sides of the chest. A new stging proposl, put forth by the ITMIG nd Interntionl Assocition for the Study of Lung Cncer, clssifies nterior medistinl nodes s N1 nd deep comprtment nodes s N2. 10,12 Becuse of the centrl nture of most thymic tumors, N2 nodes my be involved bilterlly. Guidelines on smpling of lymph nodes during surgicl tretment of thymic tumors re lcking but re urgently needed. Until such guidelines re vilble, it is prudent to smple N1 nd N2 nodes t lest unilterlly when operting on thymic mlignncies. In recent lrge dtbse studies by Filosso et l. 6 nd Ahmd et l., 5 ptients with thymic neuroendocrine tumors hd medin overll survivl of 7.5 yers, nd ptients with thymic crcinom hd medin overll survivl of 6.6 yers. In our study, medin overll survivl for ptients with thymic neuroendocrine tumors ws 7.1 yers, nd medin survivl for ptients with thymic crcinom ws 9.7 yers. The difference in survivl in ptients with thymic crcinom between our study nd the study by Ahmd et l. 5 my be explined by the fct tht Ahmd et l. s series included some ptients who did not hve surgicl therpy. Survivl dt were vilble on 836 ptients, nd surgery ws performed on 733. In our previous study of ptients with thymic crcinom, ptients who did not undergo surgery hd medin overll survivl of 4 yers; the medin overll survivl in ptients who underwent surgery ws 8.7 yers. 4 As in other studies, incomplete resection ws n dverse prognostic fctor in ptients with thymic crcinom nd thymic neuroendocrine tumors. 4 6,13,14 Although the SEER registry does not hve field for R1 or R2 resection, we believe tht debulking is good surrogte for incomplete resection. As with thymom, complete resection of thymic crcinom nd thymic neuroendocrine tumors is likely the most importnt spect of tretment. The role of neodjuvnt nd djuvnt therpy in ptients with thymic crcinom nd thymic neuroendocrine tumors is uncler. Using SEER dt on thymic crcinom, we were unble to demonstrte significnt effect of djuvnt rdition therpy, 4 but SEER does not contin informtion on chemotherpy. Ahmd et l. 5 found tht the use of ny rdition therpy hd positive impct on survivl. Ruffini et l. 14 nlyzed cohort of ptients with thymic crcinom from the Europen Society of Thorcic Surgeons dtbse nd found tht djuvnt therpy ws beneficil in improving overll survivl. Filosso et l. 6 did not find neodjuvnt or djuvnt therpy useful in ptients with thymic neuroendocrine tumors. The different findings underscore the fct tht thymic crcinoms nd thymic neuroendocrine tumor re different diseses nd will respond differently to djuvnt therpy. Studying uncommon diseses is chllenging, nd investigtors often use lrge retrospective dtbses to ssemble cohorts for nlysis. Such dtbses, like the SEER registry, hve significnt limittions nd re constrined by their retrospective nture. Although brod in its rech, the SEER dtbse is subjected to limited dt points nd potentil reporting inccurcies. Our cohort is likely selected one, nd the contributing surgeons my hve been more likely to smple nodes tht were enlrged lredy. It is likely tht the overll incidence of nodl metstses in thymic crcinom nd thymic neuroendocrine tumors is lower thn tht reported in our study. Another significnt shortcoming is the lck of stndrdized pthology review. Pthology dt re obtined from multiple centers without stndrdiztion mong the pthologists, nd ech pthologist my hve different method of nlyzing nd identifying lymph nodes in the specimen. The SEER dtbse lso lcks informtion on chemotherpy, on the ntomicl loction of the dissected lymph nodes, nd informtion on the surgicl pproch used (minimlly invsive or trditionl open surgery). Finlly, the reporting of complete resection is somewht subjective in the SEER dtbse, nd the reporting of complete thymic excision is not the sme s n R0 resection in ll cses. It is uncler how the fct tht some ptients my hve hd n incomplete resection might ffect the results of our study. In summry, nodl metstses from thymic crcinoms nd thymic neuroendocrine tumors seem to be reltively common. Nodl metstses denote poorer prognosis, nd routine nodl smpling should be incorported into surgicl tretment of thymic mlignncy. It is uncler how this recommendtion will ffect prctice ptterns considering the incresing incidence of minimlly invsive nd unilterl pproches to thymic mlignncies. Pthology specimens should be dissected meticulously to identify nodl tissue nd potentil metstses. The role of djuvnt rdition therpy is uncler, nd in our cohort, it did not prolong survivl. More studies re needed to properly clrify the incidence nd impct of nodl metstses in ptients with rre thymic tumors. The ITMIG thymic mlignncy prospective dtbse my provide n excellent pltform for future studies on thymic crcinom nd thymic neuroendocrine tumors Copyright 2015 by the Interntionl Assocition for the Study of Lung Cncer

6 Journl of Thorcic Oncology Volume 10, Number 11, November 2015 Impct of Nodl Metstses in Ptients with TC nd NETT REFERENCES 1. Pthology nd genetics of tumours of the lung, pleur, thymus nd hert. In: Kleihues P, Sobin LH, eds. World Helth Orgniztion Clssifiction of Tumours. Lyon, Frnce: IARC Press, Pp Trvis WD, Brmbill E, Burke AP, et l. WHO Clssifiction of Tumours of the Lung, Pleur, Thymus nd Hert, de Jong WK, Bluwgeers JL, Schpveld M, et l. Thymic epithelil tumours: popultion-bsed study of the incidence, dignostic procedures nd therpy. Eur J Cncer 2008;44: Weksler B, Dhupr R, Prikh V, et l. Thymic crcinom: multivrite nlysis of fctors predictive of survivl in 290 ptients. Ann Thorc Surg 2013;95: Ahmd U, Yo X, Detterbeck F, et l. Thymic crcinom outcomes nd prognosis: results of n interntionl nlysis. J Thorc Crdiovsc Surg 2015;149:95 100, 101.e1. 6. Filosso PL, Yo X, Ahmd U, et l.; Europen Society of Thorcic Surgeons Thymic Group Steering Committee. Outcome of primry neuroendocrine tumors of the thymus: joint nlysis of the Interntionl Thymic Mlignncy Interest Group nd the Europen Society of Thorcic Surgeons dtbses. J Thorc Crdiovsc Surg 2015;149: e2. 7. Kondo K, Monden Y. Lymphogenous nd hemtogenous metstsis of thymic epithelil tumors. Ann Thorc Surg 2003;76: Prk IK, Kim YT, Jeon JH, et l. Importnce of lymph node dissection in thymic crcinom. Ann Thorc Surg 2013;96: ; discussion Detterbeck FC, Nicholson AG, Kondo K, et l. The Msok-Kog stge clssifiction for thymic mlignncies: clrifiction nd definition of terms. J Thorc Oncol 2011;6:S Bhor FY, Chen DJ, Detterbeck FC, et l.; Stging nd Prognostic Fctors Committee; Advisory Bords. The ITMIG/IASLC Thymic Epithelil Tumors Stging Project: A proposed lymph node mp for thymic epithelil tumors in the forthcoming 8 th edition of the TNM clssifiction of mlignnt tumors. J Thorc Oncol 2014;9(9 Suppl 2):S88 S Detterbeck FC, Strtton K, Giroux D, et l.; Stging nd Prognostic Fctors Committee; Members of the Advisory Bords; Prticipting Institutions of the Thymic Domin. The IASLC/ITMIG Thymic Epithelil Tumors Stging Project: proposl for n evidence-bsed stge clssifiction system for the forthcoming (8 th ) edition of the TNM clssifiction of mlignnt tumors. J Thorc Oncol 2014;9(9 Suppl 2):S65 S Detterbeck FC, Asmur H, Crowley J, et l.; Stging nd Prognostic Fctors Committee; Members of the Advisory Bords; Prticipting Institutions of the Thymic Domin. The IASLC/ITMIG thymic mlignncies stging project: development of stge clssifiction for thymic mlignncies. J Thorc Oncol 2013;8: Song Z, Zhng Y. Outcomes fter surgicl resection of thymic crcinom: study from single tertiry referrl centre. Eur J Surg Oncol 2014;40: Ruffini E, Detterbeck F, Vn Remdonck D, et l.; Europen Society of Thorcic Surgeons Thymic Working Group. Thymic crcinom: cohort study of ptients from the Europen society of thorcic surgeons dtbse. J Thorc Oncol 2014;9: Copyright 2015 by the Interntionl Assocition for the Study of Lung Cncer 1647