Prognostic Factors in Thymic Epithelial Tumors Undergoing Complete Resection

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1 Prognostic Factors in Thymic Epithelial Tumors Undergoing Complete Resection Charalambos Zisis, MD, Dimitra Rontogianni, MD, Chara Tzavara, MD, Kalliopi Stefanaki, MD, Antonios Chatzimichalis, MD, Antonios Loutsidis, MD,* Kosmas Iliadis, MD, Argirios Kontaxis, MD, Theodosios Dosios, MD, PhD, and Ion Bellenis, MD Department of Thoracic Surgery and Pathology, Evangelismos Hospital, Department of Biostatistics, University of Athens, Department of Pathology, Aghia Sofia Pediatric Hospital, Department of Thoracic Surgery, Hygia Hospital, and Division of Thoracic Surgery, Athens University School of Medicine, Athens, Greece Background. The prognostic factors in thymic epithelial tumors (TET) are investigated within a 27-year period in 104 patients submitted to surgical and pathologic complete resection of TET with a mean age of years and a male to female ratio of Methods. The medical records of all patients were reviewed and six variables that could affect the shortterm and long-term survival were entered into a Cox regression model. Follow-up was obtained from medical records and telephone contacts up to September 2004 or until the patient s death. Results. Overall 5-year and 10-year survival was 83% and 78%, respectively. Univariate Cox regression analysis showed that long survival was affected by the age of the patient at the time of operation, the response of myasthenia gravis to the operation, the tumor recurrence, the histologic type according to the World Health Organization (WHO) classification, and the Masaoka stage. Multivariate analysis revealed that recurrence of the tumor (p 0.001), Masaoka stages II or III (p < 0.001), elder age of the patient at the time of operation (p 0.045), and presence of the WHO histologic types B2 or B3 (p 0.05) were bad prognostic factors. Conclusions. Recurrence of the tumor, the Masaoka staging, the WHO histologic type, and the age of the patient at the time of operation were the most important prognosticators for patients with TET submitted to complete resection of their tumor. (Ann Thorac Surg 2005;80: ) 2005 by The Society of Thoracic Surgeons Thymomas or thymic epithelial tumors (TET) are tumors of the thymus gland with diverse pathologic findings and clinical outcome. Since 1981, the Masaoka staging system, based mainly on macroscopic surgical findings [1], has been considered as the critical prognostic determinant of TET in consecutive studies [2 6]. At the same time, a controversy has arisen about the prognostic significance of the histologic typing, whereas many different histologic classification systems have been proposed in an attempt for a better description of this diversity [7 9]. The new classification of the World Health Organization (WHO), introduced in 1999 [10, 11], is based on the histology of the tumors and evaluates both the morphologic appearance and the relative ratio of neoplastic to non-neoplastic epithelial cells. However, the prognostic significance of this classification system, as well as that of the Masaoka staging, remains to be confirmed. The objective of this retrospective study is to investigate the prognostic factors in completely resected TETs Accepted for publication March 23, *Dr Loutsidis died on Feb 18, Address reprint requests to Dr Zisis, 17A, Patriarchou Grigoriou str, Glyfada, Athens, Greece; chzisis@otenet.gr. taking into consideration both the Masaoka staging system and the WHO classification. Patients and Methods From January 1975 to December 2001, 129 patients were consecutively operated on, with a curative intent for TET, in two hospitals in Athens. The inclusion criteria for the study were the following: the histologic diagnosis of TET confirmed by immunohistochemical techniques, complete resection of the tumor based on the operative and histopathologic reports, and follow-up until September 2004 or the patient s death. The histologic slides of all patients were reexamined by two independent pathologists who were not informed about the initial diagnosis and clinical course of the patients. By applying new identification and immunohistochemical techniques, 8 patients were excluded from the study because the reexamination established different histologic diagnoses; lymphomas (6) and germ-cell tumors (2). Five additional patients at Masaoka stage IV and one at Masaoka stage III were also excluded because they did not fulfill the criteria of complete resection. Eleven patients (9.56%) were lost to follow-up. The remaining 104 patients constitute the material of this study. The surgical technique utilized was similar in all pa by The Society of Thoracic Surgeons /05/$30.00 Published by Elsevier Inc doi: /j.athoracsur

2 Ann Thorac Surg ZISIS ET AL 2005;80: THYMOMA PROGNOSIS AFTER COMPLETE RESECTION 1057 tients. Access was always performed through a median sternotomy. The pericardium was not opened, unless invaded. Complete resection was performed including the tumor with the whole thymus gland and adjacent mediastinal cellulo-adipose tissue. The mediastinal pleurae were not routinely opened, unless to facilitate surgical maneuvers or to excise extensive infiltration of the mediastinal fat. The phrenic nerves were always identified while the recurrent laryngeal nerves were identified only when necessary. In patients with tumors at Masaoka stage IV, every effort was made for the complete extirpation of the disease, including resection of the adjacent organs; ie, pericardium, phrenic nerve, recurrent laryngeal nerve, pulmonary parenchyma, innominate vein, and superior vena cava. Postoperatively, adjuvant radiotherapy was applied on all patients at Masaoka stage II and chemoradiotherapy to patients at Masaoka stage III or IV. No complementary treatment was applied to patients at stage I. The Masaoka staging was redefined in all patients according to the surgical records and the histopathologic findings. In addition, all tumors were classified according to the WHO classification [11]. Follow-up was obtained from medical records and telephone contacts. Survival was measured from the day of operation until death or the last follow-up visit or contact by telephone up to September The medical records of all those patients were reviewed and their gender, age, presence of myasthenia gravis (MG), response of MG to the TET resection, redefined Masaoka tumor stage, WHO histologic type, recurrence, and survival were recorded. Results are expressed as mean standard deviation. Survival curves were plotted using the Kaplan-Meier method. Statistical differences in survival were determined by the log-rank test. The Cox proportional hazards regression model was utilized to identify the factors that may affect prognosis. Analysis of variance was used for the comparison of means and the 2 test and the Fisher s exact test to compare frequencies among different groups. The analysis was performed with the statistical program STATA (version 6.0) (Stata- Corp, College Station, TX). The significance level was set at Results Clinical and Pathologic Findings The age of the patients ranged between 17 and 84 (mean, ) years. The male to female ratio was The patients Masaoka staging in relation to the WHO classification is presented in Table 1. The patients mean age and male to female ratio did not differ significantly between the WHO classification types or between the Masaoka stages. The majority of patients with WHO types A and AB disease (55.2%) were at Masaoka stage I, whereas the majority of patients with B2 and B3 disease (58.3%) belonged to Masaoka stage II. The relation between the histologic type and the Masaoka clinical stage is significant (Fisher s exact test, p 0.006). Myasthenia gravis was present in 47 (45.2%) patients at the time of operation, whereas the age range of MG patients was 17 to 84 ( ), and their male to female ratio was 0.67 (19:28). Analytically, 4 patients (8.5%) were type A, 7 patients (14.9%) type AB, 16 (34%) type B1, 15 (31.9%) type B2, and 5 (10.7%) type B3 TET. Regarding the Masaoka staging, 19 of the MG patients (40.4%) were of stage I, 22 patients (46.8%) were of stage II, 6 (12.8%) of stage III, and none of stage IV. Myasthenia gravis is more frequent in stages I and II, as well as in types B1 and B2, but its incidence did not differ significantly between patients of different WHO histologic types or between different Masaoka stages. After resection of the TET, permanent, partial, or no remission of the MG was noticed in 10.6%, 36.2%, and 53.2% of the MG patients, respectively. Six patients presented with local recurrence and one with distal recurrence of the tumor. Three of them underwent reoperation, whereas another three with a local relapse were excluded from surgical treatment because of excessive deterioration in the clinical course of their MG. The clinical characteristics of these patients, their treatment, and outcomes are presented in Table 2. Survival Three patients (2.88%) died within thirty days after operation. One of them passed away at the time of reoperation for local relapse and another two patients on the 18th and 20th postoperative days, respectively, due to Table 1. World Health Organization (WHO) Histologic Classification and Masaoka Clinical Staging Masaoka Staging WHO Type I (%) II (%) III (%) IV (%) Total A 7(58.3) 4(33.3) 1(8.34) 0(0.0) 12 AB 9(52.9) 6(35.3) 1(5.9) 1(5.9) 17 B1 14(51.9) 13(48.1) 0(0.0) 0(0.0) 27 B2 7(23.3) 18(60.0) 5(16.7) 0(0.0) 30 B3 2(11.1) 10(55.6) 4(22.2) 2(11.1) 18 Total 39(37.5) 51(49.0) 11(10.6) 3(2.9) 104 Fisher s exact test p

3 1058 ZISIS ET AL Ann Thorac Surg THYMOMA PROGNOSIS AFTER COMPLETE RESECTION 2005;80: Table 2. Patient Recurrence: Demographic and Clinical Features Gender Age TI (mos) WHO Type Masaoka Stage Recurrence MG Treatment Outcome (Mos After Recurrence) F A III Local Absent Re-resection Alive, disease free (36) F B3 IV Local Absent Re-resection Alive with disease (60) M B3 II Distant Present TR Chemoradiation Death (24) F B2 II Local Present NR Chemoradiation Death (6) F B3 III Local Present NR Chemoradiation Death (6) F 50 9 AB II Local Present NR Chemoradiation Death (3) F 28 9 AB III Local Absent Reresection Death (0) F female; M male; MG myasthenia gravis; mos months; NR no remission; TI time interval from resection; TR total remission; WHO World Health Organization. respiratory failure. There were 21 (20.2%) late deaths. Five-year and ten-year survival was 83% and 78%, respectively. The ten-year survival for types A, AB, B1, B2, and B3 was 91%, 80%, 91%, 67%, and 66%, respectively. Fourteen of the 24 deaths were observed in MG patients. Two of them were not related to the MG (distant metastases of the TET in the former case and colorectal cancer 13 years later in the latter), but the other 12 were due to the dismal clinical course of MG. Among them, 3 patients were not suitable for surgical reresection of their locally recurrent lesion because of the severity of their MG. Analytically, the deaths according to MG in each WHO type are indicated in Table 3; survival according to MG and according to MG response to TET resection (complete, partial, or none) are shown in Figures 1 and 2. The patients with the WHO histologic types B2 and B3, either combined or separated, had more dismal survival in comparison with the group of patients of types A, AB, and B1 (log rank test p and p 0.029, respectively) (Fig 3). The same pattern is repeated when comparing groups composed of A and AB with groups composed of B2 and B3, and another group composed of type B1 separately (p 0.022). Nevertheless, the influence of the histologic type on survival was not very significant (p 0.07), this probably being a result of the small number of patients. The influence of the redefined Masaoka staging on survival was very significant (p 0.001) and patients at stages III and IV had less favorable survival (Fig 4). It is noteworthy that a type A patient of this series died 18 months after surgical resection, whereas 4 type A patients (33.3%) were at Masaoka stage II and 1 patient of the same type was at Masaoka III. Similarly, 6 AB (35.3%) Table 3. Deaths According to the World Health Organization Histologic Type and the Myasthenia Gravis (MG) MG World Health Organization A AB B1 B2 B3 Total Deaths Yes No patients were at Masaoka stage II and the 5-year survival for this type was 80%. Univariate Cox regression analysis showed that sex and presence of MG at the time of operation did not affect late outcome. On the contrary, long survival was affected by tumor recurrence, the Masaoka stage, the WHO histologic type, the age of the patient at the time of operation, and the response of the MG to the operation, as is shown in Table 4. The hazard ratio increased by 3% for each year of age added, whereas myasthenic patients with partial remission had 80% reduced hazard compared with the patients with no remission. Survival was related very significantly (p 0.001) to recurrence, which seems to be a very dismal prognostic factor with a hazard ratio equal to The group of patients with WHO histologic types B2 and B3, compared with those of the group with types A, AB, B1, had worse prognosis with a statistically significant difference (p 0.012). Finally, the patients at Masaoka stages II and III compared with those at stage I had a much worse prognosis (Table 4) (p 0.05 and relatively). Multivariate analysis was performed at two phases because a striking correlation between the Masaoka clinical stages and the WHO histologic types was found. In the first phase, excluding the Masaoka staging, multivariate analysis revealed that the recurrence of the tumor (with a hazard ratio equal to 5.78) (p 0.001), the age of the patient at the time of operation (with a hazard ratio equal to 1.03) (p 0.045), and the presence of the WHO histologic types B2 or B3 (with a mean hazard 2.5 times greater for these types compared to types A, AB, and B1 [p 0.05]) were adverse prognostic factors. Similarly, when the WHO histologic types were excluded in the second phase, the Masaoka stage, the age of the patient at the time of operation, and recurrence were found to be the prognosticators (Table 5). Patients at the Masaoka stage III had a 17.7 higher mean hazard than patients at Masaoka stage I (p 0.001). Comment The overall 10-year survival of patients in this series was 78.6%. Fourteen years after the operation the risk ratio

4 Ann Thorac Surg ZISIS ET AL 2005;80: THYMOMA PROGNOSIS AFTER COMPLETE RESECTION 1059 Fig 1. Survival and myasthenia gravis (MG). MG ; --- MG. was nearly zero and survival was 73.2%. These results are comparable with those reported by others [2, 12, 13]. The main finding of this retrospective study is a significant correlation between the WHO histologic classification and the Masaoka clinicopathologic staging. The higher the tumor stage is, the higher the malignant potential (as represented with the WHO classification scaling) that exists. This finding is in accordance with the reports of other authors from Asia [12 15] who investigated this issue. The WHO histology functions as a criterion of oncologic behavior and clinical relevance. Traditionally, it was supposed that thymomas were benign or malignant tumors, depending on the invasion of their capsule. After the introduction of the WHO classification system, it seems that the benign or malignant nature of TET is determined not only from capsule invasiveness but also from the histologic type. The grading of neoplastic deviation is described with the WHO classification system, which was mainly based on the histologic classification previously proposed by Marino and Müller-Hermelink [9] and Kirchner and colleagues [16]. However, although types A and AB are considered benign, it is possible to find a patient with a TET of type Fig 3. Survival of different World Health Organization (WHO) histologic types with grading (A, AB, B1/B2, B3) after complete thymic epithelial tumor resection compared with the overall survival. WHO-A, AB, B1; WHO-B2, B3. A or AB with unfavorable outcome, as in 5 patients of our series (1A and 4AB). In a recent series, two patients with WHO type A and one patient of type AB presented pulmonary metastases [17]. In this model of expression, thymic pathology is not strictly benign or malignant. Apparently, the definitions benign or malignant for TET are not well-demarcated. Furthermore, we found a significant correlation between the histologic type of TET and survival. Both the univariate and the multivariate analyses confirmed the prognostic value of this classification with a hazard ratio equal to 2.5 for the WHO types B2 and B3. A similar hazard ratio has been reported by others [17]. It seems that the region between B1 and B2 is prognostically significant. It is known that the types B1, B2, and B3 are categorized together in the WHO classification as low-grade TETs in contrast to types A and AB, which are supposedly benign. However, the findings of the present study indicate that patients with type B1 tumors had a more favorable outcome than those with type AB. In a similar way, some published Fig 2. Survival and response of myasthenia gravis after complete thymic epithelial tumor resection. no response; partial response; --- complete response. Fig 4. Survival at different Masaoka stages after complete thymic epithelial tumor resection. Masaoka [I]; Masaoka [II];- --- Masaoka [III]; Masaoka [IV]. (WHO World Health Organization.)

5 1060 ZISIS ET AL Ann Thorac Surg THYMOMA PROGNOSIS AFTER COMPLETE RESECTION 2005;80: series distinguish the oncologic behavior of histologic type B1 from the other types of B category (B2 and B3) and attribute to it a better prognosis [12,14]. This clinical result could be (at least partially) interpreted on the basis of immunohistochemical findings of these tumors. The TETs of type B1 have histomorphologic characteristics simulating those of a normal, immunologically active thymus gland. On the other hand, TETs of type B2 demonstrate a deviation to a less differentiated tumor, lacking the corticomedullary compartments of the normal thymus and exhibiting a morphologically or numerically abnormal population of epithelial cells. It is characteristic that in TETs of type B3, one can observe a paucity or total absence of the lymphocyte component and dominance of the neoplastic epithelial component [10]. In addition, the genetic profile in types B2 and B3 is common [18]. In recent studies, the histologic types B2, B3, and C are considered indicative of an invasive nature of the tumor [19] and adverse prognostic factors [20]. The influence of the Masaoka staging on survival of patients is well-established [2, 3, 5, 12, 13, 17, 21 27]. We detected a very strong relation between the Masaoka staging and the patients outcome as well. Stage I patients of our series had a 5-year and 10-year survival of 97% and 94%, respectively, while the relevant proportions for the patients at stage III were 45% and 35%, respectively. It is interesting that the 5-year and 10-year survival of patients at stage IV of this series was 66%. The higher survival of patients at stage IV than of those at stage III has to be attributed to the patients selection process; from the total number of patients at stage IV we only included in this study those (n 3) subjected to complete resection of the macroscopically existing disease. Unexpectedly high survival of patients at stage IV, in contrast to a poor outcome of patients at stage III, has also been reported in the past, attributed to the aggressive multimodality treatment of these patients [4]. The findings of this study confirmed the observations of other authors [6, 12, 24, 28] stating that the presence of MG at the time of operation did not affect the patients long-term outcome. However, it seems that a relation exists between the clinical course of MG after resection of the TET and the survival of patients. In this series, permanent, partial, or no remission was noticed in 10.6%, 36.2%, and 53.2% of the patients after resection of the TET. Patients with partial remission presented a statistically significant hazard ratio of 0.2 compared with the patients with no response. Such a statistical significance was not documented in cases of complete remission, potentially due to the small number of patients. It should be noted that the response rates recorded in our series differ from those reported by de Perrot and colleagues [29], who found that 63% of their patients had no symptoms after resection of the thymoma. However, in another series of 207 myasthenic patients, most pa- Table 4. Univariate Cox Regression Analysis No. of deaths (%) Hazard Ratio p Value 95% CI Gender Men 8(18.2) Ref. Women vs men 16(26.7) Age a Myasthenia No 10(17.5) Ref. Yes vs no 14(29.8) MG response after TET resection None 11(44.0) Ref. Partial vs none 2(11.7) Complete vs none 1(20.0) Recurrence No 19(19.6) Ref. Yes vs no 5(71.4) WHO type A,AB,B1 7(12.5) Ref. B2,B3 vs A,AB,B1 17(35.4) Masaoka stage I 3(7.7) Ref. II vs I 12(23.5) III vs I 8(72.7) IV vs I 1(33.3) a Mean (standard deviation). CI confidence interval; MG myasthenia gravis; Ref. Reference; TET thymic epithelial tumors; WHO World Health Organization.

6 Ann Thorac Surg ZISIS ET AL 2005;80: THYMOMA PROGNOSIS AFTER COMPLETE RESECTION 1061 Table 5. Multivariate Cox Regression Analysis at Two Phases tients (143 out of 185 having a complete follow-up) remained dependent on immunosuppressive therapy [30]. Furthermore, in a recent series of 108 patients, the rate of remission was 16%, whereas the rest required immunosuppressive medication [31]. Recurrence aggravated survival of our patients with a hazard ratio equal to A similar influence of tumor recurrence on survival has been reported by others [20, 32]. However, it should be noted that the recurrence rate of 6.7% among our patients is lower than that reported in other published series [2, 4, 15, 33]. We believe that this low rate has to be attributed to the complete resection performed to the patients of our series. Complete resection has been demonstrated in many series as the main prognostic factor for recurrence and favorable outcome [4, 6, 20, 33, 34]. Finally, the age of the patient at the time of operation was found to be a significant factor influencing the outcome of our patients. The hazard ratio increased by 3% for each year of age added. The suggestion that age is a prognostic factor has been put forward before [6, 31]. In conclusion, this retrospective study showed that recurrence of the tumor, the Masaoka clinicopathologic staging, the WHO histologic type, and age of the patient at the time of operation were the most important prognosticators for patients with TET submitted to complete resection of their tumor. References Phase A with exclusion of the Masaoka stages Hazard Ratio p Value 95% CI WHO A, AB, B1 Ref B2, B3 vs A,AB,B Recurrence No Ref Yes vs no Age Phase B with exclusion of the WHO histological types Hazard Ratio p Value 95% CI Masaoka I Ref II vs I III vs I IV vs I Age CI confidence interval; Ref reference; WHO World Health Organization. 1. Masaoka A, Monden Y, Nakahara K, Tanioka T. 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7 1062 ZISIS ET AL Ann Thorac Surg THYMOMA PROGNOSIS AFTER COMPLETE RESECTION 2005;80: Sonobe M, Nakagawa M, Ichinose M, Ikegami N, Nagasawa M, Shindo T. Thymoma. Analysis of prognostic factors. Jpn J Thorac Cardiovasc Surg 2001;49: Gripp S, Hilgers K, Wurm R, Schmitt G. Thymoma: prognostic factors and treatment outcomes. Cancer 1998;83: Moreno Egea A, Aguayo Albasini JL, Parrilla Paricio P, Sola Perez J, Garcia Lax F, Jimenez Bascunana A. Prognostic factors of thymomas. Eur J Surg Oncol 1995;21: McCart JA, Gaspar L, Inculet R, Casson AG. Predictors of survival following surgical resection of thymoma. J Surg Oncol 1993;54: Moore KH, McKenzie PR, Kennedy CW, McCaughan BC. Thymoma: trends over time. Ann Thorac Surg 2001;72: de Perrot M, Liu J, Bril V, McRae K, Bezjak A, Keshavjee SH. Prognostic significance of thymomas in patients with myasthenia gravis. Ann Thorac Surg 2002;74: Evoli A, Minisci C, Di Schino C, et al. Thymoma in patients with MG. Characteristics and long-term outcome. Neurology 2002;59: López-Cano M, Ponseti-Bosch JM, Espin-Basany E, Sánchez- García JL, Armengol-Carrasco M. Clinical and pathologic predictors of outcome in thymoma-associated myasthenia gravis. Ann Thorac Surg 2003;76: Venuta F, Rendina EA, Longo F, et al. Long-term outcome after multimodality treatment for stage III thymic tumors. Ann Thorac Surg 2003;76: Rea F, Marulli G, Girardi R, et al. Long-term survival and prognostic factors in thymic epithelial tumours. Eur J Cardiothoracic Surg 2004;26: Wilkins EW, Grillo HC, Scannell G, Moncure AC, Mathisen DJ. Role of staging in prognosis and management of thymoma. Ann Thorac Surg 1991;51: The Society of Thoracic Surgeons Policy Action Center The Society of Thoracic Surgeons (STS) is pleased to announce a new member benefit the STS Policy Action Center, a website that allows STS members to participate in change in Washington, DC. This easy, interactive, hassle-free site allows members to: Personally contact legislators with one s input on key issues relevant to cardiothoracic surgery Write and send an editorial opinion to one s local media senators and representatives about upcoming medical liability reform legislation Track congressional campaigns in one s district and become involved Research the proposed policies that help or hurt one s practice Take action on behalf of cardiothoracic surgery This website is now available at by The Society of Thoracic Surgeons Ann Thorac Surg 2005;80: /05/$30.00 Published by Elsevier Inc