Thymoma is defined as a tumor derived from epithelial

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1 Thymic Neuroendocrine Carcinoma and Thymoma Are Both Associated With Increased Risk of Extrathymic Malignancy: A 20-Year Review of a Single Institution Yi-Ting Yen, MD, Wu-Wei Lai, MD, Ming-Ho Wu, MD, Mu-Yen Lin, MD, Jia-Ming Chang, MD, I-Lin Hsu, MD, and Yau-Lin Tseng, MD, PhD Division of Thoracic Surgery, Department of Surgery, National Cheng Kung University Hospital, Tainan; Division of Thoracic Surgery, Department of Surgery, Tainan Municipal Hospital, Tainan; Division of Thoracic Surgery, Department of Surgery, National Cheng Kung University Hospital, Dou-Liou Branch; Division of Thoracic Surgery, Department of Surgery, Chia-Yi Christian Hospital, Chia-Yi; and Department of Emergency Medicine, National Cheng Kung University, Tainan, Taiwan Background. Thymoma has been reported to have increased risk of extrathymic malignancy; thymic carcinoma, however, has not been validated of this association. We retrospectively assessed the incidence of additional malignancy among patients with thymoma and thymic carcinoma, and compared it with that of other solid organ cancers. Methods. We reviewed the medical records between the years of 1988 and 2008 of 213 patients, including 131 with thymoma and 82 with thymic carcinoma. The overall incidence of additional malignancy in patients with thymic epithelial tumors, lung cancer, hepatocellular carcinoma, colorectal cancer, breast cancer, and cervical cancer between 2003 and 2008 in our institution was also computed. Results. The incidence of extrathymic malignancy in patients with thymic epithelial tumors was 12.2% (16 of 131) for thymoma and 12.2% (10 of 82) for thymic carcinoma. The overall incidence of additional malignancy between 2003 and 2008 was significantly higher among patients with thymoma than among patients with hepatocellular carcinoma, colorectal cancer, breast cancer, and cervical cancer (p 0.017, 0.022, 0.009, and 0.018, respectively). In thymic carcinoma, the likelihood of developing extrathymic malignancy was significantly higher among patients with neuroendocrine carcinoma than among patients with other thymic carcinomas (p 0.000). Extrathymic neoplasm did not pose a significant influence on the overall survival of patients with thymoma (p 0.085) and thymic carcinoma (p 0.814). Conclusions. Our data demonstrated the increased risk of extrathymic malignancies among patient with thymoma. In thymic carcinoma, this association mainly occurred in patients with neuroendocrine carcinoma. Actions for early detection of extrathymic malignancy should be considered for patients with these thymic epithelial tumors. (Ann Thorac Surg 2011;91:219 26) 2011 by The Society of Thoracic Surgeons Thymoma is defined as a tumor derived from epithelial cells of the thymus [1]. It has been well documented that thymoma is associated with many paraneoplastic syndromes, including myasthenia gravis (MG), pure red cell anemia, and immunoglobulin abnormalities [2]. Souadjian and colleagues [3] first described a series report that extrathymic malignancy should also be added as an association syndrome of thymoma in Although Engels and associates [4] suggested this phenomenon did not exist in malignant thymoma, Pan and colleagues [5] had a literature review of this issue in 2001 and documented that the average incidence of thymoma with associated extrathymic malignancy was as high as 17%. Almost all of the literature, however, discussed the Accepted for publication Sept 9, Address correspondence to Dr Tseng, Division of Thoracic Surgery, Department of Surgery, National Cheng Kung University Hospital, 138 Sheng-Li Rd, Tainan, Taiwan; tsengyl@mail.ncku.edu.tw. additional malignancy that occurred in patients with thymoma instead of in patients with thymic carcinoma. Thymic carcinoma exhibits distinctly more aggressive behavior, easy metastasis, and very poor prognosis than thymoma [6]. The adenoma-carcinoma model in other solid organ malignancies, a term that describes the stepwise progression from normal to dysplastic epithelium to carcinoma associated with the accumulation of multiple clonally selected genetic alterations [7], could not be applied to thymoma and thymic carcinoma because thymoma may recur and metastasize without overt cytologic features of malignancy [6]. It is suggested that thymic carcinoma occurs de novo from thymic epithelial cells instead of thymoma [8]. It has not been elusive whether thymic carcinoma is at increased risk of developing extrathymic malignancy. In this study, we retrospectively reviewed the patients who were diagnosed with thymoma and thymic carcinoma. The incidence of additional malignancy in patients 2011 by The Society of Thoracic Surgeons /$36.00 Published by Elsevier Inc doi: /j.athoracsur

2 220 YEN ET AL Ann Thorac Surg THYMIC TUMORS AND EXTRATHYMIC MALIGNANCY 2011;91: Table 1. Demographics of Patients With Treated Thymoma and Thymic Carcinoma from 1988 to 2008 Thymoma (n 131) Thymic Carcinoma (n 82) p Value Age, mean SD (range) (17 77) (25 77) Sex, male:female 77:54 36: Extrathymic malignancy, yes:no (incidence) 16:115 (12.2%) 10:72 (12.2%) Masaoka stage I 59 1 II 36 4 III IV 7 27 Myasthenia gravis, yes:no 60:71 1: Alive:dead 104:27 30:51 Alive with recurrence Alive with metastasis Dead of thymic tumor Dead of second neoplasm with thymoma and thymic carcinoma was elucidated and compared with that of patients with commonly encountered malignancies in our institution. Material and Methods A retrospective review of medical records between the years 1988 and 2008 was conducted among 213 patients, including 131 with thymoma and 82 with thymic carcinoma. The surgical pathologies were confirmed, and the tumors were classified according to the newly published World Health Organization (WHO) classification [9]. The incidence of extrathymic malignancy in patients with thymoma and thymic carcinoma was calculated. The overall incidence was compared with that of additional malignancy in patients with lung cancer, hepatocellular carcinoma, colorectal cancer, breast cancer, and cervical cancer in our institution between 2003 and 2008, with the aid of the disease coding and cancer registry system managed by the Cancer Center of National Cheng Kung University Hospital. The Institutional Review Board approved the use of anonymous data from standard clinical practice because no additional treatment was planned (observational study). Sixty patients with thymoma and 1 with thymic carcinoma were diagnosed as having MG, whereas 71 patients with thymoma and 81 with thymic carcinoma were not. All the patients have been followed up for at least 12 months or until their death, ranging from 1 to 212 months. The mean follow-up period was 66 months (range, 1 to 212) for patients with thymoma and 41.2 months (range, 1 to 180) for patients with thymic carcinoma. Demographic data including age, sex, follow-up period, subtype of tumor, Masaoka staging, MG, and current status of patients with thymoma and thymic carcinoma were compared. Comparisons between patients with and without extrathymic malignancy were also conducted in the thymoma group and thymic carcinoma group, respectively. All of the patients with extrathymic malignancy were divided into three groups according to the timing when extrathymic malignancies were diagnosed, with patients diagnosed before the time of thymic tumor in one, patients diagnosed simultaneously in another, and the rest in the third group. Their clinical variables were also compared. Whether there was adjuvant chemotherapy or radiation was also reviewed to evaluate the oncogenic effect for extrathymic neoplasm. The 2 test and Student s t test were used to compare variables, and the Kaplan-Meier method was adopted for analysis of overall survival of patients with and without extrathymic malignancies in thymoma and thymic carcinoma group. Comparisons of survival in each group were conducted with the log rank test. Results As listed in Table 1, the characteristics of 131 thymoma patients and 82 thymic carcinoma patients were significantly different regarding sex ratio, Masaoka staging, MG, and death related to thymic epithelial tumor or extrathymic malignancy. A total of 26 patients was identified as having other malignancies in addition to thymoma (16 patients) and thymic carcinoma (10 patients). The incidence of extrathymic malignancy in patients with thymic epithelial tumors was 12.2% for thymoma and 12.2% for thymic carcinoma. We used both the cancer registry system implemented 4 years ago and the disease coding system to compute the overall incidence of additional malignancy among patients with thymic tumors, lung cancer, hepatocellular carcinoma, colorectal cancer, breast cancer, and cervical cancer between 2003 and 2008 (Table 2). The overall incidence seemed higher among patients with thymic epithelial tumors. The difference, however, was significant only when it was compared between thymoma and hepatocellular carcinoma, colorectal cancer, breast cancer, and cervical cancer.

3 Ann Thorac Surg YEN ET AL 2011;91: THYMIC TUMORS AND EXTRATHYMIC MALIGNANCY 221 Table 2. Incidence of Second Malignant Neoplasm in Patients With Thymic Epithelial Tumors and Other Commonly Encountered Cancers Between 2003 and 2008 in Authors Institution p Value a Group Overall Incidence of Patients With Additional Malignancies Thymoma Thymic Carcinoma Thymoma 6/51 (11.76%) Thymic carcinoma 3/40 (7.50%) Lung cancer 103 /1,756 (5.87%) Hepatocellular carcinoma 73/1,858 (3.93%) Colorectal cancer 72/1,719 (4.19%) Breast cancer 64/1,890 (3.39%) Cervical cancer 43/1,109 (3.88%) a The p values were computed with 2 comparison between the incidence of additional malignancy in other solid organ cancers and that in thymoma and thymic carcinoma, respectively. The clinicopathologic features of patients with extrathymic malignancy are summarized in Table 3. There was no predilection for a certain type of extrathymic malignancy to occur in patients with thymoma and thymic carcinoma. The time when the extrathymic malignancy was diagnosed varied from 200 months before Table 3. Clinicopathologic Features of 26 Patients With Thymic Epithelial Tumors and Extrathymic Malignancies Thymic Tumor Extrathymic Malignancy Pt. No. Age, Years Sex Type Stage MG Treatment Type Interval a Status Survival a 1 74 F A I 0 R0 HCC 48 A M A I 0 R0 Esophageal SqCC 0 DOS F A I 0 R0 Breast cancer 154 A F AB I 0 R0 HCC 37 A F AB I 0 R0 AML 13 DOS M AB I 0 R0 Kaposi sarcoma 0 A F AB I 0 R0 HCC 72 A F AB I 0 R0 Lung adenocarcinoma 0 A F B1 IIb 0 R0 RT Osteogenic sarcoma 24 A F B2 III 1 R1 RT Bladder cancer 20 A F B2 III 1 R2 RT Cervical SqCC 62 A M B2 IVa 0 R2 Bladder cancer 24 DOT F B2 I 1 R0 NPC 50 DOS M B2 III 1 R0 Lung adenocarcinoma 150 A 12 & bladder cancer M B3 III 1 R0 RT HCC 5 DOS M B3 III 0 R1 RT CT Anal cancer 0 DOS M C, LE III 0 R0 Bladder cancer 133 DOT F C, NE III 1 R0 RT HCC 48 A M C, NE III 0 R0 RT Small cell lung cancer 71 DOS M C, LE III 0 R0 RT Testicular cancer 200 DOT F C, SqCC IVb 0 R2 RT CT Breast cancer 21 DOT F C, NE IVa 0 R2 RT Meningioma 4 DOT F C, SqCC III 0 R0 RT Lung BAC 0 DOT F C, NE IVb 0 R2 RT CT Cerebellar 11 DOT 32 paraganglioma M C, SqCC III 0 R0 CT Colon cancer 0 A F C, SqCC III 0 R0 Bladder cancer 28 DOT 25 a The interval and survival were counted by month. A alive; AML acute myeloid leukemia; BAC bronchoalveolar carcinoma; CT chemotherapy; DOS died of second neoplasm; DOT died of thymic tumor; F female; HCC hepatocellular carcinoma; LE lymphoepitheliomalike carcinoma; M male; MG myasthenia gravis; NE neuroendocrine carcinoma; NPC nasopharyngeal carcinoma; Pt. No. patient number; R0 R0 resection; R1 R1 resection; R2 R2 resection; RT radiotherapy; SqCC squamous cell carcinoma.

4 222 YEN ET AL Ann Thorac Surg THYMIC TUMORS AND EXTRATHYMIC MALIGNANCY 2011;91: Table 4. Comparison Between Thymoma Patients With and Without Extrathymic Malignancy Characteristics Thymoma With Extrathymic Neoplasm Thymoma Without Extrathymic Neoplasm p Value Patients, n Sex, male:female 6:10 71: Age Mean SD (Range) (40 74) (18 77) Histology A 3 7 AB 5 29 B B B Masaoka stage I 9 50 II 1 35 III 5 24 IV 1 6 Myasthenia gravis Yes 5 55 No Preop radiotherapy Yes 0 1 No Postop radiotherapy Yes 5 39 No Postop postoperative; Preop preoperative. diagnosis to 72 months after the diagnosis of thymic tumor. Twelve of the 26 patients were still alive. Six patients died of extrathymic neoplasm, and 8 patients died of thymic tumor itself. Seven of the 8 thymic carcinoma patients with additional malignancies died of thymic carcinoma itself, whereas only 1 of the 6 deaths of thymoma patients with extrathymic malignancy did. The difference in associated cancer-related death was statistically significant (p 0.000), which was also true if all the deaths were computed according to their cause, as listed in Table 1. To further verify the difference between thymoma patient with or without extrathymic malignancy, sex ratio, age of diagnosis, WHO histologic classification, and Masaoka staging of thymoma were compared but did not show any significant difference (Table 4). The incidence of extrathymic malignancy among patients with myasthenic thymoma and nonmyasthenic thymoma was not significantly different. The overall survival of thymoma patients with and without extrathymic malignancy was also computed. Extrathymic malignancy did not pose a significant influence on the overall survival of patients with thymoma (Fig 1). Comparisons of clinical variables between thymic carcinoma patients with and without extrathymic malignancies were also conducted and revealed no significant difference (Table 5). The overall survival was not significantly influenced by the existence of extrathymic malignancy, either (Fig 2). Patients with thymic carcinoma in this series belong to three subtypes, including squamous cell carcinoma (n 64), lymphoepitheliomalike carcinoma (n 11), and neuroendocrine carcinoma (n 7). Four of the 7 patients with thymic neuroendocrine tumors (all 3 of the 3 patients with carcinoid and 1 of 4 with carcinoma) had additional malignancies. The likelihood Fig 1. The overall survival of thymoma patients with extrathymic malignancy (green line) and without extrathymic malignancy (blue line) is not significantly different (p 0.085). (Cum cumulative.)

5 Ann Thorac Surg YEN ET AL 2011;91: THYMIC TUMORS AND EXTRATHYMIC MALIGNANCY 223 Table 5. Comparisons Between Thymic Carcinoma Patients With and Without Extrathymic Malignancy Characteristics Thymic Carcinoma With Extrathymic Malignancy Thymic Carcinoma Without Extrathymic Malignancy p Value Patients, n Sex, male:female 4:6 32: Age Mean SD (Range) (46 77) (25 77) Histology Squamous cell carcinoma 4 60 Lymphoepitheliomalike carcinoma 2 9 Neuroendocrine carcinoma 4 3 Masaoka stage I 0 1 II 0 4 III 7 43 IV 3 24 Myasthenia gravis Yes 1 0 No 9 72 Preop radiotherapy Yes 1 7 No 9 65 Postop radiotherapy Yes 8 47 No 2 25 Postop postoperative; Preop preoperative. for extrathymic malignancy to occur was significantly higher than for patients with thymic squamous cell carcinoma (4 of 64) or lymphoepitheliomalike carcinoma (2 of 11; p 0.000). Patients with extrathymic malignancy were further divided into three groups (Table 6). The difference was significant in the mean ages of thymic tumor diagnosis (p Fig 2. The overall survival of thymic carcinoma patients with extrathymic malignancy (green line) or without extrathymic malignancy is not significantly different (p 0.814). (Cum cumulative.) 0.048), and the existence of MG (p 0.036). Neither adjuvant chemotherapy nor radiotherapy elevated the risk for the development of extrathymic malignancy. Comment Our result showed the incidence of extrathymic malignancy in thymoma patients was comparable to that in the published literature and slightly higher than in the report of Pan and colleagues [5] from northern Taiwan and others [10-12]. Rarely, there was a comparison of the incidence of additional malignancy between patients with thymic epithelial tumors and with other solid organ cancers. Only Pan and associates [5] reported that the incidence of second malignancy among thymoma patients was significantly higher compared with that of a matched cohort of patients with nasopharyngeal carcinoma. In this series, this incidence in colorectal cancer, cervical cancer, breast cancer, and hepatocellular carcinoma was approximately 3.88% to 4.19% and was compatible with previous reports from Kaneko and Yamaguchi [13] and Aydiner and colleagues [14] that the prevalence of multiple cancers in general was approximately 1% to 4.6%. Our result revealed that the incidence of additional malignancy among thymoma patients was indeed significantly higher than among patients with colorectal cancer, breast cancer, cervical cancer, and hepatocellular carcinoma. Although the incidence was also higher than for patients with lung cancer, it did not

6 224 YEN ET AL Ann Thorac Surg THYMIC TUMORS AND EXTRATHYMIC MALIGNANCY 2011;91: Table 6. Comparisons Between Patients With Extrathymic Malignancy Diagnosed in History, Concomitantly, or During Follow-Up Extrathymic Neoplasm in History (n 9) Extrathymic Neoplasm of Concomitant Diagnosis (n 6) Extrathymic Neoplasm of Later Diagnosis (n 11) p Value Age Mean SD (Range) (40 77) (54 64) (41 74) Sex, male:female 4:5 4:2 2: Histology Thymoma Thymic carcinoma Masaoka stage I II III IV Myasthenia gravis Yes No Adjuvant chemotherapy Yes No Adjuvant radiotherapy Yes No reach statistical significance. In fact, lung cancer has been reported to have a higher incidence of associated malignancy [14, 15]. Our data also revealed this tendency, and the incidence could be even higher because second primary lung cancer was not included in our registry as an additional malignancy. The occurrence of extrathymic malignancy in patient with thymic carcinoma has not been delineated in the published literature, although the report by Engels and Pfeiffer [4] might have involved some of these data. During the past 20 years, a relatively large number of patients with thymic carcinoma were treated in our institution, offering us an opportunity to investigate this issue. The overall incidence of patients with thymic carcinoma having an extrathymic malignancy was as high as 12.2%. However, the incidence between 2003 and 2008, although a bit higher, was not significantly different between patients with thymic carcinoma and patients with other solid organ cancers. This finding might be due to the uneven distribution of thymic carcinoma patients annually and to the limited number of patients with extrathymic malignancy. Most importantly, we found that most of the additional malignancy occurred in the patients with thymic neuroendocrine carcinoma, with the incidence statistically much higher than that in patients with squamous cell carcinoma and lymphoepitheliomalike carcinoma. Thymic neuroendocrine carcinoma, including well-differentiated thymic neuroendocrine carcinomas (carcinoid) and poorly differentiated thymic neuroendocrine carcinomas (including large-cell neuroendocrine carcinoma and small-cell neuroendocrine carcinoma), has been recruited as a subtype of thymic carcinoma in the 2004 WHO classification [16]. Although some of the literature documented that thymic carcinoid was associated with multiple endocrine neoplasia type 1 [17, 18], our data did not reveal this tendency. There was no predilection of a certain extrathymic malignancy to occur in patients with thymic neuroendocrine carcinoma, which was also true for patients with thymoma. Extrathymic malignancies could be identified before, at the same time, or after the diagnosis of thymic tumor. We found that the mean age was significantly younger in patients with extrathymic malignancy diagnosed after thymoma. The association with MG was also of more significance than for patients with extrathymic malignancy detected before or simultaneously with thymoma. The literature reported that patients in whom malignancy developed after primary tumor tended to be a younger age [14], suggesting that the oncogenic effect and increased risk of the second primary cancer were caused by the adjuvant radiotherapy or chemotherapeutic agents. Our data, however, did not support this tendency because chemotherapy and radiotherapy for thymic tumor patients did not elevate their risk of additional malignancy developing. We believe that the association of MG make possible early diagnosis of thymoma [19], and the secondary malignancy finally develops because of the intrinsic effect of thymic epithelial tumor, as proposed by Souadjian and colleagues [3]. The overall survival of patients with thymic tumors was not affected by the presence of extrathymic malignancies. However, something noteworthy is that, 7 of the thymic carcinoma patients with extrathymic neoplasm

7 Ann Thorac Surg YEN ET AL 2011;91: THYMIC TUMORS AND EXTRATHYMIC MALIGNANCY 225 eventually died of thymic carcinoma itself. These patients all had thymic carcinoma with vascular invasion, which indicated a poor prognosis [20]. Conversely, the prognosis of thymoma patient with extrathymic malignancy might depend on the associated malignancy because of the relatively benign course of thymoma. Some limitations do exist in our study. The incidence of additional neoplasm in patients with lung cancer, hepatocellular carcinoma, colorectal cancer, breast cancer, and cervical cancer needs to be computed further. Also, the number of patients with thymic carcinoma was still not large enough to have a thorough analysis. Further investigation or even collaboration with other medical centers would be conducted to validate this issue. In conclusion, patients with thymic carcinoma, especially the neuroendocrine subtype, have an elevated risk of developing an extrathymic neoplasm, as documented in patients with thymoma. Myasthenia gravis does not enhance the risk of extrathymic malignancy, but may make possible early diagnosis of thymic tumor and hence disclose the occult development of an extrathymic neoplasm in the follow-up period. Actions for early detection of extrathymic neoplasm should be considered in these patients. We sincerely appreciate the assistance of Mrs Yi-Lin Wu, case manager of the cancer center, and Dr Wu-Wei Lai, chief of thoracic surgery and director of the cancer registry data bank, for access to the cancer registry database in our institution and for computing the incidence of additional malignancy for the five most commonly encountered cancers. This study was supported by grant NSC B from the National Science Council, Taiwan. References 1. Rosai J, Sobin LH. World Health Organization histological typing of tumors of the thymus. 2nd ed. New York: Springer- Verlag, Souadjian JV, Enriquez P, Silverstein MN, Pepin JM. The spectrum of diseases associated with thymoma. Coincidence or syndrome? Arch Intern Med 1974;134: Souadjian JV, Silverstein MN, Titus JL. Thymoma and cancer. Cancer 1968;22: Engels EA, Pfeiffer RM. Malignant thymoma in the United States: demographic patterns in incidence and associations with subsequent malignancies. Int J Cancer 2003;105: Pan CC, Chen PC, Wang LS, Chi KH, Chiang H. Thymoma is associated with an increased risk of second malignancy. Cancer 2001;92: Hasserjian RP, Strobel P, Marx A. Pathology of thymic tumors. Semin Thorac Cardiovasc Surg 2005;17: Leslie A, Carey FA, Pratt NR, Steele RJ. The colorectal adenoma-carcinoma sequence. Br J Surg 2002;89: Chung DA. Thymic carcinoma analysis of nineteen clinicopathological studies. Thorac Cardiovasc Surg 2000;48: Marx A, Strobel P, Zettl A, et al. In: Travis MD, Brambilla E, Muller-Hermelink HK, Harris CC, eds. Thymomas. Vol 7. World Health Organization classification of tumors pathology and genetics of tumors of the lungs, thymus and heart. Lyon: IARC, 2004: Couture MM, Mountain CF. Thymoma. Semin Surg Oncol 1990;6: Gray GF, Gutowski WT. Thymoma. A clinicopathologic study of 54 cases. Am J Surg Pathol 1979;3: Welsh JS, Thurman SA, Howard SP. Thymoma and multiple malignancies: a case of five synchronous neoplasms and literature review. Clin Med Res 2003;1: Kaneko S, Yamaguchi N. Epidemiological analysis of site relationships of synchronous and metachronous multiple primary cancers in the National Cancer Center, Japan, Jpn J Clin Oncol 1999;29: Aydiner A, Karadeniz A, Uygun K, et al. Multiple primary neoplasms at a single institution: differences between synchronous and metachronous neoplasms. Am J Clin Oncol 2000;23: Duchateau CS, Stokkel MP. Second primary tumors involving non-small cell lung cancer: prevalence and its influence on survival. Chest 2005;127: Strobel P, Marx A, Zettl A, Muller-Hermelink HK. Thymoma and thymic carcinoma: an update of the WHO classification Surg Today 2005;35: Ferolla P, Falchetti A, Filosso P, et al. Thymic neuroendocrine carcinoma (carcinoid) in multiple endocrine neoplasia type 1 syndrome: the Italian series. J Clin Endocrinol Metab 2005;90: Miller BS, Rusinko RY, Fowler L. Synchronous thymoma and thymic carcinoid in a woman with multiple endocrine neoplasia type 1: case report and review. Endocr Pract 2008;14: Kondo K, Monden Y. Thymoma and myasthenia gravis: a clinical study of 1,089 patients from Japan. Ann Thorac Surg 2005;79: Tseng YL, Wang ST, Wu MH, et al. Thymic carcinoma: involvement of great vessels indicates poor prognosis. Ann Thorac Surg 2003;76: INVITED COMMENTARY The association between thymic tumors and other intrathoracic or extrathoracic neoplasms is relatively rare and ranges between 9% and 28% according to the literature. The most frequent combination includes hematological disorders and cancer arising in the digestive tract. However, in the present report hepatoma, bladder cancer, and lung adenocarcinomas were mostly represented. When thymic tumors and other malignancies occur simultaneously or metachronously, the question is whether thymomas favor the onset of other tumors or vice versa. The difficulty to assess the epidemiologic distribution and the causes of this association is related to the rarity of thymic malignancies and the low power for individual cancers in isolated series. In addition, the length of follow-up plays an important role, because studies that have been unable to evaluate at least 10 to 15 years of follow-up are probably underestimating the problem. There are different theories concerning the pathologic basis for this association. Some authors have advocated a defect within the thymus epithelium leading to a lack of ability to fulfill its role in T-cell ontology or the potential ability of thymoma epithelial cells to stimulate T-cell proliferation; this may be extremely important when 2011 by The Society of Thoracic Surgeons /$36.00 Published by Elsevier Inc doi: /j.athoracsur