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Ann Thorac Surg 2012;93:884-888. doi:10.1016/j.athoracsur.2011.05.089
© 2012 The Society of Thoracic Surgeons
Original Articles: General Thoracic
Thymomas and Extrathymic Cancers
Benny Weksler, MD*,
Katie S. Nason, MD, MPH,
Daniel Mackey, MD,
Angela Gallagher, CRNP,
Arjun Pennathur, MD
Department of Cardiothoracic Surgery, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania
Accepted for publication May 24, 2011.
* Address correspondence to Dr Weksler, Department of Cardiothoracic Surgery, University of Pittsburgh Medical Center, 200 Lothrop St, PUH C-800, Pittsburgh, PA 15213 (Email: wekslerb{at}upmc.edu).
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Abstract
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Background: Patients with thymoma may have a predisposition toward extrathymic neoplasia. To understand the lifetime risk and incidence of extrathymic neoplasia in patients with thymoma, we evaluated extrathymic neoplasms diagnosed either before or after the diagnosis of thymoma.
Methods: We queried the Surveillance, Epidemiology, and End Results (SEER) cancer database and identified patients with thymoma and extrathymic neoplasms. We collected demographic and treatment data, calculated the incidence of each extrathymic neoplasm (adjusting for age), and compared the incidence of extrathymic neoplasm in patients with thymoma with the age-adjusted incidence in the SEER database general population.
Results: Of 2,171 patients with thymoma in the SEER database, 306 (14.1%) had extrathymic primary cancers. Extrathymic neoplasms were diagnosed before the diagnosis of thymoma in 88 patients and after the diagnosis of thymoma in 206 patients. In 12 patients, separate extrathymic neoplasms were diagnosed both before and after thymoma diagnosis. The incidence of extrathymic cancers in patients with thymoma (8,224 per 100,000 persons) was significantly higher than in the SEER general population (459 per 100,000 persons; p < 0.001). The standardized incidence ratio for extrathymic cancer was also significantly increased, in particular for lymphomas, leukemias, esophageal cancer, and lung cancer. Increased age at diagnosis (p < 0.001), longer survival after diagnosis (p < 0.001), and male sex (p = 0.041)—but not radiation therapy or surgery—were significant risk factors for the development of extrathymic cancers in patients with thymoma.
Conclusions: The incidence of extrathymic neoplasia is significantly higher in patients with thymoma than in the general population and occurs both before and after the diagnosis of thymoma.
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Introduction
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The thymus plays a central role in the immune system. Potentially autoaggressive T lymphocytes are deleted in the thymic medulla, and only T lymphocytes that maintain self-tolerance and immunity against infection are released to the general circulation. Additionally, thymic epithelial cells play a key role in the development of mature T lymphocytes. [1] Thymomas are rare neoplasms arising in thymic epithelial cells and are the most common neoplasm in the anterior mediastinum. Often thymomas have an indolent natural history, and most patients survive for many years. [2] Thymomas are associated with autoimmune disorders in 30% to 40% of patients, most commonly myasthenia gravis but also red cell aplasia and hypogammaglobulinemia [3, 4].
Extrathymic neoplasia may be more common in patients with thymoma than in the general population. [5, 6] Although most studies are small, associations with lymphoma [7] and gastrointestinal cancers [8, 9] have been reported. Published series have focused on the incidence of extrathymic malignancies detected after the diagnosis of thymoma. In order to understand the lifetime risk and incidence of extrathymic neoplasia in patients with thymoma, we investigated the association of thymoma and extrathymic neoplasms, examining both extrathymic neoplasms diagnosed before thymoma and extrathymic neoplasms diagnosed after thymoma.
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Material and Methods
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The Surveillance, Epidemiology, and End Results (SEER) database is sponsored by the National Cancer Institute and has been used to track cancer incidence and patient survival since 1973. The SEER database currently covers approximately 28% of the US population and captures 98% of all cancer cases within the surveyed geographic areas. We used the SEER 17 Registry including the Hurricane Katrina Impacted Louisiana Cases for this analysis (SEER Program [www.seer.cancer.gov]). The SEER database was queried for all cases of thymoma using the ICD-03 codes 8580 (thymoma, malignant NOS), 8581 (thymoma, malignant type A), 8582 (thymoma, malignant type AB), 8583 (thymoma, malignant type B1), 8584 (thymoma, malignant type B2), and 8585 (thymoma, malignant type B3). Codes for thymic carcinoma (8586, 8588, and 8589) were excluded. All patients with thymoma and extrathymic cancers were identified. Patients with 2, 3, or more than 3 extrathymic cancers were considered separately. The incidence of cancer in the SEER population and in patients with thymoma was calculated per 100,000 persons and adjusted for age according to the 2000 US census. Using SEER*Stat software (www.seer.cancer.gov/seerstat), version 6.6.2, standardized incidence ratio (SIR)—the ratio of the number of observed cases to the number of expected cases) was calculated to measure the relative risk of an extrathymic cancer developing. Continuous data variables were analyzed using the Student's t test. Nominal data were analyzed using crosstabs and Pearson's 
2 test. Survival curves were constructed using the Kaplan-Meier method and compared using the log-rank test. A Cox proportional hazard model was used to identify relevant variables affecting the risk of extrathymic cancers. Factors affecting the incidence of extrathymic neoplasms were analyzed using binary regression multivariate analysis. Kaplan-Meier survival curves were constructed and compared using the log-rank test. Statistical analysis was performed with SPSS statistical software package, version 19.0 (SPSS Inc, Chicago, IL). Significance was set at p < 0.05. Because all data in this study is deidentified and none of the investigators participated in data gathering or data entry into the SEER database, this study was waived from formal approval by the University of Pittsburgh institutional Review Board.
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Results
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We identified 2,171 patients with thymoma in the SEER database. Three hundred six of these patients (306/2,171, 14.1%) had 350 extrathymic neoplasms. Patient characteristics and thymoma treatment are shown in Table 1. There were 2 patients with 4 extrathymic neoplasms each, 3 patients with 3 extrathymic neoplasms each, 32 patients with 2 extrathymic neoplasms each, and 269 patients with a single extrathymic neoplasm. Extrathymic cancers were present before the diagnosis of thymoma in 88 patients (98 extrathymic neoplasms), 12 patients had diagnoses of extrathymic primary cancers both before and after the diagnosis of thymoma (25 extrathymic tumors, 12 before and 13 after), and 206 patients had 227 extrathymic primary tumors diagnosed after the thymoma was diagnosed.
Overall, extrathymic cancers were diagnosed 0.7 ± 7.5 years (median, 0; range, –29 to +26 years) from the time of the thymoma diagnosis. The mean age at diagnosis of the thymoma was 64.0 ± 11.8 years (median, 65; range, 31 to 90 years) and the mean age at diagnosis of the extrathymic cancer was 64.7 ± 12.5 years (median, 66, range; 18 to 96 years). The age-adjusted incidence of cancer in patients diagnosed with thymoma was 8,224.9 per 100,000 compared with 459.2 per 100,000 in the SEER population (p < 0.001), an 18-fold increased incidence. The most common extrathymic neoplasms in patients with thymoma were lymphoma, breast cancer, prostate cancer, and lung cancer (Table 2).
There were 110 extrathymic primary neoplasms diagnosed 6.8 ± 5.9 years (median, 5 years; range 1 to 29 years) before the diagnosis of thymoma. In this group, the mean age at the time of the thymoma diagnosis was 66.1 ± 11.7 years (median, 67; range, 35 to 90 years), and mean age at the time of the extrathymic neoplasm diagnosis was 59.3 ± 12.7 years (median, 61; range, 18 to 82 years). The age-adjusted incidence of cancer before thymoma diagnosis in patients who were subsequently diagnosed with thymoma was 3,388.6 per 100,000 persons and was 7 times higher than the age-adjusted cancer incidence in the SEER general population (p < 0.001). The most common neoplasms diagnosed before thymoma were lymphoma, breast cancer, prostate cancer, and colorectal cancer (Table 2).
There were 240 extrathymic primary neoplasms diagnosed 4.1 ± 5.2 years (median, 2 years; range, 0 to 26 years) after the thymoma diagnosis. In this group, the mean age at the time of the thymoma diagnosis was 63.0 ± 11.7 years (median, 64.5; range, 31 to 89 years) and the mean age at the time of the diagnosis of the extrathymic neoplasm was 67.2 ± 11.6 years (median, 68; range, 31 to 96 years). The age-adjusted incidence of cancer after thymoma diagnosis was 4,836.4 per 100,000 persons, 10 times higher than the age-adjusted cancer incidence in the SEER general population (p < 0.001). The most common extrathymic primary neoplasms diagnosed after thymoma diagnosis were lung cancer, breast cancer, prostate cancer, and lymphoma (Table 2).
SIRs for each malignancy are presented in Table 3. Patients with thymoma had an overall increased risk of acquiring extrathymic malignancies of 47%. The risk of lymphoma, leukemia, and esophageal cancer developing was particularly increased in patients with thymoma, with a 4-fold increased risk when compared with the general population.
The median survival for the entire cohort of 2,171 patients with thymoma was 106.0 months (95% confidence interval [CI], 92.5 to 115.5). The presence of an extrathymic cancer after the diagnosis of thymoma did not negatively affect survival. Patients with an extrathymic primary neoplasm had a median survival of 116.0 months (95% CI, 92.6 to 139.4), whereas patients with thymoma without an extrathymic primary neoplasm had a median survival of 102.0 months (95% CI, 92.0 to 112.0) (p = 0.096) (Fig 1). In multivariate analyses, age at thymoma diagnosis, survival time after thymoma diagnosis, and male sex—but not radiation therapy or surgery—were risk factors for the development of an extrathymic cancer after the diagnosis of thymoma (Table 4).
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Fig 1. Survival curve comparing patients with and without extrathymic neoplasia. There was no significant difference in survival using the log-rank test.
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Comment
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In this study patients with thymoma identified in the SEER Registry had an overall incidence of extrathymic neoplasm that was 18 times greater than that in the general SEER population. This difference was particularly striking when the incidence of lymphoma was compared between patients with and without thymoma. Our findings confirm the reports of other investigators [5, 8–12]. The use of radiation therapy or surgery to treat the thymoma did not increase the risk of extrathymic neoplasms. The incidence of extrathymic cancer was also increased before the diagnosis of thymoma. To further corroborate our hypothesis we calculated the SIR for all cancers and for each type of cancer in the full thymoma cohort and demonstrated a significantly increased risk for the development of extrathymic cancers, particularly lymphoma, esophageal cancer, and leukemia. To our knowledge this is the largest study evaluating the association between thymomas and extrathymic neoplasms, and the only study that tracked the incidence of cancer both before and after the diagnosis of thymoma.
Thymomas are often associated with autoimmune diseases, such as myasthenia gravis, aplastic anemia, and hypogammaglobulinemia. The thymic gland is responsible for T-cell lymphocyte maturation through a process of negative selection. T-cell lymphocytes travel to the thymic medulla, and those reacting strongly to self-antigens are deleted [13]. The mature lymphocytes released to the circulation are responsible for immunity and cancer immunosurveillance, while avoiding autoimmune conditions. When there is depression of T-cell immunity, the incidence of cancer increases. In a study of heart and lung transplant recipients, a population in whom T-cell immunity is suppressed to prevent rejection, the risk of cancer developing was increased 7.1 times compared with the general population [14]. In contrast, healthy patients with a high degree of lymphocyte cytotoxicity showed a significantly lower risk of cancer in an 11-year follow-up study [15]. The thymus plays an important role in both autoimmunity and cancer immunosurveillance and although unproved, it is possible that dysfunction in the thymic epithelial cells could be responsible for an increased risk for autoimmune disorders, extrathymic neoplasms, and thymic neoplasms such as thymoma. It is tempting to suggest a broader immune abnormality in patients with thymoma.
There are many difficulties in attempting to define the incidence of extrathymic malignancies in patients with thymoma. Most importantly thymoma is a rare disease. The current estimated incidence of thymoma in the United States is 0.13 cases per 100,000 persons [6]. The majority of studies linking thymoma to extrathymic neoplasia come from single-institution series. Soudjian and colleagues [5], who found only 1,208 described cases of thymoma in 136 years (from the first described case in 1832 to 1968), may have been the first to clearly link thymomas to extrathymic neoplasia, reporting a series of 146 patients diagnosed with thymomas at the Mayo Clinic. They found that the incidence of extrathymic neoplasms was 21% in patients with thymoma compared with 8% in patients with a history of parathyroid adenomas who were analyzed as a control group. Masaoka and associates [10] reported a series of 392 patients who underwent thymectomy for myasthenia gravis; 102 patients had thymomas. Nine patients experienced malignancies; 8 of the 9 (7.8%) had a diagnosis of thymoma. Welsh and colleagues [11] reported that 28% of 136 patients with thymoma acquired extrathymic cancers. The most common extrathymic cancer in their series was colorectal carcinoma. Pan and coworkers [8] reported a series of 192 patients with thymoma from Taiwan. The incidence of extrathymic neoplasm was 8%, and the most common tumor was gastric adenocarcinoma. Two patients had extrathymic tumors before the diagnosis of thymoma.
Three series have used large databases to study thymomas and extrathymic neoplasms. In a SEER registry study using the 1973 to 1998 database, Engels and Pfeiffer [7] examined extrathymic neoplasms arising after the diagnosis of thymomas in 733 patients. The incidence of extrathymic cancer was significantly elevated and 66 patients acquired extrathymic tumors., The risk for gastrointestinal cancers and lymphomas in particular was significantly elevated. Owe and associates [9] studied the Cancer Registry of Norway and found 212 patients with thymoma. Forty-four patients had 53 extrathymic malignancies and 22 patients had the extrathymic malignancy diagnosed up to 10 years after the diagnosis of thymoma. The most common tumors were gastrointestinal and respiratory cancers. Gadalla and coworkers [3] identified 668 patients with the diagnosis of thymoma in the Nationwide Swedish Cancer Registry. The incidence of extrathymic cancer was 15.8% in the thymoma population, a risk twice that of the general Swedish population. The most common extrathymic neoplasms in the Swedish patients were nonmelanoma skin cancers and non-Hodgkin's lymphomas.
The most common extrathymic cancers in our study were lymphoma, breast cancer, prostate cancer, lung cancer, and colorectal cancer. The increased incidence of lymphoma in our study is in agreement with previous studies by Souadjian and colleagues [5] and Engels and Pfeiffer [7]. However this increased incidence of lymphoma has not been found in all studies. Welsh and coworkers [11], Pan and associates [8], and Owe and colleagues [9] found a higher incidence of gastrointestinal tumors in patients with thymoma. Similarly, using SIR to assess risk, our findings of a higher overall risk for any extrathymic cancer and a higher risk of lymphoma are in agreement with the studies of Engels and Pfeiffer [7] and Gadalla and coworkers [3]. However we did not see an increased risk for nonmelanoma skin cancer as Gadalla and colleagues did; instead we observed increased risks for leukemia, lung cancer, and esophageal cancer. The reasons for these differences are unclear. It is possible that diverse populations have different risks for the development of different cancers. Owe and colleagues' [9] study was from Norway, Gadhalla and associates' [3] study was from Sweden, and Pan and coworkers' [3] study was from Taiwan, all homogenous populations that are not similar to the US population.
Because this was a retrospective study based on a large patient population database, the design is constrained by the retrospective nature of the study, the limited data points available in the database, and possibly inaccuracies in reporting. An important disadvantage in this study was the inclusion of only defined malignant neoplasms by SEER, which may have led to the exclusion of so-called benign thymomas. This may have impacted the earlier cases in the SEER registry when thymomas were more commonly classified as benign if their histologic type was a blend with few mitotic figures.
Other possible shortcomings of this study are the age adjustment of a relatively small population and the movement of patients into and out of a SEER geographic location, which may result in occurrences of thymoma or extrathymic neoplasms that are not captured by the SEER registry. We elected to perform age adjustment using a direct method that uses a weighting system to summarize a set of age-specific rates. The weighting system is based on a static population, in our case the US population according to the 2000 census. The technique used facilitates valid comparisons between populations and across time. The main disadvantage is the possible instability in small populations, but we think that our thymoma population, although small relative to the US population, is large enough to offer a valid adjustment [16].
Patients with thymoma are more likely to experience extrathymic neoplasms, in particular lymphoma. The incidence of extrathymic cancers was increased both before and after the diagnosis of thymoma and the increased incidence was not related or restricted to patients who received radiation therapy or surgery. The finding of increased incidence of extrathymic neoplasia before the diagnosis of thymoma, combined with the high incidence of autoimmune diseases in patients with thymoma, suggests an intrinsic immune abnormality for which thymoma may be a marker. Lifetime follow-up of all patients with the diagnosis of thymoma is indicated, with vigilant screening to allow early detection of extrathymic neoplasms. Further studies may help clarify the role of the immune system in the spectrum of diseases associated with thymoma.
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Acknowledgments
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The authors would like to thank Shannon Wyszomierski for her expert editorial review of the manuscript.
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References
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Abstract
Introduction
