- Email: [email protected]
Thymoma: A Population-Based Study of the Management and Outcomes for the Province of British Columbia
ORIGINAL ARTICLE
Thymoma A Population-Based Study of the Management and Outcomes for the Province of British Columbia Caroline Mariano, MD,* Diana N. Ionescu, MD,† Winson Y. Cheung, MD,* Rola H. Ali, MD,† Janessa Laskin, MD,* Ken Evans, MD,§ Hannah Carolan, MD,‡ and Nevin Murray, MD*
Introduction: Thymomas are rare neoplasms with variable clinical behavior. Our primary study aim was to analyze treatment practices and outcomes in a population-based cohort of thymoma patients. We hypothesized that stage I and II thymomas would have high cure rates with resection and adjuvant radiation, whereas locally advanced cases would benefit from multimodality therapy. Methods: All patients, diagnosed with thymoma or thymic carcinoma in British Columbia between 1994 and 2009, were identified using the British Columbia Cancer Agency Registry. Chart review was used to collect demographic and treatment data. Detailed pathology review was performed using the World Health Organization classification. Results: One hundred and seventy-one patients were identified for analysis. The 5-year overall survival was 93.3%, 88.7%, 74.6%, 43.4% for stages I, II, III, and IV, respectively. Survival varied significantly among patients with thymoma compared with thymic carcinoma. In patients with stage II disease, adjuvant radiation did not confer an overall survival or recurrence-free survival benefit. Seventy-five patients had locally advanced disease. There was practice variation in treatment of these patients. Patients with thymoma undergoing trimodality treatment had a 5-year median overall survival of 80%, whereas patients with thymic carcinoma had poor outcomes despite aggressive treatment. Conclusions: Survival rates in this population-based series were comparable to those in previously published reports. The ideal management of thymic tumors involves a multidisciplinary approach, particularly in locally advanced disease and selection of patients for adjuvant radiation therapy. Key Words: Thymoma, Thymic carcinoma, Population, Outcomes. (J Thorac Oncol. 2013;8: 109–117) Departments of *Medical Oncology, †Pathology, and ‡Radiation Oncology, British Columbia Cancer Agency, British Columbia, Canada; and §Department of Thoracic Surgery, Vancouver General Hospital, British Columbia, Canada. Disclosure: The authors declare no conflict of interest. Address for correspondence: Caroline Mariano, MD, British Columbia Cancer Agency, 600 West 10th Avenue, Vancouver, British Columbia, Canada V5Z 4E6. E-mail: [email protected] Copyright © 2012 by the International Association for the Study of Lung Cancer ISSN: 1556-0864/12/0801-109
T
hymomas are rare tumors with an incidence of approximately 0.15 cases per 100,000 person years.1 Unfortunately, little is known about the etiology of these malignancies2 and their clinical behavior can be quite variable. There has been widespread debate about their optimal classification. In 1995, the World Health Organization (WHO) proposed a new pathologic staging system that has since been widely accepted and has been proven to have prognostic value.3–5 The management of these tumors also continues to evolve. The role of surgery to treat localized disease has been well established.6 Adjuvant radiation has been used in selected cases, although its role remains controversial.7 In locally advanced and metastatic disease, a multimodality approach including chemotherapy, radiation therapy, and surgery has been used with some success,8–10 although the optimal regimen and sequencing of treatments is based on expert opinion from phase II trials rather than randomized comparisons of therapeutic strategies. Although large series have helped elucidate the clinical behavior and optimal treatment regimens of these tumors, these data are based mainly on single-institution and surgical series. Population-based series have been largely epidemiologic and have not included detailed treatment and outcome data.11,12 The aim of this study was to detail a population-based series of all of the thymoma and thymic carcinoma cases in the province of British Columbia, to include demographic, clinical, pathologic, and treatment data based on the most upto-date reporting procedures. Before any data analyses, we hypothesized that stage I and II thymomas would have high cure rates with resection and adjuvant radiation, whereas locally advanced cases would benefit from multimodality therapy.
PATIENTS AND METHODS Patient Selection Approval for this retrospective chart review and pathology review was obtained from the BC Cancer Agency and University of British Columbia Research Ethics Board. All patients diagnosed with thymoma or thymic carcinoma between January 1, 1994 and December 31, 2008 in the entire province of British Columbia (population approximately
Journal of Thoracic Oncology • Volume 8, Number 1, January 2013
109
Journal of Thoracic Oncology • Volume 8, Number 1, January 2013
Mariano et al.
4.5 million) were identified using the British Columbia Cancer Agency (BCCA) Registry. Chart review was performed to collect demographic and treatment data. Disease-specific survival information was also collected from the BCCA Survival and Outcomes unit. Vital statistics were up to date as of December 2011.
TABLE 1. Demographics n Age (yr)
Statistical Analysis Descriptive statistics were used to summarize baseline characteristics of patients in the cohort. Survival curves were generated using the Kaplan–Meier method. The methodology for reporting of outcomes and collection of data was performed using criteria suggested by the International Thymic Malignancy Interest group (ITMIG). Given the long natural history of thymoma, the preferred outcome for patients, who are treated with curative modalities with no residual disease, is freedom from recurrence, defined as the time from diagnosis to time to recurrence of thymic malignancy.13 We calculated this for all patients who had no visible disease remaining after curative treatment (either surgery or radical radiotherapy).
Demographic data are summarized in Table 1. The median age at diagnosis was 59 years, with a range of 18 to 84. Fifty percent of the patients were women. Thirty-one percent of patients were asymptomatic at presentation, whereas 20% presented with paraneoplastic syndromes. Other presenting symptoms included chest pain, cough, dyspnea, constitutional symptoms, superior vena cava syndrome, effusions, and mass effect. A variety of paraneoplastic phenomenon was observed (Table 1). Myasthenia gravis was present in 22% of the patients. Myasthenia gravis was seen more often in thymoma patients (23%, 34 of 147) than in thymic carcinoma patients (12%, 3 of 24). Other paraneoplastic phenonomena included pure red cell aplasia, hypogammaglobulinemia, hypercalcemia, motor axonal neuropathy, lympic encephalitis, and stiffperson syndrome.
110
5 5 18 22 26 19 4
Male Female
86 85
50 50
Asymptomatic Paraneoplastic syndrome Cough/dyspnea Chest pain Constitutional SVC syndrome Mass effect Pericardial effusion Pleural effusion Hematuria Thrombosis
53 35 34 29 6 4 4 3 1 1 1
31 20 20 17 4 2 2 2 0.5 0.5 0.5
Myasthenia gravis Pure red cell aplasia Hypogammaglobulinemia Hypercalcemia Motor axonal neuropathy Stiff-person syndrome Limbic encephalitis Syndrome of inappropriate ADH secretion
37 3 1 1 1 1 1 1
22 1.8
I IIa IIb III IVa IVb
16 55 21 47 18 14
9 32 12 27 11 8
Paraneoplastic phenomena
Identified Patients
Demographics and Clinical Presentation
9 8 31 38 45 33 7
Presenting symptom
RESULTS Initially, 196 patients were identified. Five patients were excluded because of unconfirmed pathology, one patient was excluded because the date of diagnosis was before 1994. One hundred and seventy-one patients (90% of the provincial population) were referred to the BCCA and were available for analysis. Median follow-up time was 52 months.
18–30 31–40 41–50 51–60 61–70 71–80 >80 Sex
Pathology and Staging Review Stage was identified using the Masaoka–Koga system.14 The pathologic diagnosis was retrieved from the original pathology report for cases reported using the WHO classification of thymic tumor in 80 cases. A comprehensive pathology review and reclassification, using the WHO diagnostic criteria, was independently performed by two pathologists, one with expertise in thoracic pathology (DNI), for the remaining cases.
%
Stage at presentation
ADH, antidiuretic hormone; SVC, superior vena cava.
Stage at Presentation As part of pathology review, the Masaoka–Koga stage was reviewed using 2011 guidelines published by the ITMIG.13 A total of 16 patients’ stage was modified based on this review. Five patients were upstaged from stage IIb to stage III, based on slide review showing invasion into pleural or pericardial structures. Four patients were originally reported to have stage II disease because of incomplete capsule. The guidelines proposed that these patients should be classified as having stage I disease. Other changes included one patient upstaged from I to II because of invasion into normal thymic tissue, and six patients whose stage was changed between IIa and IIb.
Copyright © 2012 by the International Association for the Study of Lung Cancer
Journal of Thoracic Oncology • Volume 8, Number 1, January 2013
The stage at presentation is described in Table 1. The stage distribution varied significantly with histology as outlined in Figure 1. The majority of patients with thymoma (WHO A, B, B1,B2,B3,AB) presented with early-stage disease, whereas nearly three-quarters of patients with thymic carcinoma presented with locally advanced or metastatic disease.
Survival by Stage Survival by stage within the cohort was similar to that of previously published data (Fig. 2, Table 2). Five-year overall survival was 93.3%, 88.7%, 74.6%, and 43.4% for stages I, II, III, and IV, respectively. Ten-year overall survival was 93.3%, 86.7%, 62%, and 28.9%. Progression-free survival for 5 and 10 years was 92.3% and 92.3% for stage I, respectively, 84.4% and 72.9% for stage II, 55.1% and 39.2% for stage III, respectively. For stage IV patients, only a 5-year progression-free survival could be estimated, which was 14.1%. Five-year freedom from recurrence was 100%, 92.8%, 68.0%, and 20.1% in patients with stage I, II, III, and IV, respectively (Table 2).
Management and Outcomes of Thymoma
Survival by Histology Sixty-seven patients had their WHO classification changed based on detailed pathological review. Twelve patients (7%) had WHO class A, 30 patients (17.5%) had WHO B1, 38 patients (22%) had WHO B2, 27 patients (16%) had WHO B3 17 patients (10%) had WHO AB, and 24 patients (14%) had thymic carcinoma. Thirteen percent of the patients were categorized as thymoma, but subtype analysis was not possible, when sample size was too small, or when original slides could not be obtained. Survival varied significantly among patients with thymoma (WHO class A, B1, B2, B3, and AB) compared with thymic carcinoma as illustrated in Figure 5. Five-year overall survival in patients with thymoma was 82% compared with 46% for thymic carcinoma. Survival data was also calculated by WHO subtype (Table 3). Patients with WHO class A seemed to have a poorer survival compared with the other series15. These 12 patients included two patients with disseminated disease at presentation, who did not receive any systemic therapy.
Management of Early-Stage Disease
Surgery
FIGURE 1. Stage and histology distribution.
Our series included 13 patients with stage I disease. Twelve of these patients were treated with surgery alone, and one patient had adjuvant radiation for a positive resection margin. There were no tumor recurrences. In patients with stage I and II disease (n = 92), surgery was most often a complete thymectomy (n = 57). Thirty-two patients had more extensive surgery, which involved resection of pericardium, lung tissue, and other surrounding structures. As illustrated in Table 4, more extensive surgery was associated with higher rates of R0 resection.
FIGURE 2. Overall survival by stage in all patients. Copyright © 2012 by the International Association for the Study of Lung Cancer
111
Journal of Thoracic Oncology • Volume 8, Number 1, January 2013
Mariano et al.
TABLE 2. Comparative Survival Rates Comparative Series
Current Series Stage I II III IV
N
5-yr OS
10-yr OS
5-yr PFS
16 76 47 32
93.3% 88.7% 74.6% 43.4%
93.3% 86.7% 62.0% 28.9%
92.3% 84.4% 55.1% 14.1%
10-yr PFS 5-yr FFR (n) 92.3% 72.9% 39.2% (—)
100 % (16) 92.8 (76) 68% (34) 20.1% (10)
Masoaka et al. 5-yr OSa
19
Masaoka et al.19 10-yr OS
De Jong et al. 11 5- yr OSb
66.7% 60% 58.3% 0%
82.9% 87.8% 57.6% 55.6%
96.2% 85.7% 69.6% 50%
Original data from Masaoka staging publication Population-based study from The Netherlands.OS, overall survival; PFS, progression-free survival; FFR freedom from recurrence.
a b
FIGURE 3. Progression-free survival by stage in all patients.
FIGURE 4. Freedom from recurrence after curative treatment by stage.
112
Copyright © 2012 by the International Association for the Study of Lung Cancer
Journal of Thoracic Oncology • Volume 8, Number 1, January 2013
Management and Outcomes of Thymoma
TABLE 4. Rate of R0 Resection in Patients with Stage I and II Disease by Surgery Type Type Surgery None Partial thymectomy Total thymectomy Thymectomy + further resectiona
Rate of R0 Number of Patients Resection, % 1 2 57 32
(—) 50 68 84
a Included patients receiving pericardectomy, wedge resection of lung, and innominate vein resection.
FIGURE 5. Overall survival by histology in all patients.
TABLE 3. Relationship of Overall Survival with the WHOHistologic Subtype WHO class
n
%
A AB B1 B2 B3 Thymic carcinoma Thymoma, subtype not specified
12 17 30 38 27 24 23
7 10 17 22 16 14 13
5-yr OS (%) 65.2 100 86.4 82.5 75.3 45.8 (—)
WHO, World Health Organization; OS, overall survival.
Seventy percent of the surgeries were performed at a tertiary care center by a dedicated thoracic surgery team, performing approximately 400 oncologic cases per year. Rates of R0 resection for thymoma at all stages were higher when surgery was performed at this center compared with peripheral centers.
Radiation
The use of radiation therapy in stage II disease was variable. A total of 62% of patients with stage II disease received radiation therapy. In patients with positive margins (21 of 76), 17 (81%) received adjuvant radiation. Similar proportions of stage IIa and stage IIb patients received radiation. The median dose was 50 Gy (range, 42–60), a three-field technique was used in more than 80% of patients. A total of six stage II patients (8%) had a recurrence. There was no difference observed in the overall survival or freedom from recurrence in stage II patients receiving and not receiving radiotherapy (Fig. 6).
Management of Advanced-Stage Disease In a planned analysis, we specifically accessed outcomes in locally advanced disease. This included all stage III and IVa patients and selected patients with stage IVb disease with local nodal involvement only. This accounted for a total of 75 patients, 67 of whom were offered curative treatment. There was considerable practice variation in the treatment of these patients, as illustrated in Figure 7. The dose of radiation was similar to that used in the adjuvant setting (median 50 Gy).
Approximately half of the patients received initial surgery, whereas the other half received neoadjuvant therapy. In the group with upfront surgery, 31% of patients achieved an R0 resection. In the neoadjuvant group 14 patients (40%) underwent resection and 50% had an R0 resection. There was no difference in overall survival between the group treated neoadjuvantly and the group treated postoperatively. In the locally advanced group, 17 patients received trimodality treatment including surgery, chemotherapy, and thoracic irradiation. Trimodality patients with thymoma had a 5-year median overall survival of 80%, whereas patients with thymic carcinoma had a 5-year median overall survival of 40% with no long-term survivors (Fig. 8). There was no statistical difference in overall survival between patients in the trimodality group and the rest of the locally advanced cohort.
Chemotherapy in Advanced Disease Chemotherapy was used in 29% of the patients in our series. Cisplatin and etoposide constituted the initial regimen in 65% of patients. This choice was influenced by the ability to give this regimen concurrently with thoracic irradiation. Cyclophosphamide-cisplatin-doxorubacin +/− prednisone was used in 22% of the patients. Prednisone alone and octreotide were used occasionally in the palliative setting.
Recurrence Follow-up practices were extremely variable for patient with both localized and advanced disease. A total of 23 patients (17%) had recurrence after curative treatment. Six events occurred in stage II patients, 11 in stage III patients, and six in stage IV patients (Table 5). Among patients with stage II disease, five of six patients had a positive resection margin during the original surgery. Five of 23 recurring patients had thymic carcinoma. Recurrences were classified as local, regional, or distant, per ITMIG criteria. There were 11 local recurrences to lung—nine regional recurrences and two distant recurrences. Time to recurrence ranged between 55 days and 9.6 years, median 2.8 years. Most patients received some form of treatment for recurrent disease. Modalities included surgery, radiation, and chemotherapy. Ten patients died of thymic malignancy, including one who had a treatment-related death for febrile neutropenia.
Copyright © 2012 by the International Association for the Study of Lung Cancer
113
Mariano et al.
Journal of Thoracic Oncology • Volume 8, Number 1, January 2013
FIGURE 6. Freedom from recurrence in stage II patients treated with radiation.
FIGURE 7. Initial management in patients with advanced stage disease. Xrt, radiation therapy; chemo, any chemotherapy; Rx, treatment.
Of the 13 patients alive at the time of analysis, three had repeat surgeries and have been followed for several years without evidence of recurrent disease. This group also includes five patients with recurrent disease, who were not treated. Follow-up time in this group ranged between 6 months and 6 years.
114
Prognostic Variables We examined various pretreatment factors including age, stage, paraneoplastic phenomenon, and histology for prognostic importance with respect to overall survival (Tables 6 and 7). In univariate analyses, advanced-stage thymic carcinoma histology and nonmyasthenic paraneoplastic
Copyright © 2012 by the International Association for the Study of Lung Cancer
Journal of Thoracic Oncology • Volume 8, Number 1, January 2013
Management and Outcomes of Thymoma
FIGURE 8. Outcomes in patients treated with surgery, radiation therapy, and chemotherapy. TABLE 6. Univariate Analysis of Prognostic Factors
TABLE 5. Recurrences by Stage in Patients Receiving Curative Treatment Stage
n
II III IV
76 34 10
Number of Recurrences 6 11 6
Variable % 8 32 60
phenomenae conferred a worse prognosis. In multivariate analysis, only stage and histology (thymoma versus thymic carcinoma) were statistically significant.
Second Malignancy Several studies have highlighted a possible link between thymoma and secondary malignancies.1, 2, 16, 17 Our review allowed capture of extrathymic malignancies diagnosed during the study period. A total of 19 patients (11%) were diagnosed with nonthymic malignancies (excluding basal cell carcinoma of the skin) during study and follow-up period. Nine patients had been previously diagnosed with malignancy: one seminoma, one renal cell cancer, one prostate cancer, one esophageal cancer, one Hodgkin’s lymphoma, two breast cancers, one non–small-cell lung cancer, and two lowgrade non-Hodgkin’s lymphomas. An additional three patients were diagnosed with non–small-cell lung cancer, and one with aggressive non-Hodgkin’s lymphoma at the time of thymoma diagnosis. In follow-up, seven patients were diagnosed with malignancies:two non–small-cell lung cancers, one renal cell, one breast, one melanoma, and two head and neck cancers.
DISCUSSION This series represents one of the largest and most complete population-based reports of thymoma and thymic
Stage Stage Stage Paraneoplastic Paraneoplastic Histotype Age (yr)
Comparison I vs. IV II vs. IV III vs. IV Myasthenia vs. nonMyasthenia syndromes None vs. non-Myasthenia syndromes Thymoma vs. thymic carcinoma <50 vs. > =50
Hazard Ratio
p
0.1181 0.1144 0.3717 0.2608
0.0041 0.0000 0.0043 0.0378
0.4930
0.1813
0.2021
0.0000
0.7866
0.5033
carcinoma. In this unselected population, our outcomes for thymoma based on stage were similar to that of other large, reported, institutional series.11, 18, 19 Our series highlights the variability in clinical behavior and practice variations within the province of British Columbia. Our study was limited by the retrospective nature of our data. Furthermore, a small percentage of the patients’ data (10%) was not available for analysis. This probably explains the relatively low number of stage I patients in our cohort as these patients are often not referred to the BCCA for further oncologic assessment after primary curative surgical therapy. Our median follow-up time was 5 years, and a longer follow-up may have provided more data about long-term recurrences. The reality of late recurrences underscores the importance of long-term follow-up for patients with thymoma. Our review also highlights the need for detailed pathology and staging review for these rare tumors. In early-stage disease, similar to previously published data, more extensive surgery was performed at a highvolume center to achieve R0 resection improved outcomes.
Copyright © 2012 by the International Association for the Study of Lung Cancer
115
Journal of Thoracic Oncology • Volume 8, Number 1, January 2013
Mariano et al.
ACKNOWLEDGMENTS
TABLE 7. Multivariate Analysis of Prognostic Factors Variable Stage I vs. IV Stage II vs. IV Stage III vs. IV Thymoma vs. thymic carcinoma
Hazard Ratio
p
0.1659 0.1485 0.3499 0.3116
0.0178 0.0000 0.0026 0.0004
In our series, selected patients were offered postoperative radiation therapy. Although this series was unable to demonstrate a clear-cut benefit from radiation, several larger series have supported its use.20–22 The long clinical course of this disease requires careful selection for radiotherapy, given its potential for late toxicity including coronary artery disease, thyroid dysfunction, and secondary malignancies.23 A more detailed pathological review of patients with stage II disease is currently underway to see whether size, margin status, and histologic characteristics may be able to predict which patient may benefit from a more aggressive local therapy. Our data support a multidisciplinary team approach for management of these patients, similar to previously published reports.9, 24–26 In particular, patients with thymoma had excellent results using a trimodality approach. Preoperative chemoradiation has the potential for better preoperative downstaging as has been observed in the treatment of locally advanced lung cancer.27 More effective downstaging may diminish the chance of drop metastases at the time of surgery. Preoperative chemoradiation for thymic tumors should not be associated with problematic high rates of operative mortality as has been reported in lung cancer because there is little or no resection of lung tissue itself in thymoma surgeries. The patient disposition should be made in a multidisciplinary conference including thoracic surgery, radiation oncology, medical oncology, pathology, and radiology. The treatment plan should be delineated at the time of diagnosis before initiation of any modality. Unfortunately, patients with thymic carcinoma had poor outcomes despite aggressive treatment. Innovative new therapy is clearly needed to improve results for these patients. We reported a 17% recurrence rate after curative treatment. Because most recurrences are local and potentially treatable, this again argues for long-term follow-up for these patients. To date, there are no established guidelines for routine follow-up imaging after thymoma resection. In summary we present a detailed populationbased series that highlights the many challenges clinicians face when treating thymic malignancies, where evidencebased therapy information is limited. Although advances in surgical techniques, radiation planning, systemic therapy, and supportive care have been used in the care of patients with thymic malignancies, more research and collaborative efforts are needed to produce evidence-based guidelines. International database projects and multidisplinary meetings supported by the ITMIG will undoubtedly help fulfil this need.28
116
Tom Brown Foundation provided funding for archival tissue samples (slides and blocks) retrieval for comprehensive pathology review. REFERENCES 1. Engels EA, Pfeiffer RM. Malignant thymoma in the United States: demographic patterns in incidence and associations with subsequent malignancies. Int J Cancer 2003;105:546–551. 2. Engels EA. Epidemiology of thymoma and associated malignancies. J Thorac Oncol 2010;5(10 Suppl 4):S260–S265. 3. Kondo K, Yoshizawa K, Tsuyuguchi M, et al. WHO histologic classification is a prognostic indicator in thymoma. Ann Thorac Surg 2004;77:1183–1188. 4. Nakagawa K, Asamura H, Matsuno Y, et al. Thymoma: a clinicopathologic study based on the new World Health Organization classification. J Thorac Cardiovasc Surg 2003;126:1134–1140. 5. Moran CA, Walsh G, Suster S, Kaiser L. Thymomas II: a clinicopathologic correlation of 250 cases with a proposed staging system with emphasis on pathologic assessment. Am J Clin Pathol 2012;137:451–461. 6. Gamondès JP, Balawi A, Greenland T, et al. Seventeen years of surgical treatment of thymoma: factors influencing survival. Eur J Cardiothorac Surg 1991;5:124–131. 7. Fuller CD, Ramahi EH, Aherne N, Eng TY, Thomas CR Jr. Radiotherapy for thymic neoplasms. J Thorac Oncol 2010;5(10 Suppl 4):S327–S335. 8. Yokoi K, Matsuguma H, Nakahara R, et al. Multidisciplinary treatment for advanced invasive thymoma with cisplatin, doxorubicin, and methylprednisolone. J Thorac Oncol 2007;2:73–78. 9. Venuta F, Rendina EA, Coloni GF. Multimodality treatment of thymic tumors. Thorac Surg Clin 2009;19:71–81. 10. Bretti S, Berruti A, Loddo C, et al.; Piemonte Oncology Network. Multimodal management of stages III-IVa malignant thymoma. Lung Cancer 2004;44:69–77. 11. de Jong WK, Blaauwgeers JL, Schaapveld M, Timens W, Klinkenberg TJ, Groen HJ. Thymic epithelial tumours: a population-based study of the incidence, diagnostic procedures and therapy. Eur J Cancer 2008;44:123–130. 12. Mariusdottir E, Nikulasson S, Bjornsson J, Gudbjartsson T. Thymic epithelial tumours in Iceland: incidence and histopathology, a populationbased study. APMIS 2010;118:927–933. 13. Huang J, Detterbeck FC, Wang Z, Loehrer PJ Sr. Standard outcome measures for thymic malignancies. J Thorac Oncol 2010;5:2017–2023. 14. Detterbeck FC, Nicholson AG, Kondo K, Van Schil P, Moran C. The Masaoka-Koga stage classification for thymic malignancies: clarification and definition of terms. J Thorac Oncol 2011;6(Suppl 3):S1710–S1716. 15. Chen G, Marx A, Chen WH, et al. New WHO histologic classification predicts prognosis of thymic epithelial tumors: a clinicopathologic study of 200 thymoma cases from China. Cancer 2002;95:420–429. 16. Gadalla SM, Rajan A, Pfeiffer R, et al. A population-based assessment of mortality and morbidity patterns among patients with thymoma. Int J Cancer 2011;128:2688–2694. 17. Weksler B, Nason KS, Mackey D, Gallagher A, Pennathur A. Thymomas and extrathymic cancers. Ann Thorac Surg 2012;93:884–888. 18. Kondo K, Monden Y. Therapy for thymic epithelial tumors: a clinical study of 1,320 patients from Japan. Ann Thorac Surg. 2003;76:878–84; discussion 884–885. 19. Masaoka A, Monden Y, Nakahara K, Tanioka T. Follow-up study of thymomas with special reference to their clinical stages. Cancer 1981;48:2485–2492. 20. Berman AT, Litzky L, Livolsi V, et al. Adjuvant radiotherapy for completely resected stage 2 thymoma. Cancer 2011;117:3502–3508. 21. Fernandes AT, Shinohara ET, Guo M, et al. The role of radiation therapy in malignant thymoma: a Surveillance, Epidemiology, and End Results database analysis. J Thorac Oncol 2010;5:1454–1460. 22. Fuller CD, Housman DM, Thomas CR. Radiotherapy for thymoma and thymic carcinoma. Hematol Oncol Clin North Am 2008;22:489–507. 23. Falkson CB, Bezjak A, Darling G, et al.; Lung Cancer Disease Site Group of Cancer Care Ontario’s Program in Evidence-Based Care.
Copyright © 2012 by the International Association for the Study of Lung Cancer
Journal of Thoracic Oncology • Volume 8, Number 1, January 2013
The management of thymoma: a systematic review and practice guideline. J Thorac Oncol 2009;4:911–919. 24. Lucchi M, Melfi F, Dini P, et al. Neoadjuvant chemotherapy for stage III and IVA thymomas: a single-institution experience with a long follow-up. J Thorac Oncol 2006;1:308–313. 25. Hassan M, Seoud DE. Multimodality treatments in locally advanced stage thymomas. Hematol Oncol Stem Cell Ther 2009;2:340–344.
Management and Outcomes of Thymoma
26. Spaggiari L, Casiraghi M, Guarize J. Multidisciplinary treatment of malignant thymoma. Curr Opin Oncol 2012;24:117–122. 27. Albain KS, Swann RS, Rusch VW, et al. Radiotherapy plus chemotherapy with or without surgical resection for stage III non-small-cell lung cancer: a phase III randomised controlled trial. Lancet 2009;374:379–386. 28. Detterbeck F. International thymic malignancies interest group: a way forward. J Thorac Oncol. 2010;5:S365–70.
Copyright © 2012 by the International Association for the Study of Lung Cancer
117
Thymoma A Population-Based Study of the Management and Outcomes for the Province of British Columbia Caroline Mariano, MD,* Diana N. Ionescu, MD,† Winson Y. Cheung, MD,* Rola H. Ali, MD,† Janessa Laskin, MD,* Ken Evans, MD,§ Hannah Carolan, MD,‡ and Nevin Murray, MD*
Introduction: Thymomas are rare neoplasms with variable clinical behavior. Our primary study aim was to analyze treatment practices and outcomes in a population-based cohort of thymoma patients. We hypothesized that stage I and II thymomas would have high cure rates with resection and adjuvant radiation, whereas locally advanced cases would benefit from multimodality therapy. Methods: All patients, diagnosed with thymoma or thymic carcinoma in British Columbia between 1994 and 2009, were identified using the British Columbia Cancer Agency Registry. Chart review was used to collect demographic and treatment data. Detailed pathology review was performed using the World Health Organization classification. Results: One hundred and seventy-one patients were identified for analysis. The 5-year overall survival was 93.3%, 88.7%, 74.6%, 43.4% for stages I, II, III, and IV, respectively. Survival varied significantly among patients with thymoma compared with thymic carcinoma. In patients with stage II disease, adjuvant radiation did not confer an overall survival or recurrence-free survival benefit. Seventy-five patients had locally advanced disease. There was practice variation in treatment of these patients. Patients with thymoma undergoing trimodality treatment had a 5-year median overall survival of 80%, whereas patients with thymic carcinoma had poor outcomes despite aggressive treatment. Conclusions: Survival rates in this population-based series were comparable to those in previously published reports. The ideal management of thymic tumors involves a multidisciplinary approach, particularly in locally advanced disease and selection of patients for adjuvant radiation therapy. Key Words: Thymoma, Thymic carcinoma, Population, Outcomes. (J Thorac Oncol. 2013;8: 109–117) Departments of *Medical Oncology, †Pathology, and ‡Radiation Oncology, British Columbia Cancer Agency, British Columbia, Canada; and §Department of Thoracic Surgery, Vancouver General Hospital, British Columbia, Canada. Disclosure: The authors declare no conflict of interest. Address for correspondence: Caroline Mariano, MD, British Columbia Cancer Agency, 600 West 10th Avenue, Vancouver, British Columbia, Canada V5Z 4E6. E-mail: [email protected] Copyright © 2012 by the International Association for the Study of Lung Cancer ISSN: 1556-0864/12/0801-109
T
hymomas are rare tumors with an incidence of approximately 0.15 cases per 100,000 person years.1 Unfortunately, little is known about the etiology of these malignancies2 and their clinical behavior can be quite variable. There has been widespread debate about their optimal classification. In 1995, the World Health Organization (WHO) proposed a new pathologic staging system that has since been widely accepted and has been proven to have prognostic value.3–5 The management of these tumors also continues to evolve. The role of surgery to treat localized disease has been well established.6 Adjuvant radiation has been used in selected cases, although its role remains controversial.7 In locally advanced and metastatic disease, a multimodality approach including chemotherapy, radiation therapy, and surgery has been used with some success,8–10 although the optimal regimen and sequencing of treatments is based on expert opinion from phase II trials rather than randomized comparisons of therapeutic strategies. Although large series have helped elucidate the clinical behavior and optimal treatment regimens of these tumors, these data are based mainly on single-institution and surgical series. Population-based series have been largely epidemiologic and have not included detailed treatment and outcome data.11,12 The aim of this study was to detail a population-based series of all of the thymoma and thymic carcinoma cases in the province of British Columbia, to include demographic, clinical, pathologic, and treatment data based on the most upto-date reporting procedures. Before any data analyses, we hypothesized that stage I and II thymomas would have high cure rates with resection and adjuvant radiation, whereas locally advanced cases would benefit from multimodality therapy.
PATIENTS AND METHODS Patient Selection Approval for this retrospective chart review and pathology review was obtained from the BC Cancer Agency and University of British Columbia Research Ethics Board. All patients diagnosed with thymoma or thymic carcinoma between January 1, 1994 and December 31, 2008 in the entire province of British Columbia (population approximately
Journal of Thoracic Oncology • Volume 8, Number 1, January 2013
109
Journal of Thoracic Oncology • Volume 8, Number 1, January 2013
Mariano et al.
4.5 million) were identified using the British Columbia Cancer Agency (BCCA) Registry. Chart review was performed to collect demographic and treatment data. Disease-specific survival information was also collected from the BCCA Survival and Outcomes unit. Vital statistics were up to date as of December 2011.
TABLE 1. Demographics n Age (yr)
Statistical Analysis Descriptive statistics were used to summarize baseline characteristics of patients in the cohort. Survival curves were generated using the Kaplan–Meier method. The methodology for reporting of outcomes and collection of data was performed using criteria suggested by the International Thymic Malignancy Interest group (ITMIG). Given the long natural history of thymoma, the preferred outcome for patients, who are treated with curative modalities with no residual disease, is freedom from recurrence, defined as the time from diagnosis to time to recurrence of thymic malignancy.13 We calculated this for all patients who had no visible disease remaining after curative treatment (either surgery or radical radiotherapy).
Demographic data are summarized in Table 1. The median age at diagnosis was 59 years, with a range of 18 to 84. Fifty percent of the patients were women. Thirty-one percent of patients were asymptomatic at presentation, whereas 20% presented with paraneoplastic syndromes. Other presenting symptoms included chest pain, cough, dyspnea, constitutional symptoms, superior vena cava syndrome, effusions, and mass effect. A variety of paraneoplastic phenomenon was observed (Table 1). Myasthenia gravis was present in 22% of the patients. Myasthenia gravis was seen more often in thymoma patients (23%, 34 of 147) than in thymic carcinoma patients (12%, 3 of 24). Other paraneoplastic phenonomena included pure red cell aplasia, hypogammaglobulinemia, hypercalcemia, motor axonal neuropathy, lympic encephalitis, and stiffperson syndrome.
110
5 5 18 22 26 19 4
Male Female
86 85
50 50
Asymptomatic Paraneoplastic syndrome Cough/dyspnea Chest pain Constitutional SVC syndrome Mass effect Pericardial effusion Pleural effusion Hematuria Thrombosis
53 35 34 29 6 4 4 3 1 1 1
31 20 20 17 4 2 2 2 0.5 0.5 0.5
Myasthenia gravis Pure red cell aplasia Hypogammaglobulinemia Hypercalcemia Motor axonal neuropathy Stiff-person syndrome Limbic encephalitis Syndrome of inappropriate ADH secretion
37 3 1 1 1 1 1 1
22 1.8
I IIa IIb III IVa IVb
16 55 21 47 18 14
9 32 12 27 11 8
Paraneoplastic phenomena
Identified Patients
Demographics and Clinical Presentation
9 8 31 38 45 33 7
Presenting symptom
RESULTS Initially, 196 patients were identified. Five patients were excluded because of unconfirmed pathology, one patient was excluded because the date of diagnosis was before 1994. One hundred and seventy-one patients (90% of the provincial population) were referred to the BCCA and were available for analysis. Median follow-up time was 52 months.
18–30 31–40 41–50 51–60 61–70 71–80 >80 Sex
Pathology and Staging Review Stage was identified using the Masaoka–Koga system.14 The pathologic diagnosis was retrieved from the original pathology report for cases reported using the WHO classification of thymic tumor in 80 cases. A comprehensive pathology review and reclassification, using the WHO diagnostic criteria, was independently performed by two pathologists, one with expertise in thoracic pathology (DNI), for the remaining cases.
%
Stage at presentation
ADH, antidiuretic hormone; SVC, superior vena cava.
Stage at Presentation As part of pathology review, the Masaoka–Koga stage was reviewed using 2011 guidelines published by the ITMIG.13 A total of 16 patients’ stage was modified based on this review. Five patients were upstaged from stage IIb to stage III, based on slide review showing invasion into pleural or pericardial structures. Four patients were originally reported to have stage II disease because of incomplete capsule. The guidelines proposed that these patients should be classified as having stage I disease. Other changes included one patient upstaged from I to II because of invasion into normal thymic tissue, and six patients whose stage was changed between IIa and IIb.
Copyright © 2012 by the International Association for the Study of Lung Cancer
Journal of Thoracic Oncology • Volume 8, Number 1, January 2013
The stage at presentation is described in Table 1. The stage distribution varied significantly with histology as outlined in Figure 1. The majority of patients with thymoma (WHO A, B, B1,B2,B3,AB) presented with early-stage disease, whereas nearly three-quarters of patients with thymic carcinoma presented with locally advanced or metastatic disease.
Survival by Stage Survival by stage within the cohort was similar to that of previously published data (Fig. 2, Table 2). Five-year overall survival was 93.3%, 88.7%, 74.6%, and 43.4% for stages I, II, III, and IV, respectively. Ten-year overall survival was 93.3%, 86.7%, 62%, and 28.9%. Progression-free survival for 5 and 10 years was 92.3% and 92.3% for stage I, respectively, 84.4% and 72.9% for stage II, 55.1% and 39.2% for stage III, respectively. For stage IV patients, only a 5-year progression-free survival could be estimated, which was 14.1%. Five-year freedom from recurrence was 100%, 92.8%, 68.0%, and 20.1% in patients with stage I, II, III, and IV, respectively (Table 2).
Management and Outcomes of Thymoma
Survival by Histology Sixty-seven patients had their WHO classification changed based on detailed pathological review. Twelve patients (7%) had WHO class A, 30 patients (17.5%) had WHO B1, 38 patients (22%) had WHO B2, 27 patients (16%) had WHO B3 17 patients (10%) had WHO AB, and 24 patients (14%) had thymic carcinoma. Thirteen percent of the patients were categorized as thymoma, but subtype analysis was not possible, when sample size was too small, or when original slides could not be obtained. Survival varied significantly among patients with thymoma (WHO class A, B1, B2, B3, and AB) compared with thymic carcinoma as illustrated in Figure 5. Five-year overall survival in patients with thymoma was 82% compared with 46% for thymic carcinoma. Survival data was also calculated by WHO subtype (Table 3). Patients with WHO class A seemed to have a poorer survival compared with the other series15. These 12 patients included two patients with disseminated disease at presentation, who did not receive any systemic therapy.
Management of Early-Stage Disease
Surgery
FIGURE 1. Stage and histology distribution.
Our series included 13 patients with stage I disease. Twelve of these patients were treated with surgery alone, and one patient had adjuvant radiation for a positive resection margin. There were no tumor recurrences. In patients with stage I and II disease (n = 92), surgery was most often a complete thymectomy (n = 57). Thirty-two patients had more extensive surgery, which involved resection of pericardium, lung tissue, and other surrounding structures. As illustrated in Table 4, more extensive surgery was associated with higher rates of R0 resection.
FIGURE 2. Overall survival by stage in all patients. Copyright © 2012 by the International Association for the Study of Lung Cancer
111
Journal of Thoracic Oncology • Volume 8, Number 1, January 2013
Mariano et al.
TABLE 2. Comparative Survival Rates Comparative Series
Current Series Stage I II III IV
N
5-yr OS
10-yr OS
5-yr PFS
16 76 47 32
93.3% 88.7% 74.6% 43.4%
93.3% 86.7% 62.0% 28.9%
92.3% 84.4% 55.1% 14.1%
10-yr PFS 5-yr FFR (n) 92.3% 72.9% 39.2% (—)
100 % (16) 92.8 (76) 68% (34) 20.1% (10)
Masoaka et al. 5-yr OSa
19
Masaoka et al.19 10-yr OS
De Jong et al. 11 5- yr OSb
66.7% 60% 58.3% 0%
82.9% 87.8% 57.6% 55.6%
96.2% 85.7% 69.6% 50%
Original data from Masaoka staging publication Population-based study from The Netherlands.OS, overall survival; PFS, progression-free survival; FFR freedom from recurrence.
a b
FIGURE 3. Progression-free survival by stage in all patients.
FIGURE 4. Freedom from recurrence after curative treatment by stage.
112
Copyright © 2012 by the International Association for the Study of Lung Cancer
Journal of Thoracic Oncology • Volume 8, Number 1, January 2013
Management and Outcomes of Thymoma
TABLE 4. Rate of R0 Resection in Patients with Stage I and II Disease by Surgery Type Type Surgery None Partial thymectomy Total thymectomy Thymectomy + further resectiona
Rate of R0 Number of Patients Resection, % 1 2 57 32
(—) 50 68 84
a Included patients receiving pericardectomy, wedge resection of lung, and innominate vein resection.
FIGURE 5. Overall survival by histology in all patients.
TABLE 3. Relationship of Overall Survival with the WHOHistologic Subtype WHO class
n
%
A AB B1 B2 B3 Thymic carcinoma Thymoma, subtype not specified
12 17 30 38 27 24 23
7 10 17 22 16 14 13
5-yr OS (%) 65.2 100 86.4 82.5 75.3 45.8 (—)
WHO, World Health Organization; OS, overall survival.
Seventy percent of the surgeries were performed at a tertiary care center by a dedicated thoracic surgery team, performing approximately 400 oncologic cases per year. Rates of R0 resection for thymoma at all stages were higher when surgery was performed at this center compared with peripheral centers.
Radiation
The use of radiation therapy in stage II disease was variable. A total of 62% of patients with stage II disease received radiation therapy. In patients with positive margins (21 of 76), 17 (81%) received adjuvant radiation. Similar proportions of stage IIa and stage IIb patients received radiation. The median dose was 50 Gy (range, 42–60), a three-field technique was used in more than 80% of patients. A total of six stage II patients (8%) had a recurrence. There was no difference observed in the overall survival or freedom from recurrence in stage II patients receiving and not receiving radiotherapy (Fig. 6).
Management of Advanced-Stage Disease In a planned analysis, we specifically accessed outcomes in locally advanced disease. This included all stage III and IVa patients and selected patients with stage IVb disease with local nodal involvement only. This accounted for a total of 75 patients, 67 of whom were offered curative treatment. There was considerable practice variation in the treatment of these patients, as illustrated in Figure 7. The dose of radiation was similar to that used in the adjuvant setting (median 50 Gy).
Approximately half of the patients received initial surgery, whereas the other half received neoadjuvant therapy. In the group with upfront surgery, 31% of patients achieved an R0 resection. In the neoadjuvant group 14 patients (40%) underwent resection and 50% had an R0 resection. There was no difference in overall survival between the group treated neoadjuvantly and the group treated postoperatively. In the locally advanced group, 17 patients received trimodality treatment including surgery, chemotherapy, and thoracic irradiation. Trimodality patients with thymoma had a 5-year median overall survival of 80%, whereas patients with thymic carcinoma had a 5-year median overall survival of 40% with no long-term survivors (Fig. 8). There was no statistical difference in overall survival between patients in the trimodality group and the rest of the locally advanced cohort.
Chemotherapy in Advanced Disease Chemotherapy was used in 29% of the patients in our series. Cisplatin and etoposide constituted the initial regimen in 65% of patients. This choice was influenced by the ability to give this regimen concurrently with thoracic irradiation. Cyclophosphamide-cisplatin-doxorubacin +/− prednisone was used in 22% of the patients. Prednisone alone and octreotide were used occasionally in the palliative setting.
Recurrence Follow-up practices were extremely variable for patient with both localized and advanced disease. A total of 23 patients (17%) had recurrence after curative treatment. Six events occurred in stage II patients, 11 in stage III patients, and six in stage IV patients (Table 5). Among patients with stage II disease, five of six patients had a positive resection margin during the original surgery. Five of 23 recurring patients had thymic carcinoma. Recurrences were classified as local, regional, or distant, per ITMIG criteria. There were 11 local recurrences to lung—nine regional recurrences and two distant recurrences. Time to recurrence ranged between 55 days and 9.6 years, median 2.8 years. Most patients received some form of treatment for recurrent disease. Modalities included surgery, radiation, and chemotherapy. Ten patients died of thymic malignancy, including one who had a treatment-related death for febrile neutropenia.
Copyright © 2012 by the International Association for the Study of Lung Cancer
113
Mariano et al.
Journal of Thoracic Oncology • Volume 8, Number 1, January 2013
FIGURE 6. Freedom from recurrence in stage II patients treated with radiation.
FIGURE 7. Initial management in patients with advanced stage disease. Xrt, radiation therapy; chemo, any chemotherapy; Rx, treatment.
Of the 13 patients alive at the time of analysis, three had repeat surgeries and have been followed for several years without evidence of recurrent disease. This group also includes five patients with recurrent disease, who were not treated. Follow-up time in this group ranged between 6 months and 6 years.
114
Prognostic Variables We examined various pretreatment factors including age, stage, paraneoplastic phenomenon, and histology for prognostic importance with respect to overall survival (Tables 6 and 7). In univariate analyses, advanced-stage thymic carcinoma histology and nonmyasthenic paraneoplastic
Copyright © 2012 by the International Association for the Study of Lung Cancer
Journal of Thoracic Oncology • Volume 8, Number 1, January 2013
Management and Outcomes of Thymoma
FIGURE 8. Outcomes in patients treated with surgery, radiation therapy, and chemotherapy. TABLE 6. Univariate Analysis of Prognostic Factors
TABLE 5. Recurrences by Stage in Patients Receiving Curative Treatment Stage
n
II III IV
76 34 10
Number of Recurrences 6 11 6
Variable % 8 32 60
phenomenae conferred a worse prognosis. In multivariate analysis, only stage and histology (thymoma versus thymic carcinoma) were statistically significant.
Second Malignancy Several studies have highlighted a possible link between thymoma and secondary malignancies.1, 2, 16, 17 Our review allowed capture of extrathymic malignancies diagnosed during the study period. A total of 19 patients (11%) were diagnosed with nonthymic malignancies (excluding basal cell carcinoma of the skin) during study and follow-up period. Nine patients had been previously diagnosed with malignancy: one seminoma, one renal cell cancer, one prostate cancer, one esophageal cancer, one Hodgkin’s lymphoma, two breast cancers, one non–small-cell lung cancer, and two lowgrade non-Hodgkin’s lymphomas. An additional three patients were diagnosed with non–small-cell lung cancer, and one with aggressive non-Hodgkin’s lymphoma at the time of thymoma diagnosis. In follow-up, seven patients were diagnosed with malignancies:two non–small-cell lung cancers, one renal cell, one breast, one melanoma, and two head and neck cancers.
DISCUSSION This series represents one of the largest and most complete population-based reports of thymoma and thymic
Stage Stage Stage Paraneoplastic Paraneoplastic Histotype Age (yr)
Comparison I vs. IV II vs. IV III vs. IV Myasthenia vs. nonMyasthenia syndromes None vs. non-Myasthenia syndromes Thymoma vs. thymic carcinoma <50 vs. > =50
Hazard Ratio
p
0.1181 0.1144 0.3717 0.2608
0.0041 0.0000 0.0043 0.0378
0.4930
0.1813
0.2021
0.0000
0.7866
0.5033
carcinoma. In this unselected population, our outcomes for thymoma based on stage were similar to that of other large, reported, institutional series.11, 18, 19 Our series highlights the variability in clinical behavior and practice variations within the province of British Columbia. Our study was limited by the retrospective nature of our data. Furthermore, a small percentage of the patients’ data (10%) was not available for analysis. This probably explains the relatively low number of stage I patients in our cohort as these patients are often not referred to the BCCA for further oncologic assessment after primary curative surgical therapy. Our median follow-up time was 5 years, and a longer follow-up may have provided more data about long-term recurrences. The reality of late recurrences underscores the importance of long-term follow-up for patients with thymoma. Our review also highlights the need for detailed pathology and staging review for these rare tumors. In early-stage disease, similar to previously published data, more extensive surgery was performed at a highvolume center to achieve R0 resection improved outcomes.
Copyright © 2012 by the International Association for the Study of Lung Cancer
115
Journal of Thoracic Oncology • Volume 8, Number 1, January 2013
Mariano et al.
ACKNOWLEDGMENTS
TABLE 7. Multivariate Analysis of Prognostic Factors Variable Stage I vs. IV Stage II vs. IV Stage III vs. IV Thymoma vs. thymic carcinoma
Hazard Ratio
p
0.1659 0.1485 0.3499 0.3116
0.0178 0.0000 0.0026 0.0004
In our series, selected patients were offered postoperative radiation therapy. Although this series was unable to demonstrate a clear-cut benefit from radiation, several larger series have supported its use.20–22 The long clinical course of this disease requires careful selection for radiotherapy, given its potential for late toxicity including coronary artery disease, thyroid dysfunction, and secondary malignancies.23 A more detailed pathological review of patients with stage II disease is currently underway to see whether size, margin status, and histologic characteristics may be able to predict which patient may benefit from a more aggressive local therapy. Our data support a multidisciplinary team approach for management of these patients, similar to previously published reports.9, 24–26 In particular, patients with thymoma had excellent results using a trimodality approach. Preoperative chemoradiation has the potential for better preoperative downstaging as has been observed in the treatment of locally advanced lung cancer.27 More effective downstaging may diminish the chance of drop metastases at the time of surgery. Preoperative chemoradiation for thymic tumors should not be associated with problematic high rates of operative mortality as has been reported in lung cancer because there is little or no resection of lung tissue itself in thymoma surgeries. The patient disposition should be made in a multidisciplinary conference including thoracic surgery, radiation oncology, medical oncology, pathology, and radiology. The treatment plan should be delineated at the time of diagnosis before initiation of any modality. Unfortunately, patients with thymic carcinoma had poor outcomes despite aggressive treatment. Innovative new therapy is clearly needed to improve results for these patients. We reported a 17% recurrence rate after curative treatment. Because most recurrences are local and potentially treatable, this again argues for long-term follow-up for these patients. To date, there are no established guidelines for routine follow-up imaging after thymoma resection. In summary we present a detailed populationbased series that highlights the many challenges clinicians face when treating thymic malignancies, where evidencebased therapy information is limited. Although advances in surgical techniques, radiation planning, systemic therapy, and supportive care have been used in the care of patients with thymic malignancies, more research and collaborative efforts are needed to produce evidence-based guidelines. International database projects and multidisplinary meetings supported by the ITMIG will undoubtedly help fulfil this need.28
116
Tom Brown Foundation provided funding for archival tissue samples (slides and blocks) retrieval for comprehensive pathology review. REFERENCES 1. Engels EA, Pfeiffer RM. Malignant thymoma in the United States: demographic patterns in incidence and associations with subsequent malignancies. Int J Cancer 2003;105:546–551. 2. Engels EA. Epidemiology of thymoma and associated malignancies. J Thorac Oncol 2010;5(10 Suppl 4):S260–S265. 3. Kondo K, Yoshizawa K, Tsuyuguchi M, et al. WHO histologic classification is a prognostic indicator in thymoma. Ann Thorac Surg 2004;77:1183–1188. 4. Nakagawa K, Asamura H, Matsuno Y, et al. Thymoma: a clinicopathologic study based on the new World Health Organization classification. J Thorac Cardiovasc Surg 2003;126:1134–1140. 5. Moran CA, Walsh G, Suster S, Kaiser L. Thymomas II: a clinicopathologic correlation of 250 cases with a proposed staging system with emphasis on pathologic assessment. Am J Clin Pathol 2012;137:451–461. 6. Gamondès JP, Balawi A, Greenland T, et al. Seventeen years of surgical treatment of thymoma: factors influencing survival. Eur J Cardiothorac Surg 1991;5:124–131. 7. Fuller CD, Ramahi EH, Aherne N, Eng TY, Thomas CR Jr. Radiotherapy for thymic neoplasms. J Thorac Oncol 2010;5(10 Suppl 4):S327–S335. 8. Yokoi K, Matsuguma H, Nakahara R, et al. Multidisciplinary treatment for advanced invasive thymoma with cisplatin, doxorubicin, and methylprednisolone. J Thorac Oncol 2007;2:73–78. 9. Venuta F, Rendina EA, Coloni GF. Multimodality treatment of thymic tumors. Thorac Surg Clin 2009;19:71–81. 10. Bretti S, Berruti A, Loddo C, et al.; Piemonte Oncology Network. Multimodal management of stages III-IVa malignant thymoma. Lung Cancer 2004;44:69–77. 11. de Jong WK, Blaauwgeers JL, Schaapveld M, Timens W, Klinkenberg TJ, Groen HJ. Thymic epithelial tumours: a population-based study of the incidence, diagnostic procedures and therapy. Eur J Cancer 2008;44:123–130. 12. Mariusdottir E, Nikulasson S, Bjornsson J, Gudbjartsson T. Thymic epithelial tumours in Iceland: incidence and histopathology, a populationbased study. APMIS 2010;118:927–933. 13. Huang J, Detterbeck FC, Wang Z, Loehrer PJ Sr. Standard outcome measures for thymic malignancies. J Thorac Oncol 2010;5:2017–2023. 14. Detterbeck FC, Nicholson AG, Kondo K, Van Schil P, Moran C. The Masaoka-Koga stage classification for thymic malignancies: clarification and definition of terms. J Thorac Oncol 2011;6(Suppl 3):S1710–S1716. 15. Chen G, Marx A, Chen WH, et al. New WHO histologic classification predicts prognosis of thymic epithelial tumors: a clinicopathologic study of 200 thymoma cases from China. Cancer 2002;95:420–429. 16. Gadalla SM, Rajan A, Pfeiffer R, et al. A population-based assessment of mortality and morbidity patterns among patients with thymoma. Int J Cancer 2011;128:2688–2694. 17. Weksler B, Nason KS, Mackey D, Gallagher A, Pennathur A. Thymomas and extrathymic cancers. Ann Thorac Surg 2012;93:884–888. 18. Kondo K, Monden Y. Therapy for thymic epithelial tumors: a clinical study of 1,320 patients from Japan. Ann Thorac Surg. 2003;76:878–84; discussion 884–885. 19. Masaoka A, Monden Y, Nakahara K, Tanioka T. Follow-up study of thymomas with special reference to their clinical stages. Cancer 1981;48:2485–2492. 20. Berman AT, Litzky L, Livolsi V, et al. Adjuvant radiotherapy for completely resected stage 2 thymoma. Cancer 2011;117:3502–3508. 21. Fernandes AT, Shinohara ET, Guo M, et al. The role of radiation therapy in malignant thymoma: a Surveillance, Epidemiology, and End Results database analysis. J Thorac Oncol 2010;5:1454–1460. 22. Fuller CD, Housman DM, Thomas CR. Radiotherapy for thymoma and thymic carcinoma. Hematol Oncol Clin North Am 2008;22:489–507. 23. Falkson CB, Bezjak A, Darling G, et al.; Lung Cancer Disease Site Group of Cancer Care Ontario’s Program in Evidence-Based Care.
Copyright © 2012 by the International Association for the Study of Lung Cancer
Journal of Thoracic Oncology • Volume 8, Number 1, January 2013
The management of thymoma: a systematic review and practice guideline. J Thorac Oncol 2009;4:911–919. 24. Lucchi M, Melfi F, Dini P, et al. Neoadjuvant chemotherapy for stage III and IVA thymomas: a single-institution experience with a long follow-up. J Thorac Oncol 2006;1:308–313. 25. Hassan M, Seoud DE. Multimodality treatments in locally advanced stage thymomas. Hematol Oncol Stem Cell Ther 2009;2:340–344.
Management and Outcomes of Thymoma
26. Spaggiari L, Casiraghi M, Guarize J. Multidisciplinary treatment of malignant thymoma. Curr Opin Oncol 2012;24:117–122. 27. Albain KS, Swann RS, Rusch VW, et al. Radiotherapy plus chemotherapy with or without surgical resection for stage III non-small-cell lung cancer: a phase III randomised controlled trial. Lancet 2009;374:379–386. 28. Detterbeck F. International thymic malignancies interest group: a way forward. J Thorac Oncol. 2010;5:S365–70.
Copyright © 2012 by the International Association for the Study of Lung Cancer
117