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Journal of Thoracic Oncology:
doi: 10.1097/JTO.0000000000000215
Original Articles

Prognostic Factors for Cure, Recurrence and Long-Term Survival After Surgical Resection of Thymoma

Safieddine, Najib MD*; Liu, Geoffrey MD; Cuningham, Kris MD; Ming, Tsao MD; Hwang, David MD; Brade, Anthony MD§; Bezjak, Andrea MD§; Fischer, Stefan MD*; Xu, Wei PhD; Azad, Sassan BSc*; Cypel, Marcelo MD*; Darling, Gail MD*; Yasufuku, Kazu MD*; Pierre, Andrew MD*; de Perrot, Marc MD*; Waddell, Tom MD*; Keshavjee, Shaf MD*

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Author Information

*Division of Thoracic Surgery, Department of Surgery, Toronto General Hospital; Department of Medical Oncology; Department of Pathology; §Department of Radiation Oncology; and Department of Biostatistics, Princess Margaret Cancer Centre at UHN, University of Toronto, Toronto, ON, Canada.

Disclosure: The authors declare no conflict of interest.

Address for correspondence: Shaf Keshavjee, MD, Division of Thoracic Surgery, Toronto General Hospital, UHN, 200 Elizabeth St. 9N-946, Toronto, ON, Canada, M5G 2C4. E-mail: shaf.keshavjee@uhn.ca

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Abstract

Introduction:

To determine long-term outcome and risk factors for recurrence after thymectomy.

Methods:

Patients who underwent thymectomy (n = 262) for a thymic tumor (1986–2010) were identified from a prospective database. Patients were classified according to World Helath Organization (WHO) histologic classification, Masaoka staging system, and completeness of resection. Risk factors for recurrence: WHO histology, tumor size, Masaoka stage and completeness of resection were analyzed.

Results:

Of 262 patients, 51% were female, median age was 55 years, and 39% had myasthenia gravis. Median follow-up was 7.5 years, median tumor size was 5.4 cm, and Masaoka stage distribution was: I (25%), II (47%), III (17%), IV (4%), and (7%) not classified. Of 200 patients classified under the WHO system, there were (7%) type A, (22%) type AB, and (71%) type B; 83% had complete resection. One-hundred and sixty-nine patients received adjuvant radiotherapy, eight adjuvant chemoradiotherapy and 14 neoadjuvant chemoradiotherapy. Overall survival was 95% at 5 years, 91% at 10 years and 91% at 15 years. Recurrence occurred in 12 patients and disease-related death in four patients. Five patients underwent re-resection for recurrence with survival of 2–15 years. Only Masaoka stage and tumor size were associated with statistically significant risk of recurrence on multivariate analysis.

Conclusion:

Resectable thymoma is associated with excellent prognosis. Aggressive resection of recurrent disease yielded excellent long-term results. Higher Masaoka stage is associated with a greater chance of incomplete resection. Higher Masaoka stage and increasing tumor size are independent factors associated with recurrence.

Epithelial tumors of the thymus gland are rare neoplasms that exhibit significant histologic heterogeneity. This has contributed to long-standing controversy and uncertainty regarding best predictors of outcome. More recently, however, multivariate analyses performed in several retrospective case series have demonstrated tumor Masaoka stage and completeness of resection to be consistent independent prognostic factors.1–3

Although the World Helath Organization (WHO) histologic classification4 has been increasingly adopted as the classification of choice, recent multivariate analyses have generally not shown it to be of independent prognostic value.2,3,5 There is, however, consensus that many of these tumors are relatively indolent and are associated with excellent long-term survival of greater than 75% at 10 years, warranting aggressive surgical 50 intervention.

This retrospective study of a large cohort of thymoma patients was carried out to further the understanding of the association between survival and WHO histology, tumor size, Masaoka stage, and completeness of resection.

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MATERIALS AND METHODS

This study was approved by the Research Ethics Board of University Health Network (Toronto General Hospital [TGH] and Princess Margaret Hospital). All patients with thymic tumors who underwent thymic resection at TGH between 1986 and 2010 were reviewed in this retrospective cohort. Data were collected from a prospectively maintained database, and all electronic and archived paper charts were reviewed. All surgical pathology assessments were performed at TGH. Staging was recorded according to the Masaoka staging system and extent of resection was defined as microscopically complete versus incomplete. In patients in whom resection was performed in the very early years, thymoma capsule invasion anteriorly even in the absence of extension outside of capsule used to be reported as “margin positive”. However, after careful review, the investigators (surgeons and pathologists) felt this to be inaccurate considering that this aspect of the thymic capsule lies immediately posterior to the sternum where there is no other anatomical tissue to form a classic “surgical margin”. Hence, it was felt that such cases should be considered as complete resections. This reporting method was adopted and is used consistently in all cases performed since that early period. Although the indications for adjuvant radiotherapy have evolved over the period of this study, in general, in all incomplete resections and stage 2b or greater, radiotherapy has generally been recommended. Neoadjuvant therapy was recommended only sparingly on an individual basis mostly in the context of downsizing larger tumors in the hope of achieving an R0 resection. Histologically, the WHO classification was used in many cases (200 of 262). Cases reported early in this cohort were either reported according to Lattes Bernatz24 or thymoma not otherwise specified or “benign thymoma,”19 as older slides were no longer physically available for review (Table 1). Follow-up was performed every 6 months for the first 2 years and then yearly with computed tomography thorax. Histological WHO type C (undifferentiated/poorly differentiated thymic carcinoma cases (n = 19) are reviewed in this report for completeness of the experience. However, this subtype is largely considered a separate entity and therefore is not included in any statistical analysis.

TABLE 1.
TABLE 1.
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Descriptive statistics were reported as medians with ranges for continuous variables and frequencies and proportions for categorical variables. Recurrence-free survival was calculated using the Kaplan-Meier method. Recurrence-free survival was defined as the time from surgery date to first recurrence (when identified on computed tomography scan either on routine follow-up or when done for clinical indications), death from disease, or last follow-up. There were very few events to analyze overall survival. Differences between survival curves were analyzed by Log-rank test. Multivariate analyses were performed using Cox-proportional hazard regression models. Hazard ratios and 95% confidence intervals were estimated from the multivariate model. Two-sided tests were applied. Results are considered significant if the p value is less than 0.05. An exhaustive search for potential cutoffs for tumor size was performed to determine the optimal size with the maximum effect between the large tumor and small tumor subgroups. All the other analyses are performed using SAS 9.2 (SAS Institute, Cary, NC).

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RESULTS

Of 262 patients, 133 (51%) were female, median age was 55 years (range 16–86), and 39% had myasthenia gravis. Median follow-up was 7.5 years (maximum 25 years; minimum 1 year) and median tumor size was 5.4 cm (maximum 17.5 cm, mininimum 1 cm). The Masaoka stage distribution was: I, 65 (25%); II, 123 (47%); III, 45 (17%); and IV, 10 (4%). The pathological diagnosis of “benign and otherwise not classified thymoma” was reported in 19 (7%) of patients early in the cohort. Of 200 patients with known WHO staging, the histologic distribution was: type A, 14 (7%); AB. 44 (22%); and B, 142 (71%). Forty-three were classified only according to Lattes-Bernatz and Rosai systems all of which involved patients also early on in data collection before the WHO classification was adopted at TGH. Two-hundred patients (83%) had a complete resection (R0) and 43 (17%) had an incomplete resection (41 R1: microscopic-positive margins, two R2: grossly positive margins). One-hundred and sixty-nine patients received adjuvant radiotherapy, four received adjuvant chemoradiotherapy, and 14 received neoadjuvant chemoradiotherapy. Table 2 describes characteristics and treatment by Masaoka stage. Table 3 compares WHO histology with Masaoka Stage.

TABLE 2.
TABLE 2.
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TABLE 3.
TABLE 3.
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Overall survival was 95% at 5 years, 91% at 10 years, and 91% at 15 years. Recurrence occurred in 12 patients (follow-up range 1–15 years) only three of which were local mediastinal recurrences. Disease-related death occurred in four patients. Five patients underwent re-resection for recurrent disease, four of whom had pleural metastases and one had mediastinal disease with subsequent survival of two to 15+ years at last follow-up. Three patients with recurrent disease underwent more than one re-resection including a pneumonectomy in one patient.

On univariate analysis, increased Masaoka stage and incomplete resection were associated with statistically increased risk of recurrence with p values of less than 0.0001 and less than 0.0009 respectively. Larger tumor size and increased age were also statistically significantly associated with increased recurrence as continuous predictors (p < 0.0002 and p < 0.04, respectively). Specifically, the optimal cut point for size was 7.0 cm (when it was dichotomized; p = 0.03; association with recurrence; see Fig. 2). On multivariate analysis, however, only increased Masaoka stage |(Fig. 1A, B) and size (as a continuous predictor) were associated with increased recurrence (p < 0.0001; p < 0.03) (Tables 4 and 5). Gender, WHO histology (Fig. 1C), and adjuvant radiotherapy did not prove to be statistically significant factors in relation to recurrence.

TABLE 4.
TABLE 4.
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TABLE 5.
TABLE 5.
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FIGURE 1.
FIGURE 1.
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FIGURE 2.
FIGURE 2.
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DISCUSSION

Surgically resectable thymoma remains a relatively rare tumor with an excellent long-term prognosis. It is, however, these same characteristics that have made it difficult to study this disease and determine with greater certainty a clear set of prognostic factors. Data pertaining to thymoma have largely continued to depend on reports of case series. Although the WHO histologic classification system has gained increasing acceptance, its clinical value in shaping clinical course and treatment has been difficult to define.6 Several large studies have shown tumor stage and completeness of resection to be independent risk factors on multivariate analysis.5–7 Others have suggested that patients with smaller tumors (independent of stage) may indeed have a better prognosis. Myasthenia gravis was initially described to be related to better prognosis, but this has in fact proven not to be the case upon adjusting for stage.7,8 This initial observation likely reflected earlier disease detection in patients who presented with myasthenia gravis and thus earlier stage at diagnosis. Epidemiological factors such as age and gender have also not been found to be of prognostic value.

In the present case series and in keeping with other studies,1–3 Masaoka stage was an independent prognostic factor on multivariate analysis. No recurrences were observed in patients with Masaoka stages I and II compared with stages III and IV. In addition, tumor size was also an independent prognostic factor with statistical significance. Particularly, tumors larger than 7.0 cm were associated with an increased risk of recurrence. This finding may suggest a potential indication or benefit for neoadjuvant therapy for these larger tumors; however, this would need to be studied further. Although some case series found that WHO histology is a prognostic factor and that types B2 and B3 were associated with poorer prognosis, Type B1 was found to behave similarly to types A and AB,9–11 WHO histology in our series was not an independent predictor for recurrence on both univariate and multivariate analyses.

Completeness of resection was statistically associated with recurrence on univariate analysis but was not significant on multivariate analysis. However, this series had an 83.0% R0 resection rate and few recurrences; thus, completeness of resection, as the only controllable factor, may have contributed to these results.12 The goal of obtaining clear margins warrants aggressive surgical approach.

Our protocol at UHN has generally been to give radiation to patients with Masaoka stage II and higher regardless of completeness of resection and only three patients had local mediastinal recurrence, one of whom had received postoperative radiation. Adjuvant radiation treatment remains controversial and recommendations vary especially in cases of complete resection. In cases of incomplete resection, recent studies have suggested a trend towards decreased recurrence with radiation.13–15 However, in light of several series showing completeness of resection as an independent prognostic factor and incidence of recurrence in Masaoka stage II patients being very low, mediastinal radiation to stage II patients who had a complete resection should be reconsidered. We have indeed been using adjuvant radiation more selectively in recent years.

Overall survival in surgical series of more than 100 patients at 5 years was 83–100% (stage I), 60–100% (stage II), 46–88% (stage III), and 24–70% (stage IV).3,5,7,16–18 The results observed in this study lie within this range. However, the recurrence rates observed in our center experience are lower. The cohort being studied, follow-up range and methods, however, are not dissimilar indicating any identifiable bias. As with all these case series, the indolent nature of disease, its relative infrequency, and wide range of follow-up years makes identifying recurrence an ongoing effort required prolonged follow-up. It is our institutional policy to follow patients for life wherever feasible. Surgical resection of recurrence has been advocated by several studies with survival of up to 72% at 10 years particularly in completely re-resected tumors with a second recurrence rate of only 25%.19,20 Again this is in support of aggressive surgical management. In some series, similar survival was observed for stage I and stage III if resection was complete. More extensive resection including superior vena cava resections have become more common to achieve R0 margins.21 In this present cohort, one patient remains alive and well 2 years after the third of three resections, the last of which included a completion pneumonectomy.

Thymoma remains a relatively uncommon tumor and therefore case series have been an important source of understanding the clinical course of the disease and the response to treatment. In our experience of 262 surgically resected cases, adverse prognostic factors included: incomplete resection, larger sized tumors (> 7 cm), and higher Masaoka stage. The excellent long-term survival of patients demonstrated with surgical resection with thymoma is encouraging and our data support continued efforts to safely achieve complete surgical resection wherever possible to affect long-term cure. In the few cases that do recur in the long term (Stage III and IV), further study is required to determine whether neoadjuvant or adjuvant chemotherapy and/or radiotherapy will improve the outcome.

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Keywords:

Thymoma; Survival; Thymectomy; Recurrence; Risk factors

Copyright © 2014 by the International Association for the Study of Lung Cancer

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