Ann Thorac Surg 2005;80:2002-2007
© 2005 The Society of Thoracic Surgeons
Original article: General thoracic
Surgical Management of Thymic Epithelial Tumors: A Retrospective Review of 204 Cases
Wentao Fang, MD
a
,
*
,
Wenhu Chen, MD
a
,
Gang Chen, MD
b
,
Yong Jiang, MD
a
a Department of Thoracic Surgery, Shanghai Chest Hospital, Shanghai, China
b Department of Pathology, Shanghai Chest Hospital, Shanghai, China
Accepted for publication May 17, 2005.
* Address correspondence to Dr Fang, Department of Thoracic Surgery, Shanghai Chest Hospital, 241 Huaihai Rd West, Shanghai, 200030 China (Email: vwtfang{at}hotmail.com).
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Abstract
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BACKGROUND: Thymic epithelial tumors consist of a series of neoplasm that differ morphologically and biologically. Management strategy for these tumors remains controversial.
METHODS: We retrospectively reviewed 204 thymic epithelial tumors surgically treated during the period of 1970 to 1995, and we reexamined the histologic specimens using the current World Health Organization classification.
RESULTS: One hundred eighty patients (88.2%) underwent complete resections, 17 (8.3%) received partial resections, and 7 (3.4%) received biopsies only. The complete resection rate of stages I and II tumors was significantly higher than stages III and IV tumors (98.2% vs 76.6%; p < 0.001). Twenty-four patients (11.8%) experienced 29 events of complications postoperatively, including 11 events of myasthenia gravis crisis. Myasthenia gravis, partial resection or biopsy, and stages III and IV were independent risk factors for postoperative complications. Fifteen patients (7.4%) died during hospital stays, including 6 patients from myasthenia crisis. Partial resection or biopsy and myasthenia gravis were independent risk factors for postoperative mortality. There were significantly more stage I and stage II cases in histologic types A, AB, and B1 tumors than in B2, B3, and C tumors (87.6% vs 26.4%; p < 0.001), and their complete resection rate was significantly higher than the latter group (98.9% vs 78.3%; p < 0.001). The 5-year and 10-year survival rates were 63.2% and 50.4%, respectively. Masaoka stages III and IV, histologic types B2, B3, and C, and incomplete resection were independent risk factors for poor prognosis.
CONCLUSIONS: Complete resection remains the hope of cure for thymic epithelial tumors. The treatment strategy should be based on the current World Health Organization histologic classification and the Masaoka staging system.
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Introduction
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Thymic epithelial tumors (TETs) consist of a series of neoplasm that differ morphologically as well as biologically. Wide controversies to determine the terminology and classification of TETs existed in the past. It is only recently that some consensus has started to be reached. Two major factors leading to this consensus building are the current World Health Organization (WHO) criteria for histologic classification [1], and the suggestion of a modified Masaoka staging system [2–4]. Our experience also proves that both the WHO criteria and the modified Masaoka staging are prognostic factors of TETs [5]. Although some pilot studies of neoadjuvant therapy have been reported, improvement in the management of TETs has lagged behind. Surgical exploration remains the first choice of therapy for TETs regardless of clinical staging or histologic classification in most institutions, and the indication and efficacy of adjuvant therapy remains controversial. The purpose of this study is to evaluate the long-held surgery-oriented strategy for TET management in order to form the hypothesis basis for which future clinical trials could be made to improve the outcome of TET treatment.
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Patients and Methods
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A computerized search of the medical records from 1970 to 1995 revealed 204 TET patients surgically treated at the Shanghai Chest Hospital. The medical records of these patients were reviewed for the study. The protocol of the study was approved by the Ethics Committee of the hospital.
Management Strategy
Preoperative workup included a complete history and physical examination, laboratory tests, chest roentgenorgram, computed tomographic scan. Our strategy for clinically suspected TET patients without any clinical evidence of dissemination was surgery oriented (ie, surgical exploration for histologic diagnosis and potential resection). The surgical procedure consisted of a total thymectomy, together with excision of invaded tissue when possible, through a median sternotomy or a thoracotomy based on the surgeon's judgment. Patients were operated on with every effort to remove the tumor. If complete resection was not feasible, then a partial resection (debulking) was carried out. When even a debulking was difficult, the procedure turned into a mere biopsy. Surgical specimens were further examined by our pathologists to determine the histology as well as the margins of resection.
Study Methods
Patient characteristics, surgical procedures, and postoperative courses were determined by chart review. Staging was performed according to the modified Masaoka system based on surgical and pathological findings. Because the traditional lymphocytic-epithelial classification had been used before the current study, all the histologic specimens were reexamined using the current WHO criteria for TET classification for the purpose of the study. Follow-up was completed by mail or by phone.
Statistical Analysis
Demographic characters were examined with x
2 test or Fisher's exact test when appropriate. Multivariate risk factor analysis was carried out using logistic regression. Survival was calculated using the Kaplan-Meier method and comparisons of survival were made using the log-rank test. Hazard ratios for survival were calculated using the Cox regression method. All analysis was carried out using SPSS 10.0 software (SPSS Inc, Chicago, IL) with p values less than 0.05 considered of statistical significance.
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Results
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Patients Characteristics
Demographic characteristics of the 204 patients included the following: mean age of 47.3 years (range, 14 to 72) and male to female ratio of 126:78. Presenting symptoms included cough in 68 patients (33.3%), chest pain in 57 (27.9%), dyspnea in 25 (12.3%), and superior vena cava syndrome in 8 (3.9%). Myasthenia gravis (MG) was an accompanying symptom in 33 patients (16.2%). The TET was diagnosed in 30 patients (14.7%) on routine physical examination without any subjective symptoms.
Surgical Procedures
At the time of surgical exploration, 78 tumors (38.2%) were found to have already invaded into the pericardium; 68 (33.3%) into the lung parenchyma; 52 (25.5%) into the great vessels, including the innominate veins, the superior vena cava, the aorta, or the pulmonary arteries; 8 (3.9%) into the chest wall; and 2 (1.0%) into the heart. There were also 19 tumors (9.3%) with concomitant pleural dissemination that were detected at surgery. Based on these surgical findings, the tumoral staging was stage I in 87 patients (42.6%), stage II in 22 (10.8%), stage III in 76 (37.3%), and stage IV in 19 (9.3%).
According to the surgical records, 180 procedures (88.2%) were considered as grossly complete. The remaining patients underwent either partial resection (17 cases; 8.3%) or biopsy alone (7 cases; 3.4%). The complete resection rate was significantly higher in stages I and II tumors (100%) than in stages III and IV tumors (75%; p < 0.001). Mean blood loss during surgery was 483.7 mL, and it was significantly less in the cases of complete resection (324.7 mL) or in stages I and II tumors (379.2 mL) than that in the cases of incomplete resection (1,955.4 mL; p < 0.001) or in stages III and IV tumors (1,050.0 mL; p = 0.003).
Morbidity and Mortality
Twenty-four patients (11.8%) experienced 29 events of serious complications after surgery. These included myasthenia crisis in 11 patients, respiratory failure in 3, empyema in 2, pneumonia in 2, sternum dehiscence in 2, cardiac arrest in 2, cardiac tamponade in 2, and heart failure in 1, bleeding necessitating reoperation in 1, upper gastrointestinal bleeding in 1, aspiration in 1, and Addison's syndrome in 1. Based on multivariate analysis, MG, incomplete resection, and stages III and IV tumors were identified as independent risk factors for postoperative morbidity (see Table 1).
Fifteen patients (7.4%) died after surgery before release from the hospital. The cause of death was myasthenia crisis in 6 patients, respiratory failure in 3, cardiac arrest in 2, systemic infection in 2, heart failure in 1, and aspiration in 1. Based on multivariate analysis, incomplete resection and MG were identified as independent risk factors for surgical death (see Table 1).
All 6 deaths from myasthenia crisis occurred in the 12 patients treated before 1986. Since then, steroid therapy was preoperatively added to all 21 MG patients for the optimization of symptom control, and there was no further death from myasthenia crisis. The mortality rate in non-MG patients were similar before and after 1986 (6 of 128 [4.7%] vs 2 of 43 [4.7%]; p = 0.677).
Histological Classification
The result of the reexamination according to the current WHO criteria for histological classification is listed in Table 2. Only nine tumors could not be classified. Myasthenia gravis was only diagnosed in patients with B type TETs. World Health Organization classification was significantly related to modified Masaoka staging (see Table 2; p < 0.001). There were significantly more stages I and II tumors in A (medullary), AB (mixed), and B1 (organoid) type TETs than those in B2 (cortical), B3 (well-differentiated thymic carcinoma), and C (high-grade carcinoma) type TETs (87.6% vs 26.4%; p < 0.001). The complete resection rate in the WHO types A, AB, and B1 tumors was also significantly higher than that in the WHO types B2, B3, and C tumors (98.9% vs 78.3%; p < 0.001).
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Table 2. Relationship Between World Health Organization Histologic Classification and Modified Masaoka Staging (p < 0.001)
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Long-Term Survival
The 5-year and 10-year overall survival rates of the whole group were 63.2% and 50.4%. The 5-year and 10-year survivals of stages III and IV tumors (42.5% and 30.1%) were significantly worse than those of stages I and II tumors (78.2% and 64.9%; p < 0.001) (Fig 1). Eight of the 20 stage II patients received postoperative radiotherapy. But their 5-year survival (72.9%) was not significantly different from the remaining 12 stage II patients who did not receive adjuvant radiotherapy (66.7%; p = 0.464). Patients with an incomplete resection had significantly worse 5-year and 10-year survival rates (30.5% and 7.6%) than patients with a complete resection (66.2% and 55.5%; p = 0.003) (Fig 2). World Health Organization histologic classification was also significantly related to distant prognosis, with 5-year and 10-year survivals significantly worse in the group of B2, B3, and C type TETs (47.5% and 36.7%) than in the group of A, AB, and B1 TETs (83.4% and 68.5%; p < 0.001) (Fig 3). There was no significant difference in the long-term survivals between patients with (61.7% and 46.1%) or without MG (58.7% and 39.2%; p = 0.992). Based on multivariate analysis, Masaoka stages III or IV, WHO types B2, B3, or C, and incomplete resection were revealed as independent risk factors for poor prognosis (see Table 3).
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Fig 1. Overall survival function of Masaoka stages I and II and stages III and IV thymic epithelial tumors (log-rank test; p < 0.001).
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Fig 2. Overall survival function after complete and incomplete resection (debulking or biopsy) (log-rank test; p = 0.003).
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Fig 3. Overall survival function of World Health Organization types A, AB, and B1 and types B2, B3, and C thymic epithelial tumors (log-rank test; p < 0.001).
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Comment
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Our results proved the heterogeneity of TETs in histologic manifestation, clinical and biological behavior, and response to treatment. The long-held surgery-oriented strategy was safe and effective in treating benign TETs of early stage. But the surgical outcome of invasive TETs was far from satisfactory. Modified Masaoka staging, resectability, and the WHO histologic classification for TETs were prognostic for surgical risk and long-term survival.
The purpose of surgery is (1) to acquire histological diagnosis of the tumor, (2) to stage the tumor correctly, and (3) when possible, to resect the tumor completely to cure the disease. In the current series, 88.2% tumors could be resected completely and safely with limited bleeding during operation and very low morbidity (8.3%) or mortality (3.3%). On the contrary, surgical risk is significantly increased when the tumor has invaded into the surrounding structures, especially the heart or great vessels. In patients having partial resection or biopsy alone, surgery proved to be difficult and risky. Operative bleeding increased significantly, and so were serious operative morbidity (37.5%) and mortality (37.5%). Completeness of resection was also revealed as an independent risk factor for long-term survival. Although 5-year and 10-year survival reached 66.2% and 55.5% after complete resection, the long-term survival after partial resection or biopsy alone remained dismal even with adjuvant therapy, with 5-year and 10-year survivals at rates of 30.5% and 7.6%. Our results were consistent with most of the reports in the literature, many of them indicating completeness of resection as an important prognostic factor [6–8]. Obviously for TETs that cannot be completely resected, the risk of surgical exploration greatly exceeds the benefit it may carry. Histologic diagnosis may well be achieved through less invasive procedures such as core-needle biopsy or mini-thoracotomy.
Myasthenia gravis was also identified as a risk factor for surgery in our patients. We consider it related to the perioperative management of MG symptoms. Preoperative steroid therapy was adopted for better control of symptoms by the authors since 1986, and the incidence of myasthenia crisis was significantly reduced thereafter. Our result was in conformity with the recent report from Endo and colleagues [9], showing that perioperative steroid therapy helped reduce myasthenia crisis and the need of respiratory assistance after thymectomy for MG patients. In fact, all MG-related deaths in the current series occurred before preoperative steroid therapy became routine. There was no difference in the surgical mortality induced by other causes before and after.
Complete resection was feasible in all early stage TETs in our patients. The goals of surgery were achieved safely with very few serious complications (2.7%) and no surgical deaths. With 10-year survivals as high as 70.8% and 50.4%, surgical resection is without a doubt the first choice for stages I and II TETs. Adjuvant radiotherapy has long been considered unnecessary for stage I TETs after complete resection. Still there is controversy over adjuvant radiotherapy for stage II TETs [6, 7]. Recently, Mangi and colleagues [10] reviewed 49 stage II thymomas and showed that radiation did not improve long-term survival after grossly complete resection in 14 patients having radiation in comparison with the 35 patients who did not undergo radiation. Singhal and colleagues [11] retrospectively studied adjuvant radiation therapy in 167 thymoma patients, and among them 40 patients were in stage II. They did not find any survival advantage in 20 patients receiving 45 to 55 Gy radiation in comparison with the other 20 patients who did not receive adjuvant radiation. Although there were only 20 stage II patients in our series, we also failed to detect any survival advantage in those who received postoperative radiation. This has led us to withhold radiotherapy for stage II patients to avoid probable overtreatment. Because all the series were retrospective, well-organized prospective randomized trials are needed to further prove this hypothesis.
The complete resection rate was significantly lower in stages III and IV TETs (75%, p < 0.001). Invasion into the surrounding mediastinal structures, especially the heart, the great vessels, or the trachea, makes surgery difficult and risky. Patients in the current series who are in stages III and IV had operative bleeding that averaged more than 1,000 mL. There were also significantly more serious morbidities (22.3%) and surgical deaths (16%) in these patients. In addition, long-term survival was significantly worse than stages I and II diseases, with 5-year and 10-year survivals at only 42.5% and 30.1% (p < 0.001), respectively. Statistic analysis revealed stages III and IV diseases as a predictive factor for serious surgical morbidity, mortality, and poor survival. Myojin and colleagues [12] also found increased pleural dissemination and recurrence after surgical exploration for stage III TETs, and questioned the role of "debulking" in this setting. Although in our experience adjuvant therapy may improve survival to some extent, overall the results were far from satisfactory. Chemotherapy was reported to be effective in treating TETs greater than stage III. Loehrer and colleagues [13] reported similar response rates to cisplatin, doxorubicin, and cyclophosphamide in limited stage, unresectable thymomas (overall response rate, 69.6%), as well as in metastatic or recurrent diseases (overall response rate, 50%) [14]. But in those two phase II trials, radiation instead of surgery was administered after chemotherapy. Shin and colleagues [15] found 82% of 12 unresectable TETs could be removed completely after induction chemotherapy. Theoretically the complete resection rate should translate into better survival. Berruti and colleagues [16] reported a median survival of 47.5 months in stages III and IVa TETs after induction chemotherapy with doxorubicin, cisplatin, vincristine, and cyclophosphamide. Venuta and colleagues [17] later reported an increased resection rate and prolonged survival over histologic control for stages III and IV TETs after neoadjuvant chemotherapy with cisplatin, epirubicin, and etoposide. Thus more evidence from phase III trials is still needed to prove the advantage of neoadjuvant chemotherapy. At the same time, the accuracy of clinical staging of mediastinal tumors will necessarily also be improved in order to make prospective randomized clinical trials possible.
Controversies over the histologic classification of TETs [18–21] have made it difficult to compare the results of different studies. This could partly explain the lack of consensus in the therapeutic strategy against the disease. The introduction of the WHO histologic classification has led to several large series of retrospective studies indicating its usefulness in the management of TETs. Kondo and colleagues [22] retrospectively reviewed 100 thymoma patients in the past 28 years and found significant differences in disease-free survival between types A and AB and types B1 and B2, and between type B3 and C. However, only Masaoka staging showed significant, independent effects on disease-free survival in their patients based on multivariate analysis. In the current series, WHO classification was revealed as an independent prognostic factor for long-term survival, although it was also closely related to the Masaoka staging of the tumors. The majority of WHO types A, AB, and B1 TETs (87.6%) were in stage I or II, and 98.9% of them could be completely resected. Therefore the long-term result after resection was quite satisfactory, with 5-year and 10-year survival rates at 83.4% and 68.5%, respectively. With relatively benign biological behavior and considering their lack of cytological atypia, WHO types A, AB, and B1 tumors should be treated with radical resection as a first choice of treatment. Adjuvant therapies after the complete removal of these tumors should at least be considered unnecessary, if not as a kind of overtreatment.
On the other hand, 75% of WHO classified types B2, B3, and C TETs in the current series were either stage III or IV tumors. Their resection rate (78.3%; p < 0.001) was significantly lower than types A, AB, and B1 TETs. Consequently, the long-term survival was significantly lower, with 5-year and 10-year rates at only 47.5% and 36.7%, respectively (p < 0.001). In fact their biologically malignant behavior may well be predicted from their cytological characteristics such as clear-cut atypia and architectural abnormalities [1]. In Myojin and colleagues' [12] series, 87% patients were of types B2, B3, and C TETs with the remaining 13% being type B1 tumors [12]. Achieving histologic diagnosis in clinically advanced tumors is thus of primary importance so as to avoid futile surgical exploration. So far there has not been any clinical trial of induction therapy based on histologic information. All the previously mentioned studies [13–17] on neoadjuvant chemotherapy were designed upon Masaoka staging alone. Therefore future studies aimed at increased resectability and possibly improved outcome of TETs should also be based on the knowledge of histologic classifications.
Based on the previously outlined findings, the authors conclude that surgery remains the best curative procedure for TETs. World Health Organization classified types A, AB, and B1 tumors of early stage can be resected completely and safely with favorable long-term survival. In these cases, adjuvant therapy after complete resection is not warranted. In WHO classified types B2, B3, and C tumors of advanced stage, complete resection is difficult and risky, and distant prognosis remains poor even with adjuvant therapies. The authors have suggested a grading system for TETs using both the Masaoka staging and the WHO histologic classification [5]. Clinical studies based on the Masaoka staging as well as the WHO []histologic classification may help further identify TETs of high risk. Future clinical trials will necessarily be directed at how to improve the accuracy of clinical staging in large tumors in order to increase the resection rate in surgical patients, whether early stage malignant tumors (WHO classified type B2, B3, or C) or locally advanced but relatively benign tumors (WHO classified type A, B, or B1) that still need adjuvant therapy after complete resection, and will also be directed at determining what role neoadjuvant therapy should play in the management of advanced staged tumors of different histologic types.
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Acknowledgments
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The authors thank William Beloe for revising the English syntax.
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Abstract
Introduction
