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Solitary Fibrous Tumor of the Pleura: Outcomes of 157 Complete Resections in a Single Center
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Solitary Fibrous Tumor of the Pleura: Outcomes of 157 Complete Resections in a Single Center Benoit Lahon, MD, Olaf Mercier, MD, PhD, Elie Fadel, MD, PhD, Maria Rosa Ghigna, MD, Boriana Petkova, MD, Sacha Mussot, MD, Dominique Fabre, MD, Thierry Le Chevalier, MD, and Philippe Dartevelle, MD Departments of Thoracic and Vascular Surgery and Heart-Lung Transplantation and Pathology, Marie Lannelongue Hospital, Paris, France
Background. The purpose of this study was to identify factors affecting long-term outcomes after complete resection of solitary fibrous tumors of the pleura (SFTP). Methods. This was a single-center retrospective study using data from patients operated on from January 1980 to December 2010. Results. Of the 157 patients (72 men, 85 women; median age, 58 years [13– 87 years]), 60 (38%) had symptoms. All patients had complete en bloc resection with wedge lung excision (n ⴝ 122), lobectomy (n ⴝ 15), bilobectomy (n ⴝ 3), segmentectomy (n ⴝ 1), pneumonectomy (n ⴝ 4), chest wall resection (n ⴝ 8), diaphragm resection (n ⴝ 3), or multilevel hemivertebrectomy (n ⴝ 1). The tumors were pedunculated (n ⴝ 89) or sessile (n ⴝ 68). Definitive histologic examination showed benign tumors (bSFTP) in 90 patients (57%) and malignant tumors (mSFTP) in 67 (43%) patients. Compared with the bSFTP group, the mSFTP group had significantly larger tumors (13.4 cm vs 6.4 cm; p < 0.0001) and a nonsignificantly higher propor-
tion of symptomatic patients (58% vs 23%). Overall operative mortality and morbidity rates were 0.6% and 5.7%, respectively, with no significant difference between patients with mSFTP and those with bSFTP. The 5-year survival rate was better in patients with bSFTP than in patients with mSFTP (96% vs 68%; p ⴝ 0.0003). Tumor recurrence was more common in patients with mSFTP than in those with bSFTP (16% vs 2%; p < 0.0001) and was associated with decreased survival (p ⴝ 0.02). Sessile tumors (p ⴝ 0.05), CD34-negative tumors (p ⴝ 0.005), and extensive surgical procedures (p ⴝ 0.04) were significant risk factors for tumor recurrence. Conclusions. Complete en bloc resection of SFTP provides good long-term survival. Tumor recurrence is the main risk factor for death and may occur in mSFTP despite en bloc resection and requires multimodal treatment and close follow-up. (Ann Thorac Surg 2012;94:394 – 400) © 2012 by The Society of Thoracic Surgeons
S
leagues [2] proposed a new prognostic classification scheme based on histologic findings and morphologic characteristics, with the goal of guiding the selection of strategies for treatment and postoperative follow-up. The treatment of SFTP always includes complete surgical resection complying with the principles of oncologic surgical treatment. Adjuvant therapy is considered in high-risk patients such as those with recurrent tumors or malignant sessile tumors, for which treatment is not standardized. Here, our objective was to report long-term outcomes after resection of SFTP in a single institution according to the histologic and morphologic classification [2] and to identify factors affecting survival and recurrence. To this end, we conducted a retrospective chart review of patients managed over a 30-year period at our institution.
olitary fibrous tumors of the pleura (SFTP) are rare mesenchymal tumors accounting for less than 5% of all pleural neoplasms. Approximately 900 cases have been reported in the international literature since 1931 [1]. It took more than a decade to establish the exact pathologic features of these tumors, initially known as localized mesotheliomas. Most of these tumors are pleural fibromas with benign histologic features (bSFTP) and no tendency to relapse after complete surgical resection. However a few SFTP are malignant (mSFTP) and can recur and spread, ultimately causing death. The behavior of mSFTP remains unpredictable. More specifically, histologic examination may fail to predict malignant behavior, as mSFTP comprises several tumor cell populations with various degrees of differentiation. In addition, bSFTP may transform into mSFTP after many years. In 2002, de Perrot and col-
Accepted for publication April 10, 2012. Presented at the Poster Session of the Forty-eighth Annual Meeting of The Society of Thoracic Surgeons, Fort Lauderdale, FL, Jan 28 –Feb 1, 2012. Address correspondence to Dr Mercier, Department of Thoracic and Vascular Surgery and Heart-Lung Transplantation, Marie Lannelongue Hospital, 133 Avenue de la Résistance, 92350 Le Plessis Robinson, France; e-mail: [email protected].
© 2012 by The Society of Thoracic Surgeons Published by Elsevier Inc
Material and Methods Between January 1980 and December 2010, 157 patients underwent resection for SFTP in our department. There were 85 women and 72 men (male-female ratio ⫽ 0.84), with a median age of 57 years (range, 13– 87 years). The 0003-4975/$36.00 http://dx.doi.org/10.1016/j.athoracsur.2012.04.028
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Diagnosis of SFTP Of the 157 patients, 60 (38%) were symptomatic at presentation, with a cough in 34 (22%), dyspnea in 34 (22%), chest pain in 31 (20%), hemoptysis in 3 (2%), inferior vena cava compression in 2 (1.3%), superior vena cava syndrome in 1 (0.6%), hypertrophic pulmonary osteoarthropathy (Pierre Marie-Bamberger syndrome) in 3 (2%), and hypoglycemia (Doege-Potter syndrome) in 3 (2%). The 96 asymptomatic patients presented with a welldefined rounded mass on the chest roentgenogram. All patients underwent spiral computed tomography (CT) of the chest (Fig 1), as well as cerebral CT as part of the staging workup for an intrathoracic neoplasm. Flexible bronchoscopy was also performed routinely before operation. When a pedunculated SFTP was suspected, a series of positional chest roentgenograms was obtained to look for evidence of tumor mobility, confirming the diagnosis of pleural tumor. Magnetic resonance imaging (MRI) of the chest was performed in 4 patients with large posterior SFTP to look for vertebral or foraminal involvement. 18F-fluorodeoxyglucose positron emission tomography was performed in 7 patients whose radiologic features suggested a malignant tumor. The pathologic diagnosis was obtained preoperatively by CT-guided percutaneous biopsy in 9 of 23 patients. Table 1 shows the main patient characteristics. Regarding pathologic study, CD34, vimentin, cytokeratin, CD99, actin, desmin, S-100, and Bcl-2 immunostaining have been routinely used since 1996 to confirm SFTP diagnosis. Moreover, Ki67 immunostaining was also performed to evaluate tumor aggressive behavior.
Table 1. Patient Characteristics (N ⫽ 157) Patient Characteristics
Fig 1. (A, B) Computed tomographic scans showing a giant compressive malignant solitary fibrous tumor of the pleura in the left hemithorax with heterogeneous zones indicating hemorrhage and necrosis. (C) Postoperative specimen.
following data were abstracted from the charts: age, sex, symptoms, tumor features, tumor histologic type, surgical data, recurrences, clinical course, and survival. Our institutional review board approved this retrospective study and waived the need for informed consent.
Age (y), median [range] Male-female ratio Smokers, n (%) Symptoms, n (%) Presenting symptoms, n (%) Cough Dyspnea Chest pain Hemoptysis Hypertrophic pulmonary osteoarthropathy Hypoglycemia Preoperative workup, n (%) CT only CT ⫹ MRI CT ⫹ PET CT ⫹ MRI ⫹ PET Fiberoptic bronchoscopy, n (%) Fine-needle aspiration biopsy, n (%) Preoperative diagnosis, n (%)
Patients, n (%) 57.8 [13–87] 0.84 43 (27%) 60 (38%) 34 (22%) 34 (22%) 31 (20%) 3 (2%) 3 (2%) 3 (2%) 153 (97%) 4 (2%) 5 (3%) 2 (1%) 153 (97%) 23 (15%) 9 (6%)
CT ⫽ computed tomography; MRI ⫽ magnetic resonance imaging; PET ⫽ positron emission tomography.
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Table 2. Surgical Procedures Surgical Procedure
Patients, n (%)
Single wedge resection Multiple wedge resection Segmentectomy Lobectomy Bilobectomy Pneumonectomy Associated chest wall resection Associated diaphragm resection Associated vertebral resection
104 (65%) 18 (11%) 1 (1%) 15 (10%) 3 (2%) 4 (3%) 8 (5%) 3 (2%) 1 (0.6%)
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test and categorical variables were compared using the 2 test. The ability of preoperative factors to predict mSFTP was assessed using log-logistic regression. Survival rates were calculated by life table analysis. Kaplan-Meier curves were plotted and compared using the log-rank test for the univariate analysis. A multivariate analysis of independent prognostic factors was conducted using the Cox proportional hazards stepwise model, on StatView 5 (Abacus Concepts, Berkeley, CA). Differences were considered significant when p was less than 0.05.
Results SFTP
Treatment of SFTP All patients underwent surgical treatment with the intention of achieving complete en bloc resection. Single-stage posterolateral thoracotomy was used in most patients (n ⫽ 139 [88%]). In 3 patients with suspected mediastinal vascular involvement, median sternotomy was performed. Video-assisted operations were used only in the 20 patients with small pedunculated parietal tumors that were less than 2 cm in diameter; among them, 5 patients required conversion to open posterolateral thoracotomy to achieve safe complete en bloc resection. Extended operations were required in 12 patients with involvement of extrapulmonary structures. Functional status and feasibility of complete resection were the main criteria used to select patients for extended operations. The surgical procedures are detailed in Table 2. We considered an adequate margin of at least 2 cm when resecting SFTP. SFTP were diagnosed according to the histologic criteria developed by England and coworkers [3]. Presence of any of the following criteria was taken to indicate a malignant tumor: more than 4 mitoses per 10 high-power fields, necrosis, nuclear atypia, or hypercellularity (or a combination of these criteria). Decisions about adjuvant treatments for mSFTP such as chemotherapy or localized radiation therapy were made on a case-by-case basis after discussion with the medical oncologist. Adjuvant treatment was given to 5 (3%) patients and consisted of chemotherapy alone in 1 (0.6 %) patient and chemotherapy with radiation therapy in 4 patients (2.5 %).
Operative Mortality and Long-Term Survival Operative mortality was defined as the proportion of patients who died within the first 30 days after operation or during the same hospital admission. Survival was calculated from the time of resection for SFTP to death or last follow-up, whichever occurred first. Disease-free survival (DFS) was defined as the time from resection for SFTP to last follow-up or date of disease recurrence, whichever occurred first. Follow-up data were complete for 102 patients. Of the 55 patients who were lost to follow-up, 25 had mSFTP and 30 had bSFTP.
Statistical Analysis All data are described as means ⫾ standard error. Continuous variables were compared using the Student’s t
Median tumor size as measured on the operative specimens was 9 cm (range, 0.3–30 cm) and median weight was 941 g (range, 34 –2920 g). Location was on the right side in 82 patients and on the left side in 75 patients. There were 90 (57%) pedunculated tumors and 67 sessile tumors. Tumors were benign in 90 patients (57%) and malignant in 67 (43%) patients. Multifocal involvement was noted in 13 (8%) patients at presentation; 1 patient had a liver metastasis that was diagnosed during the preoperative workup and resected subsequently.
Factors Predicting Malignancy Table 3 lists the factors associated with malignancy. Malignant tumors were more often symptomatic (p ⬍ 0.0001), large (p ⬍ 0.0001), sessile (p ⬍ 0.0001), and multifocal (p ⫽ 0.03). Neither the presence of vena cava compression nor the site of pleural origin predicted malignancy (p ⫽ 0.09 and p ⫽ 0.97, respectively).
Morbidity and Operative Mortality One patient died postoperatively (0.6%) from acute pulmonary embolism 29 days after resection for mSFTP. In-hospital morbidity was 5.7% overall, and 77% of patients with in-hospital morbidity had malignant tumors. Among the patients with bSFTP, 1 experienced acute respiratory distress syndrome and another had a transient ischemic attack. In the group with mSFTP, 7 patients experienced the following in-hospital complications: acute respiratory distress syndrome (n ⫽ 4), hemothorax (n ⫽ 1), deep vein thrombosis (n ⫽ 1), and delirium tremens (n ⫽ 1). Mean length of hospital stay was 11.5 ⫾ 4 days.
Long-Term Survival Median follow-up was 14 years. During follow-up, 32 patients died—10 with bSFTP and 22 with mSFTP. All 10 patients with bSFTP died of reasons unrelated to the tumor. Among the 22 patients with mSFTP, 9 died of recurrence, 1 of myocardial infarction, 1 of acute pulmonary embolism, 2 of multiple traumas, 1 of ovarian cancer, and 8 of unknown cause. The overall 5-, 10-, and 30-year survival rates were 86%, 77%, and 21%, respectively, with a median survival of 14 years (Fig 2). Long-term survival was better in the group
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Table 3. Factors Predicting Malignancy of Solitary Fibrous Tumor of the Pleura Factors Symptomatic, n (%) Diameter (cm), mean ⫾ SD Morphologic type Pedunculated, n (%) Sessile, n (%) Pleural location Parietal, n (%) Visceral, n (%) Locoregional spread Multifocal, n (%) Vena cava compression, n (%)
Benign
Malignant
Univariate p Value
Multivariate p Value
21 (23%) 6.4 ⫾ 4.8
39 (58%) 13.4 ⫾ 7.4
< 0.0001 < 0.0001
... < 0.0001
68 (75%) 22 (25%)
21 (31%) 46 (69%)
< 0.0001
< 0.0001
18 (20%) 72 (80%)
22 (33%) 45 (67%)
0.09
...
1 (1%) ...
13 (19%) 3
< 0.0001 0.04
0.03 ...
SD ⫽ standard deviation.
with bSFTP than in the group with mSFTP (5-year survival, 96% vs 68.1%; p ⬍ 0.001) (Fig 3). By univariate analysis, factors significantly associated with a lower long-term survival after resection for mSFTP were vena cava compression (p ⫽ 0.05), multifocal presentation (p ⫽ 0.04), resection larger than a wedge (p ⫽ 0.004), and recurrence (p ⫽ 0.003). By multivariate analysis, recurrence was the only factor significantly associated with lower survival (p ⫽ 0.02).
Recurrences Recurrences were noted in 15 (9.5%) of the 156 patients who survived beyond the postoperative period. Median time to diagnosis of recurrence was 29 months. Recurrences were significantly more common in mSFTP than in bSFTP (19% vs 1.3%, p ⬍ 0.0001). All recurrences had the same histologic features as the primary tumors. The recurrence was local in 10 (61%) patients and distant in 5 (39%). Of the 10 patients with local recurrences, 1 had a
100
77% 68%
80
Survival (%)
poor functional status contraindicating repeated resection. In the other 9 patients (2 with bSFTP and 7 with mSFTP), repeated resection was performed and no further recurrences were noted. Among these 9 patients, 1 underwent wedge pulmonary resection associated with vertebral resection for a local recurrence 11 years after video-assisted resection of a 10-cm mSFTP and was still alive at last follow-up 3 years later. Among the remaining 8 patients, we performed 4 multiple wedge resections, 3 simple wedge resections and 1 wedge resection extended to the diaphragm. Patients with distant recurrences were treated with radiation therapy and chemotherapy (n ⫽ 1), radiation therapy alone (n ⫽ 3), or chemotherapy alone (n ⫽ 1). Overall 5-year DFS was 82% (Fig 4). DFS was significantly better in the group with bSFTP than in the group with mSFTP (5-year DFS, 96% vs 59%; p ⬍ 0.0001) (Fig 5).
60
21%
40 20 0
0
At Risk (n) 75
10
20
30
16
1
b m
Years
50
Fig 2. Long-term overall survival of 157 patients after resection of solitary fibrous tumors of the pleura. Numbers of patients at risk are shown below the abscissa. The overall 5-, 10-, and 30-year survival rates were 86%, 77%, and 21%, respectively; median survival was 14 years.
Fig 3. Long-term overall survival according to histologic type. The overall 5-, 10-, and 30-year survival rates in patients with benign tumors were 96%, 87%, and 33%, respectively. Benign tumors had a better long-term survival than did malignant tumors (5-year survival, 96% vs 68.1%; p ⬍ 0.001). (bSFTP ⫽ benign solitary fibrous tumors of the pleura; mSFTP ⫽ malignant solitary fibrous tumors of the pleura; NS ⫽ not significant.)
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Disease free survival (%)
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81%
100
Table 4. Factors Associated With Tumor Recurrence
74%
80
62%
Variable
60
16%
40 20 0
0
At Risk (n) 74
10
20
30
17
1
Years
50
Fig 4. Long-term disease-free survival (DFS) in patients with solitary fibrous tumor of the pleura. Number of patients at risk is shown below the abscissa. Of 156 patients who survived beyond the postoperative period, 15 (9.5%; 13 with malignant and 2 with benign tumors) experienced recurrences after a median time of 29 months. Overall 5-, 10-, and 30-year DFS rates were 81%, 74%, and 16%, respectively.
Factors significantly associated with mSFTP recurrence were sessile morphologic type, resection larger than a wedge, and CD34-negative tumor (p ⫽ 0.005, p ⫽ 0.04, and p ⫽ 0.001, respectively) (Table 4).
Comment Our study shows that complete en bloc resection of SFTP can provide long-term survival with low postoperative
Disease free survival (%)
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100 80 60 40 20 0
0
10
20
30
Years bSFTP mSFTP Fig 5. Long-term disease-free survival (DFS) according to histologic type. Recurrences were more common among patients with malignant tumors than among those with benign tumors (5-year DFS, 94% vs 57%; p ⬍ 0.0001). (bSFTP ⫽ benign solitary fibrous tumors of the pleura; mSFTP ⫽ malignant solitary fibrous tumors of the pleura.)
Morphologic characteristics Size ⬎ 10 cm, n (%) Pedunculated, n (%) Sessile, n (%) Multifocal, n (%) Locoregional spread Parietal spread, n (%) Vena cava compression, n (%) Immunostaining CD34⫹, n (%) Surgical procedure Single wedge, n (%) Multiple wedges; other, n (%)
No Recurrence (n ⫽ 47)
Recurrence (n ⫽ 13)
15 (32%) 21 (45%) 26 (55%) 7 (15%)
4 (35%) 2 (15%) 11 (85%) 3 (23%)
0.72 0.05
5 (11%) ...
3 (20%) 3 (23%)
0.67 0.38
12 (80%)
5 (71%)
0.05
21 (45%) 26 (55%)
1 (7%) 12 (93%)
0.04
p Value
0.72
mortality and morbidity regardless of tumor size. Malignant tumors were associated with higher recurrence and mortality rates than were benign tumors. Repeated resection was associated with good outcomes after local recurrence of mSFTP. SFTP are uncommon neoplasms arising from the mesenchymal cells beneath the mesothelial lining of the pleura, as initially postulated by Klemperer and colleagues in 1931 [1]. SFTP was convincingly differentiated from pleural mesothelioma only after the introduction of immunochemical and electron microscopy techniques. Most SFTP are discovered fortuitously on standard chest roentgenograms obtained for another reason [4]. Symptoms are more common in mSFTP than in bSFTP and resolve after surgical resection [3, 5–7]. However there are no specific clinical or radiologic features to differentiate malignant from benign tumors. SFTP are usually large tumors containing clusters of various cell types that are scattered throughout the mass. This heterogeneous structure explains the unacceptably low diagnostic yield of CT-guided biopsy [8 –17]. Thus in our study, CTguided biopsy had a positive predictive value of only 39%. We believe that CT-guided biopsy should be considered only in patients with high surgical risk, patients with unresectable tumors, and patients needing extended operations. 18-Fluorodeoxyglucose positron emission tomography has also been found to be of limited diagnostic usefulness [4, 14, 18 –19]. Neither CT nor MRI reliably distinguishes mSFTP from bSFTP. Thus surgical treatment is usually performed before the benign or malignant nature of the tumor is determined. During the preoperative workup, special care should be taken to look for local spread to the mediastinum or chest wall, as well as distant metastases. MRI is particularly useful to rule out involvement of surrounding structures, mainly the spine in patients with posterior tumors [2, 9, 13, 20, 21]. Complete en bloc surgical lung-sparing resection is the
fundamental principle of oncologic thoracic surgical treatment. In our study, wedge resection was the most common surgical procedure. However, when needed, formal anatomic lung parenchymal resection (23 patients) or chest wall resection (9 patients) was performed. Video-assisted resection has been suggested for SFTP [22] and was used in our study in 20 patients with small tumors, 5 of whom required conversion to open surgical procedures to obtain R0 resection. Video-assisted resection may deserve consideration in patients with pedunculated SFTP that are smaller than 2 cm in diameter and show none of the criteria for malignancy provided that conversion to open procedures is performed if needed to achieve safe R0 resection. Incomplete resection is known to be associated with decreased survival in patients with mSFTP and with increased recurrence rates in those with bSFTP [2, 3, 9, 11, 14, 23, 24]. Even when R0 resection is achieved, recurrence remains the main risk factor for poor survival in patients with mSFTP. Recurrence rates in our study were 2.5% in the group with bSFTP and 19% in the group with mSFTP. These rates are consistent with recurrence rates reported after complete resection for SFTP (15%– 85%) [8, 12, 15, 18, 25, 26]. Long-term follow-up with CT every 6 months for 2 years and yearly thereafter is mandatory after complete resection [2, 11]. Long-term survival after bSFTP was excellent, with 96% of patients alive after 5 years. None of these patients died of SFTP. Survival in the group with mSFTP was lower, mainly because of local and general recurrences, with a 5-year survival rate of 68%. Repeated resection of local recurrences provided good outcomes, with no further recurrences. One patient underwent spine resection for a recurrence involving the intervertebral foramina. Thus extended procedures for local mSFTP recurrence may be warranted provided that R0 resection is possible. Close follow-up after resection for SFTP is crucial to ensure that recurrences are detected early. Despite the high local recurrence rate after resection for mSFTP, the role for adjuvant therapy remains controversial. To date, a multimodal therapeutic approach is not considered mandatory in patients with mSFTP. Radiation therapy is used routinely in patients with mSFTP if resection is not feasible or is incomplete. A sessile morphologic type, resection larger than a wedge, and CD34-negative tumor cells were significant risk factors for mSFTP recurrence (p ⫽ 0.005, p ⫽ 0.04, and p ⫽ 0.001, respectively). These characteristics may indicate a need for adjuvant therapy to decrease the recurrence rate. A sessile morphologic type is 1 of the SFTP classification criteria in the classification scheme developed by de Perrot and colleagues [2, 9] based on histologic and morphologic findings. Sessile mSFTP recurred in 63% of patients in their study, suggesting a need for adjuvant radiation therapy. CD34-negative immunostaining may reflect tumor dedifferentiation and a higher risk of recurrence [27–32]. Characteristics on immunochemical analysis and the extent of operation should be studied as additional criteria to be used in SFTP classification and patient selection for multimodality treatment. In conclusion, complete en bloc resection of SFTP
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provides excellent long-term survival with low postoperative morbidity and mortality and therefore remains the treatment of choice. Free-margin resection of bSFTP is curative. Recurrence is the main factor associated with poor survival after resection for mSFTP. Repeated resection is the best therapeutic option for local recurrences provided that complete resection is achieved. To date the role for adjuvant therapy remains controversial. Our findings suggest that mSFTP with sessile morphologic type, CD34-negative immunostaining results, or necessity for extended resection should be considered for adjuvant therapy to avoid recurrence.
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Solitary Fibrous Tumor of the Pleura: Outcomes of 157 Complete Resections in a Single Center Benoit Lahon, MD, Olaf Mercier, MD, PhD, Elie Fadel, MD, PhD, Maria Rosa Ghigna, MD, Boriana Petkova, MD, Sacha Mussot, MD, Dominique Fabre, MD, Thierry Le Chevalier, MD, and Philippe Dartevelle, MD Departments of Thoracic and Vascular Surgery and Heart-Lung Transplantation and Pathology, Marie Lannelongue Hospital, Paris, France
Background. The purpose of this study was to identify factors affecting long-term outcomes after complete resection of solitary fibrous tumors of the pleura (SFTP). Methods. This was a single-center retrospective study using data from patients operated on from January 1980 to December 2010. Results. Of the 157 patients (72 men, 85 women; median age, 58 years [13– 87 years]), 60 (38%) had symptoms. All patients had complete en bloc resection with wedge lung excision (n ⴝ 122), lobectomy (n ⴝ 15), bilobectomy (n ⴝ 3), segmentectomy (n ⴝ 1), pneumonectomy (n ⴝ 4), chest wall resection (n ⴝ 8), diaphragm resection (n ⴝ 3), or multilevel hemivertebrectomy (n ⴝ 1). The tumors were pedunculated (n ⴝ 89) or sessile (n ⴝ 68). Definitive histologic examination showed benign tumors (bSFTP) in 90 patients (57%) and malignant tumors (mSFTP) in 67 (43%) patients. Compared with the bSFTP group, the mSFTP group had significantly larger tumors (13.4 cm vs 6.4 cm; p < 0.0001) and a nonsignificantly higher propor-
tion of symptomatic patients (58% vs 23%). Overall operative mortality and morbidity rates were 0.6% and 5.7%, respectively, with no significant difference between patients with mSFTP and those with bSFTP. The 5-year survival rate was better in patients with bSFTP than in patients with mSFTP (96% vs 68%; p ⴝ 0.0003). Tumor recurrence was more common in patients with mSFTP than in those with bSFTP (16% vs 2%; p < 0.0001) and was associated with decreased survival (p ⴝ 0.02). Sessile tumors (p ⴝ 0.05), CD34-negative tumors (p ⴝ 0.005), and extensive surgical procedures (p ⴝ 0.04) were significant risk factors for tumor recurrence. Conclusions. Complete en bloc resection of SFTP provides good long-term survival. Tumor recurrence is the main risk factor for death and may occur in mSFTP despite en bloc resection and requires multimodal treatment and close follow-up. (Ann Thorac Surg 2012;94:394 – 400) © 2012 by The Society of Thoracic Surgeons
S
leagues [2] proposed a new prognostic classification scheme based on histologic findings and morphologic characteristics, with the goal of guiding the selection of strategies for treatment and postoperative follow-up. The treatment of SFTP always includes complete surgical resection complying with the principles of oncologic surgical treatment. Adjuvant therapy is considered in high-risk patients such as those with recurrent tumors or malignant sessile tumors, for which treatment is not standardized. Here, our objective was to report long-term outcomes after resection of SFTP in a single institution according to the histologic and morphologic classification [2] and to identify factors affecting survival and recurrence. To this end, we conducted a retrospective chart review of patients managed over a 30-year period at our institution.
olitary fibrous tumors of the pleura (SFTP) are rare mesenchymal tumors accounting for less than 5% of all pleural neoplasms. Approximately 900 cases have been reported in the international literature since 1931 [1]. It took more than a decade to establish the exact pathologic features of these tumors, initially known as localized mesotheliomas. Most of these tumors are pleural fibromas with benign histologic features (bSFTP) and no tendency to relapse after complete surgical resection. However a few SFTP are malignant (mSFTP) and can recur and spread, ultimately causing death. The behavior of mSFTP remains unpredictable. More specifically, histologic examination may fail to predict malignant behavior, as mSFTP comprises several tumor cell populations with various degrees of differentiation. In addition, bSFTP may transform into mSFTP after many years. In 2002, de Perrot and col-
Accepted for publication April 10, 2012. Presented at the Poster Session of the Forty-eighth Annual Meeting of The Society of Thoracic Surgeons, Fort Lauderdale, FL, Jan 28 –Feb 1, 2012. Address correspondence to Dr Mercier, Department of Thoracic and Vascular Surgery and Heart-Lung Transplantation, Marie Lannelongue Hospital, 133 Avenue de la Résistance, 92350 Le Plessis Robinson, France; e-mail: [email protected].
© 2012 by The Society of Thoracic Surgeons Published by Elsevier Inc
Material and Methods Between January 1980 and December 2010, 157 patients underwent resection for SFTP in our department. There were 85 women and 72 men (male-female ratio ⫽ 0.84), with a median age of 57 years (range, 13– 87 years). The 0003-4975/$36.00 http://dx.doi.org/10.1016/j.athoracsur.2012.04.028
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Diagnosis of SFTP Of the 157 patients, 60 (38%) were symptomatic at presentation, with a cough in 34 (22%), dyspnea in 34 (22%), chest pain in 31 (20%), hemoptysis in 3 (2%), inferior vena cava compression in 2 (1.3%), superior vena cava syndrome in 1 (0.6%), hypertrophic pulmonary osteoarthropathy (Pierre Marie-Bamberger syndrome) in 3 (2%), and hypoglycemia (Doege-Potter syndrome) in 3 (2%). The 96 asymptomatic patients presented with a welldefined rounded mass on the chest roentgenogram. All patients underwent spiral computed tomography (CT) of the chest (Fig 1), as well as cerebral CT as part of the staging workup for an intrathoracic neoplasm. Flexible bronchoscopy was also performed routinely before operation. When a pedunculated SFTP was suspected, a series of positional chest roentgenograms was obtained to look for evidence of tumor mobility, confirming the diagnosis of pleural tumor. Magnetic resonance imaging (MRI) of the chest was performed in 4 patients with large posterior SFTP to look for vertebral or foraminal involvement. 18F-fluorodeoxyglucose positron emission tomography was performed in 7 patients whose radiologic features suggested a malignant tumor. The pathologic diagnosis was obtained preoperatively by CT-guided percutaneous biopsy in 9 of 23 patients. Table 1 shows the main patient characteristics. Regarding pathologic study, CD34, vimentin, cytokeratin, CD99, actin, desmin, S-100, and Bcl-2 immunostaining have been routinely used since 1996 to confirm SFTP diagnosis. Moreover, Ki67 immunostaining was also performed to evaluate tumor aggressive behavior.
Table 1. Patient Characteristics (N ⫽ 157) Patient Characteristics
Fig 1. (A, B) Computed tomographic scans showing a giant compressive malignant solitary fibrous tumor of the pleura in the left hemithorax with heterogeneous zones indicating hemorrhage and necrosis. (C) Postoperative specimen.
following data were abstracted from the charts: age, sex, symptoms, tumor features, tumor histologic type, surgical data, recurrences, clinical course, and survival. Our institutional review board approved this retrospective study and waived the need for informed consent.
Age (y), median [range] Male-female ratio Smokers, n (%) Symptoms, n (%) Presenting symptoms, n (%) Cough Dyspnea Chest pain Hemoptysis Hypertrophic pulmonary osteoarthropathy Hypoglycemia Preoperative workup, n (%) CT only CT ⫹ MRI CT ⫹ PET CT ⫹ MRI ⫹ PET Fiberoptic bronchoscopy, n (%) Fine-needle aspiration biopsy, n (%) Preoperative diagnosis, n (%)
Patients, n (%) 57.8 [13–87] 0.84 43 (27%) 60 (38%) 34 (22%) 34 (22%) 31 (20%) 3 (2%) 3 (2%) 3 (2%) 153 (97%) 4 (2%) 5 (3%) 2 (1%) 153 (97%) 23 (15%) 9 (6%)
CT ⫽ computed tomography; MRI ⫽ magnetic resonance imaging; PET ⫽ positron emission tomography.
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Table 2. Surgical Procedures Surgical Procedure
Patients, n (%)
Single wedge resection Multiple wedge resection Segmentectomy Lobectomy Bilobectomy Pneumonectomy Associated chest wall resection Associated diaphragm resection Associated vertebral resection
104 (65%) 18 (11%) 1 (1%) 15 (10%) 3 (2%) 4 (3%) 8 (5%) 3 (2%) 1 (0.6%)
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test and categorical variables were compared using the 2 test. The ability of preoperative factors to predict mSFTP was assessed using log-logistic regression. Survival rates were calculated by life table analysis. Kaplan-Meier curves were plotted and compared using the log-rank test for the univariate analysis. A multivariate analysis of independent prognostic factors was conducted using the Cox proportional hazards stepwise model, on StatView 5 (Abacus Concepts, Berkeley, CA). Differences were considered significant when p was less than 0.05.
Results SFTP
Treatment of SFTP All patients underwent surgical treatment with the intention of achieving complete en bloc resection. Single-stage posterolateral thoracotomy was used in most patients (n ⫽ 139 [88%]). In 3 patients with suspected mediastinal vascular involvement, median sternotomy was performed. Video-assisted operations were used only in the 20 patients with small pedunculated parietal tumors that were less than 2 cm in diameter; among them, 5 patients required conversion to open posterolateral thoracotomy to achieve safe complete en bloc resection. Extended operations were required in 12 patients with involvement of extrapulmonary structures. Functional status and feasibility of complete resection were the main criteria used to select patients for extended operations. The surgical procedures are detailed in Table 2. We considered an adequate margin of at least 2 cm when resecting SFTP. SFTP were diagnosed according to the histologic criteria developed by England and coworkers [3]. Presence of any of the following criteria was taken to indicate a malignant tumor: more than 4 mitoses per 10 high-power fields, necrosis, nuclear atypia, or hypercellularity (or a combination of these criteria). Decisions about adjuvant treatments for mSFTP such as chemotherapy or localized radiation therapy were made on a case-by-case basis after discussion with the medical oncologist. Adjuvant treatment was given to 5 (3%) patients and consisted of chemotherapy alone in 1 (0.6 %) patient and chemotherapy with radiation therapy in 4 patients (2.5 %).
Operative Mortality and Long-Term Survival Operative mortality was defined as the proportion of patients who died within the first 30 days after operation or during the same hospital admission. Survival was calculated from the time of resection for SFTP to death or last follow-up, whichever occurred first. Disease-free survival (DFS) was defined as the time from resection for SFTP to last follow-up or date of disease recurrence, whichever occurred first. Follow-up data were complete for 102 patients. Of the 55 patients who were lost to follow-up, 25 had mSFTP and 30 had bSFTP.
Statistical Analysis All data are described as means ⫾ standard error. Continuous variables were compared using the Student’s t
Median tumor size as measured on the operative specimens was 9 cm (range, 0.3–30 cm) and median weight was 941 g (range, 34 –2920 g). Location was on the right side in 82 patients and on the left side in 75 patients. There were 90 (57%) pedunculated tumors and 67 sessile tumors. Tumors were benign in 90 patients (57%) and malignant in 67 (43%) patients. Multifocal involvement was noted in 13 (8%) patients at presentation; 1 patient had a liver metastasis that was diagnosed during the preoperative workup and resected subsequently.
Factors Predicting Malignancy Table 3 lists the factors associated with malignancy. Malignant tumors were more often symptomatic (p ⬍ 0.0001), large (p ⬍ 0.0001), sessile (p ⬍ 0.0001), and multifocal (p ⫽ 0.03). Neither the presence of vena cava compression nor the site of pleural origin predicted malignancy (p ⫽ 0.09 and p ⫽ 0.97, respectively).
Morbidity and Operative Mortality One patient died postoperatively (0.6%) from acute pulmonary embolism 29 days after resection for mSFTP. In-hospital morbidity was 5.7% overall, and 77% of patients with in-hospital morbidity had malignant tumors. Among the patients with bSFTP, 1 experienced acute respiratory distress syndrome and another had a transient ischemic attack. In the group with mSFTP, 7 patients experienced the following in-hospital complications: acute respiratory distress syndrome (n ⫽ 4), hemothorax (n ⫽ 1), deep vein thrombosis (n ⫽ 1), and delirium tremens (n ⫽ 1). Mean length of hospital stay was 11.5 ⫾ 4 days.
Long-Term Survival Median follow-up was 14 years. During follow-up, 32 patients died—10 with bSFTP and 22 with mSFTP. All 10 patients with bSFTP died of reasons unrelated to the tumor. Among the 22 patients with mSFTP, 9 died of recurrence, 1 of myocardial infarction, 1 of acute pulmonary embolism, 2 of multiple traumas, 1 of ovarian cancer, and 8 of unknown cause. The overall 5-, 10-, and 30-year survival rates were 86%, 77%, and 21%, respectively, with a median survival of 14 years (Fig 2). Long-term survival was better in the group
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Table 3. Factors Predicting Malignancy of Solitary Fibrous Tumor of the Pleura Factors Symptomatic, n (%) Diameter (cm), mean ⫾ SD Morphologic type Pedunculated, n (%) Sessile, n (%) Pleural location Parietal, n (%) Visceral, n (%) Locoregional spread Multifocal, n (%) Vena cava compression, n (%)
Benign
Malignant
Univariate p Value
Multivariate p Value
21 (23%) 6.4 ⫾ 4.8
39 (58%) 13.4 ⫾ 7.4
< 0.0001 < 0.0001
... < 0.0001
68 (75%) 22 (25%)
21 (31%) 46 (69%)
< 0.0001
< 0.0001
18 (20%) 72 (80%)
22 (33%) 45 (67%)
0.09
...
1 (1%) ...
13 (19%) 3
< 0.0001 0.04
0.03 ...
SD ⫽ standard deviation.
with bSFTP than in the group with mSFTP (5-year survival, 96% vs 68.1%; p ⬍ 0.001) (Fig 3). By univariate analysis, factors significantly associated with a lower long-term survival after resection for mSFTP were vena cava compression (p ⫽ 0.05), multifocal presentation (p ⫽ 0.04), resection larger than a wedge (p ⫽ 0.004), and recurrence (p ⫽ 0.003). By multivariate analysis, recurrence was the only factor significantly associated with lower survival (p ⫽ 0.02).
Recurrences Recurrences were noted in 15 (9.5%) of the 156 patients who survived beyond the postoperative period. Median time to diagnosis of recurrence was 29 months. Recurrences were significantly more common in mSFTP than in bSFTP (19% vs 1.3%, p ⬍ 0.0001). All recurrences had the same histologic features as the primary tumors. The recurrence was local in 10 (61%) patients and distant in 5 (39%). Of the 10 patients with local recurrences, 1 had a
100
77% 68%
80
Survival (%)
poor functional status contraindicating repeated resection. In the other 9 patients (2 with bSFTP and 7 with mSFTP), repeated resection was performed and no further recurrences were noted. Among these 9 patients, 1 underwent wedge pulmonary resection associated with vertebral resection for a local recurrence 11 years after video-assisted resection of a 10-cm mSFTP and was still alive at last follow-up 3 years later. Among the remaining 8 patients, we performed 4 multiple wedge resections, 3 simple wedge resections and 1 wedge resection extended to the diaphragm. Patients with distant recurrences were treated with radiation therapy and chemotherapy (n ⫽ 1), radiation therapy alone (n ⫽ 3), or chemotherapy alone (n ⫽ 1). Overall 5-year DFS was 82% (Fig 4). DFS was significantly better in the group with bSFTP than in the group with mSFTP (5-year DFS, 96% vs 59%; p ⬍ 0.0001) (Fig 5).
60
21%
40 20 0
0
At Risk (n) 75
10
20
30
16
1
b m
Years
50
Fig 2. Long-term overall survival of 157 patients after resection of solitary fibrous tumors of the pleura. Numbers of patients at risk are shown below the abscissa. The overall 5-, 10-, and 30-year survival rates were 86%, 77%, and 21%, respectively; median survival was 14 years.
Fig 3. Long-term overall survival according to histologic type. The overall 5-, 10-, and 30-year survival rates in patients with benign tumors were 96%, 87%, and 33%, respectively. Benign tumors had a better long-term survival than did malignant tumors (5-year survival, 96% vs 68.1%; p ⬍ 0.001). (bSFTP ⫽ benign solitary fibrous tumors of the pleura; mSFTP ⫽ malignant solitary fibrous tumors of the pleura; NS ⫽ not significant.)
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Disease free survival (%)
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81%
100
Table 4. Factors Associated With Tumor Recurrence
74%
80
62%
Variable
60
16%
40 20 0
0
At Risk (n) 74
10
20
30
17
1
Years
50
Fig 4. Long-term disease-free survival (DFS) in patients with solitary fibrous tumor of the pleura. Number of patients at risk is shown below the abscissa. Of 156 patients who survived beyond the postoperative period, 15 (9.5%; 13 with malignant and 2 with benign tumors) experienced recurrences after a median time of 29 months. Overall 5-, 10-, and 30-year DFS rates were 81%, 74%, and 16%, respectively.
Factors significantly associated with mSFTP recurrence were sessile morphologic type, resection larger than a wedge, and CD34-negative tumor (p ⫽ 0.005, p ⫽ 0.04, and p ⫽ 0.001, respectively) (Table 4).
Comment Our study shows that complete en bloc resection of SFTP can provide long-term survival with low postoperative
Disease free survival (%)
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100 80 60 40 20 0
0
10
20
30
Years bSFTP mSFTP Fig 5. Long-term disease-free survival (DFS) according to histologic type. Recurrences were more common among patients with malignant tumors than among those with benign tumors (5-year DFS, 94% vs 57%; p ⬍ 0.0001). (bSFTP ⫽ benign solitary fibrous tumors of the pleura; mSFTP ⫽ malignant solitary fibrous tumors of the pleura.)
Morphologic characteristics Size ⬎ 10 cm, n (%) Pedunculated, n (%) Sessile, n (%) Multifocal, n (%) Locoregional spread Parietal spread, n (%) Vena cava compression, n (%) Immunostaining CD34⫹, n (%) Surgical procedure Single wedge, n (%) Multiple wedges; other, n (%)
No Recurrence (n ⫽ 47)
Recurrence (n ⫽ 13)
15 (32%) 21 (45%) 26 (55%) 7 (15%)
4 (35%) 2 (15%) 11 (85%) 3 (23%)
0.72 0.05
5 (11%) ...
3 (20%) 3 (23%)
0.67 0.38
12 (80%)
5 (71%)
0.05
21 (45%) 26 (55%)
1 (7%) 12 (93%)
0.04
p Value
0.72
mortality and morbidity regardless of tumor size. Malignant tumors were associated with higher recurrence and mortality rates than were benign tumors. Repeated resection was associated with good outcomes after local recurrence of mSFTP. SFTP are uncommon neoplasms arising from the mesenchymal cells beneath the mesothelial lining of the pleura, as initially postulated by Klemperer and colleagues in 1931 [1]. SFTP was convincingly differentiated from pleural mesothelioma only after the introduction of immunochemical and electron microscopy techniques. Most SFTP are discovered fortuitously on standard chest roentgenograms obtained for another reason [4]. Symptoms are more common in mSFTP than in bSFTP and resolve after surgical resection [3, 5–7]. However there are no specific clinical or radiologic features to differentiate malignant from benign tumors. SFTP are usually large tumors containing clusters of various cell types that are scattered throughout the mass. This heterogeneous structure explains the unacceptably low diagnostic yield of CT-guided biopsy [8 –17]. Thus in our study, CTguided biopsy had a positive predictive value of only 39%. We believe that CT-guided biopsy should be considered only in patients with high surgical risk, patients with unresectable tumors, and patients needing extended operations. 18-Fluorodeoxyglucose positron emission tomography has also been found to be of limited diagnostic usefulness [4, 14, 18 –19]. Neither CT nor MRI reliably distinguishes mSFTP from bSFTP. Thus surgical treatment is usually performed before the benign or malignant nature of the tumor is determined. During the preoperative workup, special care should be taken to look for local spread to the mediastinum or chest wall, as well as distant metastases. MRI is particularly useful to rule out involvement of surrounding structures, mainly the spine in patients with posterior tumors [2, 9, 13, 20, 21]. Complete en bloc surgical lung-sparing resection is the
fundamental principle of oncologic thoracic surgical treatment. In our study, wedge resection was the most common surgical procedure. However, when needed, formal anatomic lung parenchymal resection (23 patients) or chest wall resection (9 patients) was performed. Video-assisted resection has been suggested for SFTP [22] and was used in our study in 20 patients with small tumors, 5 of whom required conversion to open surgical procedures to obtain R0 resection. Video-assisted resection may deserve consideration in patients with pedunculated SFTP that are smaller than 2 cm in diameter and show none of the criteria for malignancy provided that conversion to open procedures is performed if needed to achieve safe R0 resection. Incomplete resection is known to be associated with decreased survival in patients with mSFTP and with increased recurrence rates in those with bSFTP [2, 3, 9, 11, 14, 23, 24]. Even when R0 resection is achieved, recurrence remains the main risk factor for poor survival in patients with mSFTP. Recurrence rates in our study were 2.5% in the group with bSFTP and 19% in the group with mSFTP. These rates are consistent with recurrence rates reported after complete resection for SFTP (15%– 85%) [8, 12, 15, 18, 25, 26]. Long-term follow-up with CT every 6 months for 2 years and yearly thereafter is mandatory after complete resection [2, 11]. Long-term survival after bSFTP was excellent, with 96% of patients alive after 5 years. None of these patients died of SFTP. Survival in the group with mSFTP was lower, mainly because of local and general recurrences, with a 5-year survival rate of 68%. Repeated resection of local recurrences provided good outcomes, with no further recurrences. One patient underwent spine resection for a recurrence involving the intervertebral foramina. Thus extended procedures for local mSFTP recurrence may be warranted provided that R0 resection is possible. Close follow-up after resection for SFTP is crucial to ensure that recurrences are detected early. Despite the high local recurrence rate after resection for mSFTP, the role for adjuvant therapy remains controversial. To date, a multimodal therapeutic approach is not considered mandatory in patients with mSFTP. Radiation therapy is used routinely in patients with mSFTP if resection is not feasible or is incomplete. A sessile morphologic type, resection larger than a wedge, and CD34-negative tumor cells were significant risk factors for mSFTP recurrence (p ⫽ 0.005, p ⫽ 0.04, and p ⫽ 0.001, respectively). These characteristics may indicate a need for adjuvant therapy to decrease the recurrence rate. A sessile morphologic type is 1 of the SFTP classification criteria in the classification scheme developed by de Perrot and colleagues [2, 9] based on histologic and morphologic findings. Sessile mSFTP recurred in 63% of patients in their study, suggesting a need for adjuvant radiation therapy. CD34-negative immunostaining may reflect tumor dedifferentiation and a higher risk of recurrence [27–32]. Characteristics on immunochemical analysis and the extent of operation should be studied as additional criteria to be used in SFTP classification and patient selection for multimodality treatment. In conclusion, complete en bloc resection of SFTP
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provides excellent long-term survival with low postoperative morbidity and mortality and therefore remains the treatment of choice. Free-margin resection of bSFTP is curative. Recurrence is the main factor associated with poor survival after resection for mSFTP. Repeated resection is the best therapeutic option for local recurrences provided that complete resection is achieved. To date the role for adjuvant therapy remains controversial. Our findings suggest that mSFTP with sessile morphologic type, CD34-negative immunostaining results, or necessity for extended resection should be considered for adjuvant therapy to avoid recurrence.
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27. Fina L, Molgaard HV, Robertson D, et al. Expression of the CD34 gene in vascular endothelial cells. Blood 1990;75: 2417–26. 28. Flint A, Weiss SW. CD-34 and keratin expression distinguishes solitary fibrous tumor (fibrous mesothelioma) of pleura from desmoplastic mesothelioma. Hum Pathol 1995; 26:428 –31. 29. Nickoloff BJ. The human progenitor cell antigen (CD34) is localized on endothelial cells, dermal dendritic cells, and perifollicular cells in formalin-fixed normal skin, and on proliferating endothelial cells and stromal spindle-shaped cells in Kaposi’s sarcoma. Arch Dermatol 1991;127:523–9. 30. van de Rijn M, Lombard CM, Rouse RV. Expression of CD34 by solitary fibrous tumors of the pleura, mediastinum, and lung. Am J Surg Pathol 1994;18:814 –20. 31. Weiss SW, Nickoloff BJ. CD-34 is expressed by a distinctive cell population in peripheral nerve, nerve sheath tumors, and related lesions. Am J Surg Pathol 1993;17:1039 – 45. 32. Yokoi T, Tsuzuki T, Yatabe Y, et al. Solitary fibrous tumour: significance of p53 and CD34 immunoreactivity in its malignant transformation. Histopathology 1998;32:423–32.
Notice From the American Board of Thoracic Surgery Regarding Trainees and Candidates for Certification Who Are Called to Military Service Related to the War on Terrorism The Board appreciates the concern of those who have received emergency calls to military service. They may be assured that the Board will exercise the same sympathetic consideration as was given to candidates in recognition of their special contributions to their country during the Vietnam conflict and the Persian Gulf conflict with regard to applications, examinations, and interruption of training.
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If you have any questions about how this might affect you, please call the Board office at (312) 202-5900. John H. Calhoon, MD Chair The American Board of Thoracic Surgery
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