Ann Thorac Surg 2005;80:1847-1852
© 2005 The Society of Thoracic Surgeons
Original article: General thoracic
Pulmonary Resection for Metastatic Malignant Fibrous Histiocytoma: An Analysis of Prognostic Factors
Rakesh M. Suri, MD, DPhil
a
,
Claude Deschamps, MD
a
,
*
,
Stephen D. Cassivi, MD, MS
a
,
Francis C. Nichols, III, MD
a
,
Mark S. Allen, MD
a
,
Cathy D. Schleck, BS
b
,
Peter C. Pairolero, MD
a
a Division of General Thoracic Surgery, Mayo Clinic College of Medicine, Rochester, Minnesota
b Section of Biostatistics, Mayo Clinic College of Medicine, Rochester, Minnesota
Accepted for publication May 9, 2005.
* Address correspondence to Dr Deschamps, Division of General Thoracic Surgery, Mayo Clinic and Mayo Foundation, 200 First St SW, Rochester, MN 55905 (Email: deschamps.claude{at}mayo.edu).
Presented at the Poster Session of the Forty-first Annual Meeting of The Society of Thoracic Surgeons, Tampa, FL, Jan 24–26, 2005.
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Abstract
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BACKGROUND: Factors affecting recurrence and survival after pulmonary resection for metastatic malignant fibrous histiocytoma (MFH) are not well known.
METHODS: Records of patients undergoing pulmonary metastasectomy for MFH between January 1976 and January 2000 were analyzed.
RESULTS: There were 103 patients (46 men and 57 women). Median age was 60 years (range, 20 to 86). Malignant fibrous histiocytoma metastasis was solitary in 29 patients (28%), multiple/unilateral in 33 (32%), and multiple/bilateral in 41 (40%). Median time interval from primary tumor resection to metastasectomy was 11 months (range, 0 to 86). Wedge resection was carried out in 87 patients (84%), segmentectomy in 3 (3%), lobectomy in 3 (3%), pneumonectomy in 2 (2%), and a combination of resections in 8 (8%). Resection was complete in 93 patients (90%). Complications occurred in 11 patients (11%) and included prolonged air leak in 7, and pneumonia, empyema, atelectasis, and sepsis in 1 each. One patient died (operative mortality, 1%). Follow-up ranged from 2 weeks to 153 months (median, 18 months). Five-year survival was 21% (95% confidence interval, 14% to 31%). In the 103 patients, incomplete resection (p < 0.0001) was associated with decreased survival. Among the 93 patients with complete resection, factors associated with decreased survival included the presence of extrapulmonary disease at time of metastasectomy (p = 0.01), more than two nodules resected (p = 0.001), and adjuvant therapy after metastasectomy (p = 0.0007).
CONCLUSIONS: Pulmonary resection of metastatic MFH is safe. Improved survival was associated with the absence of extrapulmonary disease at time of metastasectomy, with fewer than three pulmonary nodules resected, and with a complete resection.
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Introduction
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Malignant fibrous histiocytoma (MFH) is the most common soft tissue sarcoma (STS) in adults [1]. Overall 5-year survival is approximately 20% to 40%, and the most common cause of death is disseminated disease. The lung is the most common site of distant metastases (5% to 40%) after resection of the primary tumor. Little information exists regarding factors associated with recurrence and survival after pulmonary resection of metastatic MFH. The purpose of this report is to review our experience in patients who underwent pulmonary metastasectomy for MFH.
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Patients and Methods
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From January 1, 1976, through January 1, 2000, all patients who underwent pulmonary resection for metastatic MFH at the Mayo Clinic in Rochester, Minnesota, were reviewed. Records were abstracted for age, sex, primary tumor histology, location, size, regional lymph node status, type and completeness of resection, operative morbidity and mortality, adjuvant therapy, local or regional recurrence, and survival. Operative deaths included patients who died within the first 30 days after surgery or during the same hospitalization. Follow-up data were acquired from review of the medical record. Recurrence rates were analyzed.
Patient survival and cumulative probability of tumor recurrence were both estimated using the Kaplan-Meier survival method [2]. Recurrence and survival were estimated starting at the date of the first pulmonary metastasectomy and are reported with 95% confidence intervals (95% CI). Univariate and multiple variable associations of potential risk factors with survival were assessed using the Cox proportional hazards regression model, with results reported as a hazard ratio and 95% CI [3]. For the endpoint of patient survival, recurrence was assessed for univariate association, considering these as time-dependent covariates in a Cox proportional hazards model. These time-dependent covariates were not considered in the multiple variable model for patient survival. All statistical tests were two-sided with an alpha level set at 0.05 for statistical significance. The Mayo Foundation Institutional Review Board granted approval for this study.
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Results
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There were 103 patients (46 men and 57 women; Table 1). Median age at the time of first pulmonary resection was 60 years and ranged from 20 to 86 years. The initial tumor was located in the lower extremity in 74 patients (72%), upper extremity in 17 (16%), trunk or retroperitoneal space in 9 (9%), and head and neck in 3 (3%). Radical resection was performed in 55 patients (53%) and local resection in 48 (47%). Resection was complete in 93 patients (90%). Median size of the primary tumor was 8.75 cm and ranged from 0.3 to 24 cm. Regional lymph nodes were involved in 2 patients. Cell type included fibrous pleomorphic in 47 patients (46%), myxoid in 3 (3%), giant cell in 2 (2%), and was not recorded in 51 (49%). The tumor was grade 1 in 2 patients, 2 in 5, 3 in 36, and 4 in 60. Sixty-seven patients (65%) had postoperative adjuvant therapy, which included chemotherapy in 13 (13%), radiation in 40 (39%), and both in 14 (14%).
The median time interval between resection of the primary tumor and detection of pulmonary metastasis was 11 months (range, 0 to 86). Ninety-nine patients (96%) were asymptomatic. Computed tomography of the chest was the primary method of diagnosis in 100 patients (97%). A preoperative needle biopsy was done in 9 patients (9%) and was diagnostic in 4 (4%). The site of the primary tumor was considered free of disease in 80 patients (78%). Twenty patients (19%) had local recurrence and 3 (3%) had liver metastases. Lung metastases were solitary in 29 patients (28%), multiple/unilateral in 33 (32%), and multiple/bilateral in 41 (40%). A posterolateral thoracotomy was done in 78 patients (76%), sternotomy in 22 (21%), and video-assisted thoracic surgery in 3 (3%). Eleven patients (11%) had staged bilateral thoracotomies. Median time interval between thoracotomies was 28 days (range, 6 to 48). The type of resection included multiple wedge resections in 61 patients (59%), single wedge in 26 (25%), segmentectomy in 3 (3%), lobectomy in 3 (3%), pneumonectomy in 2 (2%), bilobectomy in 1 (1%), and a combination in 7 (7%). The median number of metastatic nodules resected was 2 (range, 1 to 71 nodules). Cell type included fibrous in 92 patients (89%), myxoid in 4 (4%), giant cell in 2 (2%), and unknown in 5 (5%). Histologic grade of differentiation was classified as grade 2 in 2 patients (2%), 3 in 35 (34%), and 4 in 66 (64%). Locoregional lymph nodes were negative in 89 patients (86%), positive in 3 (3%), and unknown in 11 (11%). Resection of pulmonary metastatic disease was complete in 93 patients (90%).
Complications occurred in 11 patients (11%) and included a prolonged air leak in 7, and pneumonia, empyema, atelectasis, and a bronchopleural fistula in 1 patient each. One patient died (operative mortality, 1%) owing to sepsis caused by empyema secondary to a bronchopleural fistula. Median hospitalization was 6 days (range, 2 to 40). Forty-eight patients (47%) had postoperative adjuvant therapy. Forty-two patients (41%) had chemotherapy alone and 6 (6%) had a combination of both chemotherapy and external beam radiation therapy.
Follow-up was complete in patients discharged from the hospital and ranged from 2 weeks to 153 months (median, 18 months). Twenty-three patients were alive at last follow-up, 19 without evidence of recurrence, 2 with recurrence, and 2 with the status of their disease unknown. Eighty patients have died. Cause of death was MFH in 70, unrelated in 4 and unknown in 6. Overall 5-year survival after pulmonary metastasectomy in the 103 patients was 21% (95% CI, 14% to 31%) with a median survival of 19 months (Fig 1). A complete resection was associated with increased survival (p < 0.0001; Fig 2). In the 93 patients with complete resection of pulmonary metastases, the 1- and 5-year survival estimates were 75% (95% CI, 67% to 85%) and 22% (95% CI, 15% to 34%), respectively; median survival was 21 months. In the 10 patients with incomplete resection, the 1- and 5-year survival estimates were 20% (95% CI, 6% to 69%) and 0%, respectively; median survival was 5 months.
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Fig 1. Survival (death from any cause) in 103 patients who underwent resection (complete or incomplete) of metastatic pulmonary malignant fibrous histiocytoma compared with expected survival in a matched population. Zero time on abscissa represents date of first lung resection. Numbers at the bottom of the figure indicate patients at risks.
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Fig 2. Survival (death from any cause) in 93 patients who underwent complete resection compared with 10 who had incomplete resection of metastatic pulmonary malignant fibrous histiocytoma. Zero time on abscissa represents date of first lung resection. Numbers at the bottom of the figure indicate patients at risks.
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Among the 93 patients having a complete resection, factors adversely affecting survival with univariate analysis (Table 2) include presence of extrapulmonary disease at time of metastasectomy (p = 0.01; Fig 3), bilateral metastatic disease (p = 0.02; Fig 4), three or more metastatic nodules resected (p = 0.001; Fig 5), and postoperative adjuvant therapy after pulmonary metastasectomy (p = 0.0007; Fig 6, Table 2).
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Fig 3. Survival (death from any cause) in 73 patients who had the primary malignant fibrous histiocytoma controlled compared with 20 who did not have documented control before complete pulmonary resection. Zero time on abscissa represents date of first lung resection. Numbers at the bottom of the figure indicate patients at risks.
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Fig 4. Survival (death from any cause) in 33 patients who had bilateral malignant fibrous histiocytoma metastases compared with 31 who had only ipsilateral metastases and 29 who had solitary metastases. Zero time on abscissa represents date of first lung resection. Numbers at the bottom of the figure indicate patients at risks.
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Fig 5. Probability of survival (death from any cause) in 61 patients who underwent resection of 1 or 2 metastatic pulmonary malignant fibrous histiocytoma compared with 31 patients who underwent resection of three or more metastases. Zero time on abscissa represents date of first lung resection. Numbers at the bottom of the figure indicate patients at risks.
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Fig 6. Survival (death from any cause) in 43 patients who had adjuvant therapy compared with 50 who did not after complete resection of metastatic pulmonary malignant fibrous histiocytoma. Zero time on abscissa represents date of first lung resection. Numbers at the bottom of the figure indicate patients at risks.
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In a multiple variable model, those factors independently associated with decreased survival include included the presence of extrapulmonary disease at time of metastasectomy (p = 0.02), postoperative adjuvant therapy after pulmonary metastasectomy (p = 0.03), and three or more metastatic nodules resected (p = 0.006; Table 2).
Factors not significantly associated with survival included age (p = 0.50), sex (p = 0.50), type (p = 0.67), size (p = 0.65), upper location of primary tumor compared with lower (p = 0.55), other location of primary tumor compared with lower (p = 0.26), lymph node status at time of primary tumor resection (p = 0.35), histology (p = 0.71), grade (p = 0.96), surgical approach (p = 0.97), extent of resection of pulmonary metastases (p = 0.27), and disease-free interval (p = 0.28).
During follow-up, 68 patients (66%) developed recurrent pulmonary metastases. Factors affecting pulmonary recurrence with univariate analysis included younger age (p = 0.03), size of primary tumor (p = 0.04), presence of extrapulmonary disease at time of metastasectomy (p = 0.01), three or more metastatic nodules resected (p = 0.02), and postoperative adjuvant therapy after pulmonary metastasectomy (p = 0.01; Table 3). All of these factors were associated with an increased hazard for pulmonary recurrence. Forty-two patients (41%) underwent repeat pulmonary metastasectomy. Median time interval between the first pulmonary metastasectomy and the repeat resection was 8 months (range, 1 to 37). Five-year survival after repeat metastasectomy was 23% (95% CI, 13% to 42%) and median survival was 16 months.
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Comment
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Surgical resection of pulmonary metastases has been demonstrated to improve disease-free and overall survival, and is routinely performed with low perioperative risk [4, 5]. Although there have been no randomized trials testing the efficacy of metastasectomy in a prospective manner, retrospective reviews including two large multi-institutional studies have demonstrated an overall 5-year survival between 20% and 40% from all primary sites combined [4–7]. This is significantly greater than survival seen after either chemotherapy [8, 9] or radiation therapy alone [10–12].
Malignant fibrous histiocytoma is the most frequent STS in adults and commonly metastasizes to the lung. When all STS histologies are considered together, the resection of metastatic pulmonary lesions leads to median survival ranging between 19 and 24 months [13]. One study reported a median survival of 33 months in resected MFH patients. [14]. Our data compare favorably to the published experience. We found a 5-year survival of 21% and median survival of 19 months. In general, the determination of benefit from pulmonary metastasectomy is dependant upon the ability to ensure the following: (1) control of primary tumor, (2) resectability of pulmonary disease (anatomically and functionally), and (3) the absence of extrathoracic disease [15]. Despite these guidelines, there are exceptions: long-term survival has been shown after resection of both hepatic and pulmonary metastases from colorectal cancer [16]. Furthermore, even in the presence of unresectability, extirpation of pulmonary metastases may improve quality of life in selected patients [17]. Complete surgical resection of these lesions is the most significant predictor of survival. A large series of resected pulmonary STS metastases demonstrated a 5-year survival of 37%, while patients in whom pulmonary metastases were untreated had a 3-year survival of only 17% [13]. Our data demonstrate that incomplete resection of pulmonary metastases is associated with a poorer prognosis than when complete resection is achieved.
Several retrospective studies have identified patient and tumor factors affecting survival after pulmonary metastasectomy that include age, type of tumor, grade, location, disease-free interval, number of nodules, tumor doubling time, lesion resectability, and lymph node metastases [1, 13, 15]. The difficulty with these reports is that most evaluate biologically heterogeneous tumor patient populations, having little in common other than the presence of pulmonary metastasis [15]. Other investigators have applied subgroup analysis within a small cohort of related tumors such as patients with STS, in an attempt to compare similar groups. In 58 adults with STS undergoing pulmonary metastasectomy, Casson and colleagues [14] identified the presence of three or fewer nodules and MFH histology as the most important factors predicting survival.
We have identified predictors of decreased survival using both univariate and multivariate models. The histological grade of the primary tumor has been shown to correlate with the incidence of lung metastases [13]. Billingsley and coworkers [13] reported that 67% of MFH primary tumors were high grade and that 24% of treated patients subsequently developed lung metastases. We also identified higher grade tumor as an adverse independent risk factor affecting survival. The ability to achieve complete resection of both the primary tumor and of lung metastases has consistently been shown to be a significant prognostic factor for improved survival [1, 6, 7, 13].
Some of our patients failed to have the primary MFH controlled at the time of initial metastasectomy. These patients had a decreased survival in univariate analysis but the difference became nonsignificant in the multivariate model. In these patients, it was anticipated that the primary tumor would be resected in a curative fashion subsequently. The ability to completely resect pulmonary metastases is reported to range from 57% to 88% [1, 7, 14]. We were able to achieve complete resection in 93 patients (90%), which predicted improved survival in both models as compared with patients who had residual disease. Some authors have demonstrated that the presence of four or more metastatic nodules on preoperative imaging or at resection predicted decreased survival [14, 18]. Our findings of three or more pulmonary metastases adversely affecting survival is consistent with these reports. Contrary to other reports [13, 18], we found that the presence of bilateral metastatic disease also adversely impacted survival. Finally, patients selected to undergo post-metastasectomy chemotherapy or radiation therapy were less likely to survive. This observation might reflect selection bias in that patients with more aggressive tumors were more likely to receive adjuvant therapy.
Recurrent pulmonary metastases were found in two thirds of our patients and re-resection was possible in greater than half. Similar to others [1, 19], we have shown that long-term survival is possible after re-resection of MFH pulmonary metastases. Our 5-year survival after re-resection of pulmonary metastases was 23%. Although some risk factors for recurrence were the same as those for survival after the first pulmonary metastasectomy, we found that younger patients with larger primary tumors were more likely to experience intrathoracic recurrence after initial pulmonary metastasectomy.
As we have detailed in previous reports,wedge resection is our preferred procedure for pulmonary metastasectomy [16, 20]. Median sternotomy or staged bilateral thoracotomy is preferred for those patients with bilateral peripheral pulmonary metastases. We reserve more extensive anatomical resections (lobectomy/pneumonectomy) for patients where metastatic disease cannot be fully removed with a limited resection.
The limitations of this study include its retrospective design and the presence of referral bias. Although we had access to comprehensive preoperative assessments and follow up of those patients who underwent surgical therapy of the primary or lung metastases at other institutions, we are limited in our ability to accurately determine the number of surgically eligible patients at risk. Furthermore, those patients who underwent either adjuvant chemotherapy or re-resection represent a highly selected population for which observations can be made and statistical conclusions are limited. The true value of pulmonary metastasectomy will await a prospective trial.
In conclusion, pulmonary resection of metastatic MFH is safe and effective. Multiple factors affected survival after pulmonary metastasectomy for MFH. Improved survival occurs in patients in whom the primary tumor is controlled, with fewer than three pulmonary nodules resected, and who had complete resection. Repeat resection of recurrent pulmonary metastases in selected patients is warranted.
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The Society of Thoracic Surgeons Policy Action Center
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The Society of Thoracic Surgeons (STS) is pleased to announce a new member benefit—the STS Policy Action Center, a website that allows STS members to participate in change in Washington, DC. This easy, interactive, hassle-free site allows members to:
- • Personally contact legislators with one's input on key issues relevant to cardiothoracic surgery
- • Write and send an editorial opinion to one's local media
- • E-mail senators and representatives about upcoming medical liability reform legislation
- • Track congressional campaigns in one's district—and become involved
- • Research the proposed policies that help—or hurt— one's practice
- • Take action on behalf of cardiothoracic surgery
This website is now available at www.sts.org/takeaction.
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Abstract
Introduction
