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10.1245/s10434-006-9255-x
Annals of Surgical Oncology 14:1114-1122 (2007)
© 2007 Society of Surgical Oncology
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Original Article

Retroperitoneal and Truncal Sarcomas: Prognosis Depends Upon Type Not Location

Eduardo A. Perez, MD1, Juan C. Gutierrez, MD1, Frederick L. Moffat, Jr, MD1, Dido Franceschi, MD1, Alan S. Livingstone, MD1, Seth A. Spector, MD1, Joe U. Levi, MD1, Danny Sleeman, MD1 and Leonidas G. Koniaris, MD1,2

1 DeWitt Daughtry Family Department of Surgery, University of Miami Miller School of Medicine, Jackson Memorial Hospital, Miami, FL, USA
2 Alan Livingstone Chair in Surgical Oncology, University of Miami School of Medicine, 3550 Sylvester Comprehensive Cancer Center, 1475 NW 12th Ave, Miami, FL 33136, USA

Correspondence: Address correspondence and reprint requests to: Leonidas G. Koniaris, MD; E-mail: lkoniaris{at}med.miami.edu


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Background: Prognostication of truncal and retroperitoneal soft tissue sarcomas has traditionally been predicated on tumor location and grade.

Objective: To compare outcomes for patients with retroperitoneal or truncal sarcomas. Methods: Retrospective analysis of a prospective cancer data registry from 1977 to 2004 was performed and outcomes were determined.

Results: The study group numbered 312 patients (median age 58 years, 54% male, 56% Caucasian, 14% black, 29% Hispanic). The most common tumor types were liposarcoma (35.9%), leiomyosarcoma (30.1%), and malignant fibrous histiocytoma (MFH) (19.5%). Tumor distributions were retroperitoneal (38.9%), pelvic (24.7%), abdominal (18.6%) and thoracic (17.9%). Median overall survival was 74 months. Operative resection was undertaken in 89.4% of cases and multiple surgeries (range 2–5) in 42.2%. Negative resection margins were obtained in 72.7% of patients. Univariate analysis comparing retroperitoneal versus truncal location demonstrated no significant differences in survival. Survival was improved in lower grade tumors (P < 0.02). Liposarcoma and fibrosarcoma were associated with improved survival (P < 0.0001). Multivariate analysis of pre-treatment variables showed increasing age, grade, histopathology (leiomyosarcoma and MFH) and metastasis to be associated with worse outcomes. Multivariate analysis of the treatment variables showed that surgery and negative resection margins were associated with improved survival (P < 0.001). No advantage for chemoradiotherapy could be demonstrated.

Conclusions: Successful operative resection can confer prolonged disease-free survival and cure for truncal and retroperitoneal sarcomas. Histological subtype, not location, is predictive of long-term survival. Future studies should focus on histological subtype rather than tumor location for truncal and retroperitoneal sarcomas.

Key Words: Review • Sarcoma • Outcomes • Chemotheraphy • Radiation • Surgery


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Soft tissue sarcomas of the trunk and retroperitoneum are an uncommon, heterogeneous group of mesenchymal neoplasms arising from non-epithelial connective tissue sources. Sarcomas in these locations are less common than sarcomas arising in the extremities and together account for approximately one-third of all sarcomas.1,2 Historically, surgery has been the linchpin of treatment for soft tissue sarcomas in all sites alone or, in the setting of limb-sparing surgery, in combination with adjuvant and neoadjuvant radiotherapy.2,3

Accurate prognostication in sarcoma patients has been frustrated by large variations in tumor biology, stage at presentation and the relative rarity of these tumors. Determination of prognosis of truncal and retroperitoneal soft tissue sarcomas has usually been stratified by tumor location, primary tumor grade and size, and several staging systems based on these variables are now in use.4,5 The AJCC cancer staging system is a prime example, ignoring as it does the influence of histological subtype.4–6 However, histological subtype, expression of various antigenic markers and specific genetic mutations are known to influence the biological behavior of sarcomas. Several types of sarcomas have been reported to demonstrate different biological behaviors.7,8 In GIST, a marked prolongation in survival is observed with activation mutations in the type III tyrosine kinase pathway and treatment with imatinib mesylate.9–11 These recent developments demonstrate that sarcoma treatment can be morphology-specific irrespective of other variables such as location, supporting the premise that study of soft tissue neoplasms should take histological subtype into account.12

Stratification of sarcomas by histology may offer distinct advantages for determination of prognosis and treatment. Prospective randomized trials in which all histological subtypes are eligible for inclusion will fail to detect the benefit of a chemoradiotherapeutic regimen or other treatment modality with activity in only one or a restricted range of sarcoma histologies.13 We therefore report our experience with truncal and retroperitoneal sarcomas, comparing outcomes, the effects of surgery, and adjuvant therapy by histological subtype and location. Our data suggest that outcomes of truncal and retroperitoneal sarcomas are similar, but vary greatly by histology and treatment modality.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
The study was approved by the Human Subjects Research Committee at the University of Miami Hospital and Clinics and Jackson Memorial Hospital. The Tumor Registries of the University of Miami Sylvester Cancer Center and Jackson Memorial Hospital have prospectively collected sarcoma cases since 1977, and include detailed information on histological subtypes. This unduplicated data set was queried for sarcomas of the trunk and retroperitoneum using ICD-9 codes 8800, 8801, 8803, 8805, 8806, 8810, 8811, 8830, 8832, 8850, 8851, 8852, 8853, 8854, 8858, 8860, 8890, 8891, 8894, 8900, 8901, 8910, 8920, 8935, 8936, 8990, 9220, 9490, 9560. The classification of tumors into truncal and retroperitoneal groups was made following ICD-O-3 topography codes C49.3, C49.4, C49.5 and C49.6 for truncal tumors and C48.0, C48.1,C48.2 and C48.8 for retroperitoneal tumors. All data were secondarily confirmed by review of the medical records for the appropriate information. Tumors involving the shoulder girdle or hip joint were not included in the analysis. As no recent major advances in truncal and retroperitoneal sarcoma therapy have occurred other than improvement in perioperative management, we included soft tissue sarcomas over the entire time period rather than limiting our analysis to more recent experience only. Angiosarcomas, cystosarcomas, desmoid tumors and Kaposi sarcomas were excluded. Among patients aged 18 years or older, a total of 312 consecutive sarcoma cases were identified and analyzed.

Medical records examined included initial clinic notes, radiographic images, operative and pathology reports, and progress notes. Survival was determined by the tumor registries and independently verified during data collection by an internet-based search which included examination of the National Death Index. Patients lost to follow-up were censored at the time of last contact. Survival was calculated from the time of initial diagnosis to the date of last contact (or death, if the patient was deceased).

Statistical analysis was performed with SPSS 13.0 (SPSS Inc., Chicago, IL). Results are expressed as median values and 5-, 10- and 20-year survival. Only the percentages based on available data for each individual variable are given. Patients with missing data were excluded from each respective univariate and multivariate analysis. Survival in univariate analysis was measured by the Kaplan–Meier method. The log-rank test was used to compare survival within the variables studied. The Cox proportional hazards model utilizing a step backward method was used for multivariate analysis of prognostic factors determined to be significant in the univariate analysis. Statistical significance was defined as P < 0.05.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Patient Demographics
Demographics of the patients reported here are summarized in Table 1Go. Males predominated slightly by 54%, and the median age of the entire group was 58 years. White, non-Hispanic patients made up 56% of the cohort, Hispanic patients 29% and black non-Hispanic patients 14%. In 70% of the patients the initial surgical resection was performed at this medical center, the remainder presenting with recurrent disease after having undergone their primary surgery elsewhere.


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  		TABLE 1. Demographics of dataset
 
Outcomes for Truncal versus Retroperitoneal Sarcoma Are Similar
Median survival of the 188 truncal and 122 retroperitoneal sarcomas in this series is compared in Table 2Go. Two tumors had both peritoneal and retroperitoneal components and were excluded from location-related analysis. There was a trend toward larger tumors and a lower frequency of margin-negative resections in the retroperitoneal group that did not reach statistical significance. Kaplan–Meier survival was calculated for the entire series (Fig. 1AGo) and then stratified for truncal and retroperitoneal sarcomas (Fig. 1BGo). No significant difference in survival was observed between patients with truncal and retroperitoneal sarcomas (median survival 69 months for truncal versus 78 months for retroperitoneal tumors; P = 0.668). In light of this, univariate analysis was performed on pooled data from the entire series to identify significant predictors of outcomes.


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  		TABLE 2. Comparison of truncal versus retroperitoneal sarcomas
 

Figure 1
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  		FIG. 1. A Overall Kaplan–Meier survival curves for all patients with soft tissue sarcomas; B Kaplan–Meier survival curves by truncal or retroperitoneal location.

 
Outcomes for Truncal and Retroperitoneal Sarcoma
The results of univariate analysis of the effect of demographic, histopathological and therapeutic variables on median, 5-, 10- and 20-year survival are enumerated in Table 3Go. In this series, histological subtype was a significant predictor of outcome. High tumor grade, involved regional lymph nodes, the presence of metastases, positive surgical margins (grossly and microscopically positive) and the use of neoadjuvant or adjuvant chemotherapy all portended significantly poorer outcomes.


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  		TABLE 3. Patient demographics including median, 5-, 10- and 20-year survival
 
Kaplan–Meier survival by histological subtype is shown in Fig. 2Go. Overall the best prognosis was observed for liposarcoma and fibrosarcoma. The lowest survival was observed in patients with leiomyosarcoma and MFH.


Figure 2
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  		FIG. 2. A Kaplan–Meier survival curves by histological subtype; B pooled Kaplan–Meier survival curves for poor versus improved survival sarcoma histology groups.

 
Kaplan–Meier survival curves by tumor grade and by number of surgeries (single versus multiple) are shown in Fig. 3A and BGo, respectively. Grade had a highly significant impact on survival, while patients with multiple surgeries were subject to a late excess mortality that did not reach significance (P = 0.153) as compared to those undergoing a single resection.


Figure 3
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  		FIG. 3. Kaplan–Meier survival curves by A grade, and B number of resections.

 
Outcomes by Adequacy of Surgery
In Table 4Go an analysis is presented of median, 5-, 10- and 20-year survival, stratifying for surgical margin status and whether or not surgical resection was performed. Kaplan–Meier analysis of these data is presented in Fig. 4Go. Although patients with negative resection margins tended towards a higher median survival as compared to those with microscopically positive margins, this did not reach statistical significance (P = 0.252). Superior survival was observed in patients with either negative or microscopically positive margins, as compared to those with grossly positive margins or in whom resection was not performed (P < 0.001). However, even patients with grossly positive margins fared significantly better than those who did not undergo a surgical resection (P = 0.016).


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  		TABLE 4. Median survival, 5-, 10- and 20-year survival by resection quality
 

Figure 4
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  		FIG. 4. Kaplan–Meier survival curves by resection quality.

 
Do Any Subsets of Sarcoma Patients Benefit from Radiation Therapy or Chemotherapy?
In a subset analysis of the effect of radiation therapy and cytotoxic chemotherapy on survival, no difference was noted between truncal and retroperitoneal sarcomas. However, as shown in Tables 5Go and 6Go, among histological subtypes there was a trend toward improved survival associated with radiotherapy in patients with liposarcomas (median survival 121 versus 86 months; P = 0.2139). Median survival of patients with fibrosarcoma tended to improve with chemotherapy (133 versus 57 months; P = 0.091) while in patients with leiomyosarcoma survival was significantly poorer (19 versus 78 months; P = 0.014). Chemotherapy treatment also tended toward poorer survival among patients with liposarcoma (76 versus 112 months; P = 0.075). These results would suggest significant differences between histological subtypes of sarcomas with respect to tumor biology and chemosensitivity. For patients with positive macroscopic margins, a trend toward improved survival was seen (median survival 24 versus 10 months, P = 0.136) with radiation.


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  		TABLE 5. Comparison of outcomes for patients with adjuvant radiation versus no radiation
 

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  		TABLE 6. Comparison of outcomes for patients who received chemotherapy versus no chemotherapy
 
Multivariate Analysis
Variables which significantly affected survival in the univariate analysis reported above were further studied in a step-wise multivariate analysis using the Cox regression model (Table 7Go). Among the pre-operative variables, increasing age, higher grade, histopathology [leiomyosarcoma and malignant fibrous histiocytoma (MFH)] and the presence of metastasis were independently associated with poorer overall survival. Surgical excision alone, as well as surgery yielding either negative or microscopically positive margins independently predicted improved survival. The use of chemotherapy in the multivariate analysis was an independent predictor of poor out-come. Sarcoma type trended toward significance as an independent predictor of survival but did not reach statistical significance (P = 0.084).


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  		TABLE 7. Significant independent and treatment variables predictive of survival by multivariate analysis
 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
In this institutional series of 312 truncal and retroperitoneal sarcomas, we report overall 5-, 10-, and 20-year survival of 55, 37, and 17%, respectively. Multivariate analysis identified increasing age, higher grade, histopathology (leiomyosarcoma and MFH), and the presence of metastatic disease as independent variables predictive of poorer outcomes. Significant independent treatment variables identified in the multivariate analysis as portending a poor prognosis included omission of surgical resection, grossly positive surgical margins and the use of chemotherapy. Outcome was not affected in either univariate or multivariate analysis by tumor location (trunk or retroperitoneum). Oda et al.14 made similar observations in a retrospective review of 290 cases of MFH, identifying tumor depth and AJCC stage as the most important predictive prognostic factors, with tumor location having no influence on survival. In a report of 267 cases of leiomyosarcoma, Miyajima et al.15 found no correlation between tumor location and survival, with tumor size and AJCC stage being the only statistically significant prognostic factors. In our series, there was no significant difference between truncal and retroperitoneal sarcomas in all the variables studied. We therefore considered the possibility that histology rather than location of the tumor may be an important discriminator of outcome.

The relevance of this concept is underscored by recent developments in the treatment of GIST tumors. These tumors clearly have distinct biological behavior, similar outcomes in many locations, and are uniquely responsive to inhibitors of type III tyrosine kinase16. In stratifying our series by histological subtype, dramatically different survival curves were obtained, suggesting that histology-specific biological behavior, exemplified by recent advances in the management of GIST tumors, may be operative for other soft tissue sarcoma histologies.

Tumor location or site (truncal, retroperitoneal, other sites) has historically ranked prominently among prognostic factors for soft tissue sarcomas. The importance of tumor grade and surgical margin status has repeatedly been demonstrated by multivariate analysis as a predictor of survival for all tumor sites.17–22 Some studies have reported tumor size to be a significant predictor of outcome. In our analysis, tumor size did not reach statistical significance as a prognostic factor. Singer et al.20 reporting on 182 consecutive sarcomas of the trunk and retroperitoneum, identified important prognostic differences between truncal and retroperitoneal sarcomas. Microscopic or grossly positive resection margins and high-grade histology were negative predictors of survival in this analysis. Size was predictive of survival in truncal but not retroperitoneal sarcomas.

In a retrospective single institution report of 720 liposarcomas, Linehan et al.23 underscored the importance of local control in the prognosis of both retroperitoneal and visceral tumors. Our results imply that there is no difference in outcome between truncal and retroperitoneal sarcomas attributable to tumor site alone, and that truncal and retroperitoneal sarcomas could be considered as one entity. However, sarcoma histology in these locations was shown to have a very significant effect on survival. In a series of 167 patients treated at a single institution, Gronchi et al.24 showed that histologic subtype appeared to influence the pattern of tumor recurrence, which mainly was local for patients with liposarcoma but was both local and distant for patients with other histologic subtypes. Our data support consideration of soft tissue sarcomas arising in these two locations as one entity, with risk stratification based primarily on tumor grade, stage, histological subtype, and the status of surgical margins. There was very significant variation in survival between histologies, the most favorable histology being liposarcoma and the worst MFH. It will be critical, nonetheless, to confirm these findings in other independent data sets.

In the report by Singer et al.25, post-operative irradiation of truncal lesions eventuated in a 2.4-fold reduction in mortality, as compared to no survival benefit in patients with retroperitoneal sarcomas. Among retroperitoneal sarcomas, microscopic or grossly positive margins and intermediate or high-grade histology were associated with decreased survival, whereas tumor size did not affect outcome. In a single-institution report of retroperitoneal soft tissue sarcomas, Gilbeau et al.26 demonstrated a high local recurrence rate in patients treated with post-operative radiotherapy, with no significant improvement in survival.26

A recent meta-analysis of the pertinent literature regarding retroperitoneal soft tissue sarcomas also failed to show a significant radiotherapy-related survival benefit27. In our series, the number of cases with grossly positive surgical margins was small. Improved survival was observed among those who underwent adjuvant radiotherapy to the tumor bed. The role of radiotherapy in the management of retroperitoneal sarcoma is being addressed in the ACOSOG Z9031 trial.

Our results are concordant with those of previous reports that patients with axial sarcomas treated with pre-operative or post-operative chemotherapy may have increased cancer mortality. This was demonstrated in both univariate and stepwise multivariate analyses, suggesting that worse outcomes associated with chemotherapy cannot be ascribed to other independent variables such as grade.

The goal of any staging schema is to provide prognostic information to physicians and patients as well as a frame of reference for evaluation of treatment and outcome. Our analysis suggests that sarcomas of the trunk and retroperitoneum have a distinct prognosis based upon histological subtype, not location. Differences in outcome observed in patients treated with radiotherapy and chemotherapy tended to cluster in a few histological subtypes. We suggest that trials analyzing the prognosis of sarcomas by location have been insufficiently powered to detect important differences between sarcoma histologies which may bear on responsiveness to radiotherapy or cytotoxic chemotherapy.

In conclusion, this large single-institution series demonstrates long-term survival and cure for axial soft tissue sarcomas following surgical resection. Sarcomas of the trunk and retroperitoneum are prognostically similar, survival being primarily dependent on grade, stage and histologic subtype. As no clear benefit has been demonstrated with either adjuvant radiation therapy or chemotherapy, alternative trial designs that place a greater emphasis on histological subtype appear warranted.

Received for publication March 7, 2006. Accepted for publication September 25, 2006.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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