World J Surg DOI 10.1007/s00268-015-3038-0
ORIGINAL SCIENTIFIC REPORT
Visceral Fat Content Correlates with Retroperitoneal Soft Tissue Sarcoma (STS) Local Recurrence and Survival Michail Papoulas1 • Roi Weiser1 • Galia Rosen2 • Fabian Gerstenhaber1 Ofer Merimsky3 • Nir Lubezky1 • Joseph M. Klausner1 • Guy Lahat1
•
Ó Socie´te´ Internationale de Chirurgie 2015
Abstract Background Our aim was to evaluate the association between visceral fat content with soft tissue sarcoma (STS) local recurrence and survival. Methods One hundred and one computed tomography imaging studies of primary STS patients who had complete macroscopic resection at our institution between 2002 and 2012 were reviewed, and retroperitoneal and circumferential fat contents were measured. Correlations between imaging findings and clinical data were analyzed. Results Fifty-seven STS tumors (56.4 %) were retroperitoneal; of them, 65 % were high grade, median size was 15 cm (range 3–49), and the most common histological subtype was high grade liposarcoma (31.6 %). Median follow-up length for the entire cohort was 64 months (range 6–95). High visceral fat (VF) content C15 versus \15 mm was identified as a risk factor for retroperitoneal STS local recurrence; 65.1 versus 26.7 %, respectively (p = 0.04); VF content did not correlate with distant metastasis. Median overall survival (OS) length of patients with VF C15 versus \15 mm was 57 months (range 2–144) versus not reached, respectively (p = 0.007). Multivariable analysis identified VF C15 mm as an independent risk factor for decreased OS (HR: 4.2, 95 % CI 1.07–16.67). In contrast, circumferential fat content did not correlate with retroperitoneal STS patient outcomes. Conclusion High VF content is an independent adverse prognosticator associated with significantly higher rates of retroperitoneal STS local recurrence and decreased patients survival. Local tumor biology may be affected by the presence of adipose cells. Further clinical and molecular research is needed to establish this premise.
Introduction & Michail Papoulas [email protected] 1
Department of Surgery, The Sourasky Medical Center, Sackler School of Medicine, Tel-Aviv University, 6 Weitzman St., Tel-Aviv, Israel
2
Department of Radiology, The Sourasky Medical Center, Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel
3
Department of Oncology, The Sourasky Medical Center, Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel
Approximately, two-thirds of adult population in developed countries is categorized as overweight or obese [1] and their high propensity for cardiovascular diseases is well established [2–7]; in addition, substantial evidence has been provided in recent years as to the correlation between obesity and cancer [4, 5, 8–12]. Data demonstrate that high body mass index (BMI) and visceral fat (VF) content in particular are associated with increased risk of various cancer types development as well as inferior outcomes [13–15]. Moreover, numerous studies have showed that
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pro-tumorigenic molecules secreted by adipocytes enhance tumor cell proliferation, migration, and invasion [16]. These adipokines (i.e., leptin, adiponectin, etc.) may have systemic as well as local effects which induce cancer progression and metastasis [17–19]. Soft tissue sarcoma (STS) is a rare and heterogenic group of tumors accounting for less than one percent of adult solid tumors [20]. STS patients have a dismal prognosis with a 5-year survival rate of only 50 %, reflecting the relative disease’s propensity for local recurrence and distant metastasis [21]. These tumors can arise in any anatomic location, mostly in the extremities and the retroperitoneum (RSTS), often in close vicinity to adipose tissue. While the association between obesity and cancer has been established in a variety of solid tumors, the link between obesity and STS has not been described. We sought to evaluate whether increased VF content is associated with STS patients’ adverse prognosis.
Fig. 1 a Leiomyosarcoma involving the IVC in a 37-year-old male. b Vertical distance between the left posterior renal capsule and the junction of the abdominal wall and paraspinal musculature at the level of the left renal vein
Methods The study was approved by our institutional review board to be in accordance with the Declaration of Helsinki and a waiver of consent was granted for the proposed patient record review including imaging publication. The medical records of primary STS patients (n = 108) who had complete macroscopic resection at our institution between January 2002 and December 2010 were identified and evaluated. Patients with incomplete data (clinical or imaging) were excluded (n = 7); 101 patients were included in the study cohort. Clinical, imaging, and pathological data of all patients were retrospectively reviewed. All patients were evaluated preoperatively with computed tomography (CT), operated on with an intention to cure, and remained in active clinical follow-up through our out-patient clinic. Some patients were treated with systemic chemotherapy and/or radiation in accordance with the physician recommendations of the multidisciplinary planning conference. The recommendations for surgical, chemotherapeutic, and radiation treatments were based on an evaluation of clinical prognostic factors. The following demographics and clinicopathological features were included in the analysis: gender, age, primary site, tumor size, disease grade, and histology. Treatment and outcomes characteristics of all patients were evaluated; perioperative mortality (60-day or in-hospital mortality), adjuvant treatment (chemotherapy, radiation), recurrence, and long-term survival were reviewed and included in the present analysis. Preoperative CT imaging studies were reviewed by a senior radiologist (RG) and the author (PM) who were blinded to the patients’ clinical data and postoperative outcome. BMI, circumferential fat (CF), and VF diameter
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were measured. VF content was measured as previously described [22]. Briefly, VF content was measured as the vertical distance between the left posterior renal capsule and the junction of the abdominal wall and paraspinal musculature at the level of the left renal vein, and this served as a proxy for quantity of visceral fat (Fig. 1). All measurements were based on the unaffected retroperitoneal side. Patients with left kidney atrophy, large cysts, or masses that displace unilaterally the parenchyma underwent the same measurements in the right kidney. Patients with large, bilateral retroperitoneal STS tumors displacing both kidneys were excluded from the study cohort.
Statistical analysis VF content was normally distributed, ranging between 0 and 36.7 mm; the 15 mm cutoff represents the mean VF, as measured in the present series. Patients were categorized into two groups of visceral fat with the mean VF diameter used as a cutoff point (C15 vs. \15 mm). Independent predictors of overall survival (OS) were then evaluated using Cox proportional hazards regression. Missing data points were included in the analysis by assigning a specific category for missing data in order to maximize the number of patients included in the model. Variables for the final model were chosen based on whether they remained significant independent predictors of survival after adjusting for the variables forced into the model. Local recurrencefree survival (time from surgery to time of clinical evidence of local relapse) and OS (time from surgery until death, regardless of cause) were estimated by the method
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of Kaplan–Meier, and the log-rank test was used to compare survival curves. Patients were censored as of their last follow-up visit if they were alive and/or disease-free throughout the study period. All tests were two sided. For all tests, statistical significance was defined by p \ 0.05. Data were analyzed with the SPSS 17 statistical software.
Results Patients and tumor characteristics A total of 101 primary STS patients who had complete macroscopic resection at our institution are included in the study cohort; Table 1 depicts their clinical and pathological
characteristics. There were 48 men (47.5 %) and 53 (52.5 %) women; median age at the time of surgery was 60 years (range 18–83). Fifty-seven STS tumors (56.4 %) were located in the RSTS, 34 (23.6 %) in the extremities, and the remaining (n = 10, 5 %) were truncal; the majority (n = 78, 77.2 %) were high grade. Overall, the most common histological subtype was undifferentiated pleomorphic sarcoma (UPS; 32.7 %); however, in the subgroup of retroperitoneal STS patients, the most common histological subtype was high-grade liposarcoma (n = 18; 31.6 %) followed by leiomyosarcoma (n = 16; 28.1 %). Most tumors (n = 84; 83.1 %) were larger than 5 cm, 30.7 % (n = 31) were larger than 15 cm. Treatment and outcomes characteristics
Whole cohort n (%)
RSTS n (%)
Non-RSTS (%)
All patients had complete macroscopic resection at our institution; Table 2 depicts their treatment and outcome characteristics. Of them, 22 (21.7 %) had positive microscopic margins (R1 resection). Most STS patients (n = 64;
No
50 (49.5)
33 (57.9)
17 (38.6)
Table 2 Treatment and outcome characteristics
Yes
51 (50.5)
24 (42.1)
27 (61.4)
Female
53 (52.5)
32 (56.1)
21 (47.7)
Male
48 (47.5)
25 (43.9)
23 (52.3)
C15 mm
51 (50.5)
33 (57.9)
18 (40.9)
\15 mm
50 (49.5)
24 (42.1)
26 (59.1)
Table 1 Clinical and pathological characteristics Characteristics Age C60 years
Sex
VF
Primary site Extremity Retroperitoneal
34 (33.6) 57 (56.4)
Truncal
10 (10)
57 (100)
34 (77.3) 0 10 (22.7)
Tumor size 0–5 cm
12 (11.9)
3 (5.3)
9 (20.5)
5–10 cm
38 (37.6)
14 (24.6)
24 (54.5)
10–15 cm
15 (14.8)
13(22.8)
2 (4.5)
C15 cm
31 (30.7)
22 (38.6)
9 (20.5)
Unknown
5 (5)
5 (8.7)
0
G1
19 (18.8)
17 (29.8)
2 (4.5)
G2
4 (4)
3 (5.3)
1 (2.2)
G3
78 (77.2)
37 (64.9)
41 (93.3)
UPS
33 (32.7)
6 (10.5)
27 (61.4)
Leiomyosarcoma
19 (18.8)
16 (28.1)
3 (6.8)
Well differentiated LPS High grade LPS
12 (9.9) 26 (25.7)
12 (21.1) 18 (31.6)
0 8 (18.2)
Other
11 (10.9)
5 (8.7)
6 (13.6)
Disease grade
Histology
RSTS retroperitoneal STS, VF visceral fat distance, UPS undifferentiated pleomorphic sarcoma (including malignant fibrous histiocytoma and undifferentiated sarcoma), LPS liposarcoma
Characteristics
Whole cohort n (%)
RSTS n(%)
NonRSTS
26 (59.1)
Surgery Complete macroscopic resection
101 (100)
Microscopic margins Negative
71 (70.2)
45 (78.9)
Positive
22 (21.7)
11 (19.3)
11 (25)
Unknown
8 (4.1)
1 (1.8)
3 (6.9)
Chemotherapy No
64 (63.3)
39 (68.4)
25 (56.8)
Yes
29 (28.7)
15 (26.3)
14 (31.8)
Unknown
8 (8.8)
3 (5.3)
5 (11.4)
No
43 (42.6)
33 (57.9)
10 (22.7)
Yes
35 (34.6)
5 (8.7)
20 (45.5)
Unknown
23 (22.8)
19 (33.4)
4 (9.1)
No
42 (41.6)
27 (47.3)
15 (34.1)
Yes
52 (51.5)
28 (49.1)
24 (54.5)
Unknown
7 (6.9)
2 (3.6)
5 (11.4)
No
54 (53.4)
31 (54.4)
23 (52.3)
Yes
41 (40.5)
24 (42.1)
17 (38.6)
6 (9.9)
2 (3.5)
4 (9.1)
No
60 (59.4)
33 (70.2)
27 (61.5)
Yes
35 (34.5)
12 (25.6)
23 (52.4)
Unknown
6 (9.9)
2 (4.2)
4 (9.1)
Radiation
Recurrence
Local recurrence
Unknown Distant metastasis
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Fig. 2 a Overall survival in all primary STS patients (n = 91) by VF content \15 mm (blue line) versus C15 mm (green line) as a function of time from surgery. b Local recurrence in primary RSTS patients (n = 47) by VF content\15 mm (blue line) versus C15 mm (green line) as a function of time from surgery. c Overall survival in
primary RSTS patients (n = 47) by VF content \15 mm (blue line) versus C15 mm (green line) as a function of time from surgery. d Local recurrence in primary RSTS patients who had R0 resection (n = 37) by VF content \15 mm (blue line) versus C15 mm (green line) as a function of time from surgery
63.3 %) who had surgery at our institution were not treated with systemic chemotherapy, nearly one-third (n = 35; 34.6 %) were irradiated; however, only five of them were treated for RSTS. Median follow-up time for the entire cohort was 64 months, (range 6–95). Recurrence was documented in approximately half of the patients; 40.5 % (n = 41) experienced local recurrence, 34.5 % (n = 35) had distant metastasis. Recurrence patterns of both RSTS and nonRSTS patients did not significantly differ. Five- year
recurrence-free survival (RFS) and OS rates for the cohort of RSTS and non-RSTS patients were 59.5 % and 64.7 versus 66.6 % and 80.1 %, respectively.
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Visceral fat measurement Preoperative CT imaging was used to measure distance from the posterior pole of the kidney to the abdominal wall musculature as a surrogate for visceral fat as previously described [22]; imaging was available for all patients
World J Surg Table 3 Multivariable analysis of overall survival and local recurrence free survival of primary RSTS patients who had complete macroscopic resection Variables
Level
HR (95 % CI)
p value
Tumor grade
High versus low
4.44 (1.04–20.93)
0.05
Tumor size
C15 versus \ 10 cm
4.2 (1.25–16.88)
0.01
VF content Microscopic margins
C15 versus \15 mm Positive versus negative
3.44 (0.99–11.94) 2.26 (0.92–5.58)
0.04 0.08
Age
Continuous (in 10 years increments)
1.32 (0.87–3.55)
0.23
Histological subtype
LPS versus non- LPS
0.76 (0.18–1.90)
0.35
Bold values are statistically significant (p \ 0.05) HR hazard ratio, CI confidence interval, VF visceral fat, LPS liposarcoma
included in the study cohort. Mean VF distance was 15 ± 3.2 mm. Patients were divided into two groups based on measured quantity of visceral fat: VF C15 mm (n = 51) and VF \15 mm (n = 50). Kaplan–Meir OS analysis did not show that STS patients who had VF C15 versus VF \15 mm survived longer (p = 0.155; Fig. 2a); moreover, VF C15 mm did not emerge as an independent predictor of OS in the multivariable analysis for the whole cohort of STS patients. Next, we performed a subset analysis for the cohort of RSTS patients (n = 57); median LRFS (local recurrence-free survival) and OS rates for RSTS patients with VF C15 versus VF \15 mm were 25.4 months versus not reached (p = 0.004; Fig. 2b) and 57 months versus. not reached (p = 0.007), respectively, (Fig. 2c) suggesting that increased visceral fat content may have a local rather than a systemic effect on tumor behavior. In the multivariable analysis, disease grade (high vs. low), large tumor size (C15 cm), and VF C15 mm (HR 3.44, 95 % CI 0.99–11.94) emerged as statistically significant independent adverse prognostic factors of OS. Variables including age, histological type (LPS vs. non LPS), and microscopic margins (positive vs. negative) did not emerge as independent predictors of OS/LRFS (Table 3). No correlation between circumferential fat (CF) content and OS/LRFS was found (data not shown). Increased fat content in the RSTS might affect, at least in part, the ability of the surgeon to achieve negative margins resulting in inferior oncological outcomes. Therefore, we further analyzed the subgroup of RSTS patients who had complete microscopic resection (R0 resection; n = 45). As shown in our subset analysis (Fig. 2d), high VF content remained a significant prognosticator of LRFS in the of R0 resection cohort of RSTS patients.
Discussion Sarcoma treatment presents a number of challenges to both the oncologist and the surgeon. In the absence of efficient chemotherapy and the limited effect of radiotherapy in
most STS histological subtypes, radical resection with negative microscopic margins remains the mainstay of its therapy [23, 24]. Nevertheless, in spite of adequate surgery and a multidisciplinary therapeutic approach, the prognosis of STS patients is poor, with high rates of local recurrence and mortality [23–27]. Extensive effort in recent years improved our understanding of the molecular biology of numerous cancers including sarcoma; this knowledge enabled the application of targeted therapy in several specific STS subtypes [28, 29]. While the majority of such agents target cancer cells, some target its microenvironment (i.e., anti-angiogenic agents), and few affect both [29, 30]. However, despite this progress, further research is clearly needed to elucidate STS biology and to better understand the interplay between these tumors and their immediate environment. Since most RSTS tumors are in close vicinity to intra-abdominal fat, we sought to evaluate its potential effect on RSTS longterm surgical outcomes. In the present study, we show that high VF and not CF content is associated with increased local recurrence and death in a cohort of primary RSTS patients who had complete macroscopic resection at our institution. VF content was strongly associated with RSTS local failure; yet, it did not affect the occurrence of distant metastasis. In contrast, VF content did not affect local and/or distant metastasis-free survival in a cohort of non-retroperitoneal, extremity STS patients. These observations may advocate that VF has a local rather than a systemic effect on STS tumor cells. Recent data demonstrate that measures of central obesity or VF are superior to BMI as discriminators of high-risk cancer patients [14, 31–34] due to a number of structural and functional differences: VF consists of a larger nonadipocytes cellular component (i.e., fibroblasts, macrophages, etc.), has enhanced blood supply and innervation, and a greater proportion of large dysfunctional adipocytes [35]. Moreover, visceral adipocytic tissue expresses more adipokines (i.e., Adiponectin), IGF-1, VEGF, TNFa, IL-6, and angiotensinogen [35–38]; these molecules have overt pro-tumorigenic and pro-angiogenic effects [39–41].
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Ishikawa et al. suggest that adiponectin has a potential role in the progression of gastric cancer [17], whereas Park and Scherer found a positive correlation between leptin and cancer stem cell differentiation, thereby promoting tumor survival [19]. The prognostic significance of visceral obesity has been already noticed in various malignancies including respectable colorectal cancer and hepatocellular carcinoma recurrence [14, 15]. The distinctive characteristics of intra-abdominal fat may explain why VF and not CF content could potentially affect RSTS recurrence and OS. Alternatively, it is possible that increased VF content, which is associated with a higher rate of surgical complications [42–44], simply affects surgical adequacy; thus, increasing microscopic margin positivity. Our data did not demonstrate significant differences in the post-operative course (complications, blood consumption, rate of reoperations, etc.) of patients with low versus high VF content. Moreover, we performed a subset analysis of patients who had R0 resection excluding all patients who had positive or unknown margins; as depicted in Fig. 2d, VF content remained a significant predictor of RSTS local recurrence. These data support our presumption that increased local recurrence rates in patients with higher VF content reflect a biological rather than a mechanical phenomenon. One may argue that RSTS patients with high VF content are predisposed to increased tumoral microfoci within adjacent organs or retroperitoneal fat. Such observation may actually strengthen our hypothesis concerning the potential role of VF in RSTS tumoral behavior. Similar hypothesis was evaluated in vitro by Ribeiro et al. who demonstrated that periprostatic fat depot modulates prostate cancer microenvironment enhancing metaloproteinases activity, thus promoting prostate cancer cell survival and motility [45]. These data might be clinically relevant raising an intriguing question: can the surgeon change tumor microenvironment by the removal of tumor and its adjacent VF tissue? Recent data suggest that frontline aggressive surgical approach for primary RSTS is associated with improved local control [46]. Such radical resections may comprise same compartment uninvolved organs including the majority of co-localized VF tissue. It is possible that the elimination of most fatty tissue from RSTS tumoral bed and not the removal of uninvolved solid organs or microscopic tumor foci (i.e., kidney) contributed to the lower incidence of local recurrence shown by these authors as compared to other reported contemporary large RSTS series [46]. The present study has several limitations; some are inherent to the retrospective nature of our data. Moreover, the cohort which includes 101 patients is relatively small, mainly due to the obvious difficulty to obtain the preoperative imaging CT scans. Therefore, the results should be
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further validated utilizing similar, but larger STS cohorts. We presume that co-localized retroperitoneal fat and tumor cellular interactions affect patients outcome; however, we were not able to conclude whether the presence of metastatic cells within the visceral fat is associated with VF content. In order to answer this question, specimens should be prospectively evaluated for the presence of tumoral cells. In conclusion, based on current data, including our present observations, we believe that VF might have a role in RSTS local recurrence and overall adverse prognosis. Additional clinical and laboratory research is needed to establish our findings and to ascertain the potential biological effects of VF-secreted adipokines on STS cell proliferation and progression. Acknowledgments This study was supported by the Tel Aviv Sourasky Medical Center. Conflict of interest of interest.
The authors declare that they have no conflict
Disclosure There are neither commercial interests nor financial and/ or commercial support.
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29. Quesada J, Amato R (2012) The molecular biology of soft-tissue sarcomas and current trends in therapy. Sarcoma 2012:849456 30. Riedel RF (2012) Systemic therapy for advanced soft tissue sarcomas: highlighting novel therapies and treatment approaches. Cancer 118:1474–1485 31. Schoen RE, Tangen CM, Kuller LH, Burke GL, Cushman M, Tracy RP, Dobs A, Savage PJ (1999) Increased blood glucose and insulin, body size, and incident colorectal cancer. J Natl Cancer Inst 91:1147–1154 32. Moore LL, Bradlee ML, Singer MR, Splansky GL, Proctor MH, Ellison RC, Kreger BE (2004) BMI and waist circumference as predictors of lifetime colon cancer risk in Framingham Study adults. Int J Obes Relat Metab Disord 28:559–567 33. Donohoe CL, Doyle SL, Reynolds JV (2011) Visceral adiposity, insulin resistance and cancer risk. Diabetol Metab Syndr 3:12 34. Stocks T, Borena W, Strohmaier S, Bjørge T, Manjer J, Engeland A, Johansen D, Selmer R, Hallmans G, Rapp K, Concin H, Jonsson H, Ulmer H, Stattin P (2010) Cohort profile: the metabolic syndrome and cancer project (Me-Can). Int J Epidemiol 39:660–667 35. Ibrahim MM (2010) Subcutaneous and visceral adipose tissue: structural and functional differences. Obes Rev 11:11–18 36. Dusserre E, Moulin P, Vidal H (2000) Differences in mRNA expression of the proteins secreted by the adipocytes in human subcutaneous and visceral adipose tissues. Biochim Biophys Acta 1500:88–96 37. Maury E, Ehala-Aleksejev K, Guiot Y, Detry R, Vandenhooft A, Brichard SM (2007) Adipokines oversecreted by omental adipose tissue in human obesity. Am J Physiol Endocrinol Metab 293:E656–E665 38. Fried SK, Bunkin DA, Greenberg AS (1998) Omental and subcutaneous adipose tissues of obese subjects release interleukin-6: depot difference and regulation by glucocorticoid. J Clin Endocrinol Metab 83:847–850 39. Perks CM, Holly JM: Hormonal mechanisms underlying the relationship between obesity and breast cancer. Endocrinol Metab Clin North Am 2011, 40:485-507, vii 40. Giovannucci E (2001) Insulin, insulin-like growth factors and colon cancer: a review of the evidence. J Nutr 131:3109S–3120S 41. Grivennikov SI, Karin M (2011) Inflammatory cytokines in cancer: tumour necrosis factor and interleukin 6 take the stage. Ann Rheum Dis 70(Suppl 1):i104–i108 42. Doyle SL, Lysaght J, Reynolds JV (2010) Obesity and post-operative complications in patients undergoing non-bariatric surgery. Obes Rev 11:875–886 43. Ishii Y, Hasegawa H, Nishibori H, Watanabe M, Kitajima M (2005) Impact of visceral obesity on surgical outcome after laparoscopic surgery for rectal cancer. Br J Surg 92:1261–1262 44. Cecchini S, Cavazzini E, Marchesi F, Sarli L, Roncoroni L (2011) Computed tomography volumetric fat parameters versus body mass index for predicting short-term outcomes of colon surgery. World J Surg 35:415–423. doi:10.1007/s00268-0100888-3 45. Ribeiro R, Monteiro C, Cunha V, Oliveira MJ, Freitas M, Fraga A, Prı´ncipe P, Lobato C, Lobo F, Morais A, Silva V, SanchesMagalha˜es J, Oliveira J, Pina F, Mota-Pinto A, Lopes C, Medeiros R (2012) Human periprostatic adipose tissue promotes prostate cancer aggressiveness in vitro. J Exp Clin Cancer Res 31:32 46. Bonvalot S, Raut CP, Pollock RE, Rutkowski P, Strauss DC, Hayes AJ, Van Coevorden F, Fiore M, Stoeckle E, Hohenberger P, Gronchi A (2012) Technical considerations in surgery for retroperitoneal sarcomas: position paper from E-surge, a master class in sarcoma surgery, and EORTC-STBSG. Ann Surg Oncol 19:2981–2991
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ORIGINAL SCIENTIFIC REPORT
Visceral Fat Content Correlates with Retroperitoneal Soft Tissue Sarcoma (STS) Local Recurrence and Survival Michail Papoulas1 • Roi Weiser1 • Galia Rosen2 • Fabian Gerstenhaber1 Ofer Merimsky3 • Nir Lubezky1 • Joseph M. Klausner1 • Guy Lahat1
•
Ó Socie´te´ Internationale de Chirurgie 2015
Abstract Background Our aim was to evaluate the association between visceral fat content with soft tissue sarcoma (STS) local recurrence and survival. Methods One hundred and one computed tomography imaging studies of primary STS patients who had complete macroscopic resection at our institution between 2002 and 2012 were reviewed, and retroperitoneal and circumferential fat contents were measured. Correlations between imaging findings and clinical data were analyzed. Results Fifty-seven STS tumors (56.4 %) were retroperitoneal; of them, 65 % were high grade, median size was 15 cm (range 3–49), and the most common histological subtype was high grade liposarcoma (31.6 %). Median follow-up length for the entire cohort was 64 months (range 6–95). High visceral fat (VF) content C15 versus \15 mm was identified as a risk factor for retroperitoneal STS local recurrence; 65.1 versus 26.7 %, respectively (p = 0.04); VF content did not correlate with distant metastasis. Median overall survival (OS) length of patients with VF C15 versus \15 mm was 57 months (range 2–144) versus not reached, respectively (p = 0.007). Multivariable analysis identified VF C15 mm as an independent risk factor for decreased OS (HR: 4.2, 95 % CI 1.07–16.67). In contrast, circumferential fat content did not correlate with retroperitoneal STS patient outcomes. Conclusion High VF content is an independent adverse prognosticator associated with significantly higher rates of retroperitoneal STS local recurrence and decreased patients survival. Local tumor biology may be affected by the presence of adipose cells. Further clinical and molecular research is needed to establish this premise.
Introduction & Michail Papoulas [email protected] 1
Department of Surgery, The Sourasky Medical Center, Sackler School of Medicine, Tel-Aviv University, 6 Weitzman St., Tel-Aviv, Israel
2
Department of Radiology, The Sourasky Medical Center, Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel
3
Department of Oncology, The Sourasky Medical Center, Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel
Approximately, two-thirds of adult population in developed countries is categorized as overweight or obese [1] and their high propensity for cardiovascular diseases is well established [2–7]; in addition, substantial evidence has been provided in recent years as to the correlation between obesity and cancer [4, 5, 8–12]. Data demonstrate that high body mass index (BMI) and visceral fat (VF) content in particular are associated with increased risk of various cancer types development as well as inferior outcomes [13–15]. Moreover, numerous studies have showed that
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pro-tumorigenic molecules secreted by adipocytes enhance tumor cell proliferation, migration, and invasion [16]. These adipokines (i.e., leptin, adiponectin, etc.) may have systemic as well as local effects which induce cancer progression and metastasis [17–19]. Soft tissue sarcoma (STS) is a rare and heterogenic group of tumors accounting for less than one percent of adult solid tumors [20]. STS patients have a dismal prognosis with a 5-year survival rate of only 50 %, reflecting the relative disease’s propensity for local recurrence and distant metastasis [21]. These tumors can arise in any anatomic location, mostly in the extremities and the retroperitoneum (RSTS), often in close vicinity to adipose tissue. While the association between obesity and cancer has been established in a variety of solid tumors, the link between obesity and STS has not been described. We sought to evaluate whether increased VF content is associated with STS patients’ adverse prognosis.
Fig. 1 a Leiomyosarcoma involving the IVC in a 37-year-old male. b Vertical distance between the left posterior renal capsule and the junction of the abdominal wall and paraspinal musculature at the level of the left renal vein
Methods The study was approved by our institutional review board to be in accordance with the Declaration of Helsinki and a waiver of consent was granted for the proposed patient record review including imaging publication. The medical records of primary STS patients (n = 108) who had complete macroscopic resection at our institution between January 2002 and December 2010 were identified and evaluated. Patients with incomplete data (clinical or imaging) were excluded (n = 7); 101 patients were included in the study cohort. Clinical, imaging, and pathological data of all patients were retrospectively reviewed. All patients were evaluated preoperatively with computed tomography (CT), operated on with an intention to cure, and remained in active clinical follow-up through our out-patient clinic. Some patients were treated with systemic chemotherapy and/or radiation in accordance with the physician recommendations of the multidisciplinary planning conference. The recommendations for surgical, chemotherapeutic, and radiation treatments were based on an evaluation of clinical prognostic factors. The following demographics and clinicopathological features were included in the analysis: gender, age, primary site, tumor size, disease grade, and histology. Treatment and outcomes characteristics of all patients were evaluated; perioperative mortality (60-day or in-hospital mortality), adjuvant treatment (chemotherapy, radiation), recurrence, and long-term survival were reviewed and included in the present analysis. Preoperative CT imaging studies were reviewed by a senior radiologist (RG) and the author (PM) who were blinded to the patients’ clinical data and postoperative outcome. BMI, circumferential fat (CF), and VF diameter
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were measured. VF content was measured as previously described [22]. Briefly, VF content was measured as the vertical distance between the left posterior renal capsule and the junction of the abdominal wall and paraspinal musculature at the level of the left renal vein, and this served as a proxy for quantity of visceral fat (Fig. 1). All measurements were based on the unaffected retroperitoneal side. Patients with left kidney atrophy, large cysts, or masses that displace unilaterally the parenchyma underwent the same measurements in the right kidney. Patients with large, bilateral retroperitoneal STS tumors displacing both kidneys were excluded from the study cohort.
Statistical analysis VF content was normally distributed, ranging between 0 and 36.7 mm; the 15 mm cutoff represents the mean VF, as measured in the present series. Patients were categorized into two groups of visceral fat with the mean VF diameter used as a cutoff point (C15 vs. \15 mm). Independent predictors of overall survival (OS) were then evaluated using Cox proportional hazards regression. Missing data points were included in the analysis by assigning a specific category for missing data in order to maximize the number of patients included in the model. Variables for the final model were chosen based on whether they remained significant independent predictors of survival after adjusting for the variables forced into the model. Local recurrencefree survival (time from surgery to time of clinical evidence of local relapse) and OS (time from surgery until death, regardless of cause) were estimated by the method
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of Kaplan–Meier, and the log-rank test was used to compare survival curves. Patients were censored as of their last follow-up visit if they were alive and/or disease-free throughout the study period. All tests were two sided. For all tests, statistical significance was defined by p \ 0.05. Data were analyzed with the SPSS 17 statistical software.
Results Patients and tumor characteristics A total of 101 primary STS patients who had complete macroscopic resection at our institution are included in the study cohort; Table 1 depicts their clinical and pathological
characteristics. There were 48 men (47.5 %) and 53 (52.5 %) women; median age at the time of surgery was 60 years (range 18–83). Fifty-seven STS tumors (56.4 %) were located in the RSTS, 34 (23.6 %) in the extremities, and the remaining (n = 10, 5 %) were truncal; the majority (n = 78, 77.2 %) were high grade. Overall, the most common histological subtype was undifferentiated pleomorphic sarcoma (UPS; 32.7 %); however, in the subgroup of retroperitoneal STS patients, the most common histological subtype was high-grade liposarcoma (n = 18; 31.6 %) followed by leiomyosarcoma (n = 16; 28.1 %). Most tumors (n = 84; 83.1 %) were larger than 5 cm, 30.7 % (n = 31) were larger than 15 cm. Treatment and outcomes characteristics
Whole cohort n (%)
RSTS n (%)
Non-RSTS (%)
All patients had complete macroscopic resection at our institution; Table 2 depicts their treatment and outcome characteristics. Of them, 22 (21.7 %) had positive microscopic margins (R1 resection). Most STS patients (n = 64;
No
50 (49.5)
33 (57.9)
17 (38.6)
Table 2 Treatment and outcome characteristics
Yes
51 (50.5)
24 (42.1)
27 (61.4)
Female
53 (52.5)
32 (56.1)
21 (47.7)
Male
48 (47.5)
25 (43.9)
23 (52.3)
C15 mm
51 (50.5)
33 (57.9)
18 (40.9)
\15 mm
50 (49.5)
24 (42.1)
26 (59.1)
Table 1 Clinical and pathological characteristics Characteristics Age C60 years
Sex
VF
Primary site Extremity Retroperitoneal
34 (33.6) 57 (56.4)
Truncal
10 (10)
57 (100)
34 (77.3) 0 10 (22.7)
Tumor size 0–5 cm
12 (11.9)
3 (5.3)
9 (20.5)
5–10 cm
38 (37.6)
14 (24.6)
24 (54.5)
10–15 cm
15 (14.8)
13(22.8)
2 (4.5)
C15 cm
31 (30.7)
22 (38.6)
9 (20.5)
Unknown
5 (5)
5 (8.7)
0
G1
19 (18.8)
17 (29.8)
2 (4.5)
G2
4 (4)
3 (5.3)
1 (2.2)
G3
78 (77.2)
37 (64.9)
41 (93.3)
UPS
33 (32.7)
6 (10.5)
27 (61.4)
Leiomyosarcoma
19 (18.8)
16 (28.1)
3 (6.8)
Well differentiated LPS High grade LPS
12 (9.9) 26 (25.7)
12 (21.1) 18 (31.6)
0 8 (18.2)
Other
11 (10.9)
5 (8.7)
6 (13.6)
Disease grade
Histology
RSTS retroperitoneal STS, VF visceral fat distance, UPS undifferentiated pleomorphic sarcoma (including malignant fibrous histiocytoma and undifferentiated sarcoma), LPS liposarcoma
Characteristics
Whole cohort n (%)
RSTS n(%)
NonRSTS
26 (59.1)
Surgery Complete macroscopic resection
101 (100)
Microscopic margins Negative
71 (70.2)
45 (78.9)
Positive
22 (21.7)
11 (19.3)
11 (25)
Unknown
8 (4.1)
1 (1.8)
3 (6.9)
Chemotherapy No
64 (63.3)
39 (68.4)
25 (56.8)
Yes
29 (28.7)
15 (26.3)
14 (31.8)
Unknown
8 (8.8)
3 (5.3)
5 (11.4)
No
43 (42.6)
33 (57.9)
10 (22.7)
Yes
35 (34.6)
5 (8.7)
20 (45.5)
Unknown
23 (22.8)
19 (33.4)
4 (9.1)
No
42 (41.6)
27 (47.3)
15 (34.1)
Yes
52 (51.5)
28 (49.1)
24 (54.5)
Unknown
7 (6.9)
2 (3.6)
5 (11.4)
No
54 (53.4)
31 (54.4)
23 (52.3)
Yes
41 (40.5)
24 (42.1)
17 (38.6)
6 (9.9)
2 (3.5)
4 (9.1)
No
60 (59.4)
33 (70.2)
27 (61.5)
Yes
35 (34.5)
12 (25.6)
23 (52.4)
Unknown
6 (9.9)
2 (4.2)
4 (9.1)
Radiation
Recurrence
Local recurrence
Unknown Distant metastasis
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Fig. 2 a Overall survival in all primary STS patients (n = 91) by VF content \15 mm (blue line) versus C15 mm (green line) as a function of time from surgery. b Local recurrence in primary RSTS patients (n = 47) by VF content\15 mm (blue line) versus C15 mm (green line) as a function of time from surgery. c Overall survival in
primary RSTS patients (n = 47) by VF content \15 mm (blue line) versus C15 mm (green line) as a function of time from surgery. d Local recurrence in primary RSTS patients who had R0 resection (n = 37) by VF content \15 mm (blue line) versus C15 mm (green line) as a function of time from surgery
63.3 %) who had surgery at our institution were not treated with systemic chemotherapy, nearly one-third (n = 35; 34.6 %) were irradiated; however, only five of them were treated for RSTS. Median follow-up time for the entire cohort was 64 months, (range 6–95). Recurrence was documented in approximately half of the patients; 40.5 % (n = 41) experienced local recurrence, 34.5 % (n = 35) had distant metastasis. Recurrence patterns of both RSTS and nonRSTS patients did not significantly differ. Five- year
recurrence-free survival (RFS) and OS rates for the cohort of RSTS and non-RSTS patients were 59.5 % and 64.7 versus 66.6 % and 80.1 %, respectively.
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Visceral fat measurement Preoperative CT imaging was used to measure distance from the posterior pole of the kidney to the abdominal wall musculature as a surrogate for visceral fat as previously described [22]; imaging was available for all patients
World J Surg Table 3 Multivariable analysis of overall survival and local recurrence free survival of primary RSTS patients who had complete macroscopic resection Variables
Level
HR (95 % CI)
p value
Tumor grade
High versus low
4.44 (1.04–20.93)
0.05
Tumor size
C15 versus \ 10 cm
4.2 (1.25–16.88)
0.01
VF content Microscopic margins
C15 versus \15 mm Positive versus negative
3.44 (0.99–11.94) 2.26 (0.92–5.58)
0.04 0.08
Age
Continuous (in 10 years increments)
1.32 (0.87–3.55)
0.23
Histological subtype
LPS versus non- LPS
0.76 (0.18–1.90)
0.35
Bold values are statistically significant (p \ 0.05) HR hazard ratio, CI confidence interval, VF visceral fat, LPS liposarcoma
included in the study cohort. Mean VF distance was 15 ± 3.2 mm. Patients were divided into two groups based on measured quantity of visceral fat: VF C15 mm (n = 51) and VF \15 mm (n = 50). Kaplan–Meir OS analysis did not show that STS patients who had VF C15 versus VF \15 mm survived longer (p = 0.155; Fig. 2a); moreover, VF C15 mm did not emerge as an independent predictor of OS in the multivariable analysis for the whole cohort of STS patients. Next, we performed a subset analysis for the cohort of RSTS patients (n = 57); median LRFS (local recurrence-free survival) and OS rates for RSTS patients with VF C15 versus VF \15 mm were 25.4 months versus not reached (p = 0.004; Fig. 2b) and 57 months versus. not reached (p = 0.007), respectively, (Fig. 2c) suggesting that increased visceral fat content may have a local rather than a systemic effect on tumor behavior. In the multivariable analysis, disease grade (high vs. low), large tumor size (C15 cm), and VF C15 mm (HR 3.44, 95 % CI 0.99–11.94) emerged as statistically significant independent adverse prognostic factors of OS. Variables including age, histological type (LPS vs. non LPS), and microscopic margins (positive vs. negative) did not emerge as independent predictors of OS/LRFS (Table 3). No correlation between circumferential fat (CF) content and OS/LRFS was found (data not shown). Increased fat content in the RSTS might affect, at least in part, the ability of the surgeon to achieve negative margins resulting in inferior oncological outcomes. Therefore, we further analyzed the subgroup of RSTS patients who had complete microscopic resection (R0 resection; n = 45). As shown in our subset analysis (Fig. 2d), high VF content remained a significant prognosticator of LRFS in the of R0 resection cohort of RSTS patients.
Discussion Sarcoma treatment presents a number of challenges to both the oncologist and the surgeon. In the absence of efficient chemotherapy and the limited effect of radiotherapy in
most STS histological subtypes, radical resection with negative microscopic margins remains the mainstay of its therapy [23, 24]. Nevertheless, in spite of adequate surgery and a multidisciplinary therapeutic approach, the prognosis of STS patients is poor, with high rates of local recurrence and mortality [23–27]. Extensive effort in recent years improved our understanding of the molecular biology of numerous cancers including sarcoma; this knowledge enabled the application of targeted therapy in several specific STS subtypes [28, 29]. While the majority of such agents target cancer cells, some target its microenvironment (i.e., anti-angiogenic agents), and few affect both [29, 30]. However, despite this progress, further research is clearly needed to elucidate STS biology and to better understand the interplay between these tumors and their immediate environment. Since most RSTS tumors are in close vicinity to intra-abdominal fat, we sought to evaluate its potential effect on RSTS longterm surgical outcomes. In the present study, we show that high VF and not CF content is associated with increased local recurrence and death in a cohort of primary RSTS patients who had complete macroscopic resection at our institution. VF content was strongly associated with RSTS local failure; yet, it did not affect the occurrence of distant metastasis. In contrast, VF content did not affect local and/or distant metastasis-free survival in a cohort of non-retroperitoneal, extremity STS patients. These observations may advocate that VF has a local rather than a systemic effect on STS tumor cells. Recent data demonstrate that measures of central obesity or VF are superior to BMI as discriminators of high-risk cancer patients [14, 31–34] due to a number of structural and functional differences: VF consists of a larger nonadipocytes cellular component (i.e., fibroblasts, macrophages, etc.), has enhanced blood supply and innervation, and a greater proportion of large dysfunctional adipocytes [35]. Moreover, visceral adipocytic tissue expresses more adipokines (i.e., Adiponectin), IGF-1, VEGF, TNFa, IL-6, and angiotensinogen [35–38]; these molecules have overt pro-tumorigenic and pro-angiogenic effects [39–41].
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Ishikawa et al. suggest that adiponectin has a potential role in the progression of gastric cancer [17], whereas Park and Scherer found a positive correlation between leptin and cancer stem cell differentiation, thereby promoting tumor survival [19]. The prognostic significance of visceral obesity has been already noticed in various malignancies including respectable colorectal cancer and hepatocellular carcinoma recurrence [14, 15]. The distinctive characteristics of intra-abdominal fat may explain why VF and not CF content could potentially affect RSTS recurrence and OS. Alternatively, it is possible that increased VF content, which is associated with a higher rate of surgical complications [42–44], simply affects surgical adequacy; thus, increasing microscopic margin positivity. Our data did not demonstrate significant differences in the post-operative course (complications, blood consumption, rate of reoperations, etc.) of patients with low versus high VF content. Moreover, we performed a subset analysis of patients who had R0 resection excluding all patients who had positive or unknown margins; as depicted in Fig. 2d, VF content remained a significant predictor of RSTS local recurrence. These data support our presumption that increased local recurrence rates in patients with higher VF content reflect a biological rather than a mechanical phenomenon. One may argue that RSTS patients with high VF content are predisposed to increased tumoral microfoci within adjacent organs or retroperitoneal fat. Such observation may actually strengthen our hypothesis concerning the potential role of VF in RSTS tumoral behavior. Similar hypothesis was evaluated in vitro by Ribeiro et al. who demonstrated that periprostatic fat depot modulates prostate cancer microenvironment enhancing metaloproteinases activity, thus promoting prostate cancer cell survival and motility [45]. These data might be clinically relevant raising an intriguing question: can the surgeon change tumor microenvironment by the removal of tumor and its adjacent VF tissue? Recent data suggest that frontline aggressive surgical approach for primary RSTS is associated with improved local control [46]. Such radical resections may comprise same compartment uninvolved organs including the majority of co-localized VF tissue. It is possible that the elimination of most fatty tissue from RSTS tumoral bed and not the removal of uninvolved solid organs or microscopic tumor foci (i.e., kidney) contributed to the lower incidence of local recurrence shown by these authors as compared to other reported contemporary large RSTS series [46]. The present study has several limitations; some are inherent to the retrospective nature of our data. Moreover, the cohort which includes 101 patients is relatively small, mainly due to the obvious difficulty to obtain the preoperative imaging CT scans. Therefore, the results should be
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further validated utilizing similar, but larger STS cohorts. We presume that co-localized retroperitoneal fat and tumor cellular interactions affect patients outcome; however, we were not able to conclude whether the presence of metastatic cells within the visceral fat is associated with VF content. In order to answer this question, specimens should be prospectively evaluated for the presence of tumoral cells. In conclusion, based on current data, including our present observations, we believe that VF might have a role in RSTS local recurrence and overall adverse prognosis. Additional clinical and laboratory research is needed to establish our findings and to ascertain the potential biological effects of VF-secreted adipokines on STS cell proliferation and progression. Acknowledgments This study was supported by the Tel Aviv Sourasky Medical Center. Conflict of interest of interest.
The authors declare that they have no conflict
Disclosure There are neither commercial interests nor financial and/ or commercial support.
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