Incidence and predictors of synchronous liver metastases in patients with gastrointestinal stromal tumors (GISTs)

Accepted Manuscript Incidence and predictors of synchronous liver metastases in patients with gastrointestinal stromal tumors (GISTs) Apostolos Gaitanidis, Michail Alevizakos, Alexandra Tsaroucha, Constantinos Simopoulos, Michail Pitiakoudis PII: S0002-9610(17)31187-X DOI: 10.1016/j.amjsurg.2018.04.011 Reference: AJS 12861 To appear in: The American Journal of Surgery Received Date: 1 August 2017 Revised Date: 18 January 2018 Accepted Date: 16 April 2018 Please cite this article as: Gaitanidis A, Alevizakos M, Tsaroucha A, Simopoulos C, Pitiakoudis M, Incidence and predictors of synchronous liver metastases in patients with gastrointestinal stromal tumors (GISTs), The American Journal of Surgery (2018), doi: 10.1016/j.amjsurg.2018.04.011. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Abstract Background: The liver is the most common metastatic site in patients with gastrointestinal stromal tumors (GISTs). The purpose of this study is to identify the incidence and predictive factors associated with synchronous liver metastases among patients with GISTs. Methods: A retrospective review of the Surveillance Epidemiology and End Results (SEER) database was performed. Results: Overall, 2757 patients were identified, of which 276 (10%) had synchronous liver metastases. The two-year survival of patients with synchronous liver metastases was 31.9% overall and 37.1% after undergoing surgery with curative intent. Primary tumor size >5 cm (5-10 cm: OR 2.97, 95% CI: 1.03-8.55, p=0.044, >10 cm: OR 5.59, 95% CI: 1.95-16.07, p=0.001), presence of nodal metastases (OR 4.09, 95% CI: 2.01-8.33, p<0.001) and mitotic count >5 /50 HPF (OR 1.58, 95% CI: 1.01-2.47, p=0.044) were associated with the presence of liver metastases. Conclusions: One out of ten patients with GISTs presents with hepatic metastases. Primary tumor size >5 cm, presence of nodal metastases and mitotic count >5 /50 HPF are associated with a higher risk of synchronous hepatic metastases.

Incidence and predictors of synchronous liver metastases in patients with gastrointestinal stromal tumors (GISTs) Apostolos Gaitanidis, M.D. 1, Michail Alevizakos, M.D. 2, Alexandra Tsaroucha, M.D., PhD 1, Constantinos Simopoulos, M.D., PhD 1, Michail Pitiakoudis, M.D., PhD 1 1 Second Department of Surgery, Democritus University of Thrace Medical School, Alexandroupoli, Greece 2 University of Pittsburgh Medical Center, Department of Medicine, Pittsburgh, PA, USA Word count: 2125 Running title: Synchronous liver metastases and GISTs Funding: None Corresponding author: Apostolos Gaitanidis, M.D. Second Department of Surgery, University General Hospital of Alexandroupoli Democritus University of Thrace Medical School Alexandroupoli, 68100, Greece Email: agaitanidis@gmail.com Tel: +30 6943821654, Fax: +30 2551030412 1

Summary A retrospective review of the Surveillance Epidemiology and End Results database was performed to identify the incidence and predictors of synchronous liver metastases among patients with GISTs. Overall, 10% of patients had synchronous liver metastases, while primary tumor size, nodal metastases and mitotic count were independently associated with the presence of these metastases. 3

Introduction Gastrointestinal stromal tumors (GISTs) constitute the most frequent mesenchymal malignancy of the digestive tract, with an approximate incidence of 7.8 cases per million people per year. 1 Stomach represents the most common location for these tumors (40-60%), while small intestine is the second most common primary location (20-40%). 2 4 GISTs rarely metastasize to lymph nodes, but even the presence of extra-abdominal lymph node metastasis has been described. 5 The liver is the most frequent metastatic location, since there is hepatic involvement in 65% of all patients with metastatic disease, while the liver is the only site involved in 53% of these patients. 6 The liver has also been found to be the most common location of recurrence after resection (63%), while it is the only site of recurrence in 44% of patients. 6 Hepatic metastases are considered to be major factors associated with mortality, since they are present in 78% of patients with GISTs that die from their disease. 7 The presence of any synchronous metastatic disease is frequent in patients with GISTs, with a reported incidence of 15-50%. 3,8 As a result, timely detection of metastatic disease in the most commonly involved organ, the liver, is crucial. Identification of liver metastases may lead to changes in management, such as administration of preoperative imatinib and changes in operative planning. Hepatic metastases are frequently bilobar, which may preclude anatomic liver resections, but radiofrequency ablation (RFA), hepatic artery embolization and liver transplantation are effective alternatives. 9 Magnetic resonance imaging (MRI) is generally considered to be the imaging test of choice for detection of liver metastases, due to its higher specificity compared to Computed Tomography (CT) and its lack of radiation exposure. 10,11 For these reasons, the National Comprehensive Cancer Network (NCCN) guidelines recommend an individualized selection of patients with GISTs to 4

undergo MRI for anatomic delineation of liver metastases. 9 Currently, the incidence of synchronous liver metastases in the population is unknown. The purpose of this study is to identify the incidence, prognosis and predictive factors of synchronous hepatic metastatic disease among patients with GISTs. 5

Materials and Methods A retrospective review of the National Cancer Institute s Surveillance Epidemiology and End Results (SEER) database was performed for cases diagnosed between 2010 and 2013, due to information regarding the presence of liver metastases being available only for this period. SEER is a comprehensive database that collects data on various clinical and pathologic aspects related to cancer management and encompasses approximately 30% of the United States population. 12 GISTs were identified using the ICD-O-3 code 8936 (i.e. gastrointestinal stromal sarcoma). Only cases with positive histologic diagnosis and where information regarding the presence of synchronous liver metastases was available were included. Synchronous hepatic metastases were identified based on the variable CS mets at DX-liver (2010+). The Miettinen scoring system was used for histopathological classification and primary tumor sizes were separated by the cut-offs used in this scoring system. 13 Tumor locations with less than 20 cases were classified as Other. Curative surgery refers to resection of at least primary tumors, without determining whether liver resection was also performed. The study was exempted from Institutional Review Board approval, due to SEER s inclusion of unidentifiable patient information. Statistical analysis Univariate survival analysis with the log-rank test and multivariate Cox proportional hazards analysis were used to identify differences in survival among patients. Univariate analysis using student s t-test and chi-square test, as well as binary logistic regression using backward selection were employed to identify predictive factors of liver metastases. Only variables significant on univariate analysis 6

were included in multivariate analysis. A predictive scoring system was developed based on the results of the logistic regression and ROC curve analysis was then used to determine its prognostic ability. All statistical tests used two-tailed p-values and 0.05 was set as the threshold of significance. Analysis was performed on SPSS v.24 (IBM Corp., Armonk, NY). 7

Results Patient characteristics Overall, 2757 patients were identified, of which 276 (10%) had liver metastases at the time of diagnosis. Mean age at diagnosis was 63.8 ± 13.9 years and 1405 (51%) patients were males. Most primary tumors were located in the stomach (1701 patients, 61.7%), followed by the small intestine (726 patients, 26.3%). Median follow-up was 19 months and the period of follow-up was up to 47 months. Detailed clinical and pathologic features are displayed at Table 1. Prognosis of patients with synchronous liver metastases Patients with synchronous liver metastases had overall 1-year survival of 60.1%, 2-year survival of 31.9% and 3-year survival of 12.7%. Median diseasespecific survival (DSS) was not reached during follow-up, but mean DSS was 36.3 ± 1.2 months. Among patients with synchronous liver metastases, 7 also had bone metastases, 2 had brain metastases and 9 had lung metastases at the time of diagnosis. Among patients without synchronous liver metastases, 174 presented with synchronous metastatic disease, of which 10 had bone metastases and 9 had lung metastases at diagnosis, but metastatic location was not specified for the rest. Univariate survival analysis of all patients with metastatic disease at the time of diagnosis demonstrated that the presence of synchronous liver metastases (mean survival 36.34 ± 1.2 mo vs. 40.82 ± 1.18 mo, median survival not reached, p=0.012) was associated with worse disease-specific survival, along with age 65 years (p=0.006), tumor location (p=0.002) and not undergoing curative surgery (p<0.001). 8

However, the presence of synchronous liver metastases was not associated with worse DSS on multivariate analysis (p=0.31). One-year survival for patients with synchronous liver metastases that underwent curative surgery was 62.9%, 2-year survival was 37.1% and 3-year survival was 16.5%. Among all patients with metastatic disease at diagnosis that underwent curative surgery, presence of synchronous liver metastases was associated with worse DSS on univariate analysis (mean survival 40.24 ± 1.71 mo vs. 44.18 ± 1.02 mo, median survival not reached, p=0.043), along with tumor location (p<0.001), but again this association was not significant on multivariate analysis (Table 2). Among all patients with synchronous liver metastases, tumor location (p=0.028), age 65 years (p=0.036) and undergoing curative surgery (40.24 ± 1.71 mo vs. 33.95 ± 1.59 mo, p=0.016) were associated with DSS. However, only tumor location was independently associated with DSS on multivariate analysis (Figure 1, Table 3). Predictors of synchronous liver metastases On univariate analysis, male sex, colorectal/anal and retroperitoneal/peritoneal tumor location, >5 mitoses per 50 HPF, greater primary tumor size and presence of nodal metastases were associated with the presence of synchronous liver metastases. Binary logistic regression showed that mitotic count >5 /50 HPF (OR 1.58, 95% CI: 1.01-2.47, p=0.044), primary tumor size >5 cm (5-10 cm: OR 2.97, 95% CI: 1.03-8.55, p=0.044, >10 cm: OR 5.59, 95% CI: 1.95-16.07, p=0.001) and presence of nodal metastases (OR 4.09, 95% CI: 2.01-8.33, p<0.001) were associated with the presence of synchronous liver metastases (Table 4). 9

Discussion The results of this study show that 1 out of 10 patients with GISTs presents with synchronous liver metastases. Two-year survival of these patients was 31.9% overall and 37.1% after undergoing curative surgery. In addition, primary tumor location was an independent prognostic factor associated with worse DSS among patients with synchronous liver metastases. Primary tumor size >5 cm, presence of nodal metastases and mitotic count >5 /50 HPF were predictive factors associated with the presence of synchronous liver metastases. The prognosis of patients with GISTs that had metastasized to the liver was historically poor. Before the introduction of TKIs, median overall survival of patients with metastatic GISTs to the liver that sunderwent hepatic resection was 39 months compared to 12 months for patients that did not undergo complete surgical resection. 14,15 In contrast, in the current era of TKIs, survival for patients undergoing hepatic resection has improved, with reported median overall survival estimates of 90-96 months, 16,17 while median survival was not reached after follow-up in some studies 18,19 something that was also encountered in this study. Interestingly, the results of this study suggest that there may be a survival benefit in patients with GISTs metastatic to the liver undergoing curative surgery, but this was not confirmed on multivariate analysis. However, SEER does not specify whether hepatic resection was performed, whether resection was complete or not, whether RFA or hepatic arterial embolization was employed or the duration of either preoperative or postoperative TKI treatment. Therefore, the results of this study cannot contribute towards the debate regarding the appropriate surgical management of patients with metastatic GISTs to the liver. However, this study identified primary tumor location to the colon, peritoneum or retroperitoneum to be an independent predictor of worse 10

DSS among patients with GISTs and synchronous liver metastases. Though rare, extra-gastrointestinal primary tumor location (e.g. retroperitoneum) is welldocumented in the literature. 20 Primary tumor location has been previously recognized as a prognostic factor associated with survival in patients with GISTs along with other recognized risk factors, including greater tumor size, high mitotic rate, high ki-67 index, tumor grade, aneuploidy and telomerase expression. 4 The presence of metastatic disease at diagnosis is common among patients with GISTs, with a reported incidence of 15-50%, the majority of which are located in the liver. 3,8 As a result, timely detection of hepatic metastases is an issue of considerable importance. Previous studies reported the rate of liver metastases at diagnosis to be 4.6%-30.6%, 21,22 which is comparable to this study s 10%, while GISTs with synchronous liver metastases comprise 9.1%-33% of all GISTs undergoing hepatic resections. 18,21,23,24 Although the sensitivity and specificity of each imaging modality for the detection of hepatic metastases in patients with GISTs has not been described, MRI is considered the test of choice for detection and characterization of these lesions, due to its higher specificity, ability to differentiate them from other benign lesions, higher sensitivity for small liver lesions, as well as its lack of radiation exposure, 10,11,25 FDG-PET and FDG-PET/CT also have excellent sensitivity and specificity in identifying hepatic metastases in patients with colorectal cancer, 26 28 and may also be used as adjuncts in identifying metastatic disease during workup of patients with GISTs, although MRI may be preferred due to its lower radiation exposure. The latest NCCN guidelines recommend the routine performance of abdomino-pelvic CT and consideration of MRI to delineate potential hepatic metastatic disease for all GISTs 2 cm. 29 Our findings suggest that patients with primary tumors sized 2-5 cm are not associated with increased risk for liver metastatic 11

disease at diagnosis, but consideration of MRI for hepatic metastases during initial work-up would be justified for patients with tumors sized >5 cm, instead. Nodal metastases were also found to be independently associated with higher risk of hepatic metastases at diagnosis, and although their incidence in patients with GISTs is low, such metastases may be found in approximately 20% of patients younger than 40 years. 30 Although mitotic count >5 /50 HPF was found to be associated with 2.29 higher risk of hepatic metastases on univariate analysis, it was found to be associated with 0.72 times higher risk of liver metastases on multivariate analysis. However, the latter result was not significant and consequently this discrepancy may be attributed to the presence of other variables in the regression model, which appear to contribute more towards the presence of liver metastases. The findings of this study are limited by its retrospective design and the use of a large cancer database. The retrospective design of this study means that there was bias in the selection of patients for curative surgery and that there was no routine examination of all patients for the presence of liver metastases, since the choice of preoperative imaging tests in patients with GISTs is individualized. As a result, the true incidence of liver metastatic disease among newly diagnosed GISTs may be underestimated. In addition, large cancer databases are associated with tumor misclassifications, potential miscoding, missing data and limited follow-up periods. Furthermore, there is no detailed information regarding the surgical treatment of these patients, although the accuracy of the estimates pertaining to either the incidence of synchronous liver metastases or survival of patients that do not undergo curative surgery are not impacted by this limitation. SEER does not also provide information regarding the administration of TKI treatment or c-kit status, which may affect survival estimates, and the localization of nodal metastases. However, despite these 12

limitations these results provide us survival estimates with external validity in the general population regarding the survival of patients with synchronous liver metastases. In conclusion, the results of this study demonstrate that 1 out of 10 patients with GISTs may present with liver metastases at the time of diagnosis. Two-year survival of these patients is 31.9% and 37.1% for the sub-group that underwent curative surgery. Primary tumor size >5 cm, presence of nodal metastases and mitotic count >5 /50 HPF were found to be associated with increased risk for synchronous hepatic metastases. Further studies are needed to conclusively address the issues of incidence, prognosis and prediction of liver metastases at diagnosis among patients with GISTs. Acknowledgment: All the authors that contributed in the preparation of this manuscript have been mentioned. 13

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Figure legend Figure 1 Kaplan-Meier curves depicting disease-specific survival for patients with a-b) metastatic GISTs at diagnosis, c) liver metastases at diagnosis 19

Table 1. Characteristics of the patient cohort Patients without synchronous liver Patients with synchronous liver P-value metastases (n=2481) metastases (n=276) Age (y) 63.7 ± 13.8 64 ± 14.6 0.743 Sex 0.002 Male 1240 (50%) 165 (59.8%) Female 1241 (50%) 111 (40.2%) Race 0.845 White 1687 (68%) 185 (67%) Black 452 (18.2%) 52 (18.8%) Other 321 (12.9%) 39 (14.1%) Location 0.001 Stomach 1555 (62.7%) 146 (52.9%) Small intestine 673 (27.1%) 53 (19.2%) Colorectal/Anal 121 (4.9%) 19 (6.9%) Peritoneal/Retroperitoneal 55 (2.2%) 14 (5.1%) Other/Not specified 77 (3.1%) 44 (15.9%) Mitotic count <0.001 5 /50 HPF 1419 (57.2%) 63 (22.8%) 20

>5 /50 HPF 374 (15.1%) 38 (13.8%) Primary tumor size <0.001 2 cm 346 (13.9%) 10 (3.6%) 2-5 cm 780 (31.4%) 29 (10.5%) 5-10 cm 711 (28.7%) 75 (27.2%) >10 cm 531 (21.4%) 85 (30.8%) Miettinen classification <0.001 No risk 207 (8.3%) 2 (0.7%) Very low 383 (15.4%) 6 (2.2%) Low 367 (14.8%) 16 (5.8%) Moderate 259 (10.4%) 23 (8.3%) High 282 (11.4%) 32 (11.6%) Nodal metastases 69 (2.8%) 32 (11.6%) <0.001 Distant metastases 187 (7.5%) 276 (100%) <0.001 Distant metastases at diagnosis 174 (7.1%) 276 (100%) <0.001 Surgery performed 2190 (88.3%) 97 (35.5%) <0.001 Lymph nodes sampled 560 (24.4%) 58 (26.5%) 0.255 Stomach 347 (23.4%) 43 (31.4%) 21

Small intestine 165 (25.9%) 12 (24.5%) Colorectal/Anal 32 (28.3%) 3 (15.8%) Peritoneal/Retroperitoneal 16 (29.1%) 0 WD: well-differentiated, MD: moderately-differentiated, PD: poorly-differentiated, UD: undifferentiated, HPF: high-power fields 22

Table 2. Survival analysis for patients with metastatic GISTs at diagnosis P-value univariate HR (95% CI) P-value multivariate All patients Age 65 years 0.006 1.7 (0.99-2.9) 0.054 Sex 0.513 - - Race 0.628 - - Location 0.002 0.039 Stomach Reference Small intestine 0.94 (0.46-1.92) 0.861 Colorectal/Anal 2.42 (1.1-5.3) 0.028 Peritoneal/Retroperitoneal 2.52 (1.05-6.07) 0.039 Mitotic count >5 /50 0.547 - - HPF Primary tumor size 0.999 - - Miettinen classification 0.746 - - Nodal metastases 0.216 - - Synchronous liver 0.012 1.36 (0.75-2.46) 0.31 metastases Curative surgery <0.001 0.48 (0.26-0.9) 0.022 23

performed Patients that underwent curative surgery Age 65 years 0.108 - - Sex 0.461 - - Race 0.773 - - Location <0.001 <0.001 Stomach Reference Small intestine 1.1 (0.36-3.37) 0.87 Colorectal/Anal 7.25 (1.39-37.76) 0.019 Peritoneal/Retroperitoneal 11.26 (3.01-42.15) <0.001 Mitotic count >5 /50 0.276 - - HPF Primary tumor size 0.387 - - Miettinen classification 0.576 - - Nodal metastases 0.434 - - Synchronous liver 0.043 1.86 (0.66-5.27) 0.241 metastases HR: Hazard ratio, CI: Confidence Interval, HPF: high-power fields 24

Table 3. Survival analysis for patients with synchronous liver metastases P-value univariate HR (95% CI) P-value multivariate Age 65 years 0.036 1.68 (0.89-3.19) 0.11 Sex 0.974 - - Race 0.94 - - Location 0.028 0.044 Stomach Reference Small intestine 0.56 (0.23-1.36) 0.2 Colorectal/Anal 1.88 (0.77-4.6) 0.167 Peritoneal/Retroperitoneal 2.51 (0.96-6.59) 0.061 Mitotic count >5 /50 0.865 - - HPF Primary tumor size 0.837 - - Miettinen classification 0.188 - - Nodal metastases 0.732 - - Curative surgery performed 0.016 0.79 (0.39-1.6) 0.506 HR: Hazard ratio, CI: Confidence Interval, HPF: high-power fields 25

Table 4. Predictive factors of synchronous liver metastases OR (95% CI) P-value Adjusted OR P-value univariate (95% CI) multivariate Sex 0.002 0.139 Female Reference Reference Male 1.49 (1.16-1.92) 1.38 (0.9-2.12) Location 0.001 0.597 Stomach Reference Reference Small intestine 0.84 (0.6-1.16) 0.292 1.01 (0.65-1.58) 0.955 Colorectal/Anal 1.67 (1-2.79) 0.049 - Peritoneal/Retroperitoneal 2.71 (1.47-4.99) 0.001 1.72 (0.6-4.93) 0.313 Mitotic count <0.001 0.044 5 /50 HPF Reference Reference >5 /50 HPF 2.29 (1.51-3.48) 1.58 (1.01-2.47) Primary tumor size <0.001 <0.001 2 cm Reference Reference 2-5 cm 1.29 (0.62-2.67) 0.499 1.07 (0.34-3.37) 0.907 5-10 cm 3.65 (1.86-7.15) <0.001 2.97 (1.03-8.55) 0.044 >10 cm 5.54 (2.84-10.81) <0.001 5.59 (1.95-16.07) 0.001 26

Nodal metastases 5.52 (3.54-8.6) <0.001 4.09 (2.01-8.33) <0.001 OR: Odds ratio, CI: Confidence interval, WD: well-differentiated, MD: moderatelydifferentiated, PD: poorly-differentiated, UD: undifferentiated, HPF: high-power fields 27

Highlights: 10% of patients with GISTs present with synchronous liver metastases. Two-year survival of these patients is 31.9% overall and 37.1% after undergoing surgery. Primary tumor location is an independent prognostic factor associated with worse disease-specific survival among patients with synchronous liver metastases. Primary tumor size >5 cm, presence of nodal metastases and mitotic count >5 /50 HPF are independently associated with the presence of synchronous liver metastases.

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