Alexandra G Lopez-Aguiar1, Lauren M Postlewait1, Cecilia G Ethun1, Mohammad Y Zaidi1, Kristen Zhelnin2, Alyssa Krasinskas2, Maria C Russell1, David A Kooby1, Kenneth Cardona1, Bassel F El-Rayes3, Shishir K Maithel4. 1. Division of Surgical Oncology, Department of Surgery, Winship Cancer Institute, Emory University, 1365C Clifton Road NE, 2nd Floor, Atlanta, GA, 30322, USA. 2. Department of Pathology, Winship Cancer Institute, Emory University, Atlanta, GA, USA. 3. Department of Hematology Oncology, Winship Cancer Institute, Emory University, Atlanta, GA, USA. 4. Division of Surgical Oncology, Department of Surgery, Winship Cancer Institute, Emory University, 1365C Clifton Road NE, 2nd Floor, Atlanta, GA, 30322, USA. smaithe@emory.edu.
Abstract
BACKGROUND: Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) are highly vascular neoplasms treated similarly, irrespective of tumor location. The expression of pro-angiogenic factors (STAT3, VEGF, and HIF-1α) and their association with adverse pathologic factors and disease recurrence following resection remains unclear. METHODS: All patients with non-metastatic GEP-NETs who underwent curative-intent resection from 2000 to 2013 were included. Immunohistochemistry was performed for pro-angiogenic factors, Ki-67 index, and CD31 using tissue microarrays made in triplicate by a pathologist blinded to other clinicopathologic variables. Primary outcome was a 3-year recurrence-free survival (3-yrRFS); secondary outcomes were correlation of pro-angiogenic factors with Ki-67 index, adverse pathologic factors, and CD31 expression, a marker of microvascular density. RESULTS: Of 144 GEP-NETs resected, STAT3 expression was high in 12 (8%) and low in 132 (92%) pts. High STAT3 expression was associated with worse 3-yrRFS compared to low expression (55% vs 84%; p = 0.003). High VEGF expression had a 3-yrRFS of 76% vs 82% for low expression (p = 0.09). HIF-1α expression was not associated with RFS. Ki-67 ≥ 3% was associated with worse 3-yrRFS (≥ 3%: 51% vs < 3%: 84%; p < 0.001), as was the presence of increased microvascular density (CD31 > median: 75% vs CD31 < median: 86%; p = 0.04). High STAT3 expressing tumors were more likely to have a Ki-67 ≥ 3% (42% vs 7%; p < 0.001). LVI was present in 82% of high STAT3 tumors compared to only 50% with low STAT3 (p = 0.058). CD31 expression was similar between groups (58% vs 49%; p = 0.5). CONCLUSIONS: In resected GEP-NETs, high STAT3 expression is associated with an increased Ki-67 index, presence of lymphovascular invasion and worse 3-yr RFS. STAT3 may be a novel therapeutic target for patients undergoing resection of high-risk tumors.
BACKGROUND:Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) are highly vascular neoplasms treated similarly, irrespective of tumor location. The expression of pro-angiogenic factors (STAT3, VEGF, and HIF-1α) and their association with adverse pathologic factors and disease recurrence following resection remains unclear. METHODS: All patients with non-metastatic GEP-NETs who underwent curative-intent resection from 2000 to 2013 were included. Immunohistochemistry was performed for pro-angiogenic factors, Ki-67 index, and CD31 using tissue microarrays made in triplicate by a pathologist blinded to other clinicopathologic variables. Primary outcome was a 3-year recurrence-free survival (3-yrRFS); secondary outcomes were correlation of pro-angiogenic factors with Ki-67 index, adverse pathologic factors, and CD31 expression, a marker of microvascular density. RESULTS: Of 144 GEP-NETs resected, STAT3 expression was high in 12 (8%) and low in 132 (92%) pts. High STAT3 expression was associated with worse 3-yrRFS compared to low expression (55% vs 84%; p = 0.003). High VEGF expression had a 3-yrRFS of 76% vs 82% for low expression (p = 0.09). HIF-1α expression was not associated with RFS. Ki-67 ≥ 3% was associated with worse 3-yrRFS (≥ 3%: 51% vs < 3%: 84%; p < 0.001), as was the presence of increased microvascular density (CD31 > median: 75% vs CD31 < median: 86%; p = 0.04). High STAT3 expressing tumors were more likely to have a Ki-67 ≥ 3% (42% vs 7%; p < 0.001). LVI was present in 82% of high STAT3tumors compared to only 50% with low STAT3 (p = 0.058). CD31 expression was similar between groups (58% vs 49%; p = 0.5). CONCLUSIONS: In resected GEP-NETs, high STAT3 expression is associated with an increased Ki-67 index, presence of lymphovascular invasion and worse 3-yr RFS. STAT3 may be a novel therapeutic target for patients undergoing resection of high-risk tumors.
Authors: Javier Pozas; María San Román; Teresa Alonso-Gordoa; Miguel Pozas; Laura Caracuel; Alfredo Carrato; Javier Molina-Cerrillo Journal: Int J Mol Sci Date: 2019-10-08 Impact factor: 5.923