The Pancreas as a Site of Metastasis or Second Primary in Patients with Small Bowel Neuroendocrine Tumors.

BACKGROUND: The small bowel and pancreas are the most common primary sites of neuroendocrine tumors (NETs) giving rise to metastatic disease. Some patients with small bowel NETs (SBNETs) present with synchronous or metachronous pancreatic NETs (PNETs), and it is unclear whether these are separate primaries or metastases from one site to the other. METHODS: A surgical NET database including patients undergoing operations for SBNETs or PNETs was reviewed. Patients with synchronous or metachronous tumors in both the small bowel and pancreas were identified, and available tissues from primary tumors and metastases were examined using a 4-gene quantitative polymerase chain reaction (qPCR) and immunohistochemistry (IHC) panel developed for evaluating NETs of unknown primary. RESULTS: Of 338 patients undergoing exploration, 11 had NETs in both the small bowel and pancreas. Tissues from 11 small bowel tumors, 9 pancreatic tumors, and 10 metastases were analyzed. qPCR and IHC data revealed that three patients had separate SBNET and PNET primaries, and five patients had SBNETs that metastasized to the pancreas. Pancreatic tissue was unavailable in two patients, and qPCR and IHC gave discrepant results in one patient. CONCLUSIONS: NETs in both the small bowel and pancreas were found in 3% of our patients. In nearly two-thirds of evaluable patients, the pancreatic tumor was a metastasis from the SBNET primary, while in the remaining one-third of patients it represented a separate primary. Determining the origin of these tumors can help guide the choice of systemic therapy and surgical management.

The Distal Predilection of Small Bowel Neuroendocrine Tumors.

BACKGROUND: The small bowel (SB) is the most common site of neuroendocrine tumors (NETs) of the GI tract. These are described as being predominantly jejunoileal, but their exact locations within the SB have not been well defined. We sought to determine prospectively the spectrum of SBNET locations. METHODS: Patients undergoing exploration for SBNET primaries had measurement of bowel length, tumor locations, and resection length recorded. Correlations of clinicopathologic factors were performed, and analysis done utilizing Welch's t test, Chi square test, and the Kaplan-Meier method. RESULTS: Measurements were recorded in 123 patients, 107 of whom had complete information. Multifocal tumors (MTs) were found in 69 (56%) and unifocal (UTs) in 54 (44%) patients. Only 1 of 107 patients had a tumor within 100 cm of the ligament of Treitz (LT), whereas 77 of 107 (72%) had tumors within 100 cm of the ileocecal valve (ICV). No MTs were found within 100 cm of LT, whereas 41 of 60 (68%) patients had all (10) or at least one tumor (31) located within 100 cm of the ICV. MTs required a mean resection length of 108 versus 59 cm for UTs (p < 0.01). Seventy-seven percent of UTs (36/47) were within 100 cm of ICV. Tumors occurring only between > 100 cm from the LT and ICV were seen in 29 of 107 (27%) patients. CONCLUSIONS: SBNETs are frequently multifocal and most commonly located within 100 cm of the ICV. SBNETs are less prevalent proximally in the small bowel, which may result from anatomic differences in enterochromaffin cell density, hormonal factors, or environmental exposures in the distal SB.

Increased Grade in Neuroendocrine Tumor Metastases Negatively Impacts Survival.

BACKGROUND: Tumor grade is an important predictor of survival in gastroenteropancreatic (GEP) neuroendocrine tumors (NETs), as determined by Ki-67 expression and mitotic rate. NETs generally grow indolently, but some cells may acquire traits facilitating metastasis. It is unclear how frequently metastases differ in grade from their primary tumors, and whether increasing grade in metastases affects prognosis. METHODS: Ki-67 immunohistochemistry was performed on resected GEPNET specimens and cases with results for both primary tumors and concurrent metastases were identified. Grade was determined using a modified World Health Organization classification (Ki-67: G1 = 0-2%; G2 > 2-20%; G3 > 20%). RESULTS: Ki-67 was performed on both the primary tumor and metastases in 103 patients. Tumor grade was higher in metastases from 25 (24%) patients, 24 increased from G1 to G2, and 1 increased from G2 to G3; 68 (66%) patients had no change in grade (42 G1 and 26 G2), and 10 (10%) decreased from G2 to G1. No clinicopathologic factors were predictive of higher grade in metastases. The 5-year progression-free survival (PFS) was 55% for patients with stable grade versus 8% of patients with increased grade, while 5-year overall survival (OS) was 92 and 54%, respectively. The 5-year OS of patients who had stable grade with G1 and G2 primaries was 92 and 64%, respectively. CONCLUSIONS: Nearly one-third of patients had metastases with a different grade than their primary, and, when grade increased, both PFS and OS significantly decreased. Determining the grade in both the primary tumor and a metastasis is important for estimating prognosis and to help inform decisions regarding additional therapies.

Radial Recurrent Artery: Autologous Patch Graft for Acute Brachial Artery Laceration.

Brachial artery injury is the most common vascular disruption in upper extremity penetrating trauma, usually treated by primary repair or saphenous vein interposition graft. We report the case of a young male who presented after assault with stab wound to the right antecubital fossa, an asymmetric vascular exam, and unknown depth contaminated wound that warranted operative exploration. We performed open exploration through a triangular flap extension of his oblique linear laceration for both exposure and flexor surface scar contracture prophylaxis. Exploration revealed brachial artery laceration with loss of approximately 30% of vessel circumference proximal to the radial and ulnar artery bifurcation. A near-complete transection of the recurrent radial artery was also present, leading to the decision to sacrifice this vessel for use as an autologous patch graft of the injured brachial artery. Distal vascular flow was re-established, and the vessel was slightly ectatic with no evidence of stenosis. Patient suffered no complications and was discharged at post-operative day four after perioperative heparin drip on anti-platelet therapy. Autologous patch grafting in the acute setting is a less-often considered surgical option that is effective for arterial bifurcation reconstruction, which may be employed through the sacrifice of injured and redundant local branch vessels. Patch grafts are commonly utilized in planned vascular surgery, such as carotid endarterectomy, but this is the first report of autologous patch graft to an acute brachial artery injury. By combining knowledge of the lateral arm flap with the plastic surgery principles of "like replaces like", this technique avoids the stenosis associated with primary repair, the multiple anastomoses necessary for interposition grafting, the need for a secondary donor site, and provides a theoretical blood-flow advantage.

Effective cytoreduction can be achieved in patients with numerous neuroendocrine tumor liver metastases (NETLMs).

BACKGROUND: Cytoreductive surgery for neuroendocrine tumor liver metastases improves survival and symptomatic control. However, the feasibility of adequate cytoreduction in patients with many liver metastases remains uncertain. We compared patient outcomes based on the number of lesions treated to better define the efficacy of cytoreductive surgery for numerous neuroendocrine tumor liver metastases. METHODS: Patients undergoing hepatic cytoreductive surgery for gastroenteropancreatic neuroendocrine tumors were identified in our institutional surgical neuroendocrine tumor database. Imaging studies were reviewed to determine the liver tumor burden and percent cytoreduced. Overall survival and progression-free survival were compared, using the number of lesions treated, percent tumor debulked, and additional clinicopathologic characteristics. RESULTS: A total of 188 hepatic cytoreductive procedures were identified and stratified into groups according to the number of metastases treated: 1-5, 6-10, and >10. Median overall survival and progression-free survival were 89.4 and 22.5 months, respectively, and did not differ significantly between groups. Greater than 70% cytoreduction was associated with significantly better overall survival than <70% cytoreduction (134 months versus 38 months). CONCLUSION: In patients with gastroenteropancreatic neuroendocrine tumors and liver metastases, >70% cytoreduction led to improved overall survival and progression-free survival and was achieved reliably in patients undergoing debulking of >10 lesions. These data support an aggressive approach to patients with numerous neuroendocrine tumor liver metastases to achieve >70% cytoreduction.

Changes in gene expression in small bowel neuroendocrine tumors associated with progression to metastases.

BACKGROUND: Small bowel neuroendocrine tumors (SBNETs) present frequently with metastases, yet little is known about the molecular basis of this progression. This study sought to identify the serial differential expression of genes between normal small bowel, primary small bowel neuroendocrine tumors, and liver metastases. METHODS: RNA isolated from matched normal small bowel tissue, primary small bowel neuroendocrine tumors, and liver metastases in 12 patients was analyzed with whole transcriptome expression microarrays and RNA-Seq. Changes in gene expression between primary small bowel neuroendocrine tumors and normal small bowels, and liver metastases versus primary small bowel neuroendocrine tumors were calculated. Common genes that were differentially expressed serially (increasing or decreasing from normal small bowel to primary small bowel neuroendocrine tumors to liver metastases) were identified, and 10 were validated using qPCR. RESULTS: Use of 2 transcriptome platforms allowed for a robust discrimination of genes important in small bowel neuroendocrine tumors progression. Serial differential expression was validated in 7/10 genes, all of which had been described previously in abdominal cancers, and with several interacting with members of the AKT, MYC, or MAPK3 pathways. Liver metastases had consistent underexpression of PMP22, while high expression of SERPINA10 and SYT13 was characteristic of both pSBTs and liver metastases. CONCLUSION: Identification of the serial differential expression of genes from normal tissues to primary tumors to metastases lends insight into important pathways for SBNETs progression. Differential expression of various genes, including PMP22, SYT13 and SERPINA10, are associated with the progression of SBNETs and warrant further investigation.

Is Multifocality an Indicator of Aggressive Behavior in Small Bowel Neuroendocrine Tumors?

OBJECTIVES: Many patients with small bowel neuroendocrine tumors (SBNETs) have multifocal tumors (MFTs), but the frequency of MFTs has varied widely across SBNET studies. It is also unclear whether patients with MFTs have more advanced disease or worse clinical course than do those with unifocal SBNETs. We set out to determine the frequency of multifocal and unifocal SBNETs and compare clinicopathologic factors, somatostatin receptor 2 expression, and survival. METHODS: Clinicopathologic variables from 179 patients with surgically managed SBNETs were collected. Statistical comparisons were made using Welch t-test, Wilcoxon test, and Fisher's exact test. Survival was assessed using the Kaplan-Meier method. Somatostatin receptor 2 expression was analyzed by quantitative polymerase chain reaction, and Ki-67 expression by immunohistochemistry. RESULTS: Multifocal tumors were found in 45% of patients with SBNETs. Clinicopathologic factors such as grade, TNM stage, presence of distant metastases, mean somatostatin receptor 2 expression, success of imaging modalities, and preoperative and postoperative hormone levels were not significantly different between multifocal and unifocal groups. Progression-free survival and overall survival were also not significantly affected by multifocality. CONCLUSIONS: Clinicopathologic features and survival of patients with MFTs and unifocal tumors are remarkably similar. Although the etiology of MFTs is unclear, patients with MFTs do not have a more aggressive clinical course than patients with unifocal SBNETs.

Identification of primary tumors in patients presenting with metastatic gastroenteropancreatic neuroendocrine tumors.

BACKGROUND: Patients with gastroenteropancreatic neuroendocrine tumors often present with metastases. Identification of the primary tumor is important for operative management, and therefore we sought to determine our success at identifying primary tumors with diagnostic testing and operative exploration. METHODS: A clinical neuroendocrine tumor database was reviewed to identify patients presenting with metastases and primary tumor in situ. Results of radiologic, endoscopic, and operative procedures were evaluated to determine which correctly identified the primary tumor. RESULTS: There were 197 patients presenting with metastases and unresected primaries, 134 who had an operation and 63 managed nonoperatively. Primaries were identified preoperatively in 168 (84%), at operative exploration in 7, and were not found in 22 patients. Computed tomography found 150/197 primary tumors, somatostatin-receptor scintigraphy 88/155, and endoscopy 43/107. The sensitivity of computed tomography surpassed scintigraphy (76% vs 57%, P < .01). The primary was removed in 130/134 (97%) patients, and hepatic debulking was performed in 67%. Median survival for operative patients with small bowel and pancreatic tumors was 145 and 71 months, respectively. CONCLUSION: Imaging and endoscopy identified the primary tumor in most patients, and the majority of the others were found at exploration. Preoperative testing facilitated operative planning, allowing for resection of the primary and hepatic debulking in most patients.