Pancreatic Endocrine Tumors With Major Vascular Abutment, Involvement, or Encasement and Indication for Resection FREE

Malignant pancreatic endocrine tumors (PETs) may have a good prognosis.^1- 7 Unfortunately, a proportion present late with tumors that encase or invade adjacent major blood vessels.^8- 10A number of studies have shown that vascular invasion in patients with both pancreatic adenocarcinomas and advanced PETs is associated with decreased survival.^2,4,11- 15 The surgical approach to this group of patients is controversial. Based on analogies to pancreatic adenocarcinoma and limited experience with attempted surgical resection of patients with advanced PETs, for many, involvement of the superior mesenteric vein (SMV), inferior vena cava (IVC), portal vein (PV), splenic vein with extensive varices, superior mesenteric artery (SMA), aorta, or heart is considered a contraindication to surgery.^11,14,16

Recent surgical series in pancreatic adenocarcinoma question this approach.^{11,14,17- 19} The operability of pancreatic tumors is usually defined by the results of computed tomography (CT).^{9- 11,14,20- 21} However, these studies may not always accurately determine operability.¹⁴ For example, in patients with adenocarcinoma of the pancreas, when preoperative CT suggests that the tumor involves the SMV, SMA, or PV, many surgeons say that it is inoperable.^11,14,17 However, recent studies dispute this thinking and suggest that these locally advanced tumors may be resectable for benefit.^{11,14,17,22- 24} Sarcomas involving blood vessels that were previously thought to be inoperable have been recently resected with acceptable morbidity and good survival.²⁵ Because PETs are rare, there have been no systematic studies of the ability to surgically resect malignant PETs thought to abut or involve major vascular structures, with most reports involving only a few PET patients.^{9- 10,26- 33} In this study, we report our long-term results with PETs that abut or involve major vascular structures, including the PV, SMV, SMA, IVC, splenic vein with large collaterals, and the heart (interventricular septum). The findings suggest that possible/definite major vascular involvement on preoperative imaging studies should not be a contraindication to PET resection.

Since 1982 at the National Institutes of Health and since 2004 at Stanford University hospitals, 195 patients with Zollinger-Ellison syndrome and 78 patients with either functional or nonfunctional pancreatic PETs were involved in a prospective plan to perform surgical exploration for cure as described elsewhere.^34- 41 All patients at the National Institutes of Health, after confirmation of the diagnosis, underwent detailed imaging studies to determine operability.^{34,36,42- 46} Patients at Stanford University School of Medicine underwent CT. Patients were counseled to undergo surgery if they had no medical contraindication and appeared operable, and if multiple endocrine neoplasia type 1 was present and they had a tumor 2½ cm or greater in diameter.^{35- 37,40,47- 49} Patients were included with limited liver metastases.^38- 39,50 Forty-six patients (17%) were identified on CT or magnetic resonance imaging or both to have a PET that involved a major vascular structure. This included patients in whom the PET involved the heart⁵¹ or the IVC either abutted (Figure 1) or encased the SMV or PV (Figure 2 and Figure 3) or the SMA or invaded the splenic vein with large short gastric collateral vessels. Abutted means that the PET appeared to touch the vessel on CT and encased means that it surrounded the vessel. Criteria for diagnosis of Zollinger-Ellison syndrome and glucagonoma have been described elsewhere.^52- 58 A detailed past history of disease was taken.^52,58 Time from onset of the disease to exploration was determined.^35,59- 60 Multiple endocrine neoplasia type 1 was established by assessing plasma hormone levels and family history.^37,48,58,61

Forty-four of 46 patients underwent surgical exploration. The operative techniques have been described elsewhere.^{35- 36,47,62- 63} We did not use the cell saver, octreotide, or any other blood conservation measures. We did not perform frozen section on pancreatic or vascular margins. Tumors in the pancreatic head were enucleated, and body and tail were resected. If large pancreatic head tumors were present and could not be enucleated, a pancreaticoduodenectomy was performed.⁶⁴ A detailed inspection for lymph nodes was performed, and these were routinely removed.^34,65 If liver metastases were present and localized, they were wedge resected with a 1-cm margin, if possible; if this was not possible, a segmental resection or lobectomy was performed.^38- 39,50 If the SMV was resected and reconstructed, it was performed with either the proximal femoral vein or the jugular vein.^25,39 The SMA was reconstructed with the saphenous vein.^25,39 After surgery, patients underwent evaluation for disease-free status (ie, 2 weeks after resection, within 3 to 6 months after resection, and then yearly).^35,43,59,62 Disease-free status was defined as no evidence of tumor on conventional imaging studies, usually CT. For patients with functional PETs (gastrinoma or glucagonoma), complete disease-free status was also assessed by plasma hormone levels.^35- 36,59 A recurrence after resection was defined as loss of disease-free status on follow-up evaluation by developing positive imaging studies (nonfunctional PETs or functional PETs) and/or recurrent elevations of fasting hormone test results.^{35- 36,59,66} Recurrent disease was treated with chemotherapy or somatostatin analogues with or without alpha interferon, as described elsewhere.^67- 69

The Fisher exact test was used for 2-group comparisons. All continuous variables were reported as mean (SEM). The probabilities of survival were calculated and plotted according to the Kaplan-Meier method.⁷⁰

Forty-six patients (17%) were identified on preoperative imaging studies as having pancreatic PETs either involving the IVC, heart, or PV or abutting or encasing the SMV (Figures 1-3), SMA, or splenic vein with extensive collateral veins (Table 1 and Table 2). Thirty functional PET patients presented with symptoms related to Zollinger-Ellison syndrome (peptic ulcer disease, gastroesophageal reflux disease, and diarrhea), and 2 glucagonoma patients presented with a rash that was later called necrolytic migratory erythema. Although the nonfunctional PET patients each presented with pain, 6 functional PET patients also had pain as a presenting symptom (Table 1). For the patients with functional PETs, symptoms were present for approximately 5 years before the diagnosis was made. The median gastrin increase for the Zollinger-Ellison syndrome patients was 12-fold (Table 1).

Table 2 presents preoperative tumoral features assessed by imaging studies. Three primary tumors were ectopic: 2 in the interventricular septum of the heart and the other within the wall of the right hepatic duct abutting the right PV (Figure 4).

Forty-four of the 46 patients (96%) underwent surgery (2 refused surgery), and in 42 patients the primary tumor was resected (Table 3). Fifteen patients had vascular encasement located in the heart (n = 1), the IVC (n = 1), the SMA (n = 1), and the PV or SMV (n = 12) (Figures 2 and 3B and Table 3).

Resections included partial pancreatectomy (either distal or subtotal pancreatectomy) in 23 patients, Whipple proximal pancreaticoduodenectomy in 10, and total pancreatectomy in 2 (Table 4). Eighteen patients (41%) had concomitant liver resection: 10 (23%) had wedge resections and 8 (18%) had anatomic resections (Table 4). Nine patients (20%) had vascular reconstruction: each had reconstruction of the SMV and PV, whereas 1 patient had concomitant reconstruction of the SMA. The median (range) operative blood loss was 500 mL (200 mL-6.2 L). The median (range) hospital stay was 9 (7-33) days.

Table 4 presents the type and results of surgery, follow-up, and complications. The 10-year actuarial overall survival is 60%, and the disease-free survival is 30% (Figure 5). Possible prognostic factors were examined to determine whether they affected overall and disease-free survival. Most variables did not affect disease-free survival (Table 5). Patients with functional tumors had a greater long-term overall survival than those with nonfunctional tumors, but the disease-free survival was similar (P < .001) (Figure 6). The presence of lymph node metastases did not decrease disease-free survival. However, disease-free survival was decreased from 66% to 10% by the presence of liver metastases (P = .002) as well as by the use of liver resection (P = .007). The use of vascular reconstruction did not affect disease-free survival (Table 5). The use of other anti-tumor treatment following surgery significantly decreased disease-free survival (Table 5).

This article focuses on the role of surgery in removing PETs abutting, invading, or encasing a major blood vessel, usually the SMV or PV (Figures 1-3), as well as removing the primary tumor, lymph nodes, and any limited liver metastases in these patients. This study was undertaken for a number of reasons. First, a proportion of PETs show aggressive, malignant growth, which is associated with decreased survival, and the medical treatment of these large, advanced tumors is generally only marginally effective.^67,71- 73 Second, a number of studies have shown that vascular invasion in patients with pancreatic adenocarcinomas and those with advanced PETs is associated with decreased survival.^2,4,11- 15 Third, there are a number of surgical reports by different groups that resection of distant metastatic PETs, including those within the liver, may improve survival.^{38,50,74- 77}A recent consensus statement recommended that patients with limited liver metastases be considered for resection.^{3,38,50,71,74- 75,78} Fourth, recent studies in patients with exocrine adenocarcinoma of the pancreas—similar to PETs—suggest that these tumors, even when invading venous structures, may be resected with acceptable morbidity and benefit.^{11,14,17- 19} Similarly, resection of invasive sarcomas of the extremity and retroperitoneum that involve major blood vessels, resulting in the complete removal of tumors previously thought to be inoperable, has been recently reported with favorable outcomes.²⁷ Furthermore, numerous series suggested a similar approach might be feasible and perhaps beneficial in patients with advanced functional^9,28,79- 81 and nonfunctional PETs.^{9,29- 30,33,82- 84} Fifth, an aggressive PET can also cause dramatic life-threatening complications, such as massive bleeding, because of the formation of vascular shunts²⁷ or short gastric varices in the setting of splenic vein occlusion by tumor.^80,83- 86 Successful resection of these primary PETs, even in cases of early vascular involvement, may significantly delay or prevent the occurrence of such complications.

In our study, we found that resections were feasible, safe, and associated with long-term survival, even though the tumors were usually large (mean size, 5.0 cm) with metastatic disease. One important observation in this study is that tumor invaded and/or encased a major vascular structure in less than half the patients (34%), and in the remaining patients, the PET had only partial vascular involvement or vascular abutment without encasement and/or invasion of a major vascular structure. This result is similar to that in a study⁹ of patients with advanced large PETs: 50% of the patients thought to have vascular involvement from preoperative studies were found at surgery not to have vascular encasement and/or invasion of major vessels. Computed tomography and magnetic resonance imaging are reported to have excellent sensitivity for detecting vascular involvement and are the standard imaging modalities used to determine vascular involvement in patients with either pancreatic exocrine adenocarcinomas or PETs.^3,9- 11,14 In the present study, both modalities were used in the gastrinoma patients and CT in the nonfunctional PET patients. Our current preference is CT over magnetic resonance imaging because with thin slicing, timed intravenous contrast, and reconstruction, the images with CT allow the surgeon to see the disease and to plan the surgery effectively. With pancreatic adenocarcinomas, preoperative CT is reported to have excellent sensitivity for identifying involvement of major vessels; however, similar to our results in PETs, it can also have false-positive results in pancreatic adenocarcinoma, with specificity as low as 50% in some studies.^11,14 Our results demonstrate that with PETs, radiologic abutment or even possible vascular involvement is frequently not synonymous with vascular involvement at surgery. The PET was found frequently to be encroaching, abutting, or distorting the major vascular structure, without encasing it and/or invading it. In other studies, in a small number of patients with PETs, there have been reports that CT may falsely suggest vessel involvement.^9,87 The quality and technique of imaging with CT has improved during the 22 years of this study, allowing clearer imaging of vessels with fewer false-positive results. Endoscopic ultrasound is another potentially useful study for assessing major vascular involvement; however, it was not used in this study, so we are unable to comment on its utility. In our study, only 9 of the 44 patients (20%) undergoing PET resections required vascular reconstruction, demonstrating that in most patients, the PET can be removed with careful dissection without requiring vascular reconstruction. These results differ from those of pancreatic adenocarcinoma, in which venous resection is usually required with tumor involvement and in which the percentage of the patients with potentially resectable disease having major vascular involvement is much lower.^{14,17,23- 24}

In our study, despite the extensive tumor involvement, patients who underwent resection of PETs had impressive actuarial overall and disease-free survival rates at 5 years, 60% and 30%, respectively. An important prognostic factor associated with a decreased disease-free survival was the presence of liver metastases, which has been described elsewhere.^4- 7,71,88 In contrast, disease-free survival was not affected by either the extent or type of vascular involvement or by the presence of other factors that have prognostic significance for disease-free or total survival in other studies of PET patients.^{2,4,6- 7,71,88} In our study, patients with nonfunctional PETs with possible vascular involvement had a significantly decreased (P < .001) survival compared with the survival of similar patients with functional PETs. In previous reports, patients with nonfunctional PETs have poorer survival than patients with functional PETs.^1,4- 5,7,89 The decreased survival of patients with nonfunctional PETs is reported to be likely due to their more aggressive behavior or more advanced disease.^1,7 In our study, the extent of disease in the patients with functional and nonfunctional tumors was comparable, which supports the proposal that these patients have more aggressive tumors.^1,7

Unfortunately, our study, like many other surgical series of patients with advanced PETs, including those with liver metastases, does not clearly establish the value of the surgical approach taken.^76- 78,90 Nevertheless, a number of findings in our study are suggestive of surgical benefit. First, despite the decreased survival of patients with vascular involvement and/or liver metastases with malignant PETs,^{2,4,12- 13,71- 72} the overall survival rate was 60% at 5 years and 30% of patients remained disease free. These data are encouraging because, in historic controls, patients with metastatic PETs with vascular involvement who did not undergo surgery had a 5-year survival rate of 30% to 40%.^89,91 Second, in our study, these results were obtained in the setting of major pancreatic resection (79%), plus liver resection in 41%, vascular dissection in all, and reconstruction in 20%. Despite this extent of surgical dissection, there was no surgical mortality, and the surgical complication rate (27%) was well within the range of that reported in previous studies with PET resections by means of lesser procedures.^1,92- 93 Third, in the present study, 5 patients presented with upper gastrointestinal hemorrhage from gastric varices secondary to splenic vein occlusion by the PET, and the bleeding was totally ameliorated by removal of the tumor with the spleen. This experience is similar to that reported in a small number of case reports.^{8,83,85- 87,94- 96} These results suggest that the resection of the PET despite vascular involvement is of particular benefit in this group of PET patients. Fourth, medical therapies of advanced PETs have provided only modest benefits, with many studies reporting short-term disease stabilization and a small percentage of partial responses.^71- 73,97 Therefore, it has generally not been possible to downsize extensive disease in a patient with a malignant PET to make it surgically resectable, as has been performed in some other tumors.^{71- 73,98- 99} Our data suggest that major vascular involvement is not a contraindication to surgery. Because radiographic evidence of vascular involvement represented 20% of our PET population, these findings apply to a significant number of PET patients seen in the community, and such patients should be referred to a tertiary care facility where multidisciplinary expertise is available.

Correspondence: Jeffrey A. Norton, MD, Department of Surgery, Stanford University Medical Center, 300 Pasteur Dr, Room H-3591, Stanford, CA 94305-5641 (janorton@stanford.edu).

Accepted for Publication: May 20, 2010.

Author Contributions:Study concept and design: Norton, Harris, Chen, and Jensen. Acquisition of data: Norton, Harris, Chen, Visser, and Jensen. Analysis and interpretation of data: Norton, Chen, Poultsides, Kunz, Fisher, and Jensen. Drafting of the manuscript: Norton and Jensen. Critical revision of the manuscript for important intellectual content: Norton, Harris, Chen, Visser, Poultsides, Kunz, Fisher, and Jensen. Statistical analysis: Norton, Chen, Fisher, and Jensen. Obtained funding: Norton and Jensen. Administrative, technical, and material support: Norton, Harris, Chen, and Visser. Study supervision: Norton and Kunz.

Financial Disclosure: None reported.

Funding/Support: This study was partially supported by intramural funds of the National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health.