Management of patients with neuroendocrine tumors (NETs) of the pancreas causes considerable controversy because rarity of this neoplasm. The aim of the ...
POLSKI PRZEGLĄD CHIRURGICZNY 2010, 82, 7, 417–421
10.2478/v10035-010-0058-1
Surgical treatment of neuroendocrine tumors of the pancreas Sebastian Dobrowolski1, Zbigniew Śledziński1, Krzysztof Sworczak2, Małgorzata Hellmann2, Anna Babińska2 Department of General, Endocrine and Transplant Surgery, Medical University in Gdańsk1 Kierownik: prof. dr hab. Z. Śledziński Department of Endocrinology and Internal Medicine, Medical University in Gdańsk2 Kierownik: prof. dr hab. K. Sworczak Management of patients with neuroendocrine tumors (NETs) of the pancreas causes considerable controversy because rarity of this neoplasm. The aim of the study was to present our results of treatment of patients with NETs and to sum up our experience in surgical management. Material and methods. Thirty four patients with neuroendocrine tumors of the pancreas were treated in Department of General, Endocrine and Transplant Surgery of Medical University in Gdańsk (24 inulinomas and 10 nonfunctioning neuroendocrine tumors). Insulinoma was present in the head of the pancreas in 3 cases, in the body in 8 cases, and 10 patients had lesion situated within the tail. Results. Localization of the tumor in patients with organic hyperinsulinism was possible in 21 out of 24 operated patients (17 patients with use of preoperative imaging studies, 4 patients with Intraoperative ultrasonography). In 3 remaining patients the localization of the pathologic mass was impossible with use of pre- and intraoperative techniques. Conclusions. Treatment of choice of patients with neuroendocrine tumors of the pancreas is surgery. Management of patients with islet cells adenomatosis is still difficult clinical problem. Key words: insulinoma, neuroendocrine tumor, nesidioblastosis, pancreatic islet
Neuroendocrine tumors (NETs) are derived from neuroendocrine cells spread in the human body from the digestive and respiratory tracts, urinary and nervous systems (1) to the skin (2). These cells have similar features to the endocrine cells and express antigens that are also common in the nervous system (e.g. synaptophysin, neuron-specific enolase, chromogranins), what led to the term of neuroendocrine cells. Neuroendocrine tumors has different morphology and clinical presentation, especially in ability to metastasis, what cause problems with their classification. There are 15 types of neuroendocrine cells being source of the neuroendocrine tumors in the digestive tract and pancreas, where the NETs are found most frequently (1). The World Health Organization 2000 classification of
neuroendocrine tumors of the digestive tract and the pancreas identifies three tumors categories: 1) well-differentiated endocrine tumors with benign or uncertain behavior at the time of diagnosis, 2) well-differentiated endocrine tumors with low grade malignant behavior, 3) poorly differentiated endocrine carcinomas with high-grade malignant behavior. The classification was then subdivided on the basis of localization and biology of the tumors. For localization, the stomach, duodenum and jejunum, ileum, appendix, colon-rectum, and pancreas were distinguished. The biologic criteria employed were tumor size, angioinvasion, proliferative activity, histological differentiation, presence of metastases and hormonal activity. The WHO classification of neuroendocrine tumors of the pancreas is presented in tab. 1.
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S. Dobrowolski et al. Table 1. WHO classification of neuroendocrine tumors of the pancreas
1.
Well-differentiated neuroendocrine tumor Benign: confined to pancreas, 2 mitoses/HPF, >2% Ki-67-positive cells Functioning: gastrinoma, insulinoma, VIPoma, glucagonoma, somatostatinoma, ectopic hormonal syndrome Nonfunctioning 2. Well-differentiated neuroendocrine carcinoma Low grade malignant: invasion of adjacent organs and/or metastases Functioning: gastrinoma, insulinoma, VIPoma, glucagonoma, somatostatinoma, ectopic hormonal syndrome Nonfunctioning 3. Polory differentiated neuroendocrine carcinoma High grade malignant
The European Neuroendocrine Tumour Society (ENETS) in 2005 developed guidelines that were supplemented by a proposal for tumor/nodes/metastases (TNM) classification of neuroendocrine tumors (4). The ENETS classification of neuroendocrine tumors of the pancreas is presented in tab. 2. The aim of the study is to present our results of treatment of patients with neuroendocrine tumors of the pancreas and discuss the strategy of surgical management. MATERIAL AND METHODS From 1960 to 2009, 34 patients (23 females and 11 males; mean age 39.8 years; range 15
to 70) with neuroendocrine tumors of the pancreas in Department of General, Endocrine and Transplant Surgery of Medical University of Gdańsk. Among 34 analized patients, in 24 the insulinoma was diagnosed, and in the remaining 10 the hormonally inactive neuroendocrine tumor. The diagnosis of insulinoma was established by detailed history taking, physical examination, biochemical measurements (blood glucose level, serum insulin and C-peptide during overnight fasting, and a 72-hours supervised fasting hypoglycemic test), and imaging studies (ultrasonography, computes tomography, magnetic resonance). Intraoperative ultrasonography was used since 1990.
Table 2. Proposal for a TNM classification of neuroendocrine tumors of the pancreas T – primary tumor TX – primary tumor cannot be assessed T0 – no evidence of primary tumor T1 – limited to the pancreas and size 4 cm or invading duodenum or bile duct T4 – invading the wall of adjacent large vessels (celiac axis or superior mesenteric artery), stomach, spleen, colon, arenal gland For and T, add (m) for multiple tumors N – regional lymph nodes NX – regional lymph node status not assessed N0 – absence of lymph node metastasis N1 – presence of regional lymph node metastasis M – distant metastases MX – distant metastasis not assessed M0 – absencje of distant metastases M1 – odistant metastases Stage: Stage I T1 N0 M0 Stage IIa T2 N0 M0 Stage IIb T3 N0 M0 Stage IIIa T4 N0 M0 Stage IIIb any T N1 M0 Stage IV any T any N M1
Surgical treatment of neuroendocrine tumors of the pancreas
At laparotomy, after full mobilization of the pancreatic head, trunk and tail, the bimanual palpation of the pancreas was performed. Abdominal exploration of the whole abdominal cavity was done for nodal and distant metastases diagnosis, with special attention to the liver. Histopathologic diagnosis of non-active neuroendocrine pancreatic tumors was based on the percutaneous biopsy or Intraoperative pathologic examination. RESULTS Insulinoma were localized preoperatively in 17 of 24 patients. In 4 patients the tumor was found with use of Intraoperative ultrasonography. In 3 remaining patients the localization of the pathologic mass was impossible with use of pre- and intraoperative techniques. Insulinoma was present in the head of the pancreas in 3 cases, in the body in 8 cases, and 10 patients had lesion situated within the tail. In patients with detected tumors enucleation (14 patients), pancreatic distal resection (6 patients) or pancreatoduodenectomy (1 patient) were performed. In absence of any palpable mass in 3 patients “blind distal pancreatectomy” was done. Among 24 patients with organic hyperinsulinism the hypoglycemic symptoms resolved in 23 cases after surgical treatment. In one female patient after “blind distal pancreatic resection” the symptoms of hyperinsulinism did not cease. This patients was reoperated and subtotal pancreatectomy was performed with satisfactory results. In 20 resected specimens the solid benign tumor was detected, in one case the pathologic examination revealed malignant insulinoma, and in 3 cases the adenomatosis of βcells was diagnosed. Among 24 operated patients in 6 cases after enucleation of the insulinoma the pancreatic fistula occurred. After conservative treatment the fistula closed spontaneously in 4 patients after 3-6 weeks. In 2 patients the fistula disappeared after endoscopic sphincterotomy and pancreatic stent placement. Patients with hormonally non-active pancreatic tumors were treated with pancreatoduodenectomy (2 patients), enucleation (3 patients), distal pancreatectomy (3 patients), distal pancreatectomy with partial colectomy (1 patient), distal pancreatectomy with partial
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colectomy and partial gastrectomy (1 patient). DISCUSSION The incidence of neuroendocrine tumors of the pancreas has been estimated to be 1/100 000 people/1 year (5). The NETs usually present as solitary well-demarcated neoplasms without defined capsule. Their size ranges from one to several centimeters. Multiple tumors are rarely observed and should always raise the suspicion of MEN 1 or VHL. Functioning neuroendocrine tumors of the pancreas produce several symptoms, e.g. insulinoma – Whipple’s triad, gastrinoma – ZollingerEllison syndrome, VIPoma – Verner-Morrison syndrome. Nonfunctioning tumors are most often incidental finding during imaging studies of the abdomen or become clinically apparent because of size (compression/invasion of adjacent organs) or presence of metastasis. In rare cases they present as pancreatitis (6). Diagnosis of neuroendocrine tumors of the pancreas contains biochemical measurements. Most of the tumors secret large amounts of chromogranin A, which is a precursor of some endocrine peptides, that can be detected in blood serum. Biochemical diagnosis should include also hormone measurements based on clinical symptoms. Localization of neuroendocrine tumors can become difficult in some patients. High Resolution Computed Tomography is the most frequently used imaging study for detection of NETs. Somatostatinreceptor scintigraphy (Octerscan) is highlyspecific diagnostic method of most neuroendocrine tumors of the pancreas, but less useful for insulinomas. Endoscopic ultrasonography is also effective method of localization of gastrinoma and other tumors situated in the pancreatic head (7). Preoperative localization of functioning neuroendocrine tumors of the pancreas is problematic in some patients. Intraoperative diagnosis includes Intraoperative ultrasonography and bimanual palpation of pancreas. In cases with non-localized tumor “the blind distal pancreatic resection” should not be performed. The operation should be ended and preoperative diagnosis performed. The treatment of choice in patients with NETs is surgery. The surgical procedure can be performed by open or minimally invasive
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method. Benign lesions with diameter 3 cm or the tumor is malignant, the pancreatoduodenectomy, central pancreatic resection or distal pancreatectomy should be performed. The distal pancreatectomy with splenectomy has higher incidence of perioperative complications, especially infection, the spleen preserving procedure is preferred form of operation (9). Minimally invasive treatment of neuroendocrine tumors of the pancreas is reserved for patients with benign tumors qualified for enucleation or distal pancreatectomy (10). The minimally invasive techniques is controversial for treatment of patients with gastrinoma. First, incidence of duodenal gastrinoma is 3-10 times higher than pancreatic gastrinoma. Second, most of the tumors are not preoperatively localized, especially in the duodenum. Third, high percentage of tumors has malignant character and give metastasis to the regional lymph nodes. Fourth, more than 75% of gastrinoma tumors are situated in the region of the pancreatic head (gastrinoma triangle), what makes more difficult to performed laparoscopic procedure (11). The treatment of patients with advanced neuroendocrine tumors of the pancreas causes considerable controversy for the rare incidence of this tumors and therefore lack of guidelines. Controversy is caused also because of high pathologic differentiation of the NETs, that is often confusing for pathologist for statement of malignancy of the tumor or even if it is primary or metatstatic. The treatment of advanced neuroendocrine tumors with use of proton-pomp inhibitors, somatostatin analogues or interferon effectively control hormonally active lesions. Contraindications for surgical treatment of pancreatic adenocarcinoma, i.e. superior mesenteric vein invasion, distant and lymph
nodes metastases, should not be used for qualification for operation of patients with NETs. The results of surgical treatment of patients with advanced tumors are not explicit, however some retrospective studies showed enhanced survival after surgical debulking (12). The treatment of patients with organic hyperinsulinism is hindered in cases of islet cells adenomatosis (nesidioblastosis, non-insulinoma pancreatogenic hypoglycemia syndrome). The presence of this syndrome was questioned by most clinicians and pathologists. This syndrome, despite of its rarity, is important illness characterized by postprandial neuroglycopenia, negative 72-hour fasting test and lack of pancreatic tumor in imaging studies (13). However the tumor is not visible also in 30% of patients with insulinoma (14). Patients with suspicion of islet cell adenomatosis should have done investigation of pancreatic regionalization of hyperinsulinism. That is study is SAVS (selective arterial calcium stimulation with venous sampling), which can detect the increase of insulin production in the right hepatic vein after stimulation with intrarterial calcium bolus into splenic, gastroduodenal and superior mesenteric artery. The results of this test can help in decision of type and range of surgical procedure (15). The vital prognostic factor of treatment for patients with neuroendocrine tumors of the pancreas is presence of distal metastasis. The liver is the most frequent organ with metastases of NETs. The amount of liver encompassed with metastases strictly correlates with survival (16). The results of treatment with chemotherapy and/or chemoembolization of metatstatic disease is unsatisfactory. The effective method of treatment of patients with liver metastasis from neuroendocrine tumors is still liver resection, thermoablation and cryoablation (17). The treatment of choice of patients with neuroendocrine tumors of the pancreas is surgery. Preoperative localization of the tumor can be difficult in some patients, especially with islet cell adenomatosis.
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