PNETs are classified into two entities, i.e., hormone-secreting and nonfunctioning tumors. Localization of small hormone-secreting symptomatic PNETs is sometimes difficult, while nonfunctioning PNETs are easy to identify. Arterial stimulation and venous sampling is quite useful to localize such tumors. Large nonfunctioning PNETs are often malignant and those larger than 10mm should be resected. The author has experienced an 8-mm nonfunctioning PNET accompanied by lymph node metastasis. Surgical resection provides the only chance for cure, including enucleation, segmental or left pancreatectomy, and pancreatic head resection. These procedures can be performed even under laparoscopy, although laparoscopic pancreatic head resection and pancreatoduodenectomy are still in the investigational phase and should not be applied to gastrinoma. Cytoreduction or debulking surgery may be performed in metastatic cases. Somatostatin analogues, especially the long-acting one, are useful to control symptoms. The mTOR inhibitor RAD001 seems to be an effective antitumor agent, preferably in conjunction with somatostatin.

View full abstract

We conducted a nationwide survey to estimate the incidence of neuroendocrine gastrointestinal tumors newly diagnosed in Japan from 2002 through 2004. Five hundred and fourteen pancreatic endocrine tumors(PETs) were collected and analyzed. Nonfunctioning tumors(NF-PETs) constituted 47.7% of PETs. Next in frequency were insulinoma (31.7%) and gastrinoma (8.6%). Malignancy was frequent in NF-PETs (46.1%) and gastrinomas (45.5%), but only 7.4% of insulinomas were malignant. The incidence of multiple endocrine neoplasia type-1 associated with PETs was 7.4%. At present, the epidemiological investigation performed in 2005 in Japan is being analyzed, and the results of this survey will be disclosed in the very near future.

View full abstract

There have been controversies in the pathological classification of neuroendocrine tumors arising from pancreatic islet cells. The WHO classification of the pathology of these tumors reported in 2004 first designated them as pancreas endocrine tumors and further subclassified these tumors into well-differentiated endocrine tumor, well-differentiated endocrine carcinoma, poorly-differentiated endocrine carcinoma and mixed exocrine-endocrine carcinoma. For well-differentiated endocrine tumor and carcinoma, these tumors were further subclassified according to the types of pancreas islet peptide hormones which are inappropriately secreted. Prediction of the biological behavior based on the histopathological features of resected tumor specimens has been well-known to be associated with difficulties. Therefore, in a recent classification, well-differentiated endocrine tumor was further classified into"benign behavior"and"uncertain behavior"based on the pathological characteristics and endocrine features of the tumor. Pancreas endocrine tumor is relatively rare but it is important for those involved in the management of these patients to become familiar with the recent histopathological classification described above.

View full abstract

Pancreatic endocrine tumors are classified as functional or non-functional tumors and considered to be rare (approximately one in 100,000 people in Japan). Although they are small, they frequently cause characteristic symptoms due to excessive pancreatic hormone secretion. Pancreatic endocrine tumors, except for insulinoma, are often malignant. It is therefore important to detect and resect the tumor in the early stage. Since pancreatic endocrine tumors and their metastatic lesions frequently express somatostatin receptors, somatostatin receptor scintigraphy (Octreo Scan^®) is useful for detecting the localization of the tumors and their metastases. Especially, when the plasma pancreatic hormone levels are suppressed with octreotide challenge test, we recommend Octreo Scan^® for detecting the localization of the tumors and their metastases.

View full abstract

Clinicopathological findings and pancreatography of thirteen patients (male : female=7 : 6) with nonfunctioning endocrine tumors(ET) of the pancreas were reviewed. Abnormal endoscopic retrograde pancreatography(ERP) findings were observed in eight cases (62%). Tumors with lymphatic invasion, venous invasion and/or splenic vein invasion were defined as malignant ET. Four malignant ET showed abnormal ERP findings, while five ET without any ERP findings were all histologically benign. A relationship between ERP findings and histological malignant potential is suggested. Histological examination revealed that changes of the main pancreatic duct(MPD) could be classified into three patterns; 1) tumor compression of the MPD (n=3), 2) tumor infiltration into the MPD (n=2), 3) tumor with fibrous stroma proliferating around the MPD (n=3). Tumors showing the last histological findings were all immunoreactive to serotonin antibody, therefore these tumors were those of classical enterochromaffin cell carcinoid tumors.

View full abstract

Insulinomas are the most common functioning tumors of the pancreas, with an estimated incidence of 1-3 per million per year. Approximately 10% are multiple, less than 10% are malignant, and 5-10% are associated with MEN-1 syndrome. The diagnosis of insulinoma can be made by the symptoms of hypoglycemia and several tests including fasting test, fasting test with glucagon test, and hyperinsulinemic/euglycemic clamp method. Once insulinoma is diagnosed, precise localization by imaging such as, abdominal ultrasonography, abdominal CT/MRI, endoscopic ultrasonography and Arterial Stimulation Venous Sampling, are required for deciding the management of the disease. Medical management is considered for patients who are unable or unwilling to undergo surgical treatment or unresectable metastatic disease. For the management of liver metastases, surgery for mass reduction, radiofrequency thermoablation, hepatic artery embolization and chemoembolization, systemic chemotherapy or small molecule inhibitor have been developed, but there is still no consensus concerning the medical management.

View full abstract

Gastroenteropancreatic neuroendocrine tumors grow slowly. However, gastrinoma is potentially malignant and is often metastasized to the liver and/or lymph nodes when first diagnosed. Liver metastasis is the major prognostic factor in patients with gastrinoma and control of liver lesions significantly improves the survival rate. Surgery is the gold standard and best radically curative treatment for patients with gastrinoma. Patients with gastrinoma are assessed for suitability to undergo surgery or other treatments by using a combination of several diagnostic modalities such as selective arterial secretagogue injection test (SASI test), CT scan, ultrasonography and endoscopy. When surgery is considered to be unsuitable, treatment with a combination of other procedures, such as chemotherapy, somatostatin analogues, arterial embolization, chemoembolization and radiofrequency ablation, are performed. The combination of aggressive treatments for gastrinoma can improve both the symptoms and the prognosis of patients with gastrinoma.

View full abstract

Non-functioning tumors are the most frequent subtype among pancreatic endocrine tumors, followed by insulinoma and, then, gastrinoma. The other functioning endocrine tumors are rare, and in addition, many such tumors are asymptomatic and difficult to diagnose preoperatively. Diagnosis is usually made after immunohistochemical assessment of the resected specimens. However, it is important to know that tumors with insufficient hormonal study might be misdiagnosed as non-functioning, and those producing multiple hormones are not rare. Radiological findings of the common and rare pancreatic endocrine tumors are fundamentally similar. Over 50% of the rare endocrine tumors are malignant, and operation including resection of the metastatic lesions is the first choice of treatment. In unresectable cases, chemotherapy, somatostatin analogue, and/or molecular targeting therapy are used. Selection of the therapeutic modality is independent on the kinds of hormone. However, somatostatin analogue cannot be used for somatostatinoma because it does not have somatostatin receptor.

View full abstract

Pancreatic neuroendocrine tumors(PNETs) account for 1 to 2% of all pancreatic tumors. According to the status of hormone secretion, the tumors are classified into functioning and non-functioning tumors. Non-functioning tumors are almost the same entity as asymptomatic endocrine tumors. Approximately 50 to 60% of PNETs are non-functioning. Distant metastasis is found at the initial diagnosis in more than half of the patients with non-functioning PNETs; therefore, all the non-functioning PNETs should be treated as potentially malignant tumors. Because patients with non-functioning tumors present no hormone-specific symptoms, diagnostic and treatment strategy should be different from those for functioning tumors. The measurement of serum chromogranin A and the use of somatostatin receptor scintigraphy are useful diagnostic tools; however, they are not covered by the public health insurance system in Japan. Complete surgical resection is desirable if possible, otherwise somatostatin analogues, interferon alfa, anti-cancer agents and recent molecular targeting agents are the treatments of choice.

View full abstract

Therapeutic surgical strategies for neuroendocrine tumors of the pancreas are reviewed. Enucleation of the tumor, spleen-preserving distal pancreatectomy, distal pancreatectomy with splenectomy, pancreatico-duodenectomy or, rarely, duodenum preserving pancreatic head resection, and so on, are candidates for primary lesion (s). Prophylactic lymphadenectomy is considered for malignant tumors. Lymph node dissection should be done for tumors with lymph node metastasis. For liver metastasis, surgical resection is the first choice, and concentrative therapies such as chemotherapy and/or hormonal therapy are important.

View full abstract

Patients with metastatic neuroendocrine tumors often become symptomatic from hormone hypersecretion rather than from the tumor bulk. The symptoms of the hormonal syndromes resulting from peptide hormone hypersecretion by pancreatic endocrine tumors, as well as carcinoid syndrome, can often be well controlled with somatostatin analogs. Somatostatin analogs such as octreotide are highly effective in controlling the symptoms associated with carcinoid tumors, VIPomas and glucagonomas. They also slow the tumor growth and can achieve stable disease in some patients. Symptomatic patients are generally initiated on short-acting octreotide with rapid transition to the long acting formulation and subsequent titration of the dose to optimize symptom control. The accepted indications for the use of a somatostatin analog include: patients with peptide-/amine-induced syndromes with clinical symptoms, and patients with progression of metastatic disease even without a syndrome. The pre-operative use of somatostatin analogs is critical in the prevention of 'carcinoid crisis'.

View full abstract

A number of studies have noted the elevated expression of several growth factors and receptors in pancreatic neuroendocrine carcinomas. In preclinical models, disruption of these signaling pathways inhibits neuroendocrine cell growth. Several multicenter clinical trials have been conducted in patients with advanced pancreatic neuroendocrine carcinomas to evaluate molecular agents that target growth factor signaling, holding promise for improved prognoses for patients in the future.

View full abstract

We evaluated the usefulness of CPR images in comparison with multiplanar reformation (MPR) images for the staging of pancreatic head cancer in 7 preoperative cases. The CPR images allowed demonstration of the pancreatic cancer in every case. The CPR images and MPR images both allowed the detection of vascular invasion (PV, A) in every case, and both methods had a sensitivity, specificity, and accuracy of 100%. On the other hand, the CPR images did not allow the detection of invasion of retroperitoneal tissue (RP) in two cases. CPR images alone did not result in any improvement in the local staging of pancreatic cancer, probably because of the poor visualization of pancreatic tissue distant from MPD. A combination of MPR and CPR images would be more useful for the preoperative staging of pancreatic head cancer than either image alone.

View full abstract

We report a case of unresectable advanced pancreatic cancer in which transgastric endosonography-guided biliary drainage (ESBD) and endoscopic duodenal stenting provided good QOL, allowing continuation of chemotherapy. A 78-year-old man was admitted to our department with a diagnosis of unresectable pancreatic carcinoma with liver metastasis and obstructive jaundice. As endoscopic biliary drainage was not possible because of duodenal stenosis caused by cancer invasion, transgastric ESBD was performed. His jaundice subsided and chemotherapy was started. During the course, duodenal obstruction developed, which was treated with endoscopic duodenal stent placement. These endoscopic treatments enabled continuation of chemotherapy for 6 months until his death. ESBD is a useful technique for biliary drainage in difficult endoscopic biliary drainage cases and endoscopic duodenal stent placement contributes to the improvement of patients QOL.

View full abstract

The patient was a 40-year-old woman. A cystic tumor, measuring 6cm in the tail of pancreas was found by computed tomography (CT). Magnetic Resonance Image (MRI) revealed that the tumor was low signal intensity in T1-weighted MR images, and high intensity in T2-weighted MR images. Angiography revealed the hepatopetal collateral vessel because the splenic vein was occluded by this tumor. Our diagnosis was mucinous cystadenoma of the pancreas. Laparoscopic distal pancreatectomy was performed. We performed laparoscopic distal pancreatectomy in more than 20 patients with pancreatic body-tail disease. We could perform this procedure safely in spite of many collateral vessels.

View full abstract

A 50-year-old man was admitted because of weight loss and aggravation of diabetes mellitus. Contrast-enhanced computed tomography demonstrated a low density tumor measuring 30mm in diameter in the pancreas head. ERCP showed a smooth stenosis in the main pancreatic duct. EUS-guided biopsy of the tumor was performed, and it was diagnosed as islet cell tumor by the histopathological findings. During two months, the tumor doubled in size. Pancreaticoduodenectomy was performed. The diagnosis of the tumor was pure acinar cell carcinoma on the final histopathology by immunohistochemical staining (IHC) and electoron microscopy. The availability of preoperative diagnosis with IHC is considerable. The tumor markers were not decreased to the normal range in the postoperative course. Probably, this was caused by microscopical tumor persistence, whereas the patient was free of disease for 6 months with gemcitabine adjuvant chemotherapy.

View full abstract

A 64-year-old man was followed after surgery for rectal cancer performed in April 2002. In June 2004, right upper lobectomy was performed for right lung metastasis. In July 2006, an abdominal CT examination demonstrated a low density area in the pancreas tail. At first we suspected pancreatitis after several evaluations. But in April 2007, CT showed growth of the mass in the pancreas tail, and brushing cytology of the main pancreatic duct showed class V. So we diagnosed it as a new pancreatic cancer, and performed distal pancreatectomy and splenectomy in June 2007. Immunohistology showed that both lung metastasis and pancreas tumors were positive for CK20 and negative for CK7. Hence we reached the final diagnosis of metachronous pancreas metastases from rectal cancer. The patient was alive with no signs of recurrence at 12 months after the distal pancreatectomy. Cases of pancreatic metastasis from early colorectal cancer are thought to be very rare.

View full abstract