Review
Pancreatic neuroendocrine tumours

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Abstract

Pancreatic neuroendocrine tumours (PET) are rare neoplasms of the pancreas accounting for less than 5% of all primary pancreatic malignancies. Included in this group are insulinomas, gastrinomas, glucagonoma and somatostatinomas. Collectively these neoplasms are classified as functional PETs. Where a PET is not associated with a clinical syndrome due to hormone oversecretion, it is referred to as a non-functioning PET. Non-functioning PETs are pancreatic tumours with endocrine differentiation but lack a clinical syndrome of hormone hypersecretion.

The incidence of these tumours varied between 15 and 53%. Presentation is related to the mass effect of the tumour with symptoms often non-specific. Treatment is surgical excision with chemotherapy and hormonal therapy is controversial.

For functioning PETs, surgery remains the optimal therapy, however, long-term survival can be expected even in the presence of metastases. With advances in medical management, radiolabelled somatostatin therapy, hepatic arterial chemoembolisation and radiofrequency ablation, symptoms may be controlled to optimize quality of life.

Introduction

Pancreatic neuroendocrine tumours (PET) are rare neoplasms of the pancreas accounting for less than 5% of all primary pancreatic malignancies.1 It is important to distinguish PET's from the more common adenocarcinoma because the prognosis for PET's is superior, even in the face of metastatic disease.2

During embryogenesis pancreatic islet cells develop as cellular buds from intraobular ductless. This process is generally complete by birth. As islet cells demonstrate hormone coexpression in fetal life, it is thought that neuroendocrine tumours originate from multipotent cells in the ductal epithelium that retain their ability to differentiate toward the cell line found in the tumour.3 Originally described by Nicholls in 1902 as tumours originating from pancreatic islet cell lineage,4 these tumours are commonly associated with the clinical syndrome related to the hormone secreted by the tumour. Included in this group are insulinomas, gastrinomas, glucagonoma and somatostatinomas.5 Collectively these neoplasms are classified as functional PET's. Where a PET is not associated with a clinical syndrome due to hormone oversecretion it is referred to as a non-functioning PET.

Clinically these two groups present differently- one due to the effects of hormone overproduction and non-functional lesions generally due to mass effect or metastases. Although these tumours tend to be less aggressive than their adenocarcinoma counterpart they frequently metastasize to the liver.6 At the time of diagnoses, excluding insulinoma, 50–60% of PET's have metastasized.7, 8

Non-functioning PET's are pancreatic tumours with endocrine differentiation but lack a clinical syndrome of hormone hypersecretion. Although these tumours are hormonally “silent” they may produce a precursor hormone that is functionally inert, or at an amount that is too small to cause symptoms. Non-functioning tumours are slow growing and occur most commonly in the head of the pancreas.9 The incidence of non-functional tumours has varied between 15 and 53%.10, 11 This wide variation in incidence may be explained by technical advances in imaging modalities that has enabled clinically silent intra-abdominal lesions to be identified. Presentation is related to the mass effect of the tumour with symptoms resembling those of pancreatic adenocarcinoma- jaundice, abdominal pain, weight loss or the appearance of an abdominal mass are the most frequent symptoms. Patients with non-functioning PET's can present with advanced metastatic disease and relatively few symptoms.

The prognosis of patients diagnosed with a PET is difficult to predict as the natural history of these tumours is largely unknown. Studies of patients with gastrinomas, where there is treatment for the symptoms of hypersecretion and so long-term follow-up is possible, indicate that up to 40% of PET's demonstrate an indolent growth pattern.12, 13 Indeed, tumour related deaths occur in PET's that demonstrate an aggressive growth pattern – aggressive treatment should therefore be considered in these patients. One of the difficulties that exists is the definition of malignant and benign disease – PET are classified as malignant when lymph nodes are involved, distant metastases are identified or there is invasion into adjacent structures. Tumours therefore classified as benign may merely have had their natural history interrupted by surgical resection. In a study by Hochwald et al. of 136 cases of PET, the mitotic rate and necrosis shown to be of prognostic significance.14 No survival difference has been shown between functional and non-function PET's. Due to the lack of symptoms, non-functional tumours tend to present later with much larger lesions than their functional counterpart (1.9 cm vs. 4 cm).15

The commonest genetic syndrome associated with PET is the multiple endocrine neoplasia type one syndrome (MEN 1), characterized by pancreatic, pituitary and parathyroid malignancies. Less frequently adrenal and carcinoid neoplasms may also be associated with this syndrome. Inherited patterns are consistent with autosomal dominant distribution and the gene has been traced to chromosome 11q13. This MEN 1 gene is a tumour suppressor gene and in genotypic studies of families with MEN 1 is 99% accurate in detecting MEN abnormalities.10 Multiple endocrine neoplasia is most commonly associated with gastrinomas and seen in 20–30% of patients with Zollinger-Ellison syndrome (ZES).16

It is important to diagnose MEN-1 in association with ZES as tumours tend to be multifocal, less aggressive and located submucosaly in the duodenum. Pancreatic neuroendocrine tumours also occur in von Hippel Lindau syndrome and von Recklinghausen disease.

Section snippets

Localization/imaging

Transabdominal ultrasound is a cheap and widely available imaging modality. It has a sensitivity in detecting PET's ranging from 9 to 64%.17, 18 The use of endoscopic ultrasound has further improved the accuracy of preoperative ultrasound. Endoscopic ultrasound (EUS) allows high definition imaging of the walls of the stomach and duodenum and its adjacent structures, enabling lesions as small as 0.5 cm to be detected (Fig. 1).19 In addition, a tissue diagnosis may be made by fine needle

Insulinoma

Insulinomas are PET's arising from the insulin producing islet β cells, and are the commonest type of PET. Although they have a malignant potential the majority of insulinomas are benign (90%). They are generally found within the pancreatic parenchyma (Figure 5, Figure 6) equally distributed throughout the gland, with only 3% being found in ectopic locations. The duodenal mucosa is the commonest location for ectopic insulinomas. Usually they are solitary lesions, however if multiple lesions are

Gastrinoma

Gastrinomas are the second commonest PET, occurring only half as often as insulinomas. They are most frequently diagnosed in the 5th and 6th decades of life with a slight female preponderance. At the time of diagnosis 50–60% of patients will have evidence of metastases.52 In 1955 Zollinger-Ellison described a syndrome in a patient with upper jejeunal ulceration, gastric acid hypersecretion and a tumour of the non-β cells of the pancreas. Gastrin has been identified as the causative agent.

Glucagonoma

Becker et al. was the first to identify a skin disorder associated with a pancreatic neoplasm in 1942.60 The classical presentation is with the “4D's” of diabetes, dermatitis, deep vein thrombosis and depression. Glucagon has many important effects on glucose, fat and protein metabolism. It stimulates gluconeogenesis and inhibits glycolysis within the liver. In muscle it stimulates muscle breakdown and the flow of gluconeogenic amino acids alanine and glutamine from muscle to the liver. Thus in

VIPoma

Vasoactive intestinal peptide (VIP) acts on the intestinal lumen to stimulate the secretion of fluids and electrolytes into the intestine. This combines to result in a profuse watery diarrhea with loss of water, sodium, chloride and potassium from the body. This syndrome was initially noted in 195765 and further characterised by Verner and Morrisson, this syndrome now bears their name.66 The first step in the management of these patients is the correction of dehydration and electrolyte

Somatostatinoma

Somatostatin is produced by the delta cells of the pancreas and functions in a paracrine fashion to inhibit the secretion of insulin and glucagon from pancreatic islet cells. Also, it inhibits cholecystkinin mediated release of pancreatic enzymes. With these functions in mind, hypersecretion of somatostatin presents with diabetes, malabsorption, steatorrhoea, and cholelithiasis due to reduced gallbladder contractility. These symptoms are relatively non-specific and thus the majority of

Treatment for metastatic disease

Surgery offers the only curative treatment by excising the primary tumour and all lymph node metastases. In a retrospective analysis by Kazanijian et al.70 a 5 year survival of 77% was noted in patients with PET's. The presence of lymph node metastases did not adversely affect prognosis. The survival following curative resection for ZES may be as high as 86%.59 The surgical procedures performed vary from enucleation, distal pancreatectomy and pancreaticoduodenectomy. As long term survival can be

Conclusion

Pancreatic neuroendocrine tumours, although uncommon, as a group pose may dilemmas in diagnosis (especially in non-functional PET's), localization and treatment. Surgery remains the only potential curative treatment; however long-term survival can be expected even in the presence of metastases. With advances in medical management, radiolabelled somatostatin therapy, hepatic arterial chemoembolisation and radiofrequency ablation, symptoms may be controlled to optimize quality of life.

Conflict of interest

The authors have no conflict of interest.

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