Best Practice & Research Clinical Gastroenterology
`Vol. 19, No. 5, pp. 753–781, 2005
`doi:10.1016/j.bpg.2005.06.002
`available online at http://www.sciencedirect.com
`
`8 E
`
`ndocrine tumours of the pancreas
`
`Kjell O¨ berg* MD, PhD
`
`Barbro Eriksson MD, PhD
`Department of Medical Sciences, University Hospital, 751 85 Uppsala, Sweden
`
`Endocrine pancreatic tumours (EPTs) are uncommon tumours occurring in approximately 1 in
`100 000 of the population, representing 1–2% of all pancreatic neoplasms. Some of the tumours
`may be part of multiple endocrine neoplasia type one (MEN-1) syndrome or von Hippel–Lindau
`(vHL) disease. EPTs are classified as functioning or non-functioning tumours on the basis of their
`clinical manifestation. The biochemical diagnosis of EPT is based on hormones and amines
`released. Besides specific markers such as insulin, there are also general tumour markers such as
`chromogranin A, which is the most valuable marker and has been reported to be increased in
`plasma in 50–80% of patients with EPTs and correlates with tumour burden. The location of
`endocrine tumours of the pancreas includes different techniques, from endoscopic investigations
`to scintigraphy (e.g. somatostatin receptor scintigraphy) and positron emission tomography. The
`medical treatment of endocrine pancreatic tumours consists of chemotherapy, somatostatin
`analogues and a-interferon. None of these can cure a patient with malignant disease. In future,
`therapy will be custom-made and based on current knowledge of tumour biology and molecular
`genetics.
`
`Key words: endocrine pancreatic tumours; histopathology; molecular genetics; biochemistry;
`localization; medical treatment.
`
`EPIDEMIOLOGY
`
`Endocrine tumours of the pancreas (EPTs) are rare tumours. They occur in
`approximately 1 in 100 000 or represent 1–2% of all pancreatic neoplasms. 1–3 The
`incidence in autopsy studies has been reported as high as 1.5% clinically unrecognized
`or asymptomatic and usually small (diameter !1 cm).4 The tumours show no
`significant gender predilection and occur at all ages, with a peak incidence between 30
`and 60 years.5,6 Some of the tumours may be part of the multiple endocrine neoplasia
`type one syndrome (MEN-1), and these family members might present non-functioning
`
`* Corresponding author. Tel.: C46 18 611 4917; Fax: C46 18 50 7268.
`E-mail address: kjell.oberg@medsci.uu.se (K. O¨ berg).
`
`1521-6918/$ - see front matter Q 2005 Elsevier Ltd. All rights reserved.
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`endocrine pancreatic tumours when as young as 20–30 years of age.7 Less common
`than MEN-1 is von Hippel–Lindau (vHL) disease where about 15% of the patients
`present with EPT.8
`
`PATHOPHYSIOLOGY, TUMOUR BIOLOGY, SYMPTOMS
`AND BIOCHEMICAL DIAGNOSIS
`
`Originally EPTs were thought to have evolved from the islets of Langerhans themselves.
`However, more recent evidence suggests that these tumours arise from pluripotent
`stem cells in the ductal epithelium.9–11 Differentiation from a neuroendocrine lineage is
`suggested by their cytoplasmic labelling with silver stains.12 However, it is not clear
`whether benign insulin-producing tumours develop from islet stem cells.
`EPTs are categorized on the basis of their clinical manifestation into functioning and
`non-functioning tumours. Functioning tumours are associated with a clinical syndrome
`caused by inappropriate secretion of hormones. Within this group are insulinomas,
`glucagonomas, somatostatinomas, gastrinomas, VIPomas and other less common
`tumours. Non-functioning tumours or ‘non-syndromic’ tumours are not associated
`with a distinct hormonal syndrome, but may still show elevated hormone levels in the
`blood or immunoreactivity in tissue sections. Tumours with a majority of cells
`expressing and secreting pancreatic polypeptide or neurotensin are included in the
`group of non-functioning tumours. Many somatostatin-producing tumours are also
`clinically silent, because they do not cause a distinct hormonal syndrome.12 Quite
`recently, ghrelin—a novel gastrointestinal hormone produced by rat and human gastric
`X-like neuroendocrine cells which strongly stimulates growth hormone (GH)
`secretion—has been detected in endocrine pancreatic tumours. These tumours
`might express both ghrelin and the ghrelin receptor, but a distinct clinical syndrome
`related to this overproduction has not been described.13 Non-functioning tumours
`often become clinically apparent due to their large size or invasion of adjacent organs or
`to the occurrence of metastases. Quite often they are detected incidentally on
`abdominal imaging procedures for other reasons. About 30–40% of all EPTs constitute
`the group of non-functioning tumours.
`
`Histopathology
`
`The characteristic histological appearance of EPTs is a uniform cytology with scant
`mitoses. Cellular patterns can be either solid, acinar or trabecular. However, these
`different patterns exhibit no difference in biological behaviour.11,12 The majority of the
`tumours are well demarcated and solitary, showing a white–yellow or pink–brown
`colour. The diameter is usually in the range 1–5 cm. Patients with MEN-1 present
`multiple endocrine pancreatic tumours, the majority being of non-functioning type, but
`also some of them produce different hormones in different lesions. Among the
`functioning tumours insulinomas are usually the smallest, but the size of the tumours is
`not related to the severity of the hormonally induced symptoms. Non-functioning
`tumours are generally larger, often 5 cm or more. Tumours with a diameter of more
`than 2 cm have an increased risk of malignant behaviour, and those over 3 cm are usually
`malignant.11,12
`Coarse-needle aspiration biopsy is a useful method for investigating endocrine
`pancreatic tumours and their metastases. Guidance techniques include computed
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`Table 1. Negative prognostic factors of endocrine pancreatic tumours (EPTs).
`
`Metastases
`Gross invasion of adjacent organs
`Angioinvasion
`Perineural invasion
`Tumour diameter !2 cm
`Mitoses O2 per 10 HPF
`Ki-67 (MIB-1) O2%
`Necrosis
`
`tomography, transabdominal ultrasonography, and more recently endoscopic ultra-
`sonography. The cytomorphological features of EPTs are the same whether they are
`functioning or non-functioning. In general the histological pattern of a tumour does not
`allow a conclusion as to its functioning state or type of hormone production. There are
`two exceptions to this rule: amyloid deposits are indicative of
`insulinomas, and
`glandular structures containing psammoma bodies are commonly observed in
`somatostatin-producing tumours.11,12,14,15 Poorly differentiated endocrine carcinomas
`are sometimes misdiagnosed as pancreatic cancer. These highly aggressive neoplasms
`are hardly recognized as endocrine tumours at first sight, and require immunohisto-
`chemical examination to reveal their neuroendocrine phenotype (Table 1).
`They show rather pleomorphic cells with high mitotic index (O10/10 HPF). They all
`usually show also angioinvasion.3,11,12 EPTs can clearly be identified by using antibodies
`to markers common to all or most neuroendocrine cells:
`i.e. chromogranin A,
`synaptophysin, neuron-specific enolase (NSE) and protein gene product 9.5 (PGP 9.5).
`EPTs also contain cytokeratin 8, 18 and 19,6 and might also express vesicle monoamine
`transporter proteins 1 and 2 (VMAT-1 or VMAT-2). VMAT-1 has been exclusively found
`in the serotonin-containing EPTs.16 Neuropilin 2 is a novel marker expressed in
`pancreatic islet cells and DPTs; it seems to be co-localized with glucagon-expressing
`cells.17
`
`Molecular genetics
`
`Whereas the molecular basis of familial EPTs (MEN-1) and vHL syndrome has been
`recently established, little is known about the oncogenesis and the molecular basis of
`the progression of sporadic tumours.
`In contrast to other human tumours, the
`activation of an oncogene is not a common event in EPTs. Mutations in k-ras, P53, myc,
`fos, jun, src and the Rb gene have not been implicated in the pathogenesis of sporadic
`endocrine pancreatic tumours.18–23 Molecular and cytogenetic analyses have identified
`a number of chromosomal alterations in EPTs. Compared genomic hybridization
`studies have revealed that chromosomal losses have occurred slightly more frequently
`than gains, while amplifications are uncommon.24,25 Furthermore, the total number of
`genomic changes per tumour appears to be associated with both tumour volume and
`disease stage, indicating that genetic alterations accumulate during tumour progression.
`Thus large tumours with increased malignant potential—and especially metastases—
`harbour more genetic alterations than small and clinically benign neoplasms. These
`findings point towards a tumour suppressor pathway and genomic instability as
`important mechanisms associated with tumour progression. Losses of chromosome 1
`and 11q as wells as gains on 9q appear to be early events in the development of EPTs,
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`Table 2. Genetic alterations in endocrine pancreatic tumours (EPTs).
`
`Gene
`
`Mutation
`
`CGH
`
`LOH
`
`10/29 (34%)
`8/29 (28%)
`23/31 (74%)
`31/73 (42%)
`43/69 (62%)
`12/37 (32%)
`
`Locus
`1p36K
`1q32K
`3p23K
`3p25–26K
`6q22K
`9pK
`9qC
`10q23K
`11p14K
`11q13
`11q22–23
`12p12C
`15qK
`17p13K
`17pC
`18q21K
`22q12.1
`XqK
`YK
`
`VHL
`
`1/75 (1%)
`
`CDKN2A/p16
`
`1/44 (2%)
`
`8/16 (50%)
`
`PTEN
`
`1/31 (3%)
`
`MEN-1
`SDHD
`K-Ras
`SMAD3
`TP53
`
`DPC4
`
`33/155 (21%)
`0/20 (0%)
`1/39 (3%)
`0/18 (0%)
`1/40 (3%)
`
`0/41 (0%)
`
`75/111 (67%)
`20/37 (54%)
`
`15/40 (38%)
`
`23/68 (34%)
`9/12 (75%)
`11/23 (48%)
`5/14 (36%)
`
`21/102 (21%)
`16/102 (16%)
`19/102 (19%)
`19/102 (19%)
`29/102 (28%)
`0/102 (0%)
`29/102 (28%)
`14/102 (14%)
`28/102 (27%)
`31/102 (30%)
`31/102 (30%)
`23/102 (23%)
`6/102 (6%)
`2/102 (2%)
`32/102 (31%)
`6/102 (6%)
`4/102 (4%)
`14/46 (30%)
`14/56 (25%)
`
`LOH, loss of heterozygosity; CGH, comparative genetic hybridization.
`
`since they are already present in small tumours. Prevalent chromosomal alterations
`common in metastases include gains of both chromosome 4 and 7 and losses of 21q,
`implying that these chromosome imbalances may contribute to tumour dissemination
`(Table 2).26–28
`EPTs belonging to the MEN-1 syndrome present deletions on chromosome 11q13.
`Data indicate that somatic MEN-1 mutations are present in about 20% of spontaneous
`neoplasms and that 68% harbour losses of 11q13 and/or more distal parts of the long
`arm of chromosome 11.29–31 These findings indicate that another as yet unknown
`tumour suppressor gene might be involved. The inherited genetic syndromes most
`commonly associated with EPT are MEN-1 and vHL disease. The MEN-1 syndrome has
`been associated with mutations in the menin gene on chromosome 11q13. Menin is a
`presumed tumour suppressor, a nuclear protein interacting with Jun D and AP1
`transcription factor. Up to 80% of MEN-1 patients demonstrate loss of heterozygosity
`for the menin gene.31–33 Less common than MEN-1 syndrome is vHL disease. About
`14% of patients with vHL disease present with EPTs. All of these tumours have been of
`non-functioning type, and more than half of the patients have multiple tumours. The
`gene associated with vHL is located on chromosome 3p25.2. The gene protein
`products inhibit the process of transcription elongation. This gene does not appear to
`be involved in the development of sporadic EPTs.8,34
`
`Biochemical diagnosis
`
`The biochemical diagnosis is based on hormones and amines released from the EPTs
`(Figure 1). These markers can be divided into specific markers, such as insulin from an
`insulin-producing tumour, gastrin from a gastrinoma, glucagon from glucagonoma,
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`Endocrine tumours of the pancreas 757
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`Symptoms of EPT
`
`Biochemical
`screening
`
`CgA, specific
`hormones
`(symptom dep.)
`
`Normal
`
`Increased
`
`SRS
`
`Follow-up
`
`Negative
`
`Positive
`
`Histopathology,
`tumour biology
`
`CT, MRI,
`UL (biopsy)
`
`Figure 1. Diagnostic algorithm for endocrine pancreatic tumours (EPTs). CgA, chromogranin A; CT,
`computed tomography; MRI, magnetic resonance imaging.
`
`and so forth. There are also general tumour markers, the most interesting being
`chromogranin A, pancreatic polypeptide (PP), and the a-subunits of human chorionic
`gonadotrophin (hCG). Chromogranin A is a 49 kDa, monomeric, hydrophilic, acidic
`glucoprotein which is widely expressed in neuroendocrine cells and constitutes one of
`the most abundant components of secretory granules. Chromogranin A immunohis-
`tochemistry is the main step in the diagnosis of neuroendocrine tumours.
`Chromogranin A is released into the circulation and is a useful marker for
`neuroendocrine tumours. Increased levels of chromogranin A have been reported
`in 50–80% of EPTs and sometimes correlate with the tumour burden. The
`highest chromogranin A levels have been reported in so-called non-functioning
`tumours.35–40 In a recent study, combination of chromogranin A with measurement of
`PP increased the sensitivity from 84 to 96% in non-functioning tumours and from 74 to
`94% in functioning tumours.41 Serum PP alone shows a rather low sensitivity,
`somewhere between 40 and 55%. Increased circulating levels of hCG-a subunits have
`been implicated as a sign of malignancy of EPTs. About 30% of patients with EPTs
`present high levels of hCG-a. Patients with MEN-1 demonstrate high levels of
`chromogranin A, which are clearly related to the tumour burden. Specific markers will
`be discussed in relation to the different tumour types.
`
`INSULINOMAS
`
`Insulinomas are the most frequent of all functioning EPTs. The incidence of insulinoma
`was reported to be 2–4 patients per million of the population per year. Insulinomas
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`have been diagnosed in all age groups but have rarely occurred below the age of 15. The
`highest incidence is found at age 40–60 years. Females seem to be slightly more
`frequently affected.42,43 The aetiology and pathogenesis of insulinomas are unknown.
`No risk factors have been associated with these tumours. The results of recent
`clonality studies on EPTs are consistent with the hypothesis that these tumours may be
`primarily polyclonal or oligoclonal neoplasms which are eventually outgrown by a more
`aggressive cell clone that may give rise to invasive growth and metastasis.44 The
`majority of insulinomas are located in the pancreas or are directly attached to it.
`Ectopic (extrapancreatic) insulinomas with symptoms of hypoglycaemia are extremely
`rare (!2%) and are most commonly found in the duodenal wall. Tumours are equally
`distributed between the head, body and tail of the pancreas. Approximately 85% of
`insulinomas occur singly, 6–13% are multiple, and 4–6% are associated with MEN-1.
`Overall 5-year survival has been 97%.45,46
`
`Clinical symptoms
`
`Insulinomas are characterized by fasting hypoglycaemia and neuroglycopenic
`symptoms, and occasionally sympathoadrenal autonomic symptoms. The episodic
`nature of the hypoglycaemic attacks is due to the intermittent insulin secretion by the
`tumour. As the disease progresses, attacks can become more frequent and the patient
`can develop persistent hypoglycaemia. The severity of symptoms does not always
`predict malignancy or the size of the tumour. The most common symptom results from
`neuroglycopenia,
`followed by catecholamine response. Most prominent of the
`symptoms of central nervous system dysfunction includes diplopia, blurred vision,
`confusion, abnormal behaviour and amnesia. Some patients might develop loss of
`consciousness and coma or even permanent brain damage. The release of
`catecholamines produces symptoms such as sweating, weakness, hunger, tremor,
`nausea, anxiety and palpitation. The Wipple triad includes symptoms of hypoglycaemia,
`plasma glucose levels !3.0 mmol/L, and finally relief of symptoms on administration of
`glucose.47–49
`
`Diagnostic procedures
`
`Determination of plasma insulin and proinsulin concentrations by radioimmunoassay
`has greatly facilitated and simplified the diagnosis of
`insulinoma. Usually insulin,
`proinsulin, C-peptide and blood glucose are measured together to demonstrate an
`inappropriately high secretion of insulin in relation to blood glucose. About 80% of
`insulinomas are diagnosed by these tests. Inappropriately high plasma insulin levels
`during 48–72 hours fasting is also regarded as a sensitive diagnostic test. Alternatively,
`C-peptide suppression is also a valuable screening or confirmatory test for
`insulinoma.50,51 The differential diagnosis of hypoglycaemia includes hormonal
`deficiencies, hepatic insufficiency, exogenous hyperinsulinism, medication, drugs and
`enzyme defects. Occasionally differentiating insulinoma from these other causes of
`hypoglycaemia can be quite difficult. Neisidioblastosis is a rare disorder, which may
`require intraoperative biopsy to differentiate it from insulinoma. This disorder is
`characterized by replacement of normal pancreatic islets with diffuse hyperplasia of the
`islet.52 Patients with multiple myeloma or systemic lupus erythematosus (SLE) and
`hypoglycaemia may have anti-insulin antibodies. These antibodies bind and release
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`insulin in an unregulated manner, resulting in hypoglycaemia. These patients can be
`distinguished from patients with insulinoma by an anti-insulin antibody test.
`
`Endocrine tumours of the pancreas 759
`
`Prognosis and predictive factors
`
`No immunohistochemical markers are available which reliably predict a biological
`behaviour of insulinoma. The percentage of malignant insulinomas is in the range 2.4–
`17.9%, with an average of 8.4%. Insulinomas of !2 cm in diameters without signs of
`angioinvasion or metastases and showing a mitotic rate of Ki67 !2% are considered
`benign.45,46,53
`
`GASTRINOMA (ZOLLINGER–ELLISON SYNDROME)
`
`The majority of patients with Zollinger–Ellison syndrome suffer from a gastrinoma of
`the pancreas or duodenum. Gastrinomas are relatively common functionally active
`endocrine tumours of the pancreas accounting for about 20% of cases, second in
`frequency to insulinomas. Approximately 0.1% of patients with duodenal ulcers have
`evidence of Zollinger–Ellison syndrome. The reported incidence of gastrinomas is
`between 0.5 and 4 per million of the population per year. Zollinger–Ellison syndrome is
`more common in males than in females, with a ratio of 3:2. The mean age at the onset of
`symptoms is 38 years, range 7–83 years in some series. The aetiology and pathogenesis
`of sporadic gastrinomas are unknown. Approximately 20% of gastrinomas are part of
`MEN-1. No other risk factors are known. At the time of diagnosis 50–60% of tumours
`are malignant.54–56 A substantial variation has occurred in the distribution of pancreatic
`versus non-pancreatic gastrinomas. In the old Zollinger–Ellison tumour registry, 53% of
`the patients had the localization of the tumour in the pancreas, 13% in duodenum and
`jejunum.57 In contrast, more recent studies have indicated pancreatic localization of
`24% with a drop to 14% in sporadic cases, whereas a duodenal localization was found in
`49% of the cases.54 Pancreatic gastrinomas more frequently occur in the head of the
`gland. More than 90% of duodenal gastrinomas are located in the first and second part
`of the duodenum and are limited to the submucosa in 54% of patients. The anatomical
`area comprising the head of the pancreas, the superior and descending portion of the
`duodenum and the relevant lymph nodes has been called the ‘gastrinoma triangle’, since
`it harbours the vast majority of these tumours.58 Other primary sites of gastrinomas
`are being identified increasingly, including stomach, jejunum, biliary tract, liver, kidney,
`mesentery and the heart. Some peri-pancreatic and peri-duodenal
`lymph-node
`gastrinomas are thought to represent primary tumours rather than metastases from
`an occult primary in the duodenum, and some patients have been cured after resection
`of the tumour of the lymph nodes.54,55,59
`
`Clinical signs and symptoms
`
`Over 90% of patients with gastrinomas have a peptic ulcer disease. Diarrhoea is
`another common symptom caused by the large volume of gastric acid secretion. The
`low pH inactivates pancreatic enzymes, leading to malabsorption and steatorrhoea.
`Abdominal pain from either peptic ulcer disease or gastro-oesophageal reflux disease
`remains the most common symptom, occurring in more than 75% of patients.
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`Diagnostic procedure
`
`If the patient presents gastric pH below 2.5 and serum gastrin concentration above
`1000 pg/mL (normal !100 pg/mL) then the diagnosis of Zollinger–Ellison is confirmed
`and no other diagnostic studies are actually needed. Unfortunately, the majority
`(40–50%) of patients present serum gastrin concentrations between 100 and
`500 pg/mL, and in these patients a secretin test should be performed in addition to a
`determination of basal acid output (BAO) and pentagastrin-stimulated acid output
`(MAO). The secretin test is considered positive when an increase in serum gastrin over
`the pretreatment value is O200 pg/mL.60,61
`
`Prognosis and predictive factors
`
`In general, the progression of gastrinomas is relatively slow with a combined 5-year
`survival rate of 65% and 10-year survival rate of 51%. Even with metastatic disease 10-
`year survival rates of 46% for lymph-node metastases and 40% with liver metastases
`have been reported. Patients with complete tumour resection have excellent 5- and 10-
`year survival rates (90–100%). Patients with pancreatic tumours have a worse prognosis
`than those with primary tumours in the duodenum. There is no established marker to
`predict the biological behaviour of gastrinoma. However, some have found that HER-
`2/neu amplification and overexpression of epidermal growth factor (EGF) and
`hepatocyte growth factor are associated with aggressive growth.54,62,63
`
`VIPOMA (VERNER–MORRISON SYNDROME)
`
`Tumours secreting vasoactive intestinal polypeptide (VIP) have been associated with the
`watery diarrhoea syndrome.
`It has also been called Verner–Morrison syndrome,
`pancreatic cholera and WDHA (watery diarrhoea/hypokalaemia/achlorhydria)
`syndrome.
`Pancreatic VIPomas constitute about 80% of diarrhoeogenic neoplasms and 3–8% of
`all endocrine tumours in the pancreas. Approximately 50% of pancreatic VIPomas are
`malignant at the time of diagnosis. Females are affected more often than males, and the
`age of the patients ranges from 19 to 79 years (mean: 48 years). By contrast, two thirds
`of the neurogenic VIPomas are found in paediatric patients. Some VIPomas are
`associated with MEN-1. VIPomas are located in the pancreas in about 80% and outside
`the pancreas in the remaining 20%. VIPomas of the pancreas are more often located in
`the tail than in the head and the body. Extrapancreatic VIP-secreting epithelial tumours
`are exceedingly rare and include lesions in the small intestine, oesophagus and kidney.
`Neurogenic tumours such as ganglioneuromas, ganglioneuroblastomas and neuro-
`blastomas and phaeochromocytomas constitute the bulk of the extrapancreatic VIP-
`secreting tumours.64–66
`
`Clinical signs, symptoms and diagnosis
`
`The Verner–Morrison syndrome is characterized by watery diarrhoea, hypokalaemia
`and achlorhydria or, more often, hypochlorhydria. The secretory diarrhoea ranges
`between 0.5 and 15 L/24 hours and is usually the most prominent symptom at
`presentation. It results in severe loss of potassium and bicarbonate, which in turn lead
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`Endocrine tumours of the pancreas 761
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`to metabolic acidosis and dehydration. Additional features include hypercalcaemia with
`normal parathyroid hormone levels, hyperglycaemia, and occasionally flushing of the
`face and the chest. The diagnosis of a VIPoma is confirmed by measurement of plasma
`VIP, and levels above 60 pmol/L are diagnostic. Sometimes plasma PHM (peptide
`histidine methionine) is also increased.67,68
`
`Prognosis
`
`The 5-year survival rate is 59.6% for patients with metastases and 94.4%for patients
`without metastases.69
`
`GLUCAGONOMA SYNDROME
`
`Glucagonomas represent about 5% of all clinically relevant EPTs and 8–13% of
`functioning tumours. The estimated incidence of the glucagonoma syndrome is 1 per 20
`million of the population per year. Patients most often present between the ages of
`40 and 70 years (range 19–72 years), and women are slightly more often
`affected. Glucagonomas are occasionally part of MEN-1. Glucagonomas commonly
`occur in the tail of the pancreas. Extrapancreatic glucagonomas are extremely rare.70,71
`
`Clinical signs, symptoms and diagnosis
`
`The glucagonoma syndrome will reflect the catabolic action of excessively elevated
`glucagon levels. The most common presenting feature of the syndrome is necrolytic
`migratory erythema found in about 70% of all patients. The rash usually starts in the
`groin and the perineum and migrates to the distal extremities. The syndrome also
`includes mild glucose intolerance, normochromic normocytic anaemia, weight loss,
`depression, diarrhoea and a tendency to develop deep vein thrombosis. The skin rash
`may be associated with angular stomatitis, cheilitis, atrophic glossitis, alopecia,
`onycholysis, vulvovaginitis and urethritis. The cause of the rash is still unknown, but
`a direct effect of glucagon on the skin together with prostaglandin release, deficiency of
`amino acids, free fatty acids or zinc have been proposed as the underlying mechanisms.
`Marked weight loss occurs in around 65% of all patients, and diabetes mellitus is seen in
`about 50% of all cases. Normochromic and normocytic anaemia occurs in about one
`third of the patients and is probably due to direct bone-marrow suppression by
`glucagon or to the deficiency of amino acids. A tendency to venous thrombosis is
`increased, occurring in around 10–15% of all patients, and may be life-threatening.70–73
`The diagnosis of a glucagonoma is made on the basis of raised fasting plasma glucagon
`concentration together with demonstrable tumour and characteristic clinical features.
`Fasting plasma glucagon concentration is usually elevated 10- to 20-fold, but in some
`patients it may be only marginally elevated. Approximately one fifth of glucagonoma
`patients also have raised fasting levels of gastrin.
`
`Prognosis and predictive factors
`
`Approximately 60–70% of glucagonomas are already metastatic at the time of diagnosis.
`Even small glucagonomas are considered tumours of uncertain behaviour; these
`tumours tend to grow slowly, and patients may survive for many years. Occasionally, in
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`multihormonal tumours, the glucagonoma syndrome may be associated with
`or followed by another syndrome, such as hypoglycaemia syndrome or Zollinger–
`Ellison syndrome.74
`
`SOMATOSTATINOMA
`
`Somatostatinomas are rare tumours of either the pancreas or the upper small intestine,
`mainly the duodenum. Somatostatin exerts a general inhibitory effect on exocrine and
`endocrine secretion and bowel motility, which results in a so-called inhibitory
`syndrome. Somatostatinomas are not so often associated with the familial syndrome
`MEN-1 but can be part of neurofibromatosis 1 (NF-1).75 Pancreatic somatostatinomas
`are usually large (average diameter 5.1 cm), have a predilection for the pancreatic head,
`and are associated with local symptoms and/or symptoms of excessive somatostatin
`secretion.75 Between 70 and 92% demonstrate metastatic spread at diagnosis or
`operation at the mean age of 50 years.76 They may also present multiple hormone
`production (33%). Duodenal somatostatinomas tend to be smaller, with psammoma
`bodies and multisecretory activity when they are associated with von Recklinghausen
`disease (less frequently malignant).75
`
`Clinical signs, symptoms and diagnosis
`
`Most somatostatinomas are found at the time of laparotomy for cholecystectomy or
`during gastrointestinal imaging studies for cholecystectomy or during gastrointestinal
`imaging studies for abdominal pain or diarrhoea.76 The symptoms produced by
`somatostatinomas are less pronounced and less specific than those seen with other
`endocrine tumours of the pancreas.
`The clinical
`features associated with the somatostatinoma syndrome are:
`hyperglycaemia, cholelithiasis, diarrhoea, steatorrhoea, and hypochlorhydria.75 The
`patients may also present with abdominal pain, weight loss, and anaemia as signs of
`malignant disease.75 The diagnosis is established by demonstrating elevated
`somatostatin levels in a patient with a relevant history and the presence of a pancreatic
`mass; duodenal somatostatinomas may not be associated with abnormal somatostatin
`levels.
`The majority of extrapancreatic somatostatinomas are found in the duodenum but
`can also occur in the jejunum, cystic duct, colon, and rectum.75,77 Their presenting
`features are mostly related to local effects of the mass rather than the systemic effects
`of somatostatin, whereas the majority are diagnosed serendipitously during endoscopic
`procedures. Most duodenal tumours are located near the ampulla of Vater and may be
`associated with obstruction of the bile duct, pancreatitis, and gastrointestinal
`bleeding.77 These tumours are usually not associated with a secretory syndrome,
`although diabetes and cholelithiasis have occasionally been described.
`
`Prognosis and predictive factors
`
`The number of patients undergoing successful complete resection ranges from 60 to
`80%.78 Because of the malignant nature of these tumours,
`if
`imaging studies
`demonstrate a possible resectable tumour, results suggest that patients with
`somatostatinomas will benefit from surgical resection. In a review of the literature,
`
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`there was no statistically significant difference in the rate of metastases and malignancy
`between pancreatic and extrapancreatic tumours. The overall 5-year survival rate is 75,
`or 60% when metastases are present.75
`
`Endocrine tumours of the pancreas 763
`
`TUMOURS WITH ECTOPIC HORMONE PRODUCTION
`
`including ACTHomas (110 cases),
`Other rare tumours have also been reported,
`GRFomas (50 cases), neurotensinomas (50 cases) and parathyrinomas (35 cases).79
`Endocrine tumours of the pancreas can secrete enteroglucagon, cholecystokinin
`(CCK), gastric inhibitory peptide, gastrin-releasing peptide (GRP) and ghrelin in rare
`cases.
`In a recent study, 4–16% of Cushing’s syndrome cases attributable to an ectopic
`adrenocorticotrophic hormone (ACTH) syndrome originated from a pancreatic
`tumour.80,81 According to a prospective study, Cushing’s syndrome occurs in 5% of
`cases of sporadic Zollinger–Ellison syndrome.80,81 In these cases, the Cushing’s
`syndrome was severe due to the ectopic ACTH production and occurred with
`metastatic pancreatic endocrine tumours which responded poorly to chemotherapy;
`hence, the disease was associated with a poor prognosis.80 The occurrence of Cushing’s
`syndrome as the only manifestation of an EPT occurs in 37–60% of cases and may
`precede any other hormonal syndrome.
`In patients without metastatic disease, surgical resection of a GRFoma presenting
`acromegaly should be carried out; this results in resolution of the GRFoma syndrome.82
`Preoperatively, and in those patients with non-resectable lesions, it may be important
`to reduce circulating plasma growth hormone levels. As opposed to classic acromegaly,
`dopamine agonists such as bromocriptine will not normalize plasma growth hormone
`levels.83 Instead, octreotide or other somatostatin analogues will usually suppress both
`growth hormone and IGF-1 levels, which in some cases has been associated with
`pituitary shrinkage.83 In 75% of cases, octreotide decreased plasma GRF levels by more
`than 50%.83
`
`FUNCTIONALLY INACTIVE TUMOURS
`
`Endocrine tumours of the pancreas are clinically classified as non-functional or non-
`functioning when they are not related to any definite clinical syndrome.84 They are
`most often diagnosed in the 5–6th decades of life.84 In recent publications, non-
`functional tumours have increased in frequency compared to functional tumours and
`now constitute 30–50% of patient materials. Differentiation from the more aggressive
`pancreatic adenocarcinomas is extremely important.84 (Lack of hypervascularization
`and a negative octreotide scintigraphy are suggestive of the latter.)
`The reason why non-functional tumours are hormonally silent are manifold. On
`biochemical examination, many patients have elevated levels of peptides that are not
`known to produce specific clinical symptoms: e.g. PP, hCG subunits, neurotensin,
`ghrelin and chromogranins.84 In other patients, peptides well known to produce clinical
`syndromes can be detected, and the clinical ‘silence’ in these cases could be explained
`by low serum or plasma concentrations, biologically inactive mole