throbber
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.
`
`Par Pharm., Inc.
`Exhibit 1028
`Page 001
`
`

`
`754 K. O¨ berg and B. Eriksson
`
`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
`
`Par Pharm., Inc.
`Exhibit 1028
`Page 002
`
`

`
`Endocrine tumours of the pancreas 755
`
`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,
`
`Par Pharm., Inc.
`Exhibit 1028
`Page 003
`
`

`
`756 K. O¨ berg and B. Eriksson
`
`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,
`
`Par Pharm., Inc.
`Exhibit 1028
`Page 004
`
`

`
`Endocrine tumours of the pancreas 757
`
`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
`
`Par Pharm., Inc.
`Exhibit 1028
`Page 005
`
`

`
`758 K. O¨ berg and B. Eriksson
`
`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
`
`Par Pharm., Inc.
`Exhibit 1028
`Page 006
`
`

`
`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.
`
`Par Pharm., Inc.
`Exhibit 1028
`Page 007
`
`

`
`760 K. O¨ berg and B. Eriksson
`
`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
`
`Par Pharm., Inc.
`Exhibit 1028
`Page 008
`
`

`
`Endocrine tumours of the pancreas 761
`
`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
`
`Par Pharm., Inc.
`Exhibit 1028
`Page 009
`
`

`
`762 K. O¨ berg and B. Eriksson
`
`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,
`
`Par Pharm., Inc.
`Exhibit 1028
`Page 010
`
`

`
`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 molecular form

This document is available on Docket Alarm but you must sign up to view it.


Or .

Accessing this document will incur an additional charge of $.

After purchase, you can access this document again without charge.

Accept $ Charge
throbber

Still Working On It

This document is taking longer than usual to download. This can happen if we need to contact the court directly to obtain the document and their servers are running slowly.

Give it another minute or two to complete, and then try the refresh button.

throbber

A few More Minutes ... Still Working

It can take up to 5 minutes for us to download a document if the court servers are running slowly.

Thank you for your continued patience.

This document could not be displayed.

We could not find this document within its docket. Please go back to the docket page and check the link. If that does not work, go back to the docket and refresh it to pull the newest information.

Your account does not support viewing this document.

You need a Paid Account to view this document. Click here to change your account type.

Your account does not support viewing this document.

Set your membership status to view this document.

With a Docket Alarm membership, you'll get a whole lot more, including:

  • Up-to-date information for this case.
  • Email alerts whenever there is an update.
  • Full text search for other cases.
  • Get email alerts whenever a new case matches your search.

Become a Member

One Moment Please

The filing “” is large (MB) and is being downloaded.

Please refresh this page in a few minutes to see if the filing has been downloaded. The filing will also be emailed to you when the download completes.

Your document is on its way!

If you do not receive the document in five minutes, contact support at support@docketalarm.com.

Sealed Document

We are unable to display this document, it may be under a court ordered seal.

If you have proper credentials to access the file, you may proceed directly to the court's system using your government issued username and password.


Access Government Site

We are redirecting you
to a mobile optimized page.





Document Unreadable or Corrupt

Refresh this Document
Go to the Docket

We are unable to display this document.

Refresh this Document
Go to the Docket