`
`With 82 Figures
`
`C.D. Johnson and C.W. Imrie
`
`Pancreatic Disease
`
`Springer
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`C.D. Johnson, MChir, FRCS
`University Surgical Unit
`Southampton General Hospital
`Southampton, UK
`
`C.W. Imrie, BSc, MB, FRCS
`Royal Infirmary
`Glasgow, UK
`
`British Library Cataloguing in Publication Data
`Pancreatic disaase: basic science and clinical management
`1. Pancreas ’ Diseases 2. Pancreas - Cancer 3. Pancreatitis
`1. Johnson, C.D. (Colin David), 1952' II. Imrie, C.W.
`(Clement William)
`616.3’7
`ISBN 1852337117
`
`2003054423
`
`Apart from any fair dealing for the purposes of research or private study, or criticism or
`review,as permitted under the Copyright, Designs and Patents Act 1988, this publication
`may only be reproduced, stored or transmitted, in any form or by any means, with the
`prior permission in writing of the publishers, or in the case of reprographic reproduc-
`tion in accordance with the terms of licences issued by the Copyright Licensing Agency.
`Enquiries concerning reproduction outside those terms should be sent to the publishers.
`
`lSBN 1-85233-711-7 Springer-Verlag London Berlin Heidelberg
`Springer-Verlag is a part of Springer Science+Business Media
`springeronline.com
`
`© Springer—Verlag London Limited 2004
`Printed in Singapore
`
`The use of registered names, trademarks, etc. in this publication does not imply, even in
`the absence of a specific statement, that such names are exempt from the relevant laws
`and regulations and therefore free for general use.
`
`Product liability: The publisher can give no guarantee for information about drug
`dosage and application thereof contained in this book. in every individual case the
`respective user must check its accuracy by consulting other pharmaceutical literature.
`
`Typeset by EXPO Holdings, Malaysia
`
`28/3830—543210 Printed on acid-free paper SPIN 10900925
`
`Library of Congress Cataloging—in-Publication Data
`Pancreatic disease: basic science and clinical management) C.D. Johnson and
`CW. Imrie (eds).
`p. ; cm.
`Includes bibliographital references.
`lSBN 1-85233-71 1-7 (alk. paper)
`I. Pancreas-Diseases. I. Title: Pancreatic disease in the twenty-first century. II.
`Johnson, C. D. (Colin David), 1952- III. lmrie, C. W.
`lDNLM: l. Pancreatic Diseases—diagnosis. 2. Pancreatic Diseases~etiology. 3. Pancreatic
`Diseases—therapy. 4. Therapies, [nvestigaliona].W1 800 P1892 2004]
`RC857.P3225 2004
`61637—ch
`
`
`
`
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`,--.'WN-\'I'F-—1_J1‘I"-1iv'.-.
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`Neuroendocrine Tumours
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`4 GI Hormone Producing Tumours: Syndromes and
`Treatment Options
`Mary McStay and Martyn E. CaplinWW
`
`Neuroendocrine tumours of the pancreas (also called pancreatic endocrine
`tumours or islet cell tumours) may be functioning or non-functioning. Functioning
`tumours are those associated with a clinical syndrome that is cansed by hormone
`release. and are named according to the hormone that they secrete (Table 4.1).
`Non-functioning neuroendocrine tumours of the pancreas include those that have
`all the histological characteristics of a neuroendocrine pancreatic tumour (NPT),
`but no associated clinical syndrome related to hormone hypersecretion. NPTs are
`rare tumours, with an incidence of less than 1/100 000 population/year. Non-
`functioning tumours form the biggest group (30—40%), followed by gastrinomas
`and insulinomas. which have approximately the same incidence. With the
`exception of insulinomas, the majority of NPTs are malignant.
`Eight of the NPTs are well established and are included in most classifications.
`These are gastrinomas. insulinomas, VIPomas, glucagonomas, somatostatinomas,
`growth-hormone releasing factor secreting tumours (GRFomas), ACTH secreting
`tumours of the pancreas (ACTHomas), and ‘non~functioning' tumours, which may in
`fact be pancreatic polypeptide-secreting tumours (PPomas). Other rarer NPTs have
`recently been considered as causing syndromes, including NPTs causing hypercal—
`caemia (producing parathyroid hormone and parathyroid hormone—related protein),
`NPTs secreting calcitonin and NPTs causing the carcinoid syndrome.
`
`depending on their histological and functional features.
`
`Pathophysiology and Pathology of Neuroendocrine Tumours
`
`The histological diagnosis of neuroendocrine tumours relies first on the
`identification of general markers of neuroendocrine differentiation, and then cell-
`specific characterisation. Neuroendocrine differentiation is evaluated by immuno—
`histochemistry using antibodies against secretory granule proteins (chromogranin
`A, synaptophysin) and cytosolic proteins (neuron-specific enolase, protein gene
`product 9.5). The cellvspecific characterization of neuroendocrine tumours
`requires hormone immunohistochemistry. According to the World Health
`Organisation (WHO) classification, neuroendocrine tumours of the gastroen-
`teropancreatic tract are classified as well-differentiated and poorly differentiated
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`fable 4.1. The different lypes of pancrtalic neuroendocrine‘ tumours and their associated hyperfunctiunal syndromes
`Tumour location
`
`Predomi nanl hormoneCell lyp: Pen-an malignanfi
`
`Tumour
`Major clinical symptoms
`90
`Pancreas 50%
`Gasmn
`Gaslrinomas
`Recurrent peptic ulcer
`Duodenum 50%
`10
`Pancrras
`Insulin
`Insulinoma
`Hypnglycacmia (fasting or
`nocturnal)
`60
`Pancreas 90%
`Vasoactive intestinal
`Vll‘oma
`Watery diarrhoea. hypokalacmia.
`achlorhydria
`polypeptide (VIP)
`90
`Pancreas
`Diabcles mellltus. necrolyiic
`Glucagon
`migratory erylhema
`80
`Pancreas 55%
`Diabnles mellims
`Somalosralln
`Duodenum 45%
`60
`Pancreas 30%
`Growxh-hnrmone releasing»
`hormone
`Lung 50%
`lcjunum l5%
`95
`Pancreas 90%
`ACTH
`ACTHoma
`Cushing's syndrome
`30
`Pancreas [00%
`l‘l‘oma
`Hepummcgal'y, abdominal pain
`Pancreatic pnlypeptlde (PP)
`
`
`«v
`
`
`
`"=5“'21:{Bum-331453.";marznwsrawm‘ma“
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`Acromegaly
`
`
`
`smouml33129131124
`
`G B7
`
`Glucagonomn
`Somaloslatinoma
`GR Form
`
`
`
`
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`Well—differentiated tumours are positive for most markers of neuroendocrine
`differentiation in the vast majority of tumour cells. Poorly differentiated tumours
`do not express chromogranin A. but retain cytosolic markers together with synap~
`tophysin. Other helpful features used to classify these tumours, and therefore to
`attempt
`to gauge their behaviour,
`include general morphologic description;
`mitotic rate (two or more mitoses per 10 high power [x400] microscopic fields);
`proliferative index (as assessed by nuclear Ki67 expression); tumour size; evidence
`' of invasion of blood vessels, nerves, or adjacent organs by the neoplasm; predom~
`inant tumour synthesis of a specific hormone; or complete non—functionality of
`the tumour at an immunohistological level. Well-differentiated tumours are then
`named according to the specific endocrine cell of which they are composed
`(usually the cell types normally observed in the anatomical site of the tumour).
`Tumours falling into the two major categories of well-differentiated and poorly
`differentiated exhibit significant differences in phenotype and behaviour. The
`behaviour of well—differentiated tumours can be unpredictable, varying from
`benign to low—grade malignant;l according to the several clinicopathological
`parameters mentioned above, a tentative risk class is assigned to the tumour.
`Poorly differentiated (small cell) endocrine carcinomas are highly aggressive and
`are associated with a poor prognosis.
`
`MEN-1 Syndrome
`
`GI Hormone Producing Tumours: Syndromes and Treatment Options
`
`33
`
`.-'..-.-.—-1-.r-L.i—.--..'.'rg'l=1
`
`The MEN—1 syndrome is most commonly associated with primary hyperparathy-
`roidism, and tumours of the endocrine pancreas and anterior pituitary.
`This autosomal dominant inherited syndrome is associated with a germline
`genetic mutation in the MENI gene, on chromosome 11.‘ Genetic mapping studies
`show somatic loss of heterozygosity (LOH) suggesting that development of MEN]
`associated tumours is a two-step process: firstly, a germline mutation affecting the
`first MENl allele; and then a somatic inactivation of the unaffected allele by
`L0H."2 The MEN} gene was cloned in 1997'M and encodes a 610 amino acid
`protein called menin. Menin is a putative growth—suppressor protein, which
`specifically binds JunD, a transcription factor acting through the activator protein-
`1 (API complex)? API is a regulatory system within the cell, which is involved in a
`plethora of functions including apoptosis, mitosis and response to endogenous or
`exogenous growth factors.
`Characteristically, hyperparathyroidism is the initial manisfestation of MEN-1,
`usually presenting in the third decade of life, and followed by the development of
`an NPT between the ages of 35 and 50 years. Recognition of MEN-l is an impor—
`tant first step in the management of NPTs, because patients with and. without
`MEN-1 differ in clinical presentation, clinical management approaches, and also '
`prognosis. The presence of additional endocrinopathies may need specific
`management and may have an influence on the main tumour management. For-
`example, in patients with gastrinoma and hyperparathyroidism, the presence of
`hypercalcaemia resulting from hyperparathyroidism often stimulates the release
`of gastrin from the tumour, and parathyroidectomy has to be performed before
`gastrinoma surgery. Patients with MEN—1 may develop multiple tumours simulta-
`neously, and more than one type of NPT over time, thus the chances of surgical
`cure and the approach to long-term followsup will differ from patients without
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`Pancreatic Tumours
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`MEN—1. Additionally, screening of other family members of MEN-l patients is
`indicated. Systematic biological screening performed on these patients includes:
`measurement of parathyroid hormone, serum calcium, prolactin,
`luteinising
`hormone, follicle stimulating hormone, growth hormone, adrenocorticotrophic
`hormone (ACTH), morning cortisol and 24 h urinary cortisol.
`Other hereditary neoplasia syndromes associated with NPTs include neuro—
`fibromatosis type 1 and von Hippel-Lindau disease. Neurofibromatosis type 1 (NFI)
`is inherited in an autosomal dominant manner, arising from mutation of the NH
`gene. The NH gene is a tumor suppressor gene encoding a large protein
`(neurofibromin) that functions primarily as a RAS negative regulator.6 The hallmark
`feature of NH is the presence of neurofihromas arising either in the dermis or in
`peripheral nerve. However, patients also have an increased incidence of other
`tumours, including phaeochromocytomas and duodenal tumours, including somato—
`statinomas. Clinically von Hippe]-Lindau(VHL) disease displays an autosomal domi-
`nant pattern of inheritance. Germline mutation of the VHL tumour suppressor gene
`on chromosome 3 causes a hereditary cancer syndrome characterised by the devel—
`opment of retinal and central nervous system haemangioblastomas. Other tumours
`associated with VHL disease include clear cell renal carcinomas, phaechromocy-
`tomas, and neuroendocrine tumours of the pancreas?
`
`.mm-...uwn:--.-n "'I.'-\.l'ur-'|" I Ir _
`
`Gastrinomas have an annual incidence of 0.5—1.5 per 10" persons,8 the majority of
`the tumours are located either in the pancreas or the duodenum. Less frequent
`sites are the small intestine and the stomach.9 Approximately 20% of patients have
`a family history of neuroendocrine tumours, and 20~25% of patients (particularly
`those with duodenal
`tumours) have the MENl syndrome. MEN-l-associated
`gastrinomas usually present at an earlier age, and most MEN~1 patients have co-
`existing hyperparathyroidism or pituitary disease at the time of presentation. As
`gastrin is trophic for the enterochromaffin cells in the fundus of the stomach (ECL
`cells), prolonged hypergastrinaemia may lead to the development of so~called
`ECLomas, which are also mostly benign neuroendocrine tumours.10 ECLomas are
`more frequent in patients with MENl—associated gastrinoma (15»300/0) than in
`those with sporadic gastrinoma (<5%).
`Gastrinomas manifest with the characteristic Zollinger—Ellison syndrome
`(ZES), which is caused by hypergastrinaemia associated with hypersecretion of
`gastric acid. The most common symptom is abdominal pain caused by peptic
`ulceration.“ Ulcers are most commonly found in the first part of the duodenum
`(approximately 75%), and are usually single, but can be multiple. Ulcers are found
`much less often in the stomach, and in contrast to the common peptic ulcer, which
`is associated with Helicobacter pylori or ingestion of non-steroidal inflammatory
`drugs, may also by found in the second, third and fourth parts of the duodenum
`(14%), and in the jejunum (11%).” Ulcers are often recurrent and/or resistant to
`medical or surgical treatment.
`.
`Gastroesophageal reflux disease is also common. Approximately 60% of patients
`with Zollinger-Ellison Syndrome have dysphagia, or endoscopic evidence of
`erosive oesphagitis, including its complications of stricture formation, Barrett’s
`
`Clinical Syndromes of Neuroendocrine Tumours
`
`Gastrinomas
`
`-v..- r-In- .4.- m-..-.- .-
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`GI Hormone Producing Tumours: Syndromes and Treatment Options
`
`35
`
`lnsulinoma
`
`lnsulinomas have an annual incidence of 1—2/106 persons/year, and usually
`occur in patients between 30 and 60 years of age. Insulinomas are small (81%
`measure 20 mm or less),‘6 usually solitary, and are almost always confined to the
`pancreas. They are evenly distributed within the head, body and tail of the
`pancreas. Approximately 10% of the tumours are malignant tumours, these are
`usually larger than benign lesions, and can lead to widespread metastases.
`Multiple tumours occur in up to 10% of patients and should raise the possibili-
`ty of MEN—I syndrome.
`The tumour is characterised by ,hypersecretion of insulin and h'ypog'lycaemia.
`Symptoms occur as the result of hypoglycaemia and characteristically occur when
`a meal is delayed or missed, with fasting, or during exercise.‘7 Most patients
`present with neurological symptoms of hypoglycaemia, such as visual disturb-
`ances, altered mood/confusion, weakness, transient motor defects, fatigue, dizzi-
`ness, and even coma. Hypoglycaemia can also cause symptoms of adrenergic
`hyperactivation, such as hunger, palpitations, sweating and tremor. When the diag-
`nosis is made late, hypoglycaemia' may even cause permanent cerebral damage.
`The symptoms can be partially masked by a tendency to over—eat in order to
`compensate for the hypoglycaemia. For this reason, insulinoma patients are often
`overweight.18
`
`VlPoma
`
`Vasoactive intestinal polypeptide (VIP)-secreting tumours (VlPomas) account for
`less than 10% of pancreatic neuroendocrine tumours. They are much more
`
`epithelium, and perforation.”"“ A recently appreciated, important endoscopic sign
`is the presence of prominent endoscopic folds, which was present in 94% of
`patients in a large prospective series of patients.“
`The other characteristic component of the syndrome is diarrhoea, which
`occurs in the majority of patients.ll This is of the secretory or motor variety,
`and is always associated with hypersecretion of gastric acid, making it easily
`distinguishable from the diarrhoea associated with VIPomas, which is associated
`with hypochlorhydria.15 The diarrhoea may accompany, precede or follow the
`peptic ulcer disease, or in some cases it may be the only manifestation. The large
`amounts of hydrochloric acid in the upper GI tract lowers the intraluminal pH,
`producing other effects: steatorrhoea, through the inactivation of pancreatic
`lipase, and the insolubilisation of some primary bile acids; vitamin B malabsorp-
`tion, by interference with intrinsic factor-mediated vitamin BIZ absorption by the
`distal ileum.[2
`An estimated 60% of gastrinomas run a malignant course. Approximately 50%
`of patients with pancreatic or duodenal gastrinomas have lymph node and/or liver
`metastases at presentation. For many years, the main causes of death among gastri-
`noma patients were the complications of peptic ulcer disease: perforation, haem-
`orrhage and pyloric stenosis. However, with the advent of effective acidvreducing
`pharmacological agents,
`in particular proton pump inhibitors,
`the primary
`morbidity has changed to that of tumour growth and spread.
`
`'__..'
`
`
`
`
`
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`
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`Pancreatic Tumours
`
`common in women (with a femalezmale ratio of 3:1), and most frequently occur at
`around the fourth decade of life.9 Up to 90% of VlPomas originate from the
`pancreas, and are usually solitary tumours. The remaining 10% are tumours of the
`nervous system, such as ganglioneuromas, neuroblastomas and phaeochromocy-
`tomes. Approximately 5% of VIPomas are MEN-l—associated. Over 60% of
`pancreatic ViPomas are malignant, and by the time of diagnosis up to 60% have
`metastasized to lymph nodes, liver, kidneys, or bone.“'19
`The hypersecretion of VIP produces a syndrome characterised by severe secrev
`tory diarrhoea, associated with hypokalaemia and dehydration, and is commonly
`called the Verner—Morrison Syndrome. The diarrhoea is intermittent in 53% of
`patients, and continuous in 47%. The volume of diarrhoea is large, with the major~
`ity of patients having more than 3 l/day.20 The pathogenesis of the severe
`hypokalaemia is probably primarily caused by faecal loss, and if left uncorrected
`may be severe enough to cause life-threatening cardiac arrthymias. Other elec~
`trolyte abnormalities include: hypochlorhydria, hypercalcaemia, hyperglycaemia.
`and hypomagnesaemia.l7 A less frequent symptom is cutaneous flushing, which is
`characteristically erythematous, and occurs in 20% of patients.
`
`Glucagonomas
`
`f'\:‘.'/'\fiAMrpm0
`
`Glucagonomas are less than half as common as VlPomas, with an annual incidence
`of 0.01—0.1 new cases per million. They are slightly more common in women
`(55%), and usually occur after 45 years of age.21 Most glucogonomas are large soli-
`tary tumours, which are almost exclusively found in the pancreas. They generally
`exhibit highly malignant behaviour: approximately 90% of patients already have
`lymph node and/or liver metastases at presentation.8 Glucagonoma is rarely asso-
`ciated with MEN-1.
`'
`Glucagonomas secrete excessive amounts of glucagon and cause a distinct
`syndrome that
`is characterized by a specific dermatitis (necrolytz'c migratory
`erythema), weight loss. diabetes mellitus, and anaemia. The cutaneous lesions are
`one of the most common manifestations of the disease, being present in about 90%
`of patients. characteristically, the skin lesion starts as an erythematous area that
`subsequently becomes papular, with superficial blistering that frequently erodes
`and crusts. Healing is associated with hyperpigmentation of the area involved. The
`eruption is usually localized to the buttocks, groin, perineum, elbows, hands, feet
`and perioral area. The glucagon-induced hypoaminoacidaemia that develops in
`the majority of patients is implicated in the pathogenesis of the rash.
`Glucose intolerance, with or without frank diabetes mellitus, develops in 85%,
`principally due to the hyperglycaemia that results from glucagonvstimulated
`hepatic glycogenolysis and gluconeogenesis. Weight loss is almost universal, and
`probably reflects the known catabolic actions of glucagon. Weight loss may be as
`severe as 20-30kg, and may occur even with small non—metastatic tumours.
`Normochromic, normocytic anaemia develops in 60% of patients, and is probably
`caused by an inhibitory effect of prolonged hyperglucagonaemia on erythro’
`poiesis.22 Other abnormal laboratory findings commonly found include hypoalbu—
`minaemia (in 80% of patients), and hypocholesterolaemia (reduced VLDL in 80%
`of patients), which both reflect reduced hepatic synthesis.
`Less common symptoms include; deep venous thrombosis (20%), pulmonary
`emboli (10%), diarrhoea (15%), and psychiatric disturbance.
`
`O‘C'TSE‘UOUJ
`
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`
`95"?“
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`GI Hormone Producing Tumours: Syndromes and Treatment Options
`
`Somatostatinoma
`
`Somatostatinomas are usually solitary tumours, which originate in the pancreas
`or small intestine. They are rare tumours, and account for less than 5% of
`pancreatic neuroendocrine tumours. Somatostatinomas of the pancreas and
`small intestine differ in several respects: a clinical syndrome is encountered
`more frequently (18.5% versus 2.5%),
`the large size of
`the tumour
`(>20 mm)(85.5% versus 41.4%), the association with neurofibromatosis type 1
`(von Recklinghausen‘s disease)(i.2% versus 43.2%), and the presence of psam~
`moma bodies (2.5% versus 49.4%)“ The majority of somatostatinomas are
`overtly malignant at presentation, and have evidence of metastatic spread to the
`liver and/or lymph nodes.“
`Somatostatinomas release large amounts of somatostatin and cause a distinct
`clinical syndrome characterized by diabetes mellitus, gallbladder disease, and
`diarrhoea with steatorrhoea. Approximately 40% of patients with somatostatin-
`omas remain asymptomatic, and the tumour is discovered incidentally.
`The development of diabetes mellitus, which is usually mild, is likely to be
`secondary to the inhibitory action of somatostatin on insulin, glucagon and
`growth hormone release, as well as the replacement of functional pancreatic
`tissue. Gallbladder disease may be a result of somatostatin inhibition of gall-
`bladder emptying. Diarrhoea and steatorrhoea probably reflect inhibition by
`somatostatin of pancreatic secretion of enzymes and bicarbonate, gallbladder
`motility, and intestinal absorption of lipids.‘7 All of these symptoms may also
`occur in patients treated with somatostatin analogues, such as octreotide. Other
`symptoms include weight
`loss, which may be secondary to malabsorption,
`and hypochlohydria, which is probably secondary to inhibition of gastric acid
`secretion.I7
`
`syndrome, hypoglycaemia, Cushing’s syndrome and phaeochromocytoma.“
`
`GRFomas
`
`GRFomas are defined as extracranial tumours that are predominantly or exclu~
`sively composed of cells that synthesize and release growth hormone—releasing
`factor (GRF) (also known as GHRH), which leads to growth hormone (GH) hyper-
`secretion and acromegaly.,The average age of GRFoma patients at presentation is
`40years, and at variance with pituitary adenoma, GRFoma is 3 times more
`common in women than in men. Differentiation of GRF'driven acromegaly from
`GH hypersecretion from a pituitary adenorna can be difficult. Radiological
`imaging of the sella turcica is often unhelpful, since 40—45% of patients with
`GRFomas show a hypophyseal mass resembling an adenoma, usually due to hyper—
`plasia of somatotrophs. Detection of an extrahypophyseal tumour, together with
`an elevated plasma GRF level, is the most useful aid to diagnosis.
`GRFomas have been reported in the pancreas (30% of cases), bronchus (50% of
`cases, where they can be associated with bronchial carcinoid tumours), and in the
`jejunum (15% of cases). Approximately 30% of tumours are overtly malignant at
`the time of diagnosis. About 40% of patients with GRFomas have other associated
`secretory syndromes, especially through the expression of the MENsl syndrome.
`Co—existing endocrinopathies include hyperparathyroidism, Zollinger—Ellsion
`
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`These tumours are very rare, and are usually located in the pancreas (90% of
`cases). They produce ACTH and ectopic Cushing’s syndrome. The tumours often
`co-secrete, and so the syndrome is often associated with another syndrome.
`Approximately 95% have metastasised at the time of diagnosis.
`
`NPTs Causing Carcinoid Syndrome
`
`Tumours secreting 5~hydroxytryptamine (SHT) or pancreatic ‘carcinoids’ account
`for l~2 % of NPTs. These tumours also produce other peptides such as histamine,
`kinins, substance P and prostaglandins. Unless these secretory peptides are
`released directly from metastases into the systemic circulation (intestinal drainage
`is into the portal system), they do not usually cause any signs or symptoms.
`Paracrine secretion in the intestine may however cause diarrhoea. Therefore,
`systemic features of the carcinoid syndrome only usually become apparent when
`liver metastases are present, This syndrome is characterised by flushing and diar-
`rhoea, and less commonly by wheezing, abdominal pain and heart disease.
`Pancreatic carcinoids with excess production of histamine may cause an atypical
`carcinoid syndrome (generalised flushing, lacrimation, hypotension, cutaneous
`oedema, bronchoconstriction). Approximately 10% of carcinoid tumours are asso-
`ciated with MENL”
`
`NPTs Causing Hypercalcaemia
`
`Hypercalcaemia has been reported with NPTS secreting parathyroid hormone-
`related protein that mimics the actions of parathyroid hormone. The tumours are
`usually large and have metastased to the liver by the time of diagnosis.”26
`
`Nonfunctioning Tumours
`
`.."a'.rt'-:z1;_t!i-r':;-Ij;-.=_‘flf.- LL“:'-;.£rn-.1-“rwrgl'anfimfir-anfirwng team's-rm! mum _
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`
`38
`
`ACTHomas
`
`Pancreatic Tumours
`
`peptide, such as somatostatin.27
`
`is
`incidence of non-functioning pancreatic endocrine tumours
`The
`1’2/106 persons/year, and these tumours represent about 60% of the total
`number of pancreatic neuroendocrine tumours. By definition, nonfunctioning
`endocrine tumours of the pancreas are those that have all the histological char-
`acteristics of a pancreatic neuroendocrine tumour, but not associated clinical
`syndrome related to hormone hypersecretion. These tumours are often produc—
`ing hormones, but remain clinically ‘silent’ for a number of reasons. The
`peptides or hormones produced may not produce a known specific clinical-
`syndrome, for example, pancreatic polypeptide (PPomas), (x— and ,B—human
`chorionic gonadotrophin, calcitonin, and chromogranin A. In other cases, the
`tumour may produce a peptide which is Well-known to produce a clinical
`syndrome, but fails to release it, or produces it at only very low plasma concen-
`trations. It may also be that the tumour only produces biologically inactive
`precursor forms of the peptide. or that it simultaneously produces an inhibitory
`
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`Gl Hormone Producing Tumours: Syndromes and Treatment Options
`
`39
`
`The tumours are usually unifocal, and are predominantly situated in the head of
`the pancreas. Between 20 and 40% of non-functioning pancreatic neuroendocrine
`tumours are MEN—l—associated, and in this situation may be multifocal. Patients
`present with symptoms related to expanding tumour mass, most commonly jaundice
`and epigastric pain, but also with weight loss, steatorrhoea, upper gastrointestinal-
`bleeding, recurrent pancreatitis, fatigue and malaise. An increasing number are being
`detected incidentally. Reported malignancy rates at presentation are 60—90%.“ 3"
`'It should be noted that a tumour which has presented as a non-functioning
`tumour, can later turn into a functioning tumour, for example a gastrinoma.Z7
`
`Diagnosis
`
`Pancreatic neuroendocrine tumours produce specific symptoms and hormones.
`The diagnosis is therefore based on clinical symptoms, hormone measurement,
`radiological and nuclear medicine imaging and histological confirmation. The
`gold standard is histology and should be obtained wherever possible. The
`minimum diagnostic criteria for the various syndromes includes histology and
`the following tests:
`
`Fasting Gut Hormones
`
`lnsulinoma
`
`Gastrinoma
`
`The most important diagnostic test for gastrinoma is an elevated fasting serum
`gastrin in the presence of gastric acid secretion after discontinuation of acid
`reducing medications (ie. H2 receptor antagonists and proton pump inhibitors).
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`The demonstration of inappropriately high insulin levels in the presence of hypo-
`glycaemia after prolonged fasting is used to diagnose insulin-producing tumours.
`Hypoglycaemia is usually defined as a blood glucose below 2.2 mmol/l (40 mg/dl).
`Within 24 h of fasting, most patients develop hypoglycaemia, and by 72 h, virtual-
`ly all patients will be hypoglycaemic. Paired samples of insulin and glucose are
`taken every 3~4 h. The test is terminated, and intravenous glucose is administered,
`when the serum glucose drops to 2.2 mmol/l or below, and/or the patient becomes
`symptomatic. The test is considered positive for insulinoma if the ratio of plasma
`insulin (in uU/ml) to glucose (in mg/dl) is more than 0.3.A value of 20 pmol/mmol
`(insulin concentration [pmol/l] divided by glucose concentration [mmol/l]) can
`also be used to differentiate patients with and without insulinoma."
`Caution must be taken to exclude factitious hypoglycaemia, which may be partic-
`ularly prevalent amongst medical workers or in relatives of diabetic patients. This can
`be done by measurement of C~peptide (endogenous flanking peptide of insulin) and
`pro—insulin (which is elevated in up to 90% of patients with insulinoma). Levels of
`these peptides will be normal or low following administration of insulin. In the case
`of deliberate or accidental use of sulphonyureas, elevated levels of insulin and
`C-peptide are found, but proinsulin levels are normal or low. In this case, serum can
`be screened for the presence of hypoglycaemics.”
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`NOVARTIS EXHIBIT 2062
`Par v. Novartis, IPR 2016-01479
`Page 12 of 26
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`40
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`Pancreatic Tumours
`
`A level of greater than 1000 pmol/ml, is virtually diagnostic of ZES. However,
`hypergastrinaemia can also be present in a number of other conditions, including
`HelicobaCter pylori infection, and gastric outlet obstruction. Many patients with
`ZES will have only a modest elevation of fasting serum gastrin (betWeen 100 and
`lOOOpmol/l), and in these patients a secretin stimulation test may be of some
`help?5 Secretin is a potent stimulator» of gastrin release from gastrinomas, but has
`little effect on other types of gastrinaemia,
`
`Other Hormones
`
`The diagnosis of glucagonoma syndrome can be made easily by measurement of
`fasting plasma glucagon. In the vast majority of patients with the syndrome, basal
`levels of glucagon exceed the normal range by six—fold.Zl
`The Verna—Morrison syndrome can be diagnosed by demonstration of an
`elevated fasting plasma VIP level. The usual increase in plasma VIP is 50-fold
`above the normal mean concentration. A raised plasma pancreatic polypeptide
`level is frequently also seen in pancreatic VIVPomas‘32
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`Somatostatinoma
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`Plasma somatostatin levels are usually elevated in pancreatic somatostatinomas.
`Levels may however be inconclusive or normal in duodenal or small intestinal
`tumours.”
`
`GRFoma
`
`Plasma GRF (GHRH) levels are usually elevated in patients with GRFoma, and are
`normal in patients with pituitary acromegaly. Growth hormone (GH) and insulin
`like growth factor-1 (IGF~]) are invariably elevated, and GH levels fail to suppress
`after an oral glucose load in all forms of acromegaly.”
`
`ACTHoma
`
`These patients usually have an elevated plasma ACTH and high cortisol levels. This
`does not however differentiate an extra—pituitary ACTH—producing tumour from
`pituitary-dependent Cushing’s disease, with which it may share some clinical
`features. Factors favouring the diagnosis of an extra-pituitary ACTH-secreting
`tumour include, the presence of hypokalaemia with metabolic acidosis, the c0~
`secretion of other gut hormones, male sex, and advanced age.“
`
`Chromogranin A
`
`The chromogranins are a unique family of water-soluble acidic glycoproteins
`found in the storage vesicles of neuroendocrine cells and released during
`
`NOVARTIS EXHIBIT 2062
`Par v. Novartis, IPR 2016-01479
`Page 13 of 26
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`GI Hormone Producing Tumours: Syndromes and Treatment Options
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`41
`
`Assessment of Tumour - Localisation and Extent
`
`The next key step in the management of pancreatic neuroendocrine tumours is the
`determination of the primary tumour location, and the tumour extent (location
`and extent of metastases). This information is essential both for patients whose
`disease is amenable to surgical resection, and for the clinical management