C.D. Johnson and C.W. Imrie
`
`Pancreatic Disease
`
`l
`
`Basic Science and Clinical Management
`
`With 82 Figures
`
`'Springer
`
`Roxane Labs., Inc.
`Exhibit 1010
`Page 001
`
`

`
`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 disease: basic science and clinical management
`I. Pancreas - Diseases 2. Pancreas -Cancer 3. Pancreatitis
`!. johnson, C.D. (Colin David), 1952- II. Imrie, C.W.
`(Clement William)
`616.3'7
`ISBN 1852337117
`
`Library of Congress Cataloging-in-Publication Data
`Pancreatic disease: basic science and clinical management/ C. D. johnson and
`C.W. Imrie (eds).
`p.;cm.
`Includes bibliographical references.
`ISBN 1-85233-711-7 (alk. paper)
`1. Pancreas-Diseases. !. Title: Pancreatic disease in the twenty-first century. II.
`johnson, C. D. (Colin David), 1952- III. Imrie, C. W.
`[DNLM: 1. Pancreatic Diseases-diagnosis. 2. Pancreatic Diseases-etiology. 3. Pancreatic
`Diseases-therapy. 4. Therapies, Investigational. WI 800 P1892 2004)
`RC857.P3225 2004
`616.3'7 -dc21
`
`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(cid:173)
`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.
`
`ISBN 1-85233-711-7 Springer-Verlag London Berlin Heidelberg
`Springer-Verlag is a part of Springer Science+ Business Media
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`
`© Springer-Verlag London Limited 2004
`Printed in Singapore
`
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`
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`Page 002
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`

`
`Neuroendocrine Tumours
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`Roxane Labs., Inc.
`Exhibit 1010
`Page 003
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`1 Epidemiology of Pancreatic Neuroendocrine Tumours
`Helen Doran, John P. Neoptolemos, Evelyn M.l. Williams and Robert Sutton
`
`Pancreatic neuroendocrine tumours are rare neoplastic growths of endocrine
`pancreatic tissue with both neural and endocrine features, frequently causing clin(cid:173)
`ical syndromes from uncontrolled hormone secretion. 1
`2 Those tumours that cause
`'
`such syndromes have been classified as 'functional' whilst those without obvious
`hypersecretion have been classified as 'non-functional' .1
`3 However, 'non(cid:173)
`-
`functional' tumours secrete various peptides and proteins, including chromo(cid:173)
`3
`granins, plasma levels of which can be used as tumour markers. 1
`4 There are a
`•
`•
`number of well recognised syndromic tumours, the commonest being insulinoma
`and gastrinoma, although many gastrinomas arise in the duodenum (see
`Table l.l). A minority of patients presenting with pancreatic neuroendocrine
`tumours have one of four inherited disorders producing tumours at many sites:
`multiple endocrine neoplasia type 1 (MEN-1) 5
`, von Hippel-Lindau disease6 (see
`Ch. 12), neurofibromatosis7 and tuberous sclerosis.8
`
`Incidence and Prevalence
`
`Autopsy Series
`
`Pancreatic neuroendocrine tumours have been found in 0.1-1.6% of autopsies in
`unselected series.w This wide variation is likely to be attributable to varying
`methods of identification; systematic sectioning of the pancreas in transverse
`blocks 0.3-0.5 em thick, with subsequent thorough examination of all slides made
`from each block, will give higher figures. In one autopsy series using meticulous
`identification the percentage with pancreatic neuroendocrine tumours was I 0%. 16
`However, as in other endocrine glands, many tumours are small adenomas that are
`slow growing and without significant hormonal effects, and so do not present
`during life. In a 25 year study of 11 472 autopsies conducted in Hong Kong, pancre(cid:173)
`atic neuroendocrine tumours were identified in only 10 cases, only one of which
`had presented during life. 10 Another study suggests that tumours not presenting in
`life are more likely to occur in the body and tail of the gland, and contain more
`pancreatic polypeptide than any other hormone. 18 Such studies have helped to
`develop our understanding of natural history, but provide limited insight into clin(cid:173)
`ical features.
`
`5
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`o-.
`
`.,.,
`=Q
`"' ~;:;
`
`230
`
` ~
`
`Survival
`Complete resection cures most
`patients
`
`Complete resection results in
`10 year survival of 90%; less likely
`if large primary
`More favourable with complete
`resection; prolonged even with
`liver metastases
`Complete resection: five year
`survival of 95%;
`with metastases: 60%
`Complete resection associated
`with five year survival of 95%;
`with metastases, 60%
`Complete resection associated
`with five year survival of at
`least SO%
`
`Table 1.1. Principal clinical features of less rare types of pancreatic neuroendocrine tumours
`Tumour
`Symptoms
`Diagnosis
`lnsnlinoma
`Confusion, sweating, dizziness,
`Inappropriate insulin secretion
`weakness, unconsciousness,
`during hypoglycaemia from up
`relief with eating
`to 72 h fasting
`Elevated serum gastrin when
`Metastases develop in 60%
`Zollinger-Ellison syndrome of
`patient off all acid suppression
`of patients; likelihood
`severe peptic ulceration and
`correlated with size of primary
`treatment
`diarrhoea
`Necrolytic migratory erythema,
`Elevated serum glucagon. Other Metastases develop in 60% or
`weight loss, diabetes mellitus,
`hormones can be elevated
`more patients
`stomatitis, diarrhoea
`Verner-Morrison syndrome of
`profuse watery diarrhoea with
`marked hypokalaemia
`Symptomatic cholelithiasis;
`weight loss; diarrhoea and
`steatorrhoea
`Symptoms from pancreatic
`mass and/or liver metastases
`
`Gastrinoma
`
`Glu c~go noma
`
`Vipoma
`
`Somatostatinorna
`
`Non-syndromic pancreatic
`twurn ende>crine tumour
`
`Malignancy
`I Oo/o of patients develop
`metastases
`
`Hypochlorhydria, +
`hypercalcaemia; elevated
`serum VIP
`Elevated serum somatostatin
`
`Metastases develop in up to
`70% of patients; majority found
`at presentation.
`Metastases likely in about 50%
`of patients
`
`A variety of hormones may be
`elevated, including
`chromogranins
`
`Metastases develop in up
`to 50% of patients
`
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`Epidemiology of Pancreatic Neuroendocrine Tumours
`
`7
`
`Clinical and Surgical Series
`
`Clinical series have been compiled from collections of cases that include tumours
`identified incidentally on radiological imaging or pathological examination of a
`pancreatic specimen performed for another reason. In surgical series functioning
`tumours have more often been reported. 17
`19 Without assessment of the population
`•
`base from which each series was drawn, no proper epidemiological picture can be
`drawn.
`
`Prevalence
`
`For indolent neoplastic lesions such as pancreatic neuroendocrine tumours,
`prevalence is an important measure of population disease burden. Prevalence esti(cid:173)
`mates are reported at 1.0 per 100 000,20
`21 but these estimates were made over three
`•
`decades ago using older histological techniques. More recent data from the SEER
`project identified 401 islet cell tumours amongst 22 747 pancreatic cancers
`( < 2%)? However, these data are also limited, because only malignant tumours
`were included, and more importantly, most pancreatic cancers are associated with
`a survival of less than six months, quite different from most pancreatic neuro(cid:173)
`endocrine tumours.
`
`Incidence
`
`All Pancreatic Neuroendocrine Tumours
`
`There are two population-based studies that have assessed the overall incidence of
`pancreatic neuroendocrine tumours identified during life,6
`7 but in neither was the
`•
`autopsy rate reported. Watson and co-workers used cases identified in Northern
`Ireland that had been entered into a neuroendocrine tumour database compiled in
`conjunction with a specialist reference laboratory conducting hormone assays. 22
`From these data they estimated the incidence to be 2.0 per million per year.
`Eriksson and co-workers took all cases treated in Uppsala over a 20 year period
`and assumed a local population base, despite an international referral practice;
`they calculated 4.0 cases per million per yearY
`
`Insulinoma
`
`Estimates for this tumour have ranged from 0.67-4.0 cases per million per year,
`23
`24
`varying widely despite the use of reference populations.6.8·9
`•
`•
`
`Gastrinoma
`
`The reported incidence of this tumour has ranged from 0.1-4.0 cases per million
`25 with that for the defined Northern Ireland population the incidence
`per year, 23
`•
`reported by Watson and colleagues was 0.5 per million per year. 22 Historically,
`
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`8
`
`Pancreatic Tumours
`
`insulinoma was considered the most common pancreatic neuroendocrine tumour
`but more recent reports suggest that gastrinoma is more common. 22
`26 However,
`•
`the terms Zollinger-Ellison syndrome and gastrinoma have been used inter(cid:173)
`changeably, without specification as to tumour location, and most studies have
`given combined pancreatic and extra-pancreatic gastrinoma rates. Earlier studies
`cited the pancreas as the organ most frequently harbouring a gastrinoma
`(40-53%).27·28 However these reports contained a significant number of cases
`where tumour was not detected (27-34%). Small, occult duodenal gastrinomas
`account for a significant number of such cases.1·3
`
`Glucagonoma
`
`The Northern Ireland study of Watson and colleagues estimated the annual incid(cid:173)
`ence of glucagonoma at 0.05 per million (I per 20 000 000) per year, 22 accounting
`for 2.5% of all their pancreatic neuroendocrine tumours. Other estimates suggest
`that glucagonoma accounts for 8% of all syndromic pancreatic neuroendocrine
`tumours and for 5% of all pancreatic endocrine tumours presenting during life.29•30
`A more recent report suggests that glucagonoma is an underdiagnosed condition,
`because it is asymptomatic for long periods, and produces non-specific symptoms;
`this report suggests that the true incidence may approach that of insulinoma and
`gastrinoma,31 although this has not been confirmed.
`
`Vipoma
`
`VIPomas, which are usually located in the pancreas, produce the Verner-Morrison
`or WDHA (watery diarrhoea, hypokalaemia and achlorhydria) syndrome from an
`excess of vasoactive intestinal polypeptide. L3•22 Their incidence has been estimated
`23 comprising 3-5% of all pancreatic neuroen(cid:173)
`at 0.12-2.0 per million per year,6
`•
`docrine tumours. 32
`
`Ppoma
`
`Marked differences in the reported incidence of pancreatic polypeptide producing
`tumours (PPoma) have arisen because historically, many non-syndromic tumours
`were not tested for pancreatic polypeptide. The principal documented physiolo(cid:173)
`gical action of pancreatic polypeptide is inhibition of biliary and pancreatic
`exocrine secretion. 37 The incidence of pancreatic polypeptide hypersecretion is
`variable depending on the type of endocrine cell tumour; all pure PPomas present
`with elevated pancreatic polypeptide levels.37·38 Thus, although 50-75% of patients
`with non-syndromic tumours have increased basal levels of pancreatic polypep(cid:173)
`tide,18 and cells producing pancreatic polypeptide are found in 28-74% of other
`syndromic tumours, pure or dominant PPoma have been estimated to comprise
`only 1-2% of all pancreatic neuroendocrine tumours. 38
`
`Rarer Syndromic Tumours
`
`The more infrequent pancreatic neuroendocrine tumours are reported primarily
`as case series; incidence is difficult to estimate. Somatostatinomas, like gastrino-
`
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`Epidemiology of Pancreatic Neuroendocrine Tumours
`
`9
`
`mas, occur in both pancreatic and extra-pancreatic sites, although the distinction
`between sites has rarely been made. 40
`1 Somatostatinomas have been estimated to
`,4
`account for about 1% of all active neuroendocrine tumours of the gut and
`pancreasY Other very occasional tumours include those producing growth factor
`releasing hormone or growth hormone, parathyroid hormone or parathyroid
`related hormone, or adrenocorticotrophic hormone. t- J Some of these tumours
`may be misclassified as non-syndromic if a full screen of potential ectopic
`hormones is not performed.
`
`Carcinoid
`
`Carcinoid tumours of the pancreas are rare, and reports must include at least
`immunohistochemical analysis or appropriate hormone assays to avoid confusion
`from vague terminology. A detailed report is that of thirty cases collected up to
`1995,43 which found the most frequent symptom to be pain, followed by diarrhoea
`and weight loss. An atypical carcinoid syndrome characterised by skin flushing
`was found in 10 cases (33%). Elevated urinary 5-hydroxyindole acetic acid levels
`were found in 25 (83%).
`
`Small Cell Carcinoma
`
`Small cell carcinoma is a poorly differentiated pancreatic tumour composed of
`small to intermediate sized cells with neuroendocrine features. It is extremely rare
`and estimated to account for less than 1% of all (exocrine and endocrine) pancre(cid:173)
`atic malignancy. 44
`
`Non-syndromic Pancreatic Neuroendocrine Tumours
`
`The reported incidence of non-syndromic tumours has varied from 15-40%, 18
`33
`34
`•
`•
`depending on assay and classification procedures. 36 Earlier reports included
`glucagonoma and somatostatinoma as non-syndromic tumours, as these do not
`produce obvious hormone-specific symptoms when serum hormone levels are
`low. 30 However, more recent reports suggest higher numbers of non-syndromic
`tumours, because of increased accuracy in their detection U· 16
`22 (see Table 1.2).
`•
`
`Incidence Trends Over Time
`
`In the past 20 years more accurate identification of pancreatic neuroendocrine
`tumours has resulted from heightened awareness, supported by improved diag(cid:173)
`nostic technology as well as development of specialist tertiary referral units.
`Specific reports detailing changes in the incidence of these tumours over time
`suggest that the percentage of non-syndromic tumours has increased during the
`last two to three decades. 26
`32 A study from the Mayo Clinic examining insulinomas
`•
`diagnosed in Olmstead County between 1927-1986 demonstrated a significant
`increase in incidence over time, with no detectable change in age or gender distri(cid:173)
`bution,26 However, clinical practice has changed so dramatically it is not possible
`to conclude whether such an increase is real or artefactual.
`
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`10
`
`Pancreatic Tumours
`
`Table 1.2. Location, association with MEN -I and incidence of less rare types of pancreatic
`neuroendocrine tumours
`Thmour
`lnsulinoma
`Gastrinoma
`Glucagonoma
`Vipoma
`Somatostatinoma
`Non-syndromic tumour
`
`Location
`Pancreas
`SO% pancreas
`Pancreas
`Pancreas
`SO% pancreas
`Pancreas
`
`Metastases
`!Oo/o
`60%
`50-80%
`40-70%
`70%
`60%
`
`%MEN-!
`5%
`2S-40%
`10%
`5%
`45%
`20%
`
`Incidence
`1-2 per million
`1-2 per million
`0.1 per million
`0.1 per million
`< 0.1 per million
`1-2 per million
`
`Sex Distribution
`
`The overall sex distribution for all pancreatic neuroendocrine tumours appears to be
`approximately equal, with variations between syndromic types. For insulinoma most
`46 for gastrinoma the male
`series have reported a higher incidence in women;8
`18
`31 .45
`•
`•
`•
`to female ratio has been reported at 3:2;47
`48 whilst for glucagonoma it is 1:2.31
`•
`Somatostatinoma has been reported to be commoner in women 42
`49 as has
`•
`VIPoma, 18
`50 whereas small cell carcinoma has been found predominantly in men. 44
`5 1
`•
`•
`
`Age Distribution
`
`The crude median age for all pancreatic neuroendocrine tumours has been report(cid:173)
`ed to be 52 years, with children below 15 years of age rarely affected. 23
`44
`•
`lnsulinoma has a very wide age range but the crude peak incidence occurs between
`29
`40-50 years. 8
`45
`46 Gastrinomas can occur at any age and in one series children
`•
`•
`•
`formed almost one in 10 of those affectedY The peak incidence of sporadic gastri(cid:173)
`noma occurs between 40-60 years, whereas in association with multiple endocrine
`neoplasia, the peak age is between 20-40 years. 25 The reported median age for
`glucagonoma is between 40-70 years, 1
`52 for somatostatinoma between 30-
`•
`60 years42
`49 and small cell carcinoma between 40-75;44
`5 1 as the numbers are few,
`•
`•
`the ranges are wide.
`
`Geographical and Ethnic Variation
`
`There are no studies examining geographical vanatwn in a meaningful way,
`10
`although there are reported series from both east and west. 6
`•
`
`Risk Factors for Pancreatic Neuroendocrine Tumours
`
`Inherited Diseases
`
`Multiple Endocrine Neoplasia Type l(MEN-1)
`
`This syndrome is characterised by pituitary, parathyroid and pancreatic islet cell
`tumours, produced by mutation of the MEN-1 gene encoding menin,5
`55 a nuclear
`•
`protein that suppresses cell proliferation. 56 Numerous microscopic neuroen-
`
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`Epidemiology of Pancreatic Neuroendocrine Tumours
`
`II
`
`docrine tumours {0.3-5 mm in diameter) occur throughout the pancreas, occas(cid:173)
`sionally associated with one or more larger tumours. In individuals with an estab(cid:173)
`lished diagnosis of MEN-1, between 30-85% have clinical evidence of pancreatic
`neuroendocrine tumours.30·58 Autopsies of patients with MEN-1 have shown
`pancreatic neuroendocrine tumours to be invariably present, 58 but most are non(cid:173)
`syndromic and clinically silent. Thus in one surgical series of 132 patients with
`pancreatic neuroendocrine tumours, non-syndromic tumours were identified in
`only eight of 36 (22%) patients with MEN-1, the other 28 having syndromic
`tumours. 59 Of these, gastrinoma is the commonest; up to 50% of MEN-1 patients
`display typical symptoms.60 Of all patients with gastrinomas, MEN-I is present in
`one of every four. 31
`
`Von Hippel-Lindau Disease (VHL)
`
`This disease is inherited as an autosomal dominant disorder with high penetrance,
`this produces brain and spinal cord haemangioblastomas, retinal angiomas, renal
`cell carcinomas, pancreatic neuroendocrine tumours, phaeochromocytomas,
`endolymphatic sac tumours and also papillary cystadenomas of the epididymis
`and broad ligament.6 It results from mutation of the tumour suppressor VHL gene,
`and may rise de novo through somatic mutation.3·6. (See Ch. 12.)
`
`Neurofibromatosis
`
`Type 1 neurofibromatosis (NF1) affects about 1 in 4000 individuals, and is inheri(cid:173)
`ted as an autosomal dominant condition with variable penetrance of mutations in
`the tumour suppressor NFl gene encoding the protein neurofibromin; 50% of
`affected individuals have new mutations/ It is characterised by multiple pigment(cid:173)
`ed and thickened patches of skin, neurofibromata of nerves and occasionally,
`phaeochromocytomas. Pancreatic neuroendocrine tumours occur in a small
`minority of affected individuals. 1·3
`
`Tuberous Sclerosis
`
`This rare disorder arises from mutation in the tumour suppressor TSC1 or TSC2
`genes, producing focal hyperplasia of neuroglia and neuronal tissue of the brain,
`astrocytoma, rhabdomyoma of the heart, adenoma sebaceum, and uncommonly,
`pancreatic neuroendocrine tumours. 8
`
`Sporadic Pancreatic Neuroendocrine Tumours:
`
`Allelic loss of chromosome 11 Q, which includes the MEN -1 gene, is the most
`frequent chromosomal alteration in these tumours.61 Somatic mutations of the
`MEN-1 gene have been found in 25-50% of sporadic pancreatic neuroendocrine
`tumours, excepting insulinoma, in which somatic MEN-1 mutations are uncom(cid:173)
`mon.62·63 Somatic mutations of VHL have been found occasionally. It appears that
`
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`12
`
`Pancreatic Tumours
`
`many of the commoner oncogenes and tumour suppressor genes (p53,
`DPC4/SMAD4, PTEN, K-ras, c-myc, c-erb2, c-fos) are of little importance in
`pancreatic neuroendocrine tumour development, although p16/MTS1 may have a
`role in gastrinoma. 61
`64
`•
`
`Risk of Malignancy
`
`Traditional histopathological criteria of malignancy have limited application in the
`assessment of primary pancreatic neuroendocrine tumours. Thus uniformity of
`tumour cell appearance can be deceptively reassuring, whilst vascular and/or
`perineural invasion are unusual. Only the presence of local invasion and/or meta(cid:173)
`63
`stases are definitive in determining malignancy. 34
`64 Metastases are most
`•
`•
`commonly found in the liver (up to 80% of cases), less frequently in regional lymph
`nodes, whilst dissemination to other distant sites is unusual. 5
`5 Generally, tumours
`composed of cells producing eutopic hormones (that are normally produced by
`pancreatic islets) have a much lower malignancy risk that tumours producing
`ectopic hormones (gastrin, VIP, neurotensin, ACTH), which is useful in prognostic
`evaluation.64 Overt malignancy has been found in 4-16% of patients with insu(cid:173)
`linoma, 33
`67 with a large series of 951 patients reporting overt metastatases in
`46
`46
`64
`•
`•
`•
`-
`5%.46 In contrast, malignant features have been reported in 23-90% of patients
`with gastrinomas, with a consensus of around 60%. 33
`70 Over 60% of patients
`64
`68
`47
`•
`•
`-
`•
`with glucagonoma have invasive or metastatic disease,33 as do 50-75% of those
`50 Between
`49 and 50-90% of those with VIPomas. 33
`with somatostatinomas33
`•
`•
`45-90% of patients with non-syndromic tumours have been reported to have
`invasive or metastatic disease, a wide range that is probably a reflection of selec(cid:173)
`tion factors such as referral patterns, as well as methods of classification and
`management. 7
`35 The vast majority of tumours secreting hormones such as
`33
`•
`•
`ACTH, PTH and vasopressin are malignant. 64
`
`Management and Prognosis
`
`Staging
`
`Until recently (see Table l.Y4
`), there has been no relevant staging system, and only
`now are randomised controlled trials underway to test alternative strategies in
`therapy. Furthermore, gastrointestinal carcinoids and pancreatic neuroendocrine
`tumours have often been considered together as gastroenteropancreatic endocrine
`tumours, so that figures for survival are imprecise.
`
`Survival
`
`Overall Survival
`
`The Uppsala group reported a median survival from diagnosis of 8.7 years for all
`pancreatic neuroendocrine tumours, reduced to 6.7 years for those with malignant
`tumours; 80% of those with benign tumours were alive at 10 years. 2
`23 Most malig-
`•
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`Epidemiology of Pancreatic Neuroendocrine Tumours
`
`13
`
`Table 1.3. Consensus classification of pancreatic neuroendocrine tumours developed under the
`auspices of the World Health Organisation 74
`Well differentiated:
`Confined to pancreas:
`Benign behaviour:
`Nonan gioinvasive
`< 2 em in size
`Ki-67 proliferation index < 2%
`< 2 mitoses perlO high power fields
`Uncertain behaviour:
`Angioinvasion
`> 2 em in size
`Ki-67 proliferation index > 2%
`Gross local invasion or metastasis:
`Low grade malignant:
`Often have angioinvasion and/or perineural invasion
`Metastases
`
`Poorly differentiated:
`High grade malignant:
`Highly atypical cells
`Metastases
`
`nant pancreatic neuroendocrine tumours grow slowly and are generally associated
`with far longer survivals than other solid tumours. For patients with regional
`and/or distant metastases, overall 5-year survivals of between 30 and 40% have
`66
`73
`74 In patients with untreated or unresponsive metastatic
`been reported.29
`•
`•
`•
`disease, a median survival of 3-4 years has been observed from the time of diag(cid:173)
`nosis/3 approximately 8 years from the onset of symptoms. 75 Whilst curative resec(cid:173)
`tions are rarely possible for metastatic disease, combinations of therapies includ(cid:173)
`ing surgical debulking and hormonal inhibition can achieve effective palliation for
`prolonged periods/6 Now that the effects of life-threatening hypersecretion can
`usually be controlled, the commonest cause of death is liver failure from slow
`tumour progression. 36
`64.76 However, pharmacological suppression of hormonal
`·
`hypersecretion is not always effective, and the debilitating effects of liver meta(cid:173)
`stases may still warrant hepatic resection or other ablative therapies. 77
`
`Comparison of Syndromic and Non-syndromic Tumours
`
`The overall survival for syndromic tumours, especially those producing eutopic
`hormones, has been consistently longer than for non-syndromic tumours. These
`latter tend to present at a later stage; the rate of liver metastasis amongst patients
`with non-syndromic tumours has been estimated at 60-90% of cases.64 Eriksson
`and coworkers reported a 5 year survival rate of 42% for non-syndromic tumours
`17 Most series confirm non-syndromic
`compared to 80% for syndromic tumours.7
`•
`tumours to have a poorer survivaF·19 but some authors contradict this. 35·64
`80
`•
`
`Insulinoma
`
`All series report insulinoma to have an excellent prognosis because of the high in(cid:173)
`cidence of benign disease, and surgical excision is curative for most patients.78 In
`
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`

`
`14
`
`Pancreatic Tumours
`
`earlier reports, peri-operative mortality was attributed to pancreatic fistulas,
`pseudocysts and pancreatitis; more often after enucleation than after distal pancre(cid:173)
`atectomy, 19
`46 but with increasing specialisation the complications of pancreatic
`•
`surgery have fallen. Even limited metastatic disease can be cured by surgery: 5-year
`survival rates for metastatic insulinoma have been reported at 30-46%.8
`34
`•
`
`Gastrinoma
`
`Zollinger reported an overall survival of 50% at 10 years for malignant gastri(cid:173)
`noma.68 Even with liver metastasis the overall 5-year survival has been reported at
`20-38%.66
`68 Gastrinoma is associated with lymph node involvement in 60-80% of
`•
`cases. 23 Interestingly, lymph node involvement without hepatic or distant metasta(cid:173)
`sis does not appear to exert a major influence on survival from gastrinoma.48 This
`finding suggests that the presence of lymph node metastases should not necessar(cid:173)
`ily discourage an aggressive surgical approach.
`
`Other Syndromic Tumours
`
`The majority of patients with glucagonoma have metastatic disease at the time of
`presentation. However, this tumour tends to progress slowly and patients may
`survive for years without treatment.66 VIPomas, often metastatic at the time of
`diagnosis, may be associated with extended survivals, with a median of 3.6 yearsY
`Patients with pancreatic carcinoids have fared less well, the median survival being
`7 months in a series of 30 patients, 21 of whom had metastases. 79
`
`Summary
`
`Pancreatic neuroendocrine tumours are a rare group of neoplasms with complex
`patterns of behaviour requiring detailed specialist management. Interpretation of
`the current literature is limited by difficulties in classification, diagnosis and
`staging, with no randomised controlled trials that compare alternative treatments.
`Descriptive epidemiological studies are based on clinical or autopsy series with
`poorly defined reference populations. Only two population-based studies provide
`estimates of the incidence in life, one at 2.0 per million per year, the other at 4.0 per
`million per year, whilst autopsy series suggest a more frequent occurrence. The
`course of these tumours is often indolent, and although ectopic hormone produc(cid:173)
`tion can be life threatening, crude survival rates of 50% or more at 5 years have
`been recorded, even for more malignant forms. There is a need for further popu(cid:173)
`lation-based studies with accurate ascertainment to evaluate the epidemiology of
`these tumours.
`
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`Roxane Labs., Inc.
`Exhibit 1010
`Page 013
`
`

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`Epidemiology of Pancreatic Neuroendocrine Tumours
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`15
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