Premalignant conditions of the pancreas

Pathology (2002 ) 34, pp. 504– 517

GASTROINTESTINAL

PAT HO LO G Y

Premalignant conditions of the pancreas PAULINE DE LA M. HALL *, ROBB E. WILENTZ †, WILLOUW PHILIPPUS P. C. BORNMAN ‡

DE

KLERK *

AND

*Division of Anatomical Pathology, Faculty of Health Sciences, University of Cape Town, South Africa, †Department of Pathology, Johns Hopkins Medical Institutions, Baltimore, MD, USA, and ‡Division of Hepatobiliary Surgery, Faculty of Health Sciences, University of Cape Town, South Africa

Summary Premalignant conditions of the pancreas include benign tumours of the pancreas, intraepithelial neoplasia arising within pancreatic ducts, and tumours of the neuroendocrine cells of the pancreas. In addition, there is a variety of rare genetic conditions that predispose to pancreatic exocrine malignancies such as Peutz–Jeghers syndrome, hereditary non-polyposis colorectal cancer syndrome, familial pancreatitis, germline BRCA2 mutations, and pancreatic endocrine malignancies such as type 1 neurofibromatosis (von Recklinghausen ’s disease) and multiple endocrine neoplasia type 1. More controversial is the concept of chronic pancreatitis and diabetes mellitus as conditions that increase the risk of pancreatic cancer. However, there is no doubt that smoking is a potentiating factor for pancreatic cancer, especially in people who have familial/genetic risk factors. This review will include the recently proposed new nomenclature and classification system for intraepithelial neoplasia in the pancreatic ducts, an overview of the various familial syndromes that are associated with an increased risk of pancreatic tumours, the surveillance programmes that have been introduced to monitor such families, and methods for early diagnosis. Key words: Pancreatic cancer, familial pancreatic cancer, premalignant, intraepithelial neoplasia, neoplasia, carcinoma in situ. Abbreviations: ERCP, endoscopic retrograde cholangiopancreatography ; EUS, endoscopic ultrasonography; FAMMM, familial atypical multiple mole melanoma syndrome; HNPCC, hereditary non-polyposis colorectal cancer syndrome; MCN, mucinous cystic neoplasms; MEN1, multiple endocrine neoplasia type 1; MSI, microsatellite instability; NF1, type 1 neurofibromatosis; PanIN, pancreatic intraepithelial neoplasia; PJS, Peutz– Jeghers syndrome. Received 16 July, revised 3 August, accepted 6 August 2002

INTRODUCTION Pancreatic cancer is a notoriously difficult disease to diagnose, even when it is advanced, and the prognosis is invariably poor. In developed countries, pancreatic cancer is the fifth leading cause of cancer deaths.1 Growing knowledge, much of it derived from recently established pancreatic cancer registries, has led to the identification of a variety of familial syndromes that are associated with an enhanced risk of pancreatic cancer compared with the risk

in the general population.2 In most of these familial syndromes the risk is for ductal pancreatic adenocarcinoma, although there is increased risk of ampullary carcinoma in hereditary non-polyposis colorectal cancer syndrome, while the various types of islet cell tumours are associated with type 1 neurofibromatosis and multiple neuroendocrine neoplasia type 1. The results of studies of patterns of inheritance and identification of germline mutations are such that it is now possible to develop surveillance programmes for members of high risk families.3 Potentiating factors such as smoking have been identified, and the hope for the future includes the identification of further factors, education programmes, and trials of chemopreventive agents.4 The other important advance in pancreatic tissue biology has been the recognition of precursors to invasive pancreatic cancer and the introduction of a new unifying nomenclature based on the concept of pancreatic intraepithelial neoplasia.5

PRECURSORS TO INFILTRATING DUCTAL ADENOCARCINOMA: PANCREATIC INTRAEPITHELIAL NEOPLASIAS (PanINs) Background and histological diagnosis Just as there is progression from dysplasia to infiltrating carcinoma in sites like the colorectum, breast, and cervix, there is progression from non-invasive precursor lesions to infiltrating duct adenocarcinoma in the pancreas. These precursor lesions are histologically identifiable, and criteria for their identification have recently been described ( Table 1; http:// pathology.jhu.edu/ pancreas _panin).5 These precursor lesions have gone by a variety of names ( e.g., mucinous hyperplasia and duct lesions); however, they are best designated as ‘pancreatic intraepithelial neoplasias’ ( PanINs ).6 This term is preferred because it conveys the neoplastic nature of these lesions and because it is analogous to that used in other organ systems, like the cervix, breast, and prostate. The diagnosis of PanIN rests on the identification of mucinous epithelium with varying degrees of cytological and architectural atypia within the small ducts and ductules of the pancreas. This mucinous epithelium replaces the normal cuboidal cells lining these small ducts and ductules.7,8 The abnormal epithelium is flat (PanIN-1A ), papillary without atypia ( PanIN-1B ), or papillary with

ISSN 0031–3025 printed/ ISSN 1465– 3931 online/ 02/ 060504 – 14 © 2002 Royal College of Pathologists of Australasia DOI:10.1080/ 0031302021000035965

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TABLE 1

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Morphological description of pancreatic intraepithelial neoplasia ( PanIN) and mimickers of PanIN5 *

Lesion

Description

Normal pancreatic duct

Low cuboidal or flattened epithelium without mucinous change or atypia

PanIN-1A

Flattened mucinous epithelium without nuclear atypia

PanIN-1B

Papillary mucinous epithelium without nuclear atypia

PanIN-2

Flattened or papillary mucinous epithelium with mild-to-moderate nuclear atypia ( nuclear irregularity and hyperchromatism, mild-to-moderate loss of polarity, nucleoli)

PanIN-3

Flattened or papillary mucinous epithelium with severe nuclear atypia ( marked nuclear irregularity and hyperchromatism, extreme loss of polarity, cribriforming, prominent nucleoli, scattered abnormal mitoses, blebbing of epithelium into lumen)

Intraductal papillary mucinous neoplasm

Mucinous epithelium in large ducts, grossly or radiologically visible mass

Mucinous cystic neoplasm

Mucinous epithelium in cysts not connected to the native duct system, ovarian stroma, grossly or radiologically visible mass

Cancerization of ducts

Atypical epithelium partially involving a duct and/ or associated with a proximal infiltrating cancer

Squamous metaplasia

Mature squamous or transitional mucosa without atypia

Reactive atypia

Atypical epithelium with prominent nucleoli and nuclear enlargement in the setting of acute inflammation

* Reprinted with permission from the American Journal of Surgical Pathology.

atypia ( PanIN-2 ). Or, it may meet the criteria for carcinoma in situ ( PanIN-3).8,9 A histological description of these stages of intraepithelial neoplasia is outlined in Table 1.5 Histological sections of each of the grades of PanIN are shown in Fig. 1. Differential diagnosis Several different lesions enter into the differential diagnosis of pancreatic intraepithelial neoplasia. These mimickers of PanIN range from reactive to neoplastic conditions, and they include entities that affect both the large and small ducts of the pancreas. The most important lesions that may be confused with PanINs are intraductal papillary mucinous neoplasms ( IPMNs), mucinous cystic neoplasms ( MCNs), cancerisations of ducts, squamous metaplasias, and reactive atypias. Each of these lesions, however, can be distinguished from PanINs based on morphological, clinical, and even genetic grounds. Intraductal papillary mucinous neoplasms ( IPMNs) These are tumours composed of mucinous and often papillary epithelium growing within the larger ducts of the pancreas. Just like PanINs, IPMNs progress from lesions with minimal dysplasia ( intraductal papillary mucinous adenomas) to those with moderate or severe dysplasia ( intraductal papillary mucinous neoplasms with borderline atypia or carcinoma in situ ) to those with an associated infiltrating adenocarcinoma. In essence, PanINs are distinct from IPMNs because the latter are grossly or radiologically visible and are often associated with the classic endoscopic appearance of ‘mucin oozing from the ampulla of Vater’.10 Figure 2A shows an IPMN, in this case an IPMN showing carcinoma in situ involving a large duct in the pancreas, Fig. 2B shows the microscopy of a mucinous cystic neoplasm and Fig. 2C shows cancerisation of a duct, as described below. In addition, the genetics of IPMNs are different from those of PanINs. Iacobuzio-Donahue recently studied Dpc4 expression in IPMNs and found that virtually all IPMNs

express Dpc4.11 This is in contrast to PanIN: approximately 30% of PanINs-3 show inactivation of the Dpc4 gene, and hence the associated loss of the Dpc4 protein by immunohistochemistry.6 Thus, immunohistochemical expression of Dpc4 may help distinguish high-grade PanINs from IPMNs showing carcinoma in situ. Figure 3 compares the immunohistochemical labelling pattern of a PanIN-3 that has lost Dpc4 expression and an IPMN that has maintained Dpc4 expression. Mucinous cystic neoplasms ( MCNs) These are tumours similar to intraductal papillary mucinous neoplasms ( IPMNs ). Thus, it is easy to see why these neoplasms are also sometimes confused with PanINs. Like IPMNs and PanINs, MCNs are also composed of mucinous epithelium that varies in its degree of dysplasia. Just as there is progression in PanINs and IPMNs, so too is there progression in MCNs, from mucinous cystadenoma to borderline mucinous cystic neoplasm to mucinous cystic neoplasm with in situ carcinoma to invasive mucinous cystadenocarcinoma. These neoplasms are differentiated from IPMNs because they do not grow within the native duct system of the pancreas; instead, they form independent neoplastic cysts. In addition, the overwhelming majority of MCNs contain an ovarian-like stroma that is absent in both IPMNs and PanINs.12,13 Figure 2B shows an example of a MCN. Cancerisation of ducts This describes the process in which infiltrating adenocarcinoma invades from the outside of a duct into the lining of the duct or ductule. It is easy to see why this process can mimic PanIN, especially PanIN-3. Cancerisation of a duct enters the differential diagnosis when the duct lesion in question is close to an infiltrating duct adenocarcinoma or when it is only partially involved with atypical cells. Serially sectioning a block may help determine whether the atypical cells within a duct represent a PanIN or cancerisation of the duct. Figure 2C shows an example of cancerisation of a duct.

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Fig. 2 Histology of mimickers of PanIN. ( A) Intraductal papillary mucinous neoplasm ( H&E). ( B) Mucinous cystic neoplasm ( H&E). ( C) Cancerisation of a duct ( H&E).

Squamous ( transitional ) metaplasia and reactive atypia These are reactive conditions of the pancreatic ducts and are not thought to be associated with progression to infiltrating adenocarcinoma. However, they are still sometimes confused with PanINs. In squamous ( transitional ) metaplasia, mature squamous or transitional epithelium without atypia lines the duct. Reactive atypia, evidenced by nuclear and nucleolar enlargement, often can be distinguished from dysplasia ( i.e., atypia within a PanIN) by the lack of mucinous change and the presence of significant numbers of inflammatory cells, particularly polymorphonuclear leukocytes, within reactive lesions. Evidence for progression through PanIN The histological model for PanIN implies that PanINs-1 are perhaps the earliest neoplasms in the pancreas. A small subset of these earliest neoplasias will progress to PanINs-2 and PanINs-3. Finally, some PanINs-3 will, in turn, progress into infiltrating adenocarcinomas. There are three lines of evidence that support this pancreatic progression model. First, pathologists frequently find PanINs adjacent to infiltrating cancers. Cubilla and Fitzgerald compared the ducts in 227 pancreata with pancreatic cancer with those in 100 pancreata without pancreatic cancer.9 They found that papillary PanINs were three times more common in pancreata from

patients with infiltrating pancreatic cancer than they were in pancreata from patients without infiltrating pancreatic cancer. Remarkably, they identified PanINs-2 and -3 only in pancreata with infiltrating pancreatic cancer.9 Kozuka et al. 14 and Pour et al. 15 have obtained similar findings. Second, evidence suggests that PanINs can progress to infiltrating cancer over time. Furukawa et al., using threedimensional mapping techniques, have demonstrated a stepwise transformation from mild dysplasia to severe dysplasia in pancreatic duct lesions.16 More recently, Brat et al. reported three patients who developed infiltrating ductal adenocarcinomas 17 months, and 9 and 10 years after the diagnosis of PanIN-2 or PanIN-3.17 These PanINs originated in two cases of chronic pancreatitis and one case of ductal adenocarcinoma in which the cancer was entirely removed but PanIN was left at the pancreatic neck margin of excision. A similar progression has been reported by Brockie et al. 18 Third, duct lesions display some of the same genetic changes as infiltrating adenocarcinomas. For example, activating point mutations in codon 12 of the K-ras gene, common in infiltrating adenocarcinoma, have been demonstrated in both early and late PanINs.19– 24 PanINs also harbour mutations in tumour-suppressor genes, namely p16, p53, BRCA2, and DPC4. 6,25– 29 For instance, we recently showed that p16 inactivation first occurs primarily in

Fig. 1 Histology of different grades of PanIN ( H&E, low power: left; high power: right). ( A) PanIN-1A. ( B) PanIN-1B. ( C) PanIN-2. ( D) PanIN-3.

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Fig. 3 Immunohistochemical stain for Dpc4 in a PanIN-3 and an IPMN with carcinoma in situ. The PanIN-3 shows loss of Dpc4 expression, but the IPMN displays intact expression.

PanINs-2 and -3 and that DPC4 first occurs very late in neoplastic progression, in PanINs-3.6,30 A summary of this and other work on the timing of genetic alterations in PanINs is shown in Table 2.31– 38

K-ras gene mutations in pancreatic juice samples. These mutant copies of K-ras genes presumably originated in DNA shed from pancreatic intraepithelial neoplasias.

The histological– genetic progression model The work on genetic alterations in PanINs has led us to formulate a histological–genetic progression model for pancreatic duct adenocarcinoma.6– 8,39 This model is summarised in Fig. 4. K-ras gene mutations and HER–2/ neu overexpression are the earliest changes in the progression model.19,20,22,25,40,41 Alterations in the p16 gene occur at different histological stages but are found primarily in PanINs-2 and -3.25,30 DPC4, BRCA2, and p53 genes appear to be inactivated very late in the progression model.6,26,28,29 Importantly, this progression model suggests that the molecular detection of precursor lesions and early cancers is indeed possible. Like those originating in infiltrating ductal adenocarcinomas, mutant K-ras genes shed from pancreatic intraepithelial neoplasias have been identified in stool, duodenal fluid, and pancreatic juice samples.20,24,42 Berth´elemy et al. 43 reported two patients without clinical or radiological evidence of cancer who developed ductal adenocarcinomas 18 and 40 months after the detection of

FAMILIAL CONDITIONS ASSOCIATED WITH AN INCREASED RISK OF EXOCRINE PANCREATIC CANCER The development of large pancreatic cancer registries in many countries4,44– 47 and detailed family studies have helped in the identification of familial pancreatic cancer kindreds with familial syndromes, such as Peutz– Jeghers syndrome ( PJS), hereditary non-polyposis colorectal cancer ( HNPCC ) syndrome, hereditary chronic pancreatitis, familial atypical multiple mole melanoma ( FAMMM) syndrome, and a familial pancreatic cancer syndrome associated with some BRCA2 mutations. These familial syndromes will be briefly described. Approximately 10% of pancreatic cancers are associated with familial syndromes; the gene and chromosome abnormalities and relative risk by age 70 years of these syndromes are outlined in Table 3.4 In addition to the known familial syndromes that are associated with an increased risk of pancreatic cancer,4 there is another group of kindreds, with a family aggregation of pancreatic cancer, that cannot be explained by one of

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TABLE 2

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Timing of genetic events in pancreatic intraepithelial neoplasias ( PanINs) and infiltrating pancreatic ductal adenocarcinomas *

Gene and reference no. HER-2/ neu 37 K-ras 19,20,22,25,31,32,38 p16 25,30,33,34 p53 28,29,35 DPC4 36,37 BRCA226,38zz

Normal ( %)

PanIN-1A ( %)

PanIN-1B ( %)

PanIN-2 ( %)

5 0–15† 0 0 0 0

82 35 24 0 0 0

86 43 19 0 0 0

92 ‡ 55 § 0 0

PanIN-3 ( %) 100 86 71 21 31

¶

Infiltrating ( %) 69 ~ 90 ~ 95 ~ 75 ~ 55 7

* Adapted from Wilentz et al.6 † Authors are not in agreement that normal ductal epithelium harbours K-ras mutations. ‡ Insufficient numbers of PanIN-2 were present in these studies to present an accurate result. § One PanIN-2 identified by Hameed et al.29 overexpressed p53, but the total number of PanINs-2 was not reported; therefore, a percentage could not be calculated. zz BRCA2 data in PanINs are restricted to patients with germline BRCA2 inactivating mutations. ¶ Only one PanIN-3 was studied by Goggins et al. and it showed a BRCA2 germline mutation coupled with loss of heterozygosit y.

the known genetic syndromes; this group is sometimes confusingly termed ‘familial pancreatic cancer’. The gene( s) responsible for familial pancreatic cancer have not yet been identified, but the pattern of inheritance is autosomal-dominant. Unlike other familial cancer syndromes, the age of onset, sex distribution, pathology, and prognosis appear to be similar to that of the sporadic form. Other groups who are at increased risk are certain racial groups, e.g., native Hawaiians, African Americans,48 and Maoris.49 Peutz–Jeghers syndrome ( PJS) PJS is a rare, autosomal-dominant disease characterised by gastrointestinal hamartomatous polyps and by melanotic mucocutaneous lesions.50,51 Patients with PJS have been found to be at increased risk for both gastrointestinal and non-gastrointestinal cancer.52– 59 A statistically significant increase in the relative risk for cancer was noted for oesophagus, stomach, small intestine, colon, pancreas, lung, breast, uterus, and ovaries.60 In 1986, the first case of pancreatic adenocarcinoma in association with PJS was reported in a 16-year-old Caucasian boy.61 Since then, a number of studies have confirmed this association; of 53 PJS patients reported in four independent studies, six ( 11%) were diagnosed with

pancreatic adenocarcinoma.54– 56,58 In other reports dealing with large numbers of patients, 13%56,62 and 36%54 of the patients with PJS had developed pancreatic cancer. Giardiello et al. 60 performed an individual patient meta-analysis and found the cumulative risk for developing pancreatic cancer in PJS to be 36%, breast cancer 54%, and colon cancer 39%. Pancreatic carcinoma was increased 132-fold in patients with this syndrome. Germline mutations of the STK11/ LKB1 gene on the distal portion of chromosome 19p, which encodes serine/ threonine kinase, are responsible for PJS.52,53,63,64 Genetic evidence is provided to support the epidemiological clues that the PJS gene STK11/ LKB1 is a classic tumoursuppressor gene involved in pancreatic and biliary neoplasia. Furthermore, the gene appears to play a role in the development of both sporadic and familial ( PJS) pancreatic and biliary cancers.65 Studies conform to the Knudson model, wherein the same genes are activated in both familial and sporadic forms of cancer.66 Hereditary non-polyposis colorectal cancer (HNPCC) syndrome HNPCC, also known as Lynch syndrome, is an autosomaldominant familial syndrome characterised by a significantly increased risk for colorectal cancer, as well as gastric and endometrial cancer.67

Fig. 4 Histological– genetic progression model for pancreatic ductal adenocarcinoma. Adapted from Wilentz et al.6 Reprinted with permission from Cancer Research.

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TABLE 3

Risk of pancreatic cancer in familial syndromes4 *

Individual

Gene

Chromosome

Relative risk

Risk by age 70 years ( %)

No history HNPCC BRCA2 Familial pancreatic cancer FAMMM Familial pancreatitis Peutz–Jeghers syndrome

None HMLHI./ hMSH2 Brac2 Unknown P16 PRSSI STK11/ LKB1

–

1 Unknown 10 18† 20 50 132

< 0.5 Unknown 5 9–10 10 25– 40 66

2.3 13q Unknown 9p 7q 10p

* Reprinted with permission from Digestive Diseases, Karger, Basel. † Prospective risk in an asymptomatic individual who has two first-degree relatives with pancreatic cancer. Abbreviations: FAMMM, familial atypical multiple mole melanoma; HNPCC, hereditary non-polyposis colorectal cancer.

HNPCC is caused by inherited mutations of the genes involved in DNA repair during DNA replication ( DNA mismatch repair genes). Tumours that arise in patients with HNPCC often accumulate mutations that change the length of repeated DNA sequences. This is referred to as ‘microsatellite instability’ ( MSI). Germline mutations in hMLH1, hMSH268 and hMSH6/ GTBP69 have been reported. Although pancreatic cancer is rare in patients with HNPCC, it is suggested that affected individuals may be predisposed to pancreatic cancer.70,71 Lynch et al. 45,71 observed pancreatic cancer to occur at high frequency in single or selected families with HNPCC. This could not be confirmed by Watson and Lynch72 and uncertainty remains about the extent to which results could be explained by normal incidence rates of pancreatic cancer. Goggins et al. 73 reported MSI (the genetic hallmark of mutations of a DNA mismatch repair gene) in approximately 4% of pancreatic cancers, but none of these patients was known to come from a HNPCC family. Wilentz et al. subsequently reported a patient with probable HNPCC who had colon and pancreatic tumours; both tumours showed microsatellite instability.74 Finally, a recent study by Yamamoto et al. 75 included three hereditary pancreatic carcinomas from HNPCC patients, all of which showed high frequency of MSI-H. The MSI-H cancers were significantly associated with poor differentiation and the presence of wild-type K-ras and p53 genes but the patients had a significantly longer survival than those with MSI-L tumours. Furthermore, pancreatic cancers with MSI appear to have a distinct histological appearance termed the ‘medullary phenotype’ ( Fig. 5A– C).74 First described in 1998 by Goggins et al.,73 medullary carcinomas have a syncytial growth pattern, expanding tumour borders, and show extensive necrosis. The recognition of this histological growth pattern may suggest the diagnosis of HNPCC. Hereditary pancreatitis Hereditary pancreatitis is an unusual form of chronic pancreatitis with an autosomal-dominant inheritance pattern with an 80% penetrance worldwide.76 The disease usually begins in childhood with recurrent episodes of acute pancreatitis, although the age of onset may range from infancy to the third and fourth decades of life. Acute attacks are usually followed by the development of chronic pancreatitis with its various complications. The clinical and pathological features of hereditary pancreatitis resemble

those of idiopathic pancreatitis, but the clinical course may be more severe. Important protective mechanisms against the activation of pancreatic enzymes include the maintenance of relatively low intracellular calcium concentrations, the synthesis of pancreatic secretory trypsin inhibitor, the synthesis of digestive enzymes in inactive ‘pro’-enzyme forms, the physical separation of the activating enzyme ( enterokinase ) from the pancreas, and the compartmentalisation of digestive enzymes in zymogen granules within acinar cells.76 Germline mutations in the PRSS1 gene on chromosome 7q, which encodes for the cationic trypsinogen gene product, are responsible for most cases of familial pancreatitis;77,78 the known mutations are trypsinogen R1117H and N211. Mutations of the cationic trypsinogen gene may predispose to acute pancreatitis by eliminating one of the fail-safe mechanisms, as outlined above, used by the pancreas to eliminate prematurely activated trypsinogen. Thus, prematurely activated trypsinogen can lead to activation of the pancreatic enzyme cascade and result in autodigestion. Lowenfels et al. 47 showed a striking increase in the risk of developing pancreatic cancer in patients with familial pancreatitis ( 53-fold increase over the general population) with estimated risk to age 70 of about 40%. It is postulated that the increased risk of cancer seen in these patients is due to the chronic epithelial injury and repair and that the high risk of cancer reflects the long duration of chronic pancreatitis, just as prolonged ulcerative colitis is associated with an increased risk of colon cancer. Familial atypical multiple mole melanoma (FAMMM) syndrome Also known as B-K mole syndrome and dysplastic naevus syndrome, FAMMM is a rare cancer-associated genodermatosis associated with germline p16 mutations, which predisposes affected family members to develop multiple naevi, atypical ( dysplastic) naevi, and malignant melanomas. In addition, in subsets of families with FAMMM, there is also an increased risk for the development of extracutaneous nonmelanoma primary cancers, particularly carcinoma of the pancreas, and other non-colorectal gastrointestinal cancers.44,45,79,80 Inheritance is in an autosomal-dominant fashion with variable penetrance. Goldstein et al. 80 analysed 19 melanoma-prone families for germline p16 mutations and found that kindreds with germline mutations in p16 had a 22-fold increased risk for pancreatic cancer.

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Fig. 5 Medullary carcinoma of the pancreas. ( A) Tumour in the head of the pancreas with overlying duodenal mucosa. Note the syncytial growth pattern and ‘pushing borders’ of this carcinoma. The carcinoma is missing the infiltrative growth pattern and desmoplastic response of conventional ductal adenocarcinoma ( H&E ). ( B) Ovoid tumour cells with a syncytial growth pattern and intratumoural lymphoid infiltrate. These features suggest a medullary phenotype ( H&E). ( C) Tumour exhibiting a syncytial growth pattern and extensive necrosis. This extensive necrosis is seen in many medullary carcinomas ( H&E ).

BRCA2 gene-associated syndrome Two genes, BRCA1 and BRCA2 , account for the majority of hereditary breast cancers. BRCA2 is located on chromosome 13q and encodes for a protein that functions in DNA repair. Patients with germline BRCA2 mutations have an increased risk of developing breast, ovarian, pancreatic, and possibly prostate carcinoma.38 Germline BRCA2 mutations are more common in individuals of Ashkenazi Jewish descent. Carriers of germline BRCA2 mutations have a slightly less than 10-fold increased risk of developing pancreatic cancer. The observation that some patients with germline BRCA2 mutations and pancreatic cancer do not have a strong family history of breast cancer suggests an incomplete penetrance of this trait.3,4 Chronic pancreatitis The risk of pancreatic and non-pancreatic cancers is increased in patients with chronic pancreatitis, the former being significantly higher than the latter. The extent of the risk for pancreatic carcinomas in this population ranges in reports from a 2-fold increase,81 through a moderate excess,82 to an approximately 9-fold increase.83

Assessment of the increased risk of pancreatic cancer in patients with chronic pancreatitis is confounded by factors such as selection bias, alcohol consumption, and smoking. Karlson et al. 84 observed an incidence ratio of 3.8 after 10 years, but this was restricted to those who abused alcohol and excluded patients in whom pancreatic cancer developed in the first year after the diagnosis of pancreatitis. A similar observation was made by Talamini et al. 85 in a study analysing 715 cases of chronic pancreatitis; they found the incidence of pancreatic carcinoma to be 18 times greater than the expected incidence in both males and females. All of the pancreatic carcinomas arising at least 5 years after the clinical onset of pancreatitis were associated with smoking.85 Since it was found that patients with chronic pancreatitis were 75% heavy drinkers and 88% heavy smokers, it seems highly likely that smoking and alcohol usage in this patient population may underlie the association of pancreatitis and pancreas carcinoma. Talamini et al. 85 suggest that the very high incidence of pancreatic cancer in smokers is probably linked to cigarette smoking, as well as to some other factor related to chronic inflammation of the pancreas. There is disagreement among experts as to whether chronic pancreatitis is truly an independent risk factor for the development of pancreatic cancer, although there is no doubt

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that the greatest identified preventable risk factor for the development of pancreatic cancer is smoking.86

Diabetes mellitus Diabetes mellitus occurs more frequently in patients with pancreatic cancer than those in the general population.87 The question is whether or not diabetes in patients with pancreatic cancer is a pre-existing condition or secondary to the tumour, since pancreatic cancer can cause diabetes by destroying islet cells or by causing peripheral resistance to insulin. The results of previous studies have been contradictory, with many concluding that diabetes is a risk factor for pancreatic carcinoma,88– 96 and others concluding that there is no increased risk.97– 99 However, the studies concluding that diabetes is a risk factor for pancreatic cancer generally did not take into account the duration of diabetes before the diagnosis of pancreatic carcinoma. A large study by Gullo87 found that 22.8% of patients with pancreatic cancer had diabetes. The association was only significant in patients in whom diabetes was diagnosed either concomitantly with the cancer or within 2 years of the diagnosis of the cancer. It was found that with the increasing duration of diabetes, the odds ratio for the association falls progressively below 1. Thus, Gullo87 concluded that diabetes in patients with pancreatic carcinoma is frequently of recent onset and is presumably caused by the tumour and that diabetes is not a risk factor for pancreatic carcinoma. In contrast, a metaanalysis by Everhard and Wright found diabetes mellitus to impart an increased risk of developing pancreatic ductal adenocarcinoma ( relative risk, 2.1), although this study was limited to longstanding sufferers of non-insulin diabetes diagnosed after the age of 40 years.100

Other contributing factors Irrespective of whether the pancreatic cancer is or is not associated with chronic pancreatitis, long-standing diabetes, or one of the familial syndromes, smoking is a strongly associated risk factor, especially within 15 years of the diagnosis of the pancreatic cancer.92,93,95,101–104 Smoking adds significantly to the risk of pancreatic cancer in the presence of K-ras mutations and under these select circumstances a high coffee intake may add to the risk. 105,106 In contrast, the role of coffee and alcohol are much less certain and are probably not risk factors for pancreatic cancer in the usual setting.90,95,104–106 Similarly, there is uncertainty about the role of occupational hazards. Certain occupations exposed to aromatic amines such as petrochemical work, hairdressing, and rubberwork, have been implicated.107 Potential carcinogenic agents include pesticides,108 aniline derivatives, dyes and organic pigments, benzopyrene,109 metal and textile dusts, 108,110 organic solvents,111 chemicals including acrylonitrile,112 and DDT.113 The majority of pancreatic cancers, however, do not appear to be associated with occupational exposure to carcinogens.114 In those instances in which an environmental factor has been incriminated, the dose of the agent has usually been high and prolonged. Nevertheless, it remains difficult to determine the relative risk amongst these workers who may also be exposed to lifestyle risk factors such as smoking.

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FAMILIAL CONDITIONS ASSOCIATED WITH AN INCREASED RISK OF ENDOCRINE PANCREATIC CANCER Currently the familial syndromes that are recognised to have an increased risk of islet cell tumours include neurofibromatosis type 1, multiple endocrine neoplasia type 1, and von Hippel–Lindau syndrome. Diagnosis of index cases can lead to recognition of family members at risk of developing endocrine neoplasms. Ultimately, screening programmes may be developed for those at risk, thus permitting early diagnosis and potentially curative surgery. Type 1 neurofibromatosis (NF1) There is a strong association of somatostatin-producing carcinoids of the duodenum and NF1 ( formerly known as von Recklinghausen’s disease), which is an autosomal-dominant disorder characterised by neurofibromas ( plexiform or solitary), gliomas of the optical nerve, pigmented nodules of the iris ( Lisch nodules), and cutaneous hyperpigmented macules (caf´e au lait spots).115–117 In a study by Mao et al., 48% of duodenal somatostatinomas were associated with NF1, in contrast to pancreatic somatostatinomas, of which only 6.25% were associated with this disease.118 Somatostatin, a hormone normally secreted by delta islet cells, has a broad inhibiting effect on a number of gastrointestinal hormones, including insulin, glucagon, pancreatic polypeptide, gastrin, cholecystokinin-pancreozymin, secretin, and gastroinhibitory peptide.115 Somatostatin-producing tumours are situated either in the pancreas or duodenum. All the duodenal somatostatinomas are located either at the papilla of Vater or on the medial wall of the second portion of the duodenum. Patients with these tumours seldom exhibit the somatostatin syndrome ( steatorrhoea, gall stones, diabetes mellitus and hypochlorhydria ). Histologically, these tumours are usually typified by glandular/ acinar structures lined by uniform, eosinophilic, granular cells ( Fig. 6A– D). Solid or nested foci can also be present, and psammoma bodies are found in 60.7% of cases.118 Chetty and Essa119 propose that the somatostatin-producing cells arise from pancreatic duct epithelium or from heterotopic pancreatic tissue; they postulate that these cells eventually evolve into somatostatinomas. Multiple endocrine neoplasia type 1 ( MEN1) The MEN syndromes have been recognised for many decades, and it is MEN1 that is associated with islet cell tumours of the pancreas. Patients with MEN1 ( Werner’s syndrome ) typically have pituitary adenomas, parathyroid ( chief cell) hyperplasia, and pancreatic neuroendocrine adenomas ( gastrinomas, insulinomas, glucagonomas, and VIP cell tumours). MEN1 is caused by the MEN1 gene, which functions as a tumour-suppressor gene and is located in chromosome 11q13. 120 The MEN1 locus on 11q13 and other candidate tumour-suppressor loci located on 3p and 18q are known to be hemi- or homozygously mutated in a subset of pancreatic neuroendocrine tumours. Indeed, study of 16 MEN1associated pancreatic endocrine tumours showed loss of heterozygosity (LOH) at 3p in 36% of tumours.121 In addition, besides the 11q13 abnormality, more than half of the MEN1-associated tumours had additional genetic lesions

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Fig. 6 Somatostatinoma in an adult male with NF1. ( A) Tumour located adjacent to the ampulla of Vater, with overlying duodenal mucosa ( H&E, low power ). ( B) Tumour cells infiltrating through the muscularis of the duodenal wall ( H&E, high power). ( C) Tumour cells with uniform, round nuclei and eosinophilic cytoplasm ( H&E, high power). ( D) Tumour cells showing strong positive staining with an antibdy to somatostatin ( high power ).

affecting 3p or 18q. Similar results were found in nonfamilial tumours, suggesting that tumour-suppressor genes on 3p and 18q, in addition to the MEN1 gene at 11q13, are involved in the tumorigenesis of both non-familial and MEN1-associated pancreatic endocrine tumours.121

SCREENING AND PREVENTION Despite concerted efforts, little progress has been made in improving survival statistics for pancreatic cancer over the last five decades. The poor prognosis of the disease can be explained at least in part by the insidious onset of the disease that inevitably leads to a delay in diagnosing the disease at a curative stage. Therefore, progress can be made only by introducing effective screening programmes of patients at risk, together with improving methods to detect tumours at a curative stage. Ultimately, preventative strategies should be sought that will have an impact on reducing the prevalence of this disease. Formulation of screening strategies for pancreatic cancer poses major logistical and fiscal challenges even in affluent Western countries. Hruban et al. 4 calculated that to detect 28 000 pancreatic cancers amongst 35 000 000 Americans over the age of 65 years using a screening test with a 95% sensitivity and specificity will result in 1 748 600 falsepositive tests. Needless to say, this will not only evoke

unnecessary patient anxiety, but patients will be exposed to complications associated with invasive tests such as endoscopic retrograde cholangiopancreatography ( ERCP) and surgery. Therefore, screening programmes should be directed at those patients who are at considerable risk of developing pancreatic cancer. For example, family members in whom a familial syndrome such as HNPCC, FAMMM, PJS, BRCA2 syndrome, or hereditary chronic pancreatitis has been identified could be tested. Who to incorporate in screening programmes and what methods to use to detect early cancers remain uncertain. The Johns Hopkins Medical Institutions in the USA have embarked on a trial screening programme for pancreatic cancer kindreds and for patients with PJS.4 Based on previous findings, Hizawa et al. suggest that male patients with PJS may have a greater risk of pancreatic cancer than female patients,55 emphasising that a more intense screening programme may be needed for men. The methods used in the Johns Hopkins programme include a baseline evaluation consisting of a full clinical evaluation with serum CA19–9 and trypsinogen. Endoscopic ultrasonography (EUS) and dual-phase contrast spiral CT scan of the abdomen are used as first-line imaging investigations. An EUS scoring system has been devised according to various abnormalities and, in addition, pancreatic juice is collected from the duodenum after intravenous secretin ( RepliGen) stimulation for genetic

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marker studies. EUS with or without guided biopsy, tru-cut biopsy, or fine-needle aspiration biopsy is unquestionably the best imaging modality to detect premalignant and early cancers.122–126 Patients with an abnormal EUS are submitted to further tests including an ERCP with collection of pancreatic juice ( after secretin stimulation) for assessment of dysplasia and gene mutation markers ( e.g., K-ras ).20,24,127 Patients in whom a mass is diagnosed or for whom there is biopsy evidence of severe dysplasia ( PanIN3) are submitted to surgery. The results of such an intensive screening programme and aggressive surgical strategy are awaited with interest, particularly with respect to the yield of detecting tumours at the pre-invasive (curative) stage. Growing awareness of familial syndromes in which pancreatic cancer is prevalent has led to recent reports of new syndromes, for example, a syndrome of hereditary pancreatic adencarcinoma and cysts of the liver and kidneys.128 In this family study, screening for pancreatic cancer included serial serum assays for CA19–9; it is of note that serum levels were elevated in family members who did not have overt pancreatic cancer. Continued monitoring of CA19– 9 may help with the detection of early pancreatic cancer in high-risk families. While screening programmes are appropriate in the small category of patients at risk, preventative strategies are realistically the only way forward to make a significant impact on saving lives. The importance of primary preventative measures such as avoiding major risk factors, e.g., smoking, emphasising dietary measures restricting high energy intake food (rich in cholesterol and red meat), and encouraging fresh vegetables/ fruit and high fibre meals, should not be underestimated.129,130 Such changes in lifestyle might well have played a role in the slowing down in recent years of the prevalence of this disease in the United States and Europe. It has been calculated that by stopping tobacco smoking, the risk of developing pancreatic cancer is equal to non-smokers after 10–15 years and that this may prevent cancers in 68 000 people in Europe by 2020. 4

ANIMAL MODELS The increasing incidence of human pancreatic cancer in recent years has led to a growing interest in establishing animal models using a range of chemical carcinogens.131 The most important recent advances have occurred in association with the development of transgenic technology and the discovery of the mutations in the cationic trypsinogen gene responsible for hereditary forms of pancreatitis; this has led to the development of a transgenic mouse model for acute pancreatitis.132 This mutant transgene-expressing mouse model has the potential to develop spontaneous and/ or an inducible form of acute pancreatitis that resembles human hereditary pancreatitis. This could provide further insights into pathogenic mechanisms and preventative strategies aimed at preventing carcinoma of the pancreas.76,77

FUTURE DIRECTIONS A new frontier in prevention is the use of specific chemopreventative agents, either natural or pharmacological. In principle, these agents can modify carcinogen

activation and cellular uptake, inhibit aberrant signal transduction and angiogenesis, or induce apoptosis.133 This is a rapidly developing field in oncology in which dietary supplementation with antioxidants or drugs have a selective action on specific molecular targets such as the oestrogen, androgen and retinoid receptors or inducible cyclo-oxygenases.134 Some chemopreventative agents may exert their primary action on stromal rather than epithelial target cells ( e.g., COX-2 inhibitors). In cancer of the pancreas, agents containing farnesol transferase inhibitors, e.g., isoprenoid compounds, may be utilised in the future. There is also the phenomenon of deregulation of transforming growth factorb function, a common feature in pancreatic cancer, which may provide the theoretical framework for developing effective therapeutic strategies.135 ACKNOWLEDGEMENT The authors would like to thank the Cancer Association of South Africa for financial support. Address for correspondence: Professor P. Hall, Department of Anatomical Pathology, Room 210, UCT Medical School, Anzio Road, Observatory 7925, South Africa. E-mail: [email protected] a

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