tumours of the exocrine pancreas - iarc.fr · tumours of the exocrine pancreas pancreatic carcinoma...

CHAPTER 10

Tumours of the Exocrine Pancreas

Pancreatic carcinoma is a highly malignant neoplasm that stillcarries a very poor prognosis. Ductal adenocarcinoma is themost frequent type. Although cigarette smoking has beenestablished as a causative factor, the risk attributable totobacco abuse amounting to approximately 30%. An increasedrisk is also associated with hereditary pancreatitis, but addi-tional aetiological factors remain to be identified.

Significant progress has been made in the understanding ofthe molecular basis of ductal carcinomas. KRAS point muta-tions and inactivation of the tumour suppressor genes p16,TP53 and DPC4 have been identified as most frequent geneticalterations.

Non-ductal pancreatic neoplasms span a wide range of histo-logical features that need to be recognized by pathologists asseveral entities are associated with distinct opportunities fortherapy.

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Epithelial tumours

BenignSerous cystadenoma 8441/01

Mucinous cystadenoma 8470/0Intraductal papillary-mucinous adenoma 8453/0Mature teratoma 9080/0

Borderline (uncertain malignant potential)Mucinous cystic neoplasm with moderate dysplasia 8470/1Intraductal papillary-mucinous neoplasm with moderate dysplasia 8453/1Solid-pseudopapillary neoplasm 8452/1

MalignantDuctal adenocarcinoma 8500/3

Mucinous noncystic carcinoma 8480/3Signet ring cell carcinoma 8490/3Adenosquamous carcinoma 8560/3Undifferentiated (anaplastic) carcinoma 8020/3Undifferentiated carcinoma with osteoclast-like giant cells 8035/3Mixed ductal-endocrine carcinoma 8154/3

Serous cystadenocarcinoma 8441/3Mucinous cystadenocarcinoma 8470/3

– non-invasive 8470/2– invasive 8470/3

Intraductal papillary-mucinous carcinoma 8453/3– non-invasive 8453/2– invasive (papillary-mucinous carcinoma) 8453/3

Acinar cell carcinoma 8550/3Acinar cell cystadenocarcinoma 8551/3Mixed acinar-endocrine carcinoma 8154/3

Pancreatoblastoma 8971/3Solid-pseudopapillary carcinoma 8452/3Others

Non-epithelial tumours

Secondary tumours

WHO histological classification of tumours of the exocrine pancreas

TNM classification1, 2

Primary Tumour (T)TX Primary tumour cannot be assessedT0 No evidence of primary tumourTis Carcinoma in situT1 Tumour limited to the pancreas, 2 cm or less in greatest dimen-

sionT2 Tumour limited to the pancreas, more than 2 cm in greatest

dimensionT3 Tumour extends directly into any of the following: duodenum, bile

duct, peripancreatic tissues3

T4 Tumour extends directly into any of the following: stomach,spleen, colon, adjacent large vessels4

Regional Lymph Nodes (N)NX Regional lymph nodes cannot be assessedN0 No regional lymph node metastasisN1 Regional lymph node metastasis

N1a Metastasis in a single regional lymph nodeN1b Metastasis in multiple regional lymph nodes

Distant Metastasis (M)MX Distant metastasis cannot be assessedM0 No distant metastasisMI Distant metastasis

Stage groupingStage 0 Tis N0 M0Stage I T1 N0 M0

T2 N0 M0

Stage II T3 N0 M0

Stage III T1 N1 M0T2 N1 M0T3 N1 M0

Stage IVA T4 Any N M0Stage IVB Any T Any N M1

_________1 Morphology code of the International Classification of Diseases for Oncology (ICD-O) {542} and the Systematized Nomenclature of Medicine (http://snomed.org). Behaviour is coded

/0 for benign tumours, /1 for unspecified, borderline or uncertain behaviour, (/2 for in situ carcinomas) and /3 for malignant tumours.

TNM classification of tumours of the exocrine pancreas

220 Tumours of the exocrine pancreas

_________1 {1, 66}. This classification applies only to carcinomas of the exocrine pancreas.2 A help desk for specific questions about the TNM classification is available at http://tnm.uicc.org.3 Peripancreatic tissues include the surrounding retroperitoneal fat (retroperitoneal soft tissue or retroperitoneal space), including mesentery (mesenteric fat), mesocolon, greater and

lesser omentum, and peritoneum. Direct invasion to bile ducts and duodenum includes involvement of ampulla of Vater. 4 Adjacent large vessels are the portal vein, coeliac artery, and superior mesenteric and common hepatic arteries and veins (not splenic vessels).

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221Ductal adenocarcinoma

Ductal adenocarcinoma of the pancreas G. Klöppel G. AdlerR.H. Hruban S.E. KernD.S. Longnecker T.J. Partanen

DefinitionA carcinoma occurring almost exclusive-ly in adults that probably arises from andis phenotypically similar to, pancreaticduct epithelia, with mucin productionand expression of a characteristic cyto-keratin pattern.

ICD-O codesDuctal adenocarcinoma 8500/3

Mucinous noncystic carcinoma 8480/3Signet ring cell carcinoma 8490/3Adenosquamous carcinoma 8560/3Undifferentiated (anaplastic) carcinoma 8020/3Undifferentiated carcinoma with osteoclast-like giant cells 8035/3Mixed ductal-endocrine carcinoma 8154/3

EpidemiologyIncidence and geographical distributionDuctal adenocarcinoma and its variantsare the most common neoplasms in thepancreas, representing 85-90% of allpancreatic neoplasms {359, 941, 1781}.In developed countries, the annual age-

adjusted incidence rates (world standardpopulation) range from 3.1 (Herault,France) to 20.8 (central Louisiana, USA,blacks) per 100,000 males and from 2.0(Herault, France) to 11.0 (San Francisco,CA, USA, blacks) per 100,000 females{1471}. Rates from most developingcountries range from 1.0 to close to 10per 100,000. Incidence and mortalityrates are almost identical, since survivalrates for pancreatic carcinoma are verylow.

Time trendsAfter a steady increase between 1930and 1980, the incidence rates havelevelled off {593}. It is currently the fifthleading cause of cancer death inWestern countries, second only to coloncancer among malignancies of thedigestive tract.

Age and sex distributionApproximately 80% of cases manifestclinically in patients 60-80 years; casesbelow the age of 40 years are rare {1781}.The incidence of pancreatic carcinoma isslightly higher among men than women,

with a male/female ratio of 1.6 in devel-oped nations and 1.1 in developing coun-tries. Blacks have distinctly higher ratesthan whites {593}.

AetiologyThe development of pancreatic carcino-ma is strongly related to cigarette smok-ing, which carries a 2-3 fold relative risk(RR) that increases with the number ofpack-years of smoking {21}. Although theassociation between cigarette smokingand pancreatic carcinoma is not as strongas that between cigarette smoking andlung cancer (RR > 20), it has been esti-mated that a substantial reduction of thenumber of smokers in the European Unioncould save as many as 68,000 lives thatwould otherwise be lost to pancreaticcancer during the next 20 years {1293}. Chronic pancreatitis, past gastric sur-gery, occupational exposure to chemi-cals such as chlorinated hydrocarbonsolvents, radiation exposure, and dia-betes mellitus have also been associatedwith the development of pancreatic car-cinoma {593, 1100, 2080}. A markedlyincreased risk has been observed inhereditary pancreatitis {1101}. A number of dietary factors have beenputatively connected with pancreatic can-cer, including a diet low in fibre and highin meat and fat {593}. Coffee consumptionwas once thought to be a risk factor forpancreatic carcinoma, but recent studiesshowed no significant associations {593}.

Localization60-70% of pancreatic ductal adenocarci-nomas are found in the head of thegland, the remainder occur in the bodyand/or tail. Pancreatic head tumours aremainly localized in the upper half, rarelyin the uncinate process {1781}. Rarely,heterotopic pancreatic tissue gives riseto a carcinoma {596, 1898}.

Clinical featuresSymptoms and signsClinical features include abdominal pain,unexplained weight loss, jaundice andpruritus. Diabetes mellitus is present in

Fig. 10.01 Global distribution of pancreatic cancer (2000). Note the high incidence areas in North America,Europe, and the Russian Federation.

7.8

2.8

8.9

1.5

6.1

5.7

< 1.8 < 2.9 < 5.4 < 7.7 < 11.7

7.0

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70% of patients, usually with a diabeteshistory of less than 2 years. Later symp-toms are related to liver metastasis and/orinvasion of adjacent organs (stomach,colon) or of the peritoneal cavity (ascites).Occasionally, patients present with acutepancreatitis {621}, migratory throm-bophlebitis, hypoglycaemia, or hypercal-caemia {1261}.

Imaging and laboratory testsCurrently, the most important tests forestablishing the diagnosis of pancreaticcarcinoma are ultrasonography (US) andcomputerised tomography (CT) or mag-netic resonance imaging (MRI), with orwithout guided percutaneous fine-needlebiopsy, endoscopic retrograde cholan-giography (ERCP), endoscopic ultra-sonography (EUS) and tumour markerdetermination (CA 19-9, Du-Pan 2, CEA,Span-1). The sensitivity and specificity ofany of these tests alone ranges between55 and 95%. By applying combinationsof these tests, accuracy rates of morethan 95% have been achieved {2061}. On transabdominal US and on EUS, pan-creatic ductal adenocarcinomas arecharacterised as echo-poor and inhomo-geneous mass lesions in about 80% ofcases. About 10% of the tumours appearecho-rich. With increasing size, tumourstend to become inhomogeneous, withcystic and echo-rich areas. Indirect signsof a pancreatic tumour (dilatation of pan-creatic and/or common bile duct) areusually found proximal to tumours largerthan 3 cm. On EUS lymph node metas-tases appear as enlarged echo-poornodes. ERPC may demonstrate dis-

placement, narrowing, or obstruction ofthe pancreatic duct. Angiography ishelpful in preoperative management.CT shows pancreatic adenocarcinomasas hypodense masses in up to 92% ofcases {528}. Diffuse tumour involvementof the pancreas is found in about 4%. Inup to 4% the pancreatic and commonbile duct are dilated without an identifi-able mass. KRAS mutations. Mutations in codon 12of the KRAS gene have been detected inthe stool, in pancreatic juice and/orblood samples from patients with provenductal adenocarcinoma of the pancreas{224, 960, 1876}, but their diagnosticvalue in is still controversial.

Fine needle aspiration (FNA)FNA can be performed percutaneouslywith guidance by imaging techniques orunder direct visualisation at surgery.Aspirates from a typical, well to moder-ately differentiated ductal adenocarcino-ma show a cellular aspirate {32, 940}.Pancreatic juice cytology obtained fromERCP is less sensitive than percuta-neous or intraoperative FNA (76 versus90 to 100%) {32, 1242, 1311}.

MacroscopyDuctal adenocarcinomas are firm andpoorly defined masses. The cut surfacesare yellow to white. Haemorrhage andnecrosis are uncommon, but microcysticareas may occur. In surgical series, thesize of most carcinomas of the head ofthe pancreas ranges from 1.5 to 5 cm,with a mean diameter between 2.5 and3.5 cm. Carcinomas of the body/tail are

usually somewhat larger at diagnosis.Tumours with a diameter less than 2 cmare infrequent {697} and may be difficultto recognise by gross inspection. Carcinomas of the head of the pancreasusually invade the common bile ductand/or the main pancreatic duct and pro-duce stenosis that results in proximaldilatation of both duct systems.Complete obstruction of the main pan-creatic duct leads to extreme prestenoticduct dilatation with duct haustration andfibrous atrophy of the parenchyma (i.e. obstructive chronic pancreatitis).More advanced pancreatic head carci-nomas involve the ampulla of Vaterand/or the duodenal wall, causing ulcer-ations. Carcinomas in the pancreaticbody or tail obstruct the main pancreaticduct, but typically do not involve thecommon bile duct.

Tumour spread and stagingIt is an exception to find a resected car-cinoma that is still limited to the pancreas{1414}. In head carcinomas, peripancre-

Fig. 10.02 Ductal adenocarcinoma. An ill-definedpale carcinoma in the head of the pancreas.

Fig. 10.03 Ductal adenocarcinoma. A Well differentiated tumour with desmoplasia and irregular gland formation. B Well differentiated neoplasm involving a normalduct (right part).

A B

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atic tumour invasion, often via perineuralsheaths, primarily involves the retroperi-toneal fatty tissue. Subsequently, retro-peritoneal veins and nerves are invaded.Direct extension into neighbouring or-gans and/or the peritoneum is seen inadvanced cases. In carcinomas of thebody and tail, local extension is usuallygreater, because of delayed tumourdetection, and includes invasion of thespleen, stomach, left adrenal gland,colon, and peritoneum {359, 941}. Lymphatic spread of pancreatic headcarcinomas involves, in descending orderof frequency, the retroduodenal (posteriorpancreaticoduodenal) and the superiorpancreatic head groups, the inferior headand the superior body groups, and theanterior pancreaticoduodenal and theinferior body groups {359}. This lymphnode compartment is usually resectedtogether with the head of the pancreas,using a standard Whipple procedure{1955}. More distal nodal metastases mayoccur in the ligamentum hepatoduode-nale, at the coeliac trunk, the root of thesuperior mesenteric artery, and in para-aortic nodes at the level of the renal arter-ies. These lymph node compartments areonly removed if an extended Whipple pro-cedure is performed. Carcinomas of thebody and tail metastasise especially tothe superior and inferior body and taillymph node groups and the splenic hiluslymph nodes. They may also spread vialymphatic channels to pleura and lung.Haematogenous metastasis occurs, inapproximate order of frequency, to theliver, lungs, adrenals, kidneys, bones,brain, and skin {359, 941, 1231}.

StagingThe 1997 TNM classification {66} is pre-sented on page 220. Another stagingsystem has been published by the JapanPancreas Society {832}.

Histopathology Most ductal adenocarcinomas are well tomoderately differentiated. They are char-acterized by well-developed glandularstructures, which more or less imitatenormal pancreatic ducts, embedded indesmoplastic stroma. The large amountof fibrous stroma accounts for their firmconsistency. Variations in the degree ofdifferentiation within the same neoplasmare frequent, but well differentiated carci-nomas with foci of poor differentiation areuncommon.

Well differentiated carcinomas consist oflarge duct-like structures, combined withmedium-sized neoplastic glands. Tubularor cribriform patterns are typical; theremay also be small irregular papillary pro-jections without a distinct fibrovascularstalk, particularly in large duct-like struc-tures. Mitotic activity is low. In betweenthe neoplastic glands there may be a fewnon-neoplastic ducts as well as remnantsof acini and individual islets. Sometimes, the neoplastic duct-likeglands are so well differentiated that theyare difficult to distinguish from non-neo-plastic ducts. However, the mucin-con-taining neoplastic glands may be rup-tured or incompletely formed, a featurethat is not seen in normal ducts. Themucin-producing neoplastic cells tend tobe columnar, have eosinophilic andoccasionally pale or even clear cyto-plasm, and are usually larger than thoseof non-neoplastic ducts. They containlarge round to ovoid nuclei which mayvary in size, with sharp nuclear mem-branes and distinct nucleoli that are notfound in normal duct cells. Moreover,although the neoplastic cell nuclei tendto be situated at the base of the cell, theyalways show some loss of polarity. Moderately differentiated carcinomaspredominantly show a mixture of medi-um-sized duct-like and tubular structuresof variable shape, embedded in desmo-plastic stroma. Incompletely formedglands are common. Compared with thewell differentiated carcinoma, there is a

greater variation in nuclear size, chro-matin structure and prominence of nucle-oli. Mitotic figures are rather frequent. Thecytoplasm is usually slightly eosinophilic,but clear cells are occasionally abun-dant. Mucin production appears to bedecreased and intraductal in situ compo-nents are somewhat less frequent than inwell differentiated carcinomas. Foci ofpoor and irregular glandular differentia-tion are often found at the leading edgeof the neoplasm, particularly where itinvades the peripancreatic tissue.Poorly differentiated ductal carcinomasare infrequent. They are composed of amixture of densely packed, small irregularglands as well as solid tumour cell sheetsand nests, which entirely replace the aci-nar tissue. While typical large, duct-likestructures and intraductal tumour compo-nents are absent, there may be smallsquamoid, spindle cell, or anaplastic foci(comprising by definition less than 20% ofthe tumour tissue). There may be somescattered inflammatory cells. Foci ofnecrosis and haemorrhage occur. Theneoplastic cells show marked pleomor-phism, little or no mucin production, andbrisk mitotic activity. At the advancingedge of the carcinoma, the gland and theperipancreatic tissue are infiltrated bysmall clusters of neoplastic cells.

Changes in non-neoplastic pancreasAll ductal adenocarcinomas are associ-ated with more or less developedfibrosclerotic and inflammatory changes

Fig. 10.04 Poorly differentiated ductal adenocarcinoma.

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in the adjoining non-neoplastic pan-creas, due to carcinomatous ductobstructions (obstructive chronic pan-creatitis). In cases of complete occlusionof the main duct, there is markedupstream dilatation of the duct andalmost complete fibrotic atrophy of theparenchyma. In contrast to chronic pan-creatitis due to alcoholism, intraductalcalcifications are generally absent.Poorly differentiated carcinomas usuallydestroy the islets. In the well and moder-ately differentiated neoplasms, however,islets may be found entrapped in neo-plastic tissue. In addition, scatteredendocrine cells occur attached to orintermingled between neoplastic colum-nar cells. Only in exceptional cases dothe endocrine cells constitute a secondcell component of the ductal carcinoma(see mixed ductal-endocrine carcinoma).

Histochemistry and immunohistochem-istryAlthough no histochemical or immuno-histochemical marker is able to unequiv-ocally distinguish pancreatic from extra-

pancreatic adenocarcinoma, somemarkers are useful in separating ductaladenocarcinoma of the pancreas fromnon duct-type tumours or other gastroin-testinal carcinomas.Mucin. Ductal adenocarcinomas mainlystain for sulphated acid mucins but focal-ly also for neutral mucins {1714}.Immunohistochemically, most ductaladenocarcinomas express MUC1, MUC3and MUC5/6 (but not MUC2) {1918,2179}, CA 19-9, Du-Pan 2, Span-1, CA 125 and TAG72 {1714, 1884}. Theexpression patterns of CA 19-9, Du-Pan2, Span-1, CA 125 and TAG 72 are large-ly comparable in their immunoreactivityand specificity. These markers also labelthe epithelium of normal pancreatic ductsto some extent, particularly in chronicpancreatitis, and the tumour cells ofsome serous cystadenomas and acinarcell carcinomas {1282}.Carcinoembryonic antigen (CEA). Monospecific antibodies against CEA thatdo not recognise other members of theCEA family are capable of discriminatingbetween non-neoplastic duct changes,such as ductal papillary hyperplasia, anda variety of neoplasms {119}. CEA is neg-ative in serous cystadenoma.Cytokeratins, vimentin, endocrine mark-ers and enzymes. Normal pancreaticand biliary ductal cells and pancreaticcentroacinar cells express the cytoker-atins (CK) 7, 8, 18, 19 and occasionallyalso 4 {1696}. Acinar cells contain onlyCK 8 and 18, and islet cells 8, 18 andoccasionally also 19. Ductal adenocarci-nomas express the same set of cytoker-atins as the normal duct epithelium, i.e. CK 7, 8, 18 and 19. More than 50% of

the carcinomas also express CK 4{1696}, but are usually negative for CK 20{1259}. As the usual keratin patterns ofnon-duct-type pancreatic neoplasms (i.e. acinar carcinomas and endocrinetumours, CK 8, 18 and 19) and gut carci-nomas (i.e. CK 8, 18, 19 and 20) differfrom that of ductal carcinoma, it is possi-ble to distinguish these tumours on thebasis of their CK profile.Ductal adenocarcinomas are usuallynegative for vimentin {1696}. With rareexceptions (see mixed ductal-endocrinecarcinoma), they also fail to label withendocrine markers such as synapto-physin and the chromogranins, but maycontain, particularly if well differentiated,some scattered (possibly non-neoplas-tic) endocrine cells in close associationwith the neoplastic cells {167}. They aregenerally negative for pancreaticenzymes such as trypsin, chymotrypsinand lipase {739, 1282}. Growth factors and adhesion molecules.Pancreatic carcinomas overexpress epi-dermal growth factor and its receptor,c-erbB-2, transforming growth factoralpha {380, 1676, 2163}, metallothionein{1409}, CD44v6 {259, 1880} and mem-branous E-cadherin {1519}.

Ultrastructure Ductal adenocarcinoma cells are charac-terized by mucin granules in the apicalcytoplasm, irregular microvilli on the lumi-nal surface, and a more or less polarisedarrangement of the differently sizednuclei {359, 901, 1714}. The content ofthe mucin granules (0.4-2.0 μm) variesfrom solid-electron dense to filamentousand punctate; often there is a dense

Fig. 10.06 Undifferentiated carcinoma with osteoclast-like giant cells. A The carcinoma is in the uncinate process and shows haemorrhagic necrosis. B There ismarked cellular pleomorphism with scattered osteoclast-like giant cells and a well-differentiated ductal carcinoma component (left upper corner).

Fig. 10.05 Undifferentiated carcinoma exhibitingextreme pleomorphism with giant cells.

A B

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eccentric core. Some cells have featuresof gastric foveolar cells, showing gran-ules with a punctate-cerebroid structure{1714}. Loss of tumour differentiation ischaracterized by loss of cell polarity, dis-appearance of a basal lamina, appear-ance of irregular luminal spaces, andloss of mucin granules {901}.

Histological variantsAdenosquamous carcinoma and undif-ferentiated (anaplastic) carcinoma(including osteoclast-like giant celltumours), mucinous noncystic adenocar-cinoma and signet-ring cell carcinomaare considered variants of ductal adeno-carcinoma because most of these carci-nomas, even if poorly differentiated, con-tain some foci showing neoplastic glandswith ductal differentiation {288, 359, 941,947, 1781}.

Adenosquamous carcinomaThis rare neoplasm, relative frequency3-4% {941, 359, 813, 1415}, is character-ized by the presence of variable propor-tions of mucin-producing glandular ele-ments and squamous components. Thesquamous component should accountfor at least 30% of the tumour tissue. Inaddition, there may be anaplastic andspindle cell foci. Pure squamous carci-nomas are very rare.

Undifferentiated (anaplastic) carcinomaAlso called giant cell carcinoma, pleo-morphic large cell carcinoma, and sarco-matoid carcinoma, these tumours have arelative frequency of 2-7%. They arecomposed of large eosinophilic pleomor-phic cells and/or ovoid to spindle-shaped cells that grow in poorly cohe-sive formations supported by scantyfibrous stroma. Commonly the carcino-mas contain small foci of atypical glan-dular elements {359, 941, 1786, 1962}.Carcinomas consisting predominantly ofspindle cells may also contain areas ofsquamoid differentiation. High mitoticactivity as well as perineural, lymphatic,and blood vessel invasion is found inalmost all cases. Immunohistochemical-ly, some or most tumour cells expresscytokeratins and usually also vimentin{740}. Electron microscopy revealsmicrovilli and mucin granules in somecases {359}. Undifferentiated carcino-mas with a neoplastic mesenchymalcomponent (carcinosarcoma) have so farnot been described.

Undifferentiated carcinoma with osteo-clast-like giant cellsThis rare neoplasm is composed of pleo-morphic to spindle-shaped cells andscattered non-neoplastic osteoclast-likegiant cells with usually more than 20 uni-formly small nuclei. In many cases thereis an associated in situ or invasive ade-nocarcinoma {359}. The osteoclast-likegiant cells are often concentrated nearareas of haemorrhage and may containhaemosiderin and, occasionally, phago-cytosed mononuclear cells. Osteoid for-mation may also be found. Immunohistochemically, at least some ofthe neoplastic cells express cytokeratin,vimentin and p53 {740, 2095}. The osteo-clast-like giant cells, in contrast, are neg-ative for cytokeratin and p53, but positivefor vimentin, leukocyte common antigen(CD56) and macrophage markers suchas KP1 {740, 1258, 2095}.The mean age of patients with osteo-clast-like giant cell tumours is 60 yearsbut there is a wide age range from 32 to82 years {1370}. Some tumours arefound in association with mucinous cys-tic neoplasms {1258, 2095, 2198}. In theearly reports on this tumour it was sug-gested that they may have a morefavourable prognosis than the usual duc-tal adenocarcinoma {359}. More recentlya mean survival of 12 months has beenreported.

Mucinous noncystic carcinomaThis uncommon carcinoma (relative fre-quency: 1-3%) {941} has also beencalled ‘colloid’ or gelatinous carcinoma.Mucin accounts for > 50% of the tumour.The large pools of mucin are partiallylined by well-differentiated cuboidal cellsand contain clumps or strands of tumourcells. Some floating cells may be of thesignet-ring cell type.Sex and age distribution are similar tothose of ductal adenocarcinoma. Thetumours may be very large and are usu-ally well demarcated. The developmentof pseudomyxoma peritonei has beendescribed {285}. It is of interest that theinvasive component of some of the intra-ductal papillary-mucinous tumours re-sembles mucinous noncystic carcinoma.Mucinous noncystic carcinoma shouldnot be confused with mucinous cystictumour because of the much better prog-nosis of the latter (see chapter on muci-nous cystic neoplasms).

Signet-ring cell carcinomaThe extremely rare signet-ring cell carci-noma is an adenocarcinoma composedalmost exclusively of cells filled withmucin {1781, 1951}. The prognosis isextremely poor; a gastric primary shouldalways be excluded before making thisdiagnosis.

Fig. 10.07 Adenosquamous carcinoma. Note the glandular component on the left and the squamous differ-entiation on the right (arrowheads).

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Mixed ductal-endocrine carcinomaMixed ductal-endocrine carcinoma {947}has also been referred to as mixed carci-noid-adenocarcinoma, mucinous carci-noid tumour {359}, or simply mixedexocrine-endocrine tumour. This neo-plasm is characterized by an intimateadmixture of ductal and endocrine cellsin the primary tumour as well as in itsmetastases. By definition, the endocrinecells should comprise at least one thirdto one half of the tumour tissue. The duc-tal differentiation is defined by mucin pro-duction and the presence of a duct typemarker such as CEA. The endocrine cellsare characterized by the presence ofneuroendocrine markers and/or hormon-al products; immunoexpression of all fourislet hormones, amylin (IAPP), serotonin,pancreatic polypeptide (PP), and occa-sionally gastrin have been described{167}.

Mixed ductal-endocrine carcinomas, asdefined above, seem to be exceptionallyrare in the pancreas {1714, 1781}.Biologically, the mixed carcinomabehaves like the usual ductal adenocar-cinoma.Acinar cell carcinomas {739, 1694, 1985}and pancreatoblastomas {741} withsome endocrine and ductal elements,and endocrine tumours with ductal com-ponents {1372, 1941} are not discussedhere, because their behaviour is dictatedby their acinar and endocrine elements.Mixed ductal-endocrine carcinomasshould also be distinguished from ductaladenocarcinomas with scattered endo-crine cells, since scattered endocrinecells are found in 40-80% of ductal ade-nocarcinomas {167, 289} and seem tobe particularly frequent in the well differ-entiated tumours, where they are eitherlined up along the base of the neoplastic

ductal structures or lie between theneoplastic columnar cells. ‘Collisiontumours’ composed of two topographi-cally separate components are not inclu-ded in the mixed ductal-endocrine cate-gory.

Other rare carcinomas Other very rare carcinomas of probableductal phenotype include clear cell car-cinoma {359, 882, 1908, 1121} and ciliat-ed cell carcinoma (see chapter on mis-cellaneous carcinomas) {1276, 1786}.Carcinomas with ‘medullary’ histologyhave recently been described {590};these lesions are associated with wild-type KRAS status and microsatelliteinstability.The so-called microglandular carcino-mas {359} or microadenocarcinomas aredistinguished by a microglandular tosolid-cribriform pattern. They most likelydo not form an entity of their own butbelong to either the ductal, endocrine, oracinar carcinomas.

GradingA few formal grading systems have beendescribed. Miller et al. graded pancreat-ic tumours using the system of Broder,which distinguishes four grades of cellu-lar atypia. High-grade carcinomas(Broder grades 3 and 4) were larger andthe frequency of venous thrombosis andmetastasis higher than in low-gradetumours.A more recent grading system is basedon combined assessment of histologicaland cytological features and mitoticactivity {944, 1119}. If there is intratumourheterogeneity, i.e. a variation in thedegree of differentiation and mitoticactivity, the higher grade and mitoticactivity is assigned. This rule also appliesif only a minor component (less than halfof the tumour) was of lower grade. Usingthis system, there is a correlationbetween grade and survival and grade isan independent prognostic variable{944, 1119}.

Precursor lesionsPancreatic neoplasmsMucinous cystic neoplasms and intra-ductal papillary mucinous neoplasmsmay progress to invasive cancer. In thecase of mucinous cystic neoplasms, theinvasive component usually resemblesductal adenocarcinoma {1781}. In thecase of intraductal papillary-mucinousFig. 10.09 Pancreatic duct showing high-grade intraepithelial neoplasia (PanIN III).

Fig. 10.08 Mucinous non-cystic adenocarcinoma. A A mucinous carcinoma in the head of the pancreasobstructs the main pancreatic duct and impinges on the bile duct (BD). B The neoplastic cells float in poolsof mucin.

A B

BD

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carcinoma, the invasive componenteither corresponds to a usual ductal ade-nocarcinoma or to mucinous noncysticcarcinoma {1781}.

Severe ductal dysplasia – carcinoma in situThis change of the ductal epithelium ischaracterized by irregular epithelial bud-ding and bridging, small papillae lackingfibrovascular stalks, and severe nuclearabnormalities such as loss of polarity,pleomorphism, coarse chromatin, densenucleoli and mitotic figures. The lesion isoften surrounded by one or two layers offibrosclerotic tissue. Here, no attempt ismade to distinguish between severe dys-plasia and carcinoma in situ, since it isvery difficult, if not impossible, to draw aclear distinction between these two

changes, which both represent high-grade intraepithelial neoplasia. Thelesion corresponds to PanIN III in theproposed terminology of pancreaticintraepithelial neoplasia (Table 10.01). High-grade intraepithelial neoplasia iscommonly found in association with aninvasive ductal adenocarcinoma {358,555, 943}, and may represent either aprecursor to invasive carcinoma or con-tinuous intraductal extensions of theinvasive tumour. Similar duct changeshave also been described remote fromthe macroscopic tumour {1781} or yearsbefore the development of an invasiveductal carcinoma {185, 191}.

Duct changesWith the exception of high-grade intraepi-thelial neoplasia, the precursors to infil-

trating ductal adenocarcinomas are still ill-defined. Putative precursor lesions (Table10.01) include mucinous cell hypertrophy,ductal papillary hyperplasia with muci-nous cell hypertrophy (papillary ductlesion without atypia), adenomatoid (ade-nomatous) ductal hyperplasia, and squa-mous metaplasia {1781, 947}. All theselesions may show mild nuclear atypia. The evidence that some of these ductlesions (i.e. mucinous cell hypertrophyand papillary hyperplasia) may be pre-cursors to invasive carcinoma comesfrom three areas: morphological studies,clinical reports, and genetic analyses. Atthe light microscopic level, ductal papil-lary hyperplasia was found adjacent toinvasive carcinomas more frequentlythan it was in pancreases without cancer{290, 358, 943, 965}. It was also noted

Grade 1 Well differentiated Intensive 5 Little polymorphism, polar arrangement

Grade 2 Moderately differentiated Irregular 6-10 Moderate polymorphism duct like structures and tubular glands

Grade 3 Poorly differentiated glands, Abortive > 10 Marked polymorphism and increased size mucoepidermoid andpleomorphic structures

Tumour grade Glandular differentiation Mucin production Mitoses (per 10 HPF) Nuclear features

Squamous metaplasia Squamous metaplasia Epidermoid metaplasia, multilayered metaplasiaIncomplete squamous metaplasia Incomplete squamous metaplasia focal epithelial hyperplasia, focal atypical

epithelial hyperplasia, multilayered metaplasia

PanIN-IA Mucinous cell hypertrophy Mucinous cell hyperplasia, mucinous ductalhyperplasia, mucoid transformation, simplehyperplasia, flat ductal hyperplasia, mucous hypertrophy, hyperplasia with pyloric glandmetaplasia, ductal hyperplasia grade 1, non-papillaryepithelial hypertrophy, nonpapillary ductal hyperplasia

PanIN-IB Ductal papillary hyperplasia Papillary ductal hyperplasia, ductal hyperplasia grade 2Adenomatoid ductal hyperplasia Adenomatous hyperplasia, ductular cell hyperplasia

PanIN-II Any PanIN-I lesion with moderate dysplasia as defined in the text

PanIN-III Severe ductal dysplasia Ductal hyperplasia grade 3, atypical hyperplasiaCarcinoma in situ

Recommended WHO term Previous WHO classification {947} Other synonyms

Table 10.01 List of recommended terms with synonyms for focal hyperplastic and metaplastic duct lesions in the human exocrine pancreas.

Table 10.02 Histopathological grading of pancreatic ductal adenocarcinoma {1119}.

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that ductal papillary hyperplasia is simi-lar to severe dysplasia-carcinoma in situlesions seen in the vicinity of invasiveductal carcinomas {358}. Clinically, Bratet al. {185} and Brockie et al. {191} havereported a total of five patients whodeveloped infiltrating ductal adenocarci-nomas years after the identification ofatypical duct lesions in their pancreas.Finally, molecular genetic analyses ofduct lesions have demonstrated that theycontain some of the same genetic alter-ations seen in infiltrating ductal carcino-mas. For example, activating point muta-

tions in codon 12 of the KRAS geneal-terations of the p16 and TP53 tumoursuppressor genes and loss of BRCA2and DPC4 have all been reported in ductlesions {1286, 1875, 2166, 2105, 589}.Duct lesions and infiltrating cancers fromthe same pancreas may harbour identi-cal mutations {1120, 1286}. Only a minority of duct lesions mayprogress to invasive cancer, as demon-strated by recent data from a study onnormal pancreases, which showed thatall types of duct lesions and even normalepithelium may harbour KRAS mutations,

and that the lesions are evenly distributedin the pancreas and do not concentrate inthe head region where the carcinoma ismost frequent {647}. It has recently beensuggested that the term ‘PancreaticIntraepithelial Neoplasia (PanIN)’ beadopted for these duct lesions (seehttp://pathology.jhu.edu/ pancreas.panin){937}. Table 10.01 indicates the generalrelationship between the previous WHOterminology and this new proposedPanIN terminology.

Genetic susceptibilityBetween 3% and 10% of cases of pan-creatic cancer are familial {754, 1125,1126, 499}. Some arise in patients withrecognized genetic syndromes, as dis-cussed below, but in most instances thegenetic basis for the familial aggregationof pancreatic carcinomas has not beenidentified. A confounding factor is thepossibility of shared environmental fac-tors, such as tobacco use. Nevertheless,some studies show familial aggregationssuggestive of a genetic aetiology {485,577, 499, 1207} Studies of extended fam-ilies have shown a pattern suggestive ofan autosomal dominant mode of inheri-tance.

Hereditary pancreatitisThis disease is caused by germlinemutations in the cationic trypsinogengene on 7q35 {2098}. This syndrome ischaracterized by the early onset ofsevere recurrent bouts of acute pancrea-titis, and affected individuals have ashigh as a 40% lifetime risk of developingpancreatic carcinoma {1101}.

FAMMM syndrome Familial atypical multiple mole melanoma(FAMMM) is associated with germlinemutations in the p16 tumour suppressorgene on 9p. Affected individuals have an increased risk of developing bothmelanoma and pancreatic carcinoma{601, 1127, 1285, 2097}. The lifetime riskfor developing pancreatic carcinoma isabout 10%.

BRCA2The discovery of the second breast can-cer gene (BRCA2) on 13q was madepossible in large part by the discovery ofa homozygous deletion in a pancreaticcarcinoma {1697}. Pancreatic carcino-mas have been reported in some kindredwith BRCA2 mutations and familial breast

Oncogenes

KRAS 12p Point mutation > 90MYB, AKT2, AIB1 6q, 19q, 20q Amplification1 10-20HER/2-neu 17q Overexpression 70

Tumor suppressor genes

p16 9p Homozygous deletion 40Loss of heterozygosity 40and intragenic mutationPromotor 15hypermethylation

TP53 17p Loss of heterozygosity 50-70and intragenic mutation

DPC4 18q Homozygous deletion 35Loss of heterozygosity 20and intragenic mutation

BRCA2 13q Inherited intragenic mutation 7and loss of heterozygosity

MKK4 17p Homozygous deletion, 4loss of heterozygosity and intragenic mutation

LKB1/STK11 19p Loss of heterozygosity 5and intragenic mutation, homozygous deletion

ALK5 and TGF βR2 9q, 3p Homozygous deletion 4

DNA Mismatch Repair

MSH2, MLH1, others 2p, 3p, others Unknown < 5

___________________1 In cases of amplification, it is generally not possible to unambiguously identify the key oncogene due to the participa-tion of multiple genes in an amplicon.

Gene Chromosome Mechanism of alteration % of cancers

Table 10.03Genetic alterations in pancreatic ductal carcinoma.

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cancer {1514, 1934, 591, 479} identifiedgermline mutations in BRCA2 in about7% of patients with pancreatic carcino-ma. Remarkably, most pancreatic ductalcarcinoma patients with such mutationsdo not have a strong family history ofbreast or pancreatic carcinoma. A num-ber of them are, however, of AshkenaziJewish ancestry {591, 1442}.

Peutz-Jeghers syndromePatients with the Peutz-Jeghers syndromehave an increased risk of developing pan-creatic carcinoma, and recently the bi-allelic inactivation of the LKB1/STK11gene has been demonstrated in a pan-creatic carcinoma which arose in apatient with the Peutz-Jeghers syndrome{579, 1851}.

Hereditary nonpolyposis colon cancer(HNPCC) This syndrome is associated with anincreased risk of developing carcinomaof the colon, endometrium, stomach, andovary {2071}. It can be caused bygermline mutations in any one of a num-ber of DNA mismatch repair genes,including MSH2 on 2p and MLH1 on 3p{1029, 1078, 2071}. Lynch et al. havereported pancreatic carcinomas in somekindred with HNPCC, and Goggins et al.have recently reported microsatelliteinstability, a genetic change associatedwith defects in DNA mismatch repairgenes, in about 4% of pancreatic carci-nomas {590, 1130, 1487}.

GeneticsGenetic alterations are listed in Table10.03. At the chromosome level, theyinclude losses and gains of geneticmaterial as well as generalised chromo-some instability {608, 625, 626}. Themost frequent gains identified cytogenet-ically include those of chromosomes 12and 7; the most common recurrent struc-tural abnormalities involve chromosomearms 1p, 6q, 7q, 17p, 1q, 3p, 11p, and19q, and the most frequent lossesinvolve chromosomes 18, 13, 12, 17, and6 {626, 625}. Similar patterns of loss havebeen identified at the molecular level{184, 1716}, using highly polymorphicmicrosatellite markers. These includevery high rates of loss at chromosomes18q (90%), 17p (90%), 1p (60%), and 9p(85%) and moderately frequent losses at3p, 6p, 8p, 10q, 12q, 13q, 18p, 21q, and22q (25-50% of cases).

Recurrent losses of genetic material atspecific loci in a carcinoma suggest thatthese loci harbour tumour suppressorgenes which are inactivated in the carci-noma, and, indeed, the p16 gene on 9p,the Tp53 gene on 17p, and the DPC4gene on 18q are all frequently inactivat-ed in pancreatic carcinoma {1716}. Thep16 tumour suppressor gene is inacti-vated in 40% of pancreatic carcinomasby homozygous deletion, in 40% by lossof one allele coupled with an intragenicmutation in the second, and by hyperme-thylation of the p16 promoter in an addi-tional 15% {223, 1698, 2104}. The Tp53is inactivated in 75% of pancreatic carci-nomas by loss of one allele coupled withan intragenic mutation in the secondallele {1570, 1624}. The DPC4 tumoursuppressor gene is inactivated in 55% ofpancreatic carcinomas {651}, in 35% ofthe carcinomas by homozygous deletionand in 20% by loss of one allele coupledwith an intragenic mutation in the secondallele. The BRCA2 tumour suppressorgene on 13q is inactivated in about 7% ofpancreatic carcinomas {591, 1442,1697}. Remarkably, in almost all of thesecases one allele of BRCA2 is inactivatedby a germline (inherited) mutation in thegene {591}. Other tumour suppressorgenes which have been shown to beoccasionally inactivated in pancreaticcarcinoma include the genes MKK4,RB1, LKB1/STK11, and the transforminggrowth factor β receptors I and II {592,761, 1850, 1851}.Several oncogenes have been shown tobe activated in ductal adenocarcinomasof the pancreas. These include the KRASgene on chromosome 12p, which is acti-vated by point mutations in over 90% ofthe carcinomas, overexpression of theHER2-neu gene on 17q in 70% of the car-cinomas, and amplification of the AKT2gene on chromosome 19q in 10–20% ofthe carcinomas, the nuclear receptorcoactivator gene AIB1 on chromosome20q, and the MYB gene on chromosome6q {47, 292, 380, 576, 761, 1242, 2039}.Compared to normal pancreas, Smad2mRNA levels are increased in pancreaticcarcinoma, which might lead to the over-expression of components of theTGF-beta signalling pathway that isobserved in these lesions {931}.DNA mismatch repair genes, such asMLH1 and MSH2, can also play a role.Microsatellite instability resulting from theinactivation of both alleles of a DNA mis-

match repair gene has been identified in4% of pancreatic carcinomas {590}. Theyhad wild-type KRAS genes and a char-acteristic ‘medullary’ histological appear-ance, forming a distinct subset of pan-creatic adenocarcinomas (see sectionon other rare carcinomas).

Prognosis and predictive factorsDuctal adenocarcinoma is fatal in mostcases {639}. The mean survival time ofthe untreated patient is 3 months, whilethe mean survival after radical resectionvaries from 10-20 months {560, 692, 814,1955}. The overall 5-year survival rate ofpatients treated by resection is 3-4%{639}, although in selected and stage-stratified series survival figures approach-ing 25 or even 46% have been reported{560, 1955, 1966, 1976}. Unresectablecarcinomas are treated with palliativebypass operations. Response to chemo-therapy with 5-fluorouracil or gemcitabinemay be seen in up to approximately 10%of patients. Radiotherapy alone is largelyineffective {2061}.

Site, size, and stage The survival time is longer in patients withcarcinomas confined to the pancreasand less than 3 cm in diameter (17-29months) than in patients with tumours ofgreater size or retroperitoneal invasion(6-15 months) {2172}. Carcinomas of thebody or the tail of the pancreas tend topresent at a more advanced stage thanthose of the head {560, 1955, 1966,1976}. Some have found that lymph nodemetastases significantly worsen progno-sis, while others have not {710, 1955,2172}.

Residual tumour tissue Patients with no residual tumour followingresection (R0) have the most favourableprognosis of all patients undergoing sur-gical resection {2108}. This implies thatlocal spread to peripancreatic tissues,i.e. the retroperitoneal resection margin,is of utmost importance in terms of prog-nosis {1122}.

RecurrenceLocal recurrence seems to be the majorfactor determining survival after resectionof pancreatic ductal carcinoma. The mostcommon sites of recurrences are the tis-sues surrounding the large mesentericvessels {646}. Clear retroperitoneal resec-tion margin or margins are therefore

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required, if a ‘curative’ resection (R0) is tobe achieved {1122}. Second in frequencyare recurrences arising from lymph nodeor liver metastases that were too small tobe detected during surgery. The peri-toneum and the bone marrow are raresites of recurrence, although malignantcells are detected cytologically in onequarter of the patients during laparoscopyand one half of the patients when bonemarrow trepanation is performed during aWhipple procedure {870}.

GradingBased on the criteria of the grading sys-tem summarised in Table 10.02, it was

found that median postoperative survivalcorrelated significantly with tumourgrade {944}, mitotic index, and severityof cellular atypia. As grading systemsare, however, to a great extent subjec-tive, reproducibility may be low {1119}.Other studies found no relationshipbetween grade and survival {2079}.Nuclear parameters such as mediannuclear size, nuclear area, and nuclearperimeter have been shown to be ofprognostic value for ductal adenocarci-noma {477, 944}.

DNA content and proliferationNondiploid and/or aneuploid DNA content

is associated with advanced tumour stageand shorter survival {46, 105, 476, 2079}.Tumours with low argyrophylic nucleolarorganizer region (AgNOR) counts percell (< 3.25) have been reported to havea better prognosis than tumours with ahigh AgNOR count {1413}. High Ki-67labeling index is an indicator of poorprognosis, but does not seem to be anindependent prognostic parameter{1111, 1119}The immunohistochemical expression ofa number of growth factors has shownweak association with survival {21, 535}.

Early onset familial pancreatic Autosomal dominant Unknown About 30%; 100-fold increased risk adenocarcinoma associated with diabetes of pancreatic cancer; (Seattle family) {479} high risk of diabetes and pancreatitis

Hereditary pancreatitis (167800) Autosomal dominant Cationic trypsinogen (7q35) 30%; 50-fold increased risk of pancreatic cancer {1101, 499}

FAMMM: familial atypical multiple Autosomal dominant p16/CMM2 (9p21) 10% {601, 1127, 2097} mole melanoma (155600)

Familial breast cancer (600185) Autosomal dominant BRCA2 (13q12-q13) 5-10%; 6174delT in Ashkenazi Jews{1442}, 999del5 in Iceland {1934}

Ataxia-telangiectasia (208900) Autosomal recessive ATM, ATB, others (11q22-q23) Unknown; somewhat increased(heterozygote state)

Peutz-Jeghers (175200) Autosomal dominant STK11/LKB1 (19p) Unknown; somewhat increased {579}

HNPCC: hereditary non-polyposis Autosomal dominant MSH2 (2p), MLH1 (3p), others Unknown; somewhat increasedcolorectal cancer (120435) {1130, 2071}

Familial pancreatic cancer Possibly autosomal dominant Unknown Unknown; 5-10fold increased risk if a first-degree relative has

________ pancreatic cancer {499, 1128, 755} 1 Mendelian Inheritance in Man: www.ncbi.nlm.nih.gov/omim

Syndrome (MIM No)1 Mode of inheritance Gene (chromosomal location) Lifetime risk of pancreatic cancer

Table 10.04 Genetic syndromes with an increased risk of pancreatic cancer.

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231Serous cystic neoplasms

Serous cystic neoplasmsof the pancreas

C. CapellaE. SolciaG. KlöppelR.H. Hruban

Serous cystic pancreatic tumours arecystic epithelial neoplasms composed ofglycogen-rich, ductular-type epithelialcells that produce a watery fluid similar toserum. Most are benign (serous cystade-nomas), either serous microcystic adeno-ma or serous oligocystic adenoma. Onlyvery rare cases exhibit signs of malig-nancy (serous cystadenocarcinoma).A solid variant of serous cystadenoma(solid serous cystadenoma) has beendescribed {1499} but remains to beestablished as a separate disease entity.

ICD-O codesSerous cystadenoma 8441/0Serous cystdenocarcinoma 8441/3

Serous microcystic adenoma

DefinitionA benign neoplasm composed of numer-ous small cysts lined by uniform glyco-gen-rich cuboidal epithelial cells, dis-posed around a central stellate scar.

EpidemiologyThis is a rare neoplasm, accounting for 1to 2% of all exocrine pancreatic tumours{1280}. The mean age at presentation is66 years (range, 34-91 years), with a pre-dominance in women (70%) {1781}. Ithas been reported in patients with differ-ent ethnicity {327, 2151}.

AetiologyThe aetiology and pathogenesis of theneoplasm are unknown. The strikingpredilection for women suggests that sexhormones or genetic factors may play arole. An association with Von Hippel-Lindau disease has been reported {327,2026} and confirmed by recent geneticmolecular investigations {2026}.

LocalizationThe neoplasms occur most frequently(50-75%) in the body or tail; the remain-ing tumours involve the head of the pan-creas {49, 327}.

Clinical featuresAbout one third of the neoplasms pres-ent as an incidental finding at routinephysical examination or at autopsy {445}.Approximately two thirds of patientsexhibit symptoms related to local masseffects, including abdominal pain, palpa-ble mass, nausea and vomiting, andweight loss {1544}. Jaundice due toobstruction of the common bile duct isunusual, even in neoplasms originatingfrom the head of the pancreas.Pancreatic serum tumour markers aregenerally normal. Calcifications arefound in a few patients on plain abdomi-nal roentgenograms. Ultrasonography(US) and computed tomography (CT)reveal a well circumscribed, multilocularcyst, occasionally with an evident central

stellate scar and a sunburst type calcifi-cation {532, 817, 1544}. On angiography,the tumours are usually hypervascular.

MacroscopySerous microcystic adenomas are sin-gle, well-circumscribed, slightly bosse-lated, round lesions, with diametersranging from 1-25 cm in greatest dimen-sion (average, 6-10 cm). On section, theneoplasms are sponge-like and aremade up of numerous tiny cysts filledwith serous (clear watery) fluid. Thecysts range from 0.01-0.5 cm, with a fewlarger cysts of up to 2 cm in diameter.Often, the cysts are arranged around amore or less centrally located, densefibronodular core from which thin fibroussepta radiate to the periphery (centralstellate scar).

HistopathologyAt low magnification, the pattern of thecysts is similar to a sponge. The cystscontain proteinaceous fluid and are linedby a single layer of cuboidal or flattenedepithelial cells. Their cytoplasm is clearand only rarely eosinophilic and granular.The nuclei are centrally located, round tooval in shape, uniform, and have aninconspicuous nucleolus. Due to thepresence of abundant intracytoplasmicglycogen, the periodic acid-Schiff (PAS)stain without diastase digestion is posi-tive, whereas PAS-diastase and Alcianblue stains are negative {160}. Mitosesare practically absent and there is nocytological atypia. Occasionally, the neo-plastic cells form intracystic papillaryprojections, usually without a fibrovascu-lar stalk. The central fibrous stellate coreis formed of hyalinized tissue with a fewclusters of tiny cysts.

ImmunohistochemistryThe epithelial nature of these neoplasmsis reflected in their immunoreactivity forepithelial membrane antigen and cytok-eratins 7, 8, 18, and 19. In addition, theneoplastic cells may focally expressCA19-9 and B72.3 {815, 1752}. They areuniformly negative for carcinoembryonic

Fig. 10.10 Microcystic serous cystadenoma. A CTscan showing a well demarcated, spongy lesion inthe head of the pancreas. B Cut surface showing atypical honeycomb appearance and a (para-)cen-tral stellate scar (arrowhead).

A

B

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antigen (CEA), trypsin, chromogranin A,synaptophysin, S-100 protein, desmin,vimentin, factor VIII-related antigen andactin {49, 119, 445, 689, 815, 1752,1781, 2151}.

UltrastructureElectron microscopy shows a single rowof uniform epithelial cells lining the cystsand resting on a basal lamina {49, 160,915}. The apical surfaces have poorlydeveloped or no microvilli. The cyto-plasm contains numerous glycogengranules but only a few mitochondria,short profiles of endoplasmic reticulum,lipid droplets, and multivesicular bodies.Golgi complexes are rarely identified.Zymogen granules and neurosecretorygranules are absent.

GeneticsLoss of heterozygosity at the von Hippel-Lindau (VHL) gene locus, mapped tochromosome 3p25, was found in 2/2serous microcystic adenomas associat-ed with VHL disease and in 7/10 spo-radic cases {2026}. In contrast to ductaladenocarcinomas, serous microcysticadenomas have wild-type KRAS andlack immunoreactivity for TP53 {815}.

PrognosisThe prognosis of patients with this neo-plasm is excellent, since there is only aminimal risk of malignant transformation{1159}.

Serous oligocystic adenoma

DefinitionA benign neoplasm composed of few,relatively large cysts, lined by uniformglycogen-rich cuboidal epithelial cells.

SynonymsThis tumour category includes macro-cystic serous cystadenoma {257, 1062},serous oligocystic and ill-demarcatedadenoma {445}, and some cystade-nomas observed in children {2057}.Whether these neoplasms form a homo-geneous group remains to be estab-lished.

EpidemiologySerous oligocystic adenomas are muchless common than serous microcysticadenomas {445, 1062}. There is no sexpredilection. Adults are usually 60 yearsand over (age range, 30-69 years; mean,65 years); the tumour has beendescribed in two male and two femaleinfants, aged between 2 and 16 months{1781}.

AetiologyThe aetiology of this neoplasm is notknown. In children, it has been suggest-ed that the lesions may be of malforma-tive origin and not true neoplasms sincein two cases there was a cytomegalo-virus infection in the adjacent pancreas {52, 273}.

LocalizationMost serous oligocystic adenomas arelocated in the head and body of the pan-creas {1781}. In the head, they mayobstruct the periampullary portion of thecommon bile duct.

Clinical featuresIn most cases reported in adult patients,the neoplasms caused symptoms thatled to their discovery and removal. Themost common symptom was upperabdominal discomfort or pain {1781}.Other symptoms included jaundice andsteatorrhoea. In infants, the tumours pre-sented as a palpable abdominal mass{52, 273}.

MacroscopyThese neoplasms typically appear as acystic mass with a diameter of 4-10 cm(mean, 6 cm) {1781}. On cut surface,

Fig. 10.13 Serous cystadenoma. A cystic neoplasmreplaces the head of the pancreas; a portion of duo-denum is on the right.

Fig. 10.11 Serous oligocystic adenoma. This CTscan shows a macrocystic neoplasm in the head ofthe pancreas.

Fig. 10.12 Serous microcystic cystadenoma. A The lesion is well demarcated from the adjacent pancreas. B Cysts of varying size. C The epithelium is cuboidal andfocally PAS-positive.

A B C

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233Serous cystic neoplasms

there are few (occasionally only one)macroscopically visible cysts filled withwatery clear or brown fluid. The cystsusually vary between 1 and 2 cm indiameter, but cysts as large as 8 cmhave been reported {1062}. The irregu-larly arranged cysts, sometimes separat-ed by broad septa, lie within a fibrousstroma that lacks a central stellate scar.The cysts and the supporting fibrous tis-sue may extend into the adjoining pan-creatic tissue so that the tumours arepoorly demarcated.

HistopathologySerous oligocystic adenoma has gener-ally the same histological features asserous microcystic adenoma. Occasion-ally, however, the lining epithelium maybe more cuboidal and less flattened, andthe nuclei are generally larger. The cyto-plasm is either clear, due to the presenceof glycogen, or eosinophilic. The stromalframework is well developed and oftenhyalinized. The tumour border is not welldefined and small cysts often extend intothe adjoining pancreatic tissue. Theimmunohistochemical and ultrastructuralfeatures are the same as for serousmicrocystic adenoma {445, 2057}.

PrognosisThere is no evidence of malignant poten-tial {445}.

Serous cystadenocarcinoma

DefinitionA malignant cystic epithelial neoplasmcomposed of glycogen-rich cells.

EpidemiologySo far, only eight cases have been report-ed {573, 815, 1781}. These patients were

between 63 and 72 years of age; therewere four women and four men. Threepatients were Caucasian and four werefrom Japan {8, 815, 1781}.

Clinical featuresClinical symptoms reported in the casesso far observed include bleeding fromgastric varices due to tumour invasion ofthe wall of the stomach and the splenicvein, a palpable upper abdominal mass,and jaundice. Ultrasonography and CTrevealed a hyperechoic mass. CEA andCA19-9 were normal or slightly increased.

MacroscopyThese neoplasms have a spongy appear-ance {573, 879, 2182}. Their reportedsize has varied between 2.5 and 12 cm.Liver and lymph node metastases havebeen reported {573, 815, 1781, 2182}.

Invasion of the spleen and metastasis tothe gastric wall were found in one case.

HistopathologyThe histological features in the primarytumour as well as in the metastases areremarkably similar to those of serousmicrocystic adenoma, although focalmild nuclear pleomorphism can be found{573, 2182}. One carcinoma reportedshowed neural invasion and aneuploidnuclear DNA content {879}, while othercases showed vascular and perivascularinvasion {1412} or involvement of alymph node and adipose tissue {8}.

PrognosisSerous cystadenocarcinomas are slowlygrowing neoplasms and palliative resec-tion may be helpful even in advancedstages {2182}.

Fig. 10.14 Serous cystadenoma. Characteristic cuboidal epithelium forms intracystic papillary structures inthis field.

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DefinitionCystic epithelial neoplasms occurringalmost exclusively in women, showing nocommunication with the pancreatic duc-tal system and composed of columnar,mucin-producing epithelium, supportedby ovarian-type stroma. According to thegrade of intraepithelial neoplasia (dys-plasia), tumours may be classified asadenoma, borderline (low-grade malig-nant) and non-invasive or invasive carci-noma.

ICD-O codesMucinous cystadenoma 8470/0Mucinous cystic neoplasm with moderate dysplasia 8470/1Mucinous cystadenocarcinoma

non-invasive 8470/2invasive 8470/3

EpidemiologyAlthough more than 500 cases havebeen reported in the literature {328,2198}, mucinous cystic neoplasm (MCN)is still considered a rare lesion, repre-senting approximately 2-5% of all exo-crine pancreatic tumours {1781, 1932}.Changes in diagnostic criteria over theyears and the high resectability ratecompared to that of ductal adenocarci-noma may have led to an overrepresen-tation of MCNs in histopathology series.The increasing number of these lesionsseen in recent years is most likely due toadvances in diagnostic techniques,allowing early and correct recognition ofMCN.In a recent study, in which MCNs weredefined by the lack of a communicationwith the pancreatic duct system and thepresence of an ovarian type stroma, alloccurred in women {2198}. It is likely thatmany of the cases reported in men in theearly literature were intraductal papillarymucinous neoplasms (IPMNs) {328,1932, 2198}. The mean age at diagnosis is 49 years(range, 20-82 years) {1781}. Patients withmucinous cystadenocarcinomas areabout 10 years older than patients withadenomatous or borderline tumours

(54 versus 44 years), suggesting an ade-noma - carcinoma sequence {2198}.MCTNs seem to occur in patients withdifferent ethnic background {1781}.

AetiologyPancreatic MCNs share many featureswith their counterparts in the liver andretroperitoneum, including their morphol-ogy and their almost exclusive occur-rence in women {328, 2139, 404, 2198}.The possible derivation of the stromalcomponent of MCNs from the ovarian pri-mordium is supported by morphology,tendency to undergo luteinization, pres-ence of hilar-like cells, and immunophe-notypic sex cord-stromal differentiation. Ithas been hypothesized that ectopicovarian stroma incorporated duringembryogenesis in the pancreas, alongthe biliary tree or in the retroperitoneummay release hormones and growth fac-tors causing nearby epithelium to prolif-erate and form cystic tumours {2198}.Since the left primordial gonad and thedorsal pancreatic anlage lie side by sideduring the fourth and fifth weeks of devel-opment, this hypothesis could explain

the predilection of MCN for the body-tailregion of the pancreas {1977}.

LocalizationThe overwhelming majority of casesoccur in the body-tail of the pancreas{328, 1932, 2148, 2198}. The head isonly rarely involved, with a predilectionfor mucinous cystadenocarcinomas{1932, 2198}.

G. Zamboni D.S. LongneckerG. Klöppel G. Adler R.H. Hruban

Mucinous cystic neoplasmsof the pancreas

Fig. 10.16 Mucinous cystic neoplasm in the tail ofthe pancreas. The thick wall shows focal calcifica-tion.

Fig. 10.15 Mucinous cystic neoplasm. The pancreatic duct, which does not communicate with the cystlumen, has been opened over the surface of the tumour (left, arrowheads). The thick wall and irregular lin-ing of the bisected neoplasm are shown on the right.

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235Mucinous cystic neoplasms

Clinical featuresSymptoms and signsThe clinical presentation depends on thesize of the tumour. Small tumours (< 3 cm) are usually found incidentally.Larger tumours may produce symptomsthat are usually due to compression of adjacent structures, and are oftenaccompanied by a palpable abdominalmass. An association with diabetes mel-litus is relatively frequent, whereas jaun-dice is uncommon {1781}.

Serum tumour markersAn increase in the peripheral blood serumtumour markers CEA, CA 19-9, or highcyst fluid levels of CEA, CA 19-9, TAG-72,CA-15-3 or MCA (mucin-like carcinoma-associated antigen) together with a lowamylase level is suggestive of MCN. Thehighest levels of these markers are seenin cystadenocarcinoma {1063, 1804}.

ImagingAbdominal X-ray may demonstrate nodu-lar calcifications in the tumour capsuleand compression or displacement of thestomach, duodenum or colon. US andCT reveal a sharply demarcated hypoe-choic or low density mass with one ormore large loculations {1461}. Featuressuggestive of malignant transformationinclude an irregular thickening of the cystwall and/or papillary excrescences pro-jecting into the cystic cavity {201, 2060}.Magnetic resonance imaging may havea complementary role. Endoscopic retro-grade cholangiography (RCP) shows adisplacement of the main pancreaticduct and the absence of communicationwith the cystic cavity, a very importantfinding for the differential diagnosis withIPMN.Fine needle aspiration cytology (FNAC)can be performed percutaneously withCT or US guidance, or intraoperatively{1019}.

Preoperative diagnosis of MCN is impor-tant, since other types of cystic neo-plasm may be treated differently.Furthermore, MCNs must be distin-guished from an inflammatory pseudo-cyst, because drainage may be appro-priate for patients with a pseudocyst, butis disastrous for patients with MCN, sinceapparently histologically benign muci-nous cystic tumours can recur afterdrainage as invasive cystadenocarcino-mas {328, 2194}. The best approach toobtain an exact preoperative diagnosis isthe combined evaluation of all availableclinical, serological, radiological, andbiopsy findings.

MacroscopyMCNs typically present as a round masswith a smooth surface and a fibrouspseudocapsule with variable thicknessand frequent calcifications. The size ofthe tumour ranges from 2-35 cm in great-est dimension, with an average sizebetween 6 and 10 cm. The cut surfacesdemonstrate a unilocular or multiloculartumour with cystic spaces ranging from afew millimetres to several centimeters indiameter, containing either thick mucin ora mixture of mucin and haemorrhagic-necrotic material. The internal surface ofunilocular tumours is usually smooth andglistening, whereas the multiloculartumours often show papillary projectionsand mural nodules. Malignant tumoursare likely to show papillary projectionsand/or mural nodules and multilocularity{2198}. As a rule, there is no communi-cation of the tumour with the pancreaticduct system, but exceptions have beenreported {2148}.

Tumour spread and stagingInvasive mucinous cystadenocarcinomafollows the same pathways of localspread as ductal adenocarcinoma. Thefirst metastases are typically found in theregional peripancreatic lymph nodes andthe liver {1781}. Staging follows the pro-tocol for ductal adenocarcinomas.

Histopathology MCNs show two distinct components: aninner epithelial layer and an outer dense-ly cellular ovarian-type stromal layer.Large locules can be extensively denud-ed and many sections are often neededto demonstrate the epithelial lining. Theepithelium may be flat or it may formpapillary or polypoid projections, pseu-

dostratifications and crypt-like invagina-tions. The columnar cells are character-ized by basally located nuclei and abun-dant intracellular mucin which is dia-stase-PAS and Alcian blue positive.Pseudopyloric, gastric foveolar, smalland large intestinal, and squamous dif-ferentiation can also be found. About halfof the tumours contain scattered argy-rophil and argentaffin endocrine cells atthe bases of the columnar cells {33, 36,328, 2151}.

Spectrum of differentiationThis ranges from histologically benignappearing columnar epithelium toseverely atypical epithelium. Accordingto the grade of intraepithelial neoplasia(dysplasia), tumours may be classifiedas adenoma, borderline (low-grademalignant) and non-invasive or invasivecarcinoma {947}.Mucinous cystadenomas show only aslight increase in the size of the basallylocated nuclei and the absence of mitosis.Mucinous cystic neoplasms of borderlinemalignant potential exhibit papillary pro-jections or crypt-like invaginations, cellu-lar pseudostratification with crowding ofslightly enlarged nuclei, and mitoses.Mucinous cystadenocarcinomas may beinvasive or non-invasive. They showchanges of high-grade intraepithelialneoplasia which are usually focal andmay be detected only after carefulsearch of multiple sections from differentregions. The epithelial cells, which oftenform papillae with irregular branchingand budding, show nuclear stratification,severe nuclear atypia and frequentmitoses.Invasive mucinous cystadenocarcinomais characterized by invasion of the malig-nant epithelium into the stroma. The inva-sive component usually resembles thecommon ductal adenocarcinoma. How-

Fig. 10.18 Mucinous cystic neoplasm presenting asmultiloculated cystic mass in the tail of the pan-creas.

Fig. 10.17 Well differentiated columnar epitheliumsupported by ovarian-like stroma.

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ever, mucinous cystadenocarcinomaswith invasive adenosquamous carcino-ma, osteoclast-like giant cell or chorio-carcinoma have been reported {328,1530, 1571, 2194}. Invasive foci may befocal and require careful search.

StromaThe ovarian-type stroma consists ofdensely packed spindle-shaped cellswith round or elongated nuclei andsparse cytoplasm. It frequently displaysa variable degree of luteinization, char-acterized by the presence of single orclusters of epithelioid cells with round tooval nuclei and abundant clear oreosinophilic cytoplasm. Occasionally,these cells, resembling ovarian hilarcells, can be found associated with (orpresent in) nerve trunks. Stromal luteini-zation is found in decreasing order of fre-quency from adenomatous to carcinoma-tous cases {2194}. The stroma of largeMCNs may become fibrotic and hypocel-lular. Rare MCNs show mural noduleswith a sarcomatous stroma or an associ-ated sarcoma {1932, 2088, 2198}.

Immunohistochemistry The epithelial component is immunoreac-tive with epithelial markers includingEMA, CEA, cytokeratins 7, 8, 18 and 19{2151}, and it may show gastroen-teropancreatic differentiation, as is alsoobserved in ovarian and retroperitonealMCN {1714, 1910}. With increasingdegrees of epithelial atypia the characterof mucin production changes from sul-phated to sialated or neutral mucin{1932}. The neoplastic cells express gas-

tric type mucin marker M1 and PGII, theintestinal mucin markers CAR-5 andM3SI, and the pancreatic type mucinmarker DUPAN-2 and CA19-9 {119,1714, 2151, 2190}. Furthermore, pancre-atic, hepatobiliary, and retroperitonealMCNs share the same types of intraep-ithelial endocrine cells {613, 1911, 1910}.p-53 nuclear positivity in more than 10%of neoplastic cells, found in 20% of MCN,strongly correlates with mucinous cys-tadenocarcinoma {2198}.The stromal component expressesvimentin, alpha smooth muscle actin,desmin and, in a high proportion, prog-esterone and estrogen receptors {2198}.The luteinized cells are labeled with anti-bodies against tyrosine hydroxylase, cal-retinin, which have been shown to recog-nize testicular Leydig cells and hilarovarian cells, and the sex cord-stromaldifferentiation marker inhibin {2198,2206}.

UltrastructureElectron microscopy of tumours with onlymild to moderate dysplasia demon-strates columnar epithelial cells restingon a thin basement membrane. The cellsmay have well-developed microvilli andmucin granules {33}.

GeneticsActivating point mutations in codon 12 ofKRAS were found in invasive mucinouscystic neoplasms (MCNs) {117} andmucinous cystic neoplasms associatedwith osteoclast-like giant cells {1485}.Mutations of KRAS and allelic losses of6q, 9p, 8p have been reported in MCNswith sarcomatous stroma {1998}. Prognosis and predictive factorsThe prognosis of MCN, regardless of thedegree of cellular atypia, is excellent ifthe tumour is completely removed {328,410, 2060, 2198}. The prognosis of inva-sive mucinous cystadenocarcinomadepends on the extent of tumour inva-sion. Tumour recurrence and poor out-come correlate with invasion of thetumour wall and peritumoural tissues{2198}. Patients older than 50 yearsappear to have a lower survival rate{2198}. Other variables such as site,tumour size, macroscopic appearance,grade of differentiation, luteinization ofthe stroma and p53 positivity have noprognostic significance.Aneuploidy is a rare event in MCNs, islargely restricted to mucinous cystade-nocarcinomas and carries a worse prog-nosis {1792, 1932, 512}.

Fig. 10.20 Mucinous cystadenocarcinoma. Thethick wall of this cystic neoplasm is invaded bymucinous carcinoma at upper left.

Fig. 10.19 Mucinous cystadenocarcinoma. The neoplasm exhibits well differentiated and poorly differenti-ated mucinoius epithelium.

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237Intraductal papillary-mucinous neoplasms

DefinitionAn intraductal papillary mucin-producingneoplasm, arises in the main pancreaticduct or its major branches. The papillaryepithelium component, and the degreeof mucin secretion, cystic duct dilatation,and invasiveness are variable. Intra-ductal papillary-mucin neoplasms aredivided into benign, borderline, andmalignant non-invasive or invasivelesions.

ICD-O codesIntraductal papillary-mucinous adenoma

8453/0Intraductal papillary-mucinous neoplasmwith moderate dysplasia 8453/1Intraductal papillary-mucinous carcinoma

non-invasive 8453/2invasive 8453/3

Synonyms and historical annotationPapillary pancreatic neoplasms havebeen recognized for many years {247,1532}, but the distinction between muci-nous cystic neoplasms and intraductalpapillary neoplasms was not made untilthe last two decades {947, 1781, 65,1404}. Interest in IPMNs was first stimu-lated when they were recognized clini-cally {1281}, and pathological descrip-tions quickly followed {2164, 1093}. Theincidence appears to have risen sincethe first reports, but this may reflect thecombined effects of new diagnostictechniques, and progress in recognitionand classification of IPMNs {1138, 918}.It is likely that many IPMNs were classi-fied among the mucinous cystic neo-plasms as recently as a decade ago.

EpidemiologyThe incidence is low and not preciselyknown because IPMNs are not accuratelyidentified in large population-based reg-istries. Nomenclature and classificationhave been highly variable until recently,and are not yet standardized worldwide.IPMNs have been estimated to amount to1-3% of exocrine pancreatic neoplasms,with an incidence rate well below 1 per100,000 per year {1280, 1095}.

IPMNs are found in a broad age range(30-94) with a median age of diagnosis inthe 6-7th decade {1443, 2148, 556}.They occur more frequently in males thanin females {1138, 2148}. IPMNs were firstreported from France and Japan, butsubsequent reports have come from allparts of the world. Two studies providesome evidence that the incidence maybe higher among Asians than amongwhites, but issues of consistency of clas-sification require that this be further eval-uated {1095, 941}.

AetiologyThe low incidence and imprecise identifi-cation of IPMN in large databases hashindered recognition of aetiological fac-tors. In one series, most patients withIPMNs were cigarette smokers {550}.There is no consistent association withother types of pancreatic neoplasm{2198}.

LocalizationThe majority of these neoplasms occur inthe main pancreatic duct and its branch-es in the head of the pancreas {1781,330, 97}. A single cystic mass or seg-mental involvement of the duct is usual,but diffuse involvement is also described{1093, 1751, 1953}. Multicentric origin issuspected because of recurrence inpancreatic remnants following surgicalremoval of IPMNs {1088}. IPMNs mayextend to the ampulla of Vater, common-ly in association with involvement of theduct of Wirsung or the common bile duct{1781}.

Clinical featuresClinical presentation includes epigastricpain, pancreatitis, weight loss, diabetes,and jaundice {2169, 1953, 942}; somepatients have no symptoms. Some casesare detected because of dilatation of thepancreatic duct seen incidentally inimaging studies. Serum amylase andlipase are commonly elevated.Endoscopic ultrasound, ERCP, andendoscopic examination of the pancreat-ic duct {1596} may all contribute to pre-

operative diagnosis. Endoscopic biopsyor cytology may provide histological con-firmation, but definitive diagnosisrequires surgical removal and extensivehistological sampling. Serum markerssuch as CEA and CA19-9 are too insen-sitive to be of value {2148, 1953}.

MacroscopyDepending on the degree of ductaldilatation, IPMNs vary in size from 1 to 8cm in maximum dimension {17}. They arecystic and may appear multiloculated ifbranch ducts are involved. The mucinfound in IPMN is viscous or sticky andcan dilate parts of the duct that are linedby normal appearing epithelium. The lin-ing of cystic spaces may be smooth andglistening, granular, or velvet-like, the lat-ter reflecting papillary growth. When

D.S. Longnecker R.H. HrubanG. Adler G. KlöppelIntraductal papillary-mucinous

neoplasms of the pancreas

Fig. 10.21 Intraductal papillary-mucinous neoplasm.A Large neoplasm in the head of the pancreas con-taining multiple cystic spaces. B The lesion illus-trated in A sectioned to demonstrate the dilated,mucin-filled main pancreatic duct (arrowheads).

A

B

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papillary growths are large, the dilatedducts may show localized excrescencesor be filled with soft papillary masses oftissue.The pancreatic parenchyma surroundingand retrograde to the tumour is oftenpale and firm, reflecting changes ofchronic obstructive pancreatitis. Whenthere is invasion, gelatinous areas maybe identified in fibrotic tissue.

Tumour spread and stagingAdenomas, borderline tumours and non-invasive carcinomas may extend intra-ductally into adjacent portions of the ductsystem, and evidence of such extensionis often encountered adjacent to IPMNs.Recurrence following surgical resectionhas been reported in patients that hadIPMNs extending into the margin of

resection {1953}. Invasive neoplasms arestaged as ductal adenocarcinomas.

HistopathologyIPMN tumour cells are usually tall colum-nar mucin-containing epithelial cells thatline dilated ducts or cystic spaces aris-ing from dilated branch ducts. Theepithelium typically forms papillary orpseudopapillary structures, but portionsof the neoplasm may be lined by non-papillary epithelium or be denuded ofepithelium. The amount of mucin produc-tion varies widely, as does the degree ofduct dilatation {97, 872}. Goblet orPaneth cells may be present as a mani-festation of intestinal metaplasia in theneoplastic epithelium, and neuroen-docrine cells have also been demon-strated.The recently described intraductal onco-cytic papillary neoplasm probably repre-sents a rare related phenotype that issimilar macroscopically {1244, 1860}.Oncocytic IPMNs are composed of strat-ified oncocytic cells with pale pink cyto-plasmic granules that are much finerthan those seen in Paneth cells. Gobletcells may be interspersed among theoncocytic cells. A characteristic featureof the oncocytic papillary neoplasms isthe formation of ‘intraepithelial lumina’,which are spaces in the epithelium aboutone quarter the size of the cells.

Histochemistry and immunohistochemistryA variety of abnormalities have beendemonstrated in IPMNs using mucin andimmunohistochemical stains. Most IPMNs express epithelial mem-brane antigen (EMA) as well as severalcytokeratins {1917}. A variety ofendocrine cell types occur in mosttumours but account for fewer than 5 percent of the tumour cells {1676}. A change in type of mucin has been sug-gested as a marker of progression sincenormal duct cells characteristicallysecrete sulfated mucin, intraductal papil-lary-mucinous adenomas characteristi-cally secrete neutral mucin, and dysplas-tic epithelium secretes predominantlysialomucin {1138, 1916, 1186}. Nearly allIPMNs express MUC2 {2179}. Overexpression of c-erbB-2 proteinoccurs in a high fraction of IPMNs {1939,1675, 1877, 380}. A study of cell proliferation, as shown byPCNA and Ki67 labelling indices,demonstrated a progressive increase incell proliferation from normal duct epithe-lium, to adenomas, to borderlinetumours, to carcinomas {1917}. Thelabeling index in IPM carcinomas waslower than in ductal adenocarcinomas.Although immunostaining of p53 proteinwas detected in a lower fraction of IPMN(31%) than is usually seen in solid ductaladenocarcinomas, it was found only inborderline and malignant IPMN andtherefore may be a marker of progression{1939}.Failure of IPMN to elicit the production ofa collagenase that mediates invasionwas reported {2193}.

Fig. 10.22 Intraductal papillary mucinous neoplasmin the main pancreatic duct (arrowhead).

Fig. 10.23 Intraductal papillary mucinous neoplasms with (A) columnar epithelium and (B) oncocytic epithe-lium.

Fig. 10.24 Intraductal papillary-mucinous neoplasmwithin the dilated main pancreatic duct and branchducts.

A B

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239Intraductal papillary-mucinous neoplasms

Classification and grading of IPMNsIPMNs have been the source of greatconfusion that is reflected in a diversenomenclature found in case and seriesreports and in standard references{1781}. Because of the variability within atumour, it is important to sample IPMNswell, giving special emphasis to papillaryareas because this is where the highestdegree of intraepithelial neoplasia (dys-plasia) is likely to occur, and to scleroticareas that may reflect invasion. IPMNs are classified as benign, border-line, or malignant on the basis of thegreatest degree of dysplasia present. Inaccordance with the previous WHO clas-sification, lesions are specifically desig-nated as intraductal papillary-mucinousadenoma, borderline intraductal papil-lary-mucinous neoplasm, and intraductalpapillary-mucinous carcinoma, with orwithout invasion {947, 1781}. A slightly different histopathological clas-sification has been proposed by theJapan Pancreas Society (JPS) {65}, intra-ductal tumours are designated as intra-ductal papillary adenoma or adenocarci-noma. The degree of cellular atypia inadenomas is designated as slight, mod-erate, or severe. The JPS category ofadenoma with severe atypia corre-sponds to the WHO borderline lesion,although some authors also utilize a bor-derline category {2148}

Intraductal papillary-mucinous adenomaThe epithelium is comprised of tallcolumnar mucin-containing cells thatshow slight or no dysplasia, i.e. theepithelium maintains a high degree ofdifferentiation in adenomas.

Borderline intraductal papillary-mucinousneoplasmIPMNs with moderate dysplasia areplaced in the borderline category. Theepithelium shows no more than moderateloss of polarity, nuclear crowding,nuclear enlargement, pseudostratifica-tion, and nuclear hyperchromatism.Papillary areas maintain identifiable stro-mal cores, but pseudopapillary struc-tures may be present.

Intraductal papillary-mucinous carcinomaIPMNs with severe dysplastic epithelialchange are designated as carcinomaeven in the absence of invasion.Carcinomas are papillary or micropapil-lary. Cribriform growth and budding of

small clusters of epithelial cells into thelumen support the diagnosis of carcino-ma. Severe dysplasia is manifest cyto-logically as loss of polarity, loss of differ-entiated cytoplasmic features includingdiminished mucin content, cellular andnuclear pleomorphism, nuclear enlarge-ment, and the presence of mitoses(especially if suprabasal or luminal inlocation). Severely dysplastic cells maylack mucin. Non-invasive lesions aretermed non-invasive intraductal papil-lary-mucinous carcinoma. When inva-sive, an IPMN may be called a papillary-mucinous carcinoma since it is no longeronly intraductal. When IPMNs becomeinvasive, the invasive component mayassume the appearance of a tubularductal adenocarcinoma or a mucinousnoncystic carcinoma {17}. If the invasivecomponent is dominant, and is a ductal

or mucinous noncystic carcinoma, thenthat diagnosis may be used, descriptive-ly noting the association with an IPMNcomponent.

Differential diagnosisHistorically, IPMNs and mucinous cysticneoplasms (MCNs) have been confusedbecause they are both cystic and have asimilar epithelial component. However,IPMNs and MCNs are distinct entitiesand can be separated easily, becauseMCNs typically occur in women with amedian age in the fifth decade, almostalways are located in the tail or body ofthe pancreas, typically exhibit a thickwall with a cellular ‘ovarian’ stroma, andtypically fail to communicate with thepancreatic duct system.

Precursor lesionsThe criteria for classifying pancreaticintraepithelial neoplasia (PanIN) lesions(including papillary hyperplasia, seechapter on ductal adenocarcinoma ofthe pancreas) in IPMNs are not wellestablished {1144, 1744}, and need to bedefined. PanIN lesions characteristicallyoccur in intralobular ducts, are notdetected macroscopically, and are clini-cally silent {17}. It seems likely that theearliest stage of development of theIPMN would involve the progression froma flat area of mucous metaplasia to apapillary lesion in a main or branch pan-creatic duct as suggested by Nagai et al.

Fig. 10.25 Intraductal papillary-mucinous carcinoma. Intraductal papillary neoplasm (left), invasive mucinsecreting carcinoma (right).

Fig. 10.26 Intraductal papillary-mucinous carcino-ma. This tumour shows moderately differentiated(left) and well differentiated (right) areas.

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{1306}. Thus, it will be difficult to recog-nize the initial stage of an intraductalpapillary-mucinous adenoma unless adistinctive molecular marker is identified.

Genetic susceptibilityExcessive rates of colonic and gastricepithelial neoplasms were reported in agroup of 42 patients with IPMNs {106}.This suggests the possibility of a predis-posing genetic susceptibility, but no spe-cific hereditary syndrome was identified.

GeneticsActivating point mutations in codon 12 ofthe KRAS gene have been reported in40-60% of intraductal papillary mucinousneoplasms {1939, 544}. Fujii et al. exam-ined a series of IPMNs using polymorphicmicrosatellite markers and found allelicloss at 9p in 62% of the cases and at 17pand at 18q in ~40% {544}. These alleliclosses include the loci of the p16, TP53,and DPC4 tumour-suppressor genes. Inaddition to immunohistochemical evi-

dence of p53 abnormality in IPMN {544},mutations have been demonstrated intwo adenomas {876}. Overexpression ofanti-apoptotic genes in IPMN is reported{1247}.Mutations of KRAS and TP53 genes havebeen detected in DNA from pancreaticjuice of patients with IPMN {875}.

Prognosis and predictive factorsThe overall 5-year survival rate for a com-posite series was 83% {2148}. The prog-nosis is excellent for adenomas and bor-derline tumours with 3 and 5-year sur-vivals approaching 100%. The survivalrates are high for non-invasive carcino-mas, and survival rates for patients withinvasive IPMNs may also be higher thanfor patients with typical ductal adenocar-cinomas {2148, 97, 2169}. The histologi-cal classification, with major emphasison the presence or absence of invasion,and stage remain the best predictors forsurvival.As the distinction between IPMNs andMCNs has been refined, some authorsreport that MCNs are more often malig-nant than IPMNs and that the latter havea better prognosis following treatment{97}, but this was not confirmed in otherseries {1953, 551}. Expression of MUC2and MUC5AC mucins are associatedwith a good prognosis relative to ductaladenocarcinomas that do not expressthese mucins {2179, 2178}.

Differentiation markersAlcian blue stain Adenomas contain neutral mucin, {1138, 1916}

carcinomas contain sialomucinMUC1 Negative>>positive (2179}MUC2 Positive>>negative {2179}Endocrine markers < 5% of cells positive in most IPMN {1676}Epithelial membrane antigen Positive {1917}Cytokeratins 7, 8, 18, 19 Positive {1917}CEA Positive {1939}CA-19-9 Positive {1939}B72.3 Positive {1939}DUPAN-2 Seen in a minority {1939}

Oncogene productsc-erbB-2 13/17 IPMN positive, including all with {1675}

moderate or severe dysplasia {1939}p27 p27 staining exceeds cyclin E {556}

Tumour suppressor gene productsTP53 Often positive in borderline tumours and {1939}

carcinomasProliferation markers

PCNA and Ki67 Labeling index increases with progression {1917}from adenoma to carcinoma

Antibody or epitope Comments on staining in IPMN Reference

Table 10.05Summary of mucin histochemistry and immunostaining of IPMN.

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241Acinar cell carcinoma

Acinar cell carcinoma D.S. KlimstraD. Longnecker

DefinitionA carcinoma occurring mainly in adults,composed of relatively uniform neoplas-tic cells that are arranged in solid andacinar patterns and produce pancreaticenzymes.

ICD-O codesAcinar cell carcinoma 8550/3Acinar cell cystadenocarcinoma 8551/3Mixed acinar-endocrine carcinoma 8154/3

EpidemiologyAcinar cell carcinomas represent 1-2% ofall exocrine pancreatic neoplasms inadults {739, 936}. Most occur in lateadulthood, with a mean age of 62 years{825, 979, 2073}. The tumour is rare inadults under the age of 40. Pediatriccases do occur, usually manifesting inpatients 8 to 15 years of age {979, 1282}.Males are affected more frequently thanfemales, with an M:F ratio of 2:1 {739,936}.

AetiologyThe aetiology is unknown.

LocalizationAcinar cell carcinomas may arise in anyportion of the pancreas but are some-what more common in the head.

Clinical featuresSymptoms and signsMost acinar cell carcinomas present clin-ically with relatively non-specific symp-toms including abdominal pain, weightloss, nausea, or diarrhoea {739, 936,979, 2073}. Because they generally pushrather than infiltrate into adjacent struc-tures, biliary obstruction and jaundiceare infrequent presenting complaints. A well-described syndrome occurring in10-15% of patients is the lipase hyper-secretion syndrome {1781, 213, 936,975}. It is most commonly encountered inpatients with hepatic metastases, and ischaracterized by excessive secretion oflipase into the serum, with clinical symp-toms including subcutaneous fat necro-sis and polyarthralgia. Peripheral blood

eosinophilia may also be noted. In somepatients, the lipase hypersecretion syn-drome is the first presenting sign of thetumour, while in others it develops follow-ing tumour recurrence. Successful surgi-cal removal of the neoplasm may result inthe normalization of the serum lipaselevels and resolution of the symptoms.

Laboratory analysesOther than an elevation of serum lipaselevels associated with the lipase hyper-secretion syndrome, there are no specif-ic laboratory abnormalities in patientswith acinar cell carcinoma. A few casesshow increased serum alpha-fetoprotein{819, 1426, 1369, 1747}.

Imaging Acinar cell carcinomas are generallybulky with a mean size of 11 cm {979}.On abdominal CT scans, they are cir-cumscribed and have a similar density tothe surrounding pancreas. Because oftheir larger size and relatively sharp cir-cumscription, acinar cell carcinomas cangenerally be distinguished from ductaladenocarcinomas radiographically.

Fine needle aspiration cytologyThere is usually a high cellular yield fromfine needle aspiration {1446, 1978, 2015}.The cytological appearances of acinarcell carcinomas closely mimic of pancre-atic endocrine neoplasms, although thelatter are more likely to exhibit a plasma-cytoid appearance to the cells and aspeckled chromatin pattern. Immuno-histochemistry may be used on cytologi-cal specimens to confirm the diagnosis ofacinar cell carcinoma {1446, 1978}.

MacroscopyAcinar cell carcinomas are generally cir-cumscribed and may be multinodular{739, 936}. Individual nodules are softand vary from yellow to brown. Areas ofnecrosis and cystic degeneration maybe present. Occasionally, the neoplasmis found attached to the pancreatic sur-face. Extension into adjacent structures,such as duodenum, spleen, or major

vessels may occur. Multicystic examplesof acinar cell carcinoma have beenreported as acinar cell cystadenocarci-noma {229, 739, 1815}.

Tumour spread and stagingMetastases most commonly affectregional lymph nodes and the liver,although distant spread to other organsoccurs occasionally. Acinar cell carcino-mas are staged using the same protocolas ductal adenocarcinomas.

HistopathologyLarge nodules of cells are separated byhypocellular fibrous bands. The desmo-plastic stroma characteristic of ductaladenocarcinomas is generally absent.Tumour necrosis may occur and is gen-erally infarct-like in appearance. Withinthe tumour cell islands, there is an abun-dant fine microvasculature. Several architectural patterns have beendescribed. The most characteristic is theacinar pattern, with neoplastic cellsarranged in small glandular units; thereare numerous small lumina within eachisland of cells giving a cribriform appear-ance. In some instances, the lumina aremore dilated, resulting in a glandular pat-tern, although separate glandular struc-tures surrounded by stroma are usuallynot encountered. A number of the micro-

Fig. 10.27 Acinar cell carcinoma. The hypodenselobulated tumour occupies the tail of the pancreas.

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glandular tumours previously reported as‘microadenocarcinoma’ were morerecently shown to have been acinar cellcarcinomas (see chapter on miscella-neous carcinomas). The second mostcommon pattern in acinar cell carcino-mas is the solid pattern: solid nests ofcells lacking luminal formations areseparated by small vessels. Within thesenests, cellular polarization is generally notevident, but there may be an accentua-tion of polarization at the interface withthe vessels, resulting in basal nuclearlocalization in these regions and a pal-isading of nuclei along the microvascula-ture. In rare instances, a trabeculararrangement of tumour cells may bepresent, with exceptional cases alsoshowing a gyriform appearance {936}. The neoplastic cells contain minimal tomoderate amounts of cytoplasm thatmay be more abundant in cells lininglumina. The cytoplasm varies fromamphophilic to eosinophilic and is char-acteristically granular, reflecting the pres-ence of zymogen granules. In manyinstances, however, only minimal cyto-plasmic granularity may be detectable.The nuclei are generally round to ovaland relatively uniform, with markednuclear pleomorphism being exception-al. A single, prominent, central nucleolusis a characteristic finding but not invari-ably present. The mitotic rate is variable(mean 14 per 10 high power fields, range0 to > 50 per 10 high power fields).Zymogen granules are weakly positivewith PAS staining, and resistant to dia-stase. Mucin production is generally notdetectable with mucicarmine or Alcianblue stains and, if present, is limited tothe luminal membrane in acinar or glan-dular formations. The histochemical stainfor butyrate esterase can be used toidentify active lipase within the tumourcells {936, 938}. Due to the scarcity ofzymogen granules in many examples ofacinar cell carcinoma, histochemicalstains are relatively insensitive for docu-menting acinar differentiation, and veryfocal staining may be difficult to interpretwith confidence.

Immunohistochemistry Immunohistochemical identification ofpancreatic enzyme production is helpfulin confirming the diagnosis of acinar cellcarcinoma. Antibodies against trypsin,chymotrypsin, lipase, and elastase haveall been used {739, 810, 936, 1282}. Both

trypsin and chymotrypsin are detectablein over 95% of cases; lipase is less com-monly identified (approximately 70% ofcases) {936}. Pancreatic stone protein isalso commonly expressed {739}. In solidareas, immunohistochemical staining forenzymes may show diffuse cytoplasmicpositivity, whereas the reaction product isrestricted to the apical cytoplasm in aci-nar areas. Immunohistochemical markers of endo-crine and ductal differentiation may alsobe detected in acinar cell carcinomas,generally in a minor cell population {739,936}. Scattered individual cells stain forchromogranin or synaptophysin arefound in over one third of lesions. Overhalf exhibit focal CEA and B72.3 expres-sion {739, 936}. Uncommonly, there isimmunohistochemical positivity for alpha-fetoprotein, generally in cases associat-ed with elevations in serum alpha-feto-protein {819}.

UltrastructureElectron microscopy provides further evi-dence of enzyme production {675, 408,936, 1978}. Exocrine secretory featuresare consistently found, with abundantrough endoplasmic reticulum arranged inparallel arrays and relatively abundant

mitochondria. Cellular polarization is gen-erally evident, with basal basement mem-branes and apical lumina. Adjacent cellsare joined by tight junctions. Although thedistribution varies from cell to cell, mostacinar cell carcinomas exhibit electrondense zymogen granules. In polarizedcells, they are located in the apical cyto-plasm, and the secretory contents maybe seen within the luminal spaces wheregranules have fused with the apical membrane. The size range of zymogengranules in acinar cell carcinomas (125-1000 nm) is somewhat greater than thatfound in non-neoplastic acinar cells (250-1000 nm). In addition to typical zymogengranules, a second granule type, theirregular fibrillary granule, is detectedultrastructurally in many cases {302, 936,938, 1477}. It has been suggested thatirregular fibrillary granules may representa recapitulation of the fetal zymogengranules, although attempts to documentthe presence of pancreatic enzymeswithin them by immunohistochemistryhave been unconvincing {936, 938,1032}.

Acinar cell carcinoma variantsAcinar cell cystadenocarcinomaAcinar cell cystadenocarcinomas arerare, grossly cystic neoplasms withcytoarchitectural features of acinar cellcarcinomas {229, 825, 739, 1815}.

Mixed acinar-endocrine carcinomaRare neoplasms have shown a substan-tial (greater than 25%) proportion of morethan one cell type. These neoplasmshave been designated ‘mixed carcino-mas’, and, depending upon the celltypes identified, as ‘mixed acinar-endocrine carcinoma’, ‘mixed acinar-ductal carcinoma’, or ‘mixed acinar-endocrine-ductal carcinoma’ {997, 1369,2015}. Of these, the best characterized isthe mixed acinar-endocrine carcinoma{997}. In many mixed acinar-endocrinecarcinomas, the evidence for divergentdifferentiation is only provided byimmunohistochemical staining. Althoughdifferent regions of the tumours may sug-gest acinar or endocrine differentiationmorphologically, many areas have inter-mediate features, and immunohisto-chemistry generally shows a mixture ofcells expressing acinar or endocrinemarkers (or both). In exceptional cases,however, there is also morphological evi-dence of multiple lines of differentiation,

Fig. 10.28 An acinar cell carcinoma (AC) lies nearthe spleen (SP). The tumour’s cut surface is lobulat-ed.

Fig. 10.29 Acinar cell carcinoma showing well dif-ferentiated acinar structures.

SPAC

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243Acinar cell carcinoma

with some regions exhibiting obvious aci-nar features and other areas endocrinefeatures. Most reported acinar-endocrinecarcinomas have been composed pre-dominantly of acinar elements based onthe proportion of cells staining immuno-histochemically {997}. There are insuffi-cient cases recorded to suggest that thebiological behaviour of mixed acinar-endocrine carcinomas differs from that ofpure acinar cell carcinomas.

Precursor lesionsNo documented precursor lesions foracinar cell carcinomas have beendefined. Initial suggestions that so-calledatypical acinar cell nodules may repre-sent preneoplastic lesions of acinar cellshave not been substantiated by laterstudies {1094}. Atypical acinar cell nod-ules occur either because of dilatation ofthe rough endoplasmic reticulum (result-ing in reduced basophilia of the basal

cytoplasm) or depletion of zymogengranules (resulting in reduced eosino-philia of the apical cytoplasm and anincrease in nuclear:cytoplasmic ratio);these lesions are relatively common inci-dental findings in resected pancreases.

GeneticsIn contrast to ductal adenocarcinomas,acinar cell carcinomas very rarely show

KRAS mutations and TP53 immunoreac-tivity {739, 1485, 1920, 1921}.

Prognosis and predictive factorsThese neoplasms are aggressive, with amedian survival of 18 months and a5-year survival rate of less than 10%{739, 936}. Approximately 50% ofpatients have metastases at the time ofdiagnosis, and an additional 25% devel-op metastatic disease following surgicalresection of the primary tumour {936}. The most important prognostic factor istumour stage, with patients lackinglymph node or distant metastases surviv-ing longer {936}. Patients with the lipasehypersecretion syndrome were shown tohave a particularly short survival, be-cause most of these patients had wide-spread metastatic disease. Despite pooroverall survival rates, there are anecdot-al reports of survival for several years inthe presence of metastatic disease, andresponses to chemotherapy have beennoted {936}. Thus, the prognosis of aci-nar cell carcinoma may be somewhatless poor than that of ductal adenocarci-noma.No specific grading system for acinarcell carcinomas has been proposed. Noassociation between the extent of acinusformation and prognosis has beenobserved.There is an insufficient number of pedi-atric acinar cell carcinomas to allow anaccurate assessment of the biologicalbehaviour in children. Available datasuggest that acinar cell carcinomasoccurring under the age of 20 may beless aggressive than their adult counter-parts 936, 1446}.

Fig. 10.30 Acinar cell carcinoma. Solid pattern with uniform round nuclei.

Fig. 10.31 Acinar cell carcinoma showingimmunoreactivity for chromogranin.

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Pancreatoblastoma D.S. KlimstraD. Longnecker

DefinitionA malignant epithelial tumour, generallyaffecting young children, composed ofwell-defined solid nests of cells with aci-nar formations and squamoid corpus-cles, separated by stromal bands. Acinardifferentiation prevails, often associatedwith lesser degrees of endocrine or duc-tal differentiation.

ICD-O code 8971/3

EpidemiologyIncidencePancreatoblastoma is an exceedinglyrare tumour, less than 75 cases havingbeen reported {782, 939, 2117}.However, it is among the most frequentpancreatic tumours in childhood, proba-bly accounting for 30-50% of pancreaticneoplasms occurring in young children{631}.

Age and sex distributionThe majority of pancreatoblastomasoccur in children, most being under theage of 10. The median age of pediatricpatients is approximately 4 years {742,939}, and only a few cases have beendescribed in the second decade of life{782}. A number of congenital exampleshave also been documented {939}.Rarely, tumours histologically indistin-guishable from pancreatoblastomasoccur in adult patients ranging between19 and 56 years of age {939, 1053,1452}. There is a slight male predomi-nance, with an M:F ratio of 1.3:1 {939}.

AetiologyThe aetiology is unknown.

LocalizationThe head of the gland is affected inabout 50% of cases, the remainderbeing equally divided between the bodyand the tail.

Clinical featuresThe presenting features of pancreato-blastoma are generally non-specific.Especially in the pediatric age group,

many patients present with an incidental-ly detected abdominal mass {782, 939}.Related symptoms include pain, weightloss, and diarrhoea. The paraneoplasticsyndromes associated with acinar cellcarcinoma (lipase hypersecretion syn-drome) and pancreatic endocrine neo-plasms have not been described, butone patient developed Cushing syn-drome {1478}. Radiologically, pancreatoblastomas arelarge, well-defined, lobulated tumourswhich may show calcifications on CTscan {1833, 2027, 2117}.There is no consistent elevation of serumtumour markers, but some cases haveexhibited increased alpha-fetoproteinlevels {802, 939}.

MacroscopyThe size of pancreatoblastomas variesfrom 1.5-20 cm. Most tumours are soli-tary, solid neoplasms composed of well-defined lobules of soft, fleshy tissue sep-arated by fibrous bands. Areas of necro-sis may be prominent. Uncommonly the

tumours are grossly cystic, a phenome-non reported in all cases associated withthe Beckwith-Wiedeman syndrome {432}.

HistopathologyThe epithelial elements of pancreato-blastomas are highly cellular andarranged in well-defined islands separat-ed by stromal bands, producing a ‘geo-graphic’ low power appearance. Solid,hypercellular areas composed of nestsof polygonal cells alternate with regionsshowing more obvious acinar differentia-tion, with polarized cells surroundingsmall luminal spaces. In rare tumours,larger glandular spaces lined by mucin-containing cells may be seen {939}.Nuclear atypia is generally minimal. Squamoid corpuscles. One of the mostcharacteristic features of pancreatoblas-toma is the ‘squamoid corpuscle’. Theseenigmatic structures vary from largeislands of plump, epithelioid cells towhorled nests of spindled cells to franklykeratinizing squamous islands. Thenuclei of the squamoid corpuscles arelarger and more oval than those of thesurrounding cells; nuclear clearing dueto the accumulation of biotin may beseen {1895}. The frequency and compo-sition of the squamoid corpuscles variesin different regions of the tumour andbetween different cases.Stroma. Especially in pediatric cases, thestroma of pancreatoblastomas is oftenhypercellular, in some instances achiev-ing a neoplastic appearance. Rarely, thepresence of heterologous stromal ele-ments, including neoplastic bone andcartilage, has been reported {127, 939}.

Histochemistry and immunohistochemistryOver 90% of pancreatoblastomas exhibitevidence of acinar differentiation in theform of PAS-positive, diastase resistantcytoplasmic granules as well as immuno-histochemical staining for pancreaticenzymes, including trypsin, chymo-trypsin, and lipase {939, 1282, 1400}. Thestaining may be focal, often limited to theapical cytoplasm in areas of the tumourwith acinar formations. At least focal

Fig. 10.32 Pancreatoblastoma. A CT image showinga large tumour (PB) in the head of the pancreas,with hypodense areas. B The cut surface of theneoplasm demonstrates a lobulated structure.

PB

PB

A

B

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245Pancreatoblastoma

immunoreactivity for markers of endocrinedifferentiation (chromogranin or synapto-physin) is found in over two-thirds ofcases, and expression of markers of duc-tal differentiation such as CEA, DUPAN-2,or B72.3 is found in more than half ofcases {939}. In most instances, the pro-portion of cells expressing acinar markersoutnumbers the proportion expressingendocrine or ductal markers. In casesassociated with elevations in the serumlevels of alpha-fetoprotein, immunohisto-chemical positivity for AFP has beendetectable {802, 939}. Immunohistochemical evaluation of thesquamoid corpuscles has failed to definea reproducible line of differentiation forthis component {939}.

Relationship to acinar cell carcinomaBoth pancreatoblastomas and acinar cellcarcinomas consistently exhibit acinardifferentiation and may exhibit lesserdegrees of endocrine and ductal differ-entiation. {936, 939}. Histologically, aci-nar formations are characteristic of pan-creatoblastoma, and the solid areasresemble the solid pattern of acinar cellcarcinoma. Biologically, the two tumoursare also similar, with a relatively favorableprognosis in childhood, but a very poorprognosis in adulthood. For these rea-sons, some observers have suggestedthat pancreatoblastoma represents thepaediatric counterpart of acinar cell car-cinoma. Although this proposal is attrac-tive in many ways, pancreatoblastoma

remains a separately definable neoplasmwith characteristic histologic, immunohis-tochemical, and clinical features.

UltrastructureBy electron microscopy, pancreatoblas-tomas generally exhibit evidence of aci-nar differentiation {939, 1758}, with rela-tively abundant rough endoplasmic retic-ulum and mitochondria, and apicallylocated dense zymogen granules. Thezymogen granules may be round anduniform, resembling those of non-neo-plastic cells. In addition, irregular fibril-lary granules similar to those describedin acinar cell carcinomas may be found{936, 939}. In rare cases, dense-coreneurosecretory-type granules and muci-gen granules have also been observed{939}. Examination of the squamoid cor-puscles has revealed tonofilaments butno evidence of a specific line of differen-tiation.

Genetic susceptibilityIn several reported cases (all congenitalexamples), pancreatoblastomas havebeen a component of the Beckwith-Wiedeman syndrome {432}.

Prognosis Pancreatoblastomas are malignanttumours. Nodal or hepatic metastasesare present in 35% of patients {782, 939}.More widespread dissemination may alsooccur. In pediatric patients lacking evi-dence of metastatic disease at first pres-entation, the prognosis is very good,most patients being cured by a combina-tion of surgery and chemotherapy {894,1299}. In the presence of metastatic dis-ease or in adult patients with pancreato-blastomas, the outcome is usually fatal{312, 939}, the mean survival being 1.5years {939}. However, a favourableresponse to chemotherapy has beennoted in some children {235, 2027}.

Fig. 10.33 Pancreatoblastoma with squamoid corpuscule (arrowhead), surrounded by solid (left) and tubular(right) structures.

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DefinitionA usually benign neoplasm with predomi-nant manifestation in young women, com-posed of monomorphic cells forming solidand pseudopapillary structures, frequent-ly showing haemorrhagic-cystic changesand variably expressing epithelial, mes-enchymal and endocrine markers.

ICD-O codesSolid pseudopapillary neoplasm 8452/1Solid pseudopapillary carcinoma 8452/3

SynonymsSolid-cystic tumour {946}, papillary-cys-tic tumour {170}, solid and papillaryepithelial neoplasm.

EpidemiologySolid-pseudopapillary neoplasm isuncommon but has been recognizedwith increasing frequency in recent years{946, 1192, 1358}. It accounts forapproximately 1-2% of all exocrine pan-creatic tumours {359, 941, 1280}.

It occurs predominantly in adolescentgirls and young women (mean 35 years;range 8-67 years) {1781, 1072}. It is rarein men (mean, 35 years; range 25-72years) {945, 1193, 1975}. There is noapparent ethnic preference {978, 1395}.

AetiologyThe aetiology is unknown. The strikingsex and age distribution point to geneticand hormonal factors, but there are noreports indicating an association withendocrine disturbances including over-production of oestrogen or progesterone.Moreover, only very few women devel-oped a solid pseudopapillary neoplasmafter long-term use of hormonal contra-ceptives {359, 436, 1655}.

LocalizationThere is no preferential localization withinthe pancreas {1282, 1358}.

Clinical featuresUsually, the neoplasms are found inci-dentally on routine physical examinationor they cause abdominal discomfort andpain {1358}, occasionally after abdomi-nal trauma {945}. Jaundice is rare {1427},even in tumours that originate from thehead of the pancreas, and there is noassociated functional endocrine syn-drome. All known tumour markers arenormal.Ultrasonography (US) and computedtomography (CT) reveal a sharply demar-cated, variably solid and cystic masswithout any internal septation {300}. Thetumour margin may contain calcifications.Administration of contrast medium resultsin enhancement of the solid tumour parts.On angiography, the neoplasms are usu-ally hypovascular or mildly hypervascularlesions with displacement of surroundingvessels {2153}. Fine needle aspirationcytology performed under radiologicalcontrol shows monomorphic cells withround nuclei and eosinophilic or foamycytoplasm {234, 2119, 2140}.

MacroscopyThe neoplasms present as large, round,

solitary masses (average size 8-10 cm;range, 3-18 cm), and are often fluctuant.They are usually encapsulated and welldemarcated from the surrounding pan-creas. Multiple tumours are exceptional{1427}. The cut surfaces reveal lobulat-ed, light brown solid areas, zones ofhaemorrhage and necrosis, and cysticspaces filled with necrotic debris.Occasionally, the haemorrhagic-cysticchanges involve almost the entire lesionso that the neoplasm may be mistakenfor a pseudocyst. The tumour wall maycontain calcifications {1358}. A fewtumours have been found to be attachedto the pancreas or even in extrapancre-atic locations {812, 914, 945}. Invasion ofadjacent organs or the portal vein is rare{1655, 1684, 1701}.

Tumour spreadOnly few metastasizing solid-pseudo-papillary neoplasms have been reported{359, 1358}. Common metastatic sitesinclude regional lymph nodes, the liver,peritoneum, and greater omentum {300,2209, 1358}.

HistopathologyIn large neoplasms, extensive necrosis istypical and the preserved tissue is usual-ly found in the tumour periphery underthe fibrous capsule. This tissue exhibits asolid monomorphic pattern with variablesclerosis. More centrally there is apseudopapillary pattern, and these com-ponents often gradually merge into each

G. Klöppel R. HrubanJ. Lüttges S. KernD. Klimstra G. Adler

Solid-pseudopapillary neoplasm

Fig. 10.35 Solid-pseudopapillary neoplasm. Thepseudopapillary structures are lined by smallmonomorphic cells.

Fig. 10.34 Solid-pseudopapillary neoplasm. A Theround hypodense tumour (T) replaces the tail of thepancreas. B The pseudocystic neoplasm isattached to the spleen, and shows haemorrhagicnecrosis.

T

A

B

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247Solid-pseudopapillary neoplasm

other. In both patterns, the uniform poly-hedral cells are arranged around deli-cate, often hyalinized fibrovascular stalkswith small vessels {1395}. Neoplasticcells that are arranged radially around theminute fibrovascular stalks may resemble‘ependymal’ rosettes. Luminal spaces areconsistently absent. In the solid parts,disseminated aggregates of neoplasticcells with foamy cytoplasm or cholesterolcrystals surrounded by foreign body cellsmay be found. The spaces between thepseudopapillary structures are filled withred blood cells. The hyalinized connec-tive tissue strands may contain foci of cal-cification and even ossification {1193}.The neoplastic cells have either eosino-philic or clear vacuolar cytoplasm.Occasionally they contain eosinophilic,diastase-resistant PAS-positive globulesof varying size, which may also occuroutside the cells. Glycogen or mucincannot be detected. Grimelius positivecells may occur. The round to oval nucleihave finely dispersed chromatin and areoften grooved or indented. Mitoses areusually rare, but in a few instancesprominent mitotic activity is observed{1358}. In rare cases, there is also vesselinvasion {2140}. The neoplastic tissue isusually well demarcated from the normalpancreas, although a fibrous capsulemay be absent and invasion of tumourcell nests into the surrounding pancreat-ic tissue may occur {1193, 1358}.

Criteria of malignancy Although criteria of malignancy have notyet been clearly established, it appearsthat unequivocal perineural invasion,angioinvasion, or deep invasion into thesurrounding tissue indicate malignantbehaviour, and such lesions should beclassified as solid-pseudopapillary carci-noma. Nishihara et al. {1358} comparedthe histological features of three metasta-sizing and 19 nonmetastasizing solid-pseudopapillary neoplasms, and foundthat venous invasion, degree of nuclearatypia, mitotic count and prominence ofnecrobiotic cell nests (cells with pyknoticnuclei and eosinophilic cytoplasm) wereassociated with malignancy. However,neoplasms in which the above-mentionedhistological criteria of malignancy are notdetected may also give rise to metas-tases. Consequently, benign appearingsolid-pseudopapillary neoplasms must beclassified as lesions of uncertain malig-nant potential.

Histochemistry and immunohistochemistryThe most consistently positive markersfor solid-pseudopapillary neoplasms arealpha-1-antitrypsin, alpha-1-antichymo-trypsin, neuron specific enolase (NSE),vimentin and progesterone receptors{306, 945, 963, 1226}. The cellular reac-tion for alpha-1-antitrypsin and alpha-1-antichymotrypsin is always intense, butonly involves small cell clusters or singlecells, a finding that is characteristic ofthis neoplasm. Alpha-1-antitrypsin alsostains the PAS-positive globules. Staining

for NSE and vimentin, in contrast, is usu-ally diffuse. Inconsistent results have been reportedfor epithelial markers, synaptophysin,pancreatic enzymes, islet cell hormonesand other antigens such as CEA or CA19.9. Most authors report negative resultsfor chromogranin A, CEA, CA 19.9 andAFP. A few neoplasms have been foundto express S-100 {945, 1226, 1358}.Cytokeratin is detected in 30% {946} to70% {963, 2195}, depending on themethod of antigen retrieval applied.

Fig. 10.37 Solid pseudopapillary tumour. In this solid area, the uniform tumour cells are separated by vas-cular hyalinized stroma.

Fig. 10.36 Solid pseudopapillary tumour. Solid area containing cholesterol crystals and foreign body giantcells.

10b 19.7.2006 8:25 Page 247


Usually, the staining for keratin is focaland faint. The keratin profile (CK 7, 8, 18and 19) is that of the ductal cell {740,1844}. Positive immunoreactivity fortrypsin, chymotrypsin, amylase and/orphospholipase A2 has been reported{166, 1072, 1192, 1226, 1844}, but hasnot been confirmed by most otherauthors {812, 945, 1282}. Similarly, focalpositivity for glucagon, somatostatinand/or insulin has been described insome tumours {1226, 2021, 2147}, butwas not detected in most other cases{1072, 1282, 1844}.

UltrastructureThe neoplastic cells have round ormarkedly indented nuclei containing asmall single nucleolus and a narrow rim ofmarginated heterochromatin. The cellsshow abundant cytoplasm, which is richin mitochondria. Zymogen-like granulesof variable sizes (500-3000 nm) areconspicuous, probably representingdeposits of alpha-1-antitrypsin. Thecontents of these granules commonly dis-

integrate, forming multilamellated vesi-cles and lipid droplets {946, 1031, 1226,2154}. Neurosecretory-like granules havebeen described in a few tumours {867,880, 1684, 2119, 2147}. Intermediate celljunctions are rarely observed and micro-villi are lacking, but small intercellularspaces are frequent.

GeneticsIn contrast to infiltrating ductal carcino-mas, solid-pseudopapillary neoplasmsappear to have wild-type KRAS genesand do not immunoexpress p53 {512,1007, 1039}. An unbalanced transloca-tion between chromosomes 13 and 17resulting in a loss of 13q14→qter and17p11→pter has been described in onesolid-pseudopapillary neoplasm {616}.

Prognosis and predictive factorsIn general, the prognosis is good. Aftercomplete removal more than 95% of thepatients are cured. Local spread or dis-semination to the peritoneal cavity hasbeen reported in the context of abdomi-

nal trauma and rupture of the tumour{1060}. Even in patients who had localspread, recurrences {359, 999}, ormetastases {234, 1192, 1642}, long dis-ease-free periods have been recordedafter initial diagnosis and resection. Onlya few patients have died of a metastasiz-ing solid-pseudopapillary neoplasm{1192, 1395}. Histological criteria. Perineural invasion,angioinvasion, or deep invasion into thesurrounding tissue indicate malignantbehaviour, and such lesions are classi-fied as solid-pseudopapillary carcinoma.Venous invasion, a high degree ofnuclear atypia, mitotic activity and promi-nence of necrobiotic cell nests (cells withpyknotic nuclei and eosinophilic cyto-plasm) were reported to be associatedwith malignancy {1358}. DNA content. There is evidence that ananeuploid DNA content assessed by flowcytometry is associated with malignantbehaviour, although the number of casesstudied is small {867, 1358, 234}.

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Primary mesenchymal tumours of thepancreas are exceedingly rare. Leio-myosarcomas and malignant gastroin-testinal stromal tumours appear to be theleast uncommon.

Recently, solitary fibrous tumours, similarto those more commonly seen on theserosal surfaces of the pleura and peri-toneum, have been described (1118).Histologically they show bland spindle

cells in a collagenous background. Thelesional cells are positive for CD34 butnegative for KIT and desmin; focal actinpositivity may occur.

M. MiettinenJ.Y. BlayL.H. Sobin

Mesenchymal tumours of the pancreas

Miscellaneous carcinomas and lymphoma

Miscellaneous carcinomasof the pancreas

G. ZamboniG. Klöppel

Oncocytic carcinomaThese lesions are characterized by largecells with granular eosinophilic cytoplasmand large nuclei with well-defined nucle-oli. Ultrastructurally, the cells show abun-dant mitochondria and lack zymogen andneuroendocrine granules. Local invasive-ness, lymph node and pulmonary metas-tasis can occur {1781}. Differential diag-nosis includes endocrine tumour {1454}and solid pseudopapillary tumour.

Nonmucinous, glycogen-poor cyst-adenocarcinomaA large, encapsulated mass with cysticspaces lined by serous adenoma likecomponent and malignant-appearingcolumnar epithelium. The tumour cells arenegative for mucins and show oncocyticfeatures by electron microscopy {533}.

ChoriocarcinomaAn aggressive tumour, associated withelevated levels of serum human chorion-

ic gonadotrophin (hCG), composed ofcytotrophoblastic cells intermingled withsyncytiotrophoblastic cells immunoreac-tive for hCG. Choriocarcinoma can be‘pure’ or associated with mucinous cys-tadenocarcinoma {1781, 2194}.

Clear cell carcinomaA carcinoma composed of clear cells,rich in glycogen and poor in mucin,morphologically resembling renal cellcarcinoma {941}. Adenocarcinomatous,anaplastic, or intraductal papillary com-ponents can be found {1781}. A ductalphenotype has been suggested by thepattern of immunoreactivity for cytoker-atins, the lack of vimentin expression, andthe presence of KRAS mutation {1121}.

Ciliated cell carcinomaThis lesion shows the pattern of ductaladenocarcinoma, but contains many cili-ated cells, as demonstrated at the ultra-structural level {1781}.

Microglandular carcinomaAlso known as microadenocarcinoma,this lesion is characterized by cribriformor microglandular pattern of growth{941}. The same cases were reclassifiedwith immunohistochemistry as adenocar-cinoma, acinar cell carcinomas andendocrine carcinoma {1090}. Microglan-dular carcinoma is best regarded as apattern of growth rather than a distinctiveentity.

Medullary carcinomaThis recently described carcinoma showsa syncytial growth pattern and lymphoep-ithelioma-like features (see chapter onductal adenocarcinoma, other rare carci-nomas) {590}.

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250 Tumours of the endocrine pancreas

DefinitionPrimary lymphoma of the pancreas isdefined as an extranodal lymphoma aris-ing in the pancreas with the bulk of thedisease localized to this site. Contiguouslymph node involvement and distantspread may be seen but the primary clin-ical presentation is in the pancreas withtherapy directed to this site.

EpidemiologyPrimary lymphoma of the pancreas isvery rare accounting for less than 0.5%of pancreatic tumours. As with primarylymphomas occurring elsewhere in thedigestive tract, patients are more fre-quently elderly {796}.

AetiologyImmunodeficiency predisposes to pan-creatic lymphoma, both in the setting ofHIV infection {866} and as post-trans-plant lymphoproliferative disorders fol-

lowing solid organ transplantation {240}.Familial pancreatic lymphoma has beenreported in a sibling pair (brother andsister) who each presented with a high-grade B-cell lymphoma in their seventhdecade {830}. Pancreatic lymphoma hasalso been described in a patient withshort bowel syndrome {903}.

Clinical featuresThe presentation of primary pancreaticlymphoma may mimic that of carcinomaor pancreatitis {240}. Pain free jaundicecan occur {1330}. Ultrasonography mayshow an echo-poor lesion {1330}.

HistopathologyPrimary pancreatic lymphomas are usu-ally of B phenotype. Lymphomas of vari-ous types have been described, includ-ing low-grade lymphomas of diffusesmall cell type {903, 1480}, follicle centrecell lymphoma {1330, 1238}, low-grade

MALT lymphoma {1925}, and large B-celllymphoma {1529, 830}. Only extremelyrare cases of pancreatic T-cell lymphomahave been reported, including a singlecase of anaplastic large cell lymphoma(CD30 positive) of T-cell type {1179} anda case of pancreatic involvement byadult T-cell leukaemia/lymphoma {1408}.The histology of these cases varies littlefrom that seen where these lymphomatypes are encountered more frequently.

PrognosisThe distinction between lymphoma andcarcinoma is important, as pancreaticlymphomas are associated with betterprognosis and may be curable even inadvanced stages. Occasional cases ofrelapse following prolonged remissionhave been reported in cases treated bychemotherapy {1529}.

H.K. Müller-HermelinkA. ChottR.D. GascoyneA. Wotherspoon

Lymphoma of the pancreas

Secondary tumours of the pancreas E. PaálA. Kádár

EpidemiologySecondary tumours of the pancreas arein most cases part of an advancedmetastatic disease. They account for3-16% of all pancreatic malignancies,affecting males and females equally{1190, 1012, 1597, 1781}. In our experi-ence based on combined autopsy andhistology material, out of 610 neoplasmsinvolving the pancreas 26 (4.25%) weresecondary. Any age may be affected,but the highest incidence is in the 6thdecade.

LocalizationAny anatomic region of the pancreasmay be involved and there is no sitepredilection {934}. Lesions can be soli-tary, multiple, or diffuse {502}.

Clinical featuresThere are no specific symptoms for sec-ondary tumours of the pancreas.Abdominal pain, jaundice, and diabetesmight be the first sign, or in some casesan attack of acute pancreatitis {1290,1608, 1772}.

The lesions are most commonly detectedby imaging studies {934}. Fine needleaspiration can provide a rapid diagnosis{905, 645, 1250}.

OriginBoth epithelial and non-epithelial sec-ondary tumours occur in the pancreas.The pancreas may be involved by directspread (e.g. from stomach, liver, adrenalgland, retroperitoneum) or by lymphaticor haematogenous spread from distantsites {905}. Renal cell carcinoma is

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unique as a primary site since it mightgive rise to late solitary metastases{1644, 218}.

HistopathologyThe main differential diagnostic problemis to distinguish metastases from primarypancreatic neoplasms. The most prob-lematic tumours are metastases from thegastrointestinal tract, renal cell carcino-

mas, small cell carcinoma, and lym-phomas {240, 645, 1781}. Apart from theclinical and radiological signs {934}, mul-tiple tumour foci with an abrupt transitionfrom normal pancreas to the neoplastictissue without signs of chronic pancreati-tis in the surrounding parenchyma sup-port metastatic origin {2089}. Immunohis-tochemistry specific for certain primarytumours may also be helpful {1190, 1707}.

PrognosisSince in most cases pancreatic metas-tases indicate an advanced neoplasticdisease, the prognosis is generally poor.In cases of solitary metastases, com-bined adjuvant therapy and surgicalresection might be beneficial {360, 674,218, 1597}.

Secondary tumours

Fig. 10.38 Secondary tumours in the pancreas. A Metastatic small cell lung carcinoma. B Metastatic melanoma. C Metastatic renal cell carcinoma. D Metastatic gastric signet ring cell carcinoma.

A B

C D

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