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2006 8:24 Page 219

CHAPTER 10

Tumours of the Exocrine Pancreas

Pancreatic carcinoma is a highly malignant neoplasm that still


carries a very poor prognosis. Ductal adenocarcinoma is the
most frequent type. Although cigarette smoking has been
established as a causative factor, the risk attributable to
tobacco abuse amounting to approximately 30%. An increased
risk is also associated with hereditary pancreatitis, but addi-
tional aetiological factors remain to be identified.

Significant progress has been made in the understanding of


the 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 genetic
alterations.

Non-ductal pancreatic neoplasms span a wide range of histo-


logical features that need to be recognized by pathologists as
several entities are associated with distinct opportunities for
therapy.
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WHO histological classification of tumours of the exocrine pancreas


Epithelial tumours

Benign
Serous cystadenoma 8441/01 Serous cystadenocarcinoma 8441/3
Mucinous cystadenoma 8470/0 Mucinous cystadenocarcinoma 8470/3
Intraductal papillary-mucinous adenoma 8453/0 – non-invasive 8470/2
Mature teratoma 9080/0 – invasive 8470/3
Intraductal papillary-mucinous carcinoma 8453/3
Borderline (uncertain malignant potential) – non-invasive 8453/2
Mucinous cystic neoplasm with moderate dysplasia 8470/1 – invasive (papillary-mucinous carcinoma) 8453/3
Intraductal papillary-mucinous neoplasm with moderate dysplasia 8453/1 Acinar cell carcinoma 8550/3
Solid-pseudopapillary neoplasm 8452/1 Acinar cell cystadenocarcinoma 8551/3
Mixed acinar-endocrine carcinoma 8154/3
Malignant Pancreatoblastoma 8971/3
Ductal adenocarcinoma 8500/3 Solid-pseudopapillary carcinoma 8452/3
Mucinous noncystic carcinoma 8480/3 Others
Signet ring cell carcinoma 8490/3
Adenosquamous carcinoma 8560/3 Non-epithelial tumours
Undifferentiated (anaplastic) carcinoma 8020/3
Undifferentiated carcinoma with osteoclast-like giant cells 8035/3 Secondary tumours
Mixed ductal-endocrine carcinoma 8154/3

_________
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


TNM classification1, 2

Primary Tumour (T) Distant Metastasis (M)


TX Primary tumour cannot be assessed MX Distant metastasis cannot be assessed
T0 No evidence of primary tumour M0 No distant metastasis
Tis Carcinoma in situ MI Distant metastasis
T1 Tumour limited to the pancreas, 2 cm or less in greatest dimen-
sion
T2 Tumour limited to the pancreas, more than 2 cm in greatest Stage grouping
dimension Stage 0 Tis N0 M0
T3 Tumour extends directly into any of the following: duodenum, bile Stage I T1 N0 M0
duct, peripancreatic tissues3 T2 N0 M0
T4 Tumour extends directly into any of the following: stomach,
spleen, colon, adjacent large vessels4 Stage II T3 N0 M0

Regional Lymph Nodes (N) Stage III T1 N1 M0


NX Regional lymph nodes cannot be assessed T2 N1 M0
N0 No regional lymph node metastasis T3 N1 M0
N1 Regional lymph node metastasis
N1a Metastasis in a single regional lymph node Stage IVA T4 Any N M0
N1b Metastasis in multiple regional lymph nodes Stage IVB Any T Any N M1

_________
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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G. Klöppel G. Adler
Ductal adenocarcinoma of the pancreas R.H. Hruban S.E. Kern
D.S. Longnecker T.J. Partanen

Definition adjusted incidence rates (world standard with a male/female ratio of 1.6 in devel-
A carcinoma occurring almost exclusive- population) range from 3.1 (Herault, oped nations and 1.1 in developing coun-
ly in adults that probably arises from and France) to 20.8 (central Louisiana, USA, tries. Blacks have distinctly higher rates
is phenotypically similar to, pancreatic blacks) per 100,000 males and from 2.0 than whites {593}.
duct epithelia, with mucin production (Herault, France) to 11.0 (San Francisco,
and expression of a characteristic cyto- CA, USA, blacks) per 100,000 females Aetiology
keratin pattern. {1471}. Rates from most developing The development of pancreatic carcino-
countries range from 1.0 to close to 10 ma is strongly related to cigarette smok-
ICD-O codes per 100,000. Incidence and mortality ing, which carries a 2-3 fold relative risk
Ductal adenocarcinoma 8500/3 rates are almost identical, since survival (RR) that increases with the number of
Mucinous noncystic carcinoma 8480/3 rates for pancreatic carcinoma are very pack-years of smoking {21}. Although the
Signet ring cell carcinoma 8490/3 low. association between cigarette smoking
Adenosquamous carcinoma 8560/3 and pancreatic carcinoma is not as strong
Undifferentiated (anaplastic) Time trends as that between cigarette smoking and
carcinoma 8020/3 After a steady increase between 1930 lung cancer (RR > 20), it has been esti-
Undifferentiated carcinoma and 1980, the incidence rates have mated that a substantial reduction of the
with osteoclast-like giant cells 8035/3 levelled off {593}. It is currently the fifth number of smokers in the European Union
Mixed ductal-endocrine leading cause of cancer death in could save as many as 68,000 lives that
carcinoma 8154/3 Western countries, second only to colon would otherwise be lost to pancreatic
cancer among malignancies of the cancer during the next 20 years {1293}.
digestive tract. Chronic pancreatitis, past gastric sur-
Epidemiology gery, occupational exposure to chemi-
Incidence and geographical distribution Age and sex distribution cals such as chlorinated hydrocarbon
Ductal adenocarcinoma and its variants Approximately 80% of cases manifest solvents, radiation exposure, and dia-
are the most common neoplasms in the clinically in patients 60-80 years; cases betes mellitus have also been associated
pancreas, representing 85-90% of all below the age of 40 years are rare {1781}. with the development of pancreatic car-
pancreatic neoplasms {359, 941, 1781}. The incidence of pancreatic carcinoma is cinoma {593, 1100, 2080}. A markedly
In developed countries, the annual age- slightly higher among men than women, increased risk has been observed in
hereditary pancreatitis {1101}.
A number of dietary factors have been
putatively connected with pancreatic can-
cer, including a diet low in fibre and high
in meat and fat {593}. Coffee consumption
was once thought to be a risk factor for
8.9 pancreatic carcinoma, but recent studies
7.8
7.0 showed no significant associations {593}.
2.8
Localization
60-70% of pancreatic ductal adenocarci-
1.5 nomas are found in the head of the
gland, the remainder occur in the body
5.7 and/or tail. Pancreatic head tumours are
mainly localized in the upper half, rarely
6.1 in the uncinate process {1781}. Rarely,
heterotopic pancreatic tissue gives rise
to a carcinoma {596, 1898}.

Clinical features
< 1.8 < 2.9 < 11.7
Symptoms and signs
< 5.4 < 7.7
Clinical features include abdominal pain,
Fig. 10.01 Global distribution of pancreatic cancer (2000). Note the high incidence areas in North America, unexplained weight loss, jaundice and
Europe, and the Russian Federation. pruritus. Diabetes mellitus is present in

Ductal adenocarcinoma 221


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70% of patients, usually with a diabetes placement, narrowing, or obstruction of


history of less than 2 years. Later symp- the pancreatic duct. Angiography is
toms are related to liver metastasis and/or helpful in preoperative management.
invasion of adjacent organs (stomach, CT shows pancreatic adenocarcinomas
colon) or of the peritoneal cavity (ascites). as hypodense masses in up to 92% of
Occasionally, patients present with acute cases {528}. Diffuse tumour involvement
pancreatitis {621}, migratory throm- of the pancreas is found in about 4%. In
bophlebitis, hypoglycaemia, or hypercal- up to 4% the pancreatic and common
caemia {1261}. bile duct are dilated without an identifi-
able mass.
Imaging and laboratory tests KRAS mutations. Mutations in codon 12 Fig. 10.02 Ductal adenocarcinoma. An ill-defined
Currently, the most important tests for of the KRAS gene have been detected in pale carcinoma in the head of the pancreas.
establishing the diagnosis of pancreatic the stool, in pancreatic juice and/or
carcinoma are ultrasonography (US) and blood samples from patients with proven
computerised tomography (CT) or mag- ductal adenocarcinoma of the pancreas usually somewhat larger at diagnosis.
netic resonance imaging (MRI), with or {224, 960, 1876}, but their diagnostic Tumours with a diameter less than 2 cm
without guided percutaneous fine-needle value in is still controversial. are infrequent {697} and may be difficult
biopsy, endoscopic retrograde cholan- to recognise by gross inspection.
giography (ERCP), endoscopic ultra- Fine needle aspiration (FNA) Carcinomas of the head of the pancreas
sonography (EUS) and tumour marker FNA can be performed percutaneously usually invade the common bile duct
determination (CA 19-9, Du-Pan 2, CEA, with guidance by imaging techniques or and/or the main pancreatic duct and pro-
Span-1). The sensitivity and specificity of under direct visualisation at surgery. duce stenosis that results in proximal
any of these tests alone ranges between Aspirates from a typical, well to moder- dilatation of both duct systems.
55 and 95%. By applying combinations ately differentiated ductal adenocarcino- Complete obstruction of the main pan-
of these tests, accuracy rates of more ma show a cellular aspirate {32, 940}. creatic duct leads to extreme prestenotic
than 95% have been achieved {2061}. Pancreatic juice cytology obtained from duct dilatation with duct haustration and
On transabdominal US and on EUS, pan- ERCP is less sensitive than percuta- fibrous atrophy of the parenchyma
creatic ductal adenocarcinomas are neous or intraoperative FNA (76 versus (i.e. obstructive chronic pancreatitis).
characterised as echo-poor and inhomo- 90 to 100%) {32, 1242, 1311}. More advanced pancreatic head carci-
geneous mass lesions in about 80% of nomas involve the ampulla of Vater
cases. About 10% of the tumours appear Macroscopy and/or the duodenal wall, causing ulcer-
echo-rich. With increasing size, tumours Ductal adenocarcinomas are firm and ations. Carcinomas in the pancreatic
tend to become inhomogeneous, with poorly defined masses. The cut surfaces body or tail obstruct the main pancreatic
cystic and echo-rich areas. Indirect signs are yellow to white. Haemorrhage and duct, but typically do not involve the
of a pancreatic tumour (dilatation of pan- necrosis are uncommon, but microcystic common bile duct.
creatic and/or common bile duct) are areas may occur. In surgical series, the
usually found proximal to tumours larger size of most carcinomas of the head of Tumour spread and staging
than 3 cm. On EUS lymph node metas- the pancreas ranges from 1.5 to 5 cm, It is an exception to find a resected car-
tases appear as enlarged echo-poor with a mean diameter between 2.5 and cinoma that is still limited to the pancreas
nodes. ERPC may demonstrate dis- 3.5 cm. Carcinomas of the body/tail are {1414}. In head carcinomas, peripancre-

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

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atic tumour invasion, often via perineural


sheaths, 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 in
advanced cases. In carcinomas of the
body and tail, local extension is usually
greater, because of delayed tumour
detection, and includes invasion of the
spleen, stomach, left adrenal gland,
colon, and peritoneum {359, 941}.
Lymphatic spread of pancreatic head
carcinomas involves, in descending order
of frequency, the retroduodenal (posterior
pancreaticoduodenal) and the superior
pancreatic head groups, the inferior head
and the superior body groups, and the
anterior pancreaticoduodenal and the
inferior body groups {359}. This lymph
node compartment is usually resected Fig. 10.04 Poorly differentiated ductal adenocarcinoma.
together with the head of the pancreas,
using a standard Whipple procedure
{1955}. More distal nodal metastases may Well differentiated carcinomas consist of greater variation in nuclear size, chro-
occur in the ligamentum hepatoduode- large duct-like structures, combined with matin structure and prominence of nucle-
nale, at the coeliac trunk, the root of the medium-sized neoplastic glands. Tubular oli. Mitotic figures are rather frequent. The
superior mesenteric artery, and in para- or cribriform patterns are typical; there cytoplasm is usually slightly eosinophilic,
aortic nodes at the level of the renal arter- may also be small irregular papillary pro- but clear cells are occasionally abun-
ies. These lymph node compartments are jections without a distinct fibrovascular dant. Mucin production appears to be
only removed if an extended Whipple pro- stalk, particularly in large duct-like struc- decreased and intraductal in situ compo-
cedure is performed. Carcinomas of the tures. Mitotic activity is low. In between nents are somewhat less frequent than in
body and tail metastasise especially to the neoplastic glands there may be a few well differentiated carcinomas. Foci of
the superior and inferior body and tail non-neoplastic ducts as well as remnants poor and irregular glandular differentia-
lymph node groups and the splenic hilus of acini and individual islets. tion are often found at the leading edge
lymph nodes. They may also spread via Sometimes, the neoplastic duct-like of the neoplasm, particularly where it
lymphatic channels to pleura and lung. glands are so well differentiated that they invades the peripancreatic tissue.
Haematogenous metastasis occurs, in are difficult to distinguish from non-neo- Poorly differentiated ductal carcinomas
approximate order of frequency, to the plastic ducts. However, the mucin-con- are infrequent. They are composed of a
liver, lungs, adrenals, kidneys, bones, taining neoplastic glands may be rup- mixture of densely packed, small irregular
brain, and skin {359, 941, 1231}. tured or incompletely formed, a feature glands as well as solid tumour cell sheets
that is not seen in normal ducts. The and nests, which entirely replace the aci-
Staging mucin-producing neoplastic cells tend to nar tissue. While typical large, duct-like
The 1997 TNM classification {66} is pre- be columnar, have eosinophilic and structures and intraductal tumour compo-
sented on page 220. Another staging occasionally pale or even clear cyto- nents are absent, there may be small
system has been published by the Japan plasm, and are usually larger than those squamoid, spindle cell, or anaplastic foci
Pancreas Society {832}. of non-neoplastic ducts. They contain (comprising by definition less than 20% of
large round to ovoid nuclei which may the tumour tissue). There may be some
Histopathology vary in size, with sharp nuclear mem- scattered inflammatory cells. Foci of
Most ductal adenocarcinomas are well to branes and distinct nucleoli that are not necrosis and haemorrhage occur. The
moderately differentiated. They are char- found in normal duct cells. Moreover, neoplastic cells show marked pleomor-
acterized by well-developed glandular although the neoplastic cell nuclei tend phism, little or no mucin production, and
structures, which more or less imitate to be situated at the base of the cell, they brisk mitotic activity. At the advancing
normal pancreatic ducts, embedded in always show some loss of polarity. edge of the carcinoma, the gland and the
desmoplastic stroma. The large amount Moderately differentiated carcinomas peripancreatic tissue are infiltrated by
of fibrous stroma accounts for their firm predominantly show a mixture of medi- small clusters of neoplastic cells.
consistency. Variations in the degree of um-sized duct-like and tubular structures
differentiation within the same neoplasm of variable shape, embedded in desmo- Changes in non-neoplastic pancreas
are frequent, but well differentiated carci- plastic stroma. Incompletely formed All ductal adenocarcinomas are associ-
nomas with foci of poor differentiation are glands are common. Compared with the ated with more or less developed
uncommon. well differentiated carcinoma, there is a fibrosclerotic and inflammatory changes

Ductal adenocarcinoma 223


10a 19.7.2006 8:24 Page 224

pancreatic adenocarcinoma, some the carcinomas also express CK 4


markers are useful in separating ductal {1696}, but are usually negative for CK 20
adenocarcinoma of the pancreas from {1259}. As the usual keratin patterns of
non duct-type tumours or other gastroin- non-duct-type pancreatic neoplasms
testinal carcinomas. (i.e. acinar carcinomas and endocrine
Mucin. Ductal adenocarcinomas mainly tumours, CK 8, 18 and 19) and gut carci-
stain for sulphated acid mucins but focal- nomas (i.e. CK 8, 18, 19 and 20) differ
ly also for neutral mucins {1714}. from that of ductal carcinoma, it is possi-
Immunohistochemically, most ductal ble to distinguish these tumours on the
adenocarcinomas express MUC1, MUC3 basis of their CK profile.
Fig. 10.05 Undifferentiated carcinoma exhibiting and MUC5/6 (but not MUC2) {1918, Ductal adenocarcinomas are usually
extreme pleomorphism with giant cells. 2179}, CA 19-9, Du-Pan 2, Span-1, negative for vimentin {1696}. With rare
CA 125 and TAG72 {1714, 1884}. The exceptions (see mixed ductal-endocrine
expression patterns of CA 19-9, Du-Pan carcinoma), they also fail to label with
in the adjoining non-neoplastic pan- 2, Span-1, CA 125 and TAG 72 are large- endocrine markers such as synapto-
creas, due to carcinomatous duct ly comparable in their immunoreactivity physin and the chromogranins, but may
obstructions (obstructive chronic pan- and specificity. These markers also label contain, particularly if well differentiated,
creatitis). In cases of complete occlusion the epithelium of normal pancreatic ducts some scattered (possibly non-neoplas-
of the main duct, there is marked to some extent, particularly in chronic tic) endocrine cells in close association
upstream dilatation of the duct and pancreatitis, and the tumour cells of with the neoplastic cells {167}. They are
almost complete fibrotic atrophy of the some serous cystadenomas and acinar generally negative for pancreatic
parenchyma. In contrast to chronic pan- cell carcinomas {1282}. enzymes such as trypsin, chymotrypsin
creatitis due to alcoholism, intraductal Carcinoembryonic antigen (CEA). and lipase {739, 1282}.
calcifications are generally absent. Monospecific antibodies against CEA that Growth factors and adhesion molecules.
Poorly differentiated carcinomas usually do not recognise other members of the Pancreatic carcinomas overexpress epi-
destroy the islets. In the well and moder- CEA family are capable of discriminating dermal growth factor and its receptor,
ately differentiated neoplasms, however, between non-neoplastic duct changes, c-erbB-2, transforming growth factor
islets may be found entrapped in neo- such as ductal papillary hyperplasia, and alpha {380, 1676, 2163}, metallothionein
plastic tissue. In addition, scattered a variety of neoplasms {119}. CEA is neg- {1409}, CD44v6 {259, 1880} and mem-
endocrine cells occur attached to or ative in serous cystadenoma. branous E-cadherin {1519}.
intermingled between neoplastic colum- Cytokeratins, vimentin, endocrine mark-
nar cells. Only in exceptional cases do ers and enzymes. Normal pancreatic Ultrastructure
the endocrine cells constitute a second and biliary ductal cells and pancreatic Ductal adenocarcinoma cells are charac-
cell component of the ductal carcinoma centroacinar cells express the cytoker- terized by mucin granules in the apical
(see mixed ductal-endocrine carcinoma). atins (CK) 7, 8, 18, 19 and occasionally cytoplasm, irregular microvilli on the lumi-
also 4 {1696}. Acinar cells contain only nal surface, and a more or less polarised
Histochemistry and immunohistochem- CK 8 and 18, and islet cells 8, 18 and arrangement of the differently sized
istry occasionally also 19. Ductal adenocarci- nuclei {359, 901, 1714}. The content of
Although no histochemical or immuno- nomas express the same set of cytoker- the mucin granules (0.4-2.0 μm) varies
histochemical marker is able to unequiv- atins as the normal duct epithelium, from solid-electron dense to filamentous
ocally distinguish pancreatic from extra- i.e. CK 7, 8, 18 and 19. More than 50% of and punctate; often there is a dense

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

224 Tumours of the exocrine pancreas


10a 19.7.2006 8:24 Page 225

eccentric core. Some cells have features


of gastric foveolar cells, showing gran-
ules with a punctate-cerebroid structure
{1714}. Loss of tumour differentiation is
characterized by loss of cell polarity, dis-
appearance of a basal lamina, appear-
ance of irregular luminal spaces, and
loss of mucin granules {901}.

Histological variants
Adenosquamous carcinoma and undif-
ferentiated (anaplastic) carcinoma
(including osteoclast-like giant cell
tumours), mucinous noncystic adenocar-
cinoma and signet-ring cell carcinoma
are considered variants of ductal adeno-
carcinoma because most of these carci-
nomas, even if poorly differentiated, con-
tain some foci showing neoplastic glands
with ductal differentiation {288, 359, 941,
947, 1781}.
Fig. 10.07 Adenosquamous carcinoma. Note the glandular component on the left and the squamous differ-
Adenosquamous carcinoma
entiation on the right (arrowheads).
This rare neoplasm, relative frequency
3-4% {941, 359, 813, 1415}, is character-
ized by the presence of variable propor-
tions of mucin-producing glandular ele- Undifferentiated carcinoma with osteo- Mucinous noncystic carcinoma
ments and squamous components. The clast-like giant cells This uncommon carcinoma (relative fre-
squamous component should account This rare neoplasm is composed of pleo- quency: 1-3%) {941} has also been
for at least 30% of the tumour tissue. In morphic to spindle-shaped cells and called ‘colloid’ or gelatinous carcinoma.
addition, there may be anaplastic and scattered non-neoplastic osteoclast-like Mucin accounts for > 50% of the tumour.
spindle cell foci. Pure squamous carci- giant cells with usually more than 20 uni- The large pools of mucin are partially
nomas are very rare. formly small nuclei. In many cases there lined by well-differentiated cuboidal cells
is an associated in situ or invasive ade- and contain clumps or strands of tumour
Undifferentiated (anaplastic) carcinoma nocarcinoma {359}. The osteoclast-like cells. Some floating cells may be of the
Also called giant cell carcinoma, pleo- giant cells are often concentrated near signet-ring cell type.
morphic large cell carcinoma, and sarco- areas of haemorrhage and may contain Sex and age distribution are similar to
matoid carcinoma, these tumours have a haemosiderin and, occasionally, phago- those of ductal adenocarcinoma. The
relative frequency of 2-7%. They are cytosed mononuclear cells. Osteoid for- tumours may be very large and are usu-
composed of large eosinophilic pleomor- mation may also be found. ally well demarcated. The development
phic cells and/or ovoid to spindle- Immunohistochemically, at least some of of pseudomyxoma peritonei has been
shaped cells that grow in poorly cohe- the neoplastic cells express cytokeratin, described {285}. It is of interest that the
sive formations supported by scanty vimentin and p53 {740, 2095}. The osteo- invasive component of some of the intra-
fibrous stroma. Commonly the carcino- clast-like giant cells, in contrast, are neg- ductal papillary-mucinous tumours re-
mas contain small foci of atypical glan- ative for cytokeratin and p53, but positive sembles mucinous noncystic carcinoma.
dular elements {359, 941, 1786, 1962}. for vimentin, leukocyte common antigen Mucinous noncystic carcinoma should
Carcinomas consisting predominantly of (CD56) and macrophage markers such not be confused with mucinous cystic
spindle cells may also contain areas of as KP1 {740, 1258, 2095}. tumour because of the much better prog-
squamoid differentiation. High mitotic The mean age of patients with osteo- nosis of the latter (see chapter on muci-
activity as well as perineural, lymphatic, clast-like giant cell tumours is 60 years nous cystic neoplasms).
and blood vessel invasion is found in but there is a wide age range from 32 to
almost all cases. Immunohistochemical- 82 years {1370}. Some tumours are Signet-ring cell carcinoma
ly, some or most tumour cells express found in association with mucinous cys- The extremely rare signet-ring cell carci-
cytokeratins and usually also vimentin tic neoplasms {1258, 2095, 2198}. In the noma is an adenocarcinoma composed
{740}. Electron microscopy reveals early reports on this tumour it was sug- almost exclusively of cells filled with
microvilli and mucin granules in some gested that they may have a more mucin {1781, 1951}. The prognosis is
cases {359}. Undifferentiated carcino- favourable prognosis than the usual duc- extremely poor; a gastric primary should
mas with a neoplastic mesenchymal tal adenocarcinoma {359}. More recently always be excluded before making this
component (carcinosarcoma) have so far a mean survival of 12 months has been diagnosis.
not been described. reported.

Ductal adenocarcinoma 225


10a 19.7.2006 8:24 Page 226

ductal structures or lie between the


neoplastic columnar cells. ‘Collision
tumours’ composed of two topographi-
BD cally separate components are not inclu-
ded in the mixed ductal-endocrine cate-
gory.

Other rare carcinomas


Other very rare carcinomas of probable
A B ductal phenotype include clear cell car-
Fig. 10.08 Mucinous non-cystic adenocarcinoma. A A mucinous carcinoma in the head of the pancreas cinoma {359, 882, 1908, 1121} and ciliat-
obstructs the main pancreatic duct and impinges on the bile duct (BD). B The neoplastic cells float in pools ed cell carcinoma (see chapter on mis-
of mucin. cellaneous carcinomas) {1276, 1786}.
Carcinomas with ‘medullary’ histology
Mixed ductal-endocrine carcinoma Mixed ductal-endocrine carcinomas, as have recently been described {590};
Mixed ductal-endocrine carcinoma {947} defined above, seem to be exceptionally these lesions are associated with wild-
has also been referred to as mixed carci- rare in the pancreas {1714, 1781}. type KRAS status and microsatellite
noid-adenocarcinoma, mucinous carci- Biologically, the mixed carcinoma instability.
noid tumour {359}, or simply mixed behaves like the usual ductal adenocar- The so-called microglandular carcino-
exocrine-endocrine tumour. This neo- cinoma. mas {359} or microadenocarcinomas are
plasm is characterized by an intimate Acinar cell carcinomas {739, 1694, 1985} distinguished by a microglandular to
admixture of ductal and endocrine cells and pancreatoblastomas {741} with solid-cribriform pattern. They most likely
in the primary tumour as well as in its some endocrine and ductal elements, do not form an entity of their own but
metastases. By definition, the endocrine and endocrine tumours with ductal com- belong to either the ductal, endocrine, or
cells should comprise at least one third ponents {1372, 1941} are not discussed acinar carcinomas.
to one half of the tumour tissue. The duc- here, because their behaviour is dictated
tal differentiation is defined by mucin pro- by their acinar and endocrine elements. Grading
duction and the presence of a duct type Mixed ductal-endocrine carcinomas A few formal grading systems have been
marker such as CEA. The endocrine cells should also be distinguished from ductal described. Miller et al. graded pancreat-
are characterized by the presence of adenocarcinomas with scattered endo- ic tumours using the system of Broder,
neuroendocrine markers and/or hormon- crine cells, since scattered endocrine which distinguishes four grades of cellu-
al products; immunoexpression of all four cells are found in 40-80% of ductal ade- lar atypia. High-grade carcinomas
islet hormones, amylin (IAPP), serotonin, nocarcinomas {167, 289} and seem to (Broder grades 3 and 4) were larger and
pancreatic polypeptide (PP), and occa- be particularly frequent in the well differ- the frequency of venous thrombosis and
sionally gastrin have been described entiated tumours, where they are either metastasis higher than in low-grade
{167}. lined up along the base of the neoplastic tumours.
A more recent grading system is based
on combined assessment of histological
and cytological features and mitotic
activity {944, 1119}. If there is intratumour
heterogeneity, i.e. a variation in the
degree of differentiation and mitotic
activity, the higher grade and mitotic
activity is assigned. This rule also applies
if only a minor component (less than half
of the tumour) was of lower grade. Using
this system, there is a correlation
between grade and survival and grade is
an independent prognostic variable
{944, 1119}.

Precursor lesions
Pancreatic neoplasms
Mucinous cystic neoplasms and intra-
ductal papillary mucinous neoplasms
may progress to invasive cancer. In the
case of mucinous cystic neoplasms, the
invasive component usually resembles
ductal adenocarcinoma {1781}. In the
Fig. 10.09 Pancreatic duct showing high-grade intraepithelial neoplasia (PanIN III). case of intraductal papillary-mucinous

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Table 10.01
List of recommended terms with synonyms for focal hyperplastic and metaplastic duct lesions in the human exocrine pancreas.
Recommended WHO term Previous WHO classification {947} Other synonyms

Squamous metaplasia Squamous metaplasia Epidermoid metaplasia, multilayered metaplasia


Incomplete squamous metaplasia Incomplete squamous metaplasia focal epithelial hyperplasia, focal atypical
epithelial hyperplasia, multilayered metaplasia

PanIN-IA Mucinous cell hypertrophy Mucinous cell hyperplasia, mucinous ductal


hyperplasia, mucoid transformation, simple
hyperplasia, flat ductal hyperplasia, mucous
hypertrophy, hyperplasia with pyloric gland
metaplasia, ductal hyperplasia grade 1, non-papillary
epithelial hypertrophy, nonpapillary ductal hyperplasia

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


Carcinoma in situ

carcinoma, the invasive component changes, which both represent high- trating ductal adenocarcinomas are still ill-
either corresponds to a usual ductal ade- grade intraepithelial neoplasia. The defined. Putative precursor lesions (Table
nocarcinoma or to mucinous noncystic lesion corresponds to PanIN III in the 10.01) include mucinous cell hypertrophy,
carcinoma {1781}. proposed terminology of pancreatic ductal papillary hyperplasia with muci-
intraepithelial neoplasia (Table 10.01). nous cell hypertrophy (papillary duct
Severe ductal dysplasia – carcinoma High-grade intraepithelial neoplasia is lesion without atypia), adenomatoid (ade-
in situ commonly found in association with an nomatous) ductal hyperplasia, and squa-
This change of the ductal epithelium is invasive ductal adenocarcinoma {358, mous metaplasia {1781, 947}. All these
characterized by irregular epithelial bud- 555, 943}, and may represent either a lesions may show mild nuclear atypia.
ding and bridging, small papillae lacking precursor to invasive carcinoma or con- The evidence that some of these duct
fibrovascular stalks, and severe nuclear tinuous intraductal extensions of the lesions (i.e. mucinous cell hypertrophy
abnormalities such as loss of polarity, invasive tumour. Similar duct changes and papillary hyperplasia) may be pre-
pleomorphism, coarse chromatin, dense have also been described remote from cursors to invasive carcinoma comes
nucleoli and mitotic figures. The lesion is the macroscopic tumour {1781} or years from three areas: morphological studies,
often surrounded by one or two layers of before the development of an invasive clinical reports, and genetic analyses. At
fibrosclerotic tissue. Here, no attempt is ductal carcinoma {185, 191}. the light microscopic level, ductal papil-
made to distinguish between severe dys- lary hyperplasia was found adjacent to
plasia and carcinoma in situ, since it is Duct changes invasive carcinomas more frequently
very difficult, if not impossible, to draw a With the exception of high-grade intraepi- than it was in pancreases without cancer
clear distinction between these two thelial neoplasia, the precursors to infil- {290, 358, 943, 965}. It was also noted

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

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

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 and
pleomorphic structures

Ductal adenocarcinoma 227


10a 19.7.2006 8:24 Page 228

Table 10.03 and that the lesions are evenly distributed


Genetic alterations in pancreatic ductal carcinoma. in the pancreas and do not concentrate in
Gene Chromosome Mechanism of alteration % of cancers the head region where the carcinoma is
most frequent {647}. It has recently been
Oncogenes suggested that the term ‘Pancreatic
Intraepithelial Neoplasia (PanIN)’ be
KRAS 12p Point mutation > 90 adopted for these duct lesions (see
MYB, AKT2, AIB1 6q, 19q, 20q Amplification1 10-20 http://pathology.jhu.edu/ pancreas.panin)
HER/2-neu 17q Overexpression 70 {937}. Table 10.01 indicates the general
relationship between the previous WHO
Tumor suppressor genes
terminology and this new proposed
PanIN terminology.
p16 9p Homozygous deletion 40
Loss of heterozygosity 40 Genetic susceptibility
and intragenic mutation Between 3% and 10% of cases of pan-
Promotor 15 creatic cancer are familial {754, 1125,
hypermethylation 1126, 499}. Some arise in patients with
recognized genetic syndromes, as dis-
TP53 17p Loss of heterozygosity 50-70 cussed below, but in most instances the
and intragenic mutation
genetic basis for the familial aggregation
DPC4 18q Homozygous deletion 35
of pancreatic carcinomas has not been
Loss of heterozygosity 20 identified. A confounding factor is the
and intragenic mutation possibility of shared environmental fac-
tors, such as tobacco use. Nevertheless,
BRCA2 13q Inherited intragenic mutation 7 some studies show familial aggregations
and loss of heterozygosity suggestive of a genetic aetiology {485,
577, 499, 1207} Studies of extended fam-
MKK4 17p Homozygous deletion, 4 ilies have shown a pattern suggestive of
loss of heterozygosity an autosomal dominant mode of inheri-
and intragenic mutation
tance.
LKB1/STK11 19p Loss of heterozygosity 5
and intragenic mutation, Hereditary pancreatitis
homozygous deletion This disease is caused by germline
mutations in the cationic trypsinogen
ALK5 and TGF βR2 9q, 3p Homozygous deletion 4 gene on 7q35 {2098}. This syndrome is
characterized by the early onset of
severe recurrent bouts of acute pancrea-
DNA Mismatch Repair titis, and affected individuals have as
high as a 40% lifetime risk of developing
MSH2, MLH1, others 2p, 3p, others Unknown <5
pancreatic carcinoma {1101}.

___________________ FAMMM syndrome


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.
Familial atypical multiple mole melanoma
(FAMMM) is associated with germline
mutations in the p16 tumour suppressor
gene on 9p. Affected individuals have
that ductal papillary hyperplasia is simi- tions in codon 12 of the KRAS geneal- an increased risk of developing both
lar to severe dysplasia-carcinoma in situ terations of the p16 and TP53 tumour melanoma and pancreatic carcinoma
lesions seen in the vicinity of invasive suppressor genes and loss of BRCA2 {601, 1127, 1285, 2097}. The lifetime risk
ductal carcinomas {358}. Clinically, Brat and DPC4 have all been reported in duct for developing pancreatic carcinoma is
et al. {185} and Brockie et al. {191} have lesions {1286, 1875, 2166, 2105, 589}. about 10%.
reported a total of five patients who Duct lesions and infiltrating cancers from
developed infiltrating ductal adenocarci- the same pancreas may harbour identi- BRCA2
nomas years after the identification of cal mutations {1120, 1286}. The discovery of the second breast can-
atypical duct lesions in their pancreas. Only a minority of duct lesions may cer gene (BRCA2) on 13q was made
Finally, molecular genetic analyses of progress to invasive cancer, as demon- possible in large part by the discovery of
duct lesions have demonstrated that they strated by recent data from a study on a homozygous deletion in a pancreatic
contain some of the same genetic alter- normal pancreases, which showed that carcinoma {1697}. Pancreatic carcino-
ations seen in infiltrating ductal carcino- all types of duct lesions and even normal mas have been reported in some kindred
mas. For example, activating point muta- epithelium may harbour KRAS mutations, with BRCA2 mutations and familial breast

228 Tumours of the exocrine pancreas


10a 19.7.2006 8:24 Page 229

cancer {1514, 1934, 591, 479} identified Recurrent losses of genetic material at match repair gene has been identified in
germline mutations in BRCA2 in about specific loci in a carcinoma suggest that 4% of pancreatic carcinomas {590}. They
7% of patients with pancreatic carcino- these loci harbour tumour suppressor had wild-type KRAS genes and a char-
ma. Remarkably, most pancreatic ductal genes which are inactivated in the carci- acteristic ‘medullary’ histological appear-
carcinoma patients with such mutations noma, and, indeed, the p16 gene on 9p, ance, forming a distinct subset of pan-
do not have a strong family history of the Tp53 gene on 17p, and the DPC4 creatic adenocarcinomas (see section
breast or pancreatic carcinoma. A num- gene on 18q are all frequently inactivat- on other rare carcinomas).
ber of them are, however, of Ashkenazi ed in pancreatic carcinoma {1716}. The
Jewish ancestry {591, 1442}. p16 tumour suppressor gene is inacti- Prognosis and predictive factors
vated in 40% of pancreatic carcinomas Ductal adenocarcinoma is fatal in most
Peutz-Jeghers syndrome by homozygous deletion, in 40% by loss cases {639}. The mean survival time of
Patients with the Peutz-Jeghers syndrome of one allele coupled with an intragenic the untreated patient is 3 months, while
have an increased risk of developing pan- mutation in the second, and by hyperme- the mean survival after radical resection
creatic carcinoma, and recently the bi- thylation of the p16 promoter in an addi- varies from 10-20 months {560, 692, 814,
allelic inactivation of the LKB1/STK11 tional 15% {223, 1698, 2104}. The Tp53 1955}. The overall 5-year survival rate of
gene has been demonstrated in a pan- is inactivated in 75% of pancreatic carci- patients treated by resection is 3-4%
creatic carcinoma which arose in a nomas by loss of one allele coupled with {639}, although in selected and stage-
patient with the Peutz-Jeghers syndrome an intragenic mutation in the second stratified series survival figures approach-
{579, 1851}. allele {1570, 1624}. The DPC4 tumour ing 25 or even 46% have been reported
suppressor gene is inactivated in 55% of {560, 1955, 1966, 1976}. Unresectable
Hereditary nonpolyposis colon cancer pancreatic carcinomas {651}, in 35% of carcinomas are treated with palliative
(HNPCC) the carcinomas by homozygous deletion bypass operations. Response to chemo-
This syndrome is associated with an and in 20% by loss of one allele coupled therapy with 5-fluorouracil or gemcitabine
increased risk of developing carcinoma with an intragenic mutation in the second may be seen in up to approximately 10%
of the colon, endometrium, stomach, and allele. The BRCA2 tumour suppressor of patients. Radiotherapy alone is largely
ovary {2071}. It can be caused by gene on 13q is inactivated in about 7% of ineffective {2061}.
germline mutations in any one of a num- pancreatic carcinomas {591, 1442,
ber of DNA mismatch repair genes, 1697}. Remarkably, in almost all of these Site, size, and stage
including MSH2 on 2p and MLH1 on 3p cases one allele of BRCA2 is inactivated The survival time is longer in patients with
{1029, 1078, 2071}. Lynch et al. have by a germline (inherited) mutation in the carcinomas confined to the pancreas
reported pancreatic carcinomas in some gene {591}. Other tumour suppressor and less than 3 cm in diameter (17-29
kindred with HNPCC, and Goggins et al. genes which have been shown to be months) than in patients with tumours of
have recently reported microsatellite occasionally inactivated in pancreatic greater size or retroperitoneal invasion
instability, a genetic change associated carcinoma include the genes MKK4, (6-15 months) {2172}. Carcinomas of the
with defects in DNA mismatch repair RB1, LKB1/STK11, and the transforming body or the tail of the pancreas tend to
genes, in about 4% of pancreatic carci- growth factor β receptors I and II {592, present at a more advanced stage than
nomas {590, 1130, 1487}. 761, 1850, 1851}. those of the head {560, 1955, 1966,
Several oncogenes have been shown to 1976}. Some have found that lymph node
Genetics be activated in ductal adenocarcinomas metastases significantly worsen progno-
Genetic alterations are listed in Table of the pancreas. These include the KRAS sis, while others have not {710, 1955,
10.03. At the chromosome level, they gene on chromosome 12p, which is acti- 2172}.
include losses and gains of genetic vated by point mutations in over 90% of
material as well as generalised chromo- the carcinomas, overexpression of the Residual tumour tissue
some instability {608, 625, 626}. The HER2-neu gene on 17q in 70% of the car- Patients with no residual tumour following
most frequent gains identified cytogenet- cinomas, and amplification of the AKT2 resection (R0) have the most favourable
ically include those of chromosomes 12 gene on chromosome 19q in 10–20% of prognosis of all patients undergoing sur-
and 7; the most common recurrent struc- the carcinomas, the nuclear receptor gical resection {2108}. This implies that
tural abnormalities involve chromosome coactivator gene AIB1 on chromosome local spread to peripancreatic tissues,
arms 1p, 6q, 7q, 17p, 1q, 3p, 11p, and 20q, and the MYB gene on chromosome i.e. the retroperitoneal resection margin,
19q, and the most frequent losses 6q {47, 292, 380, 576, 761, 1242, 2039}. is of utmost importance in terms of prog-
involve chromosomes 18, 13, 12, 17, and Compared to normal pancreas, Smad2 nosis {1122}.
6 {626, 625}. Similar patterns of loss have mRNA levels are increased in pancreatic
been identified at the molecular level carcinoma, which might lead to the Recurrence
{184, 1716}, using highly polymorphic over-expression of components of the Local recurrence seems to be the major
microsatellite markers. These include TGF-beta signalling pathway that is factor determining survival after resection
very high rates of loss at chromosomes observed in these lesions {931}. of pancreatic ductal carcinoma. The most
18q (90%), 17p (90%), 1p (60%), and 9p DNA mismatch repair genes, such as common sites of recurrences are the tis-
(85%) and moderately frequent losses at MLH1 and MSH2, can also play a role. sues surrounding the large mesenteric
3p, 6p, 8p, 10q, 12q, 13q, 18p, 21q, and Microsatellite instability resulting from the vessels {646}. Clear retroperitoneal resec-
22q (25-50% of cases). inactivation of both alleles of a DNA mis- tion margin or margins are therefore

Ductal adenocarcinoma 229


10a 19.7.2006 8:24 Page 230

Table 10.04
Genetic syndromes with an increased risk of pancreatic cancer.
Syndrome (MIM No)1 Mode of inheritance Gene (chromosomal location) Lifetime risk of pancreatic cancer

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 increased
colorectal 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

required, if a ‘curative’ resection (R0) is to found that median postoperative survival is associated with advanced tumour stage
be achieved {1122}. Second in frequency correlated significantly with tumour and shorter survival {46, 105, 476, 2079}.
are recurrences arising from lymph node grade {944}, mitotic index, and severity Tumours with low argyrophylic nucleolar
or liver metastases that were too small to of cellular atypia. As grading systems organizer region (AgNOR) counts per
be detected during surgery. The peri- are, however, to a great extent subjec- cell (< 3.25) have been reported to have
toneum and the bone marrow are rare tive, reproducibility may be low {1119}. a better prognosis than tumours with a
sites of recurrence, although malignant Other studies found no relationship high AgNOR count {1413}. High Ki-67
cells are detected cytologically in one between grade and survival {2079}. labeling index is an indicator of poor
quarter of the patients during laparoscopy Nuclear parameters such as median prognosis, but does not seem to be an
and one half of the patients when bone nuclear size, nuclear area, and nuclear independent prognostic parameter
marrow trepanation is performed during a perimeter have been shown to be of {1111, 1119}
Whipple procedure {870}. prognostic value for ductal adenocarci- The immunohistochemical expression of
noma {477, 944}. a number of growth factors has shown
Grading weak association with survival {21, 535}.
Based on the criteria of the grading sys- DNA content and proliferation
tem summarised in Table 10.02, it was Nondiploid and/or aneuploid DNA content

230 Tumours of the exocrine pancreas


10a 19.7.2006 8:24 Page 231

C. Capella
Serous cystic neoplasms E. Solcia
of the pancreas G. Klöppel
R.H. Hruban

Serous cystic pancreatic tumours are Serous microcystic adenoma stellate scar and a sunburst type calcifi-
cystic epithelial neoplasms composed of cation {532, 817, 1544}. On angiography,
glycogen-rich, ductular-type epithelial Definition the tumours are usually hypervascular.
cells that produce a watery fluid similar to A benign neoplasm composed of numer-
serum. Most are benign (serous cystade- ous small cysts lined by uniform glyco- Macroscopy
nomas), either serous microcystic adeno- gen-rich cuboidal epithelial cells, dis- Serous microcystic adenomas are sin-
ma or serous oligocystic adenoma. Only posed around a central stellate scar. gle, well-circumscribed, slightly bosse-
very rare cases exhibit signs of malig- lated, round lesions, with diameters
nancy (serous cystadenocarcinoma). Epidemiology ranging from 1-25 cm in greatest dimen-
A solid variant of serous cystadenoma This is a rare neoplasm, accounting for 1 sion (average, 6-10 cm). On section, the
(solid serous cystadenoma) has been to 2% of all exocrine pancreatic tumours neoplasms are sponge-like and are
described {1499} but remains to be {1280}. The mean age at presentation is made up of numerous tiny cysts filled
established as a separate disease entity. 66 years (range, 34-91 years), with a pre- with serous (clear watery) fluid. The
dominance in women (70%) {1781}. It cysts range from 0.01-0.5 cm, with a few
ICD-O codes has been reported in patients with differ- larger cysts of up to 2 cm in diameter.
Serous cystadenoma 8441/0 ent ethnicity {327, 2151}. Often, the cysts are arranged around a
Serous cystdenocarcinoma 8441/3 more or less centrally located, dense
Aetiology fibronodular core from which thin fibrous
The aetiology and pathogenesis of the septa radiate to the periphery (central
neoplasm are unknown. The striking stellate scar).
predilection for women suggests that sex
hormones or genetic factors may play a Histopathology
role. An association with Von Hippel- At low magnification, the pattern of the
Lindau disease has been reported {327, cysts is similar to a sponge. The cysts
2026} and confirmed by recent genetic contain proteinaceous fluid and are lined
molecular investigations {2026}. by a single layer of cuboidal or flattened
epithelial cells. Their cytoplasm is clear
Localization and only rarely eosinophilic and granular.
The neoplasms occur most frequently The nuclei are centrally located, round to
(50-75%) in the body or tail; the remain- oval in shape, uniform, and have an
ing tumours involve the head of the pan- inconspicuous nucleolus. Due to the
creas {49, 327}. presence of abundant intracytoplasmic
glycogen, the periodic acid-Schiff (PAS)
Clinical features stain without diastase digestion is posi-
About one third of the neoplasms pres- tive, whereas PAS-diastase and Alcian
ent as an incidental finding at routine blue stains are negative {160}. Mitoses
A physical examination or at autopsy {445}. are practically absent and there is no
Approximately two thirds of patients cytological atypia. Occasionally, the neo-
exhibit symptoms related to local mass plastic cells form intracystic papillary
effects, including abdominal pain, palpa- projections, usually without a fibrovascu-
ble mass, nausea and vomiting, and lar stalk. The central fibrous stellate core
weight loss {1544}. Jaundice due to is formed of hyalinized tissue with a few
obstruction of the common bile duct is clusters of tiny cysts.
unusual, even in neoplasms originating
from the head of the pancreas. Immunohistochemistry
Pancreatic serum tumour markers are The epithelial nature of these neoplasms
B generally normal. Calcifications are is reflected in their immunoreactivity for
found in a few patients on plain abdomi- epithelial membrane antigen and cytok-
Fig. 10.10 Microcystic serous cystadenoma. A CT
scan showing a well demarcated, spongy lesion in nal roentgenograms. Ultrasonography eratins 7, 8, 18, and 19. In addition, the
the head of the pancreas. B Cut surface showing a (US) and computed tomography (CT) neoplastic cells may focally express
typical honeycomb appearance and a (para-)cen- reveal a well circumscribed, multilocular CA19-9 and B72.3 {815, 1752}. They are
tral stellate scar (arrowhead). cyst, occasionally with an evident central uniformly negative for carcinoembryonic

Serous cystic neoplasms 231


10a 19.7.2006 8:24 Page 232

Genetics
Loss of heterozygosity at the von Hippel-
Lindau (VHL) gene locus, mapped to
chromosome 3p25, was found in 2/2
serous microcystic adenomas associat-
ed with VHL disease and in 7/10 spo-
radic cases {2026}. In contrast to ductal
adenocarcinomas, serous microcystic
adenomas have wild-type KRAS and
lack immunoreactivity for TP53 {815}.
Fig. 10.13 Serous cystadenoma. A cystic neoplasm
Prognosis replaces the head of the pancreas; a portion of duo-
The prognosis of patients with this neo- denum is on the right.
plasm is excellent, since there is only a
minimal risk of malignant transformation
{1159}. Aetiology
The aetiology of this neoplasm is not
known. In children, it has been suggest-
ed that the lesions may be of malforma-
Serous oligocystic adenoma tive origin and not true neoplasms since
in two cases there was a cytomegalo-
Definition virus infection in the adjacent pancreas
A benign neoplasm composed of few, {52, 273}.
Fig. 10.11 Serous oligocystic adenoma. This CT
scan shows a macrocystic neoplasm in the head of
relatively large cysts, lined by uniform
the pancreas. glycogen-rich cuboidal epithelial cells. Localization
Most serous oligocystic adenomas are
Synonyms located in the head and body of the pan-
antigen (CEA), trypsin, chromogranin A, This tumour category includes macro- creas {1781}. In the head, they may
synaptophysin, S-100 protein, desmin, cystic serous cystadenoma {257, 1062}, obstruct the periampullary portion of the
vimentin, factor VIII-related antigen and serous oligocystic and ill-demarcated common bile duct.
actin {49, 119, 445, 689, 815, 1752, adenoma {445}, and some cystade-
1781, 2151}. nomas observed in children {2057}. Clinical features
Whether these neoplasms form a homo- In most cases reported in adult patients,
Ultrastructure geneous group remains to be estab- the neoplasms caused symptoms that
Electron microscopy shows a single row lished. led to their discovery and removal. The
of uniform epithelial cells lining the cysts most common symptom was upper
and resting on a basal lamina {49, 160, Epidemiology abdominal discomfort or pain {1781}.
915}. The apical surfaces have poorly Serous oligocystic adenomas are much Other symptoms included jaundice and
developed or no microvilli. The cyto- less common than serous microcystic steatorrhoea. In infants, the tumours pre-
plasm contains numerous glycogen adenomas {445, 1062}. There is no sex sented as a palpable abdominal mass
granules but only a few mitochondria, predilection. Adults are usually 60 years {52, 273}.
short profiles of endoplasmic reticulum, and over (age range, 30-69 years; mean,
lipid droplets, and multivesicular bodies. 65 years); the tumour has been Macroscopy
Golgi complexes are rarely identified. described in two male and two female These neoplasms typically appear as a
Zymogen granules and neurosecretory infants, aged between 2 and 16 months cystic mass with a diameter of 4-10 cm
granules are absent. {1781}. (mean, 6 cm) {1781}. On cut surface,

A B C
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 and
focally PAS-positive.

232 Tumours of the exocrine pancreas


10a 19.7.2006 8:24 Page 233

there are few (occasionally only one)


macroscopically visible cysts filled with
watery clear or brown fluid. The cysts
usually vary between 1 and 2 cm in
diameter, but cysts as large as 8 cm
have been reported {1062}. The irregu-
larly arranged cysts, sometimes separat-
ed by broad septa, lie within a fibrous
stroma 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 are
poorly demarcated.

Histopathology
Serous oligocystic adenoma has gener-
ally the same histological features as
serous microcystic adenoma. Occasion-
ally, however, the lining epithelium may
be more cuboidal and less flattened, and
the nuclei are generally larger. The cyto-
plasm is either clear, due to the presence Fig. 10.14 Serous cystadenoma. Characteristic cuboidal epithelium forms intracystic papillary structures in
this field.
of glycogen, or eosinophilic. The stromal
framework is well developed and often
hyalinized. The tumour border is not well between 63 and 72 years of age; there Invasion of the spleen and metastasis to
defined and small cysts often extend into were four women and four men. Three the gastric wall were found in one case.
the adjoining pancreatic tissue. The patients were Caucasian and four were
immunohistochemical and ultrastructural from Japan {8, 815, 1781}. Histopathology
features are the same as for serous The histological features in the primary
microcystic adenoma {445, 2057}. Clinical features tumour as well as in the metastases are
Clinical symptoms reported in the cases remarkably similar to those of serous
Prognosis so far observed include bleeding from microcystic adenoma, although focal
There is no evidence of malignant poten- gastric varices due to tumour invasion of mild nuclear pleomorphism can be found
tial {445}. the wall of the stomach and the splenic {573, 2182}. One carcinoma reported
vein, a palpable upper abdominal mass, showed neural invasion and aneuploid
and jaundice. Ultrasonography and CT nuclear DNA content {879}, while other
Serous cystadenocarcinoma revealed a hyperechoic mass. CEA and cases showed vascular and perivascular
CA19-9 were normal or slightly increased. invasion {1412} or involvement of a
Definition lymph node and adipose tissue {8}.
A malignant cystic epithelial neoplasm Macroscopy
composed of glycogen-rich cells. These neoplasms have a spongy appear- Prognosis
ance {573, 879, 2182}. Their reported Serous cystadenocarcinomas are slowly
Epidemiology size has varied between 2.5 and 12 cm. growing neoplasms and palliative resec-
So far, only eight cases have been report- Liver and lymph node metastases have tion may be helpful even in advanced
ed {573, 815, 1781}. These patients were been reported {573, 815, 1781, 2182}. stages {2182}.

Serous cystic neoplasms 233


10a 19.7.2006 8:24 Page 234

G. Zamboni D.S. Longnecker


Mucinous cystic neoplasms G. Klöppel G. Adler
of the pancreas R.H. Hruban

Definition (54 versus 44 years), suggesting an ade-


Cystic epithelial neoplasms occurring noma - carcinoma sequence {2198}.
almost exclusively in women, showing no MCTNs seem to occur in patients with
communication with the pancreatic duc- different ethnic background {1781}.
tal system and composed of columnar,
mucin-producing epithelium, supported Aetiology
by ovarian-type stroma. According to the Pancreatic MCNs share many features
grade of intraepithelial neoplasia (dys- with their counterparts in the liver and
plasia), tumours may be classified as retroperitoneum, including their morphol-
adenoma, borderline (low-grade malig- ogy and their almost exclusive occur-
nant) and non-invasive or invasive carci- rence in women {328, 2139, 404, 2198}.
noma. The possible derivation of the stromal
component of MCNs from the ovarian pri-
ICD-O codes mordium is supported by morphology, Fig. 10.16 Mucinous cystic neoplasm in the tail of
Mucinous cystadenoma 8470/0 tendency to undergo luteinization, pres- the pancreas. The thick wall shows focal calcifica-
Mucinous cystic neoplasm ence of hilar-like cells, and immunophe- tion.
with moderate dysplasia 8470/1 notypic sex cord-stromal differentiation. It
Mucinous cystadenocarcinoma has been hypothesized that ectopic
non-invasive 8470/2 ovarian stroma incorporated during the predilection of MCN for the body-tail
invasive 8470/3 embryogenesis in the pancreas, along region of the pancreas {1977}.
the biliary tree or in the retroperitoneum
Epidemiology may release hormones and growth fac- Localization
Although more than 500 cases have tors causing nearby epithelium to prolif- The overwhelming majority of cases
been reported in the literature {328, erate and form cystic tumours {2198}. occur in the body-tail of the pancreas
2198}, mucinous cystic neoplasm (MCN) Since the left primordial gonad and the {328, 1932, 2148, 2198}. The head is
is still considered a rare lesion, repre- dorsal pancreatic anlage lie side by side only rarely involved, with a predilection
senting approximately 2-5% of all exo- during the fourth and fifth weeks of devel- for mucinous cystadenocarcinomas
crine pancreatic tumours {1781, 1932}. opment, this hypothesis could explain {1932, 2198}.
Changes in diagnostic criteria over the
years and the high resectability rate
compared to that of ductal adenocarci-
noma may have led to an overrepresen-
tation of MCNs in histopathology series.
The increasing number of these lesions
seen in recent years is most likely due to
advances in diagnostic techniques,
allowing early and correct recognition of
MCN.
In a recent study, in which MCNs were
defined by the lack of a communication
with the pancreatic duct system and the
presence of an ovarian type stroma, all
occurred in women {2198}. It is likely that
many of the cases reported in men in the
early literature were intraductal papillary
mucinous neoplasms (IPMNs) {328,
1932, 2198}.
The mean age at diagnosis is 49 years
(range, 20-82 years) {1781}. Patients with
mucinous cystadenocarcinomas are Fig. 10.15 Mucinous cystic neoplasm. The pancreatic duct, which does not communicate with the cyst
about 10 years older than patients with lumen, has been opened over the surface of the tumour (left, arrowheads). The thick wall and irregular lin-
adenomatous or borderline tumours ing of the bisected neoplasm are shown on the right.

234 Tumours of the exocrine pancreas


10a 19.7.2006 8:24 Page 235

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, but
is disastrous for patients with MCN, since
apparently histologically benign muci-
nous cystic tumours can recur after
Fig. 10.17 Well differentiated columnar epithelium drainage as invasive cystadenocarcino- Fig. 10.18 Mucinous cystic neoplasm presenting as
supported by ovarian-like stroma. mas {328, 2194}. The best approach to multiloculated cystic mass in the tail of the pan-
obtain an exact preoperative diagnosis is creas.
Clinical features the combined evaluation of all available
Symptoms and signs clinical, serological, radiological, and dostratifications and crypt-like invagina-
The clinical presentation depends on the biopsy findings. tions. The columnar cells are character-
size of the tumour. Small tumours ized by basally located nuclei and abun-
(< 3 cm) are usually found incidentally. Macroscopy dant intracellular mucin which is dia-
Larger tumours may produce symptoms MCNs typically present as a round mass stase-PAS and Alcian blue positive.
that are usually due to compression with a smooth surface and a fibrous Pseudopyloric, gastric foveolar, small
of adjacent structures, and are often pseudocapsule with variable thickness and large intestinal, and squamous dif-
accompanied by a palpable abdominal and frequent calcifications. The size of ferentiation can also be found. About half
mass. An association with diabetes mel- the tumour ranges from 2-35 cm in great- of the tumours contain scattered argy-
litus is relatively frequent, whereas jaun- est dimension, with an average size rophil and argentaffin endocrine cells at
dice is uncommon {1781}. between 6 and 10 cm. The cut surfaces the bases of the columnar cells {33, 36,
demonstrate a unilocular or multilocular 328, 2151}.
Serum tumour markers tumour with cystic spaces ranging from a
An increase in the peripheral blood serum few millimetres to several centimeters in Spectrum of differentiation
tumour markers CEA, CA 19-9, or high diameter, containing either thick mucin or This ranges from histologically benign
cyst fluid levels of CEA, CA 19-9, TAG-72, a mixture of mucin and haemorrhagic- appearing columnar epithelium to
CA-15-3 or MCA (mucin-like carcinoma- necrotic material. The internal surface of severely atypical epithelium. According
associated antigen) together with a low unilocular tumours is usually smooth and to the grade of intraepithelial neoplasia
amylase level is suggestive of MCN. The glistening, whereas the multilocular (dysplasia), tumours may be classified
highest levels of these markers are seen tumours often show papillary projections as adenoma, borderline (low-grade
in cystadenocarcinoma {1063, 1804}. and mural nodules. Malignant tumours malignant) and non-invasive or invasive
are likely to show papillary projections carcinoma {947}.
Imaging and/or mural nodules and multilocularity Mucinous cystadenomas show only a
Abdominal X-ray may demonstrate nodu- {2198}. As a rule, there is no communi- slight increase in the size of the basally
lar calcifications in the tumour capsule cation of the tumour with the pancreatic located nuclei and the absence of mitosis.
and compression or displacement of the duct system, but exceptions have been Mucinous cystic neoplasms of borderline
stomach, duodenum or colon. US and reported {2148}. malignant potential exhibit papillary pro-
CT reveal a sharply demarcated hypoe- jections or crypt-like invaginations, cellu-
choic or low density mass with one or Tumour spread and staging lar pseudostratification with crowding of
more large loculations {1461}. Features Invasive mucinous cystadenocarcinoma slightly enlarged nuclei, and mitoses.
suggestive of malignant transformation follows the same pathways of local Mucinous cystadenocarcinomas may be
include an irregular thickening of the cyst spread as ductal adenocarcinoma. The invasive or non-invasive. They show
wall and/or papillary excrescences pro- first metastases are typically found in the changes of high-grade intraepithelial
jecting into the cystic cavity {201, 2060}. regional peripancreatic lymph nodes and neoplasia which are usually focal and
Magnetic resonance imaging may have the liver {1781}. Staging follows the pro- may be detected only after careful
a complementary role. Endoscopic retro- tocol for ductal adenocarcinomas. search of multiple sections from different
grade cholangiography (RCP) shows a regions. The epithelial cells, which often
displacement of the main pancreatic Histopathology form papillae with irregular branching
duct and the absence of communication MCNs show two distinct components: an and budding, show nuclear stratification,
with the cystic cavity, a very important inner epithelial layer and an outer dense- severe nuclear atypia and frequent
finding for the differential diagnosis with ly cellular ovarian-type stromal layer. mitoses.
IPMN. Large locules can be extensively denud- Invasive mucinous cystadenocarcinoma
Fine needle aspiration cytology (FNAC) ed and many sections are often needed is characterized by invasion of the malig-
can be performed percutaneously with to demonstrate the epithelial lining. The nant epithelium into the stroma. The inva-
CT or US guidance, or intraoperatively epithelium may be flat or it may form sive component usually resembles the
{1019}. papillary or polypoid projections, pseu- common ductal adenocarcinoma. How-

Mucinous cystic neoplasms 235


10a 19.7.2006 8:24 Page 236

ever, mucinous cystadenocarcinomas


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

Stroma
The ovarian-type stroma consists of
densely packed spindle-shaped cells
with round or elongated nuclei and
sparse cytoplasm. It frequently displays
a variable degree of luteinization, char-
acterized by the presence of single or
clusters of epithelioid cells with round to
oval nuclei and abundant clear or
eosinophilic cytoplasm. Occasionally,
these cells, resembling ovarian hilar
cells, can be found associated with (or
present in) nerve trunks. Stromal luteini-
zation is found in decreasing order of fre- Fig. 10.19 Mucinous cystadenocarcinoma. The neoplasm exhibits well differentiated and poorly differenti-
quency from adenomatous to carcinoma- ated mucinoius epithelium.
tous cases {2194}. The stroma of large
MCNs may become fibrotic and hypocel-
lular. Rare MCNs show mural nodules tric type mucin marker M1 and PGII, the Genetics
with a sarcomatous stroma or an associ- intestinal mucin markers CAR-5 and Activating point mutations in codon 12 of
ated sarcoma {1932, 2088, 2198}. M3SI, and the pancreatic type mucin KRAS were found in invasive mucinous
marker DUPAN-2 and CA19-9 {119, cystic neoplasms (MCNs) {117} and
Immunohistochemistry 1714, 2151, 2190}. Furthermore, pancre- mucinous cystic neoplasms associated
The epithelial component is immunoreac- atic, hepatobiliary, and retroperitoneal with osteoclast-like giant cells {1485}.
tive with epithelial markers including MCNs share the same types of intraep- Mutations of KRAS and allelic losses of
EMA, CEA, cytokeratins 7, 8, 18 and 19 ithelial endocrine cells {613, 1911, 1910}. 6q, 9p, 8p have been reported in MCNs
{2151}, and it may show gastroen- p-53 nuclear positivity in more than 10% with sarcomatous stroma {1998}.
teropancreatic differentiation, as is also of neoplastic cells, found in 20% of MCN, Prognosis and predictive factors
observed in ovarian and retroperitoneal strongly correlates with mucinous cys- The prognosis of MCN, regardless of the
MCN {1714, 1910}. With increasing tadenocarcinoma {2198}. degree of cellular atypia, is excellent if
degrees of epithelial atypia the character The stromal component expresses the tumour is completely removed {328,
of mucin production changes from sul- vimentin, alpha smooth muscle actin, 410, 2060, 2198}. The prognosis of inva-
phated to sialated or neutral mucin desmin and, in a high proportion, prog- sive mucinous cystadenocarcinoma
{1932}. The neoplastic cells express gas- esterone and estrogen receptors {2198}. depends on the extent of tumour inva-
The luteinized cells are labeled with anti- sion. Tumour recurrence and poor out-
bodies against tyrosine hydroxylase, cal- come correlate with invasion of the
retinin, which have been shown to recog- tumour wall and peritumoural tissues
nize testicular Leydig cells and hilar {2198}. Patients older than 50 years
ovarian cells, and the sex cord-stromal appear to have a lower survival rate
differentiation marker inhibin {2198, {2198}. Other variables such as site,
2206}. tumour size, macroscopic appearance,
grade of differentiation, luteinization of
Ultrastructure the stroma and p53 positivity have no
Electron microscopy of tumours with only prognostic significance.
mild to moderate dysplasia demon- Aneuploidy is a rare event in MCNs, is
strates columnar epithelial cells resting largely restricted to mucinous cystade-
Fig. 10.20 Mucinous cystadenocarcinoma. The on a thin basement membrane. The cells nocarcinomas and carries a worse prog-
thick wall of this cystic neoplasm is invaded by may have well-developed microvilli and nosis {1792, 1932, 512}.
mucinous carcinoma at upper left. mucin granules {33}.

236 Tumours of the exocrine pancreas


10a 19.7.2006 8:24 Page 237

D.S. Longnecker R.H. Hruban


Intraductal papillary-mucinous G. Adler G. Klöppel
neoplasms of the pancreas

Definition IPMNs are found in a broad age range


An intraductal papillary mucin-producing (30-94) with a median age of diagnosis in
neoplasm, arises in the main pancreatic the 6-7th decade {1443, 2148, 556}.
duct or its major branches. The papillary They occur more frequently in males than
epithelium component, and the degree in females {1138, 2148}. IPMNs were first
of mucin secretion, cystic duct dilatation, reported from France and Japan, but
and invasiveness are variable. Intra- subsequent reports have come from all
ductal papillary-mucin neoplasms are parts of the world. Two studies provide
divided into benign, borderline, and some evidence that the incidence may
malignant non-invasive or invasive be higher among Asians than among
lesions. whites, but issues of consistency of clas-
sification require that this be further eval-
ICD-O codes uated {1095, 941}.
Intraductal papillary-mucinous adenoma
8453/0 Aetiology A
Intraductal papillary-mucinous neoplasm The low incidence and imprecise identifi-
with moderate dysplasia 8453/1 cation of IPMN in large databases has
Intraductal papillary-mucinous carcinoma hindered recognition of aetiological fac-
non-invasive 8453/2 tors. In one series, most patients with
invasive 8453/3 IPMNs were cigarette smokers {550}.
There is no consistent association with
Synonyms and historical annotation other types of pancreatic neoplasm
Papillary pancreatic neoplasms have {2198}.
been recognized for many years {247,
1532}, but the distinction between muci- Localization
nous cystic neoplasms and intraductal The majority of these neoplasms occur in B
Fig. 10.21 Intraductal papillary-mucinous neoplasm.
papillary neoplasms was not made until the main pancreatic duct and its branch-
A Large neoplasm in the head of the pancreas con-
the last two decades {947, 1781, 65, es in the head of the pancreas {1781,
taining multiple cystic spaces. B The lesion illus-
1404}. Interest in IPMNs was first stimu- 330, 97}. A single cystic mass or seg- trated in A sectioned to demonstrate the dilated,
lated when they were recognized clini- mental involvement of the duct is usual, mucin-filled main pancreatic duct (arrowheads).
cally {1281}, and pathological descrip- but diffuse involvement is also described
tions quickly followed {2164, 1093}. The {1093, 1751, 1953}. Multicentric origin is
incidence appears to have risen since suspected because of recurrence in operative diagnosis. Endoscopic biopsy
the first reports, but this may reflect the pancreatic remnants following surgical or cytology may provide histological con-
combined effects of new diagnostic removal of IPMNs {1088}. IPMNs may firmation, but definitive diagnosis
techniques, and progress in recognition extend to the ampulla of Vater, common- requires surgical removal and extensive
and classification of IPMNs {1138, 918}. ly in association with involvement of the histological sampling. Serum markers
It is likely that many IPMNs were classi- duct of Wirsung or the common bile duct such as CEA and CA19-9 are too insen-
fied among the mucinous cystic neo- {1781}. sitive to be of value {2148, 1953}.
plasms as recently as a decade ago.
Clinical features Macroscopy
Epidemiology Clinical presentation includes epigastric Depending on the degree of ductal
The incidence is low and not precisely pain, pancreatitis, weight loss, diabetes, dilatation, IPMNs vary in size from 1 to 8
known because IPMNs are not accurately and jaundice {2169, 1953, 942}; some cm in maximum dimension {17}. They are
identified in large population-based reg- patients have no symptoms. Some cases cystic and may appear multiloculated if
istries. Nomenclature and classification are detected because of dilatation of the branch ducts are involved. The mucin
have been highly variable until recently, pancreatic duct seen incidentally in found in IPMN is viscous or sticky and
and are not yet standardized worldwide. imaging studies. Serum amylase and can dilate parts of the duct that are lined
IPMNs have been estimated to amount to lipase are commonly elevated. by normal appearing epithelium. The lin-
1-3% of exocrine pancreatic neoplasms, Endoscopic ultrasound, ERCP, and ing of cystic spaces may be smooth and
with an incidence rate well below 1 per endoscopic examination of the pancreat- glistening, granular, or velvet-like, the lat-
100,000 per year {1280, 1095}. ic duct {1596} may all contribute to pre- ter reflecting papillary growth. When

Intraductal papillary-mucinous neoplasms 237


10a 19.7.2006 8:24 Page 238

resection {1953}. Invasive neoplasms are


staged as ductal adenocarcinomas.

Histopathology
IPMN tumour cells are usually tall colum-
nar mucin-containing epithelial cells that
line dilated ducts or cystic spaces aris-
ing from dilated branch ducts. The
epithelium typically forms papillary or
pseudopapillary structures, but portions
Fig. 10.22 Intraductal papillary mucinous neoplasm of the neoplasm may be lined by non-
in the main pancreatic duct (arrowhead). papillary epithelium or be denuded of
epithelium. The amount of mucin produc-
tion varies widely, as does the degree of
papillary growths are large, the dilated duct dilatation {97, 872}. Goblet or
ducts may show localized excrescences Paneth cells may be present as a mani- Fig. 10.24 Intraductal papillary-mucinous neoplasm
or be filled with soft papillary masses of festation of intestinal metaplasia in the within the dilated main pancreatic duct and branch
ducts.
tissue. neoplastic epithelium, and neuroen-
The pancreatic parenchyma surrounding docrine cells have also been demon-
and retrograde to the tumour is often strated.
pale and firm, reflecting changes of The recently described intraductal onco- Histochemistry and immunohistochemistry
chronic obstructive pancreatitis. When cytic papillary neoplasm probably repre- A variety of abnormalities have been
there is invasion, gelatinous areas may sents a rare related phenotype that is demonstrated in IPMNs using mucin and
be identified in fibrotic tissue. similar macroscopically {1244, 1860}. immunohistochemical stains.
Oncocytic IPMNs are composed of strat- Most IPMNs express epithelial mem-
Tumour spread and staging ified oncocytic cells with pale pink cyto- brane antigen (EMA) as well as several
Adenomas, borderline tumours and non- plasmic granules that are much finer cytokeratins {1917}. A variety of
invasive carcinomas may extend intra- than those seen in Paneth cells. Goblet endocrine cell types occur in most
ductally into adjacent portions of the duct cells may be interspersed among the tumours but account for fewer than 5 per
system, and evidence of such extension oncocytic cells. A characteristic feature cent of the tumour cells {1676}.
is often encountered adjacent to IPMNs. of the oncocytic papillary neoplasms is A change in type of mucin has been sug-
Recurrence following surgical resection the formation of ‘intraepithelial lumina’, gested as a marker of progression since
has been reported in patients that had which are spaces in the epithelium about normal duct cells characteristically
IPMNs extending into the margin of one quarter the size of the cells. secrete sulfated mucin, intraductal papil-
lary-mucinous adenomas characteristi-
cally secrete neutral mucin, and dysplas-
tic epithelium secretes predominantly
sialomucin {1138, 1916, 1186}. Nearly all
IPMNs express MUC2 {2179}.
Overexpression of c-erbB-2 protein
occurs in a high fraction of IPMNs {1939,
1675, 1877, 380}.
A study of cell proliferation, as shown by
PCNA and Ki67 labelling indices,
demonstrated a progressive increase in
cell proliferation from normal duct epithe-
lium, to adenomas, to borderline
tumours, to carcinomas {1917}. The
labeling index in IPM carcinomas was
lower than in ductal adenocarcinomas.
Although immunostaining of p53 protein
was detected in a lower fraction of IPMN
(31%) than is usually seen in solid ductal
adenocarcinomas, it was found only in
borderline and malignant IPMN and
therefore may be a marker of progression
{1939}.
A B Failure of IPMN to elicit the production of
Fig. 10.23 Intraductal papillary mucinous neoplasms with (A) columnar epithelium and (B) oncocytic epithe- a collagenase that mediates invasion
lium. was reported {2193}.

238 Tumours of the exocrine pancreas


10a 19.7.2006 8:24 Page 239

Classification and grading of IPMNs


IPMNs have been the source of great
confusion that is reflected in a diverse
nomenclature found in case and series
reports and in standard references
{1781}. Because of the variability within a
tumour, it is important to sample IPMNs
well, giving special emphasis to papillary
areas because this is where the highest
degree of intraepithelial neoplasia (dys-
plasia) is likely to occur, and to sclerotic
areas that may reflect invasion.
IPMNs are classified as benign, border-
line, or malignant on the basis of the
greatest degree of dysplasia present. In
accordance with the previous WHO clas-
sification, lesions are specifically desig-
nated as intraductal papillary-mucinous
adenoma, borderline intraductal papil-
lary-mucinous neoplasm, and intraductal
papillary-mucinous carcinoma, with or Fig. 10.25 Intraductal papillary-mucinous carcinoma. Intraductal papillary neoplasm (left), invasive mucin
without invasion {947, 1781}. secreting carcinoma (right).
A slightly different histopathological clas-
sification has been proposed by the
Japan Pancreas Society (JPS) {65}, intra- small clusters of epithelial cells into the or mucinous noncystic carcinoma, then
ductal tumours are designated as intra- lumen support the diagnosis of carcino- that diagnosis may be used, descriptive-
ductal papillary adenoma or adenocarci- ma. Severe dysplasia is manifest cyto- ly noting the association with an IPMN
noma. The degree of cellular atypia in logically as loss of polarity, loss of differ- component.
adenomas is designated as slight, mod- entiated cytoplasmic features including
erate, or severe. The JPS category of diminished mucin content, cellular and Differential diagnosis
adenoma with severe atypia corre- nuclear pleomorphism, nuclear enlarge- Historically, IPMNs and mucinous cystic
sponds to the WHO borderline lesion, ment, and the presence of mitoses neoplasms (MCNs) have been confused
although some authors also utilize a bor- (especially if suprabasal or luminal in because they are both cystic and have a
derline category {2148} location). Severely dysplastic cells may similar epithelial component. However,
lack mucin. Non-invasive lesions are IPMNs and MCNs are distinct entities
Intraductal papillary-mucinous adenoma termed non-invasive intraductal papil- and can be separated easily, because
The epithelium is comprised of tall lary-mucinous carcinoma. When inva- MCNs typically occur in women with a
columnar mucin-containing cells that sive, an IPMN may be called a papillary- median age in the fifth decade, almost
show slight or no dysplasia, i.e. the mucinous carcinoma since it is no longer always are located in the tail or body of
epithelium maintains a high degree of only intraductal. When IPMNs become the pancreas, typically exhibit a thick
differentiation in adenomas. invasive, the invasive component may wall with a cellular ‘ovarian’ stroma, and
assume the appearance of a tubular typically fail to communicate with the
Borderline intraductal papillary-mucinous ductal adenocarcinoma or a mucinous pancreatic duct system.
neoplasm noncystic carcinoma {17}. If the invasive
IPMNs with moderate dysplasia are component is dominant, and is a ductal Precursor lesions
placed in the borderline category. The The criteria for classifying pancreatic
epithelium shows no more than moderate intraepithelial neoplasia (PanIN) lesions
loss of polarity, nuclear crowding, (including papillary hyperplasia, see
nuclear enlargement, pseudostratifica- chapter on ductal adenocarcinoma of
tion, and nuclear hyperchromatism. the pancreas) in IPMNs are not well
Papillary areas maintain identifiable stro- established {1144, 1744}, and need to be
mal cores, but pseudopapillary struc- defined. PanIN lesions characteristically
tures may be present. occur in intralobular ducts, are not
detected macroscopically, and are clini-
Intraductal papillary-mucinous carcinoma cally silent {17}. It seems likely that the
IPMNs with severe dysplastic epithelial earliest stage of development of the
change are designated as carcinoma IPMN would involve the progression from
even in the absence of invasion. Fig. 10.26 Intraductal papillary-mucinous carcino- a flat area of mucous metaplasia to a
Carcinomas are papillary or micropapil- ma. This tumour shows moderately differentiated papillary lesion in a main or branch pan-
lary. Cribriform growth and budding of (left) and well differentiated (right) areas. creatic duct as suggested by Nagai et al.

Intraductal papillary-mucinous neoplasms 239


10a 19.7.2006 8:24 Page 240

Table 10.05 dence of p53 abnormality in IPMN {544},


Summary of mucin histochemistry and immunostaining of IPMN. mutations have been demonstrated in
Antibody or epitope Comments on staining in IPMN Reference two adenomas {876}. Overexpression of
anti-apoptotic genes in IPMN is reported
Differentiation markers {1247}.
Alcian blue stain Adenomas contain neutral mucin, {1138, 1916}
Mutations of KRAS and TP53 genes have
carcinomas contain sialomucin
MUC1 Negative>>positive (2179}
been detected in DNA from pancreatic
MUC2 Positive>>negative {2179} juice of patients with IPMN {875}.
Endocrine markers < 5% of cells positive in most IPMN {1676}
Epithelial membrane antigen Positive {1917} Prognosis and predictive factors
Cytokeratins 7, 8, 18, 19 Positive {1917} The overall 5-year survival rate for a com-
CEA Positive {1939} posite series was 83% {2148}. The prog-
CA-19-9 Positive {1939} nosis is excellent for adenomas and bor-
B72.3 Positive {1939} derline tumours with 3 and 5-year sur-
DUPAN-2 Seen in a minority {1939} vivals approaching 100%. The survival
rates are high for non-invasive carcino-
Oncogene products
mas, and survival rates for patients with
c-erbB-2 13/17 IPMN positive, including all with {1675}
moderate or severe dysplasia {1939} invasive IPMNs may also be higher than
p27 p27 staining exceeds cyclin E {556} for patients with typical ductal adenocar-
cinomas {2148, 97, 2169}. The histologi-
Tumour suppressor gene products cal classification, with major emphasis
TP53 Often positive in borderline tumours and {1939} on the presence or absence of invasion,
carcinomas and stage remain the best predictors for
Proliferation markers survival.
PCNA and Ki67 Labeling index increases with progression {1917} As the distinction between IPMNs and
from adenoma to carcinoma
MCNs has been refined, some authors
report that MCNs are more often malig-
nant than IPMNs and that the latter have
{1306}. Thus, it will be difficult to recog- Genetics a better prognosis following treatment
nize the initial stage of an intraductal Activating point mutations in codon 12 of {97}, but this was not confirmed in other
papillary-mucinous adenoma unless a the KRAS gene have been reported in series {1953, 551}. Expression of MUC2
distinctive molecular marker is identified. 40-60% of intraductal papillary mucinous and MUC5AC mucins are associated
neoplasms {1939, 544}. Fujii et al. exam- with a good prognosis relative to ductal
Genetic susceptibility ined a series of IPMNs using polymorphic adenocarcinomas that do not express
Excessive rates of colonic and gastric microsatellite markers and found allelic these mucins {2179, 2178}.
epithelial neoplasms were reported in a loss at 9p in 62% of the cases and at 17p
group of 42 patients with IPMNs {106}. and at 18q in ~40% {544}. These allelic
This suggests the possibility of a predis- losses include the loci of the p16, TP53,
posing genetic susceptibility, but no spe- and DPC4 tumour-suppressor genes. In
cific hereditary syndrome was identified. addition to immunohistochemical evi-

240 Tumours of the exocrine pancreas


10a 19.7.2006 8:24 Page 241

D.S. Klimstra
Acinar cell carcinoma D. Longnecker

Definition eosinophilia may also be noted. In some vessels may occur. Multicystic examples
A carcinoma occurring mainly in adults, patients, the lipase hypersecretion syn- of acinar cell carcinoma have been
composed of relatively uniform neoplas- drome is the first presenting sign of the reported as acinar cell cystadenocarci-
tic cells that are arranged in solid and tumour, while in others it develops follow- noma {229, 739, 1815}.
acinar patterns and produce pancreatic ing tumour recurrence. Successful surgi-
enzymes. cal removal of the neoplasm may result in Tumour spread and staging
the normalization of the serum lipase Metastases most commonly affect
ICD-O codes levels and resolution of the symptoms. regional lymph nodes and the liver,
Acinar cell carcinoma 8550/3 although distant spread to other organs
Acinar cell cystadenocarcinoma 8551/3 Laboratory analyses occurs occasionally. Acinar cell carcino-
Mixed acinar-endocrine carcinoma 8154/3 Other than an elevation of serum lipase mas are staged using the same protocol
levels associated with the lipase hyper- as ductal adenocarcinomas.
Epidemiology secretion syndrome, there are no specif-
Acinar cell carcinomas represent 1-2% of ic laboratory abnormalities in patients Histopathology
all exocrine pancreatic neoplasms in with acinar cell carcinoma. A few cases Large nodules of cells are separated by
adults {739, 936}. Most occur in late show increased serum alpha-fetoprotein hypocellular fibrous bands. The desmo-
adulthood, with a mean age of 62 years {819, 1426, 1369, 1747}. plastic stroma characteristic of ductal
{825, 979, 2073}. The tumour is rare in adenocarcinomas is generally absent.
adults under the age of 40. Pediatric Imaging Tumour necrosis may occur and is gen-
cases do occur, usually manifesting in Acinar cell carcinomas are generally erally infarct-like in appearance. Within
patients 8 to 15 years of age {979, 1282}. bulky with a mean size of 11 cm {979}. the tumour cell islands, there is an abun-
Males are affected more frequently than On abdominal CT scans, they are cir- dant fine microvasculature.
females, with an M:F ratio of 2:1 {739, cumscribed and have a similar density to Several architectural patterns have been
936}. the surrounding pancreas. Because of described. The most characteristic is the
their larger size and relatively sharp cir- acinar pattern, with neoplastic cells
Aetiology cumscription, acinar cell carcinomas can arranged in small glandular units; there
The aetiology is unknown. generally be distinguished from ductal are numerous small lumina within each
adenocarcinomas radiographically. island of cells giving a cribriform appear-
Localization ance. In some instances, the lumina are
Acinar cell carcinomas may arise in any Fine needle aspiration cytology more dilated, resulting in a glandular pat-
portion of the pancreas but are some- There is usually a high cellular yield from tern, although separate glandular struc-
what more common in the head. fine needle aspiration {1446, 1978, 2015}. tures surrounded by stroma are usually
The cytological appearances of acinar not encountered. A number of the micro-
Clinical features cell carcinomas closely mimic of pancre-
Symptoms and signs atic endocrine neoplasms, although the
Most acinar cell carcinomas present clin- latter are more likely to exhibit a plasma-
ically with relatively non-specific symp- cytoid appearance to the cells and a
toms including abdominal pain, weight speckled chromatin pattern. Immuno-
loss, nausea, or diarrhoea {739, 936, histochemistry may be used on cytologi-
979, 2073}. Because they generally push cal specimens to confirm the diagnosis of
rather than infiltrate into adjacent struc- acinar cell carcinoma {1446, 1978}.
tures, biliary obstruction and jaundice
are infrequent presenting complaints. Macroscopy
A well-described syndrome occurring in Acinar cell carcinomas are generally cir-
10-15% of patients is the lipase hyper- cumscribed and may be multinodular
secretion syndrome {1781, 213, 936, {739, 936}. Individual nodules are soft
975}. It is most commonly encountered in and vary from yellow to brown. Areas of
patients with hepatic metastases, and is necrosis and cystic degeneration may
characterized by excessive secretion of be present. Occasionally, the neoplasm
lipase into the serum, with clinical symp- is found attached to the pancreatic sur-
toms including subcutaneous fat necro- face. Extension into adjacent structures, Fig. 10.27 Acinar cell carcinoma. The hypodense
sis and polyarthralgia. Peripheral blood such as duodenum, spleen, or major lobulated tumour occupies the tail of the pancreas.

Acinar cell carcinoma 241


10a 19.7.2006 8:24 Page 242

glandular tumours previously reported as mitochondria. Cellular polarization is gen-


‘microadenocarcinoma’ were more erally evident, with basal basement mem-
recently shown to have been acinar cell branes and apical lumina. Adjacent cells
carcinomas (see chapter on miscella- are joined by tight junctions. Although the
neous carcinomas). The second most SP distribution varies from cell to cell, most
AC
common pattern in acinar cell carcino- acinar cell carcinomas exhibit electron
mas is the solid pattern: solid nests of dense zymogen granules. In polarized
cells lacking luminal formations are cells, they are located in the apical cyto-
separated by small vessels. Within these plasm, and the secretory contents may
nests, cellular polarization is generally not be seen within the luminal spaces where
evident, but there may be an accentua- Fig. 10.28 An acinar cell carcinoma (AC) lies near granules have fused with the apical
tion of polarization at the interface with the spleen (SP). The tumour’s cut surface is lobulat- membrane. The size range of zymogen
the vessels, resulting in basal nuclear ed. granules in acinar cell carcinomas (125-
localization in these regions and a pal- 1000 nm) is somewhat greater than that
isading of nuclei along the microvascula- found in non-neoplastic acinar cells (250-
ture. In rare instances, a trabecular trypsin and chymotrypsin are detectable 1000 nm). In addition to typical zymogen
arrangement of tumour cells may be in over 95% of cases; lipase is less com- granules, a second granule type, the
present, with exceptional cases also monly identified (approximately 70% of irregular fibrillary granule, is detected
showing a gyriform appearance {936}. cases) {936}. Pancreatic stone protein is ultrastructurally in many cases {302, 936,
The neoplastic cells contain minimal to also commonly expressed {739}. In solid 938, 1477}. It has been suggested that
moderate amounts of cytoplasm that areas, immunohistochemical staining for irregular fibrillary granules may represent
may be more abundant in cells lining enzymes may show diffuse cytoplasmic a recapitulation of the fetal zymogen
lumina. The cytoplasm varies from positivity, whereas the reaction product is granules, although attempts to document
amphophilic to eosinophilic and is char- restricted to the apical cytoplasm in aci- the presence of pancreatic enzymes
acteristically granular, reflecting the pres- nar areas. within them by immunohistochemistry
ence of zymogen granules. In many Immunohistochemical markers of endo- have been unconvincing {936, 938,
instances, however, only minimal cyto- crine and ductal differentiation may also 1032}.
plasmic granularity may be detectable. be detected in acinar cell carcinomas,
The nuclei are generally round to oval generally in a minor cell population {739, Acinar cell carcinoma variants
and relatively uniform, with marked 936}. Scattered individual cells stain for Acinar cell cystadenocarcinoma
nuclear pleomorphism being exception- chromogranin or synaptophysin are Acinar cell cystadenocarcinomas are
al. A single, prominent, central nucleolus found in over one third of lesions. Over rare, grossly cystic neoplasms with
is a characteristic finding but not invari- half exhibit focal CEA and B72.3 expres- cytoarchitectural features of acinar cell
ably present. The mitotic rate is variable sion {739, 936}. Uncommonly, there is carcinomas {229, 825, 739, 1815}.
(mean 14 per 10 high power fields, range immunohistochemical positivity for alpha-
0 to > 50 per 10 high power fields). fetoprotein, generally in cases associat- Mixed acinar-endocrine carcinoma
Zymogen granules are weakly positive ed with elevations in serum alpha-feto- Rare neoplasms have shown a substan-
with PAS staining, and resistant to dia- protein {819}. tial (greater than 25%) proportion of more
stase. Mucin production is generally not than one cell type. These neoplasms
detectable with mucicarmine or Alcian Ultrastructure have been designated ‘mixed carcino-
blue stains and, if present, is limited to Electron microscopy provides further evi- mas’, and, depending upon the cell
the luminal membrane in acinar or glan- dence of enzyme production {675, 408, types identified, as ‘mixed acinar-
dular formations. The histochemical stain 936, 1978}. Exocrine secretory features endocrine carcinoma’, ‘mixed acinar-
for butyrate esterase can be used to are consistently found, with abundant ductal carcinoma’, or ‘mixed acinar-
identify active lipase within the tumour rough endoplasmic reticulum arranged in endocrine-ductal carcinoma’ {997, 1369,
cells {936, 938}. Due to the scarcity of parallel arrays and relatively abundant 2015}. Of these, the best characterized is
zymogen granules in many examples of the mixed acinar-endocrine carcinoma
acinar cell carcinoma, histochemical {997}. In many mixed acinar-endocrine
stains are relatively insensitive for docu- carcinomas, the evidence for divergent
menting acinar differentiation, and very differentiation is only provided by
focal staining may be difficult to interpret immunohistochemical staining. Although
with confidence. different regions of the tumours may sug-
gest acinar or endocrine differentiation
Immunohistochemistry morphologically, many areas have inter-
Immunohistochemical identification of mediate features, and immunohisto-
pancreatic enzyme production is helpful chemistry generally shows a mixture of
in confirming the diagnosis of acinar cell cells expressing acinar or endocrine
carcinoma. Antibodies against trypsin, markers (or both). In exceptional cases,
chymotrypsin, lipase, and elastase have Fig. 10.29 Acinar cell carcinoma showing well dif- however, there is also morphological evi-
all been used {739, 810, 936, 1282}. Both ferentiated acinar structures. dence of multiple lines of differentiation,

242 Tumours of the exocrine pancreas


10a 19.7.2006 8:24 Page 243

KRAS mutations and TP53 immunoreac-


tivity {739, 1485, 1920, 1921}.

Prognosis and predictive factors


These neoplasms are aggressive, with a
median survival of 18 months and a
5-year survival rate of less than 10%
{739, 936}. Approximately 50% of
patients have metastases at the time of
diagnosis, and an additional 25% devel-
op metastatic disease following surgical
resection of the primary tumour {936}.
The most important prognostic factor is
tumour stage, with patients lacking
lymph node or distant metastases surviv-
ing longer {936}. Patients with the lipase
hypersecretion syndrome were shown to
have a particularly short survival, be-
cause most of these patients had wide-
spread metastatic disease. Despite poor
overall survival rates, there are anecdot-
Fig. 10.30 Acinar cell carcinoma. Solid pattern with uniform round nuclei.
al reports of survival for several years in
the presence of metastatic disease, and
with some regions exhibiting obvious aci- cytoplasm) or depletion of zymogen responses to chemotherapy have been
nar features and other areas endocrine granules (resulting in reduced eosino- noted {936}. Thus, the prognosis of aci-
features. Most reported acinar-endocrine philia of the apical cytoplasm and an nar cell carcinoma may be somewhat
carcinomas have been composed pre- increase in nuclear:cytoplasmic ratio); less poor than that of ductal adenocarci-
dominantly of acinar elements based on these lesions are relatively common inci- noma.
the proportion of cells staining immuno- dental findings in resected pancreases. No specific grading system for acinar
histochemically {997}. There are insuffi- cell carcinomas has been proposed. No
cient cases recorded to suggest that the Genetics association between the extent of acinus
biological behaviour of mixed acinar- In contrast to ductal adenocarcinomas, formation and prognosis has been
endocrine carcinomas differs from that of acinar cell carcinomas very rarely show observed.
pure acinar cell carcinomas. There is an insufficient number of pedi-
atric acinar cell carcinomas to allow an
Precursor lesions accurate assessment of the biological
No documented precursor lesions for behaviour in children. Available data
acinar cell carcinomas have been suggest that acinar cell carcinomas
defined. Initial suggestions that so-called occurring under the age of 20 may be
atypical acinar cell nodules may repre- less aggressive than their adult counter-
sent preneoplastic lesions of acinar cells parts 936, 1446}.
have not been substantiated by later
studies {1094}. Atypical acinar cell nod-
ules occur either because of dilatation of
the rough endoplasmic reticulum (result- Fig. 10.31 Acinar cell carcinoma showing
ing in reduced basophilia of the basal immunoreactivity for chromogranin.

Acinar cell carcinoma 243


10b 19.7.2006 8:25 Page 244

D.S. Klimstra
Pancreatoblastoma D. Longnecker

Definition many patients present with an incidental- tumours are grossly cystic, a phenome-
A malignant epithelial tumour, generally ly detected abdominal mass {782, 939}. non reported in all cases associated with
affecting young children, composed of Related symptoms include pain, weight the Beckwith-Wiedeman syndrome {432}.
well-defined solid nests of cells with aci- loss, and diarrhoea. The paraneoplastic
nar formations and squamoid corpus- syndromes associated with acinar cell Histopathology
cles, separated by stromal bands. Acinar carcinoma (lipase hypersecretion syn- The epithelial elements of pancreato-
differentiation prevails, often associated drome) and pancreatic endocrine neo- blastomas are highly cellular and
with lesser degrees of endocrine or duc- plasms have not been described, but arranged in well-defined islands separat-
tal differentiation. one patient developed Cushing syn- ed by stromal bands, producing a ‘geo-
drome {1478}. graphic’ low power appearance. Solid,
ICD-O code 8971/3 Radiologically, pancreatoblastomas are hypercellular areas composed of nests
large, well-defined, lobulated tumours of polygonal cells alternate with regions
Epidemiology which may show calcifications on CT showing more obvious acinar differentia-
Incidence scan {1833, 2027, 2117}. tion, with polarized cells surrounding
Pancreatoblastoma is an exceedingly There is no consistent elevation of serum small luminal spaces. In rare tumours,
rare tumour, less than 75 cases having tumour markers, but some cases have larger glandular spaces lined by mucin-
been reported {782, 939, 2117}. exhibited increased alpha-fetoprotein containing cells may be seen {939}.
However, it is among the most frequent levels {802, 939}. Nuclear atypia is generally minimal.
pancreatic tumours in childhood, proba- Squamoid corpuscles. One of the most
bly accounting for 30-50% of pancreatic Macroscopy characteristic features of pancreatoblas-
neoplasms occurring in young children The size of pancreatoblastomas varies toma is the ‘squamoid corpuscle’. These
{631}. from 1.5-20 cm. Most tumours are soli- enigmatic structures vary from large
tary, solid neoplasms composed of well- islands of plump, epithelioid cells to
Age and sex distribution defined lobules of soft, fleshy tissue sep- whorled nests of spindled cells to frankly
The majority of pancreatoblastomas arated by fibrous bands. Areas of necro- keratinizing squamous islands. The
occur in children, most being under the sis may be prominent. Uncommonly the nuclei of the squamoid corpuscles are
age of 10. The median age of pediatric larger and more oval than those of the
patients is approximately 4 years {742, surrounding cells; nuclear clearing due
939}, and only a few cases have been to the accumulation of biotin may be
described in the second decade of life seen {1895}. The frequency and compo-
{782}. A number of congenital examples sition of the squamoid corpuscles varies
have also been documented {939}. in different regions of the tumour and
Rarely, tumours histologically indistin- between different cases.
guishable from pancreatoblastomas Stroma. Especially in pediatric cases, the
occur in adult patients ranging between PB stroma of pancreatoblastomas is often
19 and 56 years of age {939, 1053, hypercellular, in some instances achiev-
1452}. There is a slight male predomi- ing a neoplastic appearance. Rarely, the
nance, with an M:F ratio of 1.3:1 {939}. A presence of heterologous stromal ele-
ments, including neoplastic bone and
Aetiology cartilage, has been reported {127, 939}.
The aetiology is unknown.
Histochemistry and immunohistochemistry
Localization PB Over 90% of pancreatoblastomas exhibit
The head of the gland is affected in evidence of acinar differentiation in the
about 50% of cases, the remainder form of PAS-positive, diastase resistant
being equally divided between the body cytoplasmic granules as well as immuno-
and the tail. histochemical staining for pancreatic
B enzymes, including trypsin, chymo-
Clinical features Fig. 10.32 Pancreatoblastoma. A CT image showing trypsin, and lipase {939, 1282, 1400}. The
The presenting features of pancreato- a large tumour (PB) in the head of the pancreas, staining may be focal, often limited to the
blastoma are generally non-specific. with hypodense areas. B The cut surface of the apical cytoplasm in areas of the tumour
Especially in the pediatric age group, neoplasm demonstrates a lobulated structure. with acinar formations. At least focal

244 Tumours of the exocrine pancreas


10b 19.7.2006 8:25 Page 245

remains a separately definable neoplasm


with characteristic histologic, immunohis-
tochemical, and clinical features.

Ultrastructure
By electron microscopy, pancreatoblas-
tomas generally exhibit evidence of aci-
nar differentiation {939, 1758}, with rela-
tively abundant rough endoplasmic retic-
ulum and mitochondria, and apically
located dense zymogen granules. The
zymogen granules may be round and
uniform, resembling those of non-neo-
plastic cells. In addition, irregular fibril-
lary granules similar to those described
in acinar cell carcinomas may be found
{936, 939}. In rare cases, dense-core
neurosecretory-type granules and muci-
gen granules have also been observed
{939}. Examination of the squamoid cor-
Fig. 10.33 Pancreatoblastoma with squamoid corpuscule (arrowhead), surrounded by solid (left) and tubular puscles has revealed tonofilaments but
(right) structures. no evidence of a specific line of differen-
tiation.
immunoreactivity for markers of endocrine Relationship to acinar cell carcinoma
differentiation (chromogranin or synapto- Both pancreatoblastomas and acinar cell Genetic susceptibility
physin) is found in over two-thirds of carcinomas consistently exhibit acinar In several reported cases (all congenital
cases, and expression of markers of duc- differentiation and may exhibit lesser examples), pancreatoblastomas have
tal differentiation such as CEA, DUPAN-2, degrees of endocrine and ductal differ- been a component of the Beckwith-
or B72.3 is found in more than half of entiation. {936, 939}. Histologically, aci- Wiedeman syndrome {432}.
cases {939}. In most instances, the pro- nar formations are characteristic of pan-
portion of cells expressing acinar markers creatoblastoma, and the solid areas Prognosis
outnumbers the proportion expressing resemble the solid pattern of acinar cell Pancreatoblastomas are malignant
endocrine or ductal markers. In cases carcinoma. Biologically, the two tumours tumours. Nodal or hepatic metastases
associated with elevations in the serum are also similar, with a relatively favorable are present in 35% of patients {782, 939}.
levels of alpha-fetoprotein, immunohisto- prognosis in childhood, but a very poor More widespread dissemination may also
chemical positivity for AFP has been prognosis in adulthood. For these rea- occur. In pediatric patients lacking evi-
detectable {802, 939}. sons, some observers have suggested dence of metastatic disease at first pres-
Immunohistochemical evaluation of the that pancreatoblastoma represents the entation, the prognosis is very good,
squamoid corpuscles has failed to define paediatric counterpart of acinar cell car- most patients being cured by a combina-
a reproducible line of differentiation for cinoma. Although this proposal is attrac- tion of surgery and chemotherapy {894,
this component {939}. tive in many ways, pancreatoblastoma 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 1.5
years {939}. However, a favourable
response to chemotherapy has been
noted in some children {235, 2027}.

Pancreatoblastoma 245
10b 19.7.2006 8:25 Page 246

Solid-pseudopapillary neoplasm G. Klöppel


J. Lüttges
R. Hruban
S. Kern
D. Klimstra G. Adler

Definition It occurs predominantly in adolescent solitary masses (average size 8-10 cm;
A usually benign neoplasm with predomi- girls and young women (mean 35 years; range, 3-18 cm), and are often fluctuant.
nant manifestation in young women, com- range 8-67 years) {1781, 1072}. It is rare They are usually encapsulated and well
posed of monomorphic cells forming solid in men (mean, 35 years; range 25-72 demarcated from the surrounding pan-
and pseudopapillary structures, frequent- years) {945, 1193, 1975}. There is no creas. Multiple tumours are exceptional
ly showing haemorrhagic-cystic changes apparent ethnic preference {978, 1395}. {1427}. The cut surfaces reveal lobulat-
and variably expressing epithelial, mes- ed, light brown solid areas, zones of
enchymal and endocrine markers. Aetiology haemorrhage and necrosis, and cystic
The aetiology is unknown. The striking spaces filled with necrotic debris.
ICD-O codes sex and age distribution point to genetic Occasionally, the haemorrhagic-cystic
Solid pseudopapillary neoplasm 8452/1 and hormonal factors, but there are no changes involve almost the entire lesion
Solid pseudopapillary carcinoma 8452/3 reports indicating an association with so that the neoplasm may be mistaken
endocrine disturbances including over- for a pseudocyst. The tumour wall may
Synonyms production of oestrogen or progesterone. contain calcifications {1358}. A few
Solid-cystic tumour {946}, papillary-cys- Moreover, only very few women devel- tumours have been found to be attached
tic tumour {170}, solid and papillary oped a solid pseudopapillary neoplasm to the pancreas or even in extrapancre-
epithelial neoplasm. after long-term use of hormonal contra- atic locations {812, 914, 945}. Invasion of
ceptives {359, 436, 1655}. adjacent organs or the portal vein is rare
Epidemiology {1655, 1684, 1701}.
Solid-pseudopapillary neoplasm is Localization
uncommon but has been recognized There is no preferential localization within
with increasing frequency in recent years the pancreas {1282, 1358}.
{946, 1192, 1358}. It accounts for
approximately 1-2% of all exocrine pan- Clinical features
creatic tumours {359, 941, 1280}. Usually, the neoplasms are found inci-
dentally on routine physical examination
or they cause abdominal discomfort and
pain {1358}, occasionally after abdomi-
nal trauma {945}. Jaundice is rare {1427},
even in tumours that originate from the
head of the pancreas, and there is no Fig. 10.35 Solid-pseudopapillary neoplasm. The
T associated functional endocrine syn- pseudopapillary structures are lined by small
drome. All known tumour markers are monomorphic cells.
normal.
Ultrasonography (US) and computed
tomography (CT) reveal a sharply demar- Tumour spread
A cated, variably solid and cystic mass Only few metastasizing solid-pseudo-
without any internal septation {300}. The papillary neoplasms have been reported
tumour margin may contain calcifications. {359, 1358}. Common metastatic sites
Administration of contrast medium results include regional lymph nodes, the liver,
in enhancement of the solid tumour parts. peritoneum, and greater omentum {300,
On angiography, the neoplasms are usu- 2209, 1358}.
ally hypovascular or mildly hypervascular
lesions with displacement of surrounding Histopathology
vessels {2153}. Fine needle aspiration In large neoplasms, extensive necrosis is
cytology performed under radiological typical and the preserved tissue is usual-
B control shows monomorphic cells with ly found in the tumour periphery under
round nuclei and eosinophilic or foamy the fibrous capsule. This tissue exhibits a
Fig. 10.34 Solid-pseudopapillary neoplasm. A The
round hypodense tumour (T) replaces the tail of the cytoplasm {234, 2119, 2140}. solid monomorphic pattern with variable
pancreas. B The pseudocystic neoplasm is sclerosis. More centrally there is a
attached to the spleen, and shows haemorrhagic Macroscopy pseudopapillary pattern, and these com-
necrosis. The neoplasms present as large, round, ponents often gradually merge into each

246 Tumours of the exocrine pancreas


10b 19.7.2006 8:25 Page 247

other. In both patterns, the uniform poly-


hedral cells are arranged around deli-
cate, often hyalinized fibrovascular stalks
with small vessels {1395}. Neoplastic
cells that are arranged radially around the
minute fibrovascular stalks may resemble
‘ependymal’ rosettes. Luminal spaces are
consistently absent. In the solid parts,
disseminated aggregates of neoplastic
cells with foamy cytoplasm or cholesterol
crystals surrounded by foreign body cells
may be found. The spaces between the
pseudopapillary structures are filled with
red 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 globules
of varying size, which may also occur Fig. 10.36 Solid pseudopapillary tumour. Solid area containing cholesterol crystals and foreign body giant
outside the cells. Glycogen or mucin cells.
cannot be detected. Grimelius positive
cells may occur. The round to oval nuclei
have finely dispersed chromatin and are
often grooved or indented. Mitoses are
usually rare, but in a few instances
prominent mitotic activity is observed
{1358}. In rare cases, there is also vessel
invasion {2140}. The neoplastic tissue is
usually well demarcated from the normal
pancreas, although a fibrous capsule
may be absent and invasion of tumour
cell nests into the surrounding pancreat-
ic tissue may occur {1193, 1358}.

Criteria of malignancy
Although criteria of malignancy have not
yet been clearly established, it appears
that unequivocal perineural invasion,
angioinvasion, or deep invasion into the
surrounding tissue indicate malignant
behaviour, and such lesions should be
classified as solid-pseudopapillary carci- Fig. 10.37 Solid pseudopapillary tumour. In this solid area, the uniform tumour cells are separated by vas-
noma. Nishihara et al. {1358} compared cular hyalinized stroma.
the histological features of three metasta-
sizing and 19 nonmetastasizing solid-
pseudopapillary neoplasms, and found Histochemistry and immunohistochemistry for NSE and vimentin, in contrast, is usu-
that venous invasion, degree of nuclear The most consistently positive markers ally diffuse.
atypia, mitotic count and prominence of for solid-pseudopapillary neoplasms are Inconsistent results have been reported
necrobiotic cell nests (cells with pyknotic alpha-1-antitrypsin, alpha-1-antichymo- for epithelial markers, synaptophysin,
nuclei and eosinophilic cytoplasm) were trypsin, neuron specific enolase (NSE), pancreatic enzymes, islet cell hormones
associated with malignancy. However, vimentin and progesterone receptors and other antigens such as CEA or CA
neoplasms in which the above-mentioned {306, 945, 963, 1226}. The cellular reac- 19.9. Most authors report negative results
histological criteria of malignancy are not tion for alpha-1-antitrypsin and alpha-1- for chromogranin A, CEA, CA 19.9 and
detected may also give rise to metas- antichymotrypsin is always intense, but AFP. A few neoplasms have been found
tases. Consequently, benign appearing only involves small cell clusters or single to express S-100 {945, 1226, 1358}.
solid-pseudopapillary neoplasms must be cells, a finding that is characteristic of Cytokeratin is detected in 30% {946} to
classified as lesions of uncertain malig- this neoplasm. Alpha-1-antitrypsin also 70% {963, 2195}, depending on the
nant potential. stains the PAS-positive globules. Staining method of antigen retrieval applied.

Solid-pseudopapillary neoplasm 247


10b 19.7.2006 8:25 Page 248

Usually, the staining for keratin is focal integrate, forming multilamellated vesi- nal trauma and rupture of the tumour
and faint. The keratin profile (CK 7, 8, 18 cles and lipid droplets {946, 1031, 1226, {1060}. Even in patients who had local
and 19) is that of the ductal cell {740, 2154}. Neurosecretory-like granules have spread, recurrences {359, 999}, or
1844}. Positive immunoreactivity for been described in a few tumours {867, metastases {234, 1192, 1642}, long dis-
trypsin, chymotrypsin, amylase and/or 880, 1684, 2119, 2147}. Intermediate cell ease-free periods have been recorded
phospholipase A2 has been reported junctions are rarely observed and micro- after initial diagnosis and resection. Only
{166, 1072, 1192, 1226, 1844}, but has villi are lacking, but small intercellular a few patients have died of a metastasiz-
not been confirmed by most other spaces are frequent. ing solid-pseudopapillary neoplasm
authors {812, 945, 1282}. Similarly, focal {1192, 1395}.
positivity for glucagon, somatostatin Genetics Histological criteria. Perineural invasion,
and/or insulin has been described in In contrast to infiltrating ductal carcino- angioinvasion, or deep invasion into the
some tumours {1226, 2021, 2147}, but mas, solid-pseudopapillary neoplasms surrounding tissue indicate malignant
was not detected in most other cases appear to have wild-type KRAS genes behaviour, and such lesions are classi-
{1072, 1282, 1844}. and do not immunoexpress p53 {512, fied as solid-pseudopapillary carcinoma.
1007, 1039}. An unbalanced transloca- Venous invasion, a high degree of
Ultrastructure tion between chromosomes 13 and 17 nuclear atypia, mitotic activity and promi-
The neoplastic cells have round or resulting in a loss of 13q14→qter and nence of necrobiotic cell nests (cells with
markedly indented nuclei containing a 17p11→pter has been described in one pyknotic nuclei and eosinophilic cyto-
small single nucleolus and a narrow rim of solid-pseudopapillary neoplasm {616}. plasm) were reported to be associated
marginated heterochromatin. The cells with malignancy {1358}.
show abundant cytoplasm, which is rich Prognosis and predictive factors DNA content. There is evidence that an
in mitochondria. Zymogen-like granules In general, the prognosis is good. After aneuploid DNA content assessed by flow
of variable sizes (500-3000 nm) are complete removal more than 95% of the cytometry is associated with malignant
conspicuous, probably representing patients are cured. Local spread or dis- behaviour, although the number of cases
deposits of alpha-1-antitrypsin. The semination to the peritoneal cavity has studied is small {867, 1358, 234}.
contents of these granules commonly dis- been reported in the context of abdomi-

248 Tumours of the exocrine pancreas


10b 19.7.2006 8:25 Page 249

G. Zamboni
Miscellaneous carcinomas G. Klöppel
of the pancreas

Oncocytic carcinoma ic gonadotrophin (hCG), composed of Microglandular carcinoma


These lesions are characterized by large cytotrophoblastic cells intermingled with Also known as microadenocarcinoma,
cells with granular eosinophilic cytoplasm syncytiotrophoblastic cells immunoreac- this lesion is characterized by cribriform
and large nuclei with well-defined nucle- tive for hCG. Choriocarcinoma can be or microglandular pattern of growth
oli. Ultrastructurally, the cells show abun- ‘pure’ or associated with mucinous cys- {941}. The same cases were reclassified
dant mitochondria and lack zymogen and tadenocarcinoma {1781, 2194}. with immunohistochemistry as adenocar-
neuroendocrine granules. Local invasive- cinoma, acinar cell carcinomas and
ness, lymph node and pulmonary metas- Clear cell carcinoma endocrine carcinoma {1090}. Microglan-
tasis can occur {1781}. Differential diag- A carcinoma composed of clear cells, dular carcinoma is best regarded as a
nosis includes endocrine tumour {1454} rich in glycogen and poor in mucin, pattern of growth rather than a distinctive
and solid pseudopapillary tumour. morphologically resembling renal cell entity.
carcinoma {941}. Adenocarcinomatous,
Nonmucinous, glycogen-poor cyst- anaplastic, or intraductal papillary com- Medullary carcinoma
adenocarcinoma ponents can be found {1781}. A ductal This recently described carcinoma shows
A large, encapsulated mass with cystic phenotype has been suggested by the a syncytial growth pattern and lymphoep-
spaces lined by serous adenoma like pattern of immunoreactivity for cytoker- ithelioma-like features (see chapter on
component and malignant-appearing atins, the lack of vimentin expression, and ductal adenocarcinoma, other rare carci-
columnar epithelium. The tumour cells are the presence of KRAS mutation {1121}. nomas) {590}.
negative for mucins and show oncocytic
features by electron microscopy {533}. Ciliated cell carcinoma
This lesion shows the pattern of ductal
Choriocarcinoma adenocarcinoma, but contains many cili-
An aggressive tumour, associated with ated cells, as demonstrated at the ultra-
elevated levels of serum human chorion- structural level {1781}.

M. Miettinen
Mesenchymal tumours of the pancreas J.Y. Blay
L.H. Sobin

Primary mesenchymal tumours of the Recently, solitary fibrous tumours, similar cells in a collagenous background. The
pancreas are exceedingly rare. Leio- to those more commonly seen on the lesional cells are positive for CD34 but
myosarcomas and malignant gastroin- serosal surfaces of the pleura and peri- negative for KIT and desmin; focal actin
testinal stromal tumours appear to be the toneum, have been described (1118). positivity may occur.
least uncommon. Histologically they show bland spindle

Miscellaneous carcinomas and lymphoma 249


10b 19.7.2006 8:25 Page 250

H.K. Müller-Hermelink
Lymphoma of the pancreas A. Chott
R.D. Gascoyne
A. Wotherspoon

Definition lowing solid organ transplantation {240}. MALT lymphoma {1925}, and large B-cell
Primary lymphoma of the pancreas is Familial pancreatic lymphoma has been lymphoma {1529, 830}. Only extremely
defined as an extranodal lymphoma aris- reported in a sibling pair (brother and rare cases of pancreatic T-cell lymphoma
ing in the pancreas with the bulk of the sister) who each presented with a high- have been reported, including a single
disease localized to this site. Contiguous grade B-cell lymphoma in their seventh case of anaplastic large cell lymphoma
lymph node involvement and distant decade {830}. Pancreatic lymphoma has (CD30 positive) of T-cell type {1179} and
spread may be seen but the primary clin- also been described in a patient with a case of pancreatic involvement by
ical presentation is in the pancreas with short bowel syndrome {903}. adult T-cell leukaemia/lymphoma {1408}.
therapy directed to this site. The histology of these cases varies little
Clinical features from that seen where these lymphoma
Epidemiology The presentation of primary pancreatic types are encountered more frequently.
Primary lymphoma of the pancreas is lymphoma may mimic that of carcinoma
very rare accounting for less than 0.5% or pancreatitis {240}. Pain free jaundice Prognosis
of pancreatic tumours. As with primary can occur {1330}. Ultrasonography may The distinction between lymphoma and
lymphomas occurring elsewhere in the show an echo-poor lesion {1330}. carcinoma is important, as pancreatic
digestive tract, patients are more fre- lymphomas are associated with better
quently elderly {796}. Histopathology prognosis and may be curable even in
Primary pancreatic lymphomas are usu- advanced stages. Occasional cases of
Aetiology ally of B phenotype. Lymphomas of vari- relapse following prolonged remission
Immunodeficiency predisposes to pan- ous types have been described, includ- have been reported in cases treated by
creatic lymphoma, both in the setting of ing low-grade lymphomas of diffuse chemotherapy {1529}.
HIV infection {866} and as post-trans- small cell type {903, 1480}, follicle centre
plant lymphoproliferative disorders fol- cell lymphoma {1330, 1238}, low-grade

E. Paál
Secondary tumours of the pancreas A. Kádár

Epidemiology Localization The lesions are most commonly detected


Secondary tumours of the pancreas are Any anatomic region of the pancreas by imaging studies {934}. Fine needle
in most cases part of an advanced may be involved and there is no site aspiration can provide a rapid diagnosis
metastatic disease. They account for predilection {934}. Lesions can be soli- {905, 645, 1250}.
3-16% of all pancreatic malignancies, tary, multiple, or diffuse {502}.
affecting males and females equally Origin
{1190, 1012, 1597, 1781}. In our experi- Clinical features Both epithelial and non-epithelial sec-
ence based on combined autopsy and There are no specific symptoms for sec- ondary tumours occur in the pancreas.
histology material, out of 610 neoplasms ondary tumours of the pancreas. The pancreas may be involved by direct
involving the pancreas 26 (4.25%) were Abdominal pain, jaundice, and diabetes spread (e.g. from stomach, liver, adrenal
secondary. Any age may be affected, might be the first sign, or in some cases gland, retroperitoneum) or by lymphatic
but the highest incidence is in the 6th an attack of acute pancreatitis {1290, or haematogenous spread from distant
decade. 1608, 1772}. sites {905}. Renal cell carcinoma is

250 Tumours of the endocrine pancreas


10b 19.7.2006 8:25 Page 251

A B

C D
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.

unique as a primary site since it might mas, small cell carcinoma, and lym- Prognosis
give rise to late solitary metastases phomas {240, 645, 1781}. Apart from the Since in most cases pancreatic metas-
{1644, 218}. clinical and radiological signs {934}, mul- tases indicate an advanced neoplastic
tiple tumour foci with an abrupt transition disease, the prognosis is generally poor.
Histopathology from normal pancreas to the neoplastic In cases of solitary metastases, com-
The main differential diagnostic problem tissue without signs of chronic pancreati- bined adjuvant therapy and surgical
is to distinguish metastases from primary tis in the surrounding parenchyma sup- resection might be beneficial {360, 674,
pancreatic neoplasms. The most prob- port metastatic origin {2089}. Immunohis- 218, 1597}.
lematic tumours are metastases from the tochemistry specific for certain primary
gastrointestinal tract, renal cell carcino- tumours may also be helpful {1190, 1707}.

Secondary tumours 251