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Tumours of the Exocrine Pancreas

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					                       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.
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).




220 Tumours of the exocrine pancreas
                                                                                                              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
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).


222 Tumours of the exocrine pancreas
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
                                                      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
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
                                                                                                               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

226 Tumours of the exocrine pancreas
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
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
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
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
                                                                                                 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
                                                      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
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
                                                                                                     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
                                                     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
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
                                                                                              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
                                                       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
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
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
                                                                                            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
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
                                                                                                     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
                                                                                                 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
                                                                                                            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
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
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
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
                                                                                                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
                                                                                            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
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

				
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