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CHAPTER 10
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.
_________
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).
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
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).
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).
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.
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
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
PanIN-IB Ductal papillary hyperplasia Papillary ductal hyperplasia, ductal hyperplasia grade 2
Adenomatoid ductal hyperplasia Adenomatous hyperplasia, ductular cell hyperplasia
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 3 Poorly differentiated glands, Abortive > 10 Marked polymorphism and increased size
mucoepidermoid and
pleomorphic structures
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
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)
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
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
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.
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}.
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}.
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}.
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.
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
Ultrastructure
By electron microscopy, pancreatoblas-
tomas generally exhibit evidence of aci-
nar differentiation {939, 1758}, with rela-
tively abundant rough endoplasmic retic-
ulum and mitochondria, and apically
located dense zymogen granules. The
zymogen granules may be round and
uniform, resembling those of non-neo-
plastic cells. In addition, irregular fibril-
lary granules similar to those described
in acinar cell carcinomas may be found
{936, 939}. In rare cases, dense-core
neurosecretory-type granules and muci-
gen granules have also been observed
{939}. Examination of the squamoid cor-
Fig. 10.33 Pancreatoblastoma with squamoid corpuscule (arrowhead), surrounded by solid (left) and tubular puscles has revealed tonofilaments but
(right) structures. no evidence of a specific line of differen-
tiation.
immunoreactivity for markers of endocrine Relationship to acinar cell carcinoma
differentiation (chromogranin or synapto- Both pancreatoblastomas and acinar cell Genetic susceptibility
physin) is found in over two-thirds of carcinomas consistently exhibit acinar In several reported cases (all congenital
cases, and expression of markers of duc- differentiation and may exhibit lesser examples), pancreatoblastomas have
tal differentiation such as CEA, DUPAN-2, degrees of endocrine and ductal differ- been a component of the Beckwith-
or B72.3 is found in more than half of entiation. {936, 939}. Histologically, aci- Wiedeman syndrome {432}.
cases {939}. In most instances, the pro- nar formations are characteristic of pan-
portion of cells expressing acinar markers creatoblastoma, and the solid areas Prognosis
outnumbers the proportion expressing resemble the solid pattern of acinar cell Pancreatoblastomas are malignant
endocrine or ductal markers. In cases carcinoma. Biologically, the two tumours tumours. Nodal or hepatic metastases
associated with elevations in the serum are also similar, with a relatively favorable are present in 35% of patients {782, 939}.
levels of alpha-fetoprotein, immunohisto- prognosis in childhood, but a very poor More widespread dissemination may also
chemical positivity for AFP has been prognosis in adulthood. For these rea- occur. In pediatric patients lacking evi-
detectable {802, 939}. sons, some observers have suggested dence of metastatic disease at first pres-
Immunohistochemical evaluation of the that pancreatoblastoma represents the entation, the prognosis is very good,
squamoid corpuscles has failed to define paediatric counterpart of acinar cell car- most patients being cured by a combina-
a reproducible line of differentiation for cinoma. Although this proposal is attrac- tion of surgery and chemotherapy {894,
this component {939}. tive in many ways, pancreatoblastoma 1299}. In the presence of metastatic dis-
ease or in adult patients with pancreato-
blastomas, the outcome is usually fatal
{312, 939}, the mean survival being 1.5
years {939}. However, a favourable
response to chemotherapy has been
noted in some children {235, 2027}.
Pancreatoblastoma 245
10b 19.7.2006 8:25 Page 246
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
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.
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-
G. Zamboni
Miscellaneous carcinomas G. Klöppel
of the pancreas
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
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
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}.