See TARGETED THERAPY available online at
www.studentconsult.com CHAPTER
The Pancreas
Ralph H. Hruban • Christine A. lacobuzio-Donahue
Congenital Anomalies 883 Neoplasms 890
Pancreatitis 884 Cystic Neoplasms 890
Acute Pancreatitis 884 Pancreatic Carcinoma 892
Chronic Pancreatitis 888 Precursors to Pancreatic Cancer 89 2
Nonneoplastic Cysts 889 Pathogenesis 89 2
Congenital Cysts 889
Pseudocysts 889
The adult pancreas is a transversely oriented retroperito-
neal organ extending from the C-loop of the duodenum to
the hilum of the spleen (Fig. 19-1A). Although the organ
gets its name from the Greek pankreas ("all flesh"), it is in
fact a complex lobulated organ with distinct exocrine and
endocrine components.
The exocrine pancreas constitutes 80% to 85% of the organ
and is composed of acinar cells that secrete enzymes
needed for digestion. Acinar cells are pyramidally shaped
epithelial cells containing membrane-bound granules rich
in proenzymes (zymogens), including trypsinogen, chy-
motrypsinogen, procarboxypeptidase, proelastase, kalli-
kreinogen, and prophospholipase A and B. Upon secretion,
these proenzymes and enzymes are carried by a series of
ductules and ducts to the duodenum, where they are acti-
vated by proteolytic cleavage in the gastrointestinal tract
(described later).
The endocrine pancreas is composed of about 1 million
clusters of cells, the islets of Langer hans, scattered through-
out the gland. The islet cells secrete insulin, glucagon, and
somatostatin and constitute only 1% to 2% of the organ.
Diseases of the endocrine pancreas are described in detail
in Chapter 24.
Congenital Anomalies
The complex process by which the dorsal and ventral
pancreatic primordia fuse during pancreatic develop-
ment is prone to "imperfections" that frequently gives
rise to congenital variations in pancreatic anatomy. The
pancreas normally arises from the fusion of dorsal and
ventral outpouchings of the foregut. The body, the tail, and
the superiorI anterior aspect of the head of the pancreas,
as well as the accessory duct of Santorini, are derived from
CHAPTER CONTENTS
Acinar Cell Carcinoma 895
Pancreatoblastoma 895
the dorsal primordium. Normally, the ventral primordium
gives rise to the posterior I inferior part of the head of the
pancreas and drains through the main pancreatic duct into
the papilla of Vater.
Pancreas Divisum. Pancreas divisum is the most common
congenital anomaly of the pancreas, with an incidence of
3% to 10%. In most individuals, the main pancreatic duct
(the duct of Wirsung) joins the common bile duct just prox-
imal to the papilla of Vater, and the accessory pancreatic
duct (the duct of Santorini) drains into the duodenum
through a separate minor papilla (Fig. 19-1A). Pancreas
divisum is caused by a failure of fusion of the fetal duct
systems of the dorsal and ventral pancreatic primordia. As
a result, the bulk of the pancreas (formed by the dorsal
pancreatic primordium) drains into the duodenum through
the small-caliber minor papilla (Fig. 19-1B). The duct of
Wirsung in persons with divisum drains only a small
portion of the head of the gland through the papilla of
Vater. Although controversial, it has been suggested that
inadequate drainage of the pancreatic secretions through
the minor papilla, especially when combined with genetic
defects that also increases susceptibility to pancreatitis
(described later), predisposes individuals with pancreatic
divisum to chronic pancreatitis.
Annular Pancreas. Annular pancreas is a band-like ring of
normal pancreatic tissue that completely encircles the
second portion of the duodenum. Annular pancreas can
produce duodenal obstruction.
Ectopic Pancreas. Pancreatic tissue that is aberrantly situ-
ated, or ectopic, is found in about 2% of careful routine
postmortem examinations. The favored sites for ectopia
are the stomach and duodenum, followed by the jejunum,
883
884 C H A P T E R 19 The Pancreas
A. NORMAL
Duodenum
Duct of
Santorini
Minor
sphincter
Papilla
of Vater
B. PANCREAS
DIVISUM
Minor
sphincter
Papilla
of Vater
Figure 19-1 Pancreatic ductal anatomy. A, The normal ductal anatomy.
B, The ductal anatomy in pancreatic divisum. (Adapted from Gregg JA, et al:
Pancreas divisum: results of surgical intervention. Am J Surg 1983;
145:488-492.)
Meckel diverticula, and ileum. Although usually incidental
findings, these embryologic rests, composed of normal-
appearing pancreatic acini, glands, and sometimes islets of
Langerhans, may cause pain from localized inflammation,
or, rarely, may incite mucosal bleeding.
Agenesis. Very rarely the pancreas fails to develop (agen-
esis). Some cases of agenesis are caused by homozygous
germline mutations involving PDX1, a gene encoding a
homeobox transcription factor that is critical for pancreatic
development.
Pancreatitis
Pancreatitis is divided into two forms, acute and chronic,
each with its own characteristic pathologic and clinical
features. As we will discuss, both are initiated by injuries
that lead to autodigestion of the pancreas by its own
enzymes. Under normal circumstances, the following
mechanisms protect the pancreas from self-digestion by its
secreted enzymes:
• Most digestive enzymes are synthesized as inactive
proenzymes (zymogens), which are packaged within
secretory granules.
• Most proenzymes are activated by trypsin, which itself
is activated by duodenal enteropeptidase (enterokinase)
Table 19-1 Etiologic Factors in Acute Pancreatitis
Metabolic
Alcoholism
Hyperlipoproteinemia
Hypercalcemia
Drugs (e.g., azathioprine)
Genetic
Mutations in genes encoding trypsin, trypsin regulators, or proteins that
regulate calcium metabolism
Mechanical
Gallstones
Trauma
Iatrogenic injury
Operative injury
Endoscopic procedures with dye injection
Vascular
Shock
Atheroembolism
Vasculitis
Infectious
Mumps
in the small bowel; thus, intrapancreatic activation of
proenzymes is normally minimal.
• Acinar and ductal cells secrete trypsin inhibitors, includ-
ing serine protease inhibitor Kazal type l (SPINK1),
which further limit intrapancreatic trypsin activity.
Pancreatitis occurs when these protective mechanisms
are deranged or overwhelmed. As discussed later, the
clinical manifestations of pancreatitis vary widely. Acute
attacks may be mild and self-limited or present as a life-
threatening acute inflammatory process; with recurrent or
persistent pancreatitis, there may be permanent loss of
pancreatic function.
Acute Pancreatitis
Acute pancreatitis is characterized by reversible pancre-
atic parenchymal injury associated with inflammation
and has diverse etiologies, including toxic exposures
(e.g., alcohol), pancreatic duct obstruction (e.g., biliary
calculi), inherited genetic defects, vascular injury, and
infections. Acute pancreatitis is relatively common; the
annual incidence in Western countries is 10 to 20 cases per
100,000 people. Biliary tract disease and alcoholism account
for approximately 80% of cases of acute pancreatitis in
Western countries (Table 19-1). Gallstones are present in
35% to 60% of cases, and pancreatitis develops in about 5%
of patients with gallstones. The proportion of cases of acute
pancreatitis caused by excessive alcohol intake varies from
65% in the United States to 20% in Sweden to 5% or less in
southern France and the United Kingdom. The male-to-
female ratio is 1:3 in the group with biliary tract disease
and 6: 1 in those with alcoholism.
Pathogenesis. Acute pancreatitis results from inappro-
priate release and activation of pancreatic enzymes,
which destroy pancreatic tissue and elicit an acute
 Pancreatitis 885

inflammatory reaction. As we discussed, pancreatic
enzymes, including trypsin, are synthesized in an inactive
proenzyme form. Inappropriate intrapancreatic activation
of trypsin can in turn cause the activation of other proen-
zymes such as prophospholipase and proelastase, which
then degrade fat cells and damage the elastic fibers of
blood vessels, respectively. Trypsin also converts prekal-
likrein to its activated form, thus bringing into play the
kinin system and, by activation of coagulation factor XII,
the clotting and complement systems as well (Chapters 3
and 4). The resulting inflammation and small-vessel throm-
boses (which may lead to congestion and rupture of already
weakened vessels) damage acinar cells, further amplifying
intrapancreatic activation of digestive enzymes.
How inappropriate activation of pancreatic enzymes
occurs in sporadic forms of acute pancreatitis is not entirely
clear, but there is evidence for at least three major initiating
events (Fig. 19-2):
• Pancreatic duct obstruction. Obstruction is most com-
monly caused by gallstones and biliary sludge, but
can also stem from periampullary neoplasms (e.g.,
pancreatic cancer), choledochoceles (congenital cystic
dilatation of the common bile duct), parasites (particu-
larly the Ascaris lumbricoides and Clonorchis sinensis
organisms), and possibly pancreas divisum. Whatever
the cause, obstruction raises intrapancreatic ductal pres-
sure and leads to the accumulation of enzyme-rich fluid
in the interstitium. Although most pancreatic enzymes
are secreted as inactive zymogens, lipase is produced in
an active form and has the potential to cause local fat
necrosis. The death of adipocytes is hypothesized to
produce" danger" signals locally that stimulate periaci-
nar myofibroblasts and leukocytes to release proinflam-
matory cytokines and other inflammatory mediators
that initiate local inflammation and promote the devel-
opment of interstitial edema through a leaky microvas-
culature. Edema may further compromise local blood
flow, causing vascular insufficiency and ischemic injury
to acinar cells.
• Primary acinar cell injury, leading to release of diges-
tive enzymes, inflammation, and autodigestion of pan-
creatic tissues. As described later, acinar cells can be
damaged by a variety of endogenous, exogenous, and
iatrogenic insults. Oxidative stress may generate free
radicals in acinar cells, leading to membrane lipid
oxidation and the activation of transcription factors,
including APl and NF-KB, which in turn induce the
expression of chemokines that attract mononuclear

DUCT OBSTRUCTION ACINAR CELL INJURY DEFECTIVE INTRACELLULAR

TRANSPORT

•
o._t
! =='>
=

Cholelithiasis
Ampullary obstruction
Alcohol
Drugs
Trauma
Ischemia
I
Metabolic injury (experimental)
Chronic alcoholism Viruses Alcohol
Ductal concretions Hypercalcemia Duct obstruction

~ ~ ~
Interstitial edema

+
Impaired blood flow
Release of intracellular
proenzymes and lysosomal
hydro lases IY""T
Delivery of proenzymes to
oompartmeot

+ ~
Ischemia Activation of enzymes Intracellular activation
{loT oc e~,a~ of ee>yme'

Acinar cell injury

+
ACTIVATED ENZYMES

Interstitial
inflammation Damage to vessel
+ Proteolysis + Fat necrosis + walls , hemorrhage
and edema

ACUTE PANCREATITIS
Figure 19-2 Three proposed pathways in the pathogenesis of acute pancreatitis.
886 C H A P T E R 19 The Pancreas
Table 19-2 Inherited Predisposition to Pancreatitis
Gene (Chromosome Location) Protein Product
CFTR (7q31) Cystic fibrosis transmembrane
conductance regulator
PRSS1 (7q34) Serine protease 1 (trypsinogen 1)
SP/NK1 (5q32) Serine peptidase inhibitor, Kazal type 1
CASR(3q13) Calcium-sensing receptor
CTRC(1p36) Chymotrypsin C (caldecrin)
CPA1 (7q32) Carboxypeptidase A1
cells. Increased calcium flux appears to be another
important trigger for inappropriate activation of diges-
tive enzymes. Calcium has a key role in regulating
trypsin activation. When calcium levels are low, trypsin
tends to cleave and inactivate itself, but when calcium
levels are high autoinhibition is abrogated and activa-
tion of trypsinogen by trypsin is favored. It is suspected
that any factor that causes calcium levels to rise in acinar
cells may trigger excessive activation of trypsin, includ-
ing certain inherited abnormalities that affect calcium
levels (Table 19-2).
• Defective intracellular transport of pro enzymes within
acinar cells. In normal acinar cells, digestive enzymes
and lysosomal hydrolases are transported in separate
pathways. In animal models of acinar injury, the pan-
creatic proenzymes are inappropriately delivered to the
intracellular compartment containing lysosomal hydro-
lases. Proenzymes are then activated, the lysosomes are
disrupted, and the activated enzymes are released. The
role of this mechanism in human acute pancreatitis is
not clear.
Alcohol consumption may cause pancreatitis through
all of these mechanisms. Alcohol consumption transiently
increases contraction of the sphincter of Oddi (the muscle
at the Papilla of Vater), and chronic alcohol ingestion
results in the secretion of protein-rich pancreatic fluid that
leads to the deposition of inspissated protein plugs and
obstruction of small pancreatic ducts. Alcohol also has
direct toxic effects on acinar cells. Alcohol-induced oxida-
tive stress may generate free radicals in acinar cells, leading
to membrane lipid oxidation and free radical production,
which as already mentioned has been linked to activation
of the pro-inflammatory transcription factors AP1 and
NF-KB. Oxidative stress also may promote the fusion of
lysosomes and zymogen granules and alter intracellular
calcium levels, possibly through mitochondrial damage,
promoting the intraacinar activation of trypsin and other
digestive enzymes. Nevertheless, it should be noted that
most drinkers never develop pancreatitis and those who
do usually do so after many years of alcohol abuse. Thus,
key aspects of the pathophysiology of alcohol-induced
pancreatitis remain obscure.
Other proven or suspected triggers of acute pancreatitis
in the remaining sporadic cases include the following
(Table 19-1):
• Metabolic disorders, such as hypertriglyceridemia, and
hypercalcemic states, such as hyperparathyroidism
Function
Epithelial anion channel. Loss-of-function mutations alter fluid pressure and limit
bicarbonate secretion, leading to inspissation of secreted fluids and duct obstruction
Cationic trypsin. Gain-of-function mutations prevent self-inactivation of trypsin
Inhibitor of trypsin. Mutations cause loss-of-function, increasing trypsin activity
Membrane-bound receptor that senses extracellular calcium levels and controls luminal
calcium levels. Mutations may alter calcium concentrations and activate trypsin.
Degrades trypsin, protects the pancreas from trypsin-related injury
Exopeptidase involved in regulating zymogen activation
• Genetic lesions, described below
• Medications. More than 85 drugs have been implicated,
including furosemide, azathioprine, 2',3'-dideoxyino-
sine, estrogens, and many others. In most cases the
mechanism of drug-induced pancreatitis is unknown.
• Traumatic injury of acinar cells, either by blunt abdom-
inal trauma or by iatrogenic injury during surgery or
endoscopic retrograde cholangiopancreatography
• Ischemic injury of acinar cells, caused by shock, vascu-
lar thrombosis, embolism, and vasculitis
• Infections, including mumps, can lead to acute pancre-
atitis through direct acinar cell injury
Hereditary factors are increasingly being recognized as
a significant cause of pancreatitis. Hereditary pancreatitis
is characterized by recurrent attacks of severe acute pancre-
atitis often beginning in childhood and ultimately leading
to chronic pancreatitis. The disorder is genetically diverse,
but the shared feature of most forms is a defect that
increases or sustains the activity of trypsin (Table 19-2).
Three genes implicated in hereditary pancreatitis deserve
special note: PRSS1, SPINKl, and CFTR. Most hereditary
cases are due to gain-of-function mutations in the trypsino-
gen gene (also known as PRSSl). Some of these PRSSl gene
mutations make trypsin resistant to self-inactivation, abro-
gating an important negative feedback mechanism; other
mutations appear to make trypsinogen more prone to pro-
teolytic activation. Hereditary pancreatitis associated with
trypsinogen mutation has an autosomal dominant mode of
inheritance, as is typically true of disorders associated with
gain-of-function mutations.
Hereditary pancreatitis can also be caused by loss-of-
function mutations in SPINKl, already described as a gene
encoding a trypsin inhibitor. As expected, this form of
hereditary pancreatitis has an autosomal recessive mode of
inheritance.
As discussed in detail in Chapter 5, cystic fibrosis is
caused by mutations in the cystic fibrosis transmembrane
conductance regulator (CFTR) gene, and homozygous and
even heterozygous CFTR gene mutations are associated
with pancreatitis, the latter particularly in patients who
also have SPINKl mutations. Mutations in CFTR decrease
bicarbonate secretion by pancreatic ductal cells, thereby
promoting protein plugging, duct obstruction, and the
development of pancreatitis.
Of note, patients with hereditary pancreatitis have a
40 % lifetime risk of developing pancreatic cancer, yet
another example of the nefarious association of chronic
tissue injury and inflammation with neoplasia.

MORPHOLOGY
The morphology of acute pancreatitis ranges from trivial inflam-
mation and edema to severe extensive necrosis and hemor-
rhage. The basic alterations are (1) microvascular leak
and edema, (2) fat necrosis, (3) acute inflammation,
(4) destruction of pancreatic parenchyma, and (5) destruc-
tion of blood vessels and interstitial hemorrhage. The
extent of each of these alterations depends on the duration and
severity of the process.
In the milder form, acute interstitial pancreatitis, histologic
alterations are limited to mild inflammation, interstitial edema,
and focal areas of fat necrosis in the pancreas and the peri pan-
creatic fat (Fig. 19-3). Fat necrosis, as we have seen , results from
enzymatic activity of lipase. The released fatty acids combine
with calcium to form insoluble salts that impart a granular blue
microscopic appearance to the fat cells (Chapter 2).
In the more severe form, acute necrotizing pancreatitis,
there is necrosis of acinar and ductal tissues as well as islets of
Langerhans. Vascular injury can lead to hemorrhage into the
pancreatic parenchyma. Macroscopically, the pancreatic sub-
stance is red-black from hemorrhage and contains interspersed
foci of yellow-white, chalky fat necrosis (Fig. 19-4). Focal fat
necrosis may also occur adjacent to the pancreas in the omentum
and the mesentery of the bowel , and even outside the abdominal
cavity, such as in the subcutaneous fat. In most cases the peri-
toneal cavity contains a serous, slightly turbid, brown-tinged fluid
Figure 19-3 The mic roscopic field shows a region of fat nec rosis on the right
and focal pancreatic parenchymal necrosis (cen ter) .
" KEY CONCEPTS
Figure 19-4 The pancreas has been sectioned longitudinally to reveal dark
areas of hemorrhage in the head of the panc reas and a focal area of pale fat
necrosis in the peripanc reatic fat (upper left).
Pancreatitis 887
containing globules of fat (derived from the action of enzymes on
adipose tissue). In its most severe form, hemorrhagic pancre-
atitis, extensive parenchymal necrosis is accompanied by dra-
matic hemorrhage within the substance of the gland .
Clinical Features. Abdominal pain is the cardinal manifes-
tation of acute pancreatitis. Characteristically, the pain is
constant and intense and is referred to the upper back and
occasionally to the left shoulder. Its severity varies from
mild and uncomfortable to severe and incapacitating.
Anorexia, nausea, and vomiting frequentl y accompany the
pain. Elevated plasma levels of amylase and lipase support
the diagnosis of acute pancreatitis, as does the excluswn of
other causes of abdominal pain.
Full-blown acute pancreatitis is a medical emergency.
Patients usually have the sudden calamitous onset of an
"acute abdomen." Many of the systemic features of severe
acute pancreatitis can be attributed to release of toxic
enzymes, cytokines, and other mediators ~nt_o the circula-
tion and explosive activation of a systemic mflammatory
response, resulting in leukocytosis, disseminated intravascular
coagulation, edema, and acute respiratory distress syndrome.
Shock, due to the systemic inflammatory response syn-
drome (Chapters 4), and acute renal tubular necrosis may
occur.
Laboratory findings include marked elevation of s~r~m
amylase levels during the first 24 hours, followed by a ~Ismg
serum lipase level by 72 to 96 hours after the begmrung ~f
the attack. Glycosuria occurs in 10% of cases. H~pocalcem~a
may result from precipitation of calciu~ soaps m necrohc
fat. Direct visualization of the enlarged Inflamed pancreas
by CT scanning is useful in the diagnosis of pancrea~i~is ..
The key to the management of acute pancreahhs IS
"resting" the pancreas by total restriction of _o ral intake and
by supportive therapy with intravenous flmds and anal?~­
sia. Although most individuals with acute panc~~aht~s
recover fully, about 5% with severe acute pancreahhs die
in the first week of illness. Acute respiratory distress syn-
drome and acute renal failure are ominous complications.
Sequelae can include a sterile pancreatic abscess and a pan-
creatic pseudocyst (discussed later). In 40% to 60% o! patien~s
with acute necrotizing pancreatitis the necrohc debns
becomes infected, usually by gram-negative organisms
from the alimentary tract, further complicating the clinical
course. Systemic organ failure and necrosis in the pancreas
are both poor prognostic findings .
• Acute pancreatitis is a form of reversible pancreatic paren-
chymal injury associated with inflammation.
• Acute pancreatitis may be caused by
• Excessive alcohol intake
• Pancreatic duct obstruction (e.g., gallstones)
• Genetic factors (e.g., PRSS1, SPINK1)
• Traumatic injuries
• Medications
• Infections (e.g., mumps)
• Metabolic disorders leading to hypercalcemia
• Ischemia
888 C H A P T E R 19 The Pancreas
(/)
i=
~w
a:
0 plete resolution of the acute injury occurs with resto-
zc:(
a..
w repeated episodes of acinar cell injury lead to the
1-
::1
0 forming growth facto r~ (TG F- ~) and platelet-derived
c:(
• The key feature of all of these causes is that they
promote the inappropriate activation of digestive
enzymes within the substance of the pancreas
• Clinical features include acute abdominal pain, systemic
inflammatory response syndrome, and elevated serum
lipase and amylase levels
Chronic Pancreatitis
Chronic pancreatitis is defined as prolonged inflamma-
tion of the pancreas associated with irreversible destruc-
tion of exocrine parenchyma, fibrosis, and, in the late
stages, the destruction of endocrine parenchyma. The
prevalence of chronic pancreatitis ranges between 0.04 %
and 5%; most affected patients are middle-aged males. The
most common cause of chronic pancreatitis by far is long-
term alcohol abuse. In addition to alcohol, chronic pancre-
atitis has been associated with the following conditions:
• Long-standing obstruction of the pancreatic duct by
calculi or neoplasms
• Autoimmune injury to the gland
• Hereditary pancreatitis, as discussed under acute pancre-
atitis; up to 25 % of chronic pancreatitis has a genetic
basis
Pathogenesis. Chronic pancreatitis most often follows
repeated episodes of acute pancreatitis. It has been pro-
posed that acute pancreatitis initiates a sequence of peril-
obular fibrosis, duct distortion, and altered pancreatic
secretions. Over time and with multiple episodes, this can
lead to loss of pancreatic parenchyma and fibrosis .
Chronic pancreatic injury, whatever its cause, leads to
local production of inflammatory mediators that promote
fibrosis and acinar cell loss. While the cytokines produced
Figure 19-5 Comparison of the mediators in acute
and chronic pancreatitis. In acute pancreatitis acinar
injury results in release of proteolytic enzymes, leading
to a cascade of events including activation of the
clotting cascade, acute and chronic inflammation,
Resolution of pancreatitis vascular injury, and edema. In most patients, com-
ration of acinar cell mass. In chronic pancreatitis,
prod uction of profi brogenic cytokines such as trans-
growth factor (PDGF), resulting in the proliferation of
myofi broblasts, the secretion of collagen, and remod-
eling of the extracellular matrix (ECM). Repeated injury
produces irreversible loss of acinar cell mass, fi brosis,
and pancreatic insufficiency.
during chronic and acute pancreatitis are similar, fibro-
genic factors tend to predominate in chronic pancreatitis.
These fibrogenic cytokines include transforming growth
factor ~ (TGF-~) and platelet-derived growth factor, which
induce the activation and proliferation of periacinar myo-
fibroblasts (pancreatic stellate cells), resulting in the depo-
sition of collagen and fibrosis (Fig. 19-5).
Autoimmune pancreatitis is a pathogenically distinct
form of chronic pancreatitis that is associated with the
presence of IgG4-secreting plasma cells in the pancreas.
Autoimmune pancreatitis is one manifestation of IgG-
related disease (Chapter 6), which may involve multiple
tissues. Autoimmune pancreatitis may mimic the signs and
symptoms of pancreatic carcinoma. It is important to rec-
ognize because it responds to steroid therapy.
Chronic pancreatitis is characterized by fibrosis, atrophy
and dropout of acini, and variable dilation of pancreatic
ducts (Fig. 19-6A). Grossly, the gland is hard, sometimes with
visibly dilated ducts containing calcified concretions. These
changes are typically accompanied by a chronic inflammatory
infiltrate around lobules and ducts. The ductal epithelium may
be atrophied or hyperplastic or may show squamous metapla-
sia. Acinar loss is a constant feature. There is usually relative
sparing of the islets of Langerhans, which become embedded
in the sclerotic tissue and may fuse and appear enlarged, but
in advanced disease the islets also are lost. Chronic pancreatitis
caused by alcohol abuse is characterized by ductal dilatation
and intraluminal protein plugs and calcifications (Fig. 19-68).
Autoimmune pancreatitis is characterized by a duct-centric
mixed inflammatory cell infiltrate, venulitis, and increased
numbers of lgG4-secreting plasma cells.

Figure 19-6 Chronic pancreatitis. A, Extensive fibrosis and atrophy has
left only residual islets (left) and ducts (right), with a sprinkling of chronic
inflammatory cells and a few islands of acinar tissue. B, A higher power view
demonstrating dilated ducts with inspissated eosinophilic ductal concretions
in a person with alcoholic chronic pancreatitis.
Clinical Features. Chronic pancreatitis may present in
many different ways. It may follow repeated bouts of acute
pancreatitis. There may be repeated attacks of mild to mod-
erately severe abdominal pain, or persistent abdominal
and back pain. Attacks may be precipitated by alcohol
abuse, overeating (which increases demand on the pan-
creas), or the use of opiates and other drugs that increase
the tone of the sphincter of Oddi. In other patients the
disease may be entirely silent until pancreatic insufficiency
and diabetes mellitus develop due to destruction of the
exocrine and endocrine pancreas.
The diagnosis of chronic pancreatitis requires a high degree
of suspicion. During an attack of abdominal pain there may
be mild fever and mild-to-moderate elevations of serum
amylase. When the disease has been present for a long
time, however, the dropout of acinar cells may be so great
as to eliminate these diagnostic clues. Gallstone-induced
obstruction may be evident as jaundice or elevations in
serum levels of alkaline phosphatase. A very helpful
finding is visualization of calcifications within the pancreas
by computed tomography and ultrasonography. Weight
loss and edema due to low albumin from malabsorption
caused by pancreatic exocrine insufficiency also support
the diagnosis.
Although chronic pancreatitis is usually not an imme-
diately life-threatening condition, the long-term outlook
for individuals with chronic pancreatitis is poor, with a
___
Nonneoplastic cysts ....._
889
20- to 25-year mortality rate of 50%. Pancreatic exocrine
insufficiency, chronic malabsorption, and diabetes mellitus
can all lead to significant morbidity and contribute to mor-
tality. In other patients severe chronic pain is a dominant
problem. Pancreatic pseudocysts (described later) develop
in about 10% of patients. As already mentioned, patients
with hereditary pancreatitis have a 40% lifetime risk of
developing pancreatic cancer; whether this increased
cancer risk extends to other forms of chronic pancreatitis
is unclear.
il KEY CONCEPTS
• Chronic pancreatitis is characterized by irreversible injury
of the pancreas leading to fibrosis, loss of pancreatic
parenchyma, loss of exocrine and endocrine function, and
high risk of developing pseudocysts
• Chronic pancreatitis is most often caused by
• Repeated bouts of acute pancreatitis
• Chronic alcohol abuse
• Germline mutations in genes such as CFTR (the gene
encoding the transporter that is defective in cystic fibro-
sis), particularly when combined with environmental
stressors
• Clinical features include intermittent or persistent
abdominal pain, intestinal malabsorption, and diabetes
Nonneoplastic Cysts
A variety of cysts can arise in the pancreas. Most are non-
neoplastic pseudocysts (discussed later), but congenital
cysts and neoplastic cysts also occur.
Congenital Cysts
Congenital cysts are unilocular, thin-walled cysts that are
believed to result from anomalous development of the
pancreatic ducts. They range in size from microscopic
lesions to 5 em in diameter, and are lined by a glistening,
uniform cuboidal epithelium or, if the intracystic pressure
is high, by a flattened and attenuated cell layer. Congenital
cysts are enclosed in a thin, fibrous capsule and are filled
with a clear serous fluid. Congenital cysts may be sporadic,
or part of inherited conditions such as autosomal-dominant
polycystic kidney disease (Chapter 20) and von Hippel-Lindau
disease (Chapter 28). Cysts in the kidney, liver, and pan-
creas frequently coexist in polycystic kidney disease. In
von Hippel-Lindau disease vascular neoplasms are found
in the retina and cerebellum or brain stem in association
with congenital cysts (and also neoplasms) in the pancreas,
liver, and kidney.
Pseudocysts
Pseudocysts are localized collections of necrotic and hem-
orrhagic material that are rich in pancreatic enzymes and
lack an epithelial lining (hence the prefix "pseudo").
Pseudocysts account for approximately 75% of cysts in the
pancreas. They usually arise following a bout of acute pan-
creatitis, particularly one superimposed on chronic alco-
holic pancreatitis. Traumatic injury to the pancreas can also
give rise to pseudocysts.
890 C H A P T E R I9 The Pancreas
Figure 19-7 Pancreatic pseudocyst. A, Cross-section revealing a poorly
defined cyst with a necrotic brown-black wall. B, The cyst lacks a true epi -
thelial lining and instead is lined by fibrin and granulation tissue.
Pseudocysts are usually solitary and may be situated within the
pancreas, or, more commonly, in the lesser omental sac or in
the retroperitoneum between the stomach and transverse colon
or between the stomach and liver. They can even be subdia-
phragmatic (Fig. 19-7A). Pseudocysts are formed when areas
of intrapancreatic or peripancreatic hemorrhagic fat necrosis
are walled off by fibrous tissue and granulation tissue (Fig .
19-78). They range in size from 2 to 30 em in diameter.
While many pseudocysts spontaneously resolve, they
may become secondarily infected, and larger pseudocysts
may compress or even perforate into adjacent structures.
Neoplasms
A broad spectrum of exocrine neoplasms arises in the pan-
creas. Such neoplasms may be cystic or solid; some are
benign, while others are among the most lethal of all malig-
nancies. Neuroendocrine tumors also occur in the pancreas
and are discussed in Chapter 24.
Cystic Neoplasms
Cystic neoplasms are diverse tumors that range from
harmless benign cysts to lesions that may be precursors
Figure 19-8 Serous cystic neoplasm (serous cystadenoma). A, Cross-section
through a serous cystic neoplasm. Only a thin rim of normal pancreatic
parenchyma remains. The cysts are relatively small and contain clear, straw-
colored fluid. B, The cysts are lined by cuboidal epithelium without atypia.
to invasive, potentially lethal, cancers. Only 5 % to 15% of
all pancreatic cysts are neoplastic (most are pseudocysts;
see the previous section), and cystic neoplasms make up
fewer than 5% of all pancreatic neoplasms. Serous cystic
neoplasms are entirely benign, whereas others, such as
intraductal papillary mucinous neoplasms and mucinous
cystic neoplasms, are precancerous. Recent whole-exome
sequencing has identified genetic alterations specific for
each type of cystic neoplasm.
Serous cystic neoplasms are multicystic neoplasms that
usually occur in the tail of the pancreas. The cysts are small
(1 to 3 mm), lined by glycogen-rich cuboidal cells, and
contain clear, thin, straw-colored fluid (Fig. 19-8). They
account for about 25 % of all cystic neoplasms of the pan-
creas. These neoplasms arise twice as often in women as in
men and typically present in the sixth to seventh decade
of life with nonspecific symptoms such as abdominal pain.
Many are now being detected incidentally during imaging
for another indication. Serous cystic neoplasms, called
serous cystadenomas, are almost always benign and, if
small, can be safely observed. Surgical resection is curative
in the vast majority of patients. Inactivation of the VHL
tumor suppressor gene is the most common genetic abnor-
mality in serous cystic neoplasms.
Close to 95 % of mucinous cystic neoplasms arise in
women, and, in contrast to serous cystic neoplasms, they

•
•
Figure 19-9 Pancreatic mucinous cystic neoplasm with low-grade dysplasia.
A, Cross-section through a mucinous multiloculated cyst in the tail of the
pancreas. The cysts are large and filled with tenacious mucin.
B, The cysts are lined by columnar mucinous epithelium, and a dense
"ovarian" stroma is noted.
can be precursors to invasive carcinomas. These neoplasms
usually arise in the tail of the pancreas and present as pain-
less, slow-growing masses. The cystic cavities are larger
than those in serous cystic neoplasms. They are filled with
thick, tenacious mucin and lined by a columnar mucin-
producing epithelium associated with a dense stroma
similar to ovarian stroma (Fig. 19-9). Up to one third of
surgically resected mucinous cystic neoplasms harbor an
associated invasive adenocarcinoma. While surgical resec-
tion is curative for noninvasive mucinous cystic neoplasms,
half of patients with an invasive carcinoma arising in a
mucinous cystic neoplasm will die of their disease. Early
detection and treatment before an invasive cancer develops
is therefore critical. The KRAS oncogene and the TP53 and
RNF43 tumor suppressor genes are frequently mutated in
these neoplasms.
Intraductal papillary mucinous neoplasms (IPMNs) are
mucin-producing neoplasms that involve the larger ducts
of the pancreas. In contrast to mucinous cystic neoplasms,
IPMNs arise more frequently in men than in women, and
they involve the head of the pancreas more often than the
tail. Ten to twenty percent are multifocal. Two features are
Neoplasms ...._891 ___
Figure 19-10 Intraductal papillary mucinous neoplasm. A, Cross-section
through the head of the pancreas showing a prominent papillary neoplasm
distending the main pancreatic duct. B, The neoplasm involves the main
pancreatic duct (left) and extends down into the smaller ducts and ductules
(right).
useful in distinguishing IPMNs from mucinous cystic neo-
plasms: (1) absence of the dense "ovarian" stroma seen in
mucinous cystic neoplasms and (2) involvement of a pan-
creatic duct (Fig. 19-10). Just as with mucinous cystic neo-
plasms, IPMNs can progress to an invasive cancer. Early
detection and treatment of IPMNs before they progress to
an invasive cancer is therefore critical. Frequent mutations
in the GNAS and KRAS oncogenes and the TP53, SMAD4,
and RNF43 tumor suppressor genes have been reported in
these neoplasms.
The unusual solid-pseudopapillary neoplasm is seen mainly
in young women. These large, well-circumscribed malig-
nant neoplasms have solid and cystic components filled
with hemorrhagic debris. The neoplastic cells grow in solid
sheets or, as the name suggests, as pseudopapillary projec-
tions, and often appear to be poorly cohesive. These neo-
plasms often cause abdominal discomfort because of their
large size. Of note, this neoplasm is virtually always associ-
ated with hyperactivation of the Wnt signaling pathway
due to acquired activating mutations of the CTNNBl
(~-catenin) oncogene. Surgical resection is the treatment of
choice. Although some solid-pseudopapillary neoplasms
are locally aggressive, most patients are cured following
complete surgical resection of the neoplasm.
892 C H A P T E R 19 The Pancreas

The epithelial cells in PaniN show dramatic telomere

" KEY CONCEPTS shortening. A critical shortening of telomere length
• Virtually all serous cystic neoplasms are benign. in PaniN may predispose these lesions to accumulate
• Intraductal papillary mucinous neoplasms and mucinous progressive chromosomal abnormalities and to develop
cystic neoplasms are curable noninvasive cystic neoplasms invasive carcinoma (Chapter 7).
that can progress to incurable invasive carcinoma. Based on these observations, a model for progression of
• Each of the major cystic neoplasms has a relatively spe- PaniNs has been proposed (Fig. 19-12).
cific mutational profile.
Pathogenesis
Multiple genes are somatically mutated or epigenetically
Pancreatic Carcinoma silenced in each pancreatic carcinoma, consistent with their
stepwise evolution from precursor lesions, and the pat-
Infiltrating ductal adenocarcinoma of the pancreas, more terns of genetic alterations in pancreatic carcinoma as
commonly known as pancreatic cancer, is the fourth a group differs from those seen in other malignancies.
leading cause of cancer deaths in the United States, trail- Molecular alterations in pancreatic carcinogenesis are sum-
ing only lung, colon, and breast cancers, and has one of marized in Table 19-3 and include the following:
the highest mortality rates of any cancer. It was estimated
that in 2013 pancreatic cancer would strike approximately KRAS. KRAS (chromosome 12p) is the most frequently
44,000 Americans, virtually all of whom would die of their altered oncogene in pancreatic cancer, with activating
disease. The 5-year survival rate is dismal, less than 5%. point mutations being present in 90% to 95% of cases.
These point mutations result in constitutive activation of
Precursors to Pancreatic Cancer
Invasive pancreatic cancers are believed to arise from
well-defined noninvasive precursor lesions in small ducts
referred to as pancreatic intraepithelial neoplasia (PaniN,
Fig. 19-11). Just as there is a progression in the colorectum
from nonneoplastic epithelium to adenoma to invasive car-
cinoma (Chapters 7 and 17), there is a progression in the
pancreas from nonneoplastic epithelium to PaniN to inva-
sive carcinoma. The PaniN-invasive carcinoma sequence is
supported by the following observations:
• The genetic and epigenetic alterations identified in
PaniN are similar to those found in invasive cancers
(described later).
• PaniN is often found in pancreatic parenchyma adjacent
to infiltrating carcinoma.
• PaniN precedes the development of invasive cancer in
genetically engineered mouse models of pancreatic
cancer.
• Isolated case reports have documented individuals with
PaniN who later developed an invasive pancreatic Figure 19-11 Pancreatic intraepithelial neoplasia grade 3 (PaniN -3) involving
cancer. a small pancreatic duct.

NORMAL PaniN-1A PaniN-18 PaniN-2 PaniN-3 INVASIVE

CARCINOMA

Telomere shortening Inactivation of CDKN2A Inactivation of TP53,

SMAD4,
I Activating KRAS mutations I BRCA2

Figure 19-12 Model for the progression from normal ducts (far left) through PaniNs (center) to invasive carcinoma (far right). It is postulated that telomere
shortening and mutations of the oncogene KRAS occur early, that inactivation of the CDKN2A tumor suppressor gene that encodes the cell cycle regulator
p16 sta occurs in intermediate grade lesions, and that the inactivation of the TP53, SMAD4, and BRCA2 tumor suppressor genes occur in higher grade
(PaniN-3) lesions. It is important to note that while there is a general temporal sequence of changes, the accumulation of multiple mutations is more important
than their occurrence in a specific order. (Adapted from Wilentz RE, et al: Loss of expression of DPC4 in pancreatic intraepithelial neoplasia: evidence that
DPC4 inactivation occurs late in neoplastic progression. Cancer Res 2000;60:2002.)
 ___
Neoplasms ......_
893

Table 19-3 Somatic Molecular Alterations in Invasive growth, inducing cell death (apoptosis) or causing cellular
Pancreatic Adenocarcinoma senescence (Chapter 7).
Percentage
of Carcinoma Other Genes. A growing number of less common, but
Chromosomal with Genetic nonetheless important, genetic loci have been reported to
Gene Region Alteration Gene Function be damaged in pancreatic cancer (Table 19-3).
Oncogenes
12p Growth factor signal
DNA Methylation Abnormalities. Several DNA methyla-
KRAS 90
transducer tion abnormalities also occur in pancreatic cancer. Hyper-
methylation of the promoter of several tumor suppressor
AKT2 19q 10-20 Growth factor signal
transducer
genes, including CDKN2A, is associated with transcrip-
tional silencing of these genes and loss of their function.
MYB 6q 10 Transcription factor
NCOA3/A/81 20q 10 Chromatin regulator Gene Expression. In addition to DNA alterations, global
MAP2K4/MKK4 17p 5 Growth factor signal analyses of gene expression have identified several path-
transducer ways that seem to be abnormally active in pancreatic
Tumor Supprossor and DNA Repair Genes cancers. These pathways and their downstream conse-
p16/CDKN2A 9p 95 Negative cell-cycle
quences are potential targets for novel therapies and may
regulator form the basis of future screening tests. For example, the
Hedgehog signaling pathway has been shown to be acti-
TP53 17p 50-70 Response to DNA
damage
vated in pancreatic cancer and represents a potential thera-
peutic target.
SMAD4 18q 55 TGF~ pathway
GATA-6 18q 10 Transcription factor Epidemiology and Inheritance. Pancreatic cancer is pri-
RB 13q 5 Negative cell-cycle marily a disease of older adults, with 80% of cases occur-
regulator ring in people aged 60 to 80 years. It is more common in
STK11 19p 5 Regulation of cellular blacks than in whites, and it is slightly more common in
metabolism individuals of Ashkenazi Jewish descent.
ATM 11q 5 DNA damage response The strongest environmental influence is cigarette
smoking, which is believed to double the risk of pancreatic
ARIOlA 1p 4 Chromatin regulator
cancer. Even though the magnitude of this increased risk
TGFBR1 9q 2 TGF~ pathway is not great, the impact of smoking on pancreatic cancer is
TGFBR2 3p 2 TGF~ pathway significant because of the large number of people who
smoke. Consumption of a diet rich in fats has also been
implicated, but less consistently. Chronic pancreatitis and
KRAS, which is a small, GTP-binding protein that nor- diabetes mellitus are both risk factors for, and complica-
mally participates in signaling events downstream of tions of, pancreatic cancer. In an individual patient it can
growth factor receptors with intrinsic tyrosine kinase activ- be difficult to sort out whether chronic pancreatitis is the
ity (Chapters 1 and 7). KRAS signaling activates a number cause of pancreatic cancer or an effect of the disease, since
of downstream pathways that augment cell growth and small pancreatic cancers may block the pancreatic duct and
survival, most notably the MAPK and PI3K/ AKT path- produce chronic pancreatitis. A similar argument applies
ways (Chapter 7). to the association of diabetes mellitus with pancreatic
cancer, in that diabetes may develop as a consequence of
CDKN2A. The CDKN2A gene (chromosome 9p) is inacti- pancreatic cancer and new-onset diabetes mellitus in an
vated in 95% of pancreatic cancers, making it the most older patient may be the first sign that the patient has
frequently inactivated tumor suppressor gene in these pancreatic cancer.
tumors. This complex locus encodes two tumor suppressor Familial clustering of pancreatic cancer has been
proteins (Chapter 7): p16/INK4a, a cyclin-dependent reported, and a growing number of inherited genetic
kinase inhibitor that antagonizes cell cycle progression, defects are recognized to increase pancreatic cancer risk
and ARF, a protein that augments the function of the p53 (Table 19-4). Germline BRCA2 mutations account for
tumor suppressor protein. approximately 10% of pancreatic cancer cases in Ashkenazi
Jews. Patients with these mutations may not have a family
SMAD4. The SMAD4 tumor suppressor gene (chromo- history of breast or ovarian cancers. Germline mutations in
some 18q) is inactivated in 55% of pancreatic cancers. CDKN2A are associated with pancreatic cancer and are
SMAD4 encodes a protein that plays an important role in almost always observed in individuals from families with
signal transduction from the TGF-P family of cell surface an increased incidence of melanoma, which also frequently
receptors. SMAD4 is only rarely inactivated in other cancer harbors CDKN2A loss-of-function mutations.
types.

TP53. Inactivation of the TP53 tumor suppressor gene

Approximately 60% of cancers of the pancreas arise in the head
(chromosome 17p) occurs in 70% to 75% of pancreatic
of the gland, 15% in the body, and 5% in the tail; in 20% the
cancers. This gene encodes p53, a nuclear DNA-binding
neoplasm diffusely involves the entire gland. Carcinomas of the
protein that can respond to DNA damage by arresting cell
894 CHAPTER 19 The Pancreas

Table 19-4 Inherited Predisposition to Pancreatic Cancer

Increased Risk of
Risk of Pancreatic
Pancreatic Cancer by
Disorder Gene Cancer (Fold) Age 70 (%)
Peutz-Jeghers STK11 130 30-60
syndrome
Hereditary PRSSI, SPINK! 50-80 25-40
pancreatitis
Familial atypical CDKN2A 20-35 10-17
multiple-mole
melanoma
syndrome
Strong family history Unknown 14-32 8-16
(3 or more
relatives with
pancreatic cancer)
Hereditary breast and Multiple, including 4-10 5
ovarian cancer BRCAI, BRCA2,
PALP2, BRCA2
Hereditary Multiple, including 8-10 4
non-polyposis MLHI, MSH2
colorectal cancer (2p21)
(HNPCC)

pancreas are usually hard, stellate, gray-white, poorly defined

masses (Fig. 19-13A).
The vast majority of carcinomas are ductal adenocarcinomas
that recapitulate to some degree normal ductal epithelium by
Figure 19-13 Carcinoma of the pancreas. A, A cross-section through the tail
forming glands and secreting mucin. Two features are charac- of the pancreas showing normal pancreatic parenchyma and a normal pan-
teristic of pancreatic cancer; it is highly invasive (even "early" creatic duct (left), an ill-defined mass in the pancreatic substance (center)
invasive pancreatic cancers extensively invade peripancreatic with narrowing of the pancreatic duct, and dilatation of the pancreatic duct
tissues) , and it elicits an intense host reaction in the form of upstream (right) from the mass. B, Poorly formed glands are present in
dense fibrosis ("desmoplastic response"), described later. densely fibrotic stroma within the pancreatic substance; some inflammatory
Most carcinomas of the head of the pancreas obstruct the cells are also present.
distal common bile duct as it courses through the head of the
pancreas. As a consequence there is marked distention of
the biliary tree in about 50% of patients w ith carcinoma of the marked degree of desmoplasia can hinder the interpretation
head of the pancreas, and most develop jaundice. In marked of diagnostic biopsies, as much of the tissue present is
contrast, carcinomas of the body and tail of the pancreas nonneoplastic. Perineural invasion within and beyond the organ
do not impinge on the biliary tract and hence remain is common, as are lymphatic and large vessel invasion.
silent for some time. They may be quite large and most Less common morphologic variants of pancreatic cancer
are widely disseminated by the time they are discovered. include adenosquamous carcinomas, colloid carcinoma, hepa-
Pancreatic cancers often grow along nerves and invade toid carcinoma, medullary carcinoma, signet -ring cell carcinoma,
into blood vessels and the retroperitoneum. They can directly undifferentiated carcinoma, and undifferentiated carcinoma with
invade the spleen, adrenals, transverse colon, and stomach. osteoclast-like giant cells.
Peripancreatic, gastric, mesenteric, omental, and portohepatic
lymph nodes are frequently involved. Distant metastases occur,
principally to the liver and lungs.
Clinical Features. From the preceding discussion it should
Microscopically, there is no difference between carcinomas
be evident that carcinomas of the pancreas remain silent
of the head of the pancreas and those of the body and tail of
until they invade into adjacent structures. Pain is usually
the pancreas. The appearance is usually that of a moderately
the first symptom, but by the time pain appears these cancers
to poorly differentiated adenocarcinoma forming abor-
are usually beyond cure. Obstructive jaundice is associated
tive tubular structures or cell clusters and showing an
with most cases of carcinoma of the head of the pancreas,
aggressive, deeply infiltrative growth pattern (Fig. 19-138).
but it rarely draws attention to the invasive cancer soon
The malignant glands are poorly formed and are usually lined
enough. Weight loss, anorexia, and generalized malaise and
by pleomorphic cuboidal-to-columnar epithelial cells. Well-
weakness tend to be signs of advanced disease. Migratory
differentiated carcinomas are the exception. As noted earlier, a
thrombophlebitis, known as the Trousseau sign, occurs in
characteristic feature of these cancers is that they elicit an
about 10 % of patients and is attributable to the elaboration
intense desmoplastic reaction with dense stromal fibrosis. The
of platelet-activating factors and procoagulants from the

carcinoma or its necrotic products (Chapter 4). On a sad
note, Armand Trousseau (1801-1867, physician at Hotel
Dieu, Paris), for whom this sign is named, correctly sus-
pected that he had carcinoma when he developed spontane-
ously appearing and disappearing (migratory) thromboses.
The course of pancreatic carcinoma is typically brief and
progressive. Despite the tendency of lesions of the head of
the pancreas to obstruct the biliary system, fewer than 20 %
of pancreatic cancers overall are resectable at the time of
diagnosis. Most have invaded vessels and other structures
that cannot be removed surgically, or have metastasized to
distant organs. There has long been a search for tests that
could be useful in the early detection of pancreatic cancer.
Serum levels of several antigens (e.g., carcinoembryonic
antigen and CA19-9 antigen) are often elevated in
individuals with pancreatic cancer. These markers, while
useful in following an individual patient's response to
treatment, are relatively nonspecific and also lack the sen-
sitivity needed to be used as tests to screen the wider popu-
lation. Several imaging techniques, such as endoscopic
ultrasonography and computed tomography, have proved
of great value in establishing the diagnosis once it is sus-
pected, but are also not useful as screening tests.
" KEY CONCEPTS
• Cigarette smoking is the leading preventable cause of pan-
creatic cancer.
• Pancreatic cancer is one of the most aggressive of the
solid malignancies.
• Many invasive pancreatic cancer arises from histologically
well-defined precursor lesions called pancreatic intraepi-
thelial neoplasia (PaniN).
• Ductal adenocarcinomas elicit an intense desmoplastic
response.
• The genes most frequently mutated or otherwise altered in
pancreatic cancer include KRAS , p16/CDKN2A, TP53, and
SMAD4
• Clinically, most patients present with abdominal pain and
weight loss, sometimes accompanied by jaundice and
deep vein thrombosis, and succumb to the disease within
1 to 2 years.
Acinar Cell Carcinoma
Like normal acinar cells, acinar cell carcinomas form
zymogen granules and produce exocrine enzymes such as
trypsin and lipase. Fifteen percent of individuals with
acinar cell carcinoma develop the syndrome of metastatic
fat necrosis caused by the release of lipase into the
circulation.
Pancreatoblastoma
Pancreatoblastomas are rare neoplasms that occur primar-
ily in children aged 1 to 15 years. They have a distinct
microscopic appearance consisting of squamous islands
admixed with acinar cells. They are malignant neoplasms,
but survival is better with these tumors than it is for pan-
creatic ductal adenocarcinomas.
Suggested readings ...._
895 ___
SUGGESTED READINGS
Congenital Anomalies
Cano DA, Hebrok M, Zenker M: Pancreatic development and disease.
Gastroenterology 132:745-62, 2007. [A review of the normal development
of the pancreas and how development explains anomalies.]
Acute Pancreatitis
Cappel! MS: Acute pancreatitis: etiology, clinical presentation, diag-
nosis, and therapy. Med Clin North Am 92:889-923, ix-x, 2008.
[A review of acute pancreatitis.]
Frossard JL, Steer ML, Pastor CM: Acute pancreatitis. Lancet 371:143-
52, 2008. [An overview of acute pancreatitis.]
Giakoustidis A, Mudan SS, Giakoustidis 0: Dissecting the stress acti-
vating signaling pathways in acute pancreatitis. Hepatogastro-
enterology 57:653-6, 2010. [Reviews the role of nuclear factors NF-kappaB
and AP-1, TNFalpha, and TLR-4 in acute pancreatitis.]
Papachristou GI, Clermont G, Sharma A, et al: Risk and markers of
severe acute pancreatitis. Gastroenterol Clin North Am 36:277-96,
2007. [A review of the pathogenesis, immunology, and genetics of severe
acute pancreatitis by a leading expert in the field.]
Vonlaufen A, Wilson JS, Apte MV: Molecular mechanisms of pancre-
atitis: current opinion. J Gastroenterol Hepatol 23:1339-48, 2008.
[An overview of the pathogenesis of pancreatitis.]
Yadav D, Whitcomb DC: The role of alcohol and smoking in pancre-
atitis. Nat Rev Gastroenterol Hepatol 7:131-45, 2010. [Highlights the
importance of alcohol abuse in pancreatitis.]
Chronic Pancreatitis
Apte M, Pirola R, Wilson J: The fibrosis of chronic pancreatitis: new
insights into the role of pancreatic stellate cells. Antioxid Redox
Signal 15:2711-22, 2011. [A discussion of the role of stellate cells in
pancreatitis.]
Braganza JM, Lee SH, McCloy RF, et al: Chronic pancreatitis. Lancet
377:1184-97, 2011. [An overview of chronic pancreatitis.]
Kloppel G: Chronic pancreatitis, pseudotumors and other tumor-like
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LaRusch J, Whitcomb DC: Genetics of pancreatitis. Curr Opin
Gastroenterol 27:467-74, 2011. [Highlights the growing recognition of
genetics in the etiology of pancreatitis.]
Lowenfels AB, Maisonneuve P, Whitcomb DC: Risk factors for cancer
in hereditary pancreatitis. International Hereditary Pancreatitis
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Sah RP, Chari ST: Autoimmune pancreatitis: an update on classifica-
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able form of the disease.]
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and advances in pathogenesis, genetics, diagnosis, and therapy.
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Pseudocysts
Kloppel G: Pseudocysts and other non-neoplastic cysts of the pan-
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a leading expert in pancreatic pathology.]
Cystic Neoplasms
Hruban RH, Takaori K, Klimstra OS, et al: An illustrated consensus
on the classification of pancreatic intraepithelial neoplasia and
intraductal papillary mucinous neoplasms. Am J Surg Pathol
28:977-87, 2004. [Guidelines defining the difference between two common
precursor lesions.]
Tanaka M, Fernandez-Dei Castillo C, Adsay V, et al: International
consensus guidelines 2012 for the management of IPMN and MCN
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clinical management of cysts.]
Wu J, Jiao Y, Dal Molin M, et al: Whole-exome sequencing of neo-
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components of ubiquitin-dependent pathways. Proc Nat! Acad Sci
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cystic neoplasms of the pancreas reveals a mutation profile specific for
each type of cyst.]