This slide will help you to understand the pathophysiology of pancreas.

1. Pancreas
F. E. Mahjoub, M.D.
Associate Professor in Pathology
Day 1397

2. •Pancreas:
• Retro- peritoneal organ
• From C Loop of duodenum to hilum of spleen

4. • Although the pancreas does not have well-
defined anatomic subdivisions, adjacent
vessels and ligaments serve to demarcate the
organ into:
• head,
• body,
• and tail.

5. • The pancreas is really two
organs packaged into one:
• The islets of Langerhans (1 to 2 % of organ)
• The exocrine portion that makes up the bulk
of this organ and is a major source of enzymes
that are essential for digestion.

6. •Diseases affecting the
pancreas can be the source
of significant morbidity and
mortality.

7. • Unfortunately:
• The retroperitoneal location of the pancreas
• And the generally vague nature of signs and
symptoms associated with its injury or with
dysfunction of the exocrine portion allow
many pancreatic diseases to progress
undiagnosed for extended periods of time.

8. •Thus, recognition of
pancreatic disorders
requires a high
degree of suspicion.

9. •The exocrine pancreas:
• Acinar cells
• The ductules and ducts that convey their
secretions to the duodenum.

10. Acini

11. Duct (right side)

12. Duct (middle of picture)

13. • The acinar cells are responsible
for the synthesis of digestive
enzymes, which are mostly made
as inactive pro-enzymes that are
stored in zymogen granules.

14. • When acinar cells are stimulated to secrete,
the granules fuse with the apical plasma
membrane and release their contents into the
central acinar lumen.
• These secretions are transported to the
duodenum through a series of anastomosing
ducts.

15. •The epithelial cells
lining the ducts also
are active participants
in pancreatic
secretion:

16. • The cuboidal cells that line the
smaller ductules secrete
bicarbonate-rich fluid, while the
columnar cells lining the larger
ducts produce mucin.

17. • The epithelial cells of the ducts also express
the cystic fibrosis transmembrane
conductance regulator (CFTR); regulating:
• biochemical content
• and viscosity of pancreatic secretions.

18. • CFTR has a fundamental role in
the pathophysiology of
pancreatic disease in
individuals with cystic fibrosis.

19. • Autodigestion of the pancreas
(e.g., in pancreatitis) can be a
catastrophic event.
• A number of “fail-safe” mechanisms
have evolved to minimize the risk
for occurrence of this phenomenon:

21. • A majority of pancreatic enzymes
are synthesized as inactive pro-
enzymes and sequestered in
membrane-bound zymogen
granules.

22. • Activation of pro-enzymes
requires conversion of
trypsinogen to trypsin by
duodenal enteropeptidase
(also called enterokinase).

23. • Trypsin inhibitors (e.g., SPINK1,
also known as pancreatic
secretory trypsin inhibitor) also
are secreted by acinar and
ductal cells.

24. • Trypsin cleaves and inactivates
itself, a negative feedback
mechanism that normally puts
a limit on local levels of
activated trypsin.

25. • Acinar cells are remarkably
resistant to the action of
activated enzymes such as
trypsin, chymotrypsin, and
phospholipase A 2.

26. •Diseases of the exocrine
pancreas include:
• Cystic fibrosis,
• Congenital anomalies,
• Acute and chronic pancreatitis,
• Neoplasms.

27. •Congenital Anomalies

28. • Pancreatic development is a complex
process involving fusion of dorsal
and ventral primordia.
• Subtle deviations in this process
frequently give rise to congenital
variations in pancreatic anatomy.

29. • While most of these do not cause clinical
disease, variants (especially in ductal
anatomy) can present challenges to the
endoscopist and the surgeon.
• For example, failure to recognize idiosyncratic
anatomy could result in inadvertent severing
of a pancreatic duct during surgery, resulting
in pancreatitis.

30. •Anomalies:
• 1- Agenesis
• 2- Pancreatic Divisum
• 3- Annular Pancreas
• 4- Ectopic Pancreas

31. •Agenesis
• Very rarely, the pancreas may be totally
absent, a condition usually (but not invariably)
associated with additional severe
malformations that are incompatible with life.

32. • Pancreatic duodenal homeobox 1 (PDX1) is a
homeodomain transcription factor critical for
normal pancreatic development, and germline
mutations of this gene have been associated
with pancreatic agenesis.

33. •Pancreas Divisum
• Pancreas divisum is the most common
congenital anomaly of the pancreas, with an
incidence of 3% to 10%.

34. • In most individuals, the main pancreatic
duct (the duct of Wirsung) joins the
common bile duct just proximal to the
papilla of Vater, and the accessory
pancreatic duct (the duct of Santorini)
drains into the duodenum through a
separate minor papilla.

37. • Pancreas divisum is caused by
a failure of fusion of the fetal
duct systems of the dorsal and
ventral pancreatic primordia.

38. • As a result, the bulk of the pancreas
(formed by the dorsal pancreatic
primordium) drains into the
duodenum through the small-caliber
minor papilla.

39. • The duct of Wirsung in
individuals with divisum drains
only a small portion of the
head of the gland through the
papilla of Vater.

40. • More than 95% of individuals are
asymptomatic.
• The remaining 5% develop acute or chronic
pancreatitis, possibly related to inadequate
drainage of pancreatic secretions through the
minor papilla.

41. •Annular Pancreas
• Relatively uncommon variant
• A ring of pancreatic tissue completely
encircles the duodenum.

42. • It can manifest with signs and
symptoms of duodenal
obstruction such as gastric
distention and vomiting.

43. •Ectopic Pancreas
• In 2% of the population;
• Favored sites are:
• Stomach
• Duodenum,
• Followed by the jejunum,
• Meckel diverticulum,
• And ileum.

44. • Typically small (ranging from millimeters to
centimeters in diameter)
• Located in the submucosa;
• Composed of normal pancreatic acini with
occasional islets.

45. • Usually incidental and asymptomatic,
• May become inflamed, leading to pain, or—
rarely—can cause mucosal bleeding.
• Approximately 2% of pancreatic
neuroendocrine tumors arise in ectopic
pancreatic tissue.

46. •Congenital Cysts
• Congenital cysts result from anomalous
development of the pancreatic ducts.
• In polycystic disease, the kidneys, liver, and
pancreas may all contain cysts.

47. • Generally are unilocular.
• Range from microscopic to
5 cm in diameter.

48. • They are lined by either uniform cuboidal
or flattened epithelium and are enclosed
in a thin, fibrous capsule.
• Contain clear serous fluid (pancreatic
cystic neoplasms often contain mucinous
fluid).

49. •Pancreatitis

50. •Acute
•Chronic

51. •Acute
Pancreatitis

52. • In acute pancreatitis, function can return to
normal if the underlying cause of
inflammation is removed.
• By contrast, chronic pancreatitis causes
irreversible destruction of exocrine pancreas.

53. • Acute pancreatitis:
• Reversible inflammatory disorder.
• Varies in severity, from focal edema and fat
necrosis to widespread hemorrhagic necrosis.

54. • This is a relatively common
condition, with an annual
incidence of 10 to 20 per 100,000
people in the Western world.

55. •Etiology
• The most common causes (In USA) (80%):
• Impaction of gallstones within the common
bile duct,
• Closely followed excessive alcohol intake.

56. •Other causes of
pancreatitis

57. • Non–gallstone-related obstruction of the
pancreatic ducts (e.g., due to pancreatic
cancer or other periampullary neoplasms,
pancreas divisum, biliary “sludge,” or
parasites, particularly Ascaris lumbricoides
and Clonorchis sinensis).

58. • Medications including anti-
convulsants, cancer
chemotherapeutic agents,
thiazide diuretics, estrogens, and
more than 85 others in clinical
use.

59. •Infections with mumps
virus or coxsackie virus,
which can directly infect
pancreatic exocrine cells.

60. • Metabolic disorders, including
hypertriglyceridemia,
hyperparathyroidism, and
other hypercalcemic states.

61. •Ischemia due to vascular
thrombosis, embolism,
vasculitis, or shock.

62. •Trauma, both blunt
force and iatrogenic
during surgery or
endoscopy.

63. • Germline mutations involving
genes encoding pancreatic
enzymes or their inhibitors.

64. NEW
• Hereditary pancreatitis is a rare
autosomal dominant disease with
80% penetrance that is
characterized by recurrent attacks
of severe pancreatitis, usually
beginning in childhood.

65. • It is caused by mutations in
the PRSS1 gene, which encodes
trypsinogen, the proenzyme of
pancreatic trypsin.

66. • The pathogenic mutations alter
the site through which trypsin
cleaves and inactivates itself,
abrogating an important negative
feedback mechanism.

67. • This defect leads not only to the
hyperactivation of trypsin, but
also to the hyperactivation of
many other digestive enzymes
that require trypsin cleavage for
their activation.

68. • As a result of this unbridled protease activity,
the pancreas is prone to autodigestion and
injury.
• Loss-of-function mutations in genes that
encode protease inhibitors such as SPINK1 are
less commonly associated with hereditary
pancreatitis.

69. • 10% to 20% of cases of acute
pancreatitis have no identifiable
cause (idiopathic pancreatitis).

70. • Although a growing body of evidence suggests
that many may have an underlying genetic
basis. For example, a subset of these so-
called idiopathic pancreatitis patients has
underlying germ line mutations of
the CFTR gene with symptoms predominantly
restricted to the pancreas.

71. •Pathogenesis

72. • Autodigestion of the pancreas
by inappropriately activated
pancreatic enzymes.

73. • Premature activation of trypsin within the
substance of the pancreas can unleash these
proenzymes (e.g., phospholipases and
elastases), leading to tissue injury and
inflammation.

74. • Trypsin also converts prekallikrein to its
activated form, thus sparking the kinin system,
and, by activation of factor XII (Hageman
factor), also sets in motion the clotting and
complement systems.

75. • Three pathways can incite the initial enzyme
activation that may lead to acute pancreatitis:

76. • 1- Primary acinar cell injury:
• This pathogenic mechanism comes into play in
acute pancreatitis caused by ischemia, viral
infections (e.g., mumps), drugs, and direct
trauma to the pancreas.

77. • 2- Pancreatic duct obstruction: Impaction
of a gallstone or biliary sludge, or
extrinsic compression of the ductal
system by a mass blocks ductal flow,
increases intraductal pressure, and
allows accumulation of an enzyme-rich
interstitial fluid.

78. • Since lipase is secreted in an active form, local
fat necrosis may result.

79. • Injured tissues, periacinar myofibroblasts, and
leukocytes then release pro-inflammatory
cytokines that promote local inflammation
and interstitial edema through a leaky
microvasculature.

80. • Edema further compromises local
blood flow, causing vascular
insufficiency and ischemic injury
to acinar cells.

81. • 3- Defective intracellular transport of
proenzymes within acinar cells.
• In normal acinar cells, digestive enzymes
intended for zymogen granules (and
eventually extracellular release) and hydrolytic
enzymes destined for lysosomes are
transported in discrete pathways after
synthesis in the endoplasmic reticulum.

82. • However, at least in some animal models of
metabolic injury, pancreatic proenzymes and
lysosomal hydrolases become packaged
together.
• This results in proenzyme activation,
lysosomal rupture (action of phospholipases),
and local release of activated enzymes. The
role of this mechanism in human acute
pancreatitis is not clear.

84. •Alcohol consumption
may cause pancreatitis
by several mechanisms:

85. • Alcohol transiently increases pancreatic
exocrine secretion and contraction of the
sphincter of Oddi (the muscle regulating the
flow of pancreatic juice through papilla of
Vater).

86. • Alcohol also has direct toxic effects
on acinar cells, including induction of
oxidative stress in acinar cells, which
leads to membrane damage.

87. • Finally, chronic alcohol ingestion results in the
secretion of protein-rich pancreatic fluid,
which leads to the deposition of inspissated
protein plugs and obstruction of small
pancreatic ducts.

88. • The basic alterations in acute
pancreatitis are:
• 1- microvascular leakage causing edema,
• 2- necrosis of fat by lipases,
• 3- an acute inflammatory reaction,
• 4- proteolytic destruction of pancreatic
parenchyma,
• 5- destruction of blood vessels leading to
interstitial hemorrhage.

89. • In mild forms, there is interstitial edema and
focal areas of fat necrosis in the pancreas and
peripancreatic fat.
• Fat necrosis results from enzymatic
destruction of fat cells; the released fatty acids
combine with calcium to form insoluble salts
that precipitate in situ.

91. • In more severe forms, such as acute
necrotizing pancreatitis, the damage also
involves acinar and ductal cells, the islets of
Langerhans, and blood vessels.

92. • Macroscopically, the pancreas exhibits red-
black hemorrhagic areas interspersed with foci
of yellow-white, chalky fat necrosis.

93. • Fat necrosis also can occur in extrapancreatic
fat, including the omentum and bowel
mesentery, and even outside the abdominal
cavity (e.g., in subcutaneous fat).

94. • In most cases, the peritoneum contains a
serous, slightly turbid, brown-tinged fluid with
globules of fat (derived from enzymatically
digested adipose tissue).

95. • In the most severe form, hemorrhagic
pancreatitis, extensive parenchymal necrosis
is accompanied by diffuse hemorrhage within
the substance of the gland.

96. • Laboratory findings include markedly elevated
serum amylase during the first 24 hours,
followed (within 72–96 hours) by rising serum
lipase levels.

97. • Hypocalcemia can result from precipitation of
calcium in areas of fat necrosis; if persistent, it
is a poor prognostic sign.

98. • The enlarged inflamed pancreas
can be visualized by computed
tomography (CT) or magnetic
resonance imaging (MRI).

99. • The crux of the management of acute
pancreatitis is supportive therapy (e.g.,
maintaining blood pressure and alleviating
pain) and “resting” the pancreas by total
restriction of oral food and fluids.

100. • In 40% to 60% of cases of acute necrotizing
pancreatitis, the necrotic debris becomes
infected, usually by gram-negative organisms
from the alimentary tract, further
complicating the clinical course.

101. • Although most individuals with acute
pancreatitis eventually recover, some 5% die
from shock during the first week of illness;
acute respiratory distress syndrome and acute
renal failure are ominous complications.

102. • In surviving patients, sequelae
include:
• Sterile or infected pancreatic abscesses
• Pancreatic pseudocysts.

103. •Pancreatic Pseudocysts
• A common sequela of acute pancreatitis (and
in particular, alcoholic pancreatitis) is
a pancreatic pseudocyst.
• Liquefied areas of necrotic pancreatic tissue
become walled off by fibrous tissue to form a
cystic space, lacking an epithelial lining (hence
the designation pseudo).

104. • The cyst contents are rich in pancreatic
enzymes, and a laboratory assessment of the
cyst aspirate can be diagnostic.

105. • Pseudocysts account for approximately 75% of
all pancreatic cysts.
• While many pseudocysts spontaneously
resolve, they can become secondarily
infected, and larger pseudocysts can compress
or even perforate into adjacent structures.

106. • Pseudocysts usually are solitary; they
commonly are attached to the surface of the
gland and involve peripancreatic tissues such
as the lesser omental sac or the
retroperitoneum between the stomach and
transverse colon or liver.

107. • They can range in diameter from 2 cm to
30 cm.
• Since pseudocysts form by walling off areas of
hemorrhagic fat necrosis, they typically are
composed of necrotic debris encased by walls
of granulation tissue and fibroblasts lacking an
epithelial lining.
• If they get infected, a pancreatic abscess is
formed.

109. •Chronic
Pancreatitis

110. • Chronic pancreatitis is characterized by long-
standing inflammation that leads to
irreversible destruction of the exocrine
pancreas, followed eventually by loss of the
islets of Langerhans.

111. • Of note, recurrent bouts of acute pancreatitis
regardless of etiology can evolve over time
into chronic pancreatitis.
• The prevalence of chronic pancreatitis is
difficult to determine but probably ranges
between 0.04% and 5% of the U.S. population.

112. •Etiology
• By far the most common cause of chronic
pancreatitis is long-term alcohol abuse.
• Middle-aged men constitute the bulk of
patients in this etiologic group.

113. • Less common causes of chronic pancreatitis
include the following:
• Duct Obstruction. Long-standing obstruction
of pancreatic duct e.g., by pseudocysts,
calculi, neoplasms, or pancreas divisum.

114. • Tropical pancreatitis, a poorly characterized
heterogeneous disorder seen in Africa and
Asia, with a subset of cases having a
hereditary basis.

115. • Hereditary pancreatitis due to mutations in
the pancreatic trypsinogen gene (PRRS1) , or
the SPINK1 gene encoding a trypsin inhibitor.

116. • Autoimmune pancreatitis is one manifestation
of IgG-related disease, which may involve
multiple tissues.
• It is important to recognize because it
responds to steroid therapy.

117. • As many as 40% of individuals with chronic
pancreatitis have no recognizable
predisposing factors.

118. • As with acute pancreatitis, however, a growing
number of these “idiopathic” cases are
associated with inherited mutations in genes,
such as CFTR, that are important for normal
pancreatic exocrine function.

119. • Recent studies have also identified
polymorphisms in genes encoding exocrine
pancreatic enzymes, including
carboxypeptidase A1 (CPA1)and lipase (CEL) ,
that may confer increased susceptibility to
chronic pancreatitis.

120. •Pathogenesis
• Rather same as acute type

121. • In contrast to acute pancreatitis, a variety of
profibrogenic cytokines, such as transforming
growth factor-β (TGF-β), connective tissue
growth factor, and platelet-derived growth
factor, are secreted in chronic pancreatitis by
infiltrating immune cells such as macrophages.

122. • These cytokines induce the
activation and proliferation of
periacinar myofibroblasts
(“pancreatic stellate cells”), which
deposit collagen and give rise to
fibrosis.

123. • On gross evaluation, the gland is
hard, sometimes with extremely
dilated ducts and visible calcified
concretions.

124. • Chronic pancreatitis is
characterized by parenchymal
fibrosis, reduced number and
size of acini, and variable
dilation of the pancreatic ducts.

125. • Acinar loss is a constant feature, usually with
a chronic inflammatory infiltrate around
remaining lobules and ducts.
• The ductal epithelium may be atrophied or
hyperplastic or exhibit squamous metaplasia,
and ductal concretions may be noted.

126. • There is a relative sparing of the islets of
Langerhans initially.
• The remaining islets of Langerhans become
embedded in the sclerotic tissue and may fuse
and appear enlarged; eventually they also
disappear.

128. •Pancreatic
Neoplasms

129. • Pancreatic exocrine neoplasms can be:
• Cystic
• Solid

130. • Some tumors are benign,
while others are among the
most lethal of all malignancies.

131. • Cystic Neoplasms
• Cystic neoplasms are diverse tumors that
range from harmless benign cysts to invasive,
potentially lethal, cancers.

132. • Approximately 5% to 15% of all pancreatic
cysts are neoplastic; these constitute less than
5% of all pancreatic neoplasms.
• Some of these are almost always benign (e.g.,
serous cystadenoma); others, such as
mucinous cystic neoplasms, can be benign or
malignant.

133. • Serous cystadenomas:
• Acount for approximately 25% of all
pancreatic cystic neoplasms; they are
composed of glycogen-rich cuboidal cells
surrounding small cysts containing clear,
straw-colored fluid.

135. • The tumors typically manifest in the seventh
decade of life with nonspecific symptoms such
as abdominal pain;
• The female-to-male ratio is 2 : 1.

136. • These tumors are almost uniformly benign,
and surgical resection is curative in the vast
majority of patients.
• Most serous cystadenomas carry somatic loss
of function mutations of the von Hippel-
Lindau (VHL) tumor suppressor gene, which
you will recall is a negative regulator of
hypoxia-inducible factor 1 alpha (HIF-1-alpha).

137. • Mucinous Cystic Neoplasms:
• In contrast to serous cystic tumors, close to
95% of mucinous cystic neoplasms arise in
women, usually in the body or tail of the
pancreas, and manifest as painless, slow-
growing masses.

138. • The cystic spaces are filled with thick,
tenacious mucin, and the cysts are lined by a
columnar mucinous epithelium with an
associated densely cellular stroma resembling
that of the ovary.

140. • Based on the degree of cytologic and
architectural atypia in the epithelial lining,
noninvasive mucinous cystic neoplasms are
classified as harboring low-grade, moderate,
or severe dysplasia.
• Up to one-third of these cysts can be
associated with an invasive adenocarcinoma,
another important difference from the serous
tumors.

141. • Distal pancreatectomy for noninvasive
mucinous cysts typically is curative, even in
the setting of severe dysplasia.

142. • Intraductal Papillary
Mucinous Neoplasms
• In contrast with mucinous cystic neoplasms,
intraductal papillary mucinous neoplasms
(IPMNs) occur more frequently in men than in
women and more frequently involve the head
of the pancreas.

143. • IPMNs arise in the main pancreatic ducts, or
one of its major branch ducts, and lack the
cellular stroma seen in mucinous cystic
neoplasms.
• As with mucinous cystic neoplasms, the
epithelia of noninvasive IPMNs harbor various
grades of dysplasia, and a subset of lesions is
associated with invasive adenocarcinoma.

144. • In particular, “colloid” carcinomas of the
pancreas, which are adenocarcinomas
associated with abundant extracellular mucin
production, nearly always represent malignant
transformation of an IPMN.

145. • Up to two-thirds of IPMNs harbor oncogenic
mutations of GNAS on chromosome 20q13,
which encodes the alpha subunit of a
stimulatory G-protein, G s .
• Constitutive activation of this G-protein is
predicted to result in an intracellular cascade
that promotes cell proliferation.

147. •Pancreatic
Carcinoma

148. • Infiltrating ductal adenocarcinoma of the
pancreas (more commonly referred to
as pancreatic cancer) is the third leading
cause of cancer deaths in the United States,
preceded only by lung and colon cancers.

149. • Although it is substantially less common than
the other two malignancies, pancreatic
carcinoma is near the top of the list of killers
because it carries one of the highest mortality
rates.

150. • The 5-year survival rate is a dismal 8%.

151. •Pathogenesis
• Like all cancers, pancreatic cancer arises as a
consequence of inherited and acquired
mutations in cancer-associated genes.

153. • Multistep progression:
• The most common antecedent lesions of
pancreatic cancer arise in small ducts and
ductules, and are called pancreatic
intraepithelial neoplasias (PanINs).

154. • Evidence in favor of the precursor relationship
of PanINs to frank malignancy includes the
observations that these microscopic lesions
often are found adjacent to infiltrating
carcinomas and the two share a number of
genetic alterations.

155. • Moreover, the epithelial cells in PanINs show
dramatic telomere shortening, potentially
predisposing these lesions to pathogenic
chromosomal abnormalities that may
contribute to acquisition of the full spectrum
of cancer hallmarks.

156. • The recent sequencing of the pancreatic
cancer genome has confirmed that four genes
are most commonly affected by somatic
mutations in this neoplasm:
• KRAS,
• CDKN2A/p16,
• SMAD4,
• and TP53:

157. • KRAS is the most frequently altered
oncogene in pancreatic cancer; it is
activated by a point mutation in
greater than 90% of cases.

158. • These mutations impair the intrinsic GTPase
activity of the KRAS protein so that it is
constitutively active.
• In turn, KRAS activates a number of
intracellular signaling pathways that promote
carcinogenesis.

159. • The p16 (CDKN2A) gene is the most frequently
inactivated tumor suppressor gene in
pancreatic cancer, being turned off in 95% of
cases.
• The p16 protein has a critical role in cell-cycle
control; inactivation removes an important
checkpoint.

160. • The SMAD4 tumor suppressor gene is
inactivated in 55% of pancreatic cancers and
only rarely in other tumors; it codes for a
protein that plays an important role in signal
transduction downstream of the transforming
growth factor-β receptor.

161. • Inactivation of the TP53 tumor suppressor
gene occurs in 50% to 70% of pancreatic
cancers. Its gene product, p53, acts both to
enforce cell-cycle checkpoints and as an
inducer of apoptosis or senescence.
• BRCA2 is also mutated late in a subset of
pancreatic cancers.

162. • Pancreatic cancer is primarily a disease of
older adults, with 80% of cases occurring
between 60 and 80 years of age.

163. • The strongest environmental influence is
smoking, which doubles the risk.
• Long-standing chronic pancreatitis and
diabetes mellitus are also associated with a
modestly increased risk for pancreatic cancer.

164. • These two entities have a bidirectional link
with pancreatic cancer.
• Thus, for example, tumors arising in the head
of the pancreas often cause chronic
pancreatitis in the distal parenchyma, while
diabetes caused by duct obstruction and
subsequent pancreatitis may be the
manifestation of an underlying neoplasm.

165. • In fact, approximately 1% of the older adult
population with new-onset diabetes harbor an
unsuspected pancreatic cancer.

166. • Familial clustering of pancreatic cancer has
been reported, and a growing number of
inherited genetic defects are now recognized
that increase pancreatic cancer risk.

167. • For example, germ line mutations of the
familial breast/ovarian cancer gene BRCA2 are
seen in approximately 10% of cases arising in
individuals of Ashkenazi Jewish heritage.

168. • Although serum levels of many enzymes and
antigens (e.g., carcinoembryonic: CEA and
CA19-9 antigens) are elevated, these markers
are neither specific nor sensitive enough to be
useful for screening of pancreatic cancer.

169. • Approximately:
• 60% arise in the head of the gland,
• 15% in the body,
• 5% in the tail;
• 20% diffusely involves the entire organ.

170. • Carcinomas of the pancreas
usually are hard, gray-white,
stellate, poorly defined masses

172. • Two features are characteristic of pancreatic
cancer:
• It is highly invasive (even “early” invasive
pancreatic cancers invade peripancreatic
tissues extensively),
• and it elicits an intense host reaction in the
form of dense fibrosis (desmoplastic
response).

173. • Most carcinomas of the head of the pancreas
obstruct the distal common bile duct as it
courses through the head of the pancreas:
• Cholestasis and elevation of alkaline
phosphatase.

174. • In 50% of such cases, there is marked
distention of the biliary tree, and patients
typically exhibit jaundice.
• In contrast, carcinomas of the body and tail of
the pancreas do not impinge on the biliary
tract.

175. • Pancreatic cancers often extend through the
retroperitoneal space, entrapping adjacent
nerves (thus, accounting for the pain), and
occasionally invade the spleen, adrenal
glands, vertebral column, transverse colon,
and stomach.

176. • Peripancreatic, gastric, mesenteric, omental,
and portahepatic lymph nodes frequently are
involved, and the liver often is enlarged with
metastatic deposits.
• Distant metastases may occur, principally to
the lungs and bones.

177. • On microscopic examination:
• Moderately to poorly differentiated
adenocarcinoma forming abortive glands with
mucin secretion or cell clusters and exhibiting
an aggressive, deeply infiltrative growth
pattern.

178. • Dense stromal fibrosis accompanies tumor
invasion, and there is a proclivity for
perineural invasion within and beyond the
organ.
• Lymphatic invasion also is commonly seen.

179. • Less common variants of pancreatic cancer
include adenosquamous carcinomas with
focal squamous differentiation in addition to
glandular differentiation; and undifferentiated
carcinomas with osteoclast-like giant cells of
monocytic lineage intermixed within the
neoplasm.

180. The End