Pthologies of the pancreas

2.  Greek pankreas means “all flesh”
 Endocrine and exocrine functions
 Retroperitoneal location
 20 cm in length
 90 grams in men; 85 grams in women
 Has 3 parts = head, body, and tail
 Pancreatic duct system:
 Duct of Wirsung = main pancreatic duct that drains into
the duodenum at the papilla of Vater
 Duct of Santorini = accessory pancreatic duct that drains
into the duodenum through a separate minor papilla

3.  Embryologically arises from the fusion of dorsal and
ventral outpouchings of the foregut
 Exocrine pancreas
 Constitutes 80-85% of the pancreas
 Composed of acinar cells
 Produce digestive enzymes
 Endocrine pancreas
 Composed of islets of Langerhans that constitutes only 1-
2% of the pancreas
 Secretes insulin, glucagon, and somatostatin

5. Normal pancreatic anatomy

7.  Agenesis
 Total absence of the pancreas
 Rare; associated with widespread severe malformation
 incompatible with life
 Homozygous mutations in the IPF1 gene on
chromosome 13q12.1

8.  Pancreas Divisum
 Most common congenital anomaly
 Incidence : 3-10%
 Failure of the fetal duct systems of the dorsal and
ventral pancreatic primordia to fuse
 Predisposes to development of chronic pancreatitis

10.  Annular Pancreas
 Ventral primordium of the pancreas fails to rotate properly
 Congenital abnormalities of the GIT can be seen
 Down syndrome is a predisposing condition
 Encirclement of the duodenum by pancreatic parenchyma 
constriction of the duodenal lumen
 Contains large number of PP cells in its many irregularly
shaped islets
 Presents with duodenal obstruction

11.  ECTOPIC PANCREAS
 Most common in the duodenum (2nd portion)
 Seen in the stomach, jejunum, ileum, Meckel’s diverticulum,
gastric and intestinal diverticula, GB and bile ducts, large
bowel, spleen, omentum, abdominal wall
 Grossly, resembles normal pancreas  firm, yellow,
lobulated nodules measuring up to 4 cm, sharply
circumscribed from the surrounding tissues
 Central umbilication is present corresponding to the central
duct that opens into the lumen (important diagnostic sign)
 Microscopically, acinar and ductal tissues are always present;
islet tissue is found only in 1/3 of cases

13.  Group of reversible lesions characterized by inflammation of
the pancreas ranging in severity from edema and fat necrosis
to parenchymal necrosis with severe hemorrhage
 Incidence rate : 10-20 cases/100,000 (Western)
 Approximately 80% of cases = biliary tract disease or
alcoholism
 Gallstones present in 35-60% of cases of acute pancreatits
 Severe alcoholoc intake = 65% in the US
 Idiopathic = 10-20% of cases

15.  Genetic alterations
1. Cationic Trypsinogen (PRSS1)
> point mutation with G to A transitions
resulting in an arginine (R) to histidine (H)
substitution ( called R122H)
> affects a site on the cationic trypsinogen
molecule essential for the cleavage
(inactivation) of trypsin by trypsin itself 
resistant inactivation  abnormally active
trypsin activates other digestive
proenzymes  pancreatitis

16.  Genetic alterations
Cationic Trypsinogen (PRSS1)
> hereditary pancreatitis
> autosomal dominant disease with
80% penetrance
> recurrent attacks of severe
pancreatitis usually beginning in
childhood

17.  Genetic alterations
2. Serine Protease Inhibitor, Kazal Type 1 (SPINK1)
> the gene codes for a pancreatic trypsin inhibitor
> mutations in the SPINK1 gene  pancreatitis

18.  Morphology – Gross
 Gross changes vary from a swollen and edematous
well-preserved organ to a hemorrhagic and necrotic
mass of tissue
 Pancreatic substance exhibits areas of red-black
hemorrhage interspersed with foci of yellow-white,
chalky fat necrosis
 Foci of fat necrosis may also be found in the
extrapancreatic fat depots, (omentum, mesentery,
subcutis)

19.  Morphology - Gross
 Peritoneal cavity contains serous, slightly turbid,
brown-tinged fluid in which globules of fat can be
identified
 Hemorrhagic pancreatitis
 Most severe form
 Extensive parenchymal necrosis accompanied by
diffuse hemorrhage within the substance of the
gland

23.  Morphology - Microscopic
 Ranges from trivial inflammation and edema to
severe extensive necrosis and hemorrhage
 Morphologic changes
 Microvascular leakage causing edema
 Necrosis of fat by lipolytic enzymes
 An acute inflammatory reaction
 Proteolytic destruction of pancreatic parenchyma
 Destruction of blood vessels with subsequent
interstitial hemorrhage

24.  Morphology – Microscopic
 Earlier changes are represented by acinar cell
homogenization, ductal dilatation with epithelial
degeneration, diffuse interstitial edema, leukocytic
infiltration, and fibroblastic reaction extensive
necrosis and hemorrhage of pancreatic tissue

26.  Pathogenesis
 Remains controversial
 Anatomic changes strongly suggest autodigestion of the
pancreatic substance by inappropriately activated pancreatic
enzymes
 Activation of trypsin is an important triggering event in
acute pancreatitis

27. Trypsin
Trypsinogen
Activate other
proenzymes
Phospholipase Proelastase
Disintegration of fat cells
Damage elastic fibers of b.v.
Acute Pancreatitis
Prekallikrein  Kallikrein
Kinin system
Hageman factor
Clotting system
Complement system
Inflammation
Small vessel thromboses

29.  Clinical Features
 Cardinal manifestation = abdominal pain
 Pain is constant and intense and is often referred to the upper
back
 Full-blown acute pancreatitis is a medical emergency of the
first magnitude
 Symptoms are due to release of toxic enzymes, cytokines,
and other mediators with explosive activation of the systemic
inflammatory response  leukocytosis, hemolysis, DIC, fluid
sequestration, ARDS, and diffuse fat necrosis
 Peripheral vascular collapse and shock with acute renal
tubular necrosis may occur

30.  Clinical Features
 Pancreatic necrotic foci can undergo secondary
infection  infected pancreatic necrosis
 Currently regarded as the most common, most severe, and most
lethal of the infectious complications
 Occurs in 40-60% of patients with acute necrotizing pancreatitis
 Usually involves Gram-negative organisms from the alimentary
tract
 can evolve into a chronic form

31.  Clinical Features
 Laboratory findings
 Serum amylase level elevation in the first 24 hours
 Elevation of serum lipase within 72 to 96 hours
 Glycosuria occurs in 10% of cases
 Elevated serum C-reactive protein is a reliable marker for
the presence of pancreatic necrosis
 Hypocalcemia – a poor prognostic sign
 results from precipitation of calcium soaps
in the fat necrosis

32.  Clinical Features
 Management
 “Resting” the pancreas by total restriction of food and
fluids and by supportive therapy
 Medical (4-6 hrs)  deteriorate  emergency laparotomy
 Others : emergency endoscopic retrograde
cholangiopancreatography with or w/o endoscopic
papillotomy
 Presence of an upper abdominal mass suspected of being
pseudocyst and persistent rising jaundice are indications
for surgical intervention

33. SEQUELAE OF ACUTE PANCREATITIS

34.  Characterized by inflammation of the pancreas with
destruction of exocrine parenchyma, fibrosis, and, in
the late stages, the destruction of endocrine
parenchyma
 Irreversible impairment of pancreatic function
 Prevalence : 0.04-5%

35.  Etiologic factors
 Long-term alcohol abuse
 Long-standing obstruction of the pancreatic duct
 Tropical pancreatitis
 Attributed to malnutrition
 Seen in Africa and Asia
 Hereditary pancreatitis
 Mutations in the PRSS1 and SPINK1 genes
 Idiopathic chronic pancreatitis
 Mutations in cystic fibrosis transmembrane conductance
regulator (CFTR) gene

36.  Etiologic factors (Rosai and Ackerman, 9th ed)
 Obstruction of the ductal system by carcinoma or stones
 Chronic alcoholism  most common
 Hyperparathyroidism
 Genetic factors
 Polyarteritis nodosa
 Mumps
 A “tropical” form
 TB
 Sarcoidosis
 Malakoplakia
 Secondary extension of sclerosing cholangitis
 HIV

37.  Pathogenesis – Hypotheses
 Ductal obstruction by concretions
 Alcohol  increase protein concentrations in the
pancreatic juice  ductal plugs  obstruct the pancreatic
ducts
 Toxic-metabolic
 Toxins including alcohol and its metabolites can exert
toxic effect on acinar cells  accumulation of lipids in
acinar cells  acinar cell loss  parenchymal fibrosis

38.  Pathogenesis – Hypotheses
 Oxidative stress
 Alcohol-induced oxidative stress  generate free radicals
in acinar cells  membrane lipid oxidation and
activation of transcription factors (AP1 and NFκβ) 
expression of chemokines  attracts mononuclear cells
 Promotes fusion of lysosomes and zymogen granules,
acinar cell necrosis, inflammation, and fibrosis

39.  Pathogenesis – Hypotheses
 Necrosis-fibrosis
 Acute pancreatitis  perilobular fibrosis, duct distortion,
and altered pancreatic secretions  over time and with
multiple episodes  loss of pancreatic parenchyma and
fibrosis
***Chemokines have been identified in chronic pancreatitis (IL-8,
MCP-1) plus TGF-β, PDGF  induce the activation and
proliferation of periacinar myofibroblasts (pancreatic stellate
cells)  deposition of collagen  fibrosis

40.  Morphology – Gross
 Gland is hard
 Extremely dilated ducts
 Visible calcified concretions

41.  Morphology – Microscopic
 Parenchymal fibrosis
 Reduced number and size of acini with relative sparing of
the islets of Langerhans
 Variable dilation of the pancreatic ducts
 Chronic inflammatory infiltrate around lobules and ducts
 Interlobular and intralobar ducts are dilated with protein
plugs in their lumens
 Ductal epithelium is atrophied or hyperplastic or may show
squamous metaplasia
 Ductal concretions may be evident

44.  Clinical Features
 S/Sx varies = recurrent attacks of abdominal pain/back
pain
 May be entirely silent until pancreatic insufficiency or
DM develops
 Attacks are precipitated by alcohol abuse, overeating,
or the use of opiates and other drugs that increase the
tone of the sphincter of Oddi
 Diagnosis requires a high degree of suspicion

45.  Clinical Features
 Attack of abdominal pain  mild fever and mild to
moderate elevation of serum amylase (absent with
destruction of acinar cells)
 Gallstone-induced obstruction
 Jaundice
 Elevation of alkaline phosphatase
 CT and UTS – visualize calcification
 Weight loss and hypoalbuminemic edema from
malabsorption caused by exocrine pancreatic
insufficiency

46.  Acinar necrosis and acute inflammation are seen more
often in patients with persistent pain than in those who
are free of pain
 Treatment
 Pancreatic duct drainage (through pancreacojejunostomy
or endoscopic removal of ductal stones)
 Partial pancreatic resection
 Near-total pancreatectomy with or without islet
autotransplantation

47.  Prognosis
 Not an immediately life-threatening condition, long
term outlook is poor
 20-25 year mortality rate of 50%
 Hereditary pancreatitis – 40% lifetime risk of
developing pancreatic cancer; unclear for other forms

48. SEQUELAE OF CHRONIC PANCREATITIS

49.  Two main indications
 Chronic pancreatitis
 Insulin-resistant diabetes mellitus
 At present, pancreatic graft survival rates approach
90% at 1 year
 Two complications
 “graft pancreatitis”
 Pancreatic thrombosis

50.  Most often seen as complications of acute pancreatitis
 Characterized by the presence of pus and the
microbiologic identification of bacteria in over 90% of
cases

51.  Congenital Cysts
 Result from anomalous development of the pancreatic
ducts
 May be associated with polycystic disease and von
Hippel-Lindau disease
 Range from microscopic lesions to 3-5 cm in diameter
 Lined by a glistening duct type cuboidal epithelium or
by a completely attenuated cell layer
 enclosed in a thin fibrous capsule filled with clear to
turbid mucoid or serous fluid

52.  Pseudocysts
 Related to pancreatitis, trauma, and rarely, to neoplastic
obstruction of large ducts
 They can become very large, and spread beyond the
substance of the pancreas
 Microscopic
 Lack of epithelial lining
 Gross
 Wall is thick and irregular
 Inner surface is ragged
 Intraluminal content is cloudy or bloody

53.  Pseudocysts
 Complications = perforation and hemorrhage (splenic artery)
 Treatment
 Small pseudocysts located in the body or tail of the pancreas =
excision
 External drainage (preferred for the infected cysts)
 Contraindicated if the cysts connect with the ductal system
 Internal drainage
 Transgastric cystgastrostomy
 Cystojenunostomy to a Roux-en-Y loop of jejunum

55.  Only 5-15% of pancreatic cysts are neoplastic
 5% of all pancreatic neoplasms
 Can be benign, borderline malignant, or malignant

56.  Serous cystadenomas
 Benign cystic neoplasms consists of glycogen-rich low-
cuboidal cells surrounding small cysts
 Contains clear, thin, straw-colored fluid
 Account for about 25% of all cystic neoplasms of the pancreas
 Occurs twice in women than in men; 7th decade of life
 Non-specific S/Sx like abdominal pain or palpable
abdominal mass
 Treatment : surgical resection

57.  Mucinous cystic neoplasms
 Almost always arise in women
 Can be benign, borderline malignant, or malignant
 Arises in the body or tail
 Present as painless, slow-growing masses
 Cysts are lined by columnar mucinous epithelium
containing thick, tenacious mucin
 Diagnosis is only done after removal
 Treatment is distal pancreatectomy

59.  Intraductal papillary mucinous neoplasms
(IPMNs)
 Produce cysts containing mucin
 Can be benign, borderline malignant, or malignant
 Occurs more frequently in men
 Involve the head of the pancreas more often than the
tail
 Characteristic Features
 Lack the dense “ovarian” stroma
 Arise in the main pancreatic ducts

61.  Solid-pseudopapillary tumor
 Seen mainly in adolescent girls and young women
 Large, well-circumscribed masses with solid and cystic areas
 Cystic areas are filled with hemorrhagic debris and
neoplastic cells grow in solid sheets or as papillary
projections
 Can present with abdominal discomfort because of their
large size
 Alteration of the β-catenin/adenomatous polyposis coli
genetic pathway
 Locally aggressive
 Treatment : surgical resection

62.  85% of all cases of pancreatic malignancy
 4th most common cause of death from cancer (US)
 Incidence is increasing, particularly in women
 Risk factors : B-naphthylamine or benzidine exposure,
cigarette smoking, diet rich in fats, chronic pancreatitis,
and DM
 10% show familial aggregation consistent with genetic
susceptibility
 Most patients are elderly (60-80 y/o), with slight male
preponderance (1.6:1 ratio)

63.  Diagnosis is made when tumor becomes relatively large
(about 5 cm) and has extended beyond the pancreas
(85% of cases)
 Carcinomas of the body and tail grow insidiously and
often have already metastasized at the time of diagnosis
 Associated with peripheral venous thrombi in 25% of
patients
 Diagnosis : CT-scan, MRI, celiac angiography, UTZ,
ERCP, seleno-methionine scan, duodenal aspirate,
serum test
 Tumor markers : SPan1 and CA19-9 antigen

66.  Molecular Carcinogenesis
K-RAS
 K-RAS gene is the most commonly altered oncogene
 Activated by point mutation  impair GTPase activity
of K-ras gene  active protein  Ras activates several
intracellular transduction pathways  activation of
transcription factors fos and jun

67.  Molecular Carcinogenesis
p16
 p16 gene (chromosome 9p) is the most frequently inactivated
tumor suppressor gene in pancreatic cancer
 Inactivated in 95% of cases
 p16 plays a critical role in the control of the cell cycle
p53
 Inactivation of the p53 tumor suppressor gene (chromosome
17p) seen in 50-70% of pancreatic Ca
 Gene product is nuclear DNA-binding protein that acts both
as a cell cycle checkpoint and as inducer of cell death
(apoptosis)

68.  Molecular Carcinogenesis
SMAD4
 Tumor suppressor gene (chromosome 18q) is
inactivated in 55% of pancreatic cancers
 Also known as DPC4, codes for protein that plays an
important role in signal transduction from the TGF-β
family of cell surface receptors
 Normal function of this gene is to suppress growth and
promote apoptosis

69.  Molecular Carcinogenesis
Genes amplified
 AKT2 gene
 MYB gene
Inactivated tumor suppressor genes
 AIB1 gene
 BRCA2 gene
 LKB1/STK11 genes
 MKK4 gene
 TGFβ-R1 and R2 genes
 RB1 gene

70.  Molecular Carcinogenesis
Methylation abnormalities
 Hypermethylation of the promoter of a number of
suppressor genes is associated with transcriptional
silencing of the genes
Gene expression
 Identified a number of genes that are highly
overexpressed in pancreatic cancers
 Potential targets for therapeutics and may form the
basis for future screening tests

72.  Location : head of the pancreas (60%), body (15%) or tail (5%)
 Multiple tumors are found in 20% of cases
 Majority are ductal adenocarcinomas
 Poorly delineated and firm, with a yellow cut-surface
 May undergo massive cystic degeneration
 Duodenal wall is invaded by direct extension in tumors
involving the head of the pancreas causing obstruction of the
distal CBD
 Involved pancreatic ducts are dilated and plugged with
necrotic tumor

73. A cross-section through the head of the pancreas and adjacent CBD
showing both an ill-defined mass in the pancreatic substance and
the green discoloration of the duct resulting from total obstruction
to bile flow.

75.  Microscopic features
 Graded as well-differentiated, moderately differentiated,
and poorly differentiated
 LPO = glands are well formed, have a large lumen, and
are lined by one or few layers of cylindrical or cuboidal
epithelium
 Their overall LPO appearanace may be be particularly
suggestive of carcinoma except for the irregularities in
the shape and distribution of the glands and the peculiar
concentric desmoplastic stroma that surrounds them
 Perineural invasion – 90% of cases

77. Poorly formed glands are present in densely fibrotic stroma
within the pancreatic substance with presence of some
inflammatory cells.

78.  Histochemical and Immunohistochemical
features
 Positive for mucin stains
 Consistent reactivity for keratins and EMA
 Glycoprotein MUC1 is expressed in over 60% of
conventional invasive ductal carcinoma
 Others : CEA, CA19-9, B72.3, DUPAN-2, YPan-1, SPan-
1, Tn and sialosyl-Tn antigens, DF3

79.  Spread and metastasis
 Tends to metastasize to multiple LN located around the
organ
 Most commonly involved the LN around the common
hepatic artery, hepatoduodenal ligament, posterior
pancreaticoduodenal, around the superior mesenteric
artery, para-aortic, and anterior pancreatico-duodenal
 Microscopic metastasis were found in T1 and T2 lesions

80.  Spread and metastasis
 Most common sites of distant metastasis are liver,
peritoneum, lung, adrenal, bone, distant LN groups,
skin, and CNS
 Supraclavicular LN metastasis is sometimes the first
manifestation of pancreatic carcinoma

81.  Diagnosis
 Cytology
 Duodenal secretion
 Pancreatic juice
 FNAB
percutaneous
intraoperative
 Frozen section

82.  Treatment
 Surgical
 Prognosis
 Overall 5-year survival rate = 4% or less with over 90%
of patients dying within 1 year of diagnosis
 Mean survival of 3 months for untreated patients
 Even if the tumor is confined at the pancreas at the time
of diagnosis, the 5-year survival rate does not exceed
15%

83.  Prognostic Factors
 Tumor stage – most important prognostic indicator
 Microscopic grade – well-differentiated tumor have
longer survival rate
 Tumor size - <4.5 cm have better chance of curative
operation
 Blood vessel invasion and retroperitoneal margin of
resection – decreased survival
 LN metastasis

84.  Prognostic Factors
 DNA ploidy
 TGF-B1 expression – associated with well-differentiated
tumor

85. TNM classification criteria
T1 No direct extension of the primary beyond the
pancreas
T2 Limited direct extension to the duodenum, bile duct,
or stomach
T3 Advanced direct extension incompatible with surgical
resection
TX Direct extension not assessed
N0 Regional nodes not involved
N1 Regional nodes involved
NX Regional LN not assessed

86. TNM classification criteria
M0 No distant metastasis
M1 Distant metastasis present
MX Distant metastasis not assessed
TNM Stages
Stage I T1-2, N0, M0
Stage II T3, N0, M0
Stage III T1-T3, N1, M0
Stage IV Any T or N, M1

87.  Most common form of pancreatic neoplasia in
childhood, but can also occur in adults
 Reported in patients with Beckwith-Wiedemann
syndrome and familial adenomatous polyposis of the
colon
 Bimodal age distribution = mean of 2.4 and 33 years
 No sex predilection
 Mean tumor size is 10 cm and partial encapsulation is
the rule

88.  Microscopic
 Very cellular tumors, made up of uniform epithelial cells
arranged in solid sheets and nests, admixed with well-
formed acinar structures and occasional ductular
formations
 “Squamoid corpuscles” are a constant and characteristic
finding
 Immunochemistry
 Positivity for pancreatic enzymes, endocrine markers,
and CEA
 Alpha-fetoprotein may be produced by the tumor

91.  Treatment : Surgical resection