Pancreatic disorder

Pancreatic Disorder

Pancreas

• The pancreas is a gland organ participating both in the digestive and in the endocrine system.

• As endocrine:– producing several important hormones including insulin,

glucagon and somatostatin.

• As exocrine:– Secreting pancreatic juice containing digestive enzymes that

pass to the small intestine.– Enzymes: trypsin, chymotrypsin, aminopeptidase,

elastase, amylase, lipase, phopholipases and nucleases.

Development

5 weeks embryo end of 6th week

• The pancreas is developed in two parts, a dorsal and a ventral.

• The former arises as a diverticulum from the dorsal aspect of the duodenum a short distance above the hepatic diverticulum, and, growing upward and backward into the dorsal mesogastrium, forms a part of the head and uncinate process and the whole of the body and tail of the pancreas.

• The ventral part appears in the form of a diverticulum from the primitive bile-duct and forms the remainder of the head and uncinate process of the pancreas. The duct of the dorsal part (accessory pancreatic duct) therefore opens independently into the duodenum, while that of the ventral part (pancreatic duct) opens with the common bile-duct.

Coarsely lobulated, elongated, lies transversely across the abdomenand extends from the duodenum to the splenic hilum.

Three parts: head with the uncinate process, body and tail.

DuodenumSplenic hilum

Anterior aspect: directly in contact with the posterior wall of the stomach

Posterior: extends to the inferior vena cava: superior mesenteric vessels: splenic vein: left kidney

Pancreatic ducts

• Main pancreatic duct– Duct of Wirsung– Ends in the papilla or ampulla of vater in

conjunction with the common bile duct.

• Accessory pancreatic duct– Duct of Santorini– Opens independently into a minor duodenal

papilla

Pancreatic ducts

• Both ducts are joined by numerous anastomostic connections.

• When this is not the case and the duct of Santorini becomes the principal drainage – result to a condition called – pancreas divisum

Histology

Two separate components: Exocrine & Endocrine– Exocrine portion

• Constitute 80-85% of the organ• Made up of numerous small glands or acini• Lining cells: columnar to pyramidal cells radially

oriented about the gland circumference

ACINI

Endocrine portion

• Mainly represented by the Langerhan’s islet• Constitute 1%-2% of the adult pancreas• Main cell types:

B cells - insulin secreting (2/3 -3/4 of cell population)

A cells - glucagon secreting (1/5 -1/4 of cell population)

D cells - somatostatin secreting (small in number)

PP cells - pancreatic polypeptide secreting cells (scarce and located at the periphery)

Islet of Langerhans

Congenital Anomalies• Annular pancreas

– Rare embryologic abnormality in which the ventral primordium fails to rotate properly.

– Down syndrome is a predisposing condition for this anomaly.

Duct originates anteriorlyCourses to the right over the duodenum, then posteriorly to the left of the duodenum passing near the common ductFinally, joining the pancreatic duct.

Congenital Anomalies

• Gross:– There is encirclement of the duodenum by

pancreatic parenchyma -> may lead to constriction of the duodenal lumen.

• Microscopic:– Contains a large number of PP cells in its

many irregularly shaped islets.

Heterotopic pancreas

• Frequent congenital anomaly• Sites:

– Duodenum (particularly the 2nd portion)– Stomach– Jejunum– Ileum– Meckel’s diverticulum– Gastric and intestinal diverticula– Gall bladder– Bile ducts– Large bowel– Spleen (usually within or beneath the capsule)– Omentum– Abdominal wall

Pancreatitis• Acute pancreatitis

– Acute onset of abdominal pain resulting from enzymatic necrosis and inflammation of the pancreas.

• 80% of cases associated with biliary tract disease and alcoholism.

• Gallstone present in 35% to 60%• Less common causes:

– Infections with mumps, coxsackieviruses, and Mycoplasma pneumoniae

– Acute ischemia induced by vascular thrombosis, embolism, vasculitis

– Drugs – thiazide diuretics, azathioprine, estrogens, sulfonamides, furosemide, methyl dopa, procainamide

– Occlusion of pancreatic ducts by Ascaris and Clonorchis sinensis.

Morphology

The morphologic change stems directly from the action of activated pancreatic enzymes that are released into the pancreatic substance.

1. Microvascular leakage, to cause edema.

2. Necrosis of fat by lipolytic enzyme.

3. Acute inflammatory reaction.

4. Proteolytic destruction of pancreatic substance.

5. Destruction of blood vessels with subsequent interstitial hemorrhage.

Chronic pancreatitis

• Characterized by repeated bouts of mild to moderate pancreatic inflammation, with continued loss of pancreatic parenchyma and replacement by fibrous tissues.

• Etiologic factors:– Obstruction of the ductal system by carcinoma or stones– Alcoholism– Hyperparathyroidism (as a result of hypercalcemia)– Polyarteritis nodosa– Mumps, Tb, sarcoidosis

Morphology

• Gross:– Gland is hard, sometimes with dilated ducts and

grossly visible calcified concretions.– Pseudocyst formation is common.

• Microscopic:– Fibrosis.– Reduced number and size of acini.– Relative sparing of the islets of Langerhans.– Variable obstruction of pancreatic ducts of all sizes.– Chronic inflammatory infiltrates around lobules usually

present.

Cysts

• Congenital cysts– Believe to result from anomalous development of

pancreatic ducts.

– Cysts range from 3 to 5 cm in diameter.

– Lined by glistening, duct type cuboidal epithelium or a completely attenuated cell layer, enclosed in a thin fibrous capsule filled with a clear to turbid, mucoid or serous fluid.

Cysts

• Pseudocyts– Localized collection of pancreatic secretions

that develop after inflammation of the pancreas.

– Gross: wall is thick and irregular– Microscopic: devoid of lining epithelium

• Complication: perforation and hemorrhage

TUMORS

Ductal Adenocarcinoma

• General and Clinical Features– Ductal adenocarcinoma of the exocrine pancreas

comprises about 85% of all cases of pancreatic malignancy.

– Cases have been reported in workers exposed to B-naphthylamine or benzidine

– Cigarette smoking has also been cited as a risk factor.

Ductal Adenocarcinoma

• General and Clinical Features

– About 10% of pancreatic cancers show familial aggregation consistent with genetic susceptibility.

– Chronic pancreatitis is positively associated with an increased risk for pancreatic cancer, cause and effect relationship is difficult to ascertain.

Ductal Adenocarcinoma

• General and Clinical Features– Most patients are elderly– With slight male preponderance (1.6:1 ratio)– Because of its strategic location in relation to the

extrahepatic bile ducts, carcinoma of the head of the pancreas usually causes progressive jaundice that is associated with pain in at least half of the patients; however the diagnosis in most cases is made when the tumor is relatively large (5 cm) and has extended beyond the pancreas (85% of the cases).

Ductal Adenocarcinoma General and Clinical Features

• Carcinoma of the body and tail grow insidiously and has already metastasized at the time of diagnosis.

• Several diagnostic tests to detect early stage of pancreatic ca:– CT scan - nuclear magnetic resonance– Celiac angiography - sonography– Endoscopic retrograde cholangiopancreotography (ERCP)– Selenomethionine scan - duodenal aspiration– Serum test: monoclonal antibodies against various cancer-

related antigens:• SPan1• CA 19-9

Location and Gross Features

• Pancreatic carcinoma is located in the head of the pancreas in 2/3 of cases.

• 1/3 either body or tail.

• 20% of cases there are multiple tumors

• Gross:

– Most are poorly delineated and firm.

– Yellowish gray cut surface.

– Rarely undergoes massive cystic degeneration.

Location and Gross Features

• Duodenal wall is invaded by direct extension in ¼ of the tumors arising from the pancreatic head.

• Extrapancreatic extension is common and when extensive, it may be difficult to determine whether the tumor is of pancreatic in origin.

• Pancreatic ducts if involved – frequently become greatly dilated and plugged with necrotic tumor.

• The non-neoplastic pancreas distal to the tumor may show extensive atrophy, chronic inflammation and fibrosis plus ductal dilatation.

Microscopic features

• Pancreatic duct adenocarcinoma are graded

microscopically:

– Well-differentiated

– Moderately differentiated

– Poorly differentiated

Microscopic features

• Well-differentiated tumors:– Can be extremely difficult.– Attention to cytologic details.– LPO:

• Glands are well formed, large lumen and are lined by one or few layers of cylindrical or cuboidal epithelium.

• Irregular shape and distribution of the glands and peculiar desmoplastic stroma.

• Note: overall low power view may not be particularly suggestive of carcinoma.

Microscopic features

• Well-differentiated tumors:– HPO:

• Lining epithelium will show one or more features indicative of malignancy:

– Marked nuclear pleomorphism– Loss of polarity– Prominent nucleoli– Mitotic activity

• Vascular invasion particularly veins – seen in ½ of tumors.

• Perineural invasion – present in 90% of cases is an additional important diagnostic sign.

Caution:– Benign epithelial inclusions in the pancreatic

nerves.– Perineural extension of islet cells which can

occur in chronic pancreatitis.

PanIN

• Pancreatic Intraepithelial Neoplasia– Carcinoma-in-situ / Atypical hyperplasia– Believed to be precursors of Invasive ductal

adonocarcinoma

Histochemical and Immunohistochemical Features

• Most pancreatic ductal carcinomas are positive for mucin stains.

• Immunohistochem:– (+) reactivity to keratin (not much of a diagnostic help)– EMA (epithelial membrane antigen)– CEA - Tn / sialosyl-Tn antigens– CA 19-9 - DF3 antigen (mammary-type apo-mucin)

– DU-PAN2 - M1 and cathepsin– YPan-1 - pepsinogen II– Span-1 - villin

Question

• Are these histochemical and immunohistochemical studies sufficient to confirm the diagnosis of Pancreatic adenocarcinoma?

• NO

• Unfortunately, ducts in cases of chronic pancreatitis also exhibit immunoreactivity for most of these markers, thus diminishing their utility.

Molecular Genetic Features

• Structural rearrangement or loss of genes:– 1p, 3p, 6p, 8p and 17p – important in pancreatic

carcinogenesis– Mutations or accumulation of p53 – detected in half of

the cases– Mutation of the K-ras oncogene in 95% of cases– Inactivation of p16 in over 95% of cases– Overexpression of HER2 / neu oncogene in

approximately ½ of the cases

• DPC4 suppressor gene– Inactivated in approximately half of pancreatic ductal

carcinomas– NEVER inactivated in benign conditions.– Therefore:

• The immunohistochemical absence of this protein product in the ductal epithelium of a pancreatic biopsy specimen is strongly suggestive of carcinoma.

Other Microscopic Types

• Adenosquamous carcinoma• Oncocytic carcinoma• Clear cell carcinoma• Hepatoid carcinoma• Signet ring carcinoma• Mucinous (colloid carcinoma)

Endocrine Tumors

• General and clinical features– Traditionally designated as islet cell tumors– Some books – pancreatic endocrine neoplasm– Most common in adults– Few reported cases in children and newborn.

Morphologic Features

• Body and tail – most common location• Gross:

– Pinkish cast resembling spleen or congested lymph node.

– Do not have well-defined capsule.– Long standing tumors – large amount of fibrous

tissues and may contain calcium and bone.– Some may be predominantly cystic in appearance.

Morphologic Features

• Histologic:– Usually composed of small, relatively uniform

cuboidal cells with centrally located nuclei and acidophilic or amphophilic finely granular cytoplasm.

– Patterns:• Solid - any cell type• Gyriform - Beta and alpha cell type• Glandular - G or VIP cells • Nondescript

G - Gamma cells; VIP – vasoactive intestinal peptide

Morphologic Features

• Stroma:– Highly vascular– Some cases – abundant hyaline material separates

the tumor into scattered nests– Amyloid may be encountered paticularly in insulin

producing neoplasm

Unusual features of pancreatic endocrine tumors:

a. mucin production

b. black pigmentation – due to lipofuscin-type granules

c. clear cell – tends to occur in tumors associated with von Hippel-Lindau disease and may mimic renal cell ca

d. vacuolation – accumulation of cytoplasmic lipid

e. psammomma body formation

f. rhabdoid features

g. sarcomatoid transformation – include presence of skeletal muscle cells.

Specific Types• Beta cell tumors

– Most common– When functioning – referred to as insulinoma– Occur in adults – incidence equal in both sexes– Whipple Triad: characteristic of Beta cell tumor

consists of:• Mental confusion, fatigue and convulsion• Fasting blood glucose below 50 mg%• Relief of symptoms by the administration of

glucose

Specific Types• Beta cell tumors

– Over 90% - solitary– Located within the substance of the pancreas– 2% - seen in adjacent areas– 70% - measure 1.5 cm or less

• Microscopically:– May grow in solid or gyriform pattern.– Glands are usually absent.

Specific Types• Beta cell tumors

– Immunohistochemically• lesser degree of reactivity for insulin than the

normal beta cells.• Amylin – can be used for detection

AmylinAmylin is a peptide of 37 amino acids, which is also secreted by the

beta cells of the pancreas. Some of its actions:

inhibits the secretion of glucagon; slows the emptying of the stomach; sends a satiety signal to the brain.

Specific Types

• Beta cell tumors– Only 7% to 10% - are malignant– Evidence of infiltration and metastases

– Associated clinically with more pronounced hypoglycemia.

– Treatment: SURGICAL

Specific Types

• Alpha cell Tumor– Two distinct types:

• Those associated with glucagonoma syndrome• Those not associated with glucagonoma syndrome

Alpha cell tumor

• Those associated with glucagonoma syndrome (Glucagonomas)– Usually solitary and large– Nondescript microscopic pattern– Few cells positive for glucagon immnuhistochemically

(caused by abnormalities in the biosynthesis of glucagon)

• Not associated with glucagonoma syndrome– Multiple and small– Gyriform pattern of growth– Strongly immunoreactive for glucagon– Nearly always benign

Specific Types• G-cell tumors

– Referred to as Gastrinoma– Due to excessive production of gatrin– Can produce Zollinger-Ellison syndrome– Tumors often found in pancreas, duodenum and

gastric antrum– Diarrhea – seen in 1/3 of patients as a result of

excessive gastric secretion– Immunocytochemical studies: will show presence of

gastrin production by tumor cells.

Specific Types

• G-cell tumors• Treatment of choice:

– Removal of the target organs – total gastrectomy– Solitary non-metastasizing tumors - excision

Specific Types

• VIP-producing tumors– Associated with a diarrheogenic or cholera-like

syndrome in the absence of gastric hypersecretion– Due to vasoactive intestinal polypeptide (VIP)– Immunocytochem: absence of gastrin production– Tumors also contain:

• PP – pancreatic polypeptide• calcitonin • Alpha chain of hCG

Specific Types

• Delta cell tumors– Seem generally nonfunctioning at the clinical level– Produces somatostatin (growth hormone inhibiting

hormone)– Patient presentation: somatostatinoma syndrome

• Diabetes• Cholecystolithiasis• Steatorrhea• Indigestion• Hypochlorhydria• Occasionally anemia

• Zollinger–Ellison syndrome– is a triad of gastric acid hypersecretion– severe peptic ulceration– non-beta cell islet tumor of pancreas (Gastrinoma).

• In this syndrome increased levels of the hormone gastrin are produced, causing the stomach to produce excess hydrochloric acid. Often the cause is a tumor (gastrinoma) of the duodenum or pancreas producing the hormone gastrin. Gastrin then causes an excessive production of acid which can lead to peptic ulcers in almost 95% of patients.

• Gastric hyperacidity with gastric, duodenal and jejunal ulcers.

• Somatostatin – growth hormone inhibiting hormone

Question:

• One of the following is not a poduct of the endocrine function of the pancreas.– A. Insulin– B. Glucagon– C. Amylase– D. Somatostatin

Question:

The uncinate process of the pancreas is part of which of the ff?

A. Head

B. Body

C. Tail

D. None of the above

Question:

Which of the following is not true?

A. The posterior portion of the pancreas is in direct contact with the stomach.

B. The head of the pancreas is in close proximity with the 2nd portion of the duodenum.

C. The pancreas traverse across the abdomen.D. The tail ends near the splenic hilum.

Question:

The pancreatic duct that opens directly to

the duodenum:

A. Duct of Warsung

B. Bile duct

C. Duct of Santorini

D. All of the above

Question

Which of the following has the highest cell population in the Islet of Langerhans’?

A. A cells

B. B cells

C. D cells

D. PP cells

Question

True with annular pancreas:

A. Originates from the ventral bud.

B. Originates from the dorsal bud.

C. Encircle first posteriorly to the right of the duodenum.

D. Joins the bile duct to form the common bile duct.

Question:

• This is not true with ectopic pancreatic tissue.A. Function normally as the pancreas.

B. Could also develop neoplasm.

C. Most common location is the duodenum.

D. Development is via the aberrant rotation of the ventral bud.

Question

• The ff. are morphologic changes seen in acute pancreatitis except:A. Edema as a result of microvascular leak.

B. Fibrosis

C. Presence of acute inflammatory cells

D. Proteolytic destruction of the pancreatic substance.

Question

• Which is true regarding chronic pancreatitis?A. Edema as a result of microvascular leak.

B. Fibrosis

C. Presence of acute inflammatory cells

D. Proteolytic destruction of the pancreatic substance.