Biliary Tract Bile • Two major functions o Elimination of bilirubin, excess cholesterol, and xenobiotics that are insufficiently

water soluble to be excreted in urine o Emulsification of dietary fat in the gut by bile acids (cholic acid, chenodeoxycholic acid) • Unconjugated → Conjugated • Reabsorbed in terminal ileum (enterohepatic circulation) Cholestasis • Systemic retention of not only bilirubin but also other solutes eliminated in bile, particularly bile salts and cholesterol

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70% associatedBiliary Tract andPathology with inflammatory Pancreas General bowel disease, December 07 particularly1ulcerative colitis M:F = 2:1, third through fifth decades Progressive fatigue, pruritus, jaundice Chronic course Increased risk for cholangiocarcinoma

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Due to hepatocellular dysfunction or biliary obstruction Accumulation of bile pigment within the hepatic parenchyma – Kupffer cells Bile ductular proliferation Bile lakes Portal tract fibrosis

Secondary Biliary Cirrhosis • Most common cause is extrahepatic cholelithiasis • Biliary atresia, malignancies of the biliary tree and head of the pancreas, and strictures • Cholestasis • Bile duct proliferation with surrounding neutrophils • Periportal fibrosis Primary Biliary Cirrhosis • Middle-aged women • M:F = 1:10 • Possibly autoimmune o Autoantibodies to mitochondrial dehydrogenase 90% • Insidious onset, usually presenting with pruritus • Hyperbilirubinemia, jaundice, cirrhosis late • ↑ alkaline phosphatase, cholesterol

Cholelithiasis • Very common • Cholesterol stones o Bile is supersaturated with cholesterol o Gallbladder stasis o F>M o Obesity o Advancing age • Pigment stones – calcium bilirubinate salts o Asian more than Western o Chronic hemolytic syndromes


Clinical Features o Asymptomatic o Biliary colic o Cholecystitis o Gallstone ileus

Figure 1-Nonsuppurative, granulomatous destruction of medium-sized intrahepatic bile ducts = florid duct lesion

Primary Sclerosing Cholangitis • Inflammation, obliterative onion-skin fibrosis, and segmental dilatation of the obstructed intrahepatic and extrahepatic bile ducts • String of beads on ERCP

General Pathology – Biliary Tract and Pancreas by VGY Cholecystitis • Acute calculous o Obstruction of GB neck or cystic duct o RUQ pain radiating to right shoulder o Fever, nausea, leukocytosis o Potential surgical emergency • Acute acalculous – seriously ill pts • Chronic o Recurrent attacks of pain o Nausea and vomiting o Associated with fatty meals • • • • • •

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Complete obstruction of bile flow caused by destruction or absence of all or part of the extrahepatic bile ducts Acquired inflammatory disorder Normal stools to acholic stools Bile ductular proliferation on liver bx Cirrhosis by 3 to 6 months of age. Require liver transplantation

Gallbladder Carcinoma • Seventh decade • F>M • Discovered at late stage, usually incidental • Exophytic and infiltrating types • Adenocarcinoma • Local extension into liver, cystic duct, portahepatic LNs • Mean 5 yr survival 1%

Choledocholithiasis • Stones within the biliary tree • West – from gallbladder • Asia – primary ductal and intrahepatic stone formation • Symptoms due to: o Biliary obstruction o Pancreatitis o Cholangitis o Hepatic abscess Cholangitis • Acute inflammation of bile ducts • Due to biliary obstruction, usually choledocholithiasis • Bacterial infection from gut, i.e., gram negative aerobes o Fever, chills, abdominal pain, jaundice • Latin America and Near East: Fasciola hepatica, schistosomiasis • Far East: Clonorchis sinensis, Opisthorchis viverrini • AIDS: cryptosporidiosis Biliary Atresia • 1/3 of cases of neonatal cholestasis • 1 in 10,000 live births

Cholangiocarcinoma • Older pts • M>F • Painless jaundice, N/V, weight loss • Opisthorchis sinensis (liver fluke),inflammatory disease • Tumors usually small at dx yet not resectable • Klatskin tumor – arises at bifurcation • Adenocarcinoma • Mean survival 6 to 18 months


General Pathology – Biliary Tract and Pancreas by VGY

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Pancreas Brief History • Herophilus, Greek surgeon first described pancreas. • Wirsung discovered the pancreatic duct in 1642. • Pancreas as a secretory gland was investigated by Graaf in 1671. • R. Fitz established pancreatitis as a disease in 1889. • Whipple performed the first pancreatico-duodenectomy in 1935 and refined it in 1940. Pancreas • Gland with both exocrine and endocrine functions • 6-10 inch in length • 60-100 gram in weight

Head of Pancreas • Includes uncinate process • Flattened structure, 2 – 3 cm thick

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Attached to the 2nd and 3rd portions of duodenum on the right Emerges into neck on the left Border b/w head & neck is determined by GDA insertion SPDA and IPDA anastamose b/w the duodenum and the rt. lateral border

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Location: retro-peritoneum*, 2nd lumbar vertebral level Extends in an oblique, transverse position Parts of pancreas: head, neck, body and tail

Neck of Pancreas • 2.5 cm in length • Straddles SMV and PV • Antero-superior surface supports the pylorus • Superior mesenteric vessels emerge from the inferior border • Posteriorly, SMV and splenic vein confluence to form portal vein • Posteriorly, mostly no branches to pancreas

Embryology • Endodermal origin • Develops from ventral and dorsal pancreatic buds • Ventral bud becomes the uncinate process and inferior head of pancreas • Dorsal bud becomes superior head, neck, body and tail • Ventral bud duct fuses with dorsal bud duct to become mail pancreatic duct (Wirsung)

Body of Pancreas • Elongated, long structure • Anterior surface, separated from stomach by lesser sac

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Posterior surface, related to aorta, lt. adrenal gland, lt. renal vessels and upper 1/3rd of lt. kidney Splenic vein runs embedded in the post. Surface Inferior surface is covered by tran. mesocolon

Tail of Pancreas • Narrow, short segment

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Lies at the level of the 12th thoracic vertebra Ends within the splenic hilum Lies in the splenophrenic ligament

General Pathology – Biliary Tract and Pancreas by VGY • • Anteriorly, related to splenic flexure of colon May be injured during splenectomy (fistula)

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Pancreatic Duct • Main duct (Wirsung) runs the entire length of pancreas • Joins CBD at the ampulla of Vater • 2 – 4 mm in diameter, 20 secondary branches • Ductal pressure is 15 – 30 mm Hg (vs. 7 – 17 in CBD) thus preventing damage to panc. duct

Lesser duct (Santorini) drains superior portion of head and empties separately into 2nd portion of duodenum

Arterial Supply of the Pancreas • Variety of major arterial sources (celiac, SMA and splenic)

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Celiac à Common Hepatic Artery à Gastroduodenal Artery à Superior pancreaticoduodenal artery which divides into anterior and posterior branches SMA à Inferior pancreaticoduodenal artery which divides into anterior and posterior branches Anterior collateral arcade b/w anterosuperior and anteroinferior PDA Posterior collateral arcade b/w posterosuperior and posteroinferior PDA Body and tail supplied by splenic artery by about 10 branches Three biggest branches are o Dorsal pancreatic artery o Pancreatica Magna (midportion of body) o Caudal pancreatic artery (tail)

Lymphatic Drainage • Rich periacinar network that drain into 5 nodal groups o Superior nodes o Anterior nodes o Inferior nodes o Posterior PD nodes o Splenic nodes Innervation of Pancreas • Peptidergic neurons that secrete amines and peptides (somatostatin, vasoactive intestinal peptide, calcitonin generelated peptide, and galanin • Rich afferent sensory fiber network • Ganglionectomy or celiac ganglion blockade interrupt these somatic fibers (pancreatic pain*) • Peptidergic neurons that secrete amines and peptides (somatostatin, vasoactive intestinal peptide, calcitonin generelated peptide, and galanin • Rich afferent sensory fiber network • Ganglionectomy or celiac ganglion blockade interrupt these somatic fibers (pancreatic pain*)

Histology-Exocrine Pancreas • 2 major components – acinar cells and ducts • Constitute 80% to 90% of the pancreatic mass • Acinar cells secrete the digestive enzymes • 20 to 40 acinar cells coalesce into a unit called the acinus

• Venous Drainage of Pancreas • Follows arterial supply • Anterior and posterior arcades drain head and the body • Splenic vein drains the body and tail • Major drainage areas are o Suprapancreatic PV o Retropancreatic PV o Splenic vein o Infrapancreatic SMV • Ultimately, into portal vein

Centroacinar cell (2nd cell type in the acinus) is responsible for fluid and electrolyte secretion by the pancreas Ductular system - network of conduits that carry the exocrine secretions into the duodenum Acinus à small intercalated ducts à interlobular duct à pancreatic duct Interlobular ducts contribute to fluid and electrolyte secretion along with the centroacinar cells

Histology-Endocrine Pancreas • Accounts for only 2% of the pancreatic mass • Nests of cells - islets of Langerhans • Four major cell types

General Pathology – Biliary Tract and Pancreas by VGY o Alpha (A) cells secrete glucagon o Beta (B) cells secrete insulin o Delta (D) cells secrete somatostatin o F cells secrete pancreatic polypeptide B cells are centrally located within the islet and constitute 70% of the islet mass PP, A, and D cells are located at the periphery of the islet o

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secreted as proenzymes and require activation for proteolytic activity o duodenal enzyme, enterokinase, converts trypsinogen to trypsin o Trypsin, in turn, activates chymotrypsin, elastase, carboxypeptidase, and phospholipase Within the pancreas, enzyme activation is prevented by an antiproteolytic enzyme secreted by the acinar cells

Physiology – Exocrine Pancreas • Secretion of water and electrolytes originates in the centroacinar and intercalated duct cells • Pancreatic enzymes originate in the acinar cells

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Final product is a colorless, odorless, and isosmotic alkaline fluid that contains digestive enzymes (amylase, lipase, and trypsinogen) 500 to 800 ml pancreatic fluid secreted per day Alkaline pH results from secreted bicarbonate which serves to neutralize gastric acid and regulate the pH of the intestine Enzymes digest carbohydrates, proteins, and fats

Insulin • Synthesized in the B cells of the islets of Langerhans • 80% of the islet cell mass must be surgically removed before diabetes becomes clinically apparent • Proinsulin, is transported from the endoplasmic reticulum to the Golgi complex where it is packaged into granules and cleaved into insulin and a residual connecting peptide, or C peptide • Major stimulants


Bicarbonate Secretion • Bicarbonate is formed from carbonic acid by the enzyme carbonic anhydrase • Major stimulants Secretin, Cholecystokinin, Gastrin, Acetylcholine • Major inhibitors Atropine, Somatostatin, Pancreatic polypeptide and Glucagon • Secretin - released from the duodenal mucosa in response to a duodenal luminal pH < 3 Enzyme Secretion • Acinar cells secrete isozymes o amylases, lipases, and proteases • • • Major stimulants o Cholecystokinin, Acetylcholine, Secretin, VIP Synthesized in the endoplasmic reticulum of the acinar cells and are packaged in the zymogen granules Released from the acinar cells into the lumen of the acinus and then transported into the duodenal lumen, where the enzymes are activated.

Glucose, amino acids, glucagon, GIP, sulfonylurea compounds, β-Sympathetic fibers Major inhibitors



somatostatin, fibers




Glucagon • Secreted by the A cells of the islet • Glucagon elevates blood glucose levels through the stimulation of glycogenolysis and gluconeogenesis

Major stimulants

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Aminoacids, Cholinergic fibers, β-Sympathetic fibers Glucose, insulin, somatostatin, α-sympathetic fibers

Major inhibitors

Somatostatin • Secreted by the D cells of the islet • Inhibits the release of growth hormone

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Inhibits the release of almost all peptide hormones Inhibits gastric, pancreatic, and biliary secretion Used to treat both endocrine and exocrine disorders

Enzymes of the Pancreas • Amylase o only digestive enzyme secreted by the pancreas in an active form o functions optimally at a pH of 7 o hydrolyzes starch and glycogen to glucose, maltose, maltotriose, and dextrins • Lipase o function optimally at a pH of 7 to 9 o emulsify and hydrolyze fat in the presence of bile salts • Proteases o essential for protein digestion

Exocrine Pancreas • The final product of the exocrine pancreas is a clear isotonic solution with a pH in the range of 8. The 2 distinct components of exocrine secretion are enzyme secretion and water+electrolyte secretion. • Cholecystokinin is the most potent endogenous hormone known to stimulate enzyme secretion. • Secretin is the most potent endogenous stimulant of pancreatic electrolyte secretion. Endocrine Pancreas

The release of insulin into the portal blood is controlled by the concentration of blood glucose, vagal interactions, and local concentrations of somatostatin.

General Pathology – Biliary Tract and Pancreas by VGY

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The major stimulus for glucagon release is a fall in serum glucose. Pancreatic polypeptide appears to function for regulation of pancreatic exocrine secretion and biliary tract motility. Somatostatin has a gastrointestinal activity broad inhibitory spectrum of



Congenital anomalies • Agenesis • Pancreas divisum • Annular pancreas • Ectopic pancreas Acute Pancreatitis • Nonbacterial inflammatory disease caused by activation, interstitial liberation, and autodigestion of the pancreas by its own enzymes. • Inconclusive evidence regarding pathogenesis o Partial or intermittent ductal obstruction and increased ductal pressure o Biliary reflux o Duodenal juice reflux • Etiology o Gallstones and Alcohol account for 90% o Hyperlipidemia o Hypercalcemia o Familial o Pancreatic duct obstruction  Tumour  Pancreas divisum Viral infection Scorpion venom Drugs Idiopathic •


pseudocyst, phlegmon, abscess or ongoing acute pancreatic inflammation. Elevated amylase levels may occur in other acute abdominal conditions, though levels rarely exceed 500 IU/dL Urinary amylase excretion is increased and this may be very helpful in cases where the serum amylase level has returned to normal. Other lab. Findings     Moderate leukocytosis Mild bilirubin elevation (<2mg/dL) Raised Haematocrit Hypocalcaemia (Calcium being complexed with fatty acids)

Radiographic Findings o CXR and PFA non-specific findings  Sentinel loop  Pleural effusion (Left) Abdominal Ultrasonography  Lithiasis of biliary tract  Pancreatic swelling Computed Tomography with iv contrast


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Clinical Course o Early identification of patients at greater risk of complications allows them to be managed more aggressively, which appears to decrease the mortality rate. o The severity and prognosis of an attack of acute pancreatitis can be predicted by use of routinely available laboratory determinations. o Just the single finding of fluid sequestration exceeding 2 L/d for more than 2 days is reasonably accurate dividing line between severe and mild to moderate disease. Ranson’s criteria for severity o On admission      o Age >55 years WBC >16000 Blood Glucose >200 mg/dL LDH >350 iu/L AST (SGOT) > 250 iu/dL

Signs and Symptoms o Midepigastric abdominal pain o Radiating to the back o Nausea and vomiting o Fever and tachycardia o Epigastric tenderness o Abdominal distention o Bluish discoloration in the flank (Grey Turner’s sign)


Bluish discoloration periumbilically (Cullen’s sign)

After 24 hours  Hematocrit fall >10%  BUN rise >8mg/dL  Serum Ca <8mg/dL  Arterial PO <60 mmHg  Base deficit > 4mEq/L  Fluid sequestration >600 mL Predicted Mortality Rates 0-2 criteria = 2% 3 or 4 criteria = 15% 5 or 6 criteria = 40%

Diagnosis o It is supported by appropriate laboratory determinations and radiographic findings o Serum amylase is the most widely used lab test o Hyperamylasemia is commonly observed within 24 hrs. of the onset and gradually returns to normal o Persistent hyperamylasemia beyond the initial week may indicate the development of pancreatic


General Pathology – Biliary Tract and Pancreas by VGY 7 or 8 criteria = 100% • Glasgow prognostic system

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Infection à Abscess Rupture à Severe chemical peritonitis Haemorrhage

Chronic Pancreatitis • Is an entity encompassing recurrent or persistent abdominal pain of pancreatic origin combined with evidence of exocrine and endocrine insufficiency and marked pathologically by irreversible parenchymal destruction. • It is associated with alcohol abuse, Hyperparathyroidism, congenital anomalies of the pancreatic duct and pancreatic trauma. It may also be idiopathic. Neoplasms of the Pancreas Exocrine Tumours • Treatment Goals of medical treatment o Reduction of pancreatic secretory stimuli o Correction of fluid and electrolyte derangements Complications o Abscess o o o o o o Pseudocyst formation Pancreatic ascites Chronic pleural effusion Gastrointestinal bleeding Acute splenic vein thrombosis Chronic Pancreatitis A. Periampullary Carcinoma • Cancer of the head of pancreas 85% • Ampullary carcinoma 10% • Duodenal carcinomas <5% • Distal Common Bile Duct Ca <5% • Signs and Symptoms o Jaundice o Weight loss o Anorexia o Vague abdominal pain o Elevated bilirubin, Alk. Phosphatase, AST, ALT o Tumour markers CA 19-9 not sufficiently accurate o CT scan to determine the size and to detect metastatic spread o Selective celiac and mesenteric angiogram combined with portal venography to assess resectability. • Treatment o Palliation with Drainage of biliary tree with stents o Duodenal obstruction poorly palliated nonoperatively o Surgical treatment is feasible o Only 40% of pre-operatively resectable tumours are resectable, and this rate is even lower for adeno-Ca of head of pancreas. o Whipple’s pancreaticoduodenectomy • Prognosis o Overall 5 year survival 25% o Head of pancreas Ca 5-year survival <20% o Other periampullary Ca 5 year survival ~60% o Chemotherapy alone not significant benefit o Combined Radio-chemotherapy and local radiation therapy have shown some benefit at least in local tumour control. Carcinoma of Body and Tail • 30% of all cases of pancreatic Cancer • Weight loss and abdominal pain • CT scan and ERCP

Pancreatic Pseudocyst

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The term pseudocyst denotes absence of an epithelial lining in contrast to true cysts Encapsulated collections of fluid with high enzyme concentrations that arise from the pancreas. They are usually located either within or adjacent to the pancreas in the lesser sac. The walls of a pseudocyst are formed by inflammatory fibrosis of the peritoneal, mesenteric and serosal membranes which limits spread of the pancreatic juice as the lesion develops. Early or late presentation Pain is the most common finding Fever, weight loss, tenderness, palpable mass Jaundice rarely Elevated amylase and WBC in ~ 50% CT scan is the investigation of choice D/D Abscess, phlegmon, neoplastic cysts Complications


General Pathology – Biliary Tract and Pancreas by VGY • • Resectability rate <7% Poor prognosis (mean survival 5 to 6 months) o o o o o Sonography ERCP Selenomethionine Scan Duodenal Aspiration Serum Test:

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Neoplasms of the Pancreas Endocrine Tumours • Pancreatic islet cell endocrine tumour are rare and are presumed to originate from neural crest cells. • Functional endocrine tumours are conventionally named according to the major hormone produced by the hormone.

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Malignancy is determined by the presence of local invasion, the spread to regional lymph nodes, or the existence of hepatic or distant metastases. Up to 25% of pancreatic endocrine tumours are classified as non-functional based on the absence of a clinical syndrome and the lack of elevated serum hormone levels. Non-functioning tumours frequently have clinical manifestations similar to the more common exocrine malignancies Non-functioning tumours are associated with a higher malignancy rate than are their functioning counterparts. Principles of Management o Recognition of the abnormal physiologic mechanism or characteristic syndrome o Detection of hormone elevations in serum by radioimmunoassay o Localization and staging of the tumour in preparation for operative therapy. o Goals of treatment:  control of symptoms due to hormone excess  Excision of maximal neoplastic tissue  Prevention of tumour recurrence. Endocrine Pancreatic Tumours a. Insulinoma o Most common endocrine tumour o 90% benign solitary pancreatic adenomas b. Gastrinoma o Second most common o Peptic ulcer disease. o Elevated serum gastrin c. VIP-oma o Watery diarrhea, hypokalemia, achlorydria d. Somatostatinoma

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 Span-1  CA 19-9  CEA 2/3-head, 1/3-body & tail Poorly delineated, yellowish gray CS Duodenal wall à direct extension Non-neoplastic area inflammation, fibrosis à extensive atrophy, chronic

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Microscopic features:

o o

Well differentiated à dx is extremely difficult LPO – glands are well formed, 1-2 layers HPO – marked nuclear pleomorphism, loss of polarity, prominent nucleoli Perinueral invasion – 90% Pan IN / CIS

Ductal Adenocarcinoma • 85 % of pancreatic malignancies

4th most common CA in the US Risk factors: o Cigarette smoking o Chronic pancreatitis o Pancreaticobiliary ductal anomaly o Elderly Diagnosis o CT Scan o MRI o Celiac angiography •

o o IHC o Mucin (gastric & SI types) o Keratin, EMA o CEA, CA19-9 B72.3 o Pancreatic CA Associated antigens o DU PAN-2 o Y Pan-1 o Tn o Sialosyl-Tn-Antigens o DF3 Antigen o M1 o Cathepsin E o Pepsinogen II o Villin o Laminin Silver stain Chromogranin Islet cell hormones Cytogenetics: o Structural rearrangements o Mutations/ accumulation of p53 o K-ras oncogene mutation o HER2neu overexpression o Aneuploid Variants o Adenosquamous CA

General Pathology – Biliary Tract and Pancreas by VGY o Oncocytic CA o Clear cell CA o Signet ring o Mucinous CA Most common Sites of Metz o peritoneum o Lung o Adrenal o Bone o Distal lymph nodes o skin o CNS Cytology o Duodenal secretion o Pancreatic Juice o Percutaneous FNA o Intraop FNA Treatment: Surgical o Body & tail – distal pancreatectomy o Head – Whipple operation + retroperitoneal resection o Paliative bypass operation

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Mucinous Cystic Neoplasm • Younger age group • Women • Large multiloculated or unilocular lined by tall mucin producing cells • High levels of CEA • Mucinous Cyst Adenoma vs. Mucinous CystadenoCA – distinction not always clear cut

Giant Cell Tumor • large & hemorrhagic • Dual population: o Spindle cells o Multinucleated giant cells • Some cases, clear cut glandular appearance

Intraductal Neoplasm • Intraductal Papillary Carcinoma o Involve major ducts, multicentric • Mucus secreting or Mucin Producing Duct-Ectatic Tumor o Dilated ducts filled with mucus o Columnar, mucin producing, well diff o Overexpression or c-erb-2 Acinar Cell Tumor & Tumor-like Conditions • Acinar Cell Hyperplasia • Acinar Cell Adenoma • Acinar Cell Carcinoma

Microcystic Cystadenoma • A.k.a.glycogen-rick cystadenoma • Large multinucleated mass, small cysts filled with clear serous fluid

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small flat to cuboidal lining

Layer of myoepithelium IHC: EMA, LMW keratin Elderly

Acinic Cell Carcinoma • IHC o Trypsin o Lipase o Chymotrypsin o amylase • Abundant ER on EM • Metastasis present in the time of diagnosis Papillary & Solid Epithelial Neoplasm • Young women • Large with areas of necrosis and hemorrhage, some with well developed capsule • Microscopic: very cellular, simulates islet cell tumor o Pseudopapillae covered by layers of epithelial cells o Nuclei are ovoid and folded o Distict nucleoli, few mitoses

Microcystic Adenocarcinoma • Similar to microcystic adenoma but with nuclear atypia, pleomorphism, metastasis

General Pathology – Biliary Tract and Pancreas by VGY o Hyaline globules o Thick fibrovascular core with mucinous change Ultrastructure o Acinar, ductal, & endocrine differentiation IHC o Keratin, desmoplakin, trypsin, chymotrypsin, amylase & vimentin o Focal reactivity: NSE, islet cell hormones

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Haay, ang haba… Feeling ko tlga ndi na kmi trans nito e. Oist, new year na! Magbagong buhay na kau! :-p