Pancreatic Pathology Exocrine Pancreas Retroperitoneal organ, pancreatic length 20cm, mass 60-140g.

. Exocrine 85% of mass 2/3 adults pancreatic duct drains to CBD proximal to ampulla of Vater 1/3 pancreatic duct separately to duodenum Nonpalpable, unless duct obstruction occurs, tumors may be large at presentation (poor prognosis) Composed of acini (nests) and ducts Acini cuboidal to columnar cells w/cytoplasmic zymogen granules Ducts are lined by columnar epithelium Fat, alcohol stimulate secretin, cholecystokinin production These stimulate 1.5-3L of alkaline enzyme containing fluid per day Exocrine pancreas

Congenital Abnormalities Agenesis: Rare, usually associated w/multiple congenital abnormalities Annular pancreas: Encircles duodenum causing partial obstruction o Classic presentation: recurrent bilious vomiting (because obstruction is often distal to where CBD drains) Pancreas divisum: Incomplete fusion, predisposes to chronic pancreatitis o Embryologic origin of pancreas two separate glands that normally fuse (not here) Ectopic pancreas: 2% incidence, stomach, duodenum, Meckels diverticulum
Test q: An otherwise healthy 3M has occasional episodes of bilious (bile-containing) vomiting that have become progressively more frequent. What abnormality of the pancreas should be considered? Annular pancreas. (Other choices: Pancreas divisum, Pancreatic agenesis, Pancreatic heterotopia involving the stomach)

Acute pancreatitis 80% associated w/biliary tract disease (most commonly gall stone disease) or alcoholism o Gall stones travel down the cystic duct into the CBD and can become lodged at the ampulla, block drainage from pancreatic duct Presents w/abdominal pain, elevated amylase (at 1 day), elevated lipase (at 3 days) May result in shock, ARDS (life-threatening complications) May develop fat necrosis, hemorrhage, abscess, pseudocyst o When the pancreatic ducts are damaged, amylase and lipase can leak out into the tissue and cause necrosis of the tissue (especially fat). o The necrotic fat may actually calcify/saponify. Figure: Fat necrosis in acute pancreatitis Figure: Pancreatic pseudocyst. Fibrosis around it Pseudocyst lacks epithelial lining, has inflammatory cells, protein-containing fluid. Late stage of pancreatitis necrosis liquefies into cyst-like space.
Test q: Which 2 situations account for 80% of cases of acute pancreatitis? Gallstones and alcohol. (Other choices: Pancreatic adenocarcinoma and adenomas of the ampulla of Vater, Trauma and DIC, IV contrast administration and cholesterol emboli.) REPEATED x2 Test q: A 39M presents w/severe epigastric pain and hypotension. Serum amylase and lipase are markedly elevated. The most important etiologies to consider in this situation are: Alcohol and gallstones. (Other choices: Trauma and autoimmune, Adenocarcinoma and intraductal papillary mucinous tumor, -1-antitrypsin deficiency and Wilsons disease, Helicobacter and celiac sprue.) Test q: A 42F presents w/acute abdominal pain and lab eval is significant for a markedly increased serum amylase. Two days after admission, serum lipase becomes elevated as well. Which of the following is the most likely etiology for her serum enzyme elevation? Gall stones. (Other choices: Cystic fibrosis, Pancreas divisum, Solid pseudo-papillary neoplasm, Autoimmune pancreatitis) Test q: A 40M presents w/severe abdominal pain. Eval of the patient is significant for marked elevation of serum lipase and amylase. Of the following, which is the most likely etiology for the patients condition? Cholelithiasis. (Other choices: Familial pancreatitis syndrome SPINK1 deficiency, Parasitic infection, Adenocarcinoma of the pancreatic head, Atherosclerosis) Test q: A 38F w/a long history of gallbladder disease has a sudden onset of severe mid-abdominal pain. On phys exam, she has marked abdominal tenderness, particularly in the upper abdomen, and bowel sounds are reduced. An abdominal radiograph shows no free air, but there is marked soft tissue edema. Abdominal CT-scan shows decreased attenuation w/fluid density along w/many small, bright foci of calcification involving the pancreas. She is given IV fluids and nasogastric suction and recovers gradually. Which of the following serum lab findings is most likely to be reported in this disease process? Increased amylase level. (Other choices: Hyperammonemia, Hypoglycemia, Increased ALT level, Hypokalemia) REPEATED x2

Chronic pancreatitis: Middle aged male, alcoholic, or bile tract disease Occasionally due to other causes o Tumor o Cystic fibrosis o Autoimmune (increased IgG4 expressing plasma cells in pancreas) Histologically, see lots of plasma cells around the ducts. 12% have pancreas divisum Gross: hard, fibrotic (white, scar-like), may have stones or pseudocysts Micro: fibrosis, loss of acini w/sparing of the islets and ducts o Also chronic inflammatory cells

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1. Chronic pancreatitis secondary to cystic fibrosis (note fibrosis, loss of acinar cells, mucus in ducts). Histologically, cant distinguish CF pancreatitis from other pancreatitis. History can help more likely in a young patient. 2. Autoimmune pancreatitis (with abundant plasma cells).
Test q: A 45F presents w/abdominal pain and jaundice. Lab eval is significant for elevation of serum amylase, lipase, and IgG4. Endoscopic ultrasound eval demonstrates a 4cm ill-defined mass in the head of the pancreas. A core needle biopsy is performed. The needle core biopsy shows cytologically bland ductal epithelium w/surrounding fibrosis, lymphocytes, and plasma cells. The most likely diagnosis is: Autoimmune pancreatitis. (Other choices: Pancreatic adenocarcinoma ductal type, Acute pancreatitis, Intraductal papillary mucinous neoplasm, Multiple myeloma) REPEATED x2

Pancreatic Cancer Precursors pancreatic intraepithelial neoplasia/intraductal papillary mucinous neoplasm (IPMN) At presentation small in head due to obstruction, larger in body/tail (may be 8-10cm) May extend directly to the spleen, adrenal Metastasis to peripancreatic LN, liver Pancreatic cancer in head of pancreas Clinical Course Weight loss, abdominal pain, nausea, vomiting, weakness, jaundice (90% of those arising in the head) Trousseaus syndrome (only 10%): migratory thrombophlebitis caused by platelet aggregating factors secreted by the tumor <15% resectable 1 year survival <20%, 5 year 3% Pancreatic body adenocarcinoma White tissue, can look similar to chronic pancreatitis. Hard to tell grossly where tumor starts and stops.
Test q: The approximate 5yr survival in patients w/pancreatic adenocarcinoma is: 1-3%. (Other choices: 10-20, 30-40, 80-90) REPEATED x2

Adenocarcinoma Adenocarcinoma of ductal type most common w/small, irregular glands w/malignant nuclear features o Stratified nuclei, lots of nuclear atypia Often pronounced desmoplastic response, perineural invasion ( painful presentation)
Test q: Exam 2, 2007, #34: Picture question. The most reasonable differential diagnosis for the pancreatic lesion pictured below is: Adenocarcinoma vs. chronic pancreatitis. (Other choices: Mucinous cystic neoplasm vs. intraductal papillary mucinous neoplasm IPMN, Islet cell tumor vs. solid-pseudopapillary neoplasm, Adenocarcinoma vs. pancreatic intraductal neoplasia PanIN)

Adenocarcinoma

Precursor Lesions Due to the dismal prognosis of pancreatic adenocarcinoma, there is much interest in detecting and treating potentially surgically curable precursor lesions. Mucinous cystic neoplasms (least common of the 3) Mucinous cystic neoplasm o Cystic mass lesion, filled w/mucin o Single cyst that does not communicate with duct system o Ovarian type stroma o Much more common in women almost never in men o Figure: Mucinous cystic neoplasm epithelium w/papillary architecture and nuclear stratification (normal is single layer of nuclei) Intraductal papillary mucinous tumors o Often multifocal dilation of duct system o Slightly more common in men Pancreatic intraepithelial neoplasia o Microscopic preneoplastic change in existing small ducts, not a mass-forming lesion. Incidental finding.
Test q: All of the following pancreatic cystic tumors are more common in women than men EXCEPT: Intraductal papillary mucinous neoplasm. (Other choices: Mucinous cystic neoplasm, Solid-pseudopapillary neoplasm, Serous microcystic adenoma) Test q: Pancreatic lesions which are believed to be precursors of pancreatic adenocarcinoma include all of the following EXCEPT: Pseudocyst. (Other choices: Pancreatic intraepithelial neoplasia, Intraductal papillary mucinous neoplasm, Mucinous cystic neoplasm) Test q: Which of the following is true concerning mucinous cystic tumors and intraductal papillary mucinous tumors of the pancreas? Both may progress to invasive adenocarcinoma. (Other choices: Both are associated w/a high rate about 20% - of metastatic disease at presentation, Both are tumors of the endocrine pancreas, Both have a prognosis similar to pancreatic adenocarcinoma of ductal origin) REPEATED x2

Intraductal Papillary Mucinous Neoplasm Presents as cystic mass which communicates with the duct system or as a dilated duct. See big ducts w/mucin in the middle Endoscopically, abundant thick mucin may protrude from the ampulla Grossly, the papillary structures may be inapparent Endoscopic ultrasound diagnosis is reasonably specific Cytologic specimens tend to be hypocellular, composed primarily of thick mucus
Test q: A 50M has a CT scan of the abdomen followed by endoscopic ultrasound eval of the pancreas. These studies show multiple separate-appearing dilations of the pancreatic ducts. These dilations measure up to 2cm in greatest dimension. Endoscopically, thick mucin can be seen draining from the ampulla of Vater. This presentation is most typical of which of the following? Intraductal papillary mucinous neoplasm (IPMN). (Other choices: Pancreatic intraepithelial neoplasia PanIN, Mucinous cystic neoplasm MCN, Solid-pseudopapillary tumor SPPT, Pancreas divisum)

IPMN

IPMN in a large pancreatic duct

Invasive adenocarcinoma arising in assoc. w/IPMN

Pancreatic Intraductal Neoplasia (PanIN) Unlike MCN and IPMN, not a mass-forming lesion Progression from normal to increasing grade PanIN to carcinoma involves accumulation of genetic abnormalities, similar to the series of genetic changes seen in colorectal carcinoma Histologically PanIN is seen as distention of the cytoplasm with mucin and progressively increasing nuclear stratification and atypia Normal PanIN1 Telomere shortening, K-RAS mutations PanIN2 Inactivation of p16 PanIN3 Inactivation of p53, SMAD4, BRCA2 Invasive Carcinoma Above: Pancreatic Intraepithelial Neoplasia. Papillary architecture, more nuclear stratification than normal ducts.

Other Tumors (all very rare) Serous microcystic adenoma o Benign multicystic tumor Acinar cell carcinoma o Histologically similar to acinar cell carcinoma of the parotid gland o Prognosis similar to ductal-type adenocarcinoma Solid-pseudopapillary tumor o Almost exclusively seen in relatively young women, low-grade malignancy Pancreatoblastoma o Rare malignant childhood tumor
Test q: Concerning pancreatic adenocarcinoma, ductal type, all of the following are true EXCEPT: Pancreatic ductal adenocarcinomas arise from serious cystadenomas and solid-pseudopapillary tumors. (The incidence in the US is increasing, Pancreatic adenocarcinoma is more common in the pancreatic head than in the pancreatic tail, Abnormalities of k-ras, Smad4/Dpc4, and p53 genes are common in pancreatic cancers. Perineural invasion is a common histologic finding.) Test q: Concerning pancreatic adenocarcinoma, ductal type, all of the following are true EXCEPT: The incidence in the US is declining. (Other choices: Five year survival is less than 10%. Most cases are not considered resectable at presentation. Precursor lesions have been described. Perineural invasion is a common histologic finding.) Test q: Concerning the molecular pathology of pancreatic adenocarcinoma, all of the following are true EXCEPT: Cyclin D1 overexpression is the mechanism behind chemotherapy with a clinically useful antagonist. (Other choices: k-RAS mutations are thought to play an important role in tumor progression. Mutations of multiple genes are important in the progression of the lesion from a preinvasive, precancerous lesions to carcinoma. Pancreatic intraepithelial neoplasia show some of the genetic alterations of pancreatic adenocarcinoma, supporting its status as a precursor lesion.)

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1. Serous microcystic adenoma. Flattened epithelium, pink fluffy protein-containing fluid in the cysts. 2. Acinar cell carcinoma. Cells looks like acinar cells except of being arranged in nests, they run in a solid pattern. 3. Expression of a-1-antitrypsin by immunohistochemistry (brown) in an acinar cell carcinoma demonstrating acinar cell differentiation.

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4. Solid-pseudopapillary tumor. Has some papillary architecture, solid areas. 5. Pancreatoblastoma. Looks like other blastomas large nuclei, not much cytoplasm.
Test q: An 80F w/a history of renal cell carcinoma has a CT scan of the abdomen performed for other reasons that shows a 5cm multicystic mass involving the tail of the pancreas. A core needle biopsy is performed and shows multiple cysts lined by a single layer of cuboidal cells w/pale-to-clear cytoplasm. The nuclei are cytologically bland (small, round, and uniform). No mitoses are seen. No papillary architecture or invasive growth pattern is seen. This presentation is most typical of which of the following? Serous cystadenoma. (Other choices: IPMN, Pancreatic pseudocyst, Adenocarcinoma, Pancreas divisum) Test q: A 28F presents w/abdominal pain and had a CT scan of the abdomen. The CT scan demonstrated a well-circumscribed 6cm mass in the tail of the pancreas w/a mixed solid and cystic appearance. A distal pancreatectomy was subsequently performed. The tumor cells stained positive w/an immunohistochemical stain for keratin. No staining was seen w/a mucicarmine stain or an immunohistochemical stain for chromogranin. A histologic section of the tumor is shown , The diagnosis is: Solidpseudopapillary tumor. (Other choices: Squamous cell carcinoma, Islet cell tumor pancreatic endocrine neoplasm, Adenocarcinoma ductal type, Intraductal papillary mucinous neoplasm.) 2009, #33.

Cystic Lesions of the Pancreas About 10% of pancreatic tumors are cystic Differential dx of a cystic lesion of the pancreas is broad o Pseudocyst o Serous microcystic adenoma o Mucinous cystic neoplasm o Intraductal papillary mucinous neoplasm o Cystic adenocarcinoma o Cystic islet cell tumor Diagnosis commonly made here by endoscopic ultrasound exam w/EUS-guided fine needle aspiration Figure: IPMN diagnosed by EUS-guided FNA cytology Papillary architecture, mucin-containing cells Endocrine Pancreas 1 million 100-200 m islets total 1-1.5g cells 70% of cells (insulin) cells 20% of cells (glucagon) cells (somatostatin) others (pancreatic polypeptide, vasoactive intestinal polypeptide, serotonin) Figure: Normal endocrine pancreas Can see islet. In acinar cells, nuclei are fairly round w/coarse chromatin. Endocrine Pancreas

Diabetes Mellitus Group of disorders w/decreased glucose use and hyperglycemia May be primary/idiopathic or secondary to pancreatic disease, surgery, drugs, hemochromatosis, genetic endocrinopathies th 150,000 deaths/year, 7 cause of death, 3% of adults

Types of Diabetes Mellitus: Type I (IDDM) Age at onset usually <20 normal weight decreased insulin production islet cell antibodies ketoacidosis insulitis, severe atrophy, fibrosis Type I Type II (NIDDM) Age at onset usually >30 80% patients obese may have normal insulin insulin resistance no islet cell antibodies no ketoacidosis focal islet atrophy, may have amyloid

Decreased cell mass, insulin Genetics relates to MHC class II types 70% of whites with DM have HLA-DQ3.2 This confers 8x relative risk of DM 90% of patients have detectable islet cell antibodies Insulitis: T-lymphocyte infiltration

Type I Etiology: Poorly understood, but antibodies may be stimulated by a number of agents Viruses: mumps, measles, Coxsackie B, EBV, 20% congenital rubella Chemicals/toxins: pentamidine (antiparasitic) Autoimmune: 10% have other autoimmune diseases o Graves (Ab vs. TSH receptor, hyperthyroidism) o Addisons (Ab mediated adrenal cortex destruction) o Pernicious anemia (Ab vs. gastric mucosa, B12-intrinsic factor) Food: increased incidence in babies given cows milk early rather than breast fed o Ab vs. bovine serum albumin may be observed in type I o Molecular mimicry: BSA similar to p69, a -cell protein Type II 10% of population, obesity, inactivity Onset may be reversible by weight loss Genetics even more important than type I, MZ twin concordance >90% (type I 50%) Not strongly HLA linked, not autoimmune Normal insulin secretion, then nonpulsitile, then decreased Insulin resistance probably more important

Pathogenesis of Diabetes Complications Hyperglycemia leads to nonenzymatic glycosylation o HbA1c (marker for long term glycemic control) o Advanced glycosylation end products (AGE) o Traps LDL, cholesterol o Binds albumin in vascular, glomerular BM o Binds cytokine, fibroblast GF receptors o Converts to intracellular sorbital, cell edema Effects of Hyperglycemia: Polyuria if greater than renal glucose threshold, polydipsia Nonketotic hyperosmolar coma in type II o Prolonged hyperglycemic diuresis Diabetic ketoacidosis in type I o Increased glucagon/insulin ratio causes oxidation of fatty acids in liver, ketones o May exceed rate at which acetoacetic acid and -hydroxybutyrate can be used by muscle Pathology of DM in other organs Microangiopathy: thickened, PAS+ BM Atherosclerosis: hyaline arteriolosclerosis, MI, stroke, PVD (100x gangrene relative risk), increased LDL uptake, HDL degradation, platelet adhesion th Retinopathy (4 cause of blindness) Neuropathy

Histology of DM Lesions not pathognomonic, generally more severe in type I than type II Both types: decreased number of islets o Increased islet size and number in infants of mothers with DM or gestational DM Type I: o T-lymphocytic infiltrate/insulitis o Fibrosis of islets Type II: o Amyloidosis of islets (amylin)

Islets w/hyalinization in type II diabetes

Test q: A 35M has a long history of drug abuse and poorly-controlled type I diabetes mellitus. He has lower extremity cellulitis and dies with sepsis shortly after presentation to the ER. At autopsy, what is likely to be seen histologically in the pancreas? Decreased numbers of islets w/occasional residual islets with a lymphocytic infiltrate. (Other choices: Amyloidosis of the islets, Islets that are normal aside from loss of alpha cells by immunohistochemistry, Loss of acinar cells w/fibrosis and preservation of the ducts and islets.)

Islet Cell Tumors AKA pancreatic endocrine neoplasm Can be considered a low grade neuroendocrine carcinoma (like carcinoid tumors) o Small cell ca. of lung is a high-grade carcinoma Rare compared to ductal-type adenocarcinomas May be hormonally functional or silent Most behave in a benign fashion, although about 10% may metastasize Behavior cannot be predicted based on histology, but gastrinomas are more likely malignant, insulinomas more likely benign (maybe because they present earlier w/symptoms and are resected at a smaller size?) Express chomogranin and synaptophysin
Test q: All of the following neuroendocrine tumors are microscopically similar EXCEPT: small cell carcinoma of the lung. (Other choices: islet cell tumors, intestinal carcinoid tumors, bronchial carcinoid tumors) REPEATED x2

Insulinomas Most common islet cell tumor 5-10% metastasize Presents w/hypoglycemia (<50mg/dL), confusion/stupor with fasting/exercise, symptoms improve with food Gastrinoma Results in Zollinger-Ellison syndrome: peptic ulcer disease, gastric hypersecretion (diarrhea), islet cell tumor Most occur in pancreas, 10-15% in the duodenum 60% malignant Ulcers in stomach, duodenum Gastric parietal cell hyperplasia
Test q: Which type of islet cell tumor is associated w/gastric parietal cell hyperplasia and peptic ulcers (Zollinger-Ellison syndrome)? Gastrinoma. (Other choices: insulinoma, glucagonoma, VIPoma) REPEATED x2

Above: Chromogranin expression (brown) in FNA specimen from an islet cell tumor.

Test q: A 38F has had a low-volume watery diarrhea for the past 3mo. She now has mid-epigastric pain. Over-the-counter antacid meds do not relieve the pain. On phys exam, she is afebrile. On palpation, there is no abdominal tenderness and no masses. An upper GI endoscopy shows multiple 0.5mm to 1.1cm, shallow, sharply demarcated ulcerations in the first and second portions of the duodenum. She is given cimetidine. Three months later, repeat endoscopy shows that the ulcerations are still present. Which of the following analytes in serum or plasma is most likely to be increased in this patient? Gastrin. (Other choices: Insulin, Somatostatin, Glucagon, VIP) REPEATED x2

Other Islet Cell Tumors Glucagonomas o DM, migratory necrotizing skin edema, anemia Somatostatinomas o DM, cholelithiasis, steatorrhea, hypochlorhydria VIPoma o Watery diarrhea, hypokalemia, achlorhydria Carcinoid tumors (serotonin) o Carcinoid syndrome