Non-Neoplastic Pancreas Benjamin Swanson, MD, PhD Assistant Professor, Department of Pathology Benjamin.Swanson@osumc.edu Hello, I’m Ben Swanson, and I’ll be reviewing non-neoplastic pancreatic pathology. Biographic information Title, Department Information Clinical Interest Research Interest

Learning Objectives Define pancreas divisum, explain its embryologic origin and clinical manifestations. Define annular pancreas, its clinical presentation and embryologic origin. Describe the conditions, etiologic agents, clinical manifestations, and complications associated with acute and chronic pancreatitis. Understand the underlying pathophysiology resulting in the global manifestations of acute pancreatitis. At the conclusion of the lecture, I would like you to Be able to define pancreatic divisum, explaining its embryologic origin and clinical manifestatations Define annular pancreas, its clinical presentation and embryologic origin Describe the conditions, etiologic agents, clinical manifestations, and complications associated with acute and chronic pancreatitis And understand the underlying pathophysiology resulting in the global manifestations of acute pancreatitis

Congenital Anomalies Agenesis, hypoplasia Annular Pancreas divisum Aberrant pancreas (ectopic) Duct anomalies Congenital anomalies of the pancreas include agenesis, hypoplasia, annular pancreas, pancreatic divisum, aberrant pancreas (ectopic), and duct anomalies.

Annular Pancreas Pancreas arises from dorsal and ventral duodenal buds In the 6th week of normal pancreas development, the ventral pancreas with the common bile duct, rotates around the posterior duodenum In annular pancreas, a portion of the ventral primordium becomes fixed to the duodenum while the other portion rotates around the duodenum Embryologically, the pancreas arises from dorsal and ventral duodenal buds. In the sixth week of development, the ventral pancreas and the common bile duct rotate circumferentially around the duodenum. Annular pancreas, which you can see in the blue box, represents a ring of pancreas encircling the duodenum. It is hypothesized to develop due to the failure of one of the lobes of the ventral duodenal bud to regress (the ventral primordium becomes fixed to the duodenum). The other portion of primordial pancreas rotates around the pancreas. Pancreas

Annular Pancreas This remnant forms a band-like ring around the the second portion of the duodendum Can present as duodenal obstruction with gastric distension and vomiting This remnant forms a band-like ring around the second portion of the duodenum. This rare condition, accounting for 0.015% of the population, can cause duodenal obstruction, gastric distension and vomiting.

Pancreas Divisum Most common congenital anomaly of the pancreas (5-10% of population) Caused by an anomaly in the fusion of the duct systems of the primordial ventral and dorsal pancreas In complete divisum, the larger portion of the pancreas drains through the minor papilla stenosis may predispose to pancreatitis Pancreas divisum is the most common congenital anomaly of the pancreas, seen in 5-10% of the population. It is due to lack of fusion of the two duodenal (ventral and dorsal) embryologic buds. It can be complete, as seen in the first image on the left, where we have a complete separation of between the pancreatic head and the pancreatic body and tail. This causes the larger portion of pancreas to drain through the minor papilla. This can lead to stenosis and may predispose to pancreatitis. Alternatively, pancreatic divisum can be partial, as seen on the image on the right where there is some degree of fusion of the two buds, but there is an abnormal anatomy. Complete Partial

Acute Pancreatitis Can occur at any age Most commonly occurs in 3rd to 6th decade of life Early presentation (1st decade of life)  hereditary, infection or trauma Mild “edematous” pancreatitis Minimal organ dysfunction Uneventful recovery in 5-7 days Severe “necrotizing” pancreatitis Multisystem organ failure (Acute respiratory distress syndrome, Acute tubular necrosis of the kidney, Disseminated intravascular coagulation, Sepsis) Abscess and pseudocyst formation Duodenal obstruction Mortality ~10% Acute pancreatitis can occur at any age. It most commonly occurs in adults in the third to sixth decade of life. When it occurs in the first decade of life, this is suggestive of a hereditary cause, infection or trauma. In mild “edematous” pancreatitis there is minimal organ dysfunction with an uneventful recovery in 5-7 days. In contrast, severe “necrotizing” pancreatitis may present with multisystem organ failure (such as acute respiratory distress syndrome of the lungs, acute tubular necrosis of the kidneys, disseminated intrasvascular coagulation or sepsis), abscess formation in the pancreas. Furthermore, there can be duodenal obstruction and even mortality in approximately 10% of patients with severe pancreatitis.

Acute Pancreatitis Etiology Alcohol Gallstones Metabolic disorders (hyperlipidemia, hypercalcemia) Medications Infections: Viral: Mumps, coxsackie, hepatitis B, CMV, varicella-zoster, HSV, HIV Bacteria: mycoplasma, Legionella, Leptospira, salmonella Fungi: Aspergillus Parasites: Toxoplasma, cryptosporidium, Ascaris Trauma/post-procedural Vascular/shock Congenital: Pancreatic divisum Genetic: Cystic Fibrosis, alpha-1 antitrypsin deficiency Account for most cases (60-75%) The most common cause of acute pancreatitis are gallstones and alcohol, accounting for 60-75% of patients. Other causes of acute pancreatitis include metabolic disorders such as hyperlipidemia and hypercalcemia, various medications, various infections, trauma, following a medical procedure involving the pancreas and in patients with shock. Genetic causes of acute pancreatitis include cystic fibrosis and alpha-1 antitrypsin deficiency.

Pathophysiology of Acute pancreatitis Pathophysiologically, acute pancreatitis is a result of damage to the acini. Either directly or indirectly through bile reflux, this causes relase of oxygen free radicals and pancreatic enzymes which cause damage to the pancreas and surrounding tissues.

Acute Pancreatitis Macroscopic Findings Mild acute pancreatitis Swollen pale and indurated pancreas Lobules appear separated by edema Focal fat necrosis Severe acute pancreatitis Large confluent areas of fat necrosis Hemorrhagic necrosis may develop The anatomic findings in mild acute pancreatitis include a swollen, pale and indurated pancreas with lobules of the pancreas separated by edema. Grossly, fat necrosis appears as opaque white, waxy, or chalky areas. In severe acute pancreatitis, by contrast, has large confluent areas of fat necrosis that may or may not have hemorrhage.

Acute Pancreatitis Microscopic Findings Mild acute pancreatitis Interstitial acute inflammation Spotty peripancreatic fat necrosis Severe acute pancreatitis Abundant neutrophils Large areas of fat necrosis Variable levels of pancreatic necrosis Saponification Microscopically, mild acute pancreatitis shows spotty peripancreatitc fat necrosis (as indicated by the black arrow)and interstitial acute inflammation. In severe acute pancreatitis, there can be large areas of fat necrosis and variable pancreatic parenchymal necrosis spread throughout. These cases will also show abundant neutrophils, saponification (as indicated by the white arrow), hemorrhage, and venous thrombosis.

Chronic Pancreatitis Incidence Can occur at any age Alcohol related chronic pancreatitis more commonly affects males >40 yo Chronic pancreatitis in childhood represents hereditary etiologies Chronic pancreatitis can occur at any age. Alcohol-related chronic pancreatitis usually affects adults greater than 40 years of age and is more common in men. Chronic pancreatitis presenting in childhood is usually due to hereditary or tropical etiologies.

Chronic Pancreatitis Etiology Chronic alcohol ingestion Most common cause in developed countries (70%) Only 10% of alcohol abusers develop chronic pancreatitis which suggests additional factors account for its development Concurrent smoking may multiple the risk of chronic pancreatititis with 10X Duct obstruction: choledocholithiasis, tumors, scarring/stenosis Groove pancreatitis (paraduodenal wall cyst) Metabolic: hypercalcemia, hyperlipidemia Alcohol ingestion is by far the common cause of chronic pancreatitis. Approximately 70% of chronic pancreatitis cases are caused by alcohol. However, only 10% of alcohol abusers develop chronic pancreatitis, which suggests that additional factors are at play. Importantly, smoking is an additive risk factor for developing chronic pancreatitis with alcohol, with perhaps a 10 fold greater risk of developing chronic pancreatitis. Duct obstruction is another potential cause of chronic pancreatitis. Choledocholithiasis, tumors, scarring and stenosis can all cause duct obstruction and lead to chronic pancreatitis. Metabolic causes include hypercalcemia and hyperlipidemia. Groove pancreatitis (also called paraduodenal wall cyst) can also chronic pancreatitis.

Chronic Pancreatitis Etiology Tropical Aggressive form of juvenile pancreatitis which occurs in tropical developing countries May be related to malnutrition, toxins or genetic predisposition Hereditary: PRSS1, CFTR, SPINK1 Trauma Idiopathic: up to 25% of cases Tropical chronic pancreatitis is an aggressive form of juvenile pancreatitis that occurs in tropical developing countries. It is theorized to be due to malnutrition, toxin exposure and/or genetic predisposition. Genetic syndromes and trauma can also cause chronic pancreatitis. Up to 25% of cases have no known cause.  

Chronic Pancreatitis Macroscopic Findings Pancreas may be involved focally, diffusely, or segmentally Affected pancreas usually firm, indurated and fibrotic Cystically dilated pancreatic ducts Grossly, the pancreas in chronic pancreatitis is enlarged, firm, indurated and fibrotic. This can focally, segmentally, or diffusely involve the pancreas. Additionally, the pancreatic duct may be cystically dilated.

Chronic Pancreatitis Microscopic Findings Preserved lobular arrangement of the pancreas Duct and acinar atrophy leads to more prominent appearing islets of Langerhans Pancreatic duct alterations Atrophy (can be angulated) Hyperplasia (pseudopapillary or papillary) Metaplasia (squamous, mucinous, pyloric) Fibrosis Chronic inflammation Microscopically, chronic pancreatitis shows preservation of the normal lobular architecture of the pancreas. This is important for distinguishing chronic pancreatitis from pancreatic cancer. Duct and acinar atrophy are seen in an irregular distribution throughout the pancreas. Pancreatic duct alterations include: atrophy (where they appear angulated.), hyperplasia (which can be pseudopapillary or papillary) and metaplasia. Chronic inflammation is often seen, but is not the predominant feature. Scattered fibrosis is often a seen. Although the islets of Langerhans are not involved, they appear relatively increased due to the acinar atrophy.

Chronic Pancreatitis Acinar Atrophy This image demonstrates acinar atrophy. The white circle shows a preserved area of acini surrounding an islet of Langerhans. The black circle shows an area of fibrosis where only a small islet of Langerhans remains and the pancreatic acini have atrophied.

Chronic Pancreatitis Fibrosis and Chronic Inflammation This image depicts the fibrosis and chronic inflammation in chronic pancreatitis. The white arrow shows chronic inflammation while the black arrow depicts fibrosis.

Chronic Pancreatitis Spared Islets This image demonstrates the relative sparing of islets of Langerhans in chronic pancreatitis.

Pancreatic Pseudocyst Occurs as a result of pancreatitis (acute or chronic) Most commonly associated with alcohol consumption Grossly is a unilocular cyst with a ragged inner surface and a thick fibrotic wall Fluid within the cyst has few cells and has high levels of the enzyme amylase Pancreatic pseudocyst occurs most commonly as a result of acute or chronic pancreatitis. They are most commonly associated with chronic alcohol consumption. Grossly, the pseudocyst consists of a unilocular cyst with a ragged inner surface and a thick fibrotic wall. The cyst fluid on fine needle aspiration has high levels of amylase and scant numbers of cells.

Pancreatic Pseudocyst Microscopically lacks an epithelial lining (thus pseudocyst). Cyst wall lined by granulation tissue Microscopically also lacks necrosis (as opposed to an abscess) Microscopically, the pseudocyst lacks an epithelial lining. The lining of the wall has granulation tissue, inflammatory cells, and fibrosis. These pseudocysts lack necrosis, as compared to an abscess.

Summary Pancreatic divisum is a complete or partial division of the pancreas, it is caused by lack of fusion of the two embryologic duodenal buds Annular pancreas is an encircling of the duodenum by the pancreas, it is caused by failure of the ventral duodenal bud to properly rotate with the duodenum Acute pancreatitis is most commonly caused by alcohol or gallstones; it microscopically shows acute inflammation and necrosis Chronic pancreatitis microscopically shows fibrosis, acinar atrophy and chronic inflammation In summary, pancreas divisum is due to the lack of fusion of the two embryologic duodenal buds. It may be complete or partial. Annular pancreas is an encircling of the duodenum by the pancreas that is due to the failure of one of the embryologic buds to properly rotate with the duodenum. Acute pancreatitis commonly occurs with gallstone and ethanol abuse. Acute pancreatitis shows acute inflammation and necrosis. Chronic pancreatitis shows chronic inflammation, fibrosis and acinar atrophy microscopically.  

Non neoplastic pancreas quiz

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