University of ColoradoDenver
DentalSchool
Department of Pathology
PANCREAS PATHOLOGY AND DIABETES MELLITUS (Course DSBS 5516)
Francisco G. La Rosa, M.D.
Associate Professor
Department of Pathology
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LEARNING OBJECTIVES:
This chapter intends to provide the basic knowledge on exocrine and endocrine pancreas pathology at the organ, cellular and molecular levels. A basic review of the embryology, anatomy and histology of the pancreas will be provided to better understand the basic principles of pancreas pathology. Special emphasis will be given to the study of congenital and genetic anomalies, inflammatory processes, metabolic diseases, benign and malignant tumors, and diabetes mellitus.
The present outline is given to the students as an aid for their study in reviewing the most important topics of pancreas pathology and diabetes mellitus. However, this handout does not intend to replace the basic reading in textbooks and other academic literature. We recommend the reading of the corresponding sections in the book chapters 12 and 14, ‘Pathology’ by Stevens and Lowe, suggested in this course. If possible, it is recommended that the students review other bibliographic references for a more complete understanding of pancreas pathology.
This Chapter is divided in 5 sections, with the following learning objectives:
1. Describe the basic Embryology, Surgical Anatomy, Histology and Function of the exocrine and endocrine pancreas.
2. Describe the most important congenital anomalies of the pancreas.
3. Describe the most important pathologic features of Acute and Chronic Pancreatitis (clinical and laboratory features and histo-pathological findings).
4. Describe the most important Pancreatic and Islet Cell Tumors (morphologic and clinical features).
5. Describe the basic differences in the patho-physiology of Type I and Type II Diabetes Mellitus. (pathogenesis, laboratory tests, complications and treatment).
*NOTE: This handout does not necessarily follow the outline of the lecture, and we suggest not using it to follow up the oral presentation. The corresponding files are posted at:
I.Embryology, Surgical Anatomy, Histology and Function
A.Embryological Development
1.Ventral pancreas and dorsal pancreas
2.Formation of acini and islets
3.Pancreatic ducts:
a. Santorini's duct
b. Wirsung's duct
4.Ampulla of Vater
B.Surgical Anatomy
The pancreas is retroperitoneal in location, pale yellow, coarsely lobulated and J-shaped, weighing between 60-125 grams in the adult. It stretches transversely across the upper abdomen, from the curve of the second part of the duodenum to the hilum of the spleen, with a rich blood supply (6 groups of arteries and 5 major groups of draining lymphatics). The head, which has the greatest thickness, surrounds the common bile duct and is adherent to the duodenum. A constriction at the neck (formed by the superior mesenteric artery) separates the head from the body. There is no sharp distinction between the body and the tail, the narrowest portion of the pancreas.
The ductal system of the pancreas consists of a main channel, the duct of Wirsung, which begins in the tail and drains 15-30 side branches that are formed by the convergence of smaller ductules. It courses through the body of the pancreas, and joins the common bile duct (CBD) at its terminal end. In most people, the pancreatic duct and the CBD enter the duodenum together at the ampulla of Vater. There is also an accessory pancreatic duct, which may be the major duct in some people.
C.Histology and Function
The pancreas has two components:
1. Exocrine (80-85%)
2. Endocrine (15-20%)
The functional unit of the exocrine pancreas is the acinus, which is composed of pyramidal-shaped acinar cells, arranged around a central lumen. These cells synthesize inactive proenzymes, which are stored in the cell as zymogen granules and under appropriate stimuli, released into ductules, which connect the acini. The pancreas secretes l.5 to 3 liters of alkaline fluid containing enzymes and zymogens per day. Regulation of secretion is complex involving both humoral (CCK, secretin) and neural factors.
Activation of zymogens (trypsinogen, chymotrypsinogen, procarboxypeptidases,proelastase, phospholipase) occurs in the duodenum, where enterokinase facilitates conversion of trypsinogen to trypsin, and trypsin activates the other enzymes. Some enzymes are released in their active form (amylase, lipase).
Self-digestion of the pancreas does not normally occur because:
1. Enzymes are elaborated as inactive precursors, activated only in the duodenum
2. Zymogens are sequestered in membrane bound granules.
- Protease inhibitors are present within pancreatic secretions
II.Congenital Anomalies
1. Annular pancreas
2. Aberrant pancreatic tissue
3. Cystic fibrosis
a. Autosomal recessive
b. CF gene: chromosome 7
c. 1/2000 White people
d. 50% mortality before age 21
e. High sodium and chloride in sweat
f. Thick mucus precipitates
g. Obstruction of:
- pancreatic ducts: cystic dilatations surrounded by fibrosis
- bronchi and bronchioles: bronchitis, bronchiectasis, pneumonia
- bile ducts: cystic dilatations
h. Congenital cysts
4. Diffuse pancreatic islet hyperplasia
5. Absence of alpha cells
6. Zollinger Ellison Syndrome
III.ACUTE AND CHRONIC PANCREATITIS
Pancreatitis is inflammation of the pancreas, accompanied by acinar cell injury. There is a spectrum both clinically and histologically, depending on the duration and severity.
Acute pancreatitis: This most often refers to acute hemorrhagic (necrotizing) pancreatitis, which is always a medical emergency. There is a milder self-limited form termed interstitial or edematous pancreatitis.
Chronic pancreatitis: This refers to persistent or recurrent episodes of active inflammation, eventually leading to fibrosis and pancreatic insufficiency.
B1.Acute (hemorrhagic) Pancreatitis
This is an acute condition resulting from extensive destruction of pancreatic substance, occurring due to release of activated pancreatic enzymes into the parenchyma.
Patients present with severe abdominal pain, associated with increased levels of pancreatic enzymes (amylase, lipase) in the blood and/or urine, with necrosis and hemorrhage of pancreatic tissue and fat necrosis.
B1a.Major causes of acute pancreatitis
- Biliary tract disease
- Alcoholism (binge drinking?)
- Idiopathic
- Other:
Trauma
Extension from adjacent tissues
Blood-borne bacterial infection
Viral infections
Ischemia
Vasculitis
Drugs
Hyperlipidemia
Hypercalcemia
Familial
B1b.Acute Pancreatitis in AIDS patients
Increased incidence
High incidence of infections involving pancreas
Cytomegalovirus, Cryptosporidium, Mycobacterium avium intracellulare (MAI)
Medications: Didanosine, pentamidine
B1c.Pathogenesis of Acute Pancreatitis
Trypsin is felt to play a key role as it is able to activate the various proenzymes that take part in autodigestion.
Proteases cause parenchymal destruction, lipases and phospholipases cause fat necrosis (both within the organ and elsewhere within the abdominal cavity) and elastase dissolves elastic fibers within blood vessels leading to hemorrhage.
Trypsin is also able to activate the kinin system as well as (indirectly) the clotting and complement systems.
The process of autodigestion and zymogen activation may occur by one of the following mechanisms.
1.Direct acinar cell injury – autodigestion
Alcohol, ischemia, trauma may cause direct toxic injury to acinar cells.
2.Alteration of intracellular transport of enzymes
Improper activation by lysosomal hydrolases.
3.Duct obstruction
Gallstones impacted in the Ampulla of Vater can cause Pancreatic duct obstruction. The may lead to increase intraductal pressures, with intercellular enzyme leakage. However, clinical and experimental studies suggest that obstruction alone is insufficient to cause hemorrhagic pancreatitis and may need additional factors (i.e. duodenal reflux of bile acids).
B1d.Laboratory findings
Acidosis
Leukocytosis
Hyperglycemia
Hypocalcemia
Precipitation of calcium soaps (saponification) in areas of fat necrosis.
Hypertriglyceridemia
B1e.Gross appearance
Marked edema, grey-white proteolytic destruction of parenchyma, hemorrhage and chalky white fat necrosis, giving the pancreas a variegated appearance. Foci of fat necrosis can also be found in the omentum and mesentery.
B1f.The four morphologic hallmarks of acute pancreatitis
1. Destruction of pancreatic substance
2. Hemorrhage and necrosis of blood vessels
3. Fat necrosis/saponification in pancreas and peripancreatic tissue
4. Acute inflammatory infiltrate
B1g.Complications and sequelae
Systemic organ failure
Shock
Acute renal failure
Acute respiratory distress syndrome (ARDS)
Abscess formation
Pseudocyst formation
Duodenal obstruction
(Development of chronic pancreatitis uncommon)
B1h.Prognosis
Mortality rate of acute hemorrhagic pancreatitis may be as high as 30%.
B2.Chronic (relapsing) Pancreatitis
This refers to progressive destruction of pancreatic tissue by continuing inflammatory disease. Causes irreversible morphologic change and pain. Despite their similar etiologies, chronic pancreatitis is not usually preceded by an attack of classic acute pancreatitis.
B2a.Causes of Chronic Pancreatitis
Alcoholism (? chronic)
Biliary tract disease
Hypercalcemia
Hyperlipidemia
Pancreas divisum
Tropical pancreatitis
Familial pancreatitis
IDIOPATHIC (40%)
Familial (1%)
B2b.Pathogenesis of Chronic Pancreatitis
The pathophysiology is unclear. Particularly in chronic alcoholics, there may be hypersecretion of pancreatic juice with an increased protein content, in the absence of increased fluid or HCO3 secretion. Plugs formed by the precipitation of protein within ducts is an early finding. The copreciptiation of calcium carbonate results in the formation of intraductal stones, leading eventually to pressure atrophy of the pancreas.
Note: Many people believe that "Alcoholic pancreatitis" probably represents acute exacerbation of chronic asymptomatic pancreatitis rather than true acute pancreatitis.
B2c.Gross appearance
Lobular architecture is replaced by fibrous tissue, giving rise to a white appearance and a hard consistency of the parenchyma. May actually look like carcinoma.
B2d.Histology
Features include atrophy of acini, marked increase in interlobular fibrous tissue, and chronic inflammation. Ducts are dilated and contain protein plugs, which may calcify. Ductal epithelium may show squamous metaplasia, due to injury and repair.
B2e.Complications of Chronic Pancreatitis
Pancreatic pseudocyst
Malnutrition
Diabetes mellitus
Severe pain requiring narcotics
Increased incidence of pancreatic carcinoma
B2f.Prognosis
Chronic Pancreatitis is characterized by relentless and progressive loss of pancreatic parenchyma. It is associated with a mortality rate approaching 50% within 20-25 years. Causes of death include attacks of exacerbation, malnutrition, infection and the development of pancreatic carcinoma.
IV.PANCREATIC AND ISLET CELL TUMORS
Pancreatic adenocarcinoma, derived from ductal epithelium is the most common pancreatic tumor. Malignant tumors derived from acinar cells (acinic cell carcinoma) and islet cell tumors (benign or malignant) are much less common. Benign tumors are rare.
A.Pancreatic Adenocarcinoma
Pancreatic carcinoma accounts for 5% of all cancer deaths and its incidence has been slowly increasing. The peak incidence occurs within the 7th decade (rare before age 50), with tumors being more common in blacks than whites and in men than women. Most tumors arise within the head of the pancreas (60%), the remainder arising in the body (l5%) and tail (5%) with 20% diffusely involving the pancreas.
Presenting signs and symptoms are non-specific and may include weight loss, abdominal or back pain and depression. Tumors arising in the head of the pancreas or in the periampullary structures may present early with symptoms of obstructive jaundice. More commonly, however, due to its ability to grow silently with the retroperitoneum, pancreatic carcinoma is often incurable at the time of diagnosis.
A1a.Risk factors for Pancreatic Carcinoma
Smoking
Fatty diet
Exposure to chemicals: B-naphthylamine, Benzidine
Chronic pancreatitis
Mutation in K-ras and p16INK4 genes
NOT a risk factor for developing Pancreatic carcinoma: CAFFEINE
A1b.Gross appearance
Grey, yellow-white, poorly demarcated with infiltrative margins. Hard consistency due to the abundant fibrous tissue reaction (desmoplasia) elicited by the tumor.
A1c.Histology
Consists of infiltrating tumor composed of duct-like structures embedded in a desmoplastic or fibrous stroma, which replaces the acinar cell parenchyma of the pancreas.
Neoplastic glands are lined by cuboidal to columnar cells which frequently produce mucin. Neoplastic glands often invade the perineural space (perineural invasion).
A1d.Tumor Behavior
1. Local extension
Retroperitoneal spread behind pancreas
Fixation to vessels
Invasion of adjacent structures (duodenum, spleen)
Involvement of lymphatics, blood vessels, lymph nodes
2. Distant metastases
Hematogenous metastases to liver, lungs, adrenals, kidneys, bone, brain, skin.
3. Migratory thrombophlebitis (Trousseau's syndrome)
Thromboembolic phenomena occur in up to l0% of patients and include pulmonary embolism, venous thrombosis, portal vein thrombosis.
A1e.Prognosis for Pancreatic Carcinoma
Only 20% of tumors are resectable
1 year survivall0%
5 year survival l%
B.Islet Cell Tumors
Islet cell tumors are rare in comparison to pancreatic adenocarcinoma. They most commonly occur in adults and may be hormonally functional or non-functional. They may be single or be multiple and can be either benign or malignant.
B1a.Clinical syndromes of islet cell hyperfunction
1. Hyperinsulinism and hypoglycemia
2. Zollinger-Ellison syndrome - Gastrinoma
3. Multiple Endocrine Neoplasia
B1b.Beta cell tumor (Insulinoma)
This is the most common islet cell tumor and is capable of producing profound and symptomatic hypoglycemia. Patients usually present with blood glucose of less than 50 mg/dl, with hypoglycemic attacks consisting of central nervous system manifestations such as confusion, stupor or coma. These symptoms are promptly relieved by the administration of glucose.
The hypoglycemia/hyperinsulinemia may be due to:
Solitary adenomas (70%)
Multiple adenomas (10%)
Malignant islet cell tumor (10%)
(Diffuse hyperplasia - 10%)
B1c.Gross Appearance
Usually small, firm yellow-brown, encapsulated nodules.
B1d.Histology
Composed of bland appearing cells with abundant eosinophilic cytoplasm and centrally placed nuclei, arranged in nests or cords (trabeculae), resembling other neuroendocrine tumors (i.e. carcinoid)
The distinction of benign from malignant (as with most endocrine tumors) depends on clinical proof of malignancy, i.e. invasion beyond the pancreas and presence of known metastatic disease.
B1d.Zollinger-Ellison Syndrome: Gastrinoma
This syndrome is a triad of:
1. Peptic ulcer disease (severe, multiple)
2. Gastric hypersecretion, serum hypergastrinemia
3. Pancreatic islet cell tumors **
** Although gastrinomas occur most commonly in the pancreas, l0-l5% may occur in the duodenum. Unlike insulinomas, in which most tumors are benign,60% of gastrinomas are malignant. Otherwise, their histologic and gross appearances are similar.
V.TYPE I AND TYPE II DIABETES MELLITUS (DM)
Diabetes mellitus is a chronic disorder of carbohydrate, fat, and protein metabolism. A characteristic feature of diabetes mellitus is the presence of hyperglycemia due to an impaired carbohydrate (glucose) use. This may be a consequence of a defective insulin secretory response or an inability of the peripheral tissues to respond to insulin.
A.Classification and Incidence
Diabetes mellitus represents a heterogeneous group of disorders that have hyperglycemia as a common feature. It may arise secondarily from any disease causing extensive destruction of pancreatic islets, such as pancreatitis, tumors, certain drugs, iron overload (hemochromatosis), certain acquired or genetic endocrinopathies, and surgical excision. However, the most common and important forms of diabetes mellitus arise from primary disorders of the islet cell insulin system. These can be divided into two major variants that differ in their patterns of inheritance, insulin responses, and origins.
A1.Type I diabetes,also called insulin-dependent diabetes mellitus and previously referred to as juvenile onset diabetes. This variant accounts for 10% to 20% of all cases of primary diabetes.
A2.Type II diabetes, includes the remaining 80% to 90% of patients, also called non-insulin-dependent diabetes mellitus and previously referred to as adult-onset diabetes.
It should be stressed that, although the two major types of diabetes have different pathogenetic mechanisms and metabolic characteristics, the long-term complications in blood vessels, kidneys, eyes, and nerves occur in both types and are the major causes of morbidity and death from diabetes.
A3.Incidence.
Diabetes affects an estimated 13 million people in the United States. With an annual mortality rate of about 35,000, diabetes is the seventh leading cause of death in the United States. The lifetime risk of developing type II for the American adult population is estimated at 5% to 7%; for type I, the lifetime risk is about 0.5%. The prevalence of diabetes mellitus varies widely around the world and among racial and ethnic groups, probably as a reflection of genetic and environmental factors that have yet to be totally elucidate.
B.Pathogenesis
The two types are discussed separately, but first normal insulin metabolism is briefly reviewed, because many aspects of insulin release and action are important in the consideration of pathogenesis.
B1.Pathogenesis of Type I Diabetes Mellitus.
This form of diabetes results from a severe, absolute lack of insulin caused by a reduction in the beta-cell mass. Type I diabetes usually develops in childhood, becoming manifest and severe at puberty. Patients depend on insulin for survival; hence the term insulin-dependent diabetes mellitus. Without insulin, they develop serious metabolic complications such as acute ketoacidosis and coma.
Three interlocking mechanisms are responsible for the islet cell destruction: genetic susceptibility, autoimmunity, and an environmental insult.
(1) it is thought that genetic susceptibility linked to specific alleles of the class II major histocompatibility complex predisposes certain persons to the development of autoimmunity against beta cells of the islets
(2) the autoimmune reaction either develops spontaneously or, more likely, is triggered by
(3) an environmental event that alters beta cells, rendering them immunogenic. Overt diabetes appears after most of the beta cells have been destroyed. With this overview, we can discuss each of the pathogenetic influences separately.
B2.Pathogenesis of Type II Diabetes Mellitus.
Much less is known about the pathogenesis of type II diabetes, despite its being by far the more common type. There is no evidence that autoimmune mechanisms are involved. Life style clearly plays a role, as will become evident when obesity is considered. Nevertheless, genetic factors are even more important than in type I diabetes. Among identical twins, the concordance rate is 60% to 80%. In first-degree relatives with type II diabetes (and in nonidentical twins), the risk of developing disease is 20% to 40%, compared with 5% to 7% in the population at large. Unlike type I diabetes, the disease is not linked to any HLA genes. Rather, epidemiologic studies indicate that type II diabetes appears to result from a collection of multiple genetic defects, each contributing its own predisposing risk and each modified by environmental factors. Most of the hypothesized defects remain unidentified.