Pathology CASE 8

CASE 8

INTRODUCTION

A 55-year-old woman presents to the emergency department with profuse bright red bleeding with emesis diagnosed as bleeding esophageal varices. She also is icteric and is suspected of having cirrhosis. She has been followed for several years for Sjogren syndrome and Raynaud syndrome. Investigation into the cause of her cirrhosis reveals negative hepatitis antibodies but elevated antimitochondrial antibodies.

· What is the most likely underlying etiology for her liver disease?

· What is the most likely mechanism?

ANSWERS TO CASE 8: Primary Biliary Cirrhosis

Summary: A 55-year-old woman has cirrhosis and elevated antimitochondrial antibodies.

· Most likely diagnosis: Primary biliary cirrhosis.

· Most likely mechanism: The etiology of primary biliary cirrhosis is not known; however, evidence points toward an autoimmune basis to the disease.

CLINICAL CORRELATION

Introduction

This 55-year-old woman presents with bleeding esophageal varices and cirrhosis. The first priorities in her management include ABC: airway, breathing, and circulation. She should receive oxygen by a nasal cannula, and two large-bore intravenous lines should be established. Her blood pressure and heart rate should be monitored to assess for volume loss and replacement with blood as needed. Because of her liver disease, she may have a coagulopathy caused by depletion of vitamin K-dependent factors (factors II, VII, IX, and X). Transfusion with coagulation factors and initiation of vitamin K may be indicated. Endoscopic examination to determine the etiology of the upper gastrointestinal bleeding is paramount. Bleeding esophageal varices may be treated with sclerotherapy injected into the bleeding vessels. Also, a tamponade may be attempted with special esophageal devices.

After the acute situation has been addressed, attention should be directed to the etiology of her liver disease. A careful history and physical examination and selected laboratories usually yield the diagnosis. Toxic effects such as with alcohol use and infections such as with hepatitis viruses are the most common causes of cirrhosis. This patient's hepatitis serology studies are negative, but she does have a history of Sjogren syndrome, Raynaud syndrome, and antimicrosomal antibodies. These findings are consistent with primary biliary cirrhosis. Careful history may reveal pruritis years before frank cirrhosis.

Approach to Chronic Liver Disease

Definitions

Primary biliary cirrhosis (PBC): A chronic progressive cholestatic liver disease associated with intrahepatic biliary tree destruction and finally cirrhosis.

Chronic liver disease: Liver disease that lasts for 6 months or more and includes chronic hepatitis and cirrhosis.

Cirrhosis: Progressive and irreversible condition of the liver in which hepatocyte damage and destruction occur. Regenerating hepatocytes form nodules.

Discussion

Primary Biliary Cirrhosis

The etiology of primary biliary cirrhosis is not known; however, evidence points toward an autoimmune basis of the disease. Other autoimmune diseases are associated with this condition and include Sjogren syndrome, scleroderma, rheumatoid arthritis, and thyroiditis. Abberant human lymphocyte antigen (HLA) class II molecules are expressed in the biliary epithelium of patients with PBC; this might be responsible for the triggering of an inflammatory response. Defective immunoregulation allows cytotoxic T cells to damage bile ducts. A liver biopsy usually shows a portal tract infiltrate composed of mainly lymphocytes and plasma cells (see Figure 8-1). In approximately half the patients, granulomas may be seen. Destruction of medium-sized bile ducts with bile ductular proliferation will be evident. With time, hepatocyte necrosis and fibrosis are apparent. After years to decades, the clinical features of cirrhosis will be present. There is an increased synthesis of IgM because of failure to switch from immunoglobulin M (IgM) to IgG antibody synthesis. Most patients have antimitochondrial antibodies in their serum, with the antigen M2 being specific to PBC. The role of this antibody in the pathogenesis of PBC is not clear.

Features of cholestatic liver disease dominate the initial clinical picture. This includes pruritus, which may precede jaundice by years. High serum alkaline phosphatase with normal or nearly normal alanine aminotransferase (ALT) and aspartate aminotransferase (AST) is characteristic in the early part of the disease. Secondary hypercholesteremia with features such as xanthelasma may be seen. After a variable amount of time (usually years), the features of cirrhosis, such as icterus, bleeding, and ascites, may become apparent. Table 8-1 shows the laboratory findings that are consistent with a diagnosis of PBC.

Table 8-1. LABORATORY FINDINGS CONSISTENT WITH PRIMARY BILIARY CIRRHOSIS

1. High serum alkaline phosophatase

2. High serum cholesterol

3. High serum IgM

4. High antimitochondrial antibodies; M2 antibody is specific

5. Liver biopsy; portal infiltrate with lymphocytes and plasma cells; granulomas; bile duct damage with ductular proliferation; eventual cirrhosis

Management

Treatment addresses the symptoms and disease course of the patient. Because the disease is thought to be autoimmune, corticosteroids have been tried. These agents improve the biochemical and histologic picture of the disease but lead to significant osteoporosis. Patients with primary biliary cirrhosis are prone to osteoporosis caused by cholestasis and subsequent impaired malabsorption of vitamin D. Complications associated with cirrhosis require management. Liver transplantation remains the specific treatment and has a 5-year survival of at least 80 percent.

Figure 8-1. Microscopic pictograph of primary biliary cirrhosis. (Courtesy of Dr. Aaron Han, Reading, PA.)0

Cirrhosis and Chronic Hepatitis

Chronic liver disease includes chronic hepatitis and cirrhosis (see Table 8-2). In chronic hepatitis, inflammatory cells consisting of lymphocytes, macrophages, and plasma cells are present in the portal tract. Interface hepatitis and bridging necrosis are signs of active liver damage. Lymphoid aggregates are seen in cases caused by hepatitis C virus. The hallmark of irreversible liver damage is deposition of fibrous tissue. This brings about the onset of cirrhosis. Initially, the fibrosis is periportal. With time, bridging fibrosis between lobules is seen. Regenerating nodules from surviving hepatocytes complete the picture of cirrhosis. Based on the size of the nodules, there are two types of cirrhosis: micronodular (nodules less than 3 mm) and macronodular. Micronodular cirrhosis is seen in alcoholics, whereas macronodular cirrhosis is seen after hepatitis.

Table 8-2. CAUSES OF CHRONIC HEPATITIS
Viruses
	Hepatitis B and C
Autoimmune
Hereditary
	Alpha1-antitrypsin deficiency, Wilson disease
Drugs
	Methyldopa, isonicotine hydrazine, ketoconazole
Causes of cirrhosis
	Alcohol (common)
	Viral hepatitis caused by B or C (common)
	Autoimmune hepatitis
	Primary biliary cirrhosis
	Wilson disease
	Hemochromatosis
	Alpha1-antitrypsin deficiency
	Drugs: methotrexate
Complications of cirrhosis
	Portal hypertension and gastrointestinal hemorrhage
	Ascites

Autoimmune Liver Disease

Autoimmune liver disease is seen most frequently in females and is associated with other autoimmune diseases. Autoantibodies such as antinuclear, anti-smooth muscle and anti-liver and kidney microsomal antibodies (anti-LKM) are frequently present. Serum IgG levels may be elevated.

Alpha₁-Antitrypsin Deficiency

Alpha₁-antitrypsin deficiency is inherited as an autosomal recessive condition. Alpha₁-antitrypsin is a glycoprotein whose main role is to inhibit the proteolytic enzyme neutrophil elastase. Deficiency results in liver damage and emphysema, especially in smokers. Serum levels are low, and liver biopsy shows periodic acid-Schiff (PAS) positive diastase-resistant globules within the hepatocytes.

Wilson Disease

Wilson disease is inherited as an autosomal recessive condition. The copper-transporting protein ceruloplasmin is reduced in amount because of poor synthesis. There is also failure of biliary excretion of copper. As a result, free copper is deposited in various sites, including liver basal ganglia and cornea (with resultant Kayser-Fleischer rings), resulting in damage to those organs. Urinary excretion of free copper also is increased. Acute hepatitis, chronic hepatitis, cirrhosis, and extrapyramidal features (caused by basal ganglia damage) are the usual clinical features.

Hereditary Hemochromatosis

Hereditary hemochromatosis also is inherited as an autosomal recessive condition. There is an association with HLA-A3. Excessive iron absorption results in iron deposition and damage to various organs, including liver, pancreas, heart, joints, and pituitary gland. At the same time excess iron deposition is observed in the skin. This results in bronze discoloration of skin. This, along with diabetes resulting from pancreatic damage, explains the synonym of hemochromatosis, bronze diabetes. Other features include cirrhosis, cardiomyopathy, hypogonadism, and arthropathy. As females lose iron through blood loss from menstruation, the features are milder or are seen later in them.

Alcoholic Liver Disease

The spectrum of alcoholic liver disease includes fatty liver, acute hepatitis, and cirrhosis. Fatty liver (hepatic steatosis) consists of microvesicular lipid droplets in the liver cells, displacing the nucleus to the periphery. On gross inspection, the liver appears yellow and greasy. Refraining from alcohol generally leads to reversal of these changes. In acute hepatitis, there is infiltration with polymorphonucleocytes and hepatocyte necrosis. Cytoplasmic inclusions resulting from intermediate filaments known as Mallory bodies are seen. Eventually, fibrosis ensues. Finally, cirrhosis develops as an end-stage result of chronic alcohol use. The liver is small and shrunken. Microscopy reveals fibrous septae that create a micronodular and macronodular pattern with regeneration. Clincally, the patient may develop portal hypertension, ascites, jaundice, and peripheral edema.

COMPREHENSION QUESTIONS

[8.1] A 37-year-old woman presents with fatigue and pruritus. Laboratory evaluation finds the presence of antimitochondrial antibodies in her serum, but the tests for viral hepatitis antibodies were negative. A biopsy of her liver reveals numerous lymphocytes in the portal tracts, along with occasional granulomas. Which one of the substances listed below is most likely to have markedly elevated serum levels in this individual?

A. Acid phosphatase

B. Alanine aminotransferase

C. Alkaline phosphatase

D. Aspartate aminotransferase

E. Conjugated bilirubin

[8.2] A 42-year-old woman presents with signs of jaundice and hepatic failure. Physical examination finds that she has uncontrolled choreiform movements of the arms, and a rust-colored ring is seen at the periphery of both corneas. Laboratory examination finds increased serum and urine levels of copper with decreased levels of ceruloplasmin. What is the best diagnosis?

A. Alpha₁-antitrypsin deficiency

B. Budd-Chiari syndrome

C. Primary biliary cirrhosis

D. Whipple disease

E. Wilson disease

[8.3] Which one of the abnormalities listed below is most likely to be found in an individual with hereditary hemochromatosis?

A. Black cartilage

B. Blue sclera

C. Bronze skin

D. Red pupils

E. White hair

ANSWERS

[8.1] C. The presence of antimitochondrial serum antibodies, particularly to the M2 antigen, in an individual with liver disease is highly suggestive of primary biliary cirrhosis. Individuals with this autoimmune disorder, which is more common in women, develop clinical signs of cholestatic liver disease with pruritus. Before the development of jaundice, however, patients will have high serum levels of alkaline phosphatase with normal or nearly normal levels of ALT and AST.

[8.2] E. Increased serum levels of copper with decreased levels of ceruloplasmin in a patient with liver disease are diagnostic of Wilson disease. This autosomal recessive disorder is characterized by the deposition of copper in multiple sites, which include the liver, the basal ganglia, and the cornea of the eye. Destruction of the basal ganglia leads to extrapyramidal signs such as choreiform movements, whereas deposition of copper at the periphery of the cornea produces characteristic Kayser-Fleischer rings.

[8.3] C. Patients with hereditary hemochromatosis develop clinical signs because of the deposition of excess iron in many organs. The classic triad of clinical signs includes a bronze skin color, diabetes mellitus, and cirrhosis. The combination of the bronze skin color and diabetes mellitus sometimes is referred to as bronze diabetes. Deposition of iron in the islets of Langerhans in the pancreas leads to the destruction of the beta cells, and subsequent decreased levels of insulin lead to diabetes mellitus. The abnormal skin color results from the deposition of iron in the skin. In addition, deposition of iron in the adrenal cortex leads to decreased cortisol levels. This in turn will increase levels of proopiomelanocortin (POMC) and lead to increased melanin-stimulating hormone (MSH) activity.

PATHOLOGY PEARLS

· Primary biliary cirrhosis is thought to be an autoimmune disease seen predominantly in middle-aged women.

· In PBC patients, serum IgM is elevated and antimitochondrial antibody (M2 is specific) is found.

· Cirrhosis is a progressive and irreversible condition of the liver in which there occurs hepatocyte damage and destruction. Regenerating hepatocytes form nodules.

· Complications of cirrhosis include portal hypertension, gastrointestinal hemorrhage, ascites, portosystemic encephalopathy, hepatorenal syndrome, and hepatocellular carcinoma.

· Alpha₁-antitrypsin deficiency is an autosomal recessive condition in which liver damage and emphysema are the main features.

· Wilson disease is an autosomal recessive condition characterized by liver and basal ganglia damage.

· Hereditary hemochromatosis, or bronze diabetes, also is inherited in an autosomal recessive fashion. Deposition of iron and organ damage occur in liver, pancreas, heart, joints, and pituitary gland.

· In alcoholic hepatitis there occurs infiltration with polymorphonucleocytes and heaptocyte necrosis. Cytoplasmic inclusions caused by intermediate filaments known as Mallory bodies are seen.

REFERENCES

Chung RT, Podolsky DK. Cirrhosis and its complications. In: Kasper DL, Fauci AS, Longo DL, et al. Harrison's principles of internal medicine, 16th ed. New York: McGraw-Hill, 2004:1860-1862.

Crawford JM. The gastrointestinal tract. In: Kumar V, Assas AK, Fausto N, eds. Robbins and Cotran pathologic basis of disease, 7th ed. Philadelphia: Elsevier Saunders, 2004:914-915.

0.59375

Copyright © 2006 by the McGraw-Hill Companies, Inc. All rights reserved.

Key words:

primary biliary cirrhosis life expectancy                                       primary sclerosing cholangitis

primary biliary cirrhosis diet                                                        primary biliary cirrhosis symptoms

primary biliary cirrhosis stages                                                    primary biliary cirrhosis prognosis

primary biliary cirrhosis treatment                                               primary biliary cirrhosis diagnosis

Pathology CASE 7

CASE 7

INTRODUCTION

A 62-year-old man returns home from playing bingo, complaining of midline abdominal pain. He denies being hit or suffering any other trauma. Over the next few hours the pain does not remit but becomes more severe and is localized to the lower right quadrant. He also develops nausea and vomiting. He denies diarrhea and has not had similar episodes. The patient lies down in bed, and over the next 24 hours, the pain worsens and he develops fever and chills and is brought to the emergency center. On examination, he has a temperature of 102°F and appears ill. His abdomen is mildly distended and has hypoactive bowel sounds. The abdomen is diffusely tender to palpation, particularly in the right lower quadrant.

· What is the most likely diagnosis?

· What additional tests would help in making an accurate diagnosis?

ANSWERS TO CASE 7: Appendicitis

Summary: A 62-year-old man complains of midline abdominal pain. He denies being hit or suffering any other trauma. Over the next few hours, the pain worsens and is localized to the lower right quadrant. He also develops nausea and vomiting and, after 24 hours, develops fever and chills and an acute abdomen.

· Most likely diagnosis: Acute appendicitis.

· Additional diagnostic tests: CT scan of the abdomen and pelvis.

CLINICAL CORRELATION

Introduction

This older man has a typical picture of a ruptured appendicitis with sepsis. He originally had mild right lower quadrant abdominal pain, but it worsened, and after 24 hours he developed fever and chills. Perhaps the most worrisome finding on physical examination is that he "appears ill." He probably has sepsis, which is a systemic condition of infection-mediated illness. The chills probably reflect bacteremia. The emergency physician should expeditiously manage this situation, because delay could lead to morbidity or mortality, particularly in a geriatric patient. The blood pressure is not mentioned, but the patient could be in septic shock. Treatment should be addressed in a systematic manner: airway, breathing, and circulation (ABC) with oxygen administered, two large-bore intravenous lines (IVs), volume repletion for the probable volume depletion and sepsis, blood cultures, urine culture, and antibiotic therapy aimed at gram-negative bacilli and anaerobic bacteria. Blood work to be obtained includes a complete blood count and a chemistry panel to assess electrolytes and serum creatinine for kidney function. After stabilization, the patient should be taken to the operating room. If the diagnosis is unclear, a CT scan of the abdomen sometimes can help distinguish other abdominal pathologies, such as diverticulitis.

Approach to Appendicitis

Definitions

Appendicitis: Inflammation of the vermiform appendix.

Diverticulitis: Inflammation of an outpouching of the diverticulum.

Diverticulosis: A condition of outpouching of the large bowel near the taeniae coli where the blood vessels penetrate. Complications include hemorrhage (lower gastrointestinal bleeding) and inflammation.

Approach to Appendicitis and Diverticulitis

Discussion

Appendicitis

Acute appendicitis is a common disease in Western countries and is uncommon in Africa and Asia. The incidence of the disease in the United States has fallen considerably over the last 30 years; however, it remains the most common abdominal emergency in childhood, adolescence, and early adult life. Fewer than 5 percent of cases of acute appendicitis occur in patients over age 60 years.

The pathologic process begins on the mucosal surface of the appendix, and there is often an element of obstruction of the appendicular lumen by a fecalith. This may lead to pressure necrosis of the mucosa and invasion of the appendicular wall by bacteria. Common causes of obstruction include elongation or kinking of the appendix, adhesions, and neoplasias such as carcinoma and carcinoid tumors, both of which are rare. Some cases spontaneously resolve, but more commonly, infection of the wall of the appendix progresses, leading to impairment of its blood supply. When the pathologic process has extended throughout the wall of the appendix to involve the parietal peritoneum, the pain and tenderness are classically over the McBurney point at the site of the appendix. The pathologic process may continue and produce gangrene, perforation, and more generalized peritonitis. Once perforation has occurred, the advancing bacteria may be controlled by the ability of the omentum to wall off the inflammation; alternatively, the peritonitis may become more widespread. In advanced appendicitis, a mass may develop; alternatively, generalized peritonitis may lead to the septic inflammatory response syndrome (SIRS), ultimately with the development of multiple organ failure and death.

The site of the pain in appendicitis may vary. When the appendix is retrocecal in position, somatic pain may be perceived in the flank and loin rather than in the right lower quadrant. Anorexia is an almost invariable symptom in association with appendicitis. The presence of hunger usually eliminates this diagnosis. In association with anorexia, nausea is common and tends to proceed to vomiting. Diarrhea sometimes occurs and may be a result of the appendix lying in a pelvic position.

Laboratory investigations commonly performed include the peripheral white blood cell count, which may be elevated with a predominance of polymorphonuclear leukocytes. The urinalysis is usually normal. A CT scan of the abdomen may show thickening of the appendix with periappendicular inflammation and the presence of intraperitoneal fluid.

The differential diagnosis includes acute gastroenteritis, which typically has vomiting and diarrhea as prominent symptoms and abdominal pain that is less well defined. Intestinal obstruction must be considered and typically presents with vomiting and abdominal distention. Mesenteric adenitis may mimic appendicitis closely but is associated with a generalized viral illness and causes less severe pain. Inflammation of Meckel diverticulum may produce symptoms remarkably similar to those of appendicitis, and laparoscopy or laparotomy may be needed for the diagnosis. Crohn disease may closely simulate appendicitis; affected patients generally have intestinal obstruction, and usually conservative management is the best therapy. Gynecologic disorders such as pelvic inflammatory disease with cervical motion tenderness and adnexal tenderness may present similarly to appendicitis. Ureteral colic is associated with pain and tenderness of the flank area, radiating to the groin region. Other conditions include acute diverticulitis, colonic carcinoma, acute cholecystitis, and pancreatitis.

Appendicitis in the elderly may have a more rapid course. Gangrene and perforation are more common in those over age 60 years, and this may be due to a delay in diagnosis. A classic picture of the appendicitis may be lacking, and the pain may be a less prominent feature. Overall, although there has been a decline in the incidence of peritonitis, paradoxically, it has increased among the elderly. Thus, appendicitis should be at the forefront of the differential diagnosis in males with right lower quadrant pain and tenderness.

The treatment of uncomplicated appendicitis is surgical, consisting of an appendectomy. The abdomen is opened, and if the appendix is found to be normal in the absence of any other pathology, it should be removed prophylactically. At the present time, most appendixes are removed laparoscopically rather than in an open operation.

Diverticulitis

Diverticuli are blind pouches involving the bowel. They result from herniation of the mucosa through the circular muscle at the site of small penetrating blood vessels. Their walls consist of an outer layer of serosa and an inner mucosa. There is no muscle in the wall of the diverticulum. Diverticular disease is associated with increased intraluminal pressure in the large intestine with hypertrophy of both circular and longitudinal muscle layers. Diverticula can occur anywhere in the large bowel and small bowel but are found most commonly in the sigmoid colon. Muscle hypertrophy predates the development of diverticula and results in a narrowing of the bowel and, consequently, an increase in the intraluminal pressure.

Diverticular disease may produce central or left lower quadrant abdominal pain together with an alteration in bowel habit with occasional rectal bleeding. The diagnosis is confirmed by barium enema or colonoscopy, which will show muscle thickening and multiple diverticula with small orifices emerging through the colonic wall. Diverticular disease of the colon is common in Western countries and rare in central Africa, the Middle East, the Far East, and the Pacific islands. The incidence of the disease in Japan is increasing, possibly because of the adoption of a more westernized diet. African Americans residing in the United States now have an incidence of the disease equal to that of the white population. Epidemiologic studies support the concept that the disease is not racially determined but is related to changes in the environment and to dietary factors. Postmortem studies in the Western countries report an incidence of about 40 percent overall and one as high as 60 percent in those over age 60 years.

Acute or chronic inflammation within a diverticulum is designated diverticulitis. It is estimated that the approximately 20 percent of patients with diverticulosis will manifest diverticulitis. Localized inflammation, or even perforation and peritonitis, may occur. Pneumaturia, resulting from a colovesical fistula, may occur, and on occasion, fecal material may be passed in the urine. CT imaging of the abdomen remains the primary method of diagnosing the acute process, whereas barium enema and endoscopic examinations are relatively contraindicated during acute infection.

Known complications of diverticulitis include bleeding, abscess formation, peritonitis, and fistula formation. Colonic obstruction also can occur. The treatment of diverticulitis includes broad-spectrum antibiotics, intravenous fluids, and nothing by mouth until the condition settles. Frank peritonitis or abscess formation usually requires surgical intervention, commonly involving excision of the affected area, such as a sigmoid colectomy. Postoperatively, patients should be instructed to eat a high-residue diet and drink plenty of liquids.

COMPREHENSION QUESTIONS

[7.1] A 20-year-old woman presents with the sudden development of nausea, vomiting, and right lower abdominal pain. Physical examination finds a mild fever, and laboratory evaluation finds an increased peripheral leukocyte count. She is taken to surgery, where an appendectomy is performed. Which one of the following histologic changes is most likely to be present in her appendix?

A. Amorphic mucinous material within the lumen

B. Caseating granulomas within the periappendiceal fat

C. Hyperplastic lymphoid follicles within the lamina propria

D. Multinucleated giant cells within the epithelium

E. Numerous neutrophils within the muscular wall

[7.2] A 61-year-old woman presents with nausea, vomiting, and the sudden onset of left-sided abdominal pain. Physical examination finds a low-grade fever, and laboratory evaluation finds increased numbers of neutrophils in her peripheral blood. What is the most likely diagnosis?

A. Appendicitis

B. Cholecystitis

C. Colitis

D. Diverticulitis

E. Pancreatitis

[7.3] Which one of the clinical findings listed below is most likely to be present in an older individual with diverticulosis?

A. Abdominal colic caused by intestinal obstruction

B. Iron deficiency anemia caused by chronic blood loss

C. Megaloblastic anemia caused by vitamin B₁₂ deficiency

D. Steatorrhea caused by malabsorption of fat

E. Chronic diarrhea caused by decreased absorption of protein

ANSWERS

[7.1] E. The histologic hallmark of acute inflammation, such as that seen with acute appendicitis, is the presence of numerous acute inflammatory cells, namely, neutrophils. Therefore, histologic sections of an appendix surgically removed from an individual with acute appendicitis will reveal numerous neutrophils within the muscular wall. The inflammation can be so marked that it causes complete destruction of the muscular wall, which can lead to perforation and peritonitis.

[7.2] D. Acute inflammation of diverticula (diverticulitis) will produce the sudden onset of left-sided abdominal pain accompanied by fever and peripheral leukocytosis (mainly neutrophils). These clinical signs are essentially the same as those seen with acute appendicitis except that the abdominal pain is on the left side rather than the right side. As such, diverticulitis sometimes is referred to as left-sided appendicitis.

[7.3] B. Diverticulosis refers to the presence of numerous diverticula in the colon. The diverticula usually are located in the sigmoid colon in older individuals. Although they may become inflamed and produce signs of acute diverticulitis, more often they produce chronic blood loss as a result of chronic bleeding, which will lead to heme-positive stools and iron deficiency anemia.

PATHOLOGY PEARLS

· Appendicitis usually is a 24-hour disease with periumbilical pain localizing to the right lower quadrant.

· The primary treatment of appendicitis is surgical.

· Appendicitis continues to have high morbidity and mortality in older patients.

· Diverticula usually involve the left colon, particularly the sigmoid colon.

· Diverticulitis presents as left lower abdominal pain, fever, and nausea and vomiting.

· CT imaging is helpful in diagnosing both acute appendicitis and diverticulitis.

REFERENCES

Liu C, Crawford JM. The gastrointestinal tract. In: Kumar V, Assas AK, Fausto N, eds. Robbins and Cotran pathologic basis of disease, 7th ed. Philadelphia: Elsevier Saunders, 2004:854-856, 870-872.

Silen AW. Acute appendicitis and peritonitis. In: Kasper DL, Fauci AS, Longo DL, et al. Harrison's principles of internal medicine, 16th ed. New York: McGraw-Hill, 2004:1805-1806.

0

Copyright © 2006 by the McGraw-Hill Companies, Inc. All rights reserved.

Key words: 

appendicitis symptoms                              appendix

appendicitis in children                             appendicitis pictures

appendicitis pain                                       appendicitis causes

appendicitis recovery time                         acute appendicitis

PATHOLOGY CASE 6

CASE 6

INTRODUCTION

A 22-year-old woman has had recurrent episodes of diarrhea, crampy abdominal pain, and slight fever over the last 2 years. At first the episodes, which usually last 1 or 2 weeks, were several months apart, but recently they have occurred more frequently. Other symptoms have included mild joint pain and sometimes red skin lesions. On at least one occasion, her stool has been guaiac-positive, indicating the presence of occult blood. Colonoscopy reveals several sharply delineated areas with thickening of the bowel wall and mucosal ulceration. Areas adjacent to these lesions appear normal. Biopsies of the affected areas show full-thickness inflammation of the bowel wall and several noncaseating granulomas.

· What is the most likely diagnosis?

· What are the common complications of this disease?

ANSWERS TO CASE 6: Crohn Disease

Summary: A 22-year-old woman has a 2-year history of recurrent diarrhea, abdominal pain, slight fever, joint pain, and red skin lesions. Colonoscopy reveals several sharply delineated areas with thickening of the bowel wall and mucosal ulceration, which on biopsy show full-thickness inflammation of the bowel wall and several noncaseating granulomas.

· Most likely diagnosis: Crohn disease.

· Common complications of this disease: Malabsorption and malnutrition, fibrous strictures of the intestine, and fistulae to other organs, such as from bowel to skin or bowel to bladder.

CLINICAL CORRELATION

Introduction

The patient's presentation is very characteristic for inflammatory bowel disease, that is, a several-year history of diarrhea and abdominal pain. Additionally, the colonoscopy revealing full-thickness inflammation with noncaseating granulomas is consistent with Crohn disease. Crohn disease is a chronic inflammatory condition that is ubiquitous in its distribution in the gastrointestinal tract. It most commonly manifests in the small intestine, in particular the terminal ileum. The disease exhibits aggressive activity of the gastrointestinal immune system, but the exact cause is unknown. Published studies in the United States report incidence rates that vary between 1.2 and 8.8 per 100,000 population; the prevalence is 44 to 106 per 100,000. The condition is more common in the cold climates of the northeastern United States than in the south. Those of Jewish ethnicity have a high incidence. The disorder, which is slightly more common in females, has a bimodal age distribution, peaking in the early twenties and again emerging in the mid-sixties. Theories regarding pathogenesis have referred to genetics, infection, autoimmune or allergic processes, thromboembolic disorders, and dietary disorders.

Approach to Inflammatory Bowel Disease

Discussion

The predominant symptoms of Crohn disease are diarrhea, abdominal pain, and weight loss. These symptoms may be widely variable, depending on the distribution of the inflammatory lesions in the patient's intestines. The principal stimulus for diarrhea is the mucosal immune response in association with cytokine release. If the colon is involved, diarrhea may be more marked and tenesmus may occur. Abdominal pain may be due to local inflammation or obstruction if it is experienced in the central abdomen or right lower quadrant. Abscesses or fistulae also may produce pain. Secondary causes of abdominal pain in relation to Crohn disease are gallstones and renal colic. Malabsorption leading to weight loss and failure to thrive may occur in children. Fat, protein, mineral, and vitamin deficiencies may be associated with extensive or recurrent disease. About one-third of patients develop perineal symptoms or signs such as anal fistulae or fissures.

Nongastrointestinal symptoms of Crohn disease involve the skin, joints, or eyes. Skin lesions include erythema nodosum, pyoderma gangrenosa, aphthous stomatitis, and finger clubbing. The rheumatologic manifestations often present as a large joint polyarthropathy resembling ankylosing spondylitis or a small joint fleeting polyarthropathy that is like rheumatoid arthritis. The human lymphocyte antigen B-27 (HLA-B27) may be present. Inflammatory eye lesions are confined to the anterior chamber, such as uveitis, iritis, episcleritis, and conjunctivitis. A chronic active hepatitis may develop; more seriously, sclerosing cholangitis can progress to cirrhosis. There is a predisposition to gallstones when terminal ileal disease is present.

Physical Examination

Physical examination may reveal a nutritional deficiency. The extraintestinal manifestations may be apparent. Abdominal examination may suggest partial bowel obstruction, an inflammatory mass, focal areas of tenderness, or enterocutaneous fistulae. Perineal examination may reveal fistulae or abscesses. Perianal skin tags with bluish discoloration may be present. On rectal examination there may be a stricture, a palpable ulcer, or perirectal abscesses. Bloody diarrhea may be detectable. Clinical features compatible with anemia or hypoalbuminemia may be present. Hypoalbuminemia may manifest with peripheral edema.

Approach to Inflammatory Bowel Disease

Plain abdominal radiographs provide important information in the acute presentation of symptoms, as they may demonstrate intestinal obstruction or evidence of perforation. Biliary or renal calculi, arthropathy, or osteoporosis also may be detected. Endoscopy of the lower and upper gastrointestinal tract is used to identify disease and provide biopsy evidence. Barium follow-through examination or small bowel enteroclysis may demonstrate discrete lesions in the small intestine. Fistulograms are helpful to surgeons by providing information about the site of the fistula and the presence of obstruction or abscess cavity in association with it.

Computerized tomography is the mainstay in terms of providing information about thickened loops of bowel, abscesses, and fistulous tracts. Magnetic resonance imaging, including cholangiography, may be helpful. Ultrasound may reveal thickened terminal ileum, abscesses, and evidence of bilary tract disease. Ultrasound examination of the renal tract may reveal obstruction or stone formation. Endoscopic ultrasound may be useful in assessing bowel wall involvement and the extent of the disease process. Studies of bone density may be required.

Endoscopy allows detailed examination of the mucosa of the upper and lower intestines, with the added advantage of allowing biopsies of abnormal areas to be taken. Capsule endoscopy is an innovation that permits detailed photography of the small intestinal lumen. There may be eletrolyte abnormalities in Crohn disease. The erythrocyte sedimentation rate (ESR) frequently is elevated above 30 mm/h, and the serum vitamin B₁₂ level may be reduced.

Crohn Disease Versus Ulcerative Colitis

These inflammatory bowel diseases share certain features, but there are fundamental and often distinguishing features. On occasion it may be very difficult to determine whether a patient has Crohn disease or ulcerative colitis, and in these circumstances the condition often is designated indeterminate colitis. The fundamental differences between Crohn disease and ulcerative colitis are that Crohn disease begins in the submucosa and ulcerative colitis begins in the mucosa of the gut. Ulcerative colitis, as its name suggests, is a disease confined to the colon and rectum, whereas, as was stated above, Crohn disease is ubiquitous throughout the bowel. Full-thickness involvement of the bowel, although more common in Crohn disease, may occur in both disorders. Fibrosis cicatrization and fistula formation are confined almost exclusively to patients with Crohn disease. The histopathologic feature that differentiates the two conditions is the presence of granulomas in Crohn disease. Aphthoid ulcers are more likely to occur in patients with Crohn disease. Both conditions are associated with an increased incidence of colon cancer, which, however, is more likely to develop in long-standing ulcerative colitis than in Crohn disease. The incidence of malignant change in the colon or rectum of ulcerative colitis is about 20 percent after 25 years of disease activity. Many patients develop ulcerative colitis at a young age and therefore may develop cancerous changes in the colon in their forties or fifties. A further important consideration is that patients with inflammatory bowel disease live with episodes of diarrhea and occasional rectal bleeding so that the heralding features of malignancy may be observed by referring to the underlying inflammatory disease.

Treatment

Pain Control and Anti-Inflammatory Agents

The treatment of Crohn disease can be divided into four areas of management: dealing with symptoms, treating mucosal inflammation, nutritional management, and surgery. Abdominal pain and diarrhea are dealt with mostly by addressing intestinal inflammation. Pain may be due to the stretching of nerve endings as a result of distention from obstruction or inflammation. Nonsteroidal anti-inflammatory drugs (NSAIDs) should be avoided, and narcotics lead to addiction in this chronic condition. Acetominophen, Tramadol and Darvocet are used most frequently for pain control. 5-Aminosalicylic acid derivatives such as Azulfidine, Asacol, Pentasa, and Rowasa are used widely and have some effect. They are more effective in ulcerative colitis than in Crohn disease.

Steroids

Corticosteroids have been the mainstay in the acute treatment of Crohn disease for many years. Steroids should be used only when more conservative measures fail. The strategy employed is to induce remission by using high doses (prednisolone 60 mg per day) in the short term, followed by a temporary regime as soon as remission is induced. Maintenance therapy should employ the lowest dose possible. About 20 percent of patients require long-term steroids.

Second-Line Agents

Steroid sparing in long-term management can be achieved with 6-mercaptopurine. This drug is slow to act and unpredictable in terms of achieving a therapeutic response. In doses of 50 to 125 mg daily, bone marrow suppression and other side effects are rare. The antibiotic metronidazole is also used as second-line therapy with a degree of success, particularly in treating fistulae. In addition to its properties as an antibiotic, the drug has an effect on the immune system. Other antibiotics that have been used to some effect are ciprofloxacin and clarithromycin.

Immune Suppressants

The immune suppressants methorexate and cyclosporine have been shown to confer some benefit in the short term. The latest, still experimental, strategy in the treatment of Crohn disease involves the role of cytokines. Anti-tumor necrosis factor has been shown to be effective. Other cytokine therapies, such as the use of interleukin-11 (IL-11) and IL-10, have been reported to be efficacious in about 30 percent of cases.

Surgery

The cumulative risk of undergoing surgery sometime in their lives for patients with Crohn disease is nearly 90 percent, and the cumulative risk of recurrent disease at 20 years is 70 percent. Many recurrences may be asymptomatic, however. The major indication for surgery is failed medical therapy, usually in the presence of obstruction, fistula formation, and electrolyte or nutritional problems.

Controversy still exists over how radical the surgeon should be in treating Crohn disease. Some studies show that the more disease-free the margins are after the resection, the less likely there is to be recurrent disease. Conversely, there is a danger that overly radical resections will leave the patient with the short bowel syndrome and its nutritional consequences. Conservative surgery in the form of stricturoplasty for short stenotic lesions that are producing obstructions can be helpful without the loss of any bowel. For longer diseased segments, resection is preferred to bypass. For colonic Crohn disease with severe rectal and anal involvement, a proctocolectomy with ileostomy may be required. Meticulous care is required in performing anastomoses in patients with Crohn disease, as healing is often impaired and the risk of anastomotic leakage therefore is increased.

COMPREHENSION QUESTIONS

[6.1] A 44-year-old man presents with multiple episodes of bloody diarrhea accompanied by cramping abdominal pain. A colonoscopy reveals the rectum and distal colon to be unremarkable, but x-ray studies find areas of focal thickening of the wall of the proximal colon, producing a characteristic "string sign." Biopsies from the abnormal portions of the colon revealed histologic features that were diagnostic of Crohn disease. Which of the following histologic features is most characteristic of Crohn disease?

A. Dilated submucosal blood vessels with focal thrombosis

B. Increased thickness of the subepithelial collagen layer

C. Noncaseating granulomas with scattered giant cells

D. Numerous eosinophils within the lamina propria

E. Small curved bacteria identified with special silver stains

[6.2] Which one of the therapies listed below is used most often to treat an individual with a history of Crohn disease who acutely develops abdominal pain and bloody diarrhea but has no clinical evidence of obstruction or fistula formation?

A. Aspirin

B. Interleukin-10

C. Metronidazole

D. Prednisolone

E. Surgery

[6.3] What is the fundamental distinguishing feature between Crohn disease and ulcerative colitis?

A. Crohn disease begins in the rectum; ulcerative colitis may have "skip lesions."

B. Crohn disease begins in the submucosa; ulcerative colitis begins in the mucosa.

C. Crohn disease has an increased risk of malignancy; ulcerative colitis has a very low association with malignancy.

D. Crohn disease is associated with crypt abscesses; ulcerative colitis, with pericolonic abscesses.

E. Crohn disease is associated with the formation of inflammatory polyps; ulcerative colitis, with hamartomatous polyps.

ANSWERS

[6.1] C. Microscopic examination of the abnormal bowel from an individual with Crohn disease will reveal transmural inflammation with fibrosis, but the histologic feature that is most diagnostic of Crohn disease is the presence of noncaseating granulomas. This characteristic histologic feature, however, may be present in only about 50 percent of patients; however, the diagnosis of Crohn disease can still be made without finding granulomas by the characteristic clinical presentation, which includes the production of fissures, fistulae, and bowel obstruction by the transmural inflammation.

[6.2] D. In the absence of bowel obstruction or fistula formation, several types of medical therapies have been used to treat the acute inflammation associated with Crohn disease. Corticosteroids, such as high-dose prednisolone, have been used commonly to treat the acute symptoms and induce remissions. In contrast, the antibiotic metronidazole may be used to treat patients with fistula formation, whereas the use of cytokines such as interleukin-10 is experimental. Surgical resection of bowel usually is done to treat problems such as obstruction.

[6.3] B. Crohn disease and ulcerative colitis are both inflammatory bowel diseases characterized by marked acute inflammation, but the fundamental difference is that with Crohn disease the inflammation begins in the submucosa and may involve the entire bowel wall, whereas ulcerative colitis begins in the mucosa and the inflammatory response remains superficial in location. Another important difference is that the inflammation in ulcerative colitis begins in the rectum and distal portions of the colon and precedes proximally without "skip lesions," whereas the inflammation in Crohn disease can be found throughout the gastrointestinal tract.

PATHOLOGY PEARLS

· Crohn disease is transmural (full thickness) and can occur anywhere along the gastrointestinal tract.

· Intestinal strictures and fistulae are complications of Crohn disease.

· Individuals with Crohn disease have an increased risk of colon cancer, but the risk is lower than that with ulcerative colitis.

· Nongastrointestinal symptoms of Crohn disease involve the skin, joints, and eyes. Skin lesions include erythema nodosum, pyoderma gangrenosa, aphthous stomatitis, and finger clubbing.

REFERENCES

Friedman S, Blumberg RS. Inflammatory bowel disease. In: Kasper DL, Fauci AS, Longo DL, et al. Harrison's principles of internal medicine, 16th ed. New York: McGraw-Hill, 2004:1776-1788.

Liu C, Crawford JM. The gastrointestinal tract. In: Kumar V, Assas AK, Fausto N, eds. Robbins and Cotran pathologic basis of disease, 7th ed. Philadelphia: Elsevier Saunders, 2004:846-849.

0

Copyright © 2006 by the McGraw-Hill Companies, Inc. All rights reserved.

Key words:

crohn disease symptoms                                                 crohn disease diet

crohn disease vs ulcerative colitis                                    crohn disease treatment

celiac disease                                                                 diverticulitis

crohn disease in children                                                 crohn disease flare up symptoms

PATHOLOGY CASE 5

CASE 5

INTRODUCTION

A 57-year-old man complains of severe upper abdominal pain extending to his midback. He also has had fatigue and a loss in appetite over the last several weeks. Physical examination reveals generalized jaundice but no other significant findings. An upper endoscopy does not identify any mucosal ulcerations or masses. A CT scan of the abdomen shows a large mass in the head and body of the pancreas.

· What is the most likely diagnosis?

· What is the likely prognosis of this condition?

ANSWERS TO CASE 5: Pancreatic Carcinoma

Summary: A 57-year-old man has severe upper abdominal pain radiating to his midback, fatigue, loss of appetite, and generalized jaundice. A large mass in the head and body of the pancreas is noted on CT imaging.

· Most likely diagnosis: Pancreatic carcinoma.

· Likely prognosis of this condition: Poor prognosis with 5-year survival less than 5 percent.

CLINICAL CORRELATION

Introduction

The vast majority of pancreatic carcinomas involve exocrine glands and are known as adenocarcinomas. The etiology is largely unknown. However, point mutations of the K-ras gene have been observed in over 90 percent of the tumors, suggesting abnormalities at the genetic level. Pain and nonspecific systemic symptoms such as weakness and weight loss are the usual first signs of malignancy. Obstructive jaundice is seen commonly because of the preference for tumors to occur in the head of the pancreas. The symptomatic course of pancreatic carcinoma is typically brief and progressive. Radiologic workups, including abdominal CT and ultrasound, are diagnostic for the cancer and are used for staging. No specific biological tests are available for screening or early detection. Cancer of the pancreas is now the fifth most common cause of cancer-related death in the United States. The median survival period from the time of diagnosis to demise is arguably the worst of any of the cancers. The median survival for untreated advanced cases is about 3.5 months; with good treatment this increases to about 6 months. The 5-year relative survival rate of patients with this cancer is only 3 to 5 percent. Even though a Whipple operation is considered the treatment of choice for localized and early disease, fewer than 15 percent of pancreatic tumors overall are resectable at the time of diagnosis. The prognosis of pancreatic carcinoma is one of the most dismal among any malignancies ever known.

Approach to Pancreatic Cancer

Definitions

Jaundice: A yellow discoloring of the skin, mucous membranes, and eyes caused by excess bilirubin in the blood. Common causes of jaundice in adults include prehepatic causes such as intravascular hemolysis, hepatic causes such as hepatitis A and hepatic tumors, and posthepatic causes, including obstruction of the bile duct as a result of infection, tumor, or gallstones.

Exocrine gland: A gland that secretes its products through ducts or canals, such as sweat glands or mammary glands. The secretion products produce their biological effects locally.

Endocrine gland:A gland, such as the pituitary or thyroid, that secretes its products, called hormones, directly into the bloodstream. Hormones generate their biological effects at distant locations.

Pancreatic cancer and adenocarcinoma of the pancreas: By definition, pancreatic cancer includes all malignant neoplasms of the pancreas. It includes the tumors arising from the exocrine portion of pancreas such as gland-forming adenocarcinoma of the pancreas, those of ductal origin, and tumors from endocrine components. Adenocarcinoma is the most common form of cancer, accounting for over 75 percent of all pancreatic cancers.

Discussion

Normal Pancreatic Histology

The pancreas is a small, spongy gland that lies just under the curvature of the stomach and deep within the abdomen. The majority of the pancreas is composed of exocrine glands, which produce enzymes necessary for food digestion. The secretions from acinar cells, the structural unit throughout the pancreas, containing salts and enzymes, are called pancreatic fluid, which eventually drains into the pancreatic duct. The pancreatic duct usually joins the bile duct and empties its combined digestive contents into the duodenum. Additionally, the pancreas has an endocrine, or hormonal, function. Inside specialized groupings of cells called the islets of Langerhans, the pancreas produces hormones such as insulin and glucagons, among other hormones. These molecules are secreted directly into the bloodstream, eliciting numerous biological effects throughout the body.

Epidemiology

Each year about 30,000 people in the United States are diagnosed with adenocarcinoma of the pancreas. Most of them will have passed away by the end of the first year. Most patients are between the ages of 60 and 80. Men tend to be affected more often than women. The median survival period from the time of diagnosis until demise is extremely short, with a mean of 3.5 months. It has been approximated that about 30 percent of the changes that initiate cancer of the pancreas are caused by smoking and that about 8 percent are "secondary to a hereditary genetic predisposition. There does not appear to be a strong correlation between the onset of pancreatic adenocarcinoma and the drinking of alcohol or coffee.

Biochemical Tests

Laboratory results often reveal nonspecific elevated bilirubin and elevated liver function enzymes as a result of biliary obstruction. The CA 19-9 marker, a Lewis blood group-related mucin, frequently is elevated in adenocarcinoma of the pancreas, but its use in screening for or diagnosis of the cancer is not accepted in general practice. High CA 19-9 levels may be associated with but do not always indicate larger tumors and with a decreased likelihood of surgical resectability. The use of this marker is accepted more widely as a running measure in a particular individual to help reflect the stability or progression of the cancer. Point mutation of K-ras is observed in 90 percent of pancreatic cancer patients. However, the utility of a screening test for K-ras mutation is not proven clinically.

Adenocarcinoma of the Pancreas

In up to 95 percent of cases, pancreatic cancer arises from the exocrine portion of the organ. Most of the exocrine tumors (approximately 90 percent) are from ductal cells¾those which line the pancreatic ducts. Further, under the microscope, the appearance and arrangement of these carcinoma cells can appear as ductlike (or "adeno"), giving the term adenocarcinoma to this most common form of pancreatic cancer. About three-quarters of exocrine tumors of the pancreas arise in the head and neck of the pancreas. It is believed that cancer is caused by the mutations of a gene, which confer increased abnormal growth potential to cells. Among other abnormalities, an oncogene called K-ras is found to be altered in up to 95 percent of ductal adenocarcinomas of the pancreas. The Whipple operation (pancreaticoduodenectomy) typically is performed in patients with tumors localized in the head of the pancreas.

Other Malignant Tumors of the Pancreas

Neuroendocrine tumors of the pancreas (islet cell tumors) are much less common than tumors arising from the exocrine pancreas. About 75 percent of these tumors are "functioning," meaning that they are found to be producing symptoms related to one or more of the hormone peptides they secrete. The predominant peptide secreted gives the functioning islet cell tumor its name. The hormones produced by neuroendocrine tumors include insulin, gastrin, glucagon, somatostatin, neurotensin, pancreatic polypeptide (PP), vasoactive intestinal peptide (VIP), growth hormone-releasing factor (GRF), and adronocorticotropic hormone (ACTH), among others.

Typically, the symptoms produced by the excess secretion of the predominant hormone in a functioning endocrine tumor lead to the eventual diagnosis. It is not possible to determine malignancy from the histologic appearance. Malignancy is determined by finding additional metastatic sites. The natural history of neuroendocrine carcinoma tends to be favorable compared with that of pancreatic adenocarcinoma. For example, the median survival duration from the time of diagnosis for patients with nonfunctioning metastatic neuroendocrine tumors approaches 5 years. Immediate treatment of the symptomatic conditions created by the oversecretion of the hormone may be appropriate. Surgery is generally curative.

COMPREHENSION QUESTIONS

[5.1] A 51-year-old man presents with slowly progressive jaundice, weight loss, and upper abdominal pain that radiates to his midback. Physical examination finds an enlarged gallbladder in the right upper quadrant of his abdomen, and a CT scan shows an irregular mass involving the head of the pancreas. Histologic sections from this mass are most likely to reveal what abnormality?

A. Adenocarcinoma

B. Clear cell carcinoma

C. Medullary carcinoma

D. Signet ring carcinoma

E. Squamous cell carcinoma

[5.2] Which one of the tumor markers listed below is most likely to be used by a clinician who is following a 64-year-old man after surgery for pancreatic cancer to look for possible recurrence of the pancreatic cancer?

A. CA 15-3

B. CA 19-9

C. CA 27-29

D. CA-50

E. CA-125

[5.3] A 44-year-old woman presents with worsening episodes of feeling "light-headed and dizzy." She says that her symptoms are relieved if she quickly eats a candy bar. Laboratory evaluation finds that during one of these episodes her serum glucose level is decreased and her serum insulin level is increased. What is the most likely cause of her symptoms?

A. Carcinoid tumor

B. Functional hamartoma

C. Islet cell adenoma

D. Microcystic adenoma

E. Tubulovillous adenoma

ANSWERS

[5.1] A. Adenocarcinoma is the most common type of pancreatic malignancy arising from the pancreatic ducts. In contrast, squamous cell carcinomas usually originate from stratified squamous epithelium, such as the esophagus. Clear cell carcinomas can be found in the kidneys, and signet cell carcinomas can be found in the stomach. A medullary carcinoma is a type of carcinoma of the thyroid gland.

[5.2] B. CA 19-9 is currently the best available tumor marker used clinically to look for possible recurrence of pancreatic cancer after surgery. Other markers have been studied in patients with pancreatic cancer, including CA-50, SPAN-1, and DUPAN-1, but these markers have not been as useful as CA 19-9. In contrast, CA-125 is associated with ovarian cancer, whereas CA 15-3 and CA 27-29 are associated with breast cancer, particularly advanced breast cancer.

[5.3] C. Elevated serum levels of insulin that result in hypoglycemia can be caused by a tumor that secretes insulin; an insulinoma is a type of islet cell tumor of the pancreas. In contrast, carcinoid tumors, which are found in the appendix and small intestine, may secrete vasoactive substances such as serotonin. A microcystic adenoma is a rare type of benign tumor of the pancreas, and a tubulovillous adenoma is a type of neoplastic polyp of the colon.

PATHOLOGY PEARLS

· Pancreatic cancer usually has a very poor prognosis.

· Adenocarcinoma is the most common type of primary pancreatic cancer, usually arsing from the exocrine glands.

· Neuroendocrine tumors of the pancreas tend to have a better prognosis than do adenocarcinomas.

· Painless obstructive jaundice is a common presentation of pancreatic cancer.

· Depression can herald an occult pancreatic cancer.

REFERENCES

Hruban RH, Wilentza RE. The pancreas. In: Kumar V, Assas AK, Fausto N, eds. Robbins and Cotran pathologic basis of disease, 7th ed. Philadelphia: Elsevier Saunders, 2004:939-953.

Mayer RJ. Pancreatic cancer. In: Kasper DL, Fauci AS, Longo DL, et al., eds. Harrison's principles of internal medicine, 16th ed. New York: McGraw-Hill, 2004:537-538.

0

Copyright © 2006 by the McGraw-Hill Companies, Inc. All rights reserved.

Key words:

pancreatic carcinoma staging                                     pancreatic adenocarcinoma

pancreatic carcinoma symptoms                                patients with pancreatic carcinoma

pancreatic carcinoma in dogs                                     pancreatic carcinoma ppt

pancreatic carcinoma prognosis                                 pancreatic carcinoma immunohistochemistry

PATHOLOGY CASE 4

CASE 4

INTRODUCTION

A 45-year-old man with a family history of colon cancer undergoes a screening colonoscopy. No invasive carcinomas are identified, but two small pedunculated tubular adenomas are removed and one villous adenoma measuring 5 mm in diameter is biopsied.

· What is the most likely diagnosis?

· What are the syndromes that could predispose this individual to colon cancer?

· What other dietary factors could play a role in the development of colon cancer?

ANSWERS TO CASE 4: Colon Adenoma

Summary: A 45-year-old man with a family history of colon cancer underwent colonoscopy for rectal bleeding. Colonoscopic findings included several small pedunculated polyps in the right colon, all measuring less than 5 mm.

· Most likely diagnosis: Hyperplastic polyps or tubular adenomas.

· Syndromes predisposing to colon cancer: Familial adenomatous polyposis (FAP) and hereditary nonpolyposis colon cancer (HNPCC) are two common inherited colon cancer syndromes.

· Dietary factors that play a role in the development of colon cancer: Diets rich in fat and red meat and low in fiber may contribute to the development of colon cancer.

CLINICAL CORRELATION

Introduction

Colon cancer is the third most common malignant neoplasm worldwide and the second leading cause of cancer death in the United States. The peak incidence is in the seventh decade of life. Recommended screening for colon cancer for patients without increased risk starts at age 50, but for at-risk patients with a positive family history, screening should start at age 40 (some recommend 10 years earlier than the age at which the youngest index case presents). Annual fecal occult blood tests should be performed as well as digital rectal examination and flexible sigmoidoscopy every 5 years. Additional screening can be done by colonoscopy every 10 years, or a double-contrast barium enema can be done every 5 to 10 years. These recommended screening intervals may be maintained after a negative examination. For patients at high risk for cancer or with polyps, rescreening by colonoscopy at 3-year intervals is recommended. New technologies such as virtual colonography and genetic testing of stool specimens are being examined for their appropriate clinical settings. In this patient, the colonic polyps showed proliferation of tubular glands, arising from a fibromuscular base with normal colonic epithelium consistent with a polyp stalk. The polyps showed no evidence of malignant transformation (i.e., carcinoma). The diagnosis was multiple tubular adenomas of the colon.

Approach to Colon Adenomas

Definitions

Adenoma: Neoplastic proliferation of colonic epithelium that results in the formation of a polyp.

Neoplasia: Usually implies abnormal, often clonal proliferation of cells that results in the formation of a tumor.

Dysplasia: Usually the result of additional genetic abnormalities in cells that lead to further dysfunction or abnormal cell maturation.

Adenoma-dysplasia-carcinoma sequence:Model for colon cancer development that outlines the genetic pathway involved in the progression from a benign neoplastic polyp (adenoma) to frankly invasive cancer (carcinoma).

Familial adenomatous polyposis syndrome: The prototypic inherited colon cancer phenotype; affected patients have hundreds to thousands of polyps and are at high risk for cancer development.

Hereditary nonpolyposis colorectal cancer: Also known as Lynch syndrome. Often presents as right-sided colon cancer and involves mutation in mismatch repair genes. It is inherited in an autosomal dominant fashion, and affected individuals are also at high risk for extracolonic malignancies such as endometrial carcinomas.

Discussion

Polyps of the colon can be classified broadly into inflammatory/reactive, hyperplastic, and neoplastic. Inflammatory polyps can be seen in chronic colitides such as ulcerative colitis and Crohn disease. Hyperplastic polyps are some of the more frequently encountered polyps and are thought to represent nonneoplastic proliferation of colonic epithelium. There is accumulating evidence that some hyperplastic polyps may transform to adenomas through a serrated adenoma pathway. Adenomas are truly neoplastic proliferations and have the potential to transform and progress to carcinomas (see Figure 4-1). With increasing age, there is an increased incidence of adenoma formation. About 50 percent of patients who have one adenoma have additional synchronous adenomas present. Most polyps present in the rectosigmoid colon, but with increasing age, there is a tendency to see more right-sided involvement by polyps.

Figure 4-1. Colonic polyp: gross pictograph. (Courtesy of Dr. Aaron Han, Reading, PA.)0

Types of Adenomas

Adenomas can be classified on the basis of the pattern of growth: whether they are flat, sessile and broad without a stalk, or pedunculated and on a stalk. Histologically, depending on the extent of tubular gland formation versus fingerlike villous projections, they are classified as tubular adenomas, villous adenomas, or tubulovillous adenomas.

Polyposis and Inherited Colon Cancer Syndromes

Syndromes that involve the formation of multiple gastrointestinal polyps occur infrequently. Some, such as Peutz-Jeghers syndrome and Cowden disease, are autosomal dominant, resulting in the formation of nonneoplastic hamartomatous polyps; others, such as Canada-Chronkhite syndrome, are not hereditary and result in multiple juvenile polyps. Other clinically significant polyposis or colon cancer syndromes include familial adenomatous polyposis and hereditary nonpolyposis colorectal cancer.

The autosomal dominant FAP gene on chromosome 5q21 contains the tumor suppressor gene APC (adenomatous polyposis coli). Affected individuals have hundreds to thousands of polyps, typically presenting in the left colon. Almost all individuals with APC gene mutations eventually develop colon cancer. Hence, carriers usually are candidates for prophylactic colectomy. Recent studies have shown that cyclooxygenase inhibitors can suppressor polyp formation and possibly carcinoma development in patients with FAP.

Adenoma-Dysplasia-Carcinoma Sequence

A variant of FAP is Gardner syndrome, which involves the formation of osteomas of the bone, desmoid fibromatosis. HNPCC also is known as Lynch syndrome, named after the gastroenterologist Dr. Henry Lynch. The autosomal dominant inherited disease presents early in life, often with right-sided cancer, and can be associated with polyps, although much less numerous (usually fewer than 10) than what is seen in FAP. Patients with HNPCC are also at risk for extra-gastrointestinal tract tumors.

There are also less-well-defined familial cancer syndromes involving glandular elements (adenocarcinomas) that are associated with a family history or personal history of breast, ovarian, endometrial, or colon cancer.

The development of colon cancer is a multifactorial process involving not only predisposition genes but also factors such as diet (low-fiber foods, red meat, and refined carbohydrates are nonfavorable), obesity, and inactivity. Genetically, it is known that adenomas can progress and transform through additional mutations (i.e., genetic "hits") and progressively grow in size, increase in the degree of dyplasia, and acquire full malignant potential (carcinoma). Additional genes that have been shown to be involved in this process include the K-ras oncogene, the DCC (deleted in colon cancer) adhesion molecule gene, and the p53 tumor suppressor gene.

COMPREHENSION QUESTIONS

[4.1] A 25-year-old man is discovered to have colon cancer. It is noted that several members of his family also developed colon cancer at relatively young ages. Which of the following genes is most likely to be involved?

A. Hereditary nonpolyposis colorectal cancer gene

B. Mismatch repair gene

C. p53 gene

D. K-ras oncogene

[4.2] A 55-year-old man is undergoing colonoscopy and has a polyp removed. It is noted on histologic analysis to be an adenoma. Which of the following is the most accurate description of these lesions?

A. An aging change with no malignant potential

B. A reactive, nonneoplastic proliferation of cells

C. More frequently seen in the left colon

D. Not associated with familial syndromes

E. Almost always pedunculated rather than flat

[4.3] A 50-year-old man asks what he can do to decrease his risk of colon cancer. Which of the following is the best answer?

A. Increase red meat in the diet.

B. Elevate dietary carbohydrates.

C. Drink red wine occasionally.

D. Take medication that inhibits cyclooxygenase pathways.

ANSWERS

[4.1] A. Hereditary nonpolyposis colorectal carcinoma, also known as Lynch syndrome, presents as an autosomal dominant disorder characterized by the formation of colon cancer, usually early in life. The disorder is associated with the hereditary nonpolyposis colorectal cancer gene and with the formation of multiple colonic polyps, although fewer than seen in the family adenomatous polyposis syndrome.

[4.2] C. Adenomas can be seen in polyposis syndromes such as FAP and more frequently involve the left side. The other statements are not true.

[4.3] D. Inhibitors of cyclooxygenase have been shown to reduce polyp formation and may decrease the incidence of colon cancer. The other answers are factors that increase the risk for colon cancer.

PATHOLOGY PEARLS

· Colonic adenomas are neoplastic proliferations with the potential for malignant transformation.

· Inherited syndromes such as FAP and HNPCC can predispose people to developing polyps and colon cancer. One pathway is the adenoma-dysplasia-carcinoma sequence.

· Additional factors, such as diet, obesity, and activity, can affect one's risk for developing colon cancer.

REFERENCES

Fenoglio-Preiser C, Noffsinger AE, Stemmermann GN, et al. Gastrointestinal pathology, 2d ed. Philadelphia: Lippincott-Raven, 1999.

Liu C, Crawford JM. The gastrointestinal tract. In: Kumar V, Assas AK, Fausto N, eds. Robbins and Cotran pathologic basis of disease, 7 ed. Philadelphia: Elsevier Saunders, 2004:856-870.

Key words:

colon adenoma symptoms                                               colon adenoma polyp

colon tubular adenoma                                                    colon adenoma types

colon adenoma histology                                                 colon adenoma icd 9 code

colon adenoma surgery                                                   colon adenoma causes