Diseases of Digestive System

Chen, Jian Instructor Department of Pathology and Pathopsybiology cj@zju.edu.cn, 88208199 Research Building, Section B303, School of Medicine, Zhejiang University, ZiJinGang Campus

Summary
Gastritis Peptic ulceration Appendicitis Inflammatory bowel disease Barrett esophagus Gastric carcinoma, colorectal cancer Viral hepatitis Alcoholic liver disease Liver cirrhosis Pancrea diseases Gallbladder diseases Primary carcinoma of the liver

This is the normal appearance of the gastric antrum extending to the pylorus at the right of center. The first portion of the duodenum (duodenal bulb) is at the far right. In the endoscopic views below, the normal appearance of the pylorus is seen at the left, with the first portion of the duodenum at the right.

Anatomy and histology of the stomach. A, Gross anatomy. B, Microscopic view of antral mucosa. C, Microscopic view of fundic mucosa.

This is the normal appearance of the gastric fundal mucosa, with short pits lined by pale columnar mucus cells leading into long glands which contain bright pink parietal cells that secrete hydrochloric acid.

Chronic Gastritis
The presence of chronic inflammatory changes in the mucosa Helicobacter pylori, HP Mucosal atrophy Epithelial metaplasia In the Western world, the prevalence of histologic changes indicative of chronic gastritis is higher than 50% in the later decades of life.

Pathogenesis
The bacillus H. pylori. Immunologic (autoimmune), in association with pernicious anemia Toxic, as with alcohol and cigarette smoking Postsurgical, especially following antrectomy with gastroenterostomy with reflux of bilious duodenal secretions Radiation Miscellaneous-amyloidosis, graft-versus-host disease, uremia

Helicobacter pylori, HP
Identification in 1982
The 2005 Nobel Prize in Medicine

H. pylori does not invade the tissues, it induces an intense inflammatory and immune response. Strains producing VacA and CagA cause more intense tissue inflammation, more severe epithelial damage, and higher cytokine production.

Helicobacter pylori gastritis. A Steiner silver stain demonstrates the numerous darkly stained Helicobacter organisms along the luminal surface of the gastric epithelial cells. There is no tissue invasion by bacteria. (Courtesy of Dr. Melissa Upton, Department of Pathology, University of Washington, Seattle, Washington.)

Gastritis is often accompanied by infection with Helicobacter pylori. This small curved to spiral rod-shaped bacterium is found in the surface epithelial mucus of most patients with active gastritis. The rods are seen here with a methylene blue stain.

Chronic Superficial Gastritis

Varying degrees of mucosal damage Antral mucosa Lymphocytes and plasma cells infiltrate within the lamina propria

The mucosa adjacent to the ulcer shows chronic gastritis. Note the discrete band of chronic inflammation in the most superficial portion of the mucosa.

Chronic Atrophic Gastritis

Mucosa may become thinned and flattened Inflammatory infiltrate of lymphocytes and plasma cells Variable gland loss and mucosal atrophy Metaplasia Dysplasia

Chronic gastritis, showing partial replacement of the gastric mucosal epithelium by intestinal metaplasia (upper left), and inflammation of the lamina propria containing lymphocytes and plasma cells (right).

Metaplasia in CAG
Intestinal metaplasia
The replacement of gastric epithelium with columnar and goblet cells of intestinal variety. I ytpe II type
IIa type IIb type

Pyloric metaplasia
Parietal cells and Chief cells are absent

Intestinal metaplasia in chronic gastritis (arrow). Note goblet cells and lymphcyte and plasma cell infiltration (arrowhead)

Incomplete intestinal metaplasia containing goblet cells but lacking a welldefined brush border.

Alcian blue and periodic acid-Schiff stain of Barrett's mucosa with complete intestinal metaplasia. The goblet cells are intensely Alcian blue positive. The periodic acid-Schiff portion of the stain outlines a primitive luminal brush border.

Another association with gastritis is pernicious anemia. Chronic atrophic gastritis is associated with autoantibodies that block or bind intrinsic factor. Another type of autoantibody demonstrated here is anti-parietal cell antibody. The bright green immunofluorescence is seen in the paritetal cells of the gastric mucosa.

Peptic Ulcers
Peptic ulcers are chronic, most often solitary, lesions that occur in any portion of the gastrointestinal tract exposed to the aggressive action of acid/peptic juices.
Duodenum, first portion Stomach, usually antrum

Ulcers are defined histologically as a breach in the mucosa of the alimentary tract that extends through the muscularis mucosa into the submucosa or deeper.

Epidemiology
Remitting, relapsing lesions Most often diagnosed in middle-aged to older adults Appear without obvious precipitating influences Heal after a period of weeks to months of active disease

Pathogenesis
Imbalance between gastroduodenal mucosal defense mechanisms and the damaging forces H. pylori infection is a major factor in the pathogenesis of peptic ulcer Chronic use of NSAIDs Cigarette smoking Alcohol Corticosteroids

Helicobacter pylori. A Steiner silver stain demonstrates the numerous darkly stained Helicobacter organisms along the luminal surface of the gastric epithelial cells. Note that there is no tissue invasion by bacteria.

Pathogenesis
Two conditions are key for the development of peptic ulcers
(1) H. pylori infection (2) Mucosal exposure to gastric acid and pepsin

NSAIDs are the major cause of peptic ulcer disease in persons who do not have H. pylori infection

Aggravating causes of, and defense mechanisms against, peptic ulceration. The right panel shows the basis of a nonperforated ulcer, demonstrating necrosis (N), inflammation (I), granulation tissue (G), and fibrosis (S).

Morphology
The lesser curvature, in or around the border zone between the oxyntic mucosa and the antral mucosa The anterior wall of the duodenum A fairly standard, virtually diagnostic gross appearance
Round to oval Sharply punched-out defect with relatively straight walls. The margins are usually level with the surrounding mucosa or only slightly elevated. The depth of these ulcers varies, from superficial lesions involving only the mucosa and muscularis mucosa to deeply The base of a peptic ulcer is smooth and clean The surrounding mucosal folds may radiate like wheel spokes.

Seen above are gastric ulcers of small, medium, and large size on upper endoscopy. All gastric ulcers are biopsied, since gross inspection alone cannot determine whether a malignancy is present. Smaller, more sharply demarcated ulcers are more likely to be benign.

Peptic ulcer of the duodenum. Note that the ulcer is small (2 cm) with a sharply punched-out appearance. Unlike cancerous ulcers, the margins are not elevated. The ulcer base is clean.

An acute duodenal ulcer is seen in two views on upper endoscopy.

Morphology
The histologic appearance varies from active necrosis, to chronic inflammation and scarring, to healing
(1) The base and margins have a superficial thin layer of necrotic fibrinoid debris not visible to the naked eye; (2) Beneath this layer is a zone of non-specific inflammatory infiltrate, with neutrophils predominating; (3) In the deeper layers, especially in the base of the ulcer, there is active granulation tissue infiltrated with mononuclear leukocytes; (4) The granulation tissue rests on a more solid fibrous or collagenous scar.

Vessel walls within the scarred area are typically thickened by the surrounding inflammation and are occasionally thrombosed.

Medium-power detail of the base of a nonperforated peptic ulcer, demonstrating the layers of necrosis (N), inflammation (I), granulation tissue (G), and scar (S) moving from the luminal surface at the top to the muscle wall at the bottom.

Microscopically, the ulcer here is sharply demarcated, with normal gastric mucosa on the left falling away into a deep ulcer whose base contains infamed, necrotic debris. An arterial branch at the ulcer base is eroded and bleeding.

The mucosa at the upper right merges into the ulcer at the left which is eroding through the mucosa. Ulcers will penetrate over time if they do not heal. Penetration leads to pain.

Complications of Peptic Ulcers

Bleeding
Occurs in 15% to 20% of patients Most frequent complication May be life-threatening Accounts for 25% of ulcer deaths May be the first indication of an ulcer

Perforation
Occurs in about 5% of patients Accounts for two thirds of ulcer deaths Rarely, is the first indication of an ulcer

Obstruction from edema or scarring

Occurs in about 2% of patients Most often due to pyloric channel ulcers May also occur with duodenal ulcers Causes incapacitating, crampy abdominal pain Rarely, may lead to total obstruction with intractable vomiting

Complications of Peptic Ulcers

Bleeding is the chief complication Peptic ulcers are notoriously chronic, recurrent lesions Malignant transformation does not occur with duodenal ulcers and is extremely rare with gastric ulcers.

The ulcer at the right is penetrating through the muscularis and approaching an artery. Erosion of the ulcer into the artery will lead to another major complication of ulcers-hemorrhage.

The strongest association with Helicobacter pylori is with duodenal peptic ulceration--over 85% of duodenal ulcers. Seen here is a penetrating acute ulceration in the duodenum just beyond the pylorus.

Clinical Features
Epigastric gnawing, burning, or aching pain. Iron-deficiency anemia, frank hemorrhage, or perforation. The pain tends to be worse at night and occurs usually 1 to 3 hours after meals during the day Nausea, vomiting, bloating, belching, and significant weight loss Treated by antibiotics active against H. pylori, proton pump inhibitors, and hydrogen receptor antagonists

Appendicitis
Is the most common acute abdominal condition the surgeon is called on to treat. Inflammation in the right lower quadrant Adolescents and young adults
Acute Simple Appendicitis Acute Suppurative Appendicitis Acute Gangrenous Appendicitis

Morphology
Scant neutrophilic exudate throughout the mucosa, submucosa, and muscularis propria Subserosal vessels are congested Fibrinopurulent reaction over the serosa Abscess formation within the wall, along with ulcerations and foci of suppurative necrosis in the mucosa Green-black gangrenous necrosis through the wall, extending to the serosa

Acute appendicitis. The inflamed appendix shown below is red, swollen, and covered with a fibrinous exudate. For comparison, a normal appendix is shown above.

This appendix was removed surgically. The patient presented with abdominal pain that initially was generalized, but then localized to the right lower quadrant, and physical examination disclosed 4+ rebound tenderness in the right lower quadrant.

This is the tip of the appendix from a patient with acute appendicitis. The appendix has been sectioned in half. The serosal surface at the left shows a tan-yellow exudate. The cut surface at the right demonstrates yellowish-tan mucosal exudation with a hyperemic border.

Microscopically, acute appendicitis is marked by mucosal inflammation and necrosis.

Complication
Rupture Suppurative peritonitis Pyelophlebitis with thrombosis of the portal venous drainage Chronic inflammation of the appendix Cystic fibrosis

Clinical Features
(1) Pain, at first periumbilical but then localizing to the right lower quadrant; (2) Nausea and/or vomiting; (3) Abdominal tenderness, particularly in the region of the appendix; (4) Mild fever; (5) An elevation of the peripheral white blood cell count up to 15,000 to 20,000 cell/L.

Liver
Normal adult liver
The "gateway" of the liver (porta hepatis) Portal tracts Septal venules The "back door" of the liver

This is an in-situ photograph of the chest and abdominal contents. As can be seen, the liver is the largest parenchymal organ, lying just below the diaphragm. The right lobe (at the left in the photograph) is larger than the left lobe. The falciform ligament is the rough dividing line between the two lobes.

A normal liver is shown grossly for comparison

The cut surface of a normal liver has a brown color. Near the hilum here, note the portal vein carrying blood to the liver, which branches at center left, with accompanying hepatic artery and bile ducts. At the lower right is a branch of hepatic vein draining blood from the liver to the inferior vena cava.

Microarchitecture
Hexagonal lobules The cords of hepatocytes Limiting plate Kupffer cells Perisinusoidal stellate cells Terminal hepatic veins Vascular sinusoids Bile canaliculi

The liver can be divided into three zones, based upon oxygen supply. Zone 1 encircles the portal tracts where the oxygenated blood from hepatic arteries enters. Zone 3 is located around central veins, where oxygenation is poor.

Microscopic anatomy of the liver. The portal tract carries branches of the portal vein, hepatic artery, and bile duct system.

Photomicrograph of liver (trichrome stain). Note the blood-filled sinusoids and cords of hepatocytes; the delicate network of reticulin fibers in the subendothelial space of Disse stains light blue.

The portal triad consists of the portal vein, branches of the hepatic artery and tributaries to the bile duct.

The liver has its own version of macrophage known as the Kupffer cell (stained blue by uptake of trypan blue). Not only do these remove foreign particles, they also work with the spleen to destroy old RBCs.

Viral Hepatitis
Infection of the liver caused by a group of viruses having a particular affinity for the liver
Infectious mononucleosis (Epstein-Barr virus) Cytomegalovirus Yellow fever

Hepatotropic viruses cause overlapping patterns of disease

Etiology
Hepatitis viruses A (HAV), B (HBV), C (HCV), D (HDV), E (HEV), Hepatitis G virus (HGV)

Hepatitis A Virus
A benign, self-limited disease with an incubation period of 2 to 6 weeks. HAV does not cause chronic hepatitis or a carrier state and only rarely causes fulminant hepatitis. HAV occurs throughout the world and is endemic in countries with substandard hygiene and sanitation. Blood-borne transmission of HAV occurs only rarely.

Sequence of serologic markers in acute hepatitis A viral hepatitis.

Hepatitis B Virus
HBV can produce:
(1) Acute hepatitis with resolution (2) Chronic hepatitis, which may evolve to cirrhosis (3) Fulminant hepatitis with massive liver necrosis (4) The backdrop for hepatitis D virus infection

HBV also plays an important role in the development of hepatocellular carcinoma.

Hepatitis B Virus
Liver disease due to HBV is an enormous problem globally. HBV has a prolonged incubation period. HBV is a hardy virus and can withstand extremes of temperature and humidity.

Hepatitis B Virus
Risk categories for HBV infection
Transfusion Blood products Dialysis Needle-stick accidents among health care workers Intravenous drug abuse Homosexual activity

Diagrammatic representation of genomic structure and transcribed components of the hepatitis B virion. The innermost circles represent the DNA (+) strand and the DNA (-) strand of the virion. The thick bars labeled "P," "X," "pre-C," "C," "pre-SI," "pre-S2," and "S" denote the peptides derived from the virion. The outermost lines denote the mRNA transcripts of the virion. (After Kidd-Ljunggren K, Myakawa Y, Kidd AH: J Gen Virol 83:1267-1280, 2002.)

Schematic of the potential outcomes of hepatitis B infection in adults, with their approximate frequencies in the United States.

Serologic Diagnosis
HBsAg appears before the onset of symptoms, peaks during overt disease, and then declines to undetectable levels in 3 to 6 months. HBeAg, HBV-DNA, and DNA polymerase appear in the serum soon after HBsAg, and all signify active viral replication. IgM anti-HBc becomes detectable in serum shortly before the onset of symptoms, concurrent with the onset of elevation of serum aminotransferases. Over months, the IgM antibody is replaced by IgG anti-HBc. Anti-HBe is detectable shortly after the disappearance of HBeAg, implying that the acute infection has peaked and the disease is on the wane. IgG anti-HBs does not rise until the acute disease is over and is usually not detectable for a few weeks to several months after the disappearance of HBsAg. Anti-HBs may persist for life, conferring protection; this is the basis for current vaccination strategies using noninfectious HBsAg.

Sequence of serologic markers for hepatitis B viral hepatitis demonstrating (A) acute infection with resolution and (B) progression to chronic infection.

Carrier State
The carrier state is defined by the presence of HBsAg in serum for 6 months or longer after initial detection. Chronic replication of HBV virions is characterized by persistence of circulating HBsAg, HBeAg, and HBV DNA, usually with anti-HBc and occasionally with antiHBs.

Hepatitis C Virus
Hepatitis C virus (HCV) is a major cause of liver disease worldwide. The major routes of transmission are inoculations and blood transfusions. HCV could become the leading cause of chronic liver disease in the Western world. Cirrhosis may develop over 5 to 20 years after acute infection.

Diagrammatic representation of the genomic structure and transcribed components of the hepatitis C virion. The hepatitis C virion is transcribed in one single transcript, as depicted in the top line; 340 nucleotides at the 5' end and 128 nucleotides at the 3' end are not translated into protein. The protein products cleaved from the single translated peptide are shown in the bottom bar.

Schematic of the potential outcomes of hepatitis C infection in adults, with their approximate frequencies in the United States.

Serologic Diagnosis
HCV RNA is detectable in blood for 1 to 3 weeks, coincident with elevations in serum transaminases. In patients with symptoms of chronic hepatitis, HCV RNA testing must be performed to assess viral replication and to confirm the diagnosis of HCV infection.

Sequence of serologic markers for hepatitis C viral hepatitis demonstrating (A) acute infection with resolution and (B) progression to chronic relapsing infection.

Hepatitis D Virus
Causing infection only when it is encapsulated by HBsAg HDV is absolutely dependent on the genetic information provided by HBV for multiplication and causes hepatitis only in the presence of HBV.

Hepatitis D Virus
Acute coinfection occurs following exposure to serum containing both HDV and HBV. Superinfection of a chronic carrier of HBV with a new inoculum of HDV (and HBV) results in disease about 30 to 50 days later.

The differing clinical consequences of the two pattens of combined hepatitis D virus (HDV) and hepatitis B (HBV) infection.

Serologic Diagnosis
HDV RNA is detectable in the blood and liver just prior to and in the early days of acute symptomatic disease. Acute coinfection by HDV and HBV is best indicated by detection of IgM against both HDAg and HBcAg.

Sequence of serologic markers for hepatitis D viral hepatitis depicting (A) coinfection with hepatitis B virus (HBV) and (B) superinfection of an HBV carrier.

Hepatitis E Virus
An enterically transmitted, water-borne infection that occurs primarily in young to middle-aged adults. In most cases, the disease is self-limiting. HEV is not associated with chronic liver disease or persistent viremia. HEV RNA and HEV virions can be detected in stool and liver.

Other Hepatitis Viruses

HGV is transmitted by contaminated blood or blood products and possibly via sexual contact. This virus commonly co-infects patients with HIV.

The Hepatitis Viruses

HAV
Agent Icosahedra l capsid, ssRNA Fecal-oral

HBV
Enveloped dsDNA Parenteral; close contact 4-26 wk 0.1-1.0% of blood donors in U.S. and Western world 5-10% of acute infections

HCV
Enveloped ssRNA Parenteral; close contact 2-26 wk 0.2-1.0% of blood donors in U.S. and Western world >50%

HDV
Enveloped ssRNA Parenteral; close contact 4-7 wk 1-10% in drug addicts and hemophiliac s <5% coinfection, 80% upon superinfectio n No increase above HBV

HEV
Unenvelope d ssRNA Waterborne

HGV
ssRNA virus Parenteral

Transmission

Incubation period Carrier state

2-6 wk None

2-8 wk Unknown

Unknown 1-2% of blood donors in U.S.

Chronic hepatitis

None

None

None

Hepatocellula r carcinoma

No

Yes

Yes

Unknown, but unlikely

None

General Aspects of Liver Disease

(1) Patterns of hepatic injury (2) Hepatic failure and cirrhosis (3) Jaundice and cholestasis

Microscopic architecture of the liver parenchyma. Both a lobule and an acinus are represented. The classic hexagonal lobule is centered around a central vein (CV), also known as terminal hepatic venule, and has portal tracts at three of its apices. The portal tracts contain branches of the portal vein (PV), hepatic artery (HA), and the bile duct (BD) system. Regions of the lobule are generally referred to as "periportal," "midzonal," and "centrilobular," according to their proximity to portal spaces and central vein.

Patterns of Hepatic Injury

Degeneration and Intracellular Accumulation
Swelling of hepatocytes Ballooning degeneration Feathery degeneration Steatosis

Hepatitis B viral infection. A, Liver parenchyma showing hepatocytes with diffuse granular cytoplasm, so-called ground glass hepatocytes. (H&E) B, Immunoperoxidase stain for HBsAg from the same case, showing cytoplasmic inclusions of viral particles.

Here are Mallory bodies (the red globular material) composed of cytoskeletal filaments in liver cells chronically damaged from alcoholism.

The bile pigment is toxic to hepatocytes which become swollen, showing rarefaction of the cytoplasm referred to as feathery degeneration.

Intracellular accumulations of a variety of materials can occur in response to cellular injury. Here is fatty metamorphosis (fatty change) of the liver in which deranged lipoprotein transport from injury (most often alcoholism) leads to accumulation of lipid in the cytoplasm of hepatocytes.

Patterns of Hepatic Injury

Necrosis and Apoptosis
Ischemic coagulative necrosis Lytic necrosis Centrilobular necrosis Periportal necrosis Focal or spotty necrosis Bridging necrosis Submassive necrosis Massive necrosis

Spotty necrosis

Piecemeal necrosis

A mononuclear inflammatory cell infiltrate extends from portal areas and disrupts the limiting plate of hepatocytes which are undergoing necrosis, the so-called "piecemeal" necrosis of chronic active hepatitis.

Bridging necrosis

Massive necrosis, microscopic section. The portal veins are closer together than normal owing to necrosis and collapse of the intervening parenchyma. The rudimentary ductal structures are the result of early hepatocyte regeneration. An infiltrate of chronic inflammatory cells are present.

Patterns of Hepatic Injury

Inflammation
Influx of acute or chronic inflammatory cells

Regeneration
Hepatocellular proliferation is marked by mitoses, thickening of the hepatocyte cords.

Fibrosis
In response to inflammation or direct toxic insult to the liver.

Ductular reaction

Clusters of lymphocytes and hyperplastic Kupffer cells are scattered throughout the hepatic lobule as well. There is also spotty necrosis (focal necrosis of individual hepatocytes).

Acute viral hepatitis showing disruption of lobular architecture, inflammatory cells in the sinusoids, and hepatocellular apoptosis.

Chronic viral hepatitis due to hepatitis C virus, showing portal tract expansion with inflammatory cells and fibrous tissue and interface hepatitis with spillover of inflammation into the adjacent parenchyma. A lymphoid aggregate is present.

Cirrhosis resulting from chronic viral hepatitis. Note the broad scar and coarse nodular surface.

The yellow-green globular material seen in small bile ductules in the liver here is bilirubin pigment. This is hepatic cholestasis.

Clinical Features and Outcomes

Acute asymptomatic infection with recovery
serologic evidence only

Acute symptomatic hepatitis with recovery

anicteric or icteric

Chronic hepatitis
without or with progression to cirrhosis

Fulminant hepatitis
with massive to submassive hepatic necrosis

Acute Viral Hepatitis

Any one of the hepatotropic viruses can cause acute viral hepatitis
An incubation period A symptomatic preicteric phase A symptomatic icteric phase (with jaundice and scleral icterus) Convalescence

Morphology
Mildly enlarged Moderately tender to percussion Hepatocyte injury
Ballooning degeneration Hepatocyte necrosis Apoptosis

Cholestasis Kupffer cells undergo hypertrophy and hyperplasia The portal tracts are usually infiltrated with a mixture of inflammatory cells

Grossly, there are areas of necrosis and collapse of liver lobules seen here as ill-defined areas that are pale yellow. Such necrosis occurs with hepatitis.

The necrosis and lobular collapse is seen here as areas of hemorrhage and irregular furrows and granularity on the cut surface of the liver.

In this example, liver cells are dying individually (arrows) from injury by viral hepatitis. The cells are pink and without nuclei.

Chronic Hepatitis
Liver architecture is usually well preserved, Smoldering hepatocyte necrosis throughout the lobule Lymphoid aggregates and bile duct damage Macrovesicular steatosis Bridging necrosis The deposition of fibrous tissue

Morphology
Periportal septal fibrosis Bridging fibrosis Hepatocyte regenerative nodules

This is a case of viral hepatitis C which is at a high stage with extensive fibrosis and progression to macronodular cirrhosis, as evidenced by the large regenerative nodule at the center right.

This is a case of viral hepatitis C, which in half of cases leads to chronic liver disease. The extent of chronic hepatitis can be graded by the degree of activity (necrosis and inflammation) and staged by the degree of fibrosis.

This trichrome stain demonstrates the collapse of the liver parenchyma with viral hepatitis. The blue-staining areas are the connective tissue of many portal tracts that have collapsed together.

Diagrammatic representations of the morphologic features of acute and chronic hepatitis. Bridging necrosis (and fibrosis) is shown only for chronic hepatitis; bridging necrosis may also occur in acute hepatitis (not shown).

Fulminant Hepatitis
Acute: within 2 to 3 weeks Subacute: extending up to 3 months
HAV or HBV Drug and chemical toxicity Other causes

Morphology
The severity of the necrotizing process The liver may shrink to as little as 500 to 700 gm Complete destruction of hepatocytes in contiguous lobules Surprisingly little inflammatory reaction

Massive necrosis. A, Cut section of liver. The liver is small (700 gm), bile-stained, and soft. The capsule is wrinkled. B, Microscopic section. Portal tracts and terminal hepatic veins are closer together than normal, owing to necrosis and collapse of the intervening parenchyma. The rudimentary ductal structures are the result of early ductular regeneration. An infiltrate of mononuclear inflammatory cells is present.

Clinical Features
Jaundice, encephalopathy, and fetor hepaticus Coagulopathy and bleeding, cardiovascular instability, renal failure, adult respiratory distress syndrome Electrolyte and acid-base disturbances, and sepsis

There is extensive hepatocyte necrosis seen here in a case of acetaminophen overdose. The hepatocytes at the right are dead, and those at the left are dying. This pattern can be seen with a variety of hepatotoxins. Acute liver failure leads to hepatic encephalopathy.

Summary of Hepatitis
The most common primary liver infection. HAV causes a self-limited disease that never becomes chronic HBV can produce acute, chronic, and fulminant disease (1% or less), but the frequency of chronic disease is about 10%. HCV causes acute and chronic hepatitis; the acute phase is often difficult to detect and the frequency of chronic disease may reach 85%; cirrhosis develops in 20% of cases of chronic disease. In both acute and chronic hepatitis there is hepatocyte injury and cell death, and inflammation of portal tracts; chronic hepatitis may show bridging necrosis and fibrosis. Patients with longstanding HBV or HCV infections are at increased risk of developing hepatocellular carcinomas.

Liver Cirrhosis
Among the top 10 causes of death in the Western world.
Alcohol abuse Viral hepatitis Biliary disease Iron overload

Liver Cirrhosis
Cirrhosis as the end-stage of chronic liver disease is defined by three characteristics:
Bridging fibrous septae in the form of delicate bands or broad scars Parenchymal nodules containing proliferating hepatocytes encircled by fibrosis Disruption of the architecture of the entire liver

Microscopically with cirrhosis, the regenerative nodules of hepatocytes are surrounded by fibrous connective tissue that bridges between portal tracts. Within this collagenous tissue are scattered lymphocytes as well as a proliferation of bile ducts.

Classification
Portal cirrhosis Postnecrotic cirrhosis Biliary cirrhosis Congestive cirrhosis Hemochromatic cirrhosis Parasitic cirrhosis

A close-up view of a micronodular cirrhosis in a liver with fatty change demonstrates the small, yellow nodules.

Micronodular cirrhosis is seen along with moderate fatty change. Note the regenerative nodule surrounded by fibrous connective tissue extending between portal regions.

Ongoing liver damage with liver cell necrosis followed by fibrosis and hepatocyte regeneration results in cirrhosis. This produces a nodular, firm liver. The nodules seen here are larger than 3 mm and, hence, this is an example of "macronodular" cirrhosis.

In macronodular cirrhosis, the regenerative nodules are large and irregular in size and shape. The fibrous septa are often broad. Macronodular cirrhosis corresponds loosely to the older terms "post-necrotic" or "multilobular" cirrhosis and in the U.S. is most often seen following chronic active viral hepatitis.

The hepatic architecture is disturbed by broad bands of fibrosis that completely circumscribe irregularly sized and shaped nodules of regenerating hepatic parenchyma. These nodules range in size from less than 1 mm in diameter to greater than 5 mm in diameter.

Shows at higher power the broad fibrous septa which completely surround regenerating nodules of hepatic parenchyma. This patient's cirrhosis resulted from chronic active hepatitis C and there is ongoing chronic inflammation and necrosis in this liver.

Is taken at the margin of a regenerative nodule and a fibrous scar (double arrows). Note the irregular contour of the regenerative nodules and the intense chronic inflammation at the interface of the fibrous septa and the hepatic plates. This is an example of ongoing piecemeal necrosis.

Biliary cirrhosis. Sagittal section through the liver demonstrates the fine nodularity and bile staining of endstage biliary cirrhosis.

This is a case of primary biliary cirrhosis. Seen here in a portal tract is an intense chronic inflammatory infiltrate with loss of bile ductules. Micronodular cirrhosis ensues.

Primary biliary cirrhosis. A portal tract is markedly expanded by an infiltrate of lymphocytes and plasma cells. The granulomatous reaction to a bile duct undergoing destruction (florid duct lesion) is highlighted by the arrowheads.

If chronic hepatic passive congestion continues for a long time, a condition called "cardiac cirrhosis" may develop in which there is fibrosis bridging between central zonal regions, as shown below, so that the portal tracts appear to be in the center of the reorganized lobule. This process is best termed "cardiac sclerosis" because, unlike a true cirrhosis, there is minimal nodular regeneration.

The golden-brown refractile hemosiderin granules are present within hepatocytes.

Pipe-stem fibrosis of the liver due to chronic Schistosoma japonicum infection.

Pathogenesis
The most frequent are chronic hepatitis B and C and chronic alcoholism. Less frequent causes are autoimmune and biliary diseases and metabolic conditions such as hemochromatosis. Types I and III collagen are deposited in the lobule, creating delicate or broad septal tracts.

Liver fibrosis. In the normal liver, the perisinusoidal space (space of Disse) contains a delicate framework of extracellular matrix components. In liver fibrosis, stellate cells are activated to produce a dense layer of matrix material that is deposited in the perisinusoidal space. Collagen deposition blocks the endothelial fenestrations and prevents the free exchange of materials from the blood. Kuppfer cells are also activated and produce cytokines that are involved in fibrosis. Note that this illustration is not to scale; the space of Disse is actually much narrower than shown.

Pathogenesis
Hepatocellular death Regeneration Progressive fibrosis Vascular changes

Features of Cirrhosis
The parenchymal injury and consequent fibrosis are diffuse. Nodularity is part of the diagnosis. Vascular architecture is reorganized by the parenchymal damage and scarring. Fibrosis is the key feature of progressive damage to the liver.

Clinical Features
Nonspecific clinical manifestations:
Anorexia, weight loss, weakness, osteoporosis, and, in advanced disease, frank debilitation. Incipient or overt hepatic failure Gastrointestinal hemorrhage. Imbalances of pulmonary blood flow

The ultimate mechanism of most cirrhotic deaths

(1) Progressive liver failure (2) A complication related to portal hypertension (3) The development of hepatocellular carcinoma

Portal Hypertension
Results from increased resistance to portal flow at the level of the sinusoids and compression of central veins. Four major clinical consequences
Ascites The formation of portosystemic venous shunts Congestive splenomegaly Hepatic encephalopathy

Ascites
Ascites refers to the collection of excess fluid in the peritoneal cavity. Clinically detectable
>500ml

Cause massive abdominal distention Influx of neutrophils suggests secondary infection Red cells point to possible disseminated intra-abdominal cancer

Pathogenesis
Sinusoidal hypertension Percolation of hepatic lymph into the peritoneal cavity Intestinal fluid leakage Renal retention of sodium and water

Portosystemic Shunt
Veins around and within the rectum (manifest as hemorrhoids) The cardioesophageal junction (producing esophagogastric varices) The retroperitoneum The falciform ligament of the liver (involving periumbilical and abdominal wall collaterals).

Portosystemic Shunt
Esophagogastric varices that appear in about 65% of those with advanced cirrhosis of the liver and cause massive hematemes and death in about half. Dilated subcutaneous veins extending outward from the umbilicus (caput medusae)

Esophageal varices: a view of the everted esophagus and gastroesophageal junction, showing dilated submucosal veins (varices). The bluecolored varices have collapsed in this postmortem specimen.

At the lower end of the esophagus (which has been turned inside out at autopsy) are linear dark blue submucosal dilated veins known as varices. These varices are prone to bleed.

Seen here is "caput medusae" which consists of dilated veins seen on the abdomen of a patient with cirrhosis of the liver.

Splenomegaly
Long-standing congestion may cause congestive splenomegaly. Massive splenomegaly may secondarily induce a variety of hematologic abnormalities attributable to hypersplenism.
Splenomegaly Anemia, leukopenia, thrombocytopenia Correction of the blood cytopenia

One of the most common causes for splenomegaly is portal hypertension with cirrhosis of the liver. Note that this spleen also shows irregular tan-white fibrous plaques over the purple surface.

This magnetic resonance imaging (MRI) scan of the abdomen in transverse view demonstrates a small, nodular liver with cirrhosis. The spleen is enlarged from portal hypertension.

Jaundice and Cholestasis

Jaundice occurs when retention of bilirubin leads to serum levels above 2.0 mg/dL. Hepatitis and intra- or extra-hepatic obstruction of bile flow are the most common causes of jaundice involving the accumulation of conjugated bilirubin. Hemolytic anemias are the most common causes of jaundice involving the accumulation of unconjugated bilirubin. Cholestasis is the impairment of bile flow resulting in the retention of bilirubin, bile acids, and cholesterol. Serum alkaline phosphatase is usually elevated in cholestatic conditions.

The liver injury with chronic alcoholism leads to fibrosis and regeneration of the hepatocytes in nodules. This firm, nodular appearance of the liver as seen here is called cirrhosis.

Hepatic Failure
As the end point of progressive damage to the liver. The result of sudden and massive destruction of hepatic tissue.
Systemic infections Electrolyte disturbances Stress (major surgery, heart failure) Gastrointestinal bleeding

The Causes of Hepatic Failure

Acute liver failure with massive hepatic necrosis. Chronic liver disease. Hepatic dysfunction without overt necrosis

Clinical Features
Jaundice is an almost invariable finding. Hypoalbuminemia, which predisposes to peripheral edema. Hyperammonemia is attributable to defective hepatic urea cycle function. Impaired estrogen metabolism and consequent hyperestrogenemia are the putative causes of palmar erythema and spider angiomas of the skin. In the male, hyperestrogenemia also leads to hypogonadism and gynecomastia.

Hepatic Encephalopathy
A feared complication of acute and chronic liver failure. Patients show a spectrum of disturbances in brain function Stupor, to deep coma and death. Fluctuating neurologic signs include rigidity, hyperreflexia, nonspecific electroencephalographic changes and seizures. Asterixis (also called flapping tremor). Edema and an astrocytic reaction An elevation in blood ammonia

Hepatorenal Syndrome
Appears in individuals with severe liver disease, consists of the development of renal failure without primary abnormalities of the kidneys themselves. The ability to concentrate urine is retained, producing a hyperosmolar urine devoid of proteins and abnormal sediment that is surprisingly low in sodium.

The major clinical consequences of portal hypertension in the setting of cirrhosis, shown for the male. In women, oligomenorrhea, amenorrhea, and sterility are frequent, owing to hypogonadism.

Summary of Cirrhosis
The three main characteristics of cirrhosis are
(1) bridging fibrous septa (2) parenchymal nodules containing replicating hepatocytes (3) disruption of the architecture of the entire liver.

The most frequent are chronic hepatitis B and C and chronic alcoholism. Morphologic features of advanced cirrhosis are similar, regardless of the cause of the disease. The main complications of cirrhosis
Decreased liver function Portal hypertension Increased risk of hepatocellular carcinoma

Pancreatitis (For self-study)

Pancreatitis encompasses a group of disorders characterized by inflammation of the pancreas. A mild, self-limited disease A lifethreatening acute inflammatory process
Acute pancreatitis Chronic pancreatitis

Acute pancreatitis
a group of reversible lesions characterized by inflammation

Pathogenesis
Autodigestion of the pancreatic substance by inappropriately activated pancreatic enzymes. Trypsin is central in this process and activation of trypsin is thus a critical triggering event in acute pancreatitis.

Pathogenesis
Pancreatic duct obstruction Primary acinar cell injury Defective intracellular transport of proenzymes within acinar cells

Etiologic Factors in Acute Pancreatitis

Metabolic
Alcoholism Hyperlipoproteinemia Hypercalcemia Drugs (e.g., thiazide diuretics) Genetic

Mechanical
Trauma Gallstones Iatrogenic injury
Perioperative injury Endoscopic procedures with dye injection

Etiologic Factors in Acute Pancreatitis

Vascular
Shock Atheroembolism Polyarteritis nodosa

Infectious
Mumps Coxsackievirus Mycoplasma pneumoniae

Three proposed pathways in the pathogenesis of acute pancreatitis.

Morphology
Microvascular leakage causing edema Necrosis of fat by lipolytic enzymes An acute inflammatory reaction Proteolytic destruction of pancreatic parenchyma Destruction of blood vessels with subsequent interstitial hemorrhage

Acute pancreatitis. A, The microscopic field shows a region of fat necrosis (right), and focal pancreatic parenchymal necrosis (center). B, The pancreas has been sectioned longitudinally to reveal dark areas of hemorrhage in the pancreatic substance and a focal area of pale fat necrosis in the peripancreatic fat (upper left).

Clinical Features
Abdominal pain is the cardinal manifestation of acute pancreatitis. The presence of elevated plasma levels of amylase and lipase The exclusion of other causes of abdominal pain
Ruptured acute appendicitis, perforated peptic ulcer, acute cholecystitis with rupture, and occlusion of mesenteric vessels with infarction of the bowel.

Chronic Pancreatitis
Inflammation of the pancreas with destruction of exocrine parenchyma, fibrosis The destruction of endocrine parenchyma The most common cause of chronic pancreatitis is long-term alcohol abuse, and these patients are usually middleaged males.

Pathogenesis
Ductal obstruction by concretions Toxic-metabolic Oxidative stress Necrosis-fibrosis

Morphology
Parenchymal fibrosis Reduced number and size of acini with relative sparing of the islets of Langerhans Variable dilation of the pancreatic ducts

Chronic pancreatitis. A, Extensive fibrosis and atrophy has left only residual islets (left) and ducts (right), with a sprinkling of chronic inflammatory cells and acinar tissue. B, A higher-power view demonstrating dilated ducts with inspissated eosinophilic ductal concretions in a patient with alcoholic chronic pancreatitis.

Clinical Features
Repeated attacks of moderately severe abdominal pain, recurrent attacks of mild pain, or persistent abdominal and back pain. Severe pancreatic exocrine insufficiency, diabetes mellitus Pancreatic pseudocysts

Summary
Acute pancreatitis is characterized by inflammation and reversible parenchymal damage with lesions ranging from focal edema and fat necrosis to widespread parenchymal necrosis and hemorrhage; clinical manifestations vary from mild abdominal pain to a rapidly fatal vascular collapse. Chronic pancreatitis is characterized by irreversible parenchymal damage and scar formation; clinical manifestations include chronic malabsorption (due to pancreatic exocrine insufficiency) and diabetes mellitus (due to islet cell loss).Both entities share similar pathogenic mechanism, and indeed recurrent acute pancreatitis can result in chronic pancreatitis. Ductal obstruction and alcohol are the most common causes of both forms. Inappropriate activation of pancreatic digestive enzymes (due to mutations in genes encoding trypsinogen or trypsin inhibitors) and primary acinar injury (due to toxins, infections, ischemia, or trauma) also cause pancreatitis.

Esophageal Carcinoma (For selfstudy)

Squamous cell carcinomas Adenocarcinomas Worldwide, squamous cell carcinomas constitute 90% of esophageal cancers, but in the United States there has been a very large increase (three- to fivefold in the last 40 years) in the incidence of adenocarcinomas associated with Barrett esophagus.

Squamous Cell Carcinoma

Mucosal epithelial dysplasia Carcinoma in situ Invasive cancer Polypoid exophytic masses that protrude into the lumen; Necrotizing cancerous ulcerations that extend deeply and sometimes erode into the respiratory tree, aorta, or elsewhere; Diffuse infiltrative neoplasms

A, Large ulcerated squamous cell carcinoma of the esophagus. B, Low power view of cancer invasion of the submucosa.

Adenocarcinoma
Barrett esophagus is the only recognized precursor of esophageal adenocarcinoma. Large nodular masses Deeply ulcerative Diffusely infiltrative features Mucin-producing glandular tumors

Clinical Features
Esophageal carcinoma is insidious in onset and produces dysphagia and obstruction gradually and late. Weight loss, anorexia, fatigue, and weakness appear, followed by pain, usually related to swallowing. Diagnosis is usually made by imaging techniques and endoscopic biopsy. Surgical excision is rarely curative. Esophageal cancer confined to the mucosa or submucosa is amenable to surgical treatment.

Gastric Carcinoma (For self-study)

The most important and the most common (90% to 95%) of malignant tumors of the stomach The second most common tumor in the world In most countries, there has been a steady decline in both the incidence and the mortality of gastric cancer over the past six decades.

Pathogenesis
Environmental Factors
Infection by H. pylori Present in most cases of intestinal-type carcinoma Diet Nitrites derived from nitrates (water, preserved food) Smoked and salted foods, pickled vegetables, chili peppers Lack of fresh fruit and vegetables Low socioeconomic status Cigarette smoking

Host Factors Chronic gastritis Intestinal metaplasia is a precursor lesion Hypochlorhydria: favors colonization with H. pylori Partial gastrectomy Favors reflux of bilious, alkaline intestinal fluid Gastric adenomas 40% harbor cancer at time of diagnosis 30% have adjacent cancer at time of diagnosis Barrett esophagus Increased risk of gastroesophageal junction tumors Genetic Factors Slightly increased risk with blood group A Family history of gastric cancer Hereditary nonpolyposis colon cancer syndrome Familial gastric carcinoma syndrome (E-cadherin mutation)

Morphology
The lesser curvature of the antropyloric region Classified on the basis
(1) depth of invasion (2) macroscopic growth pattern (3) histologic subtype

Growth Patterns of Gastric Carcinoma

Exophytic
Protrusion of a tumor mass into the lumen

Flat or depressed
There is no obvious tumor mass within the mucosa

Excavated
A shallow or deeply erosive crater is present in the wall of the stomach

Early Gastric Carcinoma

Defined as a lesion confined to the mucosa and submucosa, regardless of the presence or absence of perigastric lymph node metastases. is not synonymous with carcinoma in situ

Diagram of growth patterns and spread of gastric carcinoma. In early gastric carcinoma (A), the tumor is confined to the mucosa and submucosa and may exhibit an exophytic, flat or depressed, or excavated conformation.

Advanced Gastric Carcinoma

Neoplasm that has extended below the submucosa into the muscular wall and has perhaps spread more widely.

Diagram of growth patterns and spread of gastric carcinoma. Advanced gastric carcinoma (B) extends into the muscularis propria and beyond. Linitis plastica is an extreme form of flat or depressed advanced gastric carcinoma.

Here is a gastric adenocarcinoma. ALL gastric ulcers and ALL gastric masses must be biopsied, because it is not possible to tell from gross appearance alone which are benign and which are malignant.

Here is a gastric ulcer in the center of the picture. It is shallow and is about 2 to 4 cm in size. This ulcer on biopsy proved to be malignant, so the stomach was resected as shown here.

Here is a much larger 3 x 4 cm gastric ulcer that led to the resection of the stomach shown here. This ulcer is much deeper with more irregular margins.

Gastric carcinoma. Gross photograph showing an illdefined, excavated central ulcer surrounded by irregular, heaped-up borders.

Histologic Subtypes of Gastric Cancer

Papillary adenocarcinoma Tubular adenocarcinoma Mucinous adenocarcinoma Signet-ring cell carcinoma Undifferentiated carcinoma Adenosquamous carcinoma

Gastric cancer. A, H&E stain demonstrating intestinal type of gastric carcinoma with gland formation by malignant cells that are invading the muscular wall of the stomach. B, Diffuse type of gastric carcinoma with signetring tumor cells.

A moderately differentiated gastric adenocarcinoma is infiltrating up and into the submucosa below the squamous mucosa of the esophagus. The neoplastic glands are variably sized.

At higher magnification, the neoplastic glands of gastric adenocarcinoma demonstrate mitoses, increased nuclear/cytoplasmic ratios, and hyperchromatism. There is a desmoplastic stromal reaction to the infiltrating glands.

At high power, this gastric adenocarcinoma is so poorly differentiated that glands are not visible. Instead, rows of infiltrating neoplastic cells with marked pleomorphism are seen. Many of the neoplastic cells have clear vacuoles of mucin.

This is a signet ring cell pattern of adenocarcinoma in which the cells are filled with mucin vacuoles that push the nucleus to one side, as shown at the arrow.

Clinical Features
Asymptomatic until late in its course Weight loss, abdominal pain, anorexia, vomiting, altered bowel habits, and less frequently dysphagia, anemic symptoms, and hemorrhage. The prognosis for gastric carcinoma depends primarily on the depth of invasion and the extent of nodal and distant metastasis at the time of diagnosis. Spread

Tumors of The Colon and Rectum (For self-study)

One of the most common malignancies of Western countries There are an estimated 148,300 new cases per year and about 56,600 deaths. Virtually 98% of all cancers in the large intestine are adenocarcinomas

Etiology and Pathogenesis

The dietary factors Use of aspirin and other NSAIDs Obesity and physical inactivity as risk factors for colon cancer

Schematic of the morphologic and molecular changes in the adenoma-carcinoma sequence. It is postulated that loss of one normal copy of the tumor suppressor gatekeeper gene APC occurs early. Indeed, individuals may be born with one mutant allele of APC, rendering them extremely likely to develop colon cancer. This is the "first hit," according to Knudson's hypothesis. The loss of the normal copy of the APC gene follows ("second hit"). Mutations of the oncogene K-RAS seem to occur next. Additional mutations or losses of heterozygosity inactivate the tumor suppressor gene p53 (on chromosome 17p) and SMAD2 and SMAD4 on chromosome 18q, leading finally to the emergence of carcinoma, in which additional mutations occur. It is important to note that while there seems to be a temporal sequence of changes, as shown, the accumulation of mutations, rather than their occurrence in a specific order, is more important.

Morphology
Cecum/ascending colon, 22%; transverse colon, 11%; descending colon, 6%; rectosigmoid colon, 55%; and other sites, 6%. Invasive tumor incites a strong desmoplastic stromal response Signet-ring appearance

Carcinoma of the cecum. The fungating carcinoma projects into the lumen but has not caused obstruction.

Carcinoma of the descending colon. This circumferential tumor has heaped-up edges and an ulcerated central portion. The arrows identify separate mucosal polyps.

Invasive adenocarcinoma of colon, showing malignant glands infiltrating the muscle wall.

Clinical Features
The appearance of fatigue, weakness, and iron-deficiency anemia Producing occult bleeding, changes in bowel habit, or crampy left lower quadrant discomfort All colorectal tumors spread by direct extension into adjacent structures and by metastasis through the lymphatics and blood vessels.

TNM Stage of CRC

The single most important prognostic indicator of colorectal carcinoma is the extent of the tumor at the time of diagnosis, the so-called stage.

Pathologic staging of colorectal cancer. Staging is based on the depth of tumor invasion.

Polyps
Non-Neoplastic Polyps Adenomatous polyps
Tubular adenomas: tubular glands Villous adenomas: villous projections Tubulovillous adenoma: a mixture of the above.

Familial adenomatous polyposis (FAP)

Diagrammatic representation of two forms of sessile polyp (hyperplastic polyp and adenoma) and of two types of adenoma (pedunculated and sessile). There is only a loose association between the tubular architecture for pedunculated adenomas and the villous architecture for sessile adenomas.

Non-neoplastic colonic polyps. A, Hyperplastic polyp; highpower view showing the serrated profile of the epithelial layer.

Non-neoplastic colonic polyps. B, Peutz-Jeghers polyp; low-power view showing the splaying of smooth muscle into the superficial portion of the pedunculated polyp.

Here are multiple adenomatous polyps of the cecum. A small portion of terminal ileum appears at the right.

Familial adenomatous polyposis in an 18-year-old woman. The mucosal surface is carpeted by innumerable polypoid adenomas.

The barium enema technique instills the radiopaque barium sulfate into the colon, producing a contrast with the wall of the colon that highlights any masses present. In this case, the classic "apple core" lesion is present, representing an encircling adenocarcinoma that constricts the lumen.

This CT image of the abdomen demonstrates an encircling mass involving the colon. This is a colonic adenocarcinoma.

Hepatocellular Carcinomas (For self-study)

More than 85% of cases of HCC occur in countries with high rates of chronic HBV infection
Viral infection (HBV, HCV) Chronic alcoholism Food contaminants (primarily aflatoxins) Tyrosinemia Hereditary hemochromatosis

Morphology
A unifocal (usually large) mass Multifocal, widely distributed nodules of variable size A diffusely infiltrative cancer All three patterns may cause liver enlargement, particularly the unifocal massive and multinodular patterns. The diffusely infiltrative tumor may blend imperceptibly into a cirrhotic liver background.

Morphology
Hepatocellular carcinomas range from well-differentiated to highly anaplastic undifferentiated lesions. All patterns of hepatocellular carcinomas have a strong propensity for invasion of vascular channels.

Hepatocellular carcinoma. A, Autopsied liver showing a unifocal, massive neoplasm replacing most of the right hepatic lobe in a noncirrhotic liver; a satellite tumor nodule is directly adjacent. B, In this microscopic view of a welldifferentiated lesion, tumor cells are arranged in nests, sometimes with a central lumen, one of which contains bile (arrow). Other tumor cells contain intracellular bile pigment.

Fibrolamellar Carcinoma
A distinctive variant of hepatocellular carcinoma Occurs in young male and female adults No association with HBV or cirrhosis risk factors Has a better prognosis

Fibrolamellar carcinoma. A, Resected specimen showing a demarcated nodule in an otherwise normal liver. B, Microscopic view showing nests and cords of malignantappearing hepatocytes separated by dense bundles of collagen.

Prognosis of HCC
It is significantly better for individuals who have a single tumor less than 2 cm in diameter and good liver function. Early detection of the tumors is critical for successful treatment.
Profound cachexia Gastrointestinal or esophageal variceal bleeding Liver failure with hepatic coma Rupture of the tumor with fatal hemorrhage

Pancreatic Carcinoma (For self-study)

Pancreatic carcinoma is near the top of the list among lethal cancers because it has one of the highest mortality rates. Carcinomas of the pancreas typically remain silent until their extension impinges on some other structure. Weight loss, anorexia, and generalized malaise and weakness are signs of advanced disease.

Carcinoma of the pancreas. A, A cross-section through the head of the pancreas and adjacent common bile duct showing both an ill-defined mass in the pancreatic substance (arrowheads) and the green discoloration of the duct resulting from total obstruction of bile flow. B, Poorly formed glands are present in a densely fibrotic (desmoplastic) stroma within the pancreatic substance.

For Advanced Reading

Robbins Basic Pathology, 8ed, Kumar et al. 2001 Pathologic Basis of Disease (Basic Pathology), 7ed Kumar et al. http://library.med.utah.edu/WebPath/webp ath.html#MENU http://10.171.121.151/pathology