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hernia in 98% of cases. The condition is diagnosed radiologically in about 5% of apparently normal asymptomatic individuals. In symptomatic cases, especially the elderly women, the clinical features are heartburn (retrosternal burning sensation) and regurgitation of gastric juice into the mouth, both of which are worsened due to heavy work, lifting weights and excessive bending.

ETIOLOGY. The basic defect is the failure of the muscle fibres of the diaphragm that form the margin of the oesophageal hiatus. This occurs due to shortening of the oesophagus which may be congenital or acquired.

Congenitally short oesophagus may be the cause of hiatus hernia in a small proportion of cases.

More commonly, it is acquired due to secondary factors which cause fibrous scarring of the oesophagus as follows:

a)Degeneration of muscle due to aging.

b)Increased intra-abdominal pressure such as in pregnancy, abdominal tumours etc.

c)Recurrent oesophageal regurgitation and spasm causing inflammation and fibrosis.

d)Increase in fatty tissue in obese people causing decreased muscular elasticity of diaphragm.

MORPHOLOGIC FEATURES. There are 3 patterns in hiatus hernia (Fig. 20.1):

i)Sliding or oesophago-gastric hernia is the most common, occurring in 85% of cases. The herniated part of the stomach appears as supradiaphragmatic bell due to sliding up on both sides of the oesophagus.

ii)Rolling or para-oesophageal hernia is seen in 10% of cases. This is a true hernia in which cardiac end of the stomach rolls up para-oesophageally, producing an intrathoracic sac.

iii)Mixed or transitional hernia constitutes the remaining 5% cases in which there is combination of sliding and rolling hiatus hernia.

Oesophageal Diverticula

Diverticula are the outpouchings of oesophageal wall at the point of weakness. They may be congenital or acquired.

Figure 20.1 Patterns of hiatus hernia.

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540 the longitudinal axis of oesophagus. They occur as a result of elevated pressure in the portal venous system, most commonly in cirrhosis of the liver (Chapter 22). Less common causes are: portal vein thrombosis, hepatic vein thrombosis (Budd-Chiari syndrome) and pylephlebitis. The lesions occur as a result of bypassing of portal venous blood from the liver to the oesophageal venous plexus. The increased venous pressure in the superficial veins of the oesophagus may result in ulceration and massive bleeding.

2. MALLORY-WEISS SYNDROME. In this condition, there is lacerations of mucosa at the gastro-oesophageal junction following minor trauma such as by vomiting, retching or vigorous coughing. Patients present with upper gastro-oesophageal bleeding.

3. RUPTURE OF THE OESOPHAGUS. Rupture of the oesophagus may occur following trauma, during oesophagoscopy, indirect injury (e.g. due to sudden acceleration and deceleration of the body) and spontaneous rupture (e.g. after overeating, extensive aerophagy etc).

PATHOGENESIS. Gastro-oesophageal reflux, to an extent, may occur in normal healthy individuals after meals and in early pregnancy. However, in some clinical conditions, the gastro-oesophageal reflux is excessive, resulting in inflammation of the lower oesophagus. These conditions are as under:

i)Sliding hiatus hernia

ii)Chronic gastric and duodenal ulcers

iii)Nasogastric intubation

iv)Persistent vomiting

v)Surgical vagotomy

vi)Neuropathy in alcoholics, diabetics

vii)Oesophagogastrostomy.

MORPHOLOGIC FEATURES. Endoscopically, the demarcation between normal squamous and columnar epithelium at the junctional mucosa is lost. The affected distal oesophageal mucosa is red, erythematous, friable and bleeds on touch. In advanced cases, there are features

of chronic disease such as nodularity, strictures, ulcerations and erosions.

Microscopically, the reflux changes in the distal oesophagus include basal cell hyperplasia and deep elongation of the papillae touching close to the surface epithelium. Inflammatory changes vary according to the stage of the disease. In early stage, mucosa and submucosa are infiltrated by some polymorphs and eosinophils; in chronic stage, there is lymphocytic infiltration and fibrosis of all the layers of the oesophageal wall.

Barrett’s Oesophagus

This is a condition in which, following reflux oesophagitis, stratified squamous epithelium of the lower oesophagus is replaced by columnar epithelium (columnar metaplasia). The condition is seen more commonly in later age and is caused by factors producing gastro-oesophageal reflux disease (described above). Barrett’s oesophagus is a premalignant condition evolving sequentially from Barrett’s epithelium (columnar metaplasia) → dysplasia → carcinoma in situ → oesophageal adenocarcinoma.

MORPHOLOGIC FEATURES. Endoscopically, the affected area is red and velvety. Hiatus hernia and peptic ulcer at squamocolumnar junction (Barrett’s ulcer) are frequently associated.

Microscopically, the most common finding is the replacement of squamous epithelium by metaplastic columnar cells. Barrett’s oesophagus may be composed of intestinal epithelium, fundic gastric glands, or cardiac mucous glands. Other cells present in the glands may be Paneth cells (Fig. 20.3), goblet cells, chief cells, parietal cells, mucus-secreting cells and endocrine cells.

Inflammatory changes, acute or chronic, are commonly accompanied. Dysplastic changes of the columnar epithelium or glands may be present.

Surveillance endoscopic biopsies are advised because Barrett’s intestinal metaplasaia may develop dysplasia.

Figure 20.3 Barrett’s oesophagus. Part of the oesophagus which is normally lined by squamous epithelium undergoes metaplastic change to columnar epithelium of intestinal type.

High-grade dysplasia may progress to invasive adenocarcinoma of the oesophagus in up to 20% cases.

Infectious Oesophagitis

A number of opportunistic infections in immunosuppressed individuals can cause oesophagitis. Some of these agents are as follows:

i)Candida (Monilial) oesophagitis

ii)Herpes simplex (Herpetic) oesophagitis

iii)Cytomegalovirus

iv)Tuberculosis.

Other Causes of Oesophagitis

i)Eosinophilic oesophagitis caused by radiation, corrosives

ii)Intake of certain drugs (anticholinergic drugs, doxycycline, tetracycline)

iii)Ingestion of hot, irritating fluids

iv)Crohn’s disease

v)Various vesiculobullous skin diseases.

TUMOURS OF OESOPHAGUS

Benign tumours of the oesophagus are uncommon and small in size (less than 3 cm). The epithelial benign tumours project as intraluminal masses arising from squamous epithelium (squamous cell papilloma), or from columnar epithelium (adenoma). The stromal or mesenchymal benign tumours are intramural masses such as leiomyoma and others like lipoma, fibroma, neurofibroma, rhabdomyoma, lymphangioma and haemangioma.

For all practical purposes, malignant tumours of the oesophagus are carcinomas because sarcomas such as leiomyosarcoma and fibrosarcoma occur with extreme rarity.

Carcinoma of Oesophagus

Carcinoma of the oesophagus is diagnosed late, after symptomatic oesophageal obstruction (dysphagia) has developed and the tumour has transgressed the anatomical limits of the organ. The tumour occurs more commonly in

men over 50 years of age. Prognosis is dismal: with standard methods of therapy (surgical resection and/or irradiation), 70% of the patients die within one year of diagnosis. Fiveyear survival rate is 5-10%.

ETIOLOGY. Although exact etiology of carcinoma of the oesophagus is not known, a number of conditions and factors have been implicated as under:

1. Diet and personal habits:

i)Heavy smoking

ii)Alcohol consumption

iii)Intake of foods contaminated with fungus

iv)Nutritional deficiency of vitamins and trace elements.

2. Oesophageal disorders:

i)Oesophagitis (especially Barrett’s oesophagus in adenocarcinoma)

ii)Achalasia

iii)Hiatus hernia

iv)Diverticula

v)Plummer-Vinson syndrome.

3. Other factors:

i)Race—more common in the Chinese and Japanese than in Western races; more frequent in blacks than whites.

ii)Family history—association with tylosis (keratosis palmaris et plantaris).

iii)Genetic factors—predisposition with coeliac disease, epidermolysis bullosa, tylosis.

iv)HPV infection—is the recent addition in etiologic factors.

At molecular level, abnormality of p53 tumour suppressor gene has been found associated with a number of above risk factors, notably with consumption of tobacco and alcohol, and in cases having proven Barrett’s oesophagus.

MORPHOLOGIC FEATURES. Carcinoma of the oesophagus is mainly of 2 types—squamous cell (epidermoid) and adenocarcinoma. The sites of predilection for each of these 2 forms is shown in Fig. 20.4,A.

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v)Carcinosarcoma consists of malignant epithelial as well as sarcomatous components.

vi)Secondary tumours rarely occur in the oesophagus from carcinomas of the breast, kidney and adrenals.

SPREAD. The oesophageal cancer spreads locally as well as to distant sites.

i)Local spread. This is the most important mode of spread and is of great importance for surgical treatment. The local spread may occur in the transverse as well as longitudinal direction. The tumour may invade below into the stomach, above into the hypopharynx, into the trachea resulting in tracheo-oesophageal fistula, and may involve larynx causing hoarseness. The tumour may invade the muscular wall of the oesophagus and involve the mediastinum, lungs, bronchi, pleura and aorta.

ii)Lymphatic spread. Submucosal lymphatic permeation may lead to multiple satellite nodules away from the main tumour. Besides, the lymphatic spread may result in metastases to the cervical, para-oesophageal, tracheobronchial and subdiaphragmatic lymph nodes.

iii)Haematogenous spread. Blood-borne metastases from the oesophageal cancer are rare, probably because the death occurs early due to invasion of important structures by other modes of spread. However, metastatic deposits by haematogenous route can occur in the lungs, liver and adrenals.

STOMACH

NORMAL STRUCTURE

The stomach is ‘gland with cavity’, extending from its junction with lower end of the oesophagus (cardia) to its junction with the duodenum (pylorus). The lesser curvature

is inner concavity on the right, while the greater curvature is the outer convexity on the left side of the stomach.

The stomach has 5 anatomical regions (Fig. 20.6):

1.Cardia is the oesophagogastric junction and lacks the sphincter.

2.Fundus is the portion above the horizontal line drawn across the oesophagogastric junction.

3.Body is the middle portion of the stomach between the fundus and the pyloric antrum.

4.Pyloric antrum is the distal third of the stomach.

5.Pylorus is the junction of distal end of the stomach with the duodenum. It has powerful sphincter muscle.

The mucosal folds in the region of the body and the fundus are loose (rugae), while the antral mucosa is somewhat flattened. Gastric canal is the relatively fixed portion of the pyloric antrum and the adjoining lesser curvature; it is the site for numerous pathological changes such as gastritis, peptic ulcer and gastric carcinoma.

The stomach receives its blood supply from the left gastric artery and the branches of the hepatic and splenic arteries with widespread anastomoses. Numerous gastric lymphatics which communicate freely with each other are also present. The innervation of the stomach is by the vagi and branches of the sympathetic which are connected with ganglia in the muscular and submucous layers.

Histologically, the wall of the stomach consists of 4 layers— serosa, muscularis, submucosa and mucosa.

1.Serosa is derived from the peritoneum which is deficient in the region of lesser and greater curvatures.

2.Muscularis consists of 3 layers of smooth muscle fibres— the outer longitudinal, the middle circular and the inner oblique. Nerve plexuses and ganglion cells are present between the longitudinal and circular layers of muscle. The pyloric sphincter is the thickened circular muscle layer at the gastroduodenal junction.

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5443. Submucosa is a layer of loose fibroconnective tissue binding the mucosa to the muscularis loosely and contains branches of blood vessels, lymphatics and nerve plexuses and ganglion cells.

4. Mucosa consists of 2 layers—superficial and deep. Between the two layers is the lamina propria composed of network of fibrocollagenic tissue with a few lymphocytes, plasma cells, macrophages and eosinophils. The mucosa is externally bounded by muscularis mucosae:

i) Superficial layer. It consists of a single layer of surface epithelium composed of regular, mucin-secreting, tall columnar cells with basal nuclei. There is a very rapid turnover of these cells. These dip down at places to form crypts (or pits or foveolae).

Cardiac mucosa is the transition zone between the oesophageal squamous mucosa and the oxyntic mucosa of the fundus and body with which it gradually merges.

Oxyntic mucosa lines both gastric fundus and body.

Antral mucosa lines the pyloric antrum.

ii) Deep layer: It consists of glands that open into the bottom of the crypts. Depending upon the structure, these glands are of 3 types:

Hydrochloric acid is produced by the parietal (oxyntic) cells by the interaction of Cl’ ions of the arterial blood with water and carbon dioxide in the presence of the enzyme, carbonic anhydrase. The degree of gastric activity is correlated with the ‘total parietal cell mass’. Injection of histamine can stimulate the production of acid component of the gastric juice, while the pepsin-secreting chief cells do not respond to histamine. Physiologically, the gastric secretions are stimulated by the food itself.

The control of gastric secretions chiefly occurs in one of the following 3 ways:

1.Cephalic phase—is stimulated by the sight, smell, taste or even thought of food. A neural reflex is initiated via branches of the vagus nerve that promotes the release of hydrochloric acid, pepsinogen and mucus.

2.Gastric phase—is triggered by the mechanical and chemical stimuli.

i)Mechanical stimulation comes from stretching of the wall of the stomach and conveying neural messages to the medulla for gastric secretion.

ii)Chemical stimulation is by digested proteins, amino acids, bile salts and alcohol which act on gastrin-producing G cells. Gastrin then passes into the blood stream and on return to the stomach promotes the release of gastric juice.

3. Intestinal phase—is triggered by the entry of proteinrich food in the small intestine. An intestinal hormone capable of stimulating gastric secretion is probably released into the blood stream.

GASTRIC ANALYSIS

In various diseases of the stomach, the laboratory tests to measure gastric secretions (consisting of gastric acid, pepsin, mucus and intrinsic factor) and serum gastrin are of particular significance (Table 20.1).

A.TESTS FOR GASTRIC SECRETIONS

1.Tests for Gastric Acid Secretions

The conventional fractional test meal (FTM) has been totally superseded by newer tests. These tests are based on the

TABLE 20.1: Gastric Analysis.

A.TESTS FOR GASTRIC SECRETIONS

1.Tests for gastric acid secretions

i)Histamine stimulation

ii)Histalog stimulation

iii)Pentagastrin (peptavlon) stimulation

iv)Insulin meal (Hollander test)

v)Tubeless analysis

2.Tests for pepsin

Pepsin inhibitors

3.Tests for mucus

Protein content of mucus

4.Tests for intrinsic factor

B.TESTS FOR GASTRIN

1.Serum gastrin

2.Gastrin provocation tests

i)Secretin test

ii)Calcium infusion test

principle of measuring basal acid output (BAO) and maximal acid output (MAO) produced by the stomach under the influence of a variety of stimulants, and then comparing the readings of BAO and MAO with the normal values.

Quantitative analysis is performed after an overnight fast. The stomach is intubated and gastric secretion collected in 4 consecutive 15-minute intervals. This unstimulated, one-hour collection after titration for the acid concentration in it, is called BAO, expressed in mEq 1-hour. Subsequently, the stomach is stimulated to secrete maximal acid which is similarly collected for one hour and the acid content called as MAO, expressed in mEq-1-hour. Two highest 15-minute acid outputs are added and then multiplied by 2; this gives the peak acid output (PAO).

The tests for gastric acid secretion are named after the stimulants used for MAO. Some of the commonly used substances are as under:

i)HISTAMINE. Histamine was the first standard stimulant used for gastric acid secretion test. Subcutaneous injection of histamine phosphate (0.04 mg/kg body weight) is given with simultaneous administration of antihistaminic agent to prevent the untoward side-effects of histamine.

ii)HISTALOG (BETAZOLE). Subcutaneous injection of histalog (1-15 mg/kg body weight) is preferable over histamine due to fewer undesired side-effects and no need for administration of antihistaminic agent.

iii)PENTAGASTRIN (PEPTAVLON). Pentagastrin is currently the most preferred agent administered in the dose of 6 μg/kg body weight. Its activity is similar to gastrin.

iv)INSULIN MEAL (HOLLANDER TEST). This test is based on the fact that in a state of hypoglycaemia, direct vagal action on the parietal cell mass is responsible for acid secretion. Hypoglycaemia induced by intravenous insulin (15 IU soluble insulin) can be used as a test for evaluating the completeness of vagotomy. No increase in acid production should occur if the vagal resection is complete.

v)TUBELESS ANALYSIS. A resin-bound dye, diagnex blue, is given orally. The release of dye by the action of gastric acid and its appearance in the urine indicates the presence of gastric acid. The test can be repeated after giving stimulant of gastric secretion.

SIGNIFICANCE

Normal value for BAO is 1.5-2.0 mEq 1-hour and for MAO is 12-40 mEq 1-hour. In gastric ulcer, the values of BAO and MAO are usually normal or slightly below normal.

Higher values are found in:

duodenal ulcer;

Zollinger-Ellison syndrome (gastrinoma); and

anastomotic ulcer.

Low value or achlorhydria are observed in:

pernicious anaemia (atrophic gastritis); and achlorhydria in the presence of gastric ulcer is highly

suggestive of gastric malignancy.

2. Tests for Pepsin

Pepsin inhibitors are used for analysis of pepsin derived from pepsinogen for research purposes. The levels of pepsin are low in atrophic gastritis.

3. Tests for Mucus

Protein content of gastric mucus is measured, normal value being 1.8 mg/ml. The level is increased in chronic hypertrophic gastritis (Ménétrier’s disease).

4. Test for Intrinsic Factor

Intrinsic factor (IF) is essential for vitamin B12 absorption from the small intestine. In its absence, the absorption of vitamin B12 is impaired as occurs in chronic atrophic gastritis and gastric atrophy. Schilling test is used for evaluation of patients with suspected pernicious anaemia but can also be used as a diagnostic test for pancreatic insufficiency resulting in impaired absorption of vitamin B12 since gastric R-binder protein is not cleared from intrinsic factor due to reduced pancreatic proteolytic activity. Schilling test is discussed on page 308.

B. TESTS FOR GASTRIN

Circulating gastrin secreted by G-cells present in the antropyloric and proximal duodenal mucosa is normally 0-200 pg/ml. It can be tested by the following methods:

1. Serum Gastrin Levels

Radioimmunoassay (RIA) is the commonly used method of measurement of serum gastrin levels. Normal fasting values are 20-150 pg/ml. The levels are high in:

atrophic gastritis (with low gastric acid secretion);

Zollinger-Ellison syndrome or gastrinoma (with high gastric acid secretion); and

following surgery on the stomach.

2. Gastrin Provocation Tests

These tests are used to differentiate between hypergastrinaemia and gastric acid hypersecretion as follows:

i)SECRETIN TEST. An intravenous injection of secretin (1 unit/kg body weight) is given. If the serum gastrin levels rise by more than 50% of basal value in 5-15 minutes, it is diagnostic of Zollinger-Ellison syndrome (gastrinoma). This rise does not occur in other conditions.

ii)CALCIUM INFUSION TEST. Intravenous infusion of calcium (5 mg/kg per hour) is given for 3 hour. Rise in serum gastrin levels by more than 50% of basal value is diagnostic of Zollinger-Ellison syndrome (gastrinoma).

CONGENITAL ANOMALIES

Pancreatic Heterotopia

Heterotopic pancreatic tissue may present clinically as a gastric mass or may be an incidental finding. Symptomatic cases may present in newborn or later in life.

Grossly, it is seen as a mass projecting into the gastric lumen, generally in the region of submucosa and less often in the muscular layer. In most cases, the mass is located in the region of antrum or pylorus.

Microscopically, both normal mature pancreatic acinar and ductal tissue are seen. Islets are seen in about a third of cases.

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MISCELLANEOUS ACQUIRED CONDITIONS

Bezoars

Bezoars are foreign bodies in the stomach, usually in patients with mental illness who chew these substances. Some of the common bezoars are as follows:

Trichobezoars composed of a ball of hair.

Phytobezoars composed of vegetable fibres, seeds or fruit skin.

Trichophytobezoars combining both hair and vegetable matter.

Acute Dilatation

Sudden and enormous dilatation of the stomach by gas or fluids due to paralysis of the gastric musculature may occur after abdominal operations, generalised peritonitis, and, in pyloric stenosis.

Gastric Rupture

The stomach may rupture rarely and prove fatal e.g. due to blunt trauma, external cardiac massage, ingestion of heavy meal or large quantity of liquid intake like beer.

INFLAMMATORY CONDITIONS

The two important inflammatory conditions of the stomach are gastritis and peptic ulcer. Rarely, stomach may be involved in tuberculosis, sarcoidosis and Crohn’s disease.

GASTRITIS

The term ‘gastritis’ is commonly employed for any clinical condition with upper abdominal discomfort like indigestion or dyspepsia in which the specific clinical signs and radiological abnormalities are absent. The condition is of great importance due to its relationship with peptic ulcer and gastric cancer. Broadly speaking, gastritis may be of 2 types—acute and chronic. Chronic gastritis can further be of various types.

A simple classification of various types of gastritis is presented in Table 20.2.

Acute Gastritis

Acute gastritis is a transient acute inflammatory involvement of the stomach, mainly mucosa.

ETIOPATHOGENESIS. A variety of etiologic agents have been implicated in the causation of acute gastritis. These are as follows:

1. Diet and personal habits:

Highly spiced food

Excessive alcohol consumption

Malnutrition

Heavy smoking.

2. Infections:

Bacterial infections e.g. Helicobacter pylori, diphtheria, salmonellosis, pneumonia, staphylococcal food poisoning.

TABLE 20.2: Classification of Gastritis.

A.ACUTE GASTRITIS

1. Acute H. pylori gastritis

2. Other acute infective gastritis (bacteria, viruses, fungi, parasites)

3. Acute non-infective gastritis

B.CHRONIC GASTRITIS

Viral infections e.g. viral hepatitis, influenza, infectious mononucleosis.

3. Drugs:

Intake of drugs like non-steroidal anti-inflammatory drugs (NSAIDs), aspirin, cortisone, phenylbutazone, indomethacin, preparations of iron, chemotherapeutic agents.

4. Chemical and physical agents:

Intake of corrosive chemicals such as caustic soda, phenol, lysol

Gastric irradiation

Freezing.

5. Severe stress:

Emotional factors like shock, anger, resentment etc.

Extensive burns

Trauma

Surgery.

The mucosal injury and subsequent acute inflammation in acute gastritis occurs by one of the following mechanisms:

1.Reduced blood flow, resulting in mucosal hypoperfusion due to ischaemia.

2.Increased acid secretion and its accumulation due to H. pylori infection resulting in damage to epithelial barrier.

3.Decreased production of bicarbonate buffer.

MORPHOLOGIC FEATURES. Grossly, the gastric mucosa is oedematous with abundant mucus and haemorrhagic spots.

Microscopically, depending upon the stage, there is variable amount of oedema and infiltration by neutrophils in the lamina propria. In acute haemorrhagic and erosive gastritis, the mucosa is sloughed off and there are haemorrhages on the surface.

Chronic Gastritis

Chronic gastritis is the commonest histological change observed in biopsies from the stomach. The microscopic change is usually poorly correlated to the symptomatology, as the change is observed in about 35% of endoscopically normal mucosal biopsies. The condition occurs more frequently with advancing age; average age for symptomatic chronic gastritis being 45 years which corresponds well with the age incidence of gastric ulcer.

ETIOPATHOGENESIS. In the absence of clear etiology of chronic gastritis, a number of etiologic factors have been implicated. All the causative factors of acute gastritis described above may result in chronic gastritis too. Recurrent attacks of acute gastritis may result in chronic gastritis. Some additional causes are as under:

1.Reflux of duodenal contents into the stomach, especially in cases which have undergone surgical intervention in the region of pylorus.

2.Infection with H. pylori is strongly implicated in the etiology of chronic gastritis and is more common.

3.Associated disease of the stomach and duodenum, such as gastric or duodenal ulcer, gastric carcinoma.

4.Chronic hypochromic anaemia, especially associated with atrophic gastritis.

5.Immunological factors such as autoantibodies to gastric parietal cells in atrophic gastritis and autoantibodies against intrinsic factor.

The mechanism of chronic gastric injury by any of the etiologic agents is by cytotoxic effect of the injurious agent on the gastric mucosal epithelium, thus breaking the barrier and then inciting the inflammatory response.

CLASSIFICATION. Based on the type of mucosa affected (i.e. cardiac, body, pyloric, antral or transitional), a clinicopathologic classification has been proposed

(Table 20.2).

1.Type A gastritis (Autoimmune gastritis). Type A gastritis involves mainly the body-fundic mucosa. It is also called autoimmune gastritis due to the presence of circulating antibodies and is sometimes associated with other autoimmune diseases such as Hashimoto’s thyroiditis and Addison’s disease. As a result of the antibodies against parietal cells and intrinsic factor, there is depletion of parietal cells and impaired secretion of intrinsic factor. These changes may lead to significant gastric atrophy where intestinal metaplasia may occur, and a small proportion of these patients may develop pernicious anaemia. Due to depletion of gastric acid-producing mucosal area, there is hypoor achlorhydria, and hyperplasia of gastrin-producing G cells in the antrum resulting in hypergastrinaemia.

2.Type B gastritis (H. pylori-related). Type B gastritis mainly involves the region of antral mucosa and is more common. It is also called hypersecretory gastritis due to excessive secretion of acid, commonly due to infection with H. pylori. These patients may have associated peptic ulcer. Unlike type A gastritis, this form of gastritis has no autoimmune basis nor has association with other autoimmune diseases.

3.Type AB gastritis (Mixed gastritis, Environmental gastritis, Chronic atrophic gastritis). Type AB gastritis affects the mucosal region of A as well as B types (body-fundic and antral mucosa). This is the most common type of gastritis in all age groups. It is also called environmental gastritis because a number of unidentified environmental factors have been implicated in its etiopathogenesis. Chronic atrophic gastritis is also used synonymously with type AB gastritis because in advanced stage, there is progression from chronic superficial gastritis to chronic atrophic gastritis, characterised by mucosal atrophy and metaplasia of intestinal or pseudopyloric type.

MORPHOLOGIC FEATURES. Grossly, the features of all forms of gastritis are inconclusive. The gastric mucosa may be normal, atrophied, or oedematous.

Histologically, criteria for categorisation are based on the following:

i) Extent of inflammatory changes in the mucosa (i.e. superficial or deep).

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ii)Activity of inflammation (i.e. quiscent or active; acute or chronic).

iii)Presence of and type of metaplasia (i.e. intestinal or pseudopyloric).

Based on above, following simple morphologic classification has been proposed:

1.Chronic superficial gastritis

2.Chronic atrophic gastritis

3.Gastric atrophy

4.Chronic hypertrophic gastritis (Ménétrier’s disease)

5.Uncommon forms of chronic gastritis.

However, Sydney system of recording of histologic changes in gastritis is more acceptable since it takes into account following multiple parameters as well:

i)Etiology (H. pylori, autoimmune, NSAIDs, infections).

ii)Location (pangastritis, predominant antral, predominant body-fundic).

iii)Morphology (depth of inflammation—superficial or deep, severity of inflammation, type of inflammation, atrophy, metaplasia).

iv)Some special features (e.g. granulomas, eosinophilic gastritis, erosions, necrosis, haemorrhages).

1.CHRONIC SUPERFICIAL GASTRITIS. As the name suggests there is inflammatory infiltrate consisting of plasma cells and lymphocytes in the superficial layer of the gastric mucosa, but there are no histological changes in the deep layer of mucosa containing gastric glands. Chronic superficial gastritis may resolve completely or may progress to chronic gastric atrophy.

H. pylori, a spiral-shaped bacteria, was first reported by Warren and Marshall in Australia in 1984 as inhabitant of the acid environment of the stomach causing gastritis. After intial skepticism, numerous workers subsequently verified its association with gastritis and peptic ulcer (Warren and Marshall shared Nobel Prize in medicine in 2005 for their discovery). It is now known that H. pylori is

causative for almost all active cases of chronic superficial gastritis and about 65% of quiscent cases. The organism is identified on the epithelial layer on the luminal surface and does not invade the mucosa (Fig. 20.8). It is not seen on areas with intestinal metaplasia. H. pylori gastritis can be diagnosed by the following techniques:

i) Invasive tests (Endoscopic biopsy):

a)histologic examination combined with special stains for identification of microorganism: Giemsa, Steiner silver or Warthin-Starry stains;

b)biopsy urease test which is quick and simple but not fully sensitive; and

c)culture of the microorganism that helps in determining

specific antibiotic sensitivity.

ii)Non-invasive tests:

a)serologic tests (Immunoblot, ELISA) which are cheap and convenient but may not be helpful in early follow-up cases; and

b)14C urea breath test.

Although most patients of chronic superficial gastritis due to H. pylori remain asymptomatic, they may develop chronic atrophic gastritis, gastric atrophy, peptic ulcer disease. H. pylori infection is now considered an independent risk factor for gastric cancer: 3-6 fold increased risk for gastric adenocarcinoma and 6-50 times risk of MALT lymphoma (Fig. 20.9).

2. CHRONIC ATROPHIC GASTRITIS. In this stage, there is inflammatory cell infiltrate in the deeper layer of the

mucosa and atrophy of the epithelial elements including destruction of the glands. Two types of metaplasia are commonly associated with atrophic gastritis:

i) Intestinal metaplasia. Intestinal metaplasia is more common and involves antral mucosa more frequently. Characteristic histologic feature is the presence of intestinal type mucus-goblet cells; Paneth cells and endocrine cells may also be present. Parietal cells are very

Figure 20.9 Consequences of long-term H. pylori gastritis.

few or absent (Fig. 20.10). Intestinal metaplasia, focal or extensive, in atrophic gastritis is significant because its incidence is high in populations having high prevalence rate of gastric cancer like in Japan. However, areas of intestinal metaplasia are not colonised by H. pylori.

ii) Pseudopyloric metaplasia. It involves the body glands which are replaced by proliferated mucus neck cells, conforming in appearance to normal pyloric glands. Its significance is not known.

3.GASTRIC ATROPHY. In this, there is thinning of the gastric mucosa with loss of glands but no inflammation though lymphoid aggregates may be present.

4.CHRONIC HYPERTROPHIC GASTRITIS (MÉNÉTRIER’S DISEASE). This is an uncommon condition characterised pathologically by enormous thickening of gastric rugal folds resembling cerebral convolutions, affecting mainly the region of fundic-body mucosa and characteristically sparing antral mucosa. The patients present with dyspepsia, haematemesis, melaena or protein-losing enteropathy.

Histologically, the gastric pits are elongated and are tortuous. The mucosa is markedly thickened and parts of

muscularis mucosae may extend into the thickened folds. Epithelium-lined cysts are commonly seen in the glandular layer. Inflammatory infiltrate is usually mild but lymphoid follicles may be present. The condition is considered significant in view of the risk of developing cancer.

5. MISCELLANEOUS FORMS OF CHRONIC GASTRITIS. A few other types of gastritis which do not fit into the description of the types of gastritis described above are as under:

i) Eosinophilic gastritis. This condition is characterised by diffuse thickening of the pyloric antrum due to oedema and extensive infiltration by eosinophils in all the layers of the wall of antrum. Eosinophilic gastritis probably has an allergic basis.

iii)Chronic follicular gastritis. This is a variant of chronic atrophic gastritis in which numerous lymphoid follicles are present in the mucosa and submucosa of the stomach.

iv)Haemorrhagic (Erosive) gastritis. In this condition, there are superficial erosions and mucosal haemorrhages, usually following severe haematemesis. The causes for such erosions and haemorrhages are duodenal-gastric reflux, administration of non-steroidal anti-inflammatory drugs (NSAIDs), portal hypertension.

v)Granulomatous gastritis. Rarely, granulomas may be present in the gastric mucosa such as in tuberculosis, sarcoidosis, Crohn’s disease, syphilis, various mycoses, and as a reaction to endogenous substance or foreign material.

PEPTIC ULCERS

Peptic ulcers are the areas of degeneration and necrosis of gastrointestinal mucosa exposed to acid-peptic secretions. Though they can occur at any level of the alimentary tract that is exposed to hydrochloric acid and pepsin, they occur most commonly (98-99%) in either the duodenum or the stomach in the ratio of 4:1. Each of the two main types may be acute or chronic.

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Figure 20.10 of gastric glands metaplasia.

A, Chronic atrophic gastritis (right) contrasted with normal pyloric mucosa (left). There is marked gastric atrophy with disappearance and appearance of goblet cells (intestinal metaplasia). B, Photomicrograph showing chronic atrophic gastritis with intestinal

550Acute Peptic (Stress) Ulcers

Acute peptic ulcers or stress ulcers are multiple, small mucosal erosions, seen most commonly in the stomach but occasionally involving the duodenum.

ETIOLOGY. These ulcers occur following severe stress. The causes are as follows:

i)Psychological stress

ii)Physiological stress as in the following:

Shock

Severe trauma

Septicaemia

Extensive burns (Curling’s ulcers in the posterior aspect of the first part of the duodenum).

Intracranial lesions (Cushing’s ulcers developing from hyperacidity following excessive vagal stimulation).

Drug intake (e.g. aspirin, steroids, butazolidine, indomethacin).

and duodenal peptic ulcers are described together below while their contrasting features are presented in Table 20.3.

INCIDENCE. Peptic ulcers are more frequent in middle-aged adults. The peak incidence for duodenal ulcer is 5th decade, while for gastric ulcer it is a decade later (6th decade). Duodenal as well as gastric ulcers are more common in males than in females. Duodenal ulcer is almost four times more common than gastric ulcer; the overall incidence of gastroduodenal ulcers being approximately 10% of the male population.

ETIOLOGY. The immediate cause of peptic ulcer disease is disturbance in normal protective mucosal ‘barrier’ by acidpepsin, resulting in digestion of the mucosa. However, in contrast to duodenal ulcers, the patients of gastric ulcer have

low-to-normal gastric acid secretions, though true achlorhydria in

response to stimulants never occurs in benign gastric ulcer.

Besides, 10-20% patients of gastric ulcer may have coexistent duodenal ulcer as well. Thus, the etiology of peptic ulcers possibly may not be explained on the basis of a single factor but is multifactorial. These factors are discussed below but the first two—H. pylori gastritis and NSAIDs-induced injury are considered most important.

1.Helicobacter pylori gastritis. About 15-20% cases infected with H. pylori in the antrum develop duodenal ulcer in their life time while gastric colonisation by H. pylori never develops ulceration and remain asymptomatic. H. pylori can be identified in mucosal samples by histologic examination, culture and serology as discussed on page 548.

2.NSAIDs-induced mucosal injury. Non-steroidal antiinflammatory drugs are most commonly used medications in the developed countries and are responsible for direct toxicity, endothelial damage and epithelial injury to both gastric as well as duodenal mucosa.

3.Acid-pepsin secretions. There is conclusive evidence that some level of acid-pepsin secretion is essential for the development of duodenal as well as gastric ulcer. Peptic ulcers never occur in association with pernicious anaemia in which there are no acid and pepsin-secreting parietal and chief cells respectively.

4.Gastritis. Some degree of gastritis is always present in the region of gastric ulcer, though it is not clear whether it is the cause or the effect of ulcer. Besides, the population distribution pattern of gastric ulcer is similar to that of chronic gastritis.

5.Other local irritants. Pyloric antrum and lesser curvature of the stomach are the sites most exposed for longer periods to local irritants and thus are the common sites for occurrence of gastric ulcers. Some of the local irritating substances implicated in the etiology of peptic ulcers are heavily spiced foods, alcohol, cigarette smoking, unbuffered aspirin.

6.Dietary factors. Nutritional deficiencies have been regarded as etiologic factors in peptic ulcers e.g. occurrence of gastric ulcer in poor socioeconomic strata, higher incidence of duodenal ulcer in parts of South India. However, malnutrition does not appear to have any causative role in peptic ulceration in European countries and the U.S.

Tract Gastrointestinal The 20 CHAPTER

5521. There is generally hypersecretion of gastric acid into the fasting stomach at night which takes place under the influence of vagal stimulation. There is high basal as well as maximal acid output (BAO and MAO) in response to various stimuli.

2.Patients of duodenal ulcer have rapid emptying of the stomach so that the food which normally buffers and neutralises the gastric acid, passes down into the small intestine, leaving the duodenal mucosa exposed to the aggressive action of gastric acid.

3.Helicobacter gastritis caused by H. pylori is seen in 95-100% cases of duodenal ulcers. The underlying mechanisms are as under:

Figure 20.11 Distribution of peptic ulcers.

duodenal ulcers are coexistent. Vast majority of the peptic ulcers are benign. Chronic duodenal ulcer never turns malignant, while chronic gastric ulcer may develop carcinoma in less than 1% of cases. Malignant gastric ulcers are larger, bowl-shaped with elevated and indurated mucosa at the margin (Fig. 20.13).

Microscopically, chronic peptic ulcers have 4 histological zones. From within outside, these are as under (Fig. 20.14):

1.Necrotic zone—lies in the floor of the ulcer and is composed of fibrinous exudate containing necrotic debris and a few leucocytes.

2.Superficial exudative zone—lies underneath the necrotic zone. The tissue elements here show coagulative necrosis giving eosinophilic, smudgy appearance with nuclear debris.

3.Granulation tissue zone—is seen merging into the necrotic zone. It is composed of nonspecific inflammatory infiltrate and proliferating capillaries.

4.Zone of cicatrisation—is seen merging into thick layer of granulation tissue. It is composed of dense fibrocollagenic scar tissue over which granulation tissue rests. Thrombosed or sclerotic arteries may cross the ulcer which on erosion may result in haemorrhage.

Figure 20.12 Benign chronic peptic ulcer. Partial gastrectomy specimen showing a punched out round to oval ulcer on the mucosa, about 1 cm in diameter (arrow) and penetrating into muscularis layer.

Figure 20.13 Chronic gastric ulcer (A) contrasted with malignant gastric ulcer (B).

COMPLICATIONS. Acute and subacute peptic ulcers usually heal without leaving any visible scar. However, healing of chronic, larger and deeper ulcers may result in complications. These are as follows:

1.Obstruction. Development of fibrous scar at or near the pylorus results in pyloric stenosis. In the case of healed duodenal ulcer, it causes duodenal stenosis. Healed ulcers along the lesser curvatures may produce ‘hourglass’ deformity due to fibrosis and contraction.

2.Haemorrhage. Minor bleeding by erosion of small blood vessels in the base of an ulcer occurs in all the ulcers and can be detected by testing the stool for occult blood. Chronic blood loss may result in iron deficiency anaemia. Severe bleeding may cause ‘coffee ground’ vomitus or melaena. A penetrating chronic ulcer may erode a major artery (e.g. left gastric, gastroduodenal or splenic artery) and cause a massive and severe hematemesis and sometimes death.

3.Perforation. A perforated peptic ulcer is an acute abdominal emergency. Perforation occurs more commonly in chronic duodenal ulcers than chronic gastric ulcers. Following sequelae may result:

i)On perforation the contents escape into the lesser sac or into the peritoneal cavity, causing acute peritonitis.

ii)Air escapes from the stomach and lies between the liver and the diaphragm giving the characteristic radiological appearance of air under the diaphragm.

iii)Subphrenic abscess between the liver and the diaphragm may develop due to infection.

iv)Perforation may extend to involve the adjacent organs e.g. the liver and pancreas.

4. Malignant transformation. The dictum ‘cancers ulcerate but ulcers rarely cancerate’ holds true for most peptic ulcers. A chronic duodenal ulcer never turns malignant, while less than 1% of chronic gastric ulcers may transform into carcinoma.

CLINICAL FEATURES. Peptic ulcers are remitting and relapsing lesions. Their chronic and recurrent behaviour is summed up the saying: ‘once a peptic ulcer patient, always a peptic ulcer patient.’ The two major forms of chronic peptic ulcers show variations in clinical features which are as follows:

1.Age. The peak incidence of duodenal ulcer is in 5th decade while that for gastric ulcer is a decade later.

2.People at risk. Duodenal ulcer occurs more commonly in people faced with more stress and strain of life (e.g. executives, leaders), while gastric ulcer is seen more often in labouring groups.

3.Periodicity. The attacks in gastric ulcers last from 2-6 weeks, with interval of freedom from 1-6 months. The attacks of duodenal ulcer, are classically worsened by ‘work, worry

and weather.’

4. Pain. In gastric ulcer, epigastric pain occurs immediately or within 2 hours after food and never occurs at night. In duodenal ulcer, pain is severe, occurs late at night (‘hunger pain’) and is usually relieved by food.

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554 5. Vomiting. Vomiting which relieves the pain is a conspicuous feature in patients of gastric ulcer. Duodenal ulcer patients rarely have vomiting but instead get heart-burn (retrosternal pain) and ‘water brash’ (burning fluid into the mouth).

6. Haematemesis and melaena. Haematemesis and melaena occur in gastric ulcers in the ratio of 60:40, while in duodenal ulcers in the ratio of 40:60. Both may occur together more commonly in duodenal ulcer than in gastric ulcer patients.

7. Appetite. The gastric ulcer patients, though have good appetite but are afraid to eat, while duodenal ulcer patients have very good appetite.

8. Diet. Patients of gastric ulcer commonly get used to a bland diet consisting of milk, eggs etc and avoid taking fried foods, curries and heavily spiced foods. In contrast, duodenal ulcer patients usually take all kinds of diets.

9. Weight. Loss of weight is a common finding in gastric ulcer patients while patients of duodenal ulcer tend to gain weight due to frequent ingestion of milk to avoid pain.

TABLE 20.4: Gastric Tumours and Tumour-like Lesions.

A.TUMOUR-LIKE LESIONS (POLYPS)

1.Hyperplastic (inflammatory) polyps

2.Hamartomatous polyps

B.BENIGN TUMOURS

1.Epithelial

Adenomas (adenomatous or neoplastic polyps)

2.Non-epithelial

Gastrointestinal spindle cell (stromal) tumours (GIST)

C.MALIGNANT TUMOURS

1.Epithelial (90%)

(i)Adenocarcinoma

(ii)Others

2.Non-epithelial (2%)

(i)Leiomyosarcoma

(ii)Leiomyoblastoma (epithelioid leiomyoma)

3.Carcinoid tumour (3%)

4.Lymphoma (4%)

Microscopically, they are composed of irregular hyperplastic glands, which may show cystic change. The lining epithelium is mostly superficial gastric type but antral glands, chief cells and parietal cells may be present. These lesions do not have cellular atypia and do not have malignant potential.

Hamartomatous Polyps

Hamartomatous polyps are not true neoplasms but are malformations. They are of various types such as gastric polyps of the Peutz-Jeghers syndrome (page 582), juvenile polyp, pancreatic heterotopia, heterotopia of Brunner’s glands and inflammatory fibroid polyps (eosinophilic granulomatous polyps).

B. BENIGN TUMOURS

Adenomas (Adenomatous or Neoplastic Polyps)

Adenomas, also, referred to as adenomatous or neoplastic polyps, are true benign epithelial neoplasms and are much rare in the stomach than in the large intestine. They are also found more often in the region of pyloric antrum. They are commonly associated with atrophic gastritis and pernicious anaemia. Morphologically, adenomatous polyps of the stomach resemble their counterparts in the large bowel and are described on page 583.

Stromal Tumours

Stomach may be the site for occurrence of various uncommon benign tumours of stromal cell origin e.g. leiomyomas (being the most common); others are neurofibromas, schwannomas and lipomas. They are usually firm, circumscribed nodules, less than 4 cm in size and appear as submucosal nodules. They resemble in gross and microscopic appearance with their counterparts in other parts of the body.

Currently, the term gastrointestinal stromal tumours (GISTs) is used for a group of uncommon benign tumours composed of spindle cells or stromal cells but lacking the

true phenotypic features of smooth muscle cells, neural cells or Schwann cells. They are uncommon but as compared to other sites in the GIT, are most common in the stomach. Their behaviour is generally benign but may be recurrent, aggressive or even metastasis may occur.

C. MALIGNANT TUMOURS

Gastric Carcinoma

INCIDENCE. Carcinoma of the stomach comprises more than 90% of all gastric malignancies and is the leading cause of cancer-related deaths in countries where its incidence is high. The highest incidence is between 4th to 6th decades of life and is twice more common in men than in women.

ETIOLOGY. A number of etiologic factors have been implicated in causation of gastric cancer. These are as under:

1.H. pylori infection. H. pylori infection of the stomach is an important risk factor for the development of gastric cancer. Epidemiologic studies throughout world have shown that a seropositivity with H. pylori is associated with 3 to 6 times higher risk of development of gastric cancer. It may be mentioned here that similar association of H. pylori infection exists with gastric lymphomas (MALT type) as well.

2.Dietary factors. Epidemiological studies suggest that dietary factors are most significant in the etiology of gastric cancer. The evidences in support of this are multifold:

i)Occurrence of gastric cancer in the region of gastric canal (i.e. along the lesser curvature and the pyloric antrum) where irritating foods exert their maximum effect.

ii)Populations consuming certain foodstuffs have high risk of developing gastric cancer e.g. ingestion of smoked foods, high intake of salt, pickled raw vegetables, high intake of carcinogens as nitrates in foods and drinking water, nitrites as preservatives for certain meats etc. However, intake of green leafy vegetables, citrus fruits and animal fats has been reported to have protective role in gastric cancer.

iii)Tobacco smoke, tobacco juice and consumption of alcohol have all been shown to have carcinogenic effect on gastric mucosa.

3.Geographical factors. There are geographic variations in the incidence of gastric cancer. Japan, Chile and Italy have the highest recorded death rate from gastric cancer, while the incidence is considerably low in the US, UK and Canada. The higher incidence in certain geographic regions is the result of environmental influences as observed from the finding of incidence of gastric cancer in the next generation of Japanese immigrants to the US which is comparable to that of native Americans.

4.Racial factors. Within the country, different ethnic groups may have variations in incidence of gastric cancer e.g. incidence is higher in Blacks, American Indians, Chinese in Indonesia, North Wales than other parts of Wales.

5.Genetic factors. Genetic influences have some role in the etiology of gastric cancer. Not more than 4% of patients of gastric cancer have a family history of this disease. Individuals with blood group A have higher tendency to develop gastric cancer (Recall that the peptic ulcer is more

555

i)Ulcerative carcinoma

ii)Fungating (Polypoid) carcinoma

iii)Scirrhous carcinoma (Linitis plastica)

iv)Colloid (Mucoid) carcinoma

v)Ulcer-cancer

In addition to the above classification, gastric carcinomas have been classified, on the basis of extent of invasion, into 2 groups:

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ii)Gastric distension and vomiting

iii)Loss of weight (cachexia)

iv)Loss of appetite (anorexia)

v)Anaemia, weakness, malaise.

The most common complication of gastric cancer is

haemorrhage (in the form of haematemesis and/or melaena); others are obstruction, perforation and jaundice.

Gastric carcinoma remains undiagnosed until late when the symptoms appear. Therefore, the prognosis is generally poor; 5-year survival rate being 5-15% from the time of diagnosis of advanced gastric carcinoma. However, 5-year survival rate for early gastric carcinoma is far higher (93-99%) and hence the need for early diagnosis of the condition.

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Figure 20.19 A, Ulcerative carcinoma stomach. The luminal surface of the stomach in the region of pyloric canal shows an elevated irregular growth with ulcerated surface and raised margins. B, Malignant cells forming irregular glands with stratification are seen invading the layers of the stomach wall. C, Linitis plastica. The wall of the stomach in the region of pyloric canal is markedly thickened and fibrotic while the mucosal folds are lost. D, Microscopy shows characteristic signet ring tumour cells having abundant mucinous cytoplasm positive for mucicarmine (inbox). The stroma is desmoplastic.

ulcerations. Cut section shows lesions in the mucosa and submucosa but in late stage whole thickness of the gut wall may be affected.

2. Polypoid type, which produces large protruding mass into the lumen with ulcerated surface.

Lymph node involvement may occur in either of the two patterns.

Microscopically, gastric lymphomas are most often nonHodgkin’s lymphomas of the following types:

High-grade large cell immunoblastic lymphoma being the most common.

Low-grade small lymphocytic well-differentiated B-cell lymphoma referred to as MALToma is the next in frequency (arising from Mucosa Associated Lymphoid

Tissue). The term pseudolymphoma is sometimes used for non-invasive stage of MALToma.

SMALL INTESTINE

NORMAL STRUCTURE

Anatomically, the small bowel having a length of 550-650 cm, includes the duodenum, jejunum and ileum and tends to become narrower throughout its course.

Histologically, the small bowel is identified by recognition of villi. The wall of the small intestine consists of 4 layers:

1. The serosa is the outer covering of the small bowel which is complete except over a part of the duodenum.

2.The muscularis propria is composed of 2 layers of smooth muscle tissue—outer thinner longitudinal and inner thicker circular layer. These muscles are functionally important for peristalsis. Between the two layers of muscle lie ganglionated plexus, myenteric plexus of Auerbach.

3.The submucosa is composed of loose fibrous tissue with blood vessels and lacteals in it. It contains a gangliated plexus, Meissner’s plexus, having fewer and smaller cells than the Auerbach’s plexus.

4.The mucosa consists of glandular epithelium overlying the lamina propria composed of loose connective tissue and contains phagocytic cells and abundance of lymphoid cells (Peyer’s patches in the ileum) and plasma cells. It is supported externally by thin layer of smooth muscle fibres, muscularis mucosae. The mucous membrane is thrown into folds or plicae which are more in the jejunum and less in the ileum, thus increasing the absorptive surface enormously. The absorptive surface is further increased by the intestinal villi. Villi are finger-like or leaf-like projections which contain

3types of cells:

i)Simple columnar cells. They perform absorptive function due to the presence of brush border consisting of large number of microvilli.

ii)Goblet cells. These are mucus-secreting cells and are interspersed between the columnar cells.

iii)Endocrine cells. These are scattered in the villi as well as are widely distributed throughout the gastrointestinal tract. These cells have various synonyms as under:

Kulchitsky cells, after the name of its discoverer.

Enterochromaffin cells, due to their resemblance to chromaffin cells of the adrenal medulla.

Argentaffin cells, as the intracytoplasmic granules stain positively with silver salts by reduction reaction (argyrophil cells, on the other hand, require the addition of exogenous reducing substance for staining).

Endocrine cells, as these specialised cells are considered to be part of APUD cell system (having common properties as Amine content, amine Precursor Uptake and Decarboxylation). APUD cells are considered to be endodermal in origin, while previously they were thought to be neural crest derivative. Other endocrine cells belonging to the APUD cell system are C-cells of the thyroid, chromaffin cells of the adrenal medulla, certain cells of the carotid body, bronchi, hypothalamus, pituitary and sympathetic ganglia.

Endocrine cells are heavily populated in the proximal small bowel as this is the most active site for absorption and secretory activities. They are sparse in the colon which is less active site for such functions.

The duodenum contains distinctively branched Brunner’s glands present in the submucosa and going up to muscularis mucosae. The deeper layer of the mucosa of the small intestine elsewhere contains intestinal glands or crypts of Lieberkuhn. They are lined by columnar cells, goblet cells, endocrine cells and Paneth cells. Paneth cells are normally exclusively found in the small intestine and occasionally in the caecum. These cells are characterised by the presence of supranuclear granules rich in lysozyme.

The blood supply of the whole of small intestine, except the first part of the duodenum, is by the superior mesenteric artery which supplies blood by mesenteric arterial arcades and the straight arteries.

The main functions of the small intestine are digestion and absorption so that ultimately nutrients passing into the bloodstream are utilised by the cells in metabolism. The mucosal layer of the small intestine has remarkable capacity for regeneration and new lining is laid every 3-4 days.

CONGENITALANOMALIES

Intestinal Atresia and Stenosis

Intestinal atresia is congenital absence of lumen, most commonly affecting the ileum or duodenum. The proximal segment has a blind end which is separated from distal segment freely, or the two segments are joined by a fibrous cord. The condition must be recognised early and treated surgically, as otherwise it is incompatible with life.

Intestinal stenosis is congenital narrowing of the lumen affecting a segment of the small intestine. Intestinal segment above the level of obstruction is dilated and that below it is collapsed.

Meckel’s Diverticulum

Meckel’s diverticulum is the most common congenital anomaly of the gastrointestinal tract, occurring in 2% of population. It is more common in males. The anomaly is commonly situated on the antimesenteric border of the ileum, about 1 meter above the ileocaecal valve. Like other true diverticula, Meckel’s diverticulum is an outpouching containing all the layers of the intestinal wall in their normal orientation (Fig. 20.20). It is almost always lined by small intestinal type of epithelium; rarely it may contain islands of gastric mucosa and ectopic pancreatic tissue. Embryologic origin of Meckel’s diverticulum is from incomplete obliteration of vitellointestinal duct. (Other anomalies resulting from the remnants of vitellointestinal duct are vitelline sinus and vitelline cyst).

The common complications of Meckel’s diverticulum are perforation, haemorrhage and diverticulitis.

In addition to congenital Meckel’s diverticulum, acquired diverticula also occur in the small intestine. These are commonly multiple (diverticulosis), frequently located on the mesenteric border, and are sometimes associated with malabsorption.

Intestinal Malrotation

Malrotation is a developmental abnormality of the midgut (i.e. the portion of intestine between the duodenojejunal flexure and the middle of transverse colon). Due to failure of normal rotation of midgut, the following consequences can occur:

i)Exomphalos i.e. intestinal eventration at the umbilicus.

ii)Misplacement of the caecum, appendix and ascending colon.

iii)Mobile caecum.

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Pathology Systemic III SECTION

Figure 20.21 Ileocaecal intussusception.

When the blood flow in the hernial sac is obstructed, it results in strangulated hernia. Obstruction to the venous drainage and arterial supply may result in infarction or gangrene of the affected loop of intestine. The gross and microscopic appearance of strangulated intestine is the same as that of infarction of intestine.

Intussusception

Intussusception is the telescoping of a segment of intestine into the segment below due to peristalsis. The telescoped segment is called the intussusceptum and lower receiving segment is called the intussuscipiens. The condition occurs more commonly in infants and young children, more often in the ileocaecal region when the portion of ileum invaginates into the ascending colon without affecting the position of the ileocaecal valve (Fig. 20.21). Less common forms are ileoileal and colo-colic intussusception.

In children, the cause is usually not known though enlargement of the lymphoid tissue in the terminal ileum has been suggested by some. In the case of adults, the usual causes are foreign bodies and tumours.

The main complications of intussusception are intestinal obstruction, infarction, gangrene, perforation and peritonitis.

Volvulus

Volvulus is the twisting of loop of intestine upon itself through 180° or more. This leads to obstruction of the intestine as well as cutting off of the blood supply to the affected loop. The usual causes are bands and adhesions (congenital or acquired) and long mesenteric attachment. The condition is more common in the sigmoid colon than the small bowel.

ISCHAEMIC BOWEL DISEASE (ISCHAEMIC ENTEROCOLITIS)

Ischaemic lesions of the gastrointestinal tract may occur in the small intestine and/or colon; the latter is called ischaemic colitis or ischaemic enterocolitis and is commonly referred to

as ischaemic bowel disease. In either case, the cause of 563 ischaemia is compromised mesenteric circulation, while ischaemic effect is less likely to occur in the stomach, duodenum and rectum due to abundant collateral blood supply.

Depending upon the extent and severity of ischaemia, 3 patterns of pathologic lesions can occur (Fig. 20.22):

1. Transmural infarction, characterised by full thickness involvement i.e. transmural ischaemic necrosis and gangrene of the bowel.

2 Mural infarction, characterised by haemorrhagic gastroenteropathy (haemorrhage and necrosis). The ischaemic effect in mural infarction is limited to mucosa, submucosa and superficial muscularis, while mucosal infarction is confined to mucosal layers superficial to muscularis mucosae.

3. Ischaemic colitis, due to chronic colonic ischaemia causing fibrotic narrowing of the affected bowel.

These pathologic patterns are described below:

Transmural Infarction

iii) Mesenteric venous occlusion is less common cause of fullthickness infarction of the bowel. The causes are as under:

Figure 20.22 Schematic diagram to show the three types of ischaemic bowel disease depending upon the extent of involvement.

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Figure 20.23 Haemorrhagic infarct of the small intestine. The infarcted area is swollen, dark in colour and coated with fibrinous exudate.

A sharp line of demarcation separates infarcted area from the normal bowel (arrow).

Intestinal sepsis e.g. appendicitis

Portal venous thrombosis in cirrhosis of the liver

Tumour invasion

Use of oral contraceptives

iv) Miscellaneous causes: Strangulated hernia Torsion

Fibrous bands and adhesions.

MORPHOLOGIC FEATURES. Grossly, irrespective of the underlying etiology, infarction of the bowel is haemorrhagic (red) type (page 126). A varying length of the small bowel may be affected. In the case of colonic infarction, the distribution area of superior and inferior mesenteric arteries (i.e. splenic flexure) is more commonly involved. The affected areas become dark purple and markedly congested and the peritoneal surface is coated with fibrinous exudate. The wall is thickened, oedematous and haemorrhagic. The lumen is dilated and contains blood and mucus. In arterial occlusion, there is sharp line of demarcation between the infarcted bowel and the normal intestine, whereas in venous occlusion the infarcted area merges imperceptibly into the normal bowel

(Fig. 20.23).

Microscopically, there is coagulative necrosis and ulceration of the mucosa and there are extensive submucosal haemorrhages. The muscularis is less severely affected by ischaemia. Subsequently, inflammatory cell infiltration and secondary infection occur, leading to gangrene of the bowel (Fig. 20.24).

The condition is clinically characterised by ‘abdominal angina’ in which the patient has acute abdominal pain, nausea, vomiting, and sometimes diarrhoea. The disease is rapidly fatal, with 50-70% mortality rate.

Figure 20.24 Infarct small intestine, microscopic appearance. The mucosa in the infarcted area shows coagulative necrosis and submucosal haemorrhages: muscularis is also partly affected. Inflammatory cell infiltration is marked at the line of demarcation between the infarcted and normal bowel.

Mural and Mucosal Infarction (Haemorrhagic

Gastroenteropathy, Membranous Colitis)

Mural and mucosal infarctions are limited to superficial layers of the bowel wall, sparing the deeper layer of the muscularis and the serosa. The condition is also referred to

as haemorrhagic gastroenteropathy, and in the case of colon as membranous colitis.

ETIOPATHOGENESIS. Haemorrhagic gastroenteropathy results from conditions causing non-occlusive hypoperfusion (compared from transmural infarction which occurs from occlusive causes). These are as under:

Shock

Cardiac failure

Infections

Intake of drugs causing vasoconstriction e.g. digitalis, norepinephrine.

MORPHOLOGIC FEATURES. Grossly, the lesions affect variable length of the bowel. The affected segment of the bowel is red or purple but without haemorrhage and exudation on the serosal surface. The mucosa is oedematous at places, sloughed and ulcerated at other places. The lumen contains haemorrhagic fluid.

Microscopically, there is patchy ischaemic necrosis of mucosa, vascular congestion, haemorrhages and inflammatory cell infiltrate. The changes may extend into superficial muscularis but deeper layer of muscularis and serosa are spared. Secondary bacterial infection may supervene resulting in pseudomembranous enterocolitis.

Clinically, as in transmural infarction, the features of abdominal pain, nausea, vomiting and diarrhoea are present, but the changes are reversible and curable. With adequate

therapy, normal morphology is completely restored in superficial lesions, while deeper lesions may heal by fibrosis leading to stricture formation.

Ischaemic Colitis

Although this condition affects primarily colon in the region of splenic flexure, it is described here due to its apparent pathogenetic relationship with ischaemic injury. Ischaemic colitis is characterised by chronic segmental colonic ischaemia followed by chronic inflammation and healing by fibrosis and scarring causing obstruction (ischaemic stricture).

Grossly, most frequently affected site is the splenic flexure; other site is rectum. Ischaemic colitis passes through 3 stages: infarct, transient ischaemia and ischaemic stricture. However, the surgical submitted specimens generally are of the ischaemic stricture. External surface of the affected area is fusiform or saccular. On cut section, there are patchy, segmental and longitudinal mucosal ulcers. Thus, the gross appearance can be confused with either of the two types of inflammatory bowel disease.

Microscopically, the ulcerated areas of the mucosa show granulation tissue. The submucosa is characteristically thickened due to inflammation and fibrosis. The muscularis may also show inflammatory changes and patchy replacement by fibrosis. The blood vessels may show atheromatous emboli, organising thrombi and endarteritis obliterans.

NECROTISING ENTEROCOLITIS

Necrotising enterocolitis is an acute inflammation of the terminal ileum and ascending colon, occurring primarily in premature and low-birth-weight infants within the first week of life and less commonly in full-term infants.

ETIOLOGY. The condition has been considered as a variant of the spectrum of ischaemic bowel disease. Important factors in the etiology of this disorder, thus, are as follows:

1.Ischaemia

2.Hypoxia/anoxia of the bowel due to bypassing of blood from the affected area

3.Bacterial infection and endotoxins

4.Establishment of feeding

5.Infants fed on commercial formulae than breast-fed, implying the role of immunoprotective factors.

MORPHOLOGIC FEATURES. Grossly, the affected segment of the bowel is dilated, necrotic, haemorrhagic and friable. Bowel wall may contain bubbles of air (pneumatosis intestinalis).

Microscopically, the changes are variable depending upon the stage. Initial changes are confined to mucosa and show oedema, haemorrhage and coagulative necrosis. A pseudomembrane composed of necrotic epithelium, fibrin and inflammatory cells may develop. As the ischaemic process extends to the subjacent layers, muscle layer is also involved and may lead to perforation and peritonitis.

In healed cases, stricture formation, malabsorption and short bowel syndrome are the usual complications.

INFLAMMATORY BOWEL DISEASE

(CROHN’S DISEASE AND ULCERATIVE COLITIS)

DEFINITION. The term ‘inflammatory bowel disease (IBD)’ is commonly used to include 2 idiopathic bowel diseases having many similarities but the conditions usually have distinctive morphological appearance. These 2 conditions are Crohn’s disease (regional enteritis) and ulcerative colitis:

1.Crohn’s disease or Regional enteritis is an idiopathic chronic ulcerative IBD, characterised by transmural, noncaseating granulomatous inflammation, affecting most commonly the segment of terminal ileum and/or colon, though any part of the gastrointestinal tract may be involved.

2.Ulcerative colitis is an idiopathic form of acute and chronic ulcero-inflammatory colitis affecting chiefly the mucosa and submucosa of the rectum and descending colon, though sometimes it may involve the entire length of the large bowel.

Both these disorders primarily affect the bowel but may have systemic involvement in the form of polyarthritis, uveitis, ankylosing spondylitis, skin lesions and hepatic involvement. Both diseases can occur at any age but are more frequent in 2nd and 3rd decades of life. Females are affected slightly more often.

ETIOPATHOGENESIS. The exact etiology of IBD remains unknown. However, multiple factors are implicated which can be considered under the following 3 groups:

1.Genetic factors. Genetic factors are implicated in the etiopathogenesis of IBD is supported by the following evidences:

i)There is about 3 to 20 times higher incidence of occurrence of IBD in first-degree relatives. This is due to genetic defect causing diminished epithelial barrier function.

ii)Overall, there is approximately 50% chance of development of IBD (Crohn’s disease about 60% concordance, ulcerative colitis about 6% concordance) in monozygotic twins.

iii)Although no specific and consistent gene association with IBD has been seen, genome wide search has revealed that disease-predisposing loci are present in chromosomes 16q, 12p, 6p, 14q and 5q. In particular, CARD15 (caspase- associated recruitment domain containing protein 15) on chromosome 16q is expressed by several cells in the intestinal mocosa which in mutated form results in loss of its function and renders an individual about 50-times higher risk to develop Crohn’s disease.

iv)HLA studies show that ulcerative colitis is more common in HLA-DRB1-alleles while Crohn’s disease is more common in HLA-DR7 and DQ4 alleles.

2.Immunologic factors. Defective immunologic regulation in IBD has been shown to play significant role in the pathogenesis of IBD:

i) Defective regulation of immune suppression. In a normal individual, there is lack of immune responsiveness to dietary

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566antigens and commensal flora in the intestinal lumen. The mechanism responsible for this is by activation of CD4+ T cells secreting cytokines inhibitory to inflammation (IL-10, TGF-β) which suppress inflammation in the gut wall. In IBD, this immune mechanism of suppression of inflammation is defective and thus results in uncontrolled inflammation.

ii) Transgenic mouse experimental model studies. Gene ‘knock out’ studies on colitis in mice have revealed that multiple immune abnormalities may be responsible for IBD as under:

a)Deletion of inflammation inhibitory cytokines (e.g. IL-2, IL-10, TGF-β) or their receptors.

b)Deletion of molecules responsible for T cell recognition (e.g. T cell antigen receptors, MHC class II).

c)Interference with normal epithelial barrier function in the intestine (e.g. blocking N-cadherin, deletion of multi-drug resistance MDR gene).

iii) Type of inflammatory cells. In both types of IBD, activated CD4+ T cells are present in the lamina propria and in the

peripheral blood. These cells either activate other inflammatory cells (e.g. macrophages and B cells), or recruit more inflammatory cells by stimulation of homing receptor on leucocytes and vascular endothelium. There are two main types of CD4+ T cells in IBD:

TH1 cells secrete proinflammatory cytokines IFN-γ and TNF which induce transmural granulomatous inflammation seen in Crohn’s disease. IL-12 initiates TH1 cytokine pathway.

TH2 cells secrete IL-4, IL-5 and IL-13 which induce superficial mucosal inflammation characteristically seen in ulcerative colitis.

3. Exogenous factors. In addition to role of genetic factors and deranged T-cell mediated immunity, a role for several exogenous and environmental factors has been assigned: i) Microbial factors: At different times, role of a variety of microbes in initiation of inflammatory response by the body has been suspected. Accordingly, several microorganism species (bacteria, viruses, protozoa and fungi) have been

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TABLE 20.7: Micro-organisms Causing Infective Enterocolitis.

A.BACTERIAL ENTEROCOLITIS

1.Entero-invasive bacteria

(i)Tuberculosis

(ii)Salmonella

(iii)Campylobacter jejuni

(iv)Shigella

(v)Escherichia coli

(vi)Yersinia enterocolitica

2.Enterotoxin-producing bacteria

(i)Vibrio cholerae

B.VIRAL ENTEROCOLITIS

C.FUNGAL ENTEROCOLITIS

(i)Candidiasis

(ii)Mucormycosis

D.PROTOZOAL AND METAZOAL INFESTATIONS

(i)Giardia lamblia

(ii)Entamoeba histolytica

(iii)Balantidium coli

(iv)Taenia solium

(v)Ascaris lumbricoides

(vi)Ancylostoma duodenale

(vii)Strongyloides stercoralis

primary tuberculosis of the ileocaecal region is quite common in developing countries including India. In the prepasteurisation era, it used to occur by ingestion of unpasteurised cow’s milk infected with Mycobacterium bovis. But now-a-days due to control of tuberculosis in cattle and pasteurisation of milk, virtually all cases of intestinal tuberculosis are caused by M. tuberculosis. The predominant changes are in the mesenteric lymph nodes without any significant intestinal lesion.

Grossly, the affected lymph nodes are enlarged, matted and caseous (tabes mesenterica). Eventually, there is healing by fibrosis and calcification (Fig. 20.29,A).

Microscopically, in the initial stage, there is primary complex or Ghon’s focus in the intestinal mucosa as occurs elsewhere in primary tuberculous infection (page 153). Subsequently, the mesenteric lymph nodes are affected which show typical tuberculous granulomatous inflammatory reaction with caseation necrosis. Tuberculous peritonitis may occur due to spread of the infection.

2. SECONDARY INTESTINAL TUBERCULOSIS. Selfswallowing of sputum in patients with active pulmonary tuberculosis may cause secondary intestinal tuberculosis, most commonly in the terminal ileum and rarely in the colon.

Grossly, the intestinal lesions are prominent than the lesions in regional lymph nodes as in secondary pulmonary tuberculosis (Fig. 20.29,B). The lesions begin in the Peyer’s patches or the lymphoid follicles with formation of small ulcers that spread through the lymphatics to form large ulcers which are transverse to the long axis of the bowel, (c.f. typhoid ulcers of small intestine, described below). These ulcers may be coated with caseous material. Serosa may be studded with visible tubercles. In advanced cases, transverse fibrous strictures and intestinal obstruction are seen (Fig. 20.30,A, B).

Histologically, the tuberculous lesions in the intestine are similar to those observed elsewhere i.e. presence of tubercles. Mucosa and submucosa show ulceration and the muscularis may be replaced by variable degree of fibrosis (Fig. 20.30,C). Tuberculous peritonitis may be observed.

3. HYPERPLASTIC CAECAL TUBERCULOSIS. This is a variant of occurring secondary to pulmonary tuberculosis.

Grossly, the caecum and/or ascending colon are thickwalled with mucosal ulceration. Clinically, the lesion is palpable and may be mistaken for carcinoma

(Fig. 20.29,C).

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Figure 20.31 A, Typhoid ulcers in the small intestine appear characteristically oval with their long axis parallel to the long axis of the bowel. B, Blood picture in typhoid fever showing neutropenia and relative lymphocytosis.

Persistence of organism in the gallbladder or urinary tract may result in passage of organisms in the faeces or urine creating a ‘carrier state’ which is a source of infection to others.

Bacterial Food Poisoning

This is a form of acute bacterial illness that occurs following ingestion of food or water contaminated with bacteria other than those that cause specific acute intestinal infections like typhoid, paratyphoid, cholera or dysentery bacilli. The illness results from either bacterial invasion or bacterial toxigenic effect on the bowel.

The commonest causes of bacterial food poisoning resulting in enteritis or enterocolitis are as under:

1. Staphylococcal food poisoning. Staphylococcus aureus infection acquired from contaminated food produces either mild food poisoning by enterotoxins, or may cause more severe form of the illness called pseudomembranous enterocolitis

described below. Staphylococcal food poisoning occurs due to liberation of enterotoxins by the bacteria.

2.Clostridial food poisoning. Infection with anaerobic organisms Clostridium welchii, following consumption of contaminated meat results in acute food poisoning (page 181). The illness occurs both by bacterial invasion as well as by toxins.

3.Botulism. This is a severe form of paralysing illness caused by ingestion of organism, Clostridium botulinum, which produces neurotoxin.

4.Salmonella food poisoning (Salmonellosis). This is an infection (and not caused by toxins) occurring due to food contaminated by S. typhimurium or S. enteritidis. The condition manifests with fever, vomiting, and diarrhoea. Death may result from depletion of water and electrolytes.

Dysenteries

The term ‘dysentery’ is used to mean diarrhoea with abdominal cramps, tenesmus and passage of mucus in the stools, from any cause. There are 2 main forms of dysen- teries—bacillary and amoebic.

1. BACILLARY DYSENTERY. Bacillary dysentery is the term used for infection by shigella species: S. dysenteriae, S. flexneri, S. boydii and S. sonnei. Infection occurs by foeco-oral route and is seen with poor personal hygiene, in densely populated areas, and with contaminated food and water. The common housefly plays a role in spread of infection.

Grossly, the lesions are mainly found in the colon and occasionally in the ileum. Superficial transverse ulcerations of mucosa of the bowel wall occur in the region of lymphoid follicles but perforation is seldom seen. The intervening intact mucosa is hyperaemic and oedematous. Following recovery from the acute attack, complete healing usually takes place.

Microscopically, the mucosa overlying the lymphoid follicles is necrosed. The surrounding mucosa shows congestion, oedema and infiltration by neutrophils and lymphocytes. The mucosa may be covered by greyishyellow ‘pseudomembrane’ composed of fibrinosuppurative exudate.

The complications of bacillary dysentery are haemorrhage, perforation, stenosis, polyarthritis and iridocyclitis.

2. AMOEBIC DYSENTERY. This is due to infection by Entamoeba histolytica. It is more prevalent in the tropical countries and primarily affects the large intestine. Infection occurs from ingestion of cyst form of the parasite. The cyst wall is dissolved in the small intestine from where the liberated amoebae pass into the large intestine. Here, they invade the epithelium of the mucosa, reach the submucosa and produce the characteristic flask-shaped ulcers.

Grossly, early intestinal lesions appear as small areas of elevation on the mucosal surface. In advanced cases, typical flask-shaped ulcers having narrow neck and broad base are seen. They are more conspicuous in the caecum, rectum and in the flexures (Fig. 20.32).

Microscopically, the ulcerated area shows chronic inflammatory reaction consisting of lymphocytes, plasma cells, macrophages and eosinophils. The trophozoites of Entamoeba are seen in the inflammatory exudate and are concentrated at the advancing margin of the lesion. Intestinal amoebae characteristically have ingested red cells in their cytoplasm. Oedema and vascular congestion are present in the area surrounding the ulcers.

Complications of intestinal amoebic ulcers are: amoebic liver abscess or amoebic hepatitis, perforation, haemorrhage and formation of amoeboma which is a tumour-like mass.

PSEUDOMEMBRANOUS ENTEROCOLITIS (ANTIBIOTIC-ASSOCIATED DIARRHOEA)

Pseudomembranous enterocolitis is a form of acute inflammation of colon and/or small intestine characterised by formation of ‘pseudomembrane’ over the site of mucosal injury.

ETIOLOGY. Numerous studies have established the overgrowth of Clostridium difficile with production of its toxin in the etiology of antibiotic-associated diarrhoea culminating in pseudomembranous colitis. Oral antibiotics such as clindamycin, ampicillin and the cephalosporins are more often (20%) associated with antibiotic-associated diarrhoea, while development of pseudomembranous colitis may occur in 1-10% cases.

Pseudomembrane formation may also occur in various other conditions as under:

Staphylococcal enterocolitis

Bacillary (Shigella) dysentery Candida enterocolitis

Figure 20.32 Amoebic ulcers large intestine. A, The luminal surface shows multiple ulcers some of which are deep and are flask-shaped with narrow neck and broad base (arrow) containing necrotic tissue and undermined margins. B, Trophozoites of Entamoeba histolytica are seen at the margin of ulcer (arrow).

MORPHOLOGIC FEATURES. Grossly, the lesions may be confined, to the large intestine or small intestine, or both may be involved. The mucosa of the bowel is covered by patchy, raised yellow-white plaques. Elsewhere, the mucosa is congested and may show small mucosal ulcerations.

Microscopically, the ‘pseudomembrane’ is composed of network of fibrin and mucus, in which are entangled inflammatory cells and mucosal epithelial cells. There is focal necrosis of surface epithelial cells. The lamina propria contains inflammatory cell infiltrate, mainly neutrophils. The submucosa has congested capillaries and may show microthrombi. The inflammation spreads laterally rather than deeply.

MALABSORPTION SYNDROME

DEFINITION AND CLASSIFICATION

The malabsorption syndrome (MAS) is characterised by impaired intestinal absorption of nutrients especially of fat; some other substances are proteins, carbohydrates, vitamins and minerals. MAS is subdivided into 2 broad groups:

Primary MAS, which is due to primary deficiency of the absorptive mucosal surface and of the associated enzymes. Secondary MAS, in which mucosal changes result secondary to other factors such as diseases, surgery, trauma and drugs.

Each of the two main groups has a number of causes listed in Table 20.8.

CLINICAL FEATURES

The clinical manifestations of MAS vary according to the underlying cause. However, some common symptoms are as follows:

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574  TABLE 20.8: Classification of Malabsorption Syndrome.

I.PRIMARY MALABSORPTION

1.Coeliac sprue

2.Collagenous sprue

3.Tropical sprue

4.Whipple’s disease

5.Disaccharidase deficiency

6.Allergic and eosinophilic gastroenteritis II. SECONDARY MALABSORPTION

1.Impaired digestion

(i)Mucosal damage e.g. in tuberculosis, Crohn’s disease, lymphoma, amyloidosis, radiation injury, systemic sclerosis

(ii)Hepatic and pancreatic insufficiency

(iii)Resection of bowel

(iv)Drugs e.g. methotrexate, neomycin, phenindione etc.

2.Impaired absorption

(i)Short or stagnant bowel (blind loop syndrome) from surgery or disease resulting in abnormal proliferation of microbial flora

(ii)Acute infectious enteritis

(iii)Parasitoses e.g. Giardia, Strongyloides, hookworms

INVESTIGATIONS

When MAS is suspected on clinical grounds, the following investigations (laboratory tests) and endoscopic biopsy) may be carried out to confirm it:

I. LABORATORY TESTS:

1. Tests for fat malabsorption:

i)Faecal analysis for fat content

ii)Microscopic analysis for faecal fat

iii)Blood lipid levels after a fatty meal

iv)Tests based on absorption of radioactive-labelled fat.

2. Tests for protein malabsorption:

i)Bile acid malabsorption

ii)Radioactive-labelled glycine breath test.

iii)Prothrombin time (vitamin K deficiency)

iv)Secretin and other pancreatic tests.

3. Tests for carbohydrate malabsorption:

i)D-xylose tolerance test

ii)Lactose tolerance test

iii)Hydrogen breath test

iv)Bile acid breath test

4. Vitamin B12, malabsorption: i) Schilling test (page 308).

II. INTESTINAL MUCOSAL BIOPSY:

Mucosal biopsy of small intestine is essential for making the diagnosis of MAS and also evaluation of a patient on followup. The availability of endoscopes has enabled easy viewing of affected mucosa directly and taking mucosal biopsy under vision; this has largely replaced the earlier per-oral CrosbyKugler capsule biopsy of small intestine. The biopsy should first be examined under dissecting microscope before histologic sectioning.

Normal villous (Fig. 20.33,A). Under the dissecting microscope, the normal jejunal mucosa has tall, slender,

finger-shaped or leaf-shaped villi. It is lined by tall columnar absorptive epithelium and has scattered lymphocytes in the lamina propria.

Villous atrophy. Variable degree of flattening of intestinal mucosa in MAS is the commonest pathological change in mucosal pattern and is referred to as villous atrophy. It may be of 2 types—partial and subtotal/total type.

Partial villous atrophy is the mild form of the lesion in which villi fuse with each other and thus become short and broad, commonly called as convolutions and irregular ridges (Fig. 20.33,B). The epithelial cells show compensatory hyperplasia suggesting a turnover of these cells (Fig. 20.34,A). Lamina propria shows increased cellular infiltrate, predominantly of plasma cells.

Partial villous atrophy is commonly found in children and adults with diarrhoea, parasitic infestations, Crohn’s disease, ulcerative colitis and malabsorption due to drugs and radiation injury.

Subtotal/Total villous atrophy is the severe form of the lesion in which there is flattening of mucosa due to more advanced villous fusion (Fig. 20.33,C). The surface epithelium is cuboidal and there is increased plasma cell infiltrate in the lamina propria (Fig. 20.34,B).

Subtotal and total villous atrophy is exhibited by a number of conditions such as nontropical sprue, tropical sprue, intestinal lymphomas, carcinoma, protein-calorie malnutrition etc.

IMPORTANT TYPES OF MAS

Coeliac Sprue (Non-tropical Sprue, Gluten-Sensitive

Enteropathy, Idiopathic Steatorrhoea)

This is the most important cause of primary malabsorption occurring in temperate climates. The condition is characterised by significant loss of villi in the small intestine and thence diminished absorptive surface area. The condition occurs in 2 forms:

Childhood form, seen in infants and children and is commonly referred to as coeliac disease.

Adult form, seen in adolescents and early adult life and used

to be called idiopathic steatorrhoea.

In either case, there is genetic abnormality resulting in sensitivity to gluten (a protein) and its derivative, gliadin, present in diets such as grains of wheat, barley and rye. Serum antibodies—IgA antigliadin and IgA antiendomysial, have been found but is not known whether these antibodies are primary or appear secondary to tissue damage.

The symptoms are usually relieved on elimination of gluten from the diet. The role of heredity is further supported by the observation of familial incidence and HLA association of the disease. Exact pathogenesis of the condition is not clear. However, following hypotheses are significant in causing mucosal cell damage:

1.Hypersensitivity reaction as seen by gluten-stimulated antibodies.

2.Toxic effect of gluten due to inherited enzyme deficiency in the mucosal cells.

575

576 The lesions are relieved by removal of the patient from the tropical area and by oral administration of antibiotics but gluten-free diet has no role in improvement.

Whipple’s Disease (Intestinal Lipodystrophy)

This is an uncommon bacterial disease involving not only the intestines but also various other systems such as central nervous system, heart, blood vessels, skin, joints, lungs, liver, spleen and kidneys. The disease is more common in males in 4th to 5th decades of life. Patients may present with features of malabsorption or may have atypical presentation in the form of migratory polyarthritis, neurological disturbances and focal hyperpigmentation of the skin.

Histologically, the affected tissues show presence of characteristic macrophages containing PAS-positive granules and rod-shaped micro-organisms (Whipple’s bacilli). These macrophages are predominantly present in the lamina propria of the small intestine and mesenteric lymph nodes.

Although small intestine is about 6 meter long, but for obscure reasons, benign as well as malignant tumours in it

descending order of frequency, are: leiomyomas, adenomas and vascular tumours (haemangioma, lymphangioma). Amongst the malignant tumours, the most frequently encountered, in descending frequency, are: carcinoid tumours, lymphomas (Fig. 20.35) and adenocarcinoma. All these tumours are identical in morphology to those seen elsewhere in the alimentary tract. Carcinoid tumour, a peculiar neoplasm most common in the midgut, is described below.

Carcinoid Tumour (Argentaffinoma)

Carcinoid tumour or argentaffinoma is a generic term applied to tumours originating from endocrine cells (synonyms: argentaffin cells, Kulchitsky cells, enterochromaffin cells) belonging to APUD cell system and are therefore also called as apudomas (page 561). The endocrine cells are distributed throughout the mucosa of GI tract. These cells have secretory granules which stain positively with silver salts (argentaffin granules) or many stain after addition of exogenous reducing

Figure 20.35 Lymphoma small intestine. The polypoid growth is seen projecting into lumen while the covering mucosa is ulcerated.

agent (non-argentaffin or argyrophil granules). Accordingly, carcinoid tumour may be argentaffin or argyrophil type. Depending upon the embryologic derivation of the tissues where the tumour is located, these are classified as foregut, midgut, and hindgut carcinoids.

Midgut carcinoids, seen in terminal ileum and appendix are the most common (60-80%) and are more often argentaffin positive.

Hindgut carcinoids, occurring in rectum and colon are more commonly argyrophil type, and comprise about 1020% of carcinoids.

Foregut carcinoids, located in the stomach, duodenum and oesophagus are also argyrophil type and are encountered as frequently as in the hindgut (10-20%).

Other uncommon locations are the bronchus, trachea, gallbladder, and Meckel’s diverticulum.

Appendix and terminal ileum, the two most common sites for carcinoids, depict variation in their age and sex incidence and biologic behaviour:

Appendiceal carcinoids, occur more frequently in 3rd and 4th decades of life without any sex predilection, are often solitary and behave as locally malignant tumours.

Ileal carcinoids, on the other hand, are seen more often in later age (7th decade) with female preponderance, are more commonly multiple and behave like metastasising carcinomas.

MORPHOLOGIC FEATURES. Grossly, all carcinoids are small, button-like submucosal elevations with intact or ulcerated overlying mucosa. They are usually small; those larger than 2 cm are more often metastasising. Ileal and gastric carcinoids are commonly multiple, whereas

locations in longitudinal section.

appendiceal carcinoids commonly involve the tip of the organ and are solitary (Fig. 20.36). Cut section of all the carcinoids is bright yellow.

Histologically, the tumour cells may be arranged in a variety of patterns—solid nests, sheets, cords, trabeculae and clusters, all of which show characteristic palisading of the peripheral cells. Acinar arrangement and rosettes are rarely seen. The tumour cells are classically small, monotonous, having uniform nuclei and poorly-defined cell boundaries (Fig. 20.37). The argentaffin carcinoids show eosinophilic granules in the cytoplasm which stain positively by the argentaffin reaction. Mitotic figures are rare. However, the cytologic features are a poor guide for distinguishing clinically benign from malignant behaviour of the tumour, but all carcinoids infiltrate the bowel wall.

CARCINOID SYNDROME. Carcinoid tumours that metastasise, especially to the liver, are sometimes associated with the carcinoid syndrome. The syndrome consists of the following features:

1.Intermittent attacks of flushing of the skin of face

2.Episodes of watery diarrhoea

3.Abdominal pain

4.Attacks of dyspnoea due to bronchospasm

5.Right-sided heart failure due to involvement of tricuspid and pulmonary valves and endocardium (page 451).

A number of secretory products in a functioning carcinoid tumour have been demonstrated:

i)5-Hydroxytryptamine (5-HT, serotonin)

ii)5-Hydroxytryptophan

iii)5-Hydroxy-indole acetic acid (5-HIAA)

iv)Histamine

v)Kallikrein

vi)Bradykinin

However, 5-HT and its degradation product, 5-HIAA, are particularly significant in the production of carcinoid syndrome. 5-HT, a potent vasodilator and smooth muscle stimulant, is normally synthesised in the endocrine cells of the gut from dietary tryptophan. Tryptophan is first hydroxylated to 5-hydroxytryptophan, then decarboxylated to 5-HT and further oxidised to 5-HIAA by the monoamine oxidase in the liver cells. It is then excreted in the urine. This capacity to synthesise 5-HT and 5-HIAA is markedly elevated in primary and hepatic metastatic carcinoids. Midgut carcinoids have rich decarboxylating enzymes and are thus able to produce large quantities of 5-HT and 5-HIAA, accounting for high frequency of carcinoid syndrome in them. Foregut and hindgut carcinoids, on the other hand, lack decarboxylating enzymes and, therefore, are less often associated with carcinoid syndrome.

APPENDIX

NORMAL STRUCTURE

Appendix is a vestigial organ which serves no useful purpose in human beings but instead becomes the site of trouble at times. It is like a diverticulum of the caecum, usually lying behind the caecum and varies in length from 4 to 20 cm (average 7 cm).

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578Histologically, appendix has four layers in its wall— mucosa, submucosa, muscularis and serosa. The mucosa has patchy distribution of crypts and the submucosa has abundant lymphoid tissue. Argentaffin and nonargentaffin endocrine cells are present in the base of mucosal glands just as in the small intestine. The muscularis of the appendix has two layers (inner circular and outer longitudinal) as elsewhere in the alimentary tract.

Two important diseases involving the appendix are

Figure 20.38 Acute appendicitis. Gross appearance of longitudinally opened appendix showing impacted faecolith in the lumen and exudate on the serosa.

MORPHOLOGIC FEATURES. Grossly, the appearance depends upon the stage at which the acutely-inflamed appendix is examined. In early acute appendicitis, the organ is swollen and serosa shows hyperaemia. In welldeveloped acute inflammation called acute suppurative appendicitis, the serosa is coated with fibrinopurulent exudate and engorged vessels on the surface. In further advanced cases called acute gangrenous appendicitis, there is necrosis and ulcerations of mucosa which extend through the wall so that the appendix becomes soft and friable and the surface is coated with greenish-black gangrenous necrosis (Fig. 20.38).

Microscopically, the most important diagnostic histological criterion is the neutrophilic infiltration of the muscularis. In early stage, the other changes besides acute inflammatory changes, are congestion and oedema of the appendiceal wall. In later stages, the mucosa is sloughed off, the wall becomes necrotic, the blood vessels may get thrombosed and there may be neutrophilic abscesses in the wall. In either case, an impacted foreign body, faecolith, or concretion may be seen in the lumen (Fig. 20.39).

Thus, there is good correlation between macroscopic and microscopic findings in acute appendicitis.

CLINICAL COURSE. The patient presents with features of acute abdomen as under:

1.Colicky pain, initially around umbilicus but later localised to right iliac fossa

2.Nausea and vomiting

3.Pyrexia of mild grade

4.Abdominal tenderness

5.Increased pulse rate

6.Neutrophilic leucocytosis.

An attack of acute appendicitis predisposes the appendix

to repeated attacks (recurrent acute appendicitis) and thus surgery has to be carried out. If appendicectomy is done at a later stage following acute attack (interval appendicectomy), pathological changes of healing by fibrosis of the wall and chronic inflammation are observed.

COMPLICATIONS. If the condition is not adequately managed, the following complications may occur:

1.Peritonitis. A perforated appendix as occurs in gangrenous appendicitis may cause localised or generalised peritonitis.

2.Appendix abscess. This is due to rupture of an appendix giving rise to localised abscess in the right iliac fossa. This abscess may spread to other sites such as between the liver and diaphragm (subphrenic abscess), into the pelvis between the urinary bladder and rectum, and in the females may involve uterus and fallopian tubes.

3.Adhesions. Late complications of acute appendicitis are fibrous adhesions to the greater omentum, small intestine and other abdominal structures.

4.Portal pylephlebitis. Spread of infection into mesenteric veins may produce septic phlebitis and liver abscess.

5.Mucocele. Distension of distal appendix by mucus following recovery from an attack of acute appendicitis is referred to as mucocele. It occurs generally due to proximal obstruction but sometimes may be due to a benign or malignant neoplasm in the appendix. An infected mucocele may result in formation of empyema of the appendix.

TUMOURS OF APPENDIX

Tumours of the appendix are quite rare. These include: carcinoid tumour (the most common), pseudomyxoma peritonei and adenocarcinoma.

CARCINOID TUMOUR. It is already described on page 576. Both argentaffin and argyrophil types are encountered, the former being more common.

Grossly, carcinoid tumour of the appendix is mostly situated near the tip of the organ and appears as a circumscribed nodule, usually less than 1 cm in diameter, involving the wall but metastases are rare.

Histologically, carcinoid tumour of the appendix resembles other carcinoids of the midgut.

PSEUDOMYXOMA PERITONEI. Pseudomyxoma peritonei 579 is appearance of gelatinous mucinous material around the appendix admixed with epithelial tumour cells. It is generally

due to mucinous collection from benign mucinous cystadenoma of the ovary or mucin-secreting carcinoma of the appendix.

ADENOCARCINOMA. It is an uncommon tumour in the appendix and is morphologically similar to adenocarcinoma elsewhere in the alimentary tract.

LARGE INTESTINE

580CONGENITAL MALFORMATIONS Hirschsprung’s Disease (Congenital Megacolon)

The term ‘megacolon’ is used for any form of marked dilatation of the entire colon or its segment and may occur as a congenital or acquired disorder. Congenital form characterised by congenital absence of ganglion cells in the bowel wall (enteric neurons) is called Hirschsprung’s disease. As a result, the aganglionic segment remains contracted. Genetically, Hirschsprung’s disease is a heterogeneous disorder as under:

1.Autosomal dominant inheritance with mutation in RET proto-oncogene in some cases.

2.Autosomal recessive form with mutation in endothelin-B receptor gene in many other cases.

Depending upon the length of the segment affected by aganglionosis in Hirschsprung’s disease, following patterns are recognised:

1.Classic form: Anganglionosis from distal colorectal region to proximal dilated colon.

2.Short segment (rectal and recto-sigmoid) form: Aganglionosis involving a few centimeters of the rectum and rectosigmoid only.

3.Ultra-short form: Aganglionosis is in a very small segment which can be missed in a biopsy.

4.Long segment (subtotal colonic) form: Aganglionosis involves most of the colon from rectosigmoid to the ileocaecal valve, and sometimes may even extend into smll bowel.

Figure 20.40 Hirschsprung’s disease, diagrammatic representation of the pathologic changes.

5. Zonal colonic aganglionosis: A short segment is nvolved in agnaglionosis in which the ganglia cells are absent both above and below the aganglionic segment.

In addition to congenital megacolon discussed above, megacolon may occur from certain acquired causes as under:

i.Obstructive e.g. due to tumour, post-inflammatory strictures.

ii.Endocrine e.g. in myxoedema, cretinism.

iii.CNS disorders e.g. spina bifida, paraplegia, parkinsonism.

iv.Psychogenic e.g. emotional disturbances, psychiatric disorders.

v.Chagas’ disease due to infection with Trypanosoma cruzi is the only example resulting in acquired loss of ganglion cells. In all other acquired causes listed above, the bowel innervation is normal.

COLITIS

Colitis may occur in isolation but more commonly involvement of small intestine is also present (enterocolitis). In view of the considerable overlapping of enteritis and colitis, these lesions have already been described under small intestine (page 578). Table 20.9 presents a classification of the various types of colitis/enterocolitis.

 TABLE 20.9: Classification of Colitis/Enterocolitis.

I.ISCHAEMIC BOWEL DISEASE Ischaemic colitis (‘Membranous’ colitis)

II.INFLAMMATORY BOWEL DISEASE

1.Ulcerative colitis

2.Crohn’s disease

III.OTHER INFLAMMATORY LESIONS

1.Infective enterocolitis (Dysenteries—bacillary, amoebic, other parasitic)

2.‘Pseudomembranous’ enterocolitis (Antibiotic-associated diarrhoea)

3.Necrotising enterocolitis

MISCELLANEOUS LESIONS

Diverticulosis Coli

Diverticula are the outpouchings or herniations of the mucosa and submucosa of the colon through the muscle wall. Diverticular disease, as it is commonly known, is rare under 30 years of age and is seen more commonly as the age advances. Multiple diverticula of the colon are very common in the Western societies, probably due to ingestion of lowfibre diet but is seen much less frequently in tropical countries and in Japan. Diverticulosis is often asymptomatic and may be detected as an incidental finding at autopsy. However, a proportion of patients develop clinical symptoms such as low abdominal pain, distension, constipation and sometimes intermittent bleeding.

Based on the etiologic role of low fibre diet, pathogenesis of diverticular disease of the colon can be explained as under:

1.Increased intraluminal pressure such as due to low fibre content of the diet causing hyperactive peristalsis and thereby sequestration, of mucosa and submucosa.

2.Muscular weakness of the colonic wall at the junction of the muscularis with submucosa.

MORPHOLOGIC FEATURES. Grossly, diverticulosis is seen most commonly in the sigmoid colon (95%) but any other part of the entire colon may be involved. They may vary in number from a few to several hundred. They appear as small, spherical or flask-shaped outpouchings, usually less than 1 cm in diameter, commonly extend into appendices epiploicae and may contain inspissated faeces. They are connected to the intestinal lumen by a narrow neck.

Histologically, the flask-shaped structures extend from the intestinal lumen through the muscle layer. The colonic wall in the affected area is thin and is composed of atrophic mucosa, compressed submucosa and thin or deficient muscularis. However, muscularis propria in between the diverticular protrusions is hypertrophied. While diverticular disease may remain asymptomatic, inflammatory changes in the diverticula (diverticulitis) produce clinical symptoms.

The complications of diverticulosis and diverticulitis are perforation, haemorrhage, intestinal obstruction and fistula formation.

Melanosis Coli

Melanosis coli is a peculiar condition in which mucosa of the large intestine acquires brown-black colouration. The condition is said to occur in individuals who are habitual users of cathartics of anthracene type.

Grossly, the mucosal surface is intact and is pigmented brown-black.

Microscopically, large number of pigment-laden macrophages are seen in the lamina propria. The nature of this pigment is found to be both melanin and lipofuscin.

Haemorrhoids (Piles)

Haemorrhoids or piles are the varicosities of the haemorrhoidal veins. They are called ‘internal piles’ if dilatation is of superior haemorrhoidal plexus covered over by mucous membrane, and ‘external piles’ if they involve inferior haemorrhoidal plexus covered over by the skin. They are common lesions in elderly and pregnant women. They commonly result from increased venous pressure. The possible causes include the following:

1.Portal hypertension

2.Chronic constipation and straining at stool

3.Cardiac failure

4.Venous stasis of pregnancy

5.Hereditary predisposition

6.Tumours of the rectum.

Microscopically, thin-walled and dilated tortuous veins are seen under the rectal mucosa (internal piles) or anal skin (external piles). Secondary changes and complications that may occur include: thrombosis, haemorrhage, inflammation, scarring and strangulation (prolapsed piles).

Angiodysplasia

Angiodysplasia is a submucosal telangiectasia affecting caecum and right colon that causes recurrent acute and chronic haemorrhage. The condition is more common in the elderly past 6th decade. The pathogenesis is obscure but is possibly due to mechanical obstruction of the veins.

MISCELLANEOUS INFLAMMATORY CONDITIONS

‘Fistula-in-ano’ is a well known and common condition in which one or more fistulous tracts pass from the internal opening at the pectinate line through the internal sphincter on to the skin surface. The condition probably results from infection of the anal glands.

Histologically, nonspecific inflammatory changes are seen.

‘Anal fissure’ is an ulcer in the anal canal below the level of the pectinate line, mostly in midline and posteriorly. The common cause is trauma due to passage of hard stools, followed by chronic infection.

‘Solitary rectal ulcer syndrome’ is a condition characterised usually by solitary, at times multiple, rectal ulcers with prolapse of rectal mucosa and development of proctitis. The histological appearance is quite characteristic. Besides ulceration and inflammation of the rectal mucosa, lamina propria is occupied by spindle-shaped fibroblasts and smooth muscle cells. The condition is also called as ‘localised form of colitis cystica profunda’ and must be differentiated from ‘diffuse form of colitis cystica profunda’ seen in cases of ulcerative colitis. Submucosal cysts lined by foreign body giant cells and containing gas are also seen in ‘pneumatosis cystoides

intestinalis’.

LARGE INTESTINAL POLYPS AND TUMOURS

Large bowel is the most common site for a variety of benign and malignant tumours, majority of which are of epithelial

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582  TABLE 20.10: Polyps and Tumours of the Large Intestine.

I.COLORECTAL POLYPS

A.Non-neoplastic polyps

1.Hyperplastic (metaplastic) polyps

2.Hamartomatous polyps

(i)Peutz-Jeghers polyps and polyposis

(ii)Juvenile (Retention) polyps and polyposis

3.Inflammatory polyps (Pseudopolyps)

4.Lymphoid polyps

B.Neoplastic polyps (Adenomas)

1.Tubular adenoma (Adenomatous polyp)

2.Villous adenoma (Villous papilloma)

3.Tubulovillous adenoma (Papillary adenoma, villoglandular adenoma)

C.Familial polyposis syndromes

1.Familial polyposis coli (Adenomatosis)

2.Gardner’s syndrome

3.Turcot’s syndrome

4.Juvenile polyposis syndrome

II.OTHER BENIGN COLORECTAL TUMOURS

(Leiomyomas, leiomyoblastoma, neurilemmoma, lipoma and vascular tumours)

polyps. A classification of polyps, alongwith benign tumours

COLORECTAL POLYPS

A polyp is defined as any growth or mass protruding from the mucous membrane into the lumen. Polyps are much more common in the large intestine than in the small intestine and are more common in the rectosigmoid colon than the proximal colon. Polyps are broadly classified into 2 groups— non-neoplastic and neoplastic. Non-neoplastic polyps have further subtypes indicating their mode of origin. Neoplastic polyps, on the other hand, include epithelial tumours, both benign and malignant (Table 20.10).

A. NON-NEOPLASTIC POLYPS

Non-neoplastic polyps are more common and include the following 4 subtypes:

Hyperplastic (Metaplastic) Polyps

The hyperplastic or metaplastic polyps are the most common amongst all epithelial polyps, particularly in the

rectosigmoid. They are called ‘hyperplastic’ because there is epithelial hyperplasia at the base of the crypts, and ‘metaplastic’ as there are areas of cystic metaplasia. They may be seen at any age but are more common in the elderly (6th-7th decade).

Grossly, hyperplastic polyps are generally multiple, sessile, smooth-surfaced and small (less than 0.5 cm). Microscopically, they are composed of long and cystically dilated glands and crypts lined by normal epithelial cells. Their lining is partly flat and partly papillary. The luminal border of the lining epithelium is often serrated or sawtoothed.

Hyperplastic polyps are usually symptomless and have no malignant potential unless there is a coexistent adenoma.

Hamartomatous Polyps

These are tumour-like lesions composed of abnormal mixture of tissues indigenous to the part. They are further of 2 types:

PEUTZ-JEGHERS POLYPS AND POLYPOSIS. PeutzJeghers syndrome is autosomal dominant defect, characterised by hamartomatous intestinal polyposis and melanotic pigmentation of lips, mouth and genitalia. The polyps may be located in the stomach, small intestine or colon but are most common in the jejunum and ileum. The most common age is adolescence and early childhood.

Grossly, these polyps are of variable size but are often large, multiple and pedunculated and more commonly situated in the small intestine.

Microscopically, the most characteristic feature is the treelike branching of muscularis mucosae. The lining epithelium is by normal-appearing epithelial cells. The glands may show hyperplasia and cystic change

(Fig. 20.41).

Peutz-Jeghers polyps do not undergo malignant transformation unless a coexistent adenoma is present. However, patients with Peutz-Jeghers syndrome are more prone to certain other cancers such as of pancreas, lung, breast, ovary and uterus.

JUVENILE (RETENTION) POLYPS. Juvenile or retention polyps, another form of hamartomatous polyps, occur more commonly in children below 5 years of age. Solitary juvenile polyps occur more often in the rectum, while juvenile polyposis may be present anywhere in the large bowel.

Grossly, juvenile polyps are spherical, smooth-surfaced, about 2 cm in diameter and are often pedunculated. Microscopically, the classical appearance is of cystically dilated glands containing mucus and lined by normal mucus-secreting epithelium. The stroma may show inflammatory cell infiltrate if there is chronic ulceration of the surface (Fig. 20.42).

Most cases, on becoming symptomatic in the form of rectal bleeding, are removed. In common with other nonneoplastic polyps, they are also not precancerous.

Inflammatory Polyps (Pseudopolyps)

Inflammatory polyps or pseudopolyps appear due to reepithelialisation of the undermined ulcers and overhanging margins in inflammatory bowel disease, most frequently in ulcerative colitis (colitis polyposa) and sometimes in Crohn’s disease.

Grossly, they are usually multiple, cylindrical to rounded overgrowths of mucosa and may vary from minute nodules to several centimeters in size.

Microscopically, the centre of inflammatory polyp consists of connective tissue core that shows some inflammatory cell infiltrate and is covered superficially by regenerating epithelial cells and some cystically-dilated glands.

These lesions have no malignant potential; carcinomas seen in long-standing cases of ulcerative colitis arise in the region of epithelial dysplasia and not from the polyps.

Lymphoid Polyps

Reactive hyperplasia of lymphoid tissue that is normally also more prominent in the rectum and terminal ileum, gives rise to localised or diffuse lymphoid polyps, also called rectal tonsils. Localised form occurs more often in the rectum in elderly, while diffuse form is seen at younger age and in children.

Grossly, they are solitary or multiple, tiny elevated lesions. Microscopically, they are composed of prominent lymphoid follicles with germinal centres located in the submucosa and mucosa, and are covered by epithelium that may be inflamed.

They are benign lesions and have to be distinguished from malignant lymphoma.

B. NEOPLASTIC POLYPS (ADENOMAS)

Neoplastic polyps are colorectal adenomas which have potential for malignant change while polypoid carcinoma is

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Pathology Systemic III SECTION

Figure 20.43 Adenomas (neoplastic polyps)—three main varieties.

the term used for invasive epithelial tumours. Adenomas have 3 main varieties (tubular, villous and tubulovillous), each of which represents a difference in the growth pattern of the same neoplastic process and variable biological behaviour.

Tubular Adenoma (Adenomatous Polyp)

Tubular adenomas or adenomatous polyps are the most common neoplastic polyps (75%). They are common beyond 3rd decade of life and have slight male preponderance. They occur most often in the distal colon and rectum. They may be found singly as sporadic cases, or multiple tubular adenomas as part of familial polyposis syndrome with autosomal dominant inheritance pattern. Tubular adenomas may remain asymptomatic or may manifest by rectal bleeding.

Grossly, adenomatous polyps may be single or multiple, sessile or pedunculated, vary in size from less than 1 cm to large, spherical masses with an irregular surface. Usually, the larger lesions have recognisable stalks.

Microscopically, the usual appearance is of benign tumour overlying muscularis mucosa and is composed of branching tubules which are embedded in the lamina propria. The lining epithelial cells are of large intestinal type with diminished mucus secreting capacity, large nuclei and increased mitotic activity (Fig. 20.43,A). However, tubular adenomas may show variable degree of cytologic atypia ranging from atypical epithelium restricted within the glandular basement membrane called as ‘carcinoma in situ’ to invasion into the fibrovascular stromal core termed as frank adenocarcinoma.

Malignant transformation is present in about 5% of tubular adenomas; the incidence being higher in larger adenomas.

Villous Adenoma (Villous Papilloma)

Villous adenomas or villous papillomas of the colon are much less common than tubular adenomas. The mean age at which they appear is 6th decade of life with approximatey equal sex incidence. They are seen most often in the distal colon and rectum, followed in decreasing frequency, by rest of the colon.

Grossly, villous adenomas are round to oval exophytic masses, usually sessile, varying in size from 1 to 10 cm or more in diameter. Their surface may be haemorrhagic or ulcerated.

Microscopically, the characteristic histologic feature is the presence of many slender, finger-like villi, which appear to arise directly from the area of muscularis mucosae. Each of the papillae has fibrovascular stromal core that is covered by epithelial cells varying from apparently benign to anaplastic cells. Excess mucus secretion is sometimes seen (Fig. 20.43,B).

Villous adenomas are invariably symptomatic; rectal bleeding, diarrhoea and mucus being the common features. The presence of severe atypia, carcinoma in situ and invasive carcinoma are seen more frequently. Invasive carcinoma has been reported in 30% of villous adenomas.

Tubulovillous Adenoma

(Papillary Adenoma, Villoglandular Adenoma)

Tubulovillous adenoma is an intermediate form of pattern between tubular adenoma and villous adenoma. It is also

known by other names like papillary adenoma and villoglandular adenoma. The distribution of these adenomas is the same as for tubular adenomas.

Grossly, tubulovillous adenomas may be sessile or pedunculated and range in size from 0.5-5 cm. Microscopically, they show intermediate or mixed pattern, characteristic vertical villi and deeper part showing tubular pattern (Fig. 20.43,C).

The behaviour of tubulovillous adenoma is intermediate between tubular and villous adenomas.

The contrasting features of non-neoplastic and neoplastic colorectal polyps are given in Table 20.11.

C. FAMILIAL POLYPOSIS SYNDROMES

Familial polyposis syndromes are a group of disorders with multiple polyposis of the colon with autosomal dominant inheritance pattern. Important conditions included in familial polyposis are:

1.Familial polyposis coli (adenomatosis)

2.Gardner’s syndrome

3.Turcot’s syndrome

4.Juvenile polyposis syndrome

Some other conditions in which multiple polyposis of colon occur but do not have familial basis are Peutz-Jeghers syndrome (hamartomatous), Cronkhite-Canada syndrome (inflammatory), and nodular lymphoid hyperplasia. The familial polyposis syndromes are as follows.

Familial Polyposis Coli (Adenomatosis)

This hereditary disease is defined as the presence of more than 100 neoplastic polyps (adenomas) on the mucosal surface of the colon; the average number is about 1000 (Fig. 20.44). Adenomatosis can be distinguished from multiple adenomas in which the number of adenomas is fewer, not exceeding 100. The condition has autosomal dominant transmission and is due to germline mutations in APC gene which results in occurrence of hundreds of adenomas which progress to invasive cancer. The average age at diagnosis is 2nd and 3rd decades of life with equal incidence in both the sexes.

Grossly and microscopically, the commonest pattern is that of adenomatous polyps (tubular adenomas) discussed above.

The malignant potential of familial polyposis coli is very high. Colorectal cancer develops virtually in 100% of cases by age of 50 years if not treated with colectomy. This subject of ‘adenoma-carcinoma sequence’ has been discussed again on page 586.

Gardner’s Syndrome

Gardner’s syndrome is combination of familial polyposis coli and certain extra-colonic lesions such as multiple osteomas (particularly of the mandible and maxilla), sebaceous cysts

straddled with multiple polyoid structures (arrow) of varying sizes many of which are pedunculated.

Tract Gastrointestinal The 20 CHAPTER

586 and connective tissue tumours. The number of polyps in Gardner’s syndrome is generally fewer than in the familial polyposis coli but their clinical behaviour is identical.

Turcot’s Syndrome

Turcot’s syndrome is combination of familial polyposis coli and malignant neoplasms of the central nervous system.

Juvenile Polyposis Syndrome

Juvenile polyposis is appearance of multiple juvenile polyps in the colon, stomach and small intestine but their number is not as high as in familial polyposis coli. Family history in some cases may show autosomal dominant inheritance pattern, while it may be negative in others. They resemble the typical juvenile polyps as regards their age (under 5 years), sex distribution and morphology. They lack the malignant potential.

duration changes the bacterial flora of the bowel, thus resulting in production of carcinogenic substances.

3. Adenoma-carcinoma sequence. There is strong evidence to suggest that colonic adenocarcinoma evolves from preexisting adenomas, referred to as adenoma-carcinoma sequence (Fig. 20.45). The following evidences are cited to support this hypothesis:

i)In a case with early invasive cancer, the surrounding tissue often shows preceding changes of evolution from adenoma → hyperplasia → dysplasia → carcinoma in situ → invasive carcinoma.

ii)Incidence of adenomas in a population is directly proportionate to the prevalence of colorectal cancer.

iii)The risk of adenocarcinoma colon declines with endoscopic removal of all identified adenomas.

iv)Peak incidence of adenomas generally precedes by some years to a few decades the peak incidence for colorectal cancer.

v)The risk of malignancy increases with the following

adenoma-related factors:

a)Number of adenomas: familial polyposis coli syndrome almost certainly evolves into malignancy.

b)Size of adenomas: large size increases the risk.

c)Type of adenomas: greater villous component associated with higher prevalence.

4.Hereditary non-polyposis colonic cancer (HNPCC or Lynch syndrome). HNPCC is an autosomal dominant condition in which colorectal cancer is seen in at least two generations of first-degree relatives before the age of 50 years, without evidence of familial polyposis coli. There are germline mutations in mismatch repair genes, human mutL homolog abbreviated as hMLH2 located on chromosome 2 and hMLH1 on chromosome 3 resulting in DNA instability. In HNPCC, colon cancer appears at a relatively younger age (<50 years), association with multiple primary cancers at different sites (e.g. endometrium, ovary), preferred location in proximal colon and better prognosis than other sporadic colon cancer cases.

5.Other factors. Presence of certain pre-existing diseases such as inflammatory bowel disease (especially ulcerative colitis) and diverticular disease for long duration increase the risk of developing colorectal cancer subsequently. It may be recalled here that low fibre diet is implicated in the pathogenesis of diverticular disease as well. Besides, there is an etiologic role of tobacco smoking in development of colorectal cancer in youger patients.

GENETIC BASIS OF COLORECTAL CARCINOGENESIS.

Studies by molecular genetics have revealed that there are sequential multistep mutations in evolution of colorectal cancer from adenomas by one of the following two mechanisms:

1. APC mutation/ β-catenin mechanism. This pathway of multiple mutations is generally associated with morphologically identifiable changes as described above in adenoma-carcinoma sequence. These changes are as under: i) Loss of tumour suppressor APC (adenomatous polyposis coli) gene located on the long arm of chromosome 5 (5q) is present