NORMAL STRUCTURE AND FUNCTION

The mouth and teeth masticate the food prior to swallowing and digestion. At the same time digestion is initiated by the addition of salivary amylases and lipases.

The mouth is lined by stratified squamous epithelium overlying richly vascular connective tissue. The epithelium is of variable thickness, being thickest over the tongue where there are also papillary projections which account for its rougher texture. The epithelium is mostly non-keratinised, except over the lips, gums and hard palate where slight keratinisation occurs. Elsewhere pathological keratinisation (keratosis) results in the formation of white plaques on the mucosa; this is termed leukoplakia.

The teeth consist principally of dentine, which is similar to bone; it is composed of a collagen matrix mineralised by calcium phosphate (apatite) crystals. It differs from bone, however, in that its cellular constituents (odontoblasts) form a layer over the surface of the dentine, from which long tubular processes ramify through the tissue. The dentine is covered over the exposed part of the tooth (crown) by enamel, which is composed almost entirely of inorganic material arranged in stacked crystalline rods. The dentine of the root is covered by a thin layer of cementum which, as its name implies, attaches the tooth to the periodontal ‘ligament’ lining the socket. Centrally, the tooth has a connective tissue core, the pulp, which links with the narrow root canal.

The salivary glands are usually categorised as either major or minor. The major glands are the parotid, submandibular and sublingual glands; minor glands are scattered throughout the oral cavity. The parotids enclose branches of the facial nerve and a few lymph nodes. The glandular tissue comprises multiple small secretory acini lined by plump cells containing zymogen granules and surrounded by supporting myoepithelial cells. The secretion has a low protein content, hence these glandular units are referred to as serous acini. Small ducts lined by cuboidal epithelium drain the glandular lobules and unite to form the main secretory (Stensen’s) duct. The submandibular glands contain both serous and mucus-secreting cells in mixed acini; the sublingual and minor salivary glands are predominantly or entirely mucus-secreting. The main ducts of the submandibular glands (Wharton’s ducts) are lined by partly ciliated epithelium to facilitate drainage of the more viscid mucous secretion.

Hare-lip and cleft palate

Hare-lip may appear as a sporadic defect of development but may also occur as an inherited condition exhibiting male sex linkage. The inherited form occurs both with and without a cleft palate. Where a cleft palate exists alone, a proportion of the cases are due to a dominant gene of low penetrance. Other cases are not genetically determined, as for example in the rubella syndrome (Ch. 5).

Hare-lip may be unilateral or bilateral; it may involve the lip only, or extend upwards and backwards to include the floor of the nose and the alveolar ridge. Cleft palate may vary considerably, from a small defect in the soft palate, which causes little disability, to a complete separation of the hard palate combined with hare-lip. With extensive lesions, there may be considerable difficulty with feeding as the child is unable to suck.

Dental caries

Caries (‘tooth decay’) is the result of acid destruction of the calcified components of the teeth (Fig. 15.1). These structures are in a dynamic equilibrium between de- and re-mineralisation. When the pH falls below 5.5, de-mineralisation outstrips re-mineralisation; erosion of enamel is followed by loss of dentine. The acid is produced by bacteria, usually specific strains of Streptococcus mutans, acting mainly on refined sugar which is trapped in contact with the enamel by ‘plaque’—a mixture of adhesive sugar residues and bacteria. Thus, a lack of oral hygiene, excessive consumption of sugars and under-development of dentine contribute to the development of caries. Penetration of the dentine is followed by bacterial invasion; this can infect the pulp, causing pulpitis.

Fig. 15.1 Dental caries. Longitudinal sections of adjacent teeth showing characteristic erosion of enamel and dentine.

(Courtesy of Professor C J Smith, Sheffield.)

Gingivitis

Acute gingivitis (inflammation of the gums) is an uncommon infection caused by the anaerobic Borrelia vincentii and fusiform bacilli. It is a severe ulcerative disease, formerly referred to as Vincent’s infection, which can spread widely along the gum margins and deeply to destroy bone.

Chronic gingivitis, by contrast, is a very common condition which represents the response of the gum to adjacent bacterial plaque. Proliferation of anaerobic bacteria, and possibly their production of proteolytic enzymes, leads to chronic periodontitis and gradual destruction of the supporting tissues of the teeth. This results in loosening and eventual loss of teeth.

Inflammatory disorders

The oral mucous membrane is affected in a wide variety of mucocutaneous inflammatory disorders such as acute erythema multiforme, lichen planus, Behçet’s syndrome and many others. However, some conditions (discussed below) are restricted to the oral mucosa.

Reparative lesions

The oral mucosa is frequently subjected to minor trauma. In some individuals the reparative processes that follow prove excessive, and the surplus fibrovascular tissue appears as a polyp. Such a reparative lesion in the mouth is termed an epulis, of which ‘congenital’ and giant cell forms are recognised. There is also a similar angiomatous ‘tumour’ of pregnancy, and many of the so-called haemangiomas and fibromas of the mouth have the same histogenesis.

Oral leukoplakia and epithelial dysplasia

Leukoplakia (‘white plaque’) is a clinical term for patches of keratosis on the squamous epithelium that cannot be categorised as any other definable lesion, e.g. lichen planus or frictional keratosis. These lesions may be pre-cancerous: up to 18% of leukoplakias become oral cancer. Thus, in leukoplakia there is hyperkeratosis and hyperplasia of the squamous epithelium with, in some cases, dysplastic changes that herald the onset of malignant change. The finding of dysplasia on histological assessment is currently the best predictor of progression.

In the UK and USA, leukoplakia is associated with heavy cigarette smoking, excessive alcohol consumption and poor dental hygiene. The high incidence in India and Sri Lanka is attributed to the habit of chewing ‘quids’ made up of tobacco dust, areca nut and lime wrapped in a betel leaf.

Tumours

Cancer of the lip is more common than intra-oral cancers and occurs mainly in elderly people. It has a definite relationship to sunlight exposure; therefore, it is much more common on the lower than the upper lip. Lip cancers are usually well-differentiated squamous carcinomas which spread directly into surrounding tissues, and through lymphatics to the regional nodes.

Intra-oral cancers most frequently affect the tongue and commonly develop in areas of leukoplakia (Fig. 15.2); many oral carcinomas are associated with leukoplakia when diagnosed. The predisposing causes are therefore the same as those for leukoplakia but with the possibility that human papillomavirus (HPV) could also be implicated. ‘High-risk’ HPVs (mainly type 16 or 18) are more frequently associated with oral squamous carcinoma than low-risk HPVs. Like lip cancers, oral cancers are usually squamous carcinomas. Initially they are painless and can remain undetected, especially if situated on the posterior third of the tongue, until fixation and swelling interfere with swallowing and speech. Late presentation with nodal metastases and direct spread to vital structures explains the much poorer prognosis of cancer of the tongue compared to that of cancer of the lip.

Fig. 15.2 Oral cancer. Ulcerated squamous cell carcinoma (arrowed) arising from buccal mucosa.

(Courtesy of Mr P McAndrew, Rotherham.)

Pharyngitis

Tonsillitis

The faucial tonsils are collections of lymphoid tissue covered by non-keratinising squamous epithelium thrown into a series of clefts; these can harbour debris and act as a nidus for infection. The tonsils are thus a frequent site for bacterial infection, producing either an acute inflammation or, more frequently, recurring chronic inflammation leading to tonsillar enlargement (through lymphoid hyperplasia) and general debility.

Tumours

The pharynx can be the site of squamous carcinoma and of intermediate or ‘transitional’ cell carcinomas, the latter exhibiting features of epithelium transitional between squamous and columnar, respiratory-type epithelium. However, most carcinomas in this site are anaplastic (undifferentiated). In addition, the tonsils may be involved by lymphomas.

Nasopharyngeal carcinoma is of interest because of the wide geographical variation in its incidence. It is an uncommon carcinoma in Caucasians, but in some parts of China (particularly Canton) the frequency is 100-fold higher than in European populations. Males are more frequently affected than females. There appears to be a link with prior infection with Epstein–Barr (EB) virus, and the susceptible Chinese show a relatively higher frequency of the histocompatibility haplotypes HLA-A2 and -Bw46.

Sialadenitis

Acute bacterial sialadenitis (inflammation of the salivary glands) is uncommon. It arises by ascending infection from the mouth and occurs in patients with abnormal dryness of the mouth (xerostomia), either as part of a generalised dehydration or as a result of an autoimmune-induced atrophy of the salivary glands (Sjögren’s syndrome). Acute enlargement of the salivary glands is usually due to mumps virus infection.

Recurrent sialadenitis is seen in patients who have some degree of duct obstruction, hyposecretion of saliva and ascending infection. Duct obstruction can be due to a stone (calculus) or to fibrosis. Hyposecretion may be a direct consequence of duct obstruction but may also be due to the acinar atrophy resulting from sialadenitis itself. Bacterial infection leads to recurrent acute inflammation and also acts as a nidus for stone formation.

Tumours

Pleomorphic adenoma: a benign mixed tumour

Warthin’s tumour (adenolymphoma): a benign tumour

Muco-epidermoid tumour: both benign and malignant forms exist

Adenoid cystic carcinoma: has a tendency for perineural invasion

Pleomorphic adenoma

At least two-thirds of all salivary tumours are accounted for by the pleomorphic adenoma or ‘mixed tumour’, and over 80% occur in the parotid gland. As the name implies, this has a varied histological appearance and is composed of a mixture of stromal and epithelial elements (Fig. 15.3). The myxoid stroma, which is rich in proteoglycans, is thought to be produced by myoepithelial cells; thus, despite its biphasic appearance, it is a purely epithelial neoplasm. Occasionally the stroma has a cartilaginous appearance. Pleomorphic adenomas are essentially benign tumours but are prone to local recurrence if surgical removal is incomplete. The facial nerve is vulnerable during attempts at surgical removal. A very small proportion undergo malignant change and are capable of metastasising; these are termed malignant mixed tumours.

Fig. 15.3 Pleomorphic salivary adenoma. These benign neoplasms consist of a mixture of proliferating epithelium and mucinous connective tissue resembling cartilage surrounded by a capsule of fibrous and compressed salivary tissue.

NORMAL STRUCTURE AND FUNCTION

The oesophagus is a muscular tube lined mostly by squamous epithelium. It extends from the pharynx to the cardia of the stomach and is about 25cm long in the adult. At the upper end there is the cricopharyngeal sphincter; close to the lower end there is a functional sphincter whose position can be determined only by manometry. The upper sphincter contains striated muscle fibres enabling voluntary control over the initiation of swallowing, whereas the remainder of the muscular tube is composed of smooth muscle which propels the food bolus by peristalsis and is under autonomic control. Entry of food into the stomach is facilitated by relaxation of the distal sphincter. Protection of the lower oesophagus against regurgitation of gastric contents is achieved by the distal sphincter assisted by constricting muscle bands in the diaphragm, and an acute valve-like angle of entry into the stomach. The distal 1.5–2cm of the oesophagus is situated below the diaphragm and is lined by columnar mucosa of cardiac type. The squamo-columnar junction is clearly visible on endoscopy and is usually found at about 40cm (measured from the incisor teeth). Proximal extension of this junction is found in hiatus hernia or when there is columnar metaplasia.

The squamous lining of the oesophagus consists of a layer of non-keratinising squamous epithelium overlying connective tissue papillae containing blood vessels and lymphatics. A narrow layer one to two cells thick at the base of the epithelium forms the proliferative compartment from where cells migrate upwards, mature and desquamate at the surface (Fig. 15.4). These cells acquire an increasing glycogen content as they mature. Scattered argyrophil (neuroendocrine) cells and melanoblasts can also be found in the basal layer.

Fig. 15.4 Basal cell hyperplasia in reflux oesophagitis. Normal cell proliferation and migration in the squamous epithelium. In reflux oesophagitis, increased proliferation to compensate for increased cell desquamation results in basal zone hyperplasia and elongation of connective tissue papillae.

Heterotopic tissue

Patches of fundic-type gastric mucosa are occasionally found above the distal sphincter and separated from the columnar lining of the distal oesophagus. These are assumed to be congenitally misplaced (heterotopic) gastric tissue rather than an acquired change; they can lead to ulceration and stricturing due to local acid/pepsin secretion.

Atresia

Atresia is a failure of embryological canalisation. It is more frequent than agenesis of the oesophagus, which is extremely rare. Atresia is usually associated with an abnormal connection (fistula) between the patent part of the oesophagus and the trachea. The affected child cannot swallow and develops an aspiration bronchopneumonia. Urgent surgical correction is required.

Diverticula

Diverticula are outpouchings of the wall of a hollow viscus. Some represent a saccular dilatation of the full thickness of the wall; others are formed by herniation of mucosa through a defect in the muscle coat. Diverticula are more common in the pharynx but can develop in the oesophagus by either traction (external forces pulling on the wall) or pulsion (forcible distension). These diverticula differ from congenital forms in lacking a muscle coat in their wall. They frequently become permanently distended with retained food and cause difficulties in swallowing (dysphagia).

Hiatus hernia

Defined as the presence of part of the stomach above the diaphragmatic orifice, hiatus hernia is the commonest mechanical disorder of the oesophagus and is found in c. 25% of people undergoing investigation for dyspepsia. The herniation of the stomach with subsequent retraction of the oesophagus is largely due to increased intra-abdominal pressure and loss of diaphragmatic muscular tone with ageing. Predisposing factors include obesity, lifting heavy loads, frequent coughing fits, tight-fitting clothes and frequent bending. The consequent incompetence of the oesophageal sphincter results in regurgitation of gastric contents leading to gastro-oesophageal reflux disease (GORD). Hiatus hernia of itself is usually asymptomatic; the condition presents with the symptoms and complications of GORD.

Achalasia

Achalasia is an uncommon condition in which the contractility of the lower oesophagus is lost and there is a failure of relaxation at the sphincter (cardiospasm).

Normal functioning of the oesophagus is dependent upon the integrity of its co-ordinated muscular activity, which in turn relies on normal neuronal transmission of peristaltic signals. Thus dysphagia may arise from fibrosis and atrophy of the smooth muscle, as occurs in progressive systemic sclerosis, or by destruction or degeneration of the intrinsic nerves. The latter can occur in neurotropic infections such as Chagas’ disease (South American trypanosomiasis), or by unknown mechanisms as in the condition of achalasia.

Achalasia results in slowing or retention of the food bolus with increasing obstruction and dilatation of the oesophagus. The cause of this condition is unknown, but there are reduced numbers of ganglion cells in the myenteric plexus, and both myelinated and unmyelinated axons of the extra-oesophageal vagus nerves show Wallerian degeneration (Ch. 6).

Oesophageal varices

Varices are localised dilatations of veins. The veins of the lower oesophagus are a potential site for porto-systemic shunting of blood when portal venous flow through the liver is impaired. Therefore, in portal hypertension (most commonly resulting from cirrhosis of the liver) the submucosal veins of the oesophagus become congested and dilate (Ch. 16). These enlarged veins elevate the mucosa and protrude into the oesophageal lumen where they are easily traumatised by the passage of food. Haemorrhage is thus a frequent complication and, because of the relatively high pressure within the vascular bed, can be torrential and life-threatening.

Mallory–Weiss tears

Two American physicians’ names are associated with rupture of the oesophageal mucosa resulting from repeated retching or vomiting. The mucosa tears in the distal oesophagus close to the gastro-oesophageal junction. This is an important cause of upper gastrointestinal haemorrhage. Bleeding usually stops after 24–48 hours and the tears heal within 10 days or so.

Oesophagitis

Reflux oesophagitis

Gastro-oesophageal reflux disease (GORD) is very common and is diagnosed when regurgitation causes symptoms or damages the mucosa. There is poor correlation between symptoms and oesophagitis; some patients with severe symptoms have little or no damage to the oesophageal lining whereas others with obvious inflammation on endoscopy may be asymptomatic. Clinically, GORD should be diagnosed on the basis of symptoms alone; the characteristic complaint is an awareness of acid regurgitation with central chest pain or discomfort—‘heartburn’. A defective sphincter mechanism at the cardia predisposes to this gastro-oesophageal reflux, which is therefore an invariable accompaniment of hiatus hernia. Smokers are more likely to have GORD, as are obese people.

Benign tumours

Benign tumours are uncommon and comprise about 5% of all neoplasms of the oesophagus; the type most frequently encountered is a leiomyoma. The behaviour of smooth muscle tumours in the alimentary tract is generally difficult to predict (see below) but those arising in the oesophagus are almost invariably benign. Other benign non-epithelial tumours—lipomas, haemangiomas and fibromas—are rare. The only benign epithelial tumour of note is squamous papilloma. Compared with squamous carcinoma (see below) these are rare lesions, certainly in terms of clinical presentation, but are of interest because they are likely to share a common pathogenesis with squamous papillomas at other sites being linked to human papillomavirus (HPV) infection.

Carcinoma

Wide geographic variation in incidence

Links with environmental factors

Two main types: squamous carcinoma and adenocarcinoma

Most adenocarcinomas arise from metaplastic columnar epithelium (Barrett’s oesophagus)

There are two main types of oesophageal carcinoma—squamous and adenocarcinoma. These differ markedly in their aetiology and epidemiology.

Squamous carcinoma

Squamous carcinoma is much more common in males than in females and shows marked geographical variation in incidence. In European countries, the age-standardised annual incidence is around 5 per 100000 population in males and 1 per 100000 in females. However, there are some well-defined high-risk areas, such as north-west France and northern Italy, where the incidence rises to 30 per 100000 in males and 2 per 100000 in females. Globally there are more striking differences. Regions with very high incidence have been identified in Iran, South Africa, Brazil and Central China. In Henan Province in China the mortality rate from carcinoma of the oesophagus exceeds 100 per 100 000 in males and 50 per 100 000 in females.

Epidemiological studies in high-incidence areas have indicated that a high dietary intake of tannic acid, in the form of strong tea or sorghum wheat, or dietary deficiencies of riboflavin, vitamin A and possibly zinc may be important, but other factors such as fungal contamination of foodstuffs, opium usage and thermal injury may also be involved. In Western countries, cigarette smoking and the drinking of alcoholic spirits are associated with a higher incidence.

A factor of current interest is the possible involvement of HPV. Some oesophageal squamous cancers contain HPV in their cells, and viruses of similar subtype can be found in intact and apparently normal oesophageal mucosa. It is therefore possible that virus integrated into the host genome can bring about oncogene activation and carcinogenesis. The involvement of papillomaviruses in the development of bovine oesophageal carcinoma is well established.

Non-specific chronic oesophagitis is common among the general population in high-incidence areas, and biopsies will frequently reveal dysplasia. The squamous epithelium shows cellular pleomorphism: there is disordered maturation with immature cells and mitotic activity appearing close to the surface. The degree of atypia can be categorised as low- or high-grade dysplasia; the latter condition will proceed to invasive carcinoma if surgical resection is not performed. As in the oropharynx, dysplasia is sometimes associated with abnormal keratosis—leukoplakia.

Adenocarcinoma

In the lower third of the oesophagus, adenocarcinomas are the predominant type. They usually develop on the basis of a Barrett’s oesophagus. The incidence has risen dramatically in recent years among white, middle-aged men in European countries and the USA; the reported annual increase in the white male population of the USA is close to 10% which exceeds that of any other malignancy in that population. Although the incidence of adenocarcinoma has increased, it is still a rare disease; in the year 2000 the numbers of new cases in Western countries varied between 1 and 5 per 100000 white males. Nevertheless this incidence approaches, and in some areas exceeds, that of squamous carcinoma of the oesophagus.

Carcinoma of the oesophagus, either squamous or adenocarcinoma, usually commences as an ulcer, but spreads to become annular and constricting so that the patient develops dysphagia (difficulty in swallowing) (Fig. 15.5). However, by the time most patients present, direct spread outside the oesophagus has occurred and the surgical resection rate is only about 40%. Resectability and ultimate survival can be improved by pre-operative chemo-irradiation. Those patients who cannot be surgically treated may undergo chemo- or radiotherapy alone, or receive palliative laser therapy. Unfortunately, a substantial proportion of patients are simply intubated to facilitate adequate nutrition. The long-term outlook is therefore very poor; only 5% survive for 5 years. Most patients die from local disease and bronchopneumonia exacerbated by malnutrition. Unlike many forms of cancer, metastases are uncommon at autopsy.

Fig. 15.5 Carcinoma of the oesophagus. The oesophagus has been opened to reveal an ulcerated tumour partly obstructing its lumen. Blood loss from the ulcerated surface can lead to anaemia, and the partial obstruction causes dysphagia.

Other tumours

Other rare malignant tumours arising in the oesophagus include malignant melanoma (from the melanocytes that are present in very small numbers in normal mucosa), small cell anaplastic carcinoma from neuroendocrine precursors, mixed adenosquamous carcinomas and sarcomas.

NORMAL STRUCTURE AND FUNCTION

The stomach acts essentially as a ‘mixing’ reservoir for food during acid–pepsin digestion. Hydrochloric acid and pepsin are, however, only two of many products of the gastric mucosa.

Histologically, the stomach can be divided into three regions—the cardia, body and antrum. The surface of the gastric mucosa and its pits (foveolae) are lined throughout by columnar mucus-secreting epithelium. The mucus secreted by these cells, together with contributions from the antral mucous glands, forms a viscid gel covering the mucosa—the gastric mucus barrier (Fig. 15.6). Bicarbonate and sodium ions, also secreted by surface epithelial cells, diffuse into the unstirred gel and buffer the hydrogen ions entering from the luminal aspect. A pH gradient is thus established, ranging from 1 or 2 at the luminal surface of the barrier, to neutrality at the plasma membrane of the epithelium. The glandular component varies from region to region.

Fig. 15.6 The gastric mucus barrier. The surface epithelial cells (supplemented by foveolar and glandular mucous cells) secrete viscid mucus which forms an unstirred layer between the epithelium and the gastric lumen. The surface cells also secrete sodium and bicarbonate ions into the mucus gel and a pH gradient is established. This constitutes the major defence against acid attack.

The cardiac (or junctional) mucosa is a narrow zone immediately below the termination of the squamous-lined oesophagus; it comprises simple tubular or cystic glands, lined by mucus-secreting cells, in which endocrine cells are scattered.

Body mucosa lines the proximal two-thirds of the stomach and consists of tightly packed tubular glands, the upper parts of which are lined by parietal cells (acid producing) and the lower parts by chief cells (pepsinogen) (Fig. 15.7A). In addition to acid, the parietal cells secrete intrinsic factor, essential for vitamin B₁₂ absorption. Other cells present in body mucosa are mucous neck cells and endocrine cells. The neck cells are found at the bases of the gastric pits, i.e. at the junction between foveolar lining cells and glandular cells, and contain the stem cells of the mucosa together with some immature foveolar cells. The majority of the endocrine cells are so-called enterochromaffin-like (ECL) cells which are readily identifiable by silver staining (argyrophil) techniques. These cells modulate parietal cell activity by releasing histamine in response to stimulatory hormones such as gastrin.

Fig. 15.7 Structure of the gastric mucosa. Body (corpus) mucosa where the tubular glands contain specialised secretory cells. The ‘neck’ cells represent the proliferative compartment of the gastric pit from where the majority of cells migrate upwards to replenish exfoliated surface cells, and a minority move downwards to replace glandular cells. Antral mucosa, predominantly composed of mucus-secreting cells but with scattered endocrine cells.

Antral (or pyloric) mucosa occupies a roughly triangular region proximal to the pylorus, with its base about one-third of the distance along the lesser curvature and its apex a few centimetres from the pylorus on the greater curve. The antral glands are more branched, tortuous and less tightly packed than those in the body (Fig. 15.7B). The glands are lined by mucus-secreting cells with faintly granular cytoplasm and basal nuclei, together with endocrine cells. There may be occasional parietal cells. The endocrine cells of the antrum produce several hormones: G cells secreting gastrin are the most numerous, but others include D cells (which secrete somatostatin), EC cells (5-hydroxytryptamine, 5-HT), P cells (bombesin) and S cells (secretin).

Diaphragmatic hernia

Maldevelopment of the diaphragm can lead to defects though which the stomach, together with parts of the intestine and the spleen, herniate into the left thoracic cavity. Usually only part of the stomach is dislocated into the thorax, but after birth it may become expanded by swallowed air and can rapidly compress the lungs and, very rarely, cause death from respiratory failure.

Pyloric stenosis

An abnormal hypertrophy of the circular muscle coat at the pylorus can cause outflow obstruction from the stomach. The condition, found in approximately 4 per 1000 live births, usually presents 2–3 weeks after birth with projectile vomiting. It is four to five times more common in males than in females. The primary abnormality appears to lie in the enteric nervous system at this site; the interstitial cells of Cajal (see p. 378) are either absent or abnormal.

Acute gastritis

Acute gastritis is almost invariably an acute response to an irritant ‘chemical’ injury by drugs or alcohol. The principal drugs involved are non-steroidal anti-inflammatory drugs (NSAIDs), including aspirin, but many others have been implicated. These agents cause a prompt exfoliation of surface epithelial cells and diminished secretion of mucus such that the protective barrier against acid attack (see below) may be compromised. Many of their effects are probably mediated by an inhibition of prostaglandin synthesis.

Depending on the severity of the injury, the mucosal response varies from vasodilatation and oedema of the lamina propria, to erosion and haemorrhage. An erosion is an area of partial loss of the mucosa, as opposed to an ulcer where the full thickness, i.e. below the muscularis mucosae, is lost. The erosions in acute gastritis are frequently multiple and the resultant haemorrhage can be severe and life-threatening. Fortunately, the lesions are transient and heal rapidly by regeneration, so that erosions may well have disappeared 24–48 hours after the bleeding episode.

An acute neutrophilic gastritis (i.e. one in which polymorph infiltration is a dominant feature) is characteristic of the initial response to Helicobacter pylori infection. Acute Helicobacter gastritis is a transient phase which in the majority of individuals is subclinical and over the course of 3–4 weeks gives way to chronic gastritis. In a minority of individuals the infection is spontaneously eradicated and the inflammatory response resolves. The pathological features of acute bacterial gastritis are summarised in Table 15.1.

Chronic gastritis

Helicobacter-associated chronic gastritis

The commonest cause of chronic gastritis is bacterial infection by Helicobacter pylori. This is a Gram-negative organism that inhabits a peculiarly protected niche closely applied to the surface epithelium beneath the mucous barrier where the pH approaches neutrality. Besides taking advantage of this acid-protected niche, the organism has its own intrinsic acid buffering mechanism using its urease and ammonia production to neutralise hydrogen ions gaining access to its periplasmic space. The organism binds to the surface cells and, depending on its virulence, exerts cytopathic effects that lead to accelerated cell exfoliation and a polymorph and chronic inflammatory cell response (Fig. 15.8). H. pylori is found in over 90% of biopsies showing active chronic (type B) gastritis but is very uncommon in the autoimmune type. The gastritis resolves after successful eradication of infection with antibiotics. Interestingly, the organism is found only on gastric epithelium and does not colonise duodenal (or any other intestinal) epithelium.

Fig. 15.8 Gastritis resulting from Helicobacter pylori infection. At low magnification, the biopsy reveals an influx of chronic inflammatory cells into the mucosa and lymphoid follicle formation. A section specially stained to reveal numerous minute curved Helicobacter adherent to the mucosal surface.

The neutrophil polymorph response provoked by H. pylori is mediated partly by leukotactic complement components liberated through activation of the alternative pathway (Ch. 9), but principally by bacteria-induced production of interleukin-8 by epithelial cells, macrophages and endothelial cells. Polymorphs subsequently release proteases, reactive oxygen metabolites (ROMs) and reactive nitrogen species into the mucosa. ROM production by leukocytes is enhanced by cytokines, such as tumour necrosis factor-alpha (TNF-alpha), and their cytopathic effects may be responsible for the glandular loss (atrophy) that characterises longstanding chronic gastritis. Anti-H. pylori IgA, IgG and IgM antibodies are produced locally by plasma cells in the lamina propria as part of a Th2-mediated response (Ch. 9); these antibodies have a role in the prevention of bacterial adhesion and in opsonisation, but fail to eliminate the infection.

Histologically, Helicobacter-associated gastritis affects the entire stomach mucosa but to a variable degree. The majority of patients have diffuse involvement of the antrum and body with gradual glandular atrophy, replacement fibrosis and intestinal metaplasia. The loss of parietal cells leads to hypochlorhydria and a reduction in the secreted signals that modulate the growth and differentiation of progenitor cells in the gastric mucosa; this could explain the link between atrophy and metaplasia. Patients with widespread gastritis have an increased risk of gastric ulcer and carcinoma compared with uninfected individuals. A second main pattern is where the antrum is markedly inflamed but with little involvement of body mucosa. These individuals have increased acid output rendering the body mucosa more hostile to H. pylori colonisation. Patients with this antrum-predominant gastritis have a greater risk of duodenal ulcer. Overall, however, only 10–15% of individuals infected with H. pylori develop peptic ulcer disease, and the risk of gastric cancer is about 1–3%. The histological features of acute and chronic gastritis are summarised in Table 15.1.

Other forms of gastritis

Less common forms of chronic gastritis have been distinguished from the three major types discussed above.

In lymphocytic gastritis the main histological feature is the presence of numerous mature lymphocytes within the surface epithelium. This form is occasionally seen in patients who have peculiarly heaped-up erosions running along prominent rugal folds. Most patients are histologically H. pylori-negative at the time of diagnosis but most show serological evidence of infection. Some cases are related to villous atrophy and altered small intestinal function.

Eosinophilic gastritis is characterised by oedema and a large number of eosinophils in the inflammatory cell infiltrate. It is thought to be an allergic response to a dietary antigen to which the patient has become sensitised, or in some countries to parasitic infestation.

Granulomatous gastritis is a rare form of gastritis in which epithelioid cell granulomas are found. Such granulomas can be part of Crohn’s disease (p. 385) or sarcoidosis, but after exclusion of these causes there remains an isolated granulomatous gastritis of unknown aetiology.

Acute ulcers

Acute peptic ulcers develop:

Deeper extension of the erosions in acute gastritis resulting from NSAIDs or acute alcohol overdosage can produce frank ulcers. Acute ulcers occur also in a heterogeneous group of conditions where stress seems to be the common denominator. For example, ulcers may be found following severe burns (Curling’s ulcer), major trauma or cerebrovascular accidents. Such ulcers probably arise as a consequence of mucosal ischaemia, which lowers the mucosal resistance to acid. Extreme hyperacidity, as seen for example in patients with gastrin-secreting tumours (Zollinger–Ellison syndrome), can lead to multiple acute ulcers in the antrum, the duodenum and even the jejunum.

Chronic ulcers

Chronic peptic ulcers (Fig. 15.9) seem to occur most frequently at mucosal junctions. Thus gastric ulcers are often found where antral meets body-type mucosa on the lesser curvature; duodenal ulcers are found in the proximal duodenum close to the pylorus; oesophageal peptic ulcers are found in the squamous epithelium just above the cardio-oesophageal junction; and stromal ulcers—those occurring following construction of a gastro-enterostomy linking stomach and jejunum—are found in the jejunal mucosa immediately adjacent to the gastric mucosa of the stromal margin. This suggests that ulceration is most likely to occur where acid and pepsin first come into contact with a susceptible mucosa.

Fig. 15.9 Chronic gastric ulcer. Histological section through the ulcer revealing a deep breach of the main muscle layers and haemorrhage around an artery (arrowed) in the ulcer base. The patient presented with a profuse haematemesis (vomiting blood) and underwent emergency partial gastrectomy.

Pathogenesis

For many years peptic ulceration has been attributed to excessive acid production. However, there are many problems with this hypothesis. People with gastric ulcers frequently have normal or even subnormal acid production, and over one-half of duodenal ulcer patients do not have hyperacidity. Conversely, many people who are hypersecretors of acid do not get ulcers. Furthermore, while most ulcers respond initially to anti-acid treatment there are frequent relapses. It has therefore become increasingly apparent that mucosal defence against acid attack is of considerable importance (Fig. 15.10). Failure of the mucosal defence mechanisms means that ulcers can result from normal or even decreased quantities of acid.

Fig. 15.10 Peptic ulceration. ‘An ulcer represents the adverse outcome of a conflict between aggressive forces in the stomach or duodenum and the defence mechanisms.’ (Sir Francis Avery-Jones) Normal. Acid/pepsin attack is balanced by the mucus barrier and other defence mechanisms. Increased attack. Hyperacidity (as in the Zollinger–Ellison syndrome) or NSAIDs may bring about the ulceration of ‘normal’ mucosa in the stomach and duodenum. Weakened mucosal defence. This is the major factor in peptic ulceration. Chronic inflammation in the gastric and duodenal mucosa resulting from Helicobacter pylori infection can lead to ulceration in the presence of normal or even reduced levels of acid. Duodenal inflammation results from infection of patches of acid-induced gastric metaplasia in the first part of the duodenum.

Gastric ulcers

The pH of the gastric juice under fasting conditions is extremely acidic (between 1 and 2) so that any unprotected gastric mucosa would rapidly undergo auto-digestion.

The mucosal defences against acid attack consist of:

• a mucus–bicarbonate barrier

• the surface epithelium.

The mucus barrier is the more important of the two lines of defence. The pit-lining and surface epithelial cells of the stomach secrete viscid neutral glycoproteins which form a layer of unstirred mucus on the surface. The mucus itself has acid-resistant properties, but its protective power is greatly enhanced by the establishment of a buffering gradient within the layer brought about by bicarbonate ions.

The surface epithelium constitutes a second line of defence; for its proper functioning it requires integrity of both the apical plasma membrane as a barrier to ion transfer, and cellular metabolic functions, including the production of bicarbonate. These functions are dependent upon an adequate mucosal blood supply.

Ulceration can follow either destruction or removal of the mucus barrier, or a loss of integrity of the surface epithelium. Dissolution of the mucus layer can occur as a primary event as a consequence of duodeno-gastric reflux. The regurgitated bile from the duodenum strips off the mucus barrier and paves the way for acid attack. Acid and bile in combination damage the surface epithelial cells, increasing the permeability of the mucosa. This causes the congestion and oedema of the lamina propria seen in reflux gastritis.

The epithelial barrier may be damaged by the effect of NSAIDs blocking the synthesis of the prostaglandins that normally protect the epithelium. Epithelial injury is also a consequence of H. pylori infection, produced either directly by cytotoxins and ammonia or indirectly as a result of the inflammatory reaction. Thus, in peptic ulcers in the stomach, breakdown of mucosal defence is much more important than excessive acid production.

Duodenal ulcers

Increased production of acid assumes more importance in the pathogenesis of duodenal ulceration; about one-half of such patients have an elevated maximal acid secretion, and even those with a normal maximal acid output may have inappropriately sustained acid secretion without the normal sharp fall-off of acid production during sleep. It has been shown that H. pylori-infected individuals secrete two to six times as much acid as non-infected controls when stimulated by gastrin-releasing peptide. Nevertheless, excess acidity is not the entire explanation and mucosal defence is also important.

The factors causing lowered resistance in the stomach do not usually apply in the duodenum: Helicobacter does not colonise normal duodenal epithelium; the duodenal mucosa is tolerant of bile and pancreatic alkaline secretions; and drugs are generally diluted or absorbed before reaching the duodenum. Nevertheless, Helicobacter is involved in duodenal ulceration because there is gastric metaplasia in response to excess acid. Gastric metaplasia (i.e. a change from intestinal absorptive cells to gastric surface mucous cells) paves the way for colonisation by Helicobacter, which in turn sets up chronic inflammation in the duodenum (duodenitis) and predisposes to ulceration. Furthermore, NSAID-induced ulcers can arise in the duodenum with, or without, pre-existing duodenitis.

Carcinoma of the stomach

Majority are adenocarcinomas

Many arise on a background of chronic gastritis and intestinal metaplasia

Most cases present when clinically advanced

Early cases (carcinoma confined to mucosa or submucosa) have a good prognosis

All gastric ulcers must be regarded as potentially malignant

The incidence of gastric carcinoma, like that of carcinoma of the oesophagus, varies widely both between and within countries. There is a notably high incidence in Japan, China, Colombia and Finland, but even in these countries, as elsewhere in the world, the incidence of carcinoma of the stomach is declining. Despite this fall, gastric cancer is still the second most common fatal malignancy (after lung cancer) in the world, accounting for around 10% of all cancer deaths, with an estimated 750 000 new cases diagnosed annually.

Dysplasia and early gastric cancer

The dysplasia–carcinoma sequence is thought to characterise the development of most gastric cancers, but the finding of dysplasia is relatively uncommon in low-incidence countries such as the UK and USA. Most cancers are advanced at the time of initial diagnosis; in the USA 65% of cases present at an advanced stage (pT3/T4) with nearly 85% of tumours accompanied by lymph node metastases at diagnosis. This accounts for the poor prognosis of gastric cancer, which generally has only a 10–15% survival rate at 5 years after diagnosis. Much better results, however, are obtained when patients undergo radical operations with extensive lymph node clearance. Patients who have such ‘potentially curative resections’ with removal of all regional nodes have a 60% chance of surviving 5 years.

Gastric cancers are classified as either ‘early’ or ‘advanced’ on their depth of invasion into the stomach wall (Fig. 15.11). Early gastric cancer (pT1) is confined to either the mucosa (intra-mucosal carcinoma) or submucosa; advanced gastric cancer extends into or beyond the main muscle coats (pT2–4). Cancers can still be ‘early’ even if lymphatic spread has occurred to regional lymph nodes. The importance of this categorisation lies in their differing prognosis: patients with early gastric cancer have a 5-year survival in excess of 90%. The prognosis of advanced cases rests largely on whether surgery has been truly ‘curative’ in removing the entire tumour. Thus, involvement of the resection margins by carcinoma carries a dire prognosis, as does the presence of covert hepatic or distant lymph node metastases. The best guide to prognosis in potentially curative cases appears to be the number of involved lymph nodes and, to some extent, the histological type of carcinoma.

Fig. 15.11 The spread of gastric cancer. Direct spread and lymph node metastases categorised according to the TNM scheme. Spread confined the mucosa or submucosa is classified as ‘early’, whereas any degree of spread into, or beyond, the main muscle layer is ‘advanced’. The prognosis is highly dependent upon the extent of direct spread.

Morphology

Foci of high-grade dysplasia and intra-mucosal carcinoma may be endoscopically visible as slightly elevated plaques or shallow depressions. Histologically, they may be distinguished according to whether invasion of the lamina propria has occurred, but this can be excluded in high-grade dysplasia only by examination of multiple sections from the entire area of involvement. From a practical point of view the distinction is academic; if either of these lesions is diagnosed in a gastric biopsy, resection is essential. With increasing size, the elevated lesions develop into polypoid and later into fungating carcinomas, while the depressed areas present an excavated ulcerated appearance mimicking that seen in chronic peptic ulcer. The distinction between carcinoma and chronic peptic ulcer cannot be made with certainty on clinical, endoscopic or radiological grounds, so that all gastric ulcers should be subjected to cytology or multiple biopsies both before and after therapy.

Carcinomas of the stomach are almost exclusively adenocarcinomas derived from mucus-secreting epithelial cells. Like other carcinomas, they can be graded according to their degree of differentiation; poorly differentiated carcinomas behave more aggressively than well-differentiated types. However, a better guide to histogenesis results from division into either ‘intestinal’ or ‘diffuse’ types according to the scheme devised by Lauren (Fig. 15.12).

• Intestinal-type carcinomas show glandular formations lined by mucus-secreting cells with plentiful cytoplasm; in other words they resemble colorectal adenocarcinomas. They tend to have an expansile growth pattern with a well-demarcated ‘pushing’ border.

• Diffuse carcinomas, on the other hand, consist of chains of non-cohesive, single cells infiltrating the wall with a poorly demarcated invasive margin. Mucus secretion is generally less apparent, and usually takes the form of intracytoplasmic vacuoles which may compress the nucleus to form so-called ‘signet ring’ cells.

Fig. 15.12 Gastric cancer. An ulcerated cancer of the stomach, initially thought to be a chronic peptic ulcer but biopsies revealed adenocarcinoma. The carcinoma has spread through the wall and breached the peritoneal surface (pT3; arrowed). The two main histological types of gastric adenocarcinoma are: intestinal-type comprising tubular or glandular formations of cohesive cells, and diffuse-type composed of scattered clusters of non-cohesive cells which, in this example, contain a large clear mucin vacuole with compressed nuclei, so-called signet-ring cells (arrowed).

Intestinal-type gastric carcinomas carry a better prognosis than the diffuse type, but this is largely explained by the greater extent of spread of diffuse carcinomas at the time of diagnosis. Interestingly, the intestinal form predominates in high-incidence countries and has a strong correlation with pre-existing Helicobacter-associated chronic gastritis. Diffuse carcinomas predominate in low-incidence countries; this may reflect the increased contribution of genetic factors or EBV infection to cancer development among these populations. Certainly, both autosomal dominant hereditary gastric cancer and EBV-associated cancers are of diffuse type.

Carcinomas spread directly to involve the serosa (pT3), which can lead to peritoneal dissemination. This can result in the formation of a malignant effusion (ascites) or involvement of other organs by transcoelomic spread, of which metastases in the ovaries (Krukenberg tumours) are a classic example. Depending upon the site of the tumour, direct spread can also occur into the pancreas, transverse colon (when fistulation can occur), liver and spleen (pT4). Lymphatic spread is initially to perigastric nodes along both curvatures of the stomach, then to nodes along the right and left gastric, coeliac and splenic arteries (pN1–3). Spread to non-regional nodes such as retro-pancreatic, mesenteric and para-aortic groups is considered to be distant metastasis (M1). Rarely, spread to even more distant nodes is encountered, like the classical involvement of left supraclavicular nodes (Troisier’s sign). Blood-stream spread occurs via the portal vein; liver metastases are frequently evident at the time of presentation.

Other malignant tumours

Adenocarcinomas comprise over 90% of all gastric malignancies. Other malignant tumours include neuroendocrine (carcinoid) tumours (p. 396), malignant stromal tumours and lymphomas.

Lymphomas

The stomach is the commonest site for primary lymphomas to arise in the gastrointestinal tract, accounting for around 40% of all cases, and the incidence is steadily increasing. Lymphomas of the stomach represent about 5% of all gastric malignancies and are most frequently of the non-Hodgkin B-cell type; they are closely related to preceding H. pylori infection.

The normal gastric mucosa is virtually devoid of lymphocytes. H. pylori infection provokes an influx of lymphocytes and plasma cells in an active chronic inflammatory reaction. In keeping with a Th2-mediated response, lymphoid follicles with germinal centres appear in the gastric mucosa together with an increase in intra-epithelial lymphocytes in the immediately overlying epithelium. These features recapitulate those of a mucosa-associated lymphoid tissue (MALT); this acquired MALT provides the tissue of origin for gastric B-cell lymphomas. As with gastric carcinoma, epidemiological studies reveal a much increased risk for the subsequent development of gastric lymphoma when H. pylori-infected individuals are compared with uninfected controls. Indeed, patients with these low-grade B-cell lymphomas (marginal zone lymphomas) are almost always H. pylori-positive. A few cases will result from longstanding H. heilmannii gastritis, a much less common infection contracted from pet cats. In these cross-species Helicobacter infections, the predominant Th2 response favours lymphoma development over adenocarcinoma.

The emergence of a monoclonal proliferation of B-lymphocytes associated with aggressive features, evinced by invasion and destruction of epithelium (lympho-epithelial lesions) and replacement of germinal centres by atypical centrocyte-like B-cells, is characteristic of a low-grade malignant MALT lymphoma (Fig. 15.13). Monoclonality is detected using the polymerase chain reaction to show that a significant proportion of the lymphoid cells contain identically rearranged immunoglobulin heavy chain genes.

Fig. 15.13 H. pylori-related low-grade (marginal zone) lymphoma in the stomach. A dense infiltrate of lymphocytes occupies the mucosa and extends deeply into the submucosa. At high magnification, glands and the deep parts of the gastric pits are surrounded and infiltrated by lymphocytes including atypical forms. These lympho-epithelial lesions (arrowed) are a precursor to destruction of glands by the malignant infiltrate.

High-grade (large-cell) lymphomas consist of dense sheets of large ‘blast’ cells and are almost invariably of B-cell lineage. The transition from chronic gastritis to low-grade and then to high-grade lymphoma is associated with specific, reproducible genetic changes, but the cause remains unknown. Interestingly, the low-grade B-cell lymphomas appear to require the continuing antigenic stimulation of Th2 cells to maintain B-cell proliferation. As a consequence, these lymphomas can show complete regression following successful elimination of H. pylori infection. Deeply infiltrating (pT2–4) low-grade tumours and all high-grade lymphomas require treatment with chemo- and/or radiotherapy. Even so, high-grade lymphomas have a relatively good prognosis (compared to adenocarcinoma) when confined to the stomach (50% survival at 5 years), but the outlook worsens considerably when penetration of the serosa (pT3–4) or involvement of regional lymph nodes has occurred. The stomach may also be involved by lymphomas that have arisen elsewhere; the outlook in these systematised cases depends upon the overall extent, histological type and grade of the lymphoma.

NORMAL STRUCTURE AND FUNCTION

Large intestine

The large intestine has several functions:

The large intestine can be divided into six parts—caecum, ascending colon, transverse colon, descending colon, sigmoid and rectum. These divisions are imprecise, but are useful for describing the sites and extent of disease.

Appendix

The appendix arises from the caecum. It is a blind-ended structure lined internally by colonic-type mucosa, surrounded by submucosa and muscle coats. In children and young adults the mucosa contains numerous prominent lymphoid follicles. In the elderly, the lumen often shows fibrous obliteration.

Atresia and stenosis

Atresia represents either a failure of the gut to canalise or a failure of a segment to develop during fetal growth. A congenital stenosis is a constriction of the bowel arising during fetal development. These lesions are most commonly found in the duodenum or small intestine, and are rare in the colon. Duodenal atresia seems to be a failure of organ development, and around 30% of affected children also have Down’s syndrome; jejuno-ileal atresia commonly appears to be the result of an intra-uterine accident, such as incarceration of the midgut in the physiological umbilical hernia or some other form of vascular occlusion.

Malrotation

The commonest type of malrotation occurs when the large bowel fails to descend into the right iliac fossa after emerging from the physiological umbilical hernia. This means that the caecum remains high in the abdomen and the bands that should fix it in the right iliac fossa (Ladd’s bands) cross the duodenum and compress it, causing extrinsic obstruction.

Duplication and diverticula

Duplication of the bowel may either present as a tubular double-barrelled appearance, or form a cyst in the mesentery. These anomalies can produce an abdominal mass, cause intestinal obstruction, or initiate a volvulus (p. 392). Congenital diverticula are outpouchings of the full thickness of the bowel wall and are found mainly in the duodenum and jejunum. These rarely have clinical consequences, but some patients develop bacterial overgrowth, steatorrhoea and vitamin B₁₂ malabsorption. The diverticula can also undergo perforation and haemorrhage.

Meckel’s diverticulum

Meckel’s diverticulum arises as a result of incomplete regression of the vitello-intestinal duct, such that a tubular diverticulum is present in the ileum. The diverticulum is usually lined by normal small-intestinal mucosa, but occasionally it may contain heterotopic gastric or pancreatic elements. If gastric elements are present, acid and peptic secretion may lead to ulceration at the mouth of the diverticulum and give rise to haemorrhage and perforation. The diverticulum may also become inflamed and present as an acute abdomen which can mimic appendicitis.

Meconium ileus

The term meconium ileus refers to small-intestinal obstruction resulting from thickening and desiccation (inspissation) of the viscid meconium produced by children with cystic fibrosis (Ch. 7). It is seen in about 15% of affected babies and may be complicated by perforation, secondary atresia or volvulus.

Hirschsprung’s disease

Hirschsprung’s disease, or aganglionosis of the intestine, results from a failure of migration of neuroblasts from the vagus into the developing gut, such that the intramural parasympathetic nerve plexuses fail to develop. The distal colon and rectum have an additional parasympathetic supply from extramural nerves derived from the sacral plexus. Under normal circumstances the parasympathetic tone, which controls the contraction of the circular muscle coat, is modulated at the ganglia by the sympathetic innervation. However, in the absence of the myenteric ganglia, the intact extramural parasympathetic supply is unchecked by sympathetic modulation and results in spasm of the circular muscle leading to intestinal obstruction. There is a proliferation of cholinergic nerves derived from this extramural supply throughout the affected segment, and their high content of acetylcholinesterase can be utilised to diagnose Hirschsprung’s disease in frozen sections of rectal mucosa.

Hirschsprung’s disease affects the distal large intestine, extending proximally from the anorectal junction for a variable distance. The rectum and distal colon are usually involved, but the extent varies from 1–2cm to total colonic aganglionosis, or even extension into the small intestine. The effects of the aganglionosis vary from life-threatening total obstruction to mild cases causing chronic constipation. The main cause of death in Hirschsprung’s disease is the development of an acute enterocolitis with endotoxaemia.

Anorectal anomalies

A large variety of malformations have been described that affect the termination of the large bowel. These include:

Anorectal anomalies occur in approximately 1:5000 live births. Most are amenable to surgical correction.

Coeliac disease

Results from sensitivity to gluten components in cereals

Toxic components act largely indirectly through the immune reaction

Diagnosis by finding villous atrophy and crypt hyperplasia on duodenal or jejunal biopsy

Clinically, results in malabsorption but may present with ‘non-specific’ symptoms or anaemia

Complicated by splenic atrophy and, less commonly, lymphoma and small-intestinal ulceration

Coeliac disease is due to an abnormal reaction to gluten, a constituent of wheat, rye and barley, which results in damage to the surface enterocytes of the small intestine and severely reduces their absorptive capacity.

Incidence and clinical manifestations

Overt coeliac disease affects about 1 in 2000 individuals in the UK, but in the west of Ireland this rises to 1 in 300. Surveys in Europe, South America, Australasia and the USA have shown that approximately 0.5–1% of these populations have undetected coeliac disease. Although coeliac disease can be diagnosed at any age, it presents most frequently in either early childhood or in the third or fourth decades. In contrast to the equal sex distribution in children, there are twice as many females diagnosed as adults. Although the classical features of ‘malabsorption syndrome’—diarrhoea, steatorrhoea, weight loss and fatigue—are seen in severe cases, most patients have milder, less easily recognised, symptoms such as bloating and indigestion, or are largely asymptomatic and present with an unexplained iron-deficiency anaemia. In the UK, the diagnosis is made increasingly in patients with atypical symptoms or anaemia.

Aetiology and pathogenesis

The toxic components of gluten are gliadin and glutenin, but the mechanism by which they induce tissue damage remains uncertain. Gluten is partially digested in the small intestine, but many gluten peptides are resistant to intestinal peptidases like pepsin and chymotrypsin. Although these toxic peptides have direct effects on intestinal permeability through the disruption of tight junctions between enterocytes, it seems increasingly likely that tissue injury is more a consequence of the immune response than a direct effect. A long-established factor in the immune reaction to gluten components is the possession of particular HLA (human leukocyte antigen) genes. Nearly all patients with coeliac disease possess either the HLA-DQ2 or the HLA-DQ8 heterodimer. However, HLA-DQ2 is present in approximately one-third of non-affected Caucasian populations, demonstrating that it contributes to, but is not sufficient for, disease development. The potential importance of HLA-DQ2 lies in its ability to bind the toxic gluten peptides and present them to T-cells.

Evidence of the importance of perturbed T-cell function comes from the recent identification of a disease-related region at 4q27; this harbours the genes for interleukin (IL)-2 and IL-21. IL-2, secreted in an autocrine manner by antigen-stimulated T-cells, is a key cytokine for T-cell activation and proliferation, while IL-21 enhances T-, B- and NK-cell proliferation and interferon-gamma production. One of the gluten peptides (part of alpha gliadin) appears to induce IL-15 production by enterocytes and dendritic cells. IL-15 is also important in T-cell activation and may induce expression of a major histocompatability complex chain-related molecule (MICA) on enterocytes as well as upregulating NKG2D, an activating receptor on intra-epithelial lymphocytes (IELs). The interaction between activated IELs and enterocytes expressing MICA results in direct enterocyte killing.

Morphology

Under normal circumstances, enterocytes are constantly shed from the tips of the villi and replenished by migration of cells up the villi from the proliferative compartment in the crypts (Fig. 15.14). The entire cycle from cell birth through functional maturation to extrusion takes about 72 hours. Moderately accelerated cell loss can be compensated for by increased cell proliferation. With higher rates of cell loss, a stage is soon reached when the increased proliferative compartment cannot maintain a normal number of maturing and functioning ‘end cells’, the size of this compartment diminishes, and villous atrophy results. Shrinkage of villi and reduction in epithelial surface area are thus inevitable consequences of any injury causing a high rate of cell loss in the small intestine. In coeliac disease the ultimate stage of this process is seen; despite a marked increase in size of the proliferative compartment, evidenced by elongation, hypercellularity and high mitotic activity of the crypts (crypt hyperplasia), there is a flat surface (total villous atrophy; Fig. 15.15) and even this is populated by immature cells incapable of proper absorptive activity. Fully developed coeliac disease is therefore characterised by a total malabsorption, affecting sugars, fatty acids, monoglycerides, amino acids, water and electrolytes; the failure to absorb fat is the dominant abnormality in most cases. The loss of mature surface epithelial cells also causes disaccharidase deficiency, so that patients become intolerant of lactose and other sugars. The degenerate surface epithelium is infiltrated by large numbers of T-lymphocytes (IELs). Damaged epithelial cells may release TNF-alpha; this enhances the proliferation and migration of IELs (Fig. 15.16).

Fig. 15.14 Cell proliferation and maturation in the small intestine. See text for details.

Fig. 15.15 Coeliac disease. Normal jejunal mucosa. Total villous atrophy in coeliac disease. See text for details.

Fig. 15.16 Coeliac disease. Jejunal biopsy from a patient with coeliac disease showing severe villous atrophy and crypt elongation (hyperplasia). Higher power view of shortened villus showing increased numbers of lymphocytes in the surface epithelium and lamina propria.

The lesion is more severe in the proximal small intestine—the duodenum and proximal jejunum—and may spare the ileum, although the latter is susceptible to injury if exposed to gluten. In addition to malabsorption, intestinal hormone production from the proximal small bowel is impaired; there may be secondary reduction in pancreatic secretion and bile flow as a result of reduced production or release of pancreozymin, secretin and cholecystokinin. Thus gallstones are commonly present in older patients.

Lesser degrees of gluten intolerance short of classical coeliac disease are increasingly recognised. Investigation of older patients with unexplained weight loss or anaemia sometimes brings to light an increase in IELs with or without mild villous atrophy in duodenal biopsies. Such patients also respond to gluten withdrawal.

Complications

Now that the primary lesion and clinical consequences of coeliac disease can be managed by gluten-free diets, the later effects of the disease are becoming of greater concern. Osteoporosis and sub-fertility have been attributed to coeliac disease but the increase in frequency is small. Of more importance, there is a low but definitely increased risk of malignant lymphoma in the small intestine, and a modest increase in other gastrointestinal cancers. Outside of coeliac disease, the majority of small bowel lymphomas are of B-cell lineage, but in coeliacs they are frequently of a large cell type derived from T-cells (enteropathy-associated T-cell lymphoma). The patient presents with haemorrhage, perforation, small-bowel obstruction or systemic symptoms. A few patients with coeliac disease develop ulceration of the small intestine which is non-lymphomatous; microscopic examination simply reveals non-specific chronic inflammation (chronic ulcerative enteritis).

Tropical sprue

Pathological changes identical to those found in coeliac disease (but usually less severe) are evident in tropical sprue, a form of malabsorption found, as the name indicates, in the tropics and sub-tropics but not apparently in Africa. It occurs most frequently in South-East Asia and the Caribbean. Tropical sprue is characterised by chronic diarrhoea, weight loss and a macrocytic anaemia due to folate or vitamin B₁₂ deficiency. A gluten-free diet has little or no benefit, but the condition may be relieved by broad-spectrum antibiotics. The cause of the disease remains uncertain, but abnormal bacterial colonisation of the upper small bowel is probably involved. Plasma levels of the gut hormones enteroglucagon and motilin are increased, the former slowing intestinal transit.

Repeated bacterial and viral infections are virtually the norm in tropical countries and these may lead to mucosal changes falling short of those seen in tropical sprue. In tropical Africa, for instance, jejunal biopsies from apparently healthy subjects will reveal reduced villous height and increased inflammatory cells when compared to normal Europeans. These minor morphological abnormalities found in asymptomatic residents of tropical countries have been called ‘tropical enteropathy’ but from a local perspective could be considered ‘normal’.

Giardiasis

Mild malabsorption sometimes occurs in giardiasis (see p. 384).

Salmonella

Food poisoning by Salmonella organisms is a common and increasing problem in many countries. Salmonella infection of food poisoning type (salmonellosis) is generally confined to the gastrointestinal tract. In some patients this results in vomiting and profuse watery diarrhoea, usually with colicky, peri-umbilical pain suggesting predominantly gastric and small-intestinal involvement. However, in others the features relate to the large intestine, with frequent, small-volume, bloody motions, tenesmus and tenderness over the sigmoid colon. In the latter cases, sigmoidoscopy discloses a range of abnormalities varying from mucosal oedema and hyperaemia, to mucosal friability with slough formation and contact or spontaneous haemorrhage. The histological appearances are similarly varied. Some biopsies show oedema, focal interstitial haemorrhage and a mild increase in neutrophil polymorphs; more severe cases show a marked increase in polymorphs, with occasional crypts distended by polymorphs and mucus in the lumen (‘mucoid crypt abscesses’). The crypt pattern, however, remains normal. The disease usually resolves within 10 days as the immune response clears the infection.

Typhoid fever is caused by Salmonella enterica serotype Typhi (S. typhi), and remains a major public health problem in many regions of the world; over 16 million cases are reported each year worldwide. In contrast to the gastroenteritis caused by most Salmonella species, typhoid fever is not a typical diarrhoeal disease and the intestinal pathology is characterised by a macrophage, not a polymorph, infiltrate. Patients usually present with prolonged fever, headache, abdominal discomfort and general debility. Around 10% of these develop severe complicated disease and without specific treatment 5–30% of all patients may die. S. typhi is ingested in contaminated food or water, passes through the stomach and then invades the gut epithelium, possibly in the distal ileum. After penetration through the epithelium, Salmonella are ingested by macrophages and several pro-inflammatory reactions are initiated (e.g. production of cytokines, increased expression of adhesion molecules and upregulation of genes involved in apoptosis). There is further recruitment of macrophages and these may facilitate systemic spread of the bacteria as Salmonella-infected macrophages can survive for several hours. In this way, infected cells pass into the liver and spleen and can be found also in bone marrow and blood. Some find their way back to the intestine. Shedding of S. typhi in the faeces of an infected individual is an essential step in the transmission of typhoid fever.

Bacillary dysentery

Bacillary dysentery is an acute infection of the large intestine characterised by painful diarrhoea, often with blood and mucus in the stools. Shigella sonnei is the commonest cause; it produces relatively minor lesions and seldom causes ulceration. However, Sh. flexneri and Sh. dysenteriae can produce necrosis, sloughing and haemorrhage, giving rise to a picture closely resembling ulcerative colitis.

Campylobacter colitis

Since the early 1900s Campylobacter organisms have been known to cause dysentery and abortion in cattle and domestic animals, but recognition of their role in human disease is relatively recent. Contamination of milk and water supplies with C. jejuni and C. coli is now recognised as a frequent cause of severe gastroenteritis and colitis, particularly in debilitated and malnourished individuals. The histological changes seen in rectal biopsies are non-specific, and are similar to those seen in other forms of infective colitis.

Cholera

Cholera is a form of secretory diarrhoea resulting from infection with Vibrio cholerae. The cholera toxin binds to a specific receptor on epithelial cells which leads to increased adenylate cyclase activity; this in turn results in high cyclic AMP levels in the intestinal mucosa. The affected enterocytes secrete fluid and sodium ions, and the ensuing watery diarrhoea can be extreme, with overwhelming fluid loss and a rapidly fatal outcome. Because the effects are mediated by an exotoxin and there is no bacterial invasion of host tissues, the histological changes are remarkably slight; the mucosa shows mild oedema and goblet cell depletion.

Neonatal diarrhoea

In some of the diarrhoeas of neonates and infants, various strains of Escherichia coli can be isolated. Such infections are more common in bottle-fed infants, and epidemics may occur in children’s wards. Certain defined enteropathogenic serotypes are involved, and these differ from non-pathogenic types in their powers of adhesion to colonocytes and their ability to invade the mucosa. Diarrhoea may be severe, leading to dehydration and death. At autopsy, the small- and large-intestinal mucosa shows mucosal congestion and oedema with focal ulceration.

Staphylococcal enterocolitis

Enterocolitis due to staphylococcal infection is rare, but potentially fatal. The injudicious use of broad-spectrum antibiotics may alter the normal ecology of the intestinal bacterial flora so that the way is open for invasion by organisms that are either completely foreign to the bowel or normally present only in small numbers. The most dangerous of these is Staphylococcus aureus, which, when present in large numbers, can produce sufficient endotoxin to cause a severe enterocolitis. Staphylococcal enterocolitis is usually the result of cross-infection, and typically affects the hospital inpatient who has had contact with an antibiotic-resistant staphylococcus, in particular meticillin-resistant S. aureus (MRSA).

Patients present with sudden onset of severe diarrhoea, accompanied by shock and dehydration. The course can be relatively mild and respond to treatment, but with MRSA is often severe and carries a high mortality. There is widespread superficial ulceration predominantly affecting the small intestine. Microscopically there is acute inflammation of the mucosa with intense congestion and widespread necrosis. The surface of the mucosa is covered by an exudate containing numerous staphylococci.

Gonococcal proctitis

Gonococcal proctitis (inflammation of the rectum) is an acute exudative inflammatory condition which develops by genito-anal spread in females, and results from anal intercourse in males. The histological changes are non-specific, but the demonstration of numerous Gram-negative diplococci in the exudate leads to a presumptive diagnosis. As with other forms of infective colitis, definitive diagnosis depends on culture of the organisms.

Tuberculosis

Tuberculosis is almost entirely confined to the small intestine. In primary infection, an inconspicuous intestinal lesion is accompanied by gross enlargement of mesenteric nodes. This was the form of infection characteristic of bovine tuberculosis, a variety now virtually eliminated from the UK through the introduction of tubercle-free herds of cattle and the pasteurisation of milk.

Secondary tuberculous enteritis is a complication of extensive pulmonary tuberculosis which results from the swallowing of infected sputum. The typical alimentary lesion is ulceration of the ileum, the ulcer having formed by coalescence of caseous foci in the mucosa and submucosa. As the ulcers enlarge they follow the path of the lymphatics around the circumference of the intestine and eventually encircle the bowel. Healing is by fibrosis, and strictures may result from subsequent cicatrisation. The inflammatory exudate on the serosal aspect of the bowel may organise and form fibrous adhesions.

Ileo-caecal tuberculosis is a distinctive form of infection consisting of an ulcerative, granulomatous and fibrotic process occurring around the ileo-caecal valve, with variable extension into both ileum and caecum. The thickening and stenosis present a picture that is frequently indistinguishable from Crohn’s disease, although, in tuberculosis, distinct pale tubercles can be seen in the serosa. Patients recognised as having active intra-abdominal tuberculosis are treated by chemotherapy, but surgery may be required for the treatment of complications or for diagnosis. The major complications are intestinal obstruction by strictures and adhesions, perforation of ulcers (although this is uncommon because of the marked fibrous reaction), and malabsorption resulting from widespread mucosal involvement or blockage to lymphatic drainage.

Actinomycosis

Actinomycosis usually presents as a localised chronic inflammatory process most commonly related to the appendix or caecal area. The organism, Actinomyces israelii, is a normal commensal of the mouth, and when swallowed may resist acid digestion and infect the bowel. The infection is protracted and characterised by chronic suppuration and the formation of sinuses (openings on to the skin) and fistulae (abnormal connections with other hollow viscera). Histology reveals inflamed granulation tissue, and foci of suppuration containing the characteristic colonies of organisms visible to the naked eye as ‘sulphur granules’ in the watery pus.

Whipple’s disease

Whipple’s disease is a rare bacterial infection usually involving the small intestine. The causative organism has been identified as Tropheryma whippelii, and this infection, in combination with alterations in immune responsiveness, produces multisystem involvement with joint pains, weight loss, pigmentation, lymphadenopathy and malabsorption. The mucosa from affected individuals shows infiltration of the lamina propria by numerous granular macrophages containing abundant glycoprotein. On electron microscopy, the Whipple bacillus and granular material derived from the bacterial cell wall can be found in these macrophages. Patients usually respond to prolonged treatment with tetracyclines.

Clostridium difficile enteritis

Some patients taking a broad-spectrum antibiotic develop diarrhoea resulting from overgrowth of the intestinal commensal bacterium, C. difficile. In most patients this is not severe and responds to withdrawal of the antibiotic; this is generally referred to as antibiotic-associated colitis. However, in a small proportion (generally elderly or post-operative subjects) a fulminant enteritis with profuse diarrhoea and dehydration can lead to death in the more debilitated patients. On biopsy, there is superficial loss of epithelial cells and a volcano-like eruption of mucin, polymorphs and fibrin forming a pseudomembrane on the surface; this is pseudomembranous colitis. C. difficile is a Gram-positive bacillus that is non-invasive but produces a highly cytopathic toxin (toxin A) which is responsible for the enteritis.

Lymphogranuloma venereum

Proctitis due to lymphogranuloma venereum is principally a disease of females. This chlamydial infection begins in the genital tract and is thought to spread to the rectum via lymphatics. The deeper tissues are most heavily involved, and rectal stricture is the likely clinical problem. While non-specific chronic inflammation is usually pronounced, granulomas are a characteristic histological finding and these may show central necrosis when the disease is active.

Giardiasis

Infection with the protozoan parasite Giardia lamblia produces a generally mild malabsorption state. It is a cause of ‘traveller’s diarrhoea’ and of diarrhoea in childhood, in people with IgA deficiency, and following gastric surgery. It has been suggested that the malabsorption state is due to heavy infestation blocking access of nutrients to the surface epithelium; however, this is unlikely, as the numbers of organisms are rarely sufficient.

Amoebiasis

Amoebiasis is a disease of the large intestine resulting from infection with the protozoan Entamoeba histolytica. It is worldwide in its distribution, though more prevalent in the tropics than in temperate climates. Vegetative forms are present in the large bowel in infected individuals; these are passed in the stools, encyst into a more resistant form, and may survive in food and fluid and be re-ingested later. The cysts pass unharmed through the stomach; on reaching the intestine the cyst wall is dissolved, liberating the active amoebae (Fig. 15.17). These secrete a cytolytic enzyme which enables them to pass through the intestinal epithelium and, in disrupting the mucosa, release red blood cells which they then ingest. Contamination of food and water is brought about by human carriers, infected rats, or flies. Carriers may either be individuals known to have suffered an attack in the past, or be apparently healthy people, some of whom may have symptomless lesions in the bowel. Direct spread via anal intercourse is another recognised route of infection.

Fig. 15.17 Amoebiasis. High-power view of disintegrating colonic mucosa covered in an exudate in which there are large numbers of trophozoites. Some of these contain ingested red blood cells.

The disease can lead to discrete oval ulcers, which are characteristically ‘flask-shaped’ in section, or to a diffuse colitis. Blood-stream spread can result in liver abscesses, a potentially fatal complication.

Balantidiasis

Balantidiasis is a rare form of colitis caused by the ciliated protozoan Balantidium coli. It may be acute or chronic. Most cases are found in tropical or sub-tropical countries among debilitated, malnourished individuals. Gross and microscopic findings in the tissues are much like those in amoebiasis. The organism is readily detected by microscopy in both the lumen and the mucosa: it is so large as to dwarf the surrounding host cells.

Schistosomiasis

Infestation of the large intestine by Schistosoma occurs most commonly with S. mansoni and S. japonicum but can also be found with S. haematobium. Humans may become infected while wading or bathing in water contaminated with the second larval stage (cercaria) of the fluke. The cercariae penetrate the skin, enter venules, and are carried through the circulation to the portal veins in the liver, where they mature to form the adult flukes (Fig. 15.18). The adults migrate to either the submucosal veins of the gut or the venous plexus in the bladder, where they lay their eggs. The ova pass through the intestinal wall into the faeces or through the bladder wall into the urine. The cycle is completed in water contaminated with egg-containing urine or faeces. The eggs hatch out, liberating miracidia (first larval stage) which infect a snail, the intermediate host within which the second larval stage of cercariae develop, later to emerge in their free-swimming form.

Fig. 15.18 Life-cycle of Schistosoma. See text for details.

The pathological changes in schistosomiasis are essentially the result of an inflammatory reaction to the eggs in the tissues of the intestinal wall. Lesions are commonest in the rectum and left colon and are then nearly always due to S. mansoni; S. haematobium may be responsible if the lesions are in the right side of the colon and the appendix.

Cryptosporidiosis

Cryptosporidiosis is caused by a coccidial organism of the genus Cryptosporidium. These are common parasites in a variety of reptiles, birds and mammals. They are a frequent cause of diarrhoea in children, and are increasingly encountered in AIDS sufferers. Infection usually results from drinking contaminated water. Severe acute colitis with surface exudation and ulceration may result. Cryptosporidia cannot be recognised in stool specimens, so a biopsy or mucosal scraping is needed to make the diagnosis.

Crohn’s disease

Chronic inflammatory disorder of unknown aetiology

Small bowel most commonly affected, but any part of the gut may be involved

Characterised by transmural inflammation with granulomas

Thickened and fissured bowel leads to intestinal obstruction and fistulation

In 1932, Burrill Bernard Crohn and his colleagues established regional enteritis as a distinct entity. Previously, the condition had been confused with intestinal tuberculosis, then a common disease in Western countries. The chronic inflammation and ulceration in Crohn’s disease predominantly affect the terminal ileum, but all parts of the alimentary tract from the mouth to the anus may be involved and more than one site may be affected. ‘Satellite’ lesions can also occur in skin remote from the peri-anal area. However, involvement outside the small and large intestine is uncommon. About two-thirds of patients have only small-intestinal involvement, about one-sixth only large-intestinal involvement, and in one-sixth of patients both small and large bowel are affected.

Crohn’s disease usually presents with either small-intestinal obstruction or abdominal pain which may mimic acute appendicitis; other presentations can relate to its complications (see below). The course of the disease is chronic, with exacerbations and remissions not always linked to therapy. Onset is usually in early adult life, with about half of all cases beginning between the ages of 20 and 30 years and 90% between 10 and 40 years. Slightly more males than females are affected.

Morphology

Intestinal involvement by Crohn’s disease is frequently segmental; that is, lengths of diseased bowel are separated by apparently normal tissue. Such separated segments of disease are referred to as ‘skip lesions’.

The earliest evidence of involvement visible with the naked eye is the presence of small discrete shallow ulcers with a haemorrhagic rim. These ulcers have been likened to the common aphthous ulcers of the mouth and are thus often described as ‘aphthoid’; however, there is no aetiological link between the two conditions. Later, the more characteristic longitudinal ulcers develop which progress into deep fissures (Fig. 15.19). The process comes to involve the full thickness of the wall and subsequent fibrosis leads to considerable narrowing in the diseased segments (Fig. 15.20). This produces a characteristic radiological sign where only a trickle of contrast medium passes through the affected segment (the ‘string sign’). Where longitudinal fissures cross oedematous transverse mucosal folds, a ‘cobblestone’ appearance results. The mesenteric lymph nodes are enlarged by reactive hyperplasia and may also contain granulomas.

Fig. 15.19 Comparison of the lesions of Crohn’s disease and those of ulcerative colitis.

Fig. 15.20 Crohn’s disease. The terminal ileum is severely narrowed due to thickening of the bowel wall by the chronic inflammatory process. On the right, the lumen is passively dilated in response to the presence of the obstructive lesion.

Microscopy reflects the gross appearances. Inflammatory involvement is discontinuous: it is focal or patchy. Collections of lymphocytes and plasma cells are found, mainly in the mucosa and submucosa, but usually affecting all layers (transmural inflammation). The classical microscopic feature of Crohn’s disease is the presence of granulomas. These consist of epithelioid macrophages and giant cells surrounded by a cuff of lymphocytes. The giant cells are usually of the Langhans’ type, but may resemble foreign body giant cells. The granulomas are distinguished from those of tuberculosis by the absence of central caseous necrosis. While they are virtually diagnostic of the condition, granulomas are found in only 60% of cases of Crohn’s disease; in their absence the diagnosis must be based on a summation of the less specific histological changes. In addition to the aggregated transmural pattern of inflammation, these changes include the finding of vertical fissure ulcers and marked submucosal oedema, lymphangiectasia, fibrosis and neuromatoid hyperplasia (enlargement and proliferation of submucosal nerves).

Ulcerative colitis

Chronic relapsing inflammatory disorder, but may have an acute fulminating presentation

Aetiology is unknown

Affects only colon and rectum, sometimes confined to the latter

Diffuse superficial inflammation

Acute complications include toxic dilatation, perforation, haemorrhage and dehydration; the chronic complications are anaemia, liver disease and malignant change

In temperate climates ulcerative colitis is the commonest cause of diarrhoea associated with the passage of blood, mucus and pus. It is a non-specific inflammatory disorder of the large intestine, usually commencing in the rectum and extending proximally to a varying extent. Unlike Crohn’s disease, ulcerative colitis is confined to the large intestine. Involvement of the terminal ileum in a so-called ‘backwash ileitis’ is occasionally seen, but this is thought to represent chronic inflammation provoked by incompetence of the ileo-caecal valve, rather than an actual part of the disease.

Morphology

Ulcerative colitis is continuous in its distribution. Thus the disease, which is typically maximal in the rectum, extends proximally and continuously to involve the colon. Some cases are confined to the rectum (proctitis), others to the rectum and sigmoid (distal colitis), while others may exhibit a total colitis extending into the caecum. The disease does not involve the mucosa of the anal transitional zone or the anal canal, but a small proportion of patients do have anal tags and fissures.

The ulcers are irregular in outline and orientation and become confluent (Fig. 15.21); they extend horizontally to undermine adjacent, less involved, mucosa which remains as discrete islands. Usually the ulceration remains superficial (see Fig. 15.19), involving mucosa and submucosa, but in severe cases there is extension into the main muscle coats and perforation is likely. There is intense hyperaemia of the intact mucosa and haemorrhage from the ulcers.

Fig. 15.21 Ulcerative colitis. The colonic mucosa is extensively ulcerated and haemorrhagic.

Microscopically, there is diffuse infiltration of the mucosa by mixed acute and chronic inflammatory cells. Polymorphs are seen in the interstitium, but are particularly evident as aggregates within distended crypts (crypt abscesses). There are widespread degenerative changes in surface and crypt lining epithelium, with marked depletion of their mucin content. Crypts undergo destruction during the acute phase, and when regeneration occurs they are frequently distorted by branching or dilatation. This disturbance of the crypt pattern is a useful diagnostic pointer in quiescent cases, when the inflammatory features may have totally subsided. Thus, in longstanding disease, rectal biopsy will reveal crypt atrophy and distortion, and there may be metaplastic features such as the acquisition of Paneth cells. Ulcerative colitis is a recognised premalignant condition, and a few cases will reveal epithelial dysplasia.

Pathogenesis of inflammatory bowel disease

Genetically determined over-reaction by immune system to gut bacterial components

Bacterial antigens gain access via increased mucosal permeability

Failure to downregulate cytokine production

Th1 type cell-mediated reaction in Crohn’s disease; Th2 type cell-mediated reaction in ulcerative colitis

Blocking of interleukins is leading to novel therapies

Acute ischaemia

Acute mesenteric ischaemia is a life-threatening emergency with mortality rates between 60% and 100%. Sudden ischaemia results in varying degrees of infarction of the bowel wall. Such infarcts can be classified, according to the depth of involvement, as mucosal, mural or transmural (Fig. 15.22).

Fig. 15.22 Acute intestinal infarction and its outcome.

Chronic ischaemia

Chronic ischaemia leads to two main problems:

Strictures are encountered most often in the large intestine, particularly in the ‘watershed’ area around the splenic flexure of the colon. The patients generally present with the consequences of large bowel obstruction. Chronic mesenteric insufficiency is used to describe a condition in which there is insufficient blood flow to the small intestine to satisfy the demands of increased motility, secretion and absorption that develop after meals. The insufficiency is usually manifest as pain (so-called ‘mesenteric angina’), but patients may also have diarrhoea and malabsorption.

Necrotising enterocolitis

Necrotising enterocolitis (NEC) is an uncommon condition arising from a combination of ischaemia and infection. NEC is the most serious acquired gastrointestinal disease in the newborn, accounting for 1–3% of neonatal intensive care unit admissions. It carries a high risk of death with mortality rates between 20% and 50%. The disease manifests as abdominal distension and bloody stools with respiratory and circulatory disturbances. No single bacterial pathogen has been consistently identified, but organisms are frequently isolated and include E. coli, Klebsiella, C. difficile and Clostridium perfrigens. Prematurity is the only consistent risk factor; an immature mucosal barrier coupled with an impaired humoral (secretory IgA) and cellular immune response to bacteria are the suggested mechanisms. A substantially higher incidence of NEC has been found in formula-fed infants compared with exclusively breast-fed babies, suggesting that the former lack a degree of immuno-protection.

The disease can also (rarely) affect adults where it is caused by infection with Clostridium perfringens Type C, which produces a powerful beta-toxin. A peculiar form of NEC was that found among natives of Papua New Guinea after ceremonial feasting on huge quantities of sweet potato and inadequately cooked pork, including pig intestines. This condition was referred to as ‘pigbel’, pidgin English for abdominal pain after eating pig!

Adults with NEC present with severe abdominal pain and diarrhoea. Paralytic ileus develops and progresses to intestinal infarction, sepsis and shock. The appearances are typically those of gas gangrene, with either segmental or total involvement of the small and large intestines by coagulative necrosis and intramural gas bubble formation.

Vascular anomalies

Vascular anomalies in the gut are uncommon but enter into the differential diagnosis of gastrointestinal haemorrhage. Their classification is confused; some are congenital malformations that form part of recognised syndromes, while other, possibly identical, lesions are claimed to be acquired. Congenital types include arteriovenous malformations and telangiectasias; acquired forms are usually termed angiodysplasias. Angiodysplasia of the colon is an occasional cause of blood loss from the large bowel. This condition is more common in the elderly and can be diagnosed by mesenteric angiography.

Diverticular disease

Diverticula are herniations of mucosa into the intestinal wall. The herniations are of the pulsion type and form at sites of potential weakness, notably where lymphoid aggregates breach the muscularis mucosae. They extend through the muscularis propria at the point of entry or exit of blood vessels and bulge into the subserosa.

Diverticula can be found anywhere in the intestinal tract, but the colon, and particularly the sigmoid, is by far the commonest site (Fig. 15.23). Most diverticula occur between the mesenteric and anti-mesenteric longitudinal muscle bands—the taenia coli. The affected segment of colon shows thickening of the muscularis propria, and prominence of the mucosal folds so that they almost occlude the lumen and have a ‘concertina-like’ appearance. The disease is generally acknowledged to result from a deficiency of fibre in the diet. Sigmoid motility is peculiarly sensitive to the bulk of the colonic contents and when this is low, as with a low-fibre diet, abnormally high intra-luminal pressures are generated which push the mucosa into the wall.

Fig. 15.23 Diverticulosis of the sigmoid colon. The mucosal surface is ridged due to hypertrophy of the underlying muscle. The openings of the diverticula can be seen between the mucosal ridges.

Complications

Diverticular disease presents as abdominal pain and altered bowel habit, but it is also prone to develop some serious complications, the most common being diverticulitis (Fig. 15.24) The faecal contents can lead to abrasion of the herniated mucosa, or a microscopic perforation in the apex of a diverticulum can occur, which allows infection by faecal organisms and the development of a suppurative diverticulitis. This in turn can cause a peri-colic abscess and a fistula may form into the bladder, vagina or small intestine; more seriously, a peri-diverticular abscess may perforate and produce a generalised faecal peritonitis.

Fig. 15.24 Complications of diverticulosis.

Diverticula can be the source of haemorrhage from the colon. This usually arises from areas of granulation tissue in an inflamed diverticulum, but the precise source is sometimes difficult to identify.

Intussusception

An intussusception is an invagination of one segment of bowel into another, thus causing intestinal obstruction. A lesion in the wall of the bowel disturbs normal peristaltic contractions, forcing the lesion and a segment of proximal bowel into a distal segment. Several lesions can act as the apex of an intussusception, including polyps, ingested foreign bodies, a Meckel’s diverticulum, an area of intramural haemorrhage (e.g. in Henoch–Schönlein purpura; Ch. 23) and lymphoid hyperplasia. Such hyperplasia close to the ileo-caecal valve is the cause of the ileo-colic intussusception, the most common form of this disorder.

Volvulus and strangulation

Intestinal obstruction can result from a twist in the bowel that occludes its lumen (volvulus) or when a segment of bowel becomes trapped in a defect in either the posterior peritoneum or mesentery (internal herniation), or herniates into an inguinal or para-umbilical peritoneal sac. The neck of the sac may then constrict the bowel and compromise its blood supply (strangulation). Volvulus occurs around a ‘fulcrum’ such as a Meckel’s diverticulum or a congenital band of fibrous tissue, or around an abnormally long mesentery. About two-thirds of cases affect the small intestine; most of the remaining one-third affect the sigmoid colon.

Polyps

A polyp is simply a protuberant growth and there is thus a wide variety of histological types. These can be broadly divided into epithelial and mesenchymal polyps (of which the latter are distinctly uncommon), and into benign and malignant categories (Table 15.7). Even epithelial polyps are rare in the small intestine and some, such as metaplastic polyps, are confined to the large bowel. Thus, the following account is confined to large-intestinal polyps.

Table 15.7 Polyps of the large intestine

Benign epithelial polyps

Benign epithelial polyps fall into four categories: adenomas, and inflammatory, hamartomatous and metaplastic polyps.

Malignant epithelial polyps

Examples of malignant epithelial polyps are polypoid carcinomas and ‘carcinoid’ polyps. Some adenocarcinomas develop as protuberant growths and appear endoscopically as polyps, hence the term ‘polypoid carcinoma’. The vast majority of adenocarcinomas, however, arise within pre-existing adenomas (polypoid or ‘flat’) and these constitute the bulk of ‘malignant polyps’. A very small minority of polyps are neoplasms derived from neuroendocrine cells (see p. 396); such carcinoid polyps have a low malignant potential and only give rise to metastases late in their course. Thus, complete local removal is usually curative.

Benign mesenchymal polyps

Mesenchymal polyps are uncommon. The benign forms are lipomas, haemangiomas, lymphangiomas and fibromas. Stromal tumours (GIST) are less likely to present as polyps, and are of uncertain malignant potential.

Malignant mesenchymal polyps

Malignant varieties include the sarcomas equivalent to the benign tumours, and malignant lymphomatous polyps.

Molecular pathology of the adenoma–carcinoma sequence

In no other tumour system are the genetic events underlying the development of carcinoma as clearly understood as they are in colorectal cancer. In recent years, however, it has become increasingly clear that acquired epigenetic changes are of major importance. The genetic/epigenetic abnormalities are:

Defects in DNA repair

Mutation or loss of function of the TP53 gene is not the only way in which DNA repair can be compromised. Highly conserved genes have been discovered that recognise mismatched nucleotides in complementary DNA strands and orchestrate the enzymes that effect repairs. Defects in these genes and the ensuing replication errors are manifest as microsatellite instability. Alterations in two mismatch repair genes, hMLH1 and hMSH2, have been identified in most kindreds with hereditary non-polyposis colorectal cancer (HNPCC, Lynch syndrome). Similar alterations in these and other ‘housekeeper’ genes are found in sporadic cancers, with around 15% of cases showing high microsatellite instability.

The sequence of these genetic events in causing colorectal cancer is not as critical as the overall accumulation of changes, but the different prevalences of mutations and deletions between adenomas and invasive carcinoma do suggest that there is a preferred order (Fig. 15.26).

Fig. 15.26 Molecular genetics of adenoma–carcinoma sequence. Analysis of adenomas, small and large, and of invasive carcinomas and their metastases reveals a cascade of gene mutations, deletions and activations corresponding to the altered behaviour of the tumour cells. However, epigenetic changes are also of critical importance.

NORMAL STRUCTURE AND FUNCTION

The anal canal begins at the upper border of the internal sphincter at the level of the insertion of the puborectalis portion of levator ani (the so-called anorectal ring), and extends down to the groove between the terminal ends of the internal and external sphincters. It is 30–40 mm long.

Histologically, the upper part of the canal is lined by rectal-type glandular mucosa, the lower part by non-keratinising squamous epithelium. The upper end of the squamous portion is clearly delineated by the pectinate (or dentate) line. Proximal to this is a narrow zone of ‘transitional’ mucosa, consisting of columnar epithelium with multilayered small basal cells, which merges with the rectal-type mucosa of the upper segment.

The sensory nerves of the anal canal and the muscle sphincters are of vital importance in the control of defecation.

Haemorrhoids (‘piles’)

Haemorrhoids are varicosities resulting from dilatation of the internal haemorrhoidal venous plexus. The mechanisms involved in their formation are not clearly understood, although chronic constipation with straining at stool is most commonly invoked. As such they are largely a consequence of the low-residue ‘Western’ diet and are relatively uncommon in developing countries.

Haemorrhoids present with rectal bleeding as streaks of blood on the outside of the stool. They may prolapse through the anal verge and can undergo secondary thrombosis and inflammation, whereupon they become acutely painful.

Tumours