Gastrointestinal Tract Pathology PDF

Systemic Pathology GASTROINTESTINAL TRACT PATHOLOGY Objectives Describe the common clinical presentations of common gastrointestinal diseases Understand the pathophysiology behind selected common non-neoplastic conditions affecting the gastrointestinal...

Systemic Pathology GASTROINTESTINAL TRACT PATHOLOGY Objectives Describe the common clinical presentations of common gastrointestinal diseases Understand the pathophysiology behind selected common non-neoplastic conditions affecting the gastrointestinal tract (GIT) Describe the pathogenesis and pathology of tumours of the stomach and gastrointestinal tract, including selected associated cancer syndromes Outline I. Anatomy, Physiology and Congenital Conditions of the GIT a. Normal Anatomy and Function b. Manifestations of GI diseases c. Congenital anomalies: Meckel diverticulum, pyloric stenosis, Hirschsprung disease etc. II. Oesophagus a. Obstruction: Mechanical vs Functional b. Causes of Bleeding: Lacerations / perforation and Varices c. Oesophagitis: Reflux oesophagitis (GERD), Eosinophilic oesophagitis (EoE) etc. d. Barrett oesophagus e. Tumours: Adenocarcinoma, Squamous cell carcinoma III. Stomach a. Gastropathy, Acute gastritis and Chronic gastritis: Helicobacter pylori, Autoimmune etc. b. Peptic ulcer disease (PUD) c. Other causes of gastric bleeding: Stress-related and non-stress related d. Miscellaneous non-neoplastic conditions: Gastritis cystica, hypertrophic gastropathies e. Dysplasia f. Polyps: Inflammatory/hyperplastic, fundic gland polyps, adenomas g. Tumours: Adenocarcinoma, lymphoma, neuroendocrine tumour (NET), gastrointestinal stromal tumour (GIST) IV. Small intestine and colon a. Intestinal obstruction (IO): Hernia, adhesions, volvulus, intussusception b. Ischaemic bowel disease c. Angiodysplasia d. Malabsorption and Diarrhoea: Cystic fibrosis, celiac disease etc. e. Infectious enterocolitis f. Irritable bowel syndrome (IBS) g. Inflammatory bowel disease (IBD): Crohn disease and Ulcerative colitis h. Other forms of colitis: Diversion colitis, microscopic colitis (lymphocytic, collagenous), Graft vs host disease i. Diverticular disease j. Polyps: Non-neoplastic vs neoplastic k. Colorectal cancer: Polyposis vs non-polyposis syndromes, and colorectal adenocarcinoma G.Soon | Pathweb | Department of Pathology, NUHS | 2020 1 Systemic Pathology GASTROINTESTINAL TRACT PATHOLOGY V. Anal canal a. Haemorrhoids b. Tumours VI. Vermiform appendix a. Acute appendicitis b. Tumours VII. Peritoneal cavity a. Peritonitis b. Tumours References Kumar V, Abbas A, Aster J. Robbins & Cotran Pathologic Basis of Disease. 9th ed. WHO Classification of Tumours Editorial Board. Digestive system tumours. Lyon (France): International Agency for Research on Cancer; 2019. (WHO classification of tumours series, 5th ed.; vol1). Image credits Department of Pathology, Yong Loo Lin School of Medicine, National University of Singapore Pathopic© Accessible at: https://alf3.urz.unibas.ch/pathopic/e/copyright.htm Note: Pathweb Study Notes are based on the key topics covered in the lectures in the Yong Loo Lin School of Medicine, as well as additional topics covered in major texts. For more comprehensive discussion on specific pathology topics, readers are advised to refer to the recommended texts in your respective courses. G.Soon | Pathweb | Department of Pathology, NUHS | 2020 2 Systemic Pathology GASTROINTESTINAL TRACT PATHOLOGY I. ANATOMY, PHYSIOLOGY AND CONGENITAL CONDITIONS OF THE GIT Normal anatomy and function Hollow tube extending from oral cavity to anus, with regional variations in structure and function Important functions: Motility, secretion, digestion, absorption and excretion Manifestations of GI diseases GI diseases may be (i) Limited to GIT e.g. peptic ulcer (ii) Manifestation of systemic disorder e.g. CMV infection (iii) Presents as a systemic disorder but resulting from GI problem e.g. Iron deficiency anaemia from bleeding PUD, vitamin deficiencies due to malabsorption Cardinal signs and symptoms: Abdominal / chest pain, altered ingestion of food (nausea, vomiting, dysphagia, anorexia), altered bowel movements (diarrhoea or constipation), GI bleeding Complications: Acute – dehydration, sepsis, bleeding, perforation. Chronic: Malabsorption (malnutrition, deficiency states), obstruction Congenital anomalies Depends on the nature and timing of the insult during gestation Presence of congenital GI anomalies should prompt evaluation of other organs as many organs develop simultaneously during embryogenesis Atresia, fistulae and duplications May occur in any part of the GIT Agenesis = absence; atresia = incomplete development (often resulting in a thin non-canalised cord); stenosis = developmental or acquired luminal narrowing due to thickening of the wall. Causes complete / partial mechanical obstruction requiring surgical repair o Oesophageal atresia: may be associated with a fistula connecting the oesophagus to the tracheobronchial tree (tracheo-oesophageal fistula); fistula may also be present without atresia. Results in aspiration, pneumonia, fluid and electrolyte imbalances o Intestinal atresia: frequently duodenal, or imperforate anus (most common) Diaphragmatic hernia, omphalocele and gastroschisis Diaphragmatic hernia = when incomplete formation of the diaphragm allows herniation of the abdominal viscera into the thoracic cavity. If severe, may result in pulmonary hypoplasia o Hiatus hernia = Due to separation of diaphragmatic crura and widening of space between muscular crura and esophageal wall. Can be congenital or acquired. Associated with reflux oesophagitis and may be a cause of lower oesophageal sphincter incompetence; may be G.Soon | Pathweb | Department of Pathology, NUHS | 2020 3 Systemic Pathology GASTROINTESTINAL TRACT PATHOLOGY complicated by ulceration, bleeding, perforation, strangulation (paraoesophageal hernia), increased risk of oesophageal and gastric adenocarcinoma Omphalocele = incomplete closure of abdominal musculature, with herniation of the abdominal viscera into a ventral membranous sac. Due to failure of midgut to return to abdomen during midgut rotation. 40% of infants have other associated birth defects (especially heart and renal anomalies) Gastroschisis = similar to omphalocele except it involves all layers of the abdominal wall from peritoneum to skin and therefore has no covering sac. Due to defective ingrowth of mesoderm, impaired midline fusion or inappropriate apoptosis. 10-15% may have associated intestinal atresia, but associated anomalies are otherwise rare. Ectopia Ectopia = normally formed tissues in an abnormal site (‘developmental rests’). Common in GIT e.g. ectopic gastric mucosa in upper oesophagus (‘inlet patch’) or small bowel/colon, ectopic pancreatic tissue in oesophagus / stomach. Can cause inflammation and scarring with occult bleeding and/or pain Meckel diverticulum True diverticulum = blind outpouching of the GIT that communicates with the lumen and includes all three layers of the bowel wall Acquired diverticulum = lacks or has an attenuated muscularis propria e.g. in sigmoid colon Meckel diverticulum is the most common true diverticulum as a result of failed involution of the vitelline duct (connects lumen of developing gut on the antimesenteric side to yolk sac). Often contains ectopic gastric tissue which may result in occult bleeding ‘Rule of ‘2’s’ = occurs in 2% of population, within 2 feet (60 cm) of ileocaecal valve, 2 inches (5 cm) long, twice as common in males and most often symptomatic by age 2 (although only 4% are ever symptomatic) Pyloric stenosis Congenital vs acquired (e.g. antral gastritis / peptic ulcers at pylorus, carcinomas of distal stomach or pancreas) Congenital hypertrophic pyloric stenosis is 3-5x more common in males and has strong but multifactorial pattern of inheritance and genetic basis Hyperplasia of the pyloric muscularis propria +/- oedema and inflammation results in gastric outlet obstruction, usually presenting between 3-6th wks of life as projectile non-bilious vomiting after feeding. Surgical splitting of the muscularis (myotomy) is curative Hirschsprung disease (congenital aganglionic megacolon) 1 in 5000 live births; 10% of all cases occur in Down syndrome Absence of neural crest derived ganglion cells (both Meissner submucosal and Auerbach myenteric plexus) in the distal colon due to (1) premature arrest of normal migration of neural crest cells from G.Soon | Pathweb | Department of Pathology, NUHS | 2020 4 Systemic Pathology GASTROINTESTINAL TRACT PATHOLOGY caecum to rectum, or (2) premature death of ganglion cells. This results in absent peristalsis and functional obstruction, with dilatation of the proximal unaffected bowel segment Presents with failure to pass meconium in the immediate postnatal period, followed by constipation, abdominal distension and bilious vomiting, which may be complicated by enterocolitis, fluid and electrolyte imbalances, perforation and peritonitis. Treatment: surgical resection II. OESOPHAGUS Extends from epiglottis in pharynx to gastro-oesophageal junction Clinical presentations: Dysphagia, haemetemesis, odynophagia (painful swallowing), heartburn Non-neoplastic conditions: congenital anomalies, obstruction, lacerations/perforation, varices, oesophagitis, Barrett oesophagus Tumours: most commonly adenocarcinoma and squamous cell carcinoma Obstruction Structural (mechanical) vs functional (dysmotility i.e. disruption of the coordinated waves of peristaltic contractions following swallowing) Mechanical obstruction: stenosis / strictures due to inflammation and scarring (GERD, radiation, caustic injury), mucosal webs or rings, cancer Functional: Achalasia = triad of (1) incomplete lower oesophageal sphincter (LES) relaxation, (2) increased LES tone and (3) aperistalsis of the oesophagus. o Primary achalasia = due to distal oesophageal inhibitory neuronal (ganglion cell) degeneration. Cause is unknown o Secondary achalasia = e.g. Chagas disease where Trypanosoma cruzi infection causes destruction of the myenteric plexus, failure of peristalsis and oesophageal dilatation; diabetic autonomic neuropathy etc. Lacerations / perforation One of the causes of haemetemesis Mallory-Weiss tears = superficial longitudinal tears near the GEJ, most often associated with severe retching due to acute alcohol intoxication. Thought to be due to failure of the reflex oesophageal musculature relaxation preceding the antiperistaltic contractile wave, causing stretching and tearing of the oesophagus by the refluxed gastric contents. Does not usually require surgical intervention Boerhaave syndrome = transmural tearing and rupture of the distal oesophagus, also usually associated with vomiting, causing severe mediastinitis. Requires urgent surgical intervention. Varices Tortuous dilated veins primarily within submucosa and lamina propria of distal oesophagus and proximal stomach G.Soon | Pathweb | Department of Pathology, NUHS | 2020 5 Systemic Pathology GASTROINTESTINAL TRACT PATHOLOGY Consequence of portal hypertension, which causes the development of porto- systemic collateral channels. Present in nearly 50% of cirrhotic patients, with variceal rupture and bleeding in 25-40% (manifesting as haematemesis +/- melena) which is an emergency treated medically or endoscopically. However, 30% or more of patients with variceal haemorrhage still die from hypovolemic shock, hepatic coma etc., and those that survive may have recurrent bleeds with mortality risk. Surveillance with prophylactic treatment with beta- blockers to reduce portal blood flow and endoscopic variceal ligation helps mitigate the risk. Oesophagitis Reflux oesophagitis (gastro-oesophageal reflux disease or GERD): Most frequent cause of oesophagitis. Reflux of gastric juices +/- duodenal bile results in oesophageal mucosal injury o Pathogenesis: (1) Transient LES relaxation: mediated by vagal pathways and triggered by gastric distension, stress, swallowing-induced (2) Abrupt increase in intra-abdominal pressure: causes forceful opening of a relatively hypotensive LES e.g. coughing, straining. Stratified squamous epithelium of the oesophagus is resistant to abrasion from foods but sensitive to acid, triggering an inflammatory response. o Risk factors: alcohol, smoking, obesity, CNS depressants, pregnancy, hiatal hernia, delayed gastric emptying and increased gastric volume o Clinical features: Most common in individuals above 40, but can occur in infants and children. Usually presents with heartburn, dysphagia, sore throat and acid regurgitation. May be complicated by ulceration, haemetemesis, melena, strictures, Barrett oesophagus. Proton-pump inhibitors (PPI) to reduce gastric acidity provides symptomatic relief o Endoscopy: Erythema +/- erosions, ulceration o Histology: basal zone hyperplasia, elongation of the lamina propria papillae, intraepithelial eosinophils and neutrophils Eosinophilic oesophagitis: most common cause of GERD-like symptoms in children living in developed countries. Strongly associated with atopy - food allergy, allergic rhinitis, asthma or modest peripheral eosinophilia. Histology = large numbers of intraepithelial eosinophils. Treatment = dietary restriction to food allergens and topical / systemic corticosteroids. A subset may respond to PPIs. Chemical: irritants e.g. alcohol, corrosive acids/alkalis, pill-induced, chemotherapy Radiation: vascular injury resulting in mucosal damage Infections (immunocompetent vs immunocompromised): Herpes simplex virus (HSV) [punched-out ulcers, epithelial viral nuclear inclusions], cytomegalovirus (CMV) [shallower ulcers, stromal nuclear and cytoplasmic inclusions], fungal e.g. Candidiasis [adherent gray-white pseudomembranes, fungal hyphae] Graft-vs-host disease: basal epithelial cell apoptosis without significant acute inflammation Involvement by skin diseases e.g. bullous pemphigoid G.Soon | Pathweb | Department of Pathology, NUHS | 2020 6 Systemic Pathology GASTROINTESTINAL TRACT PATHOLOGY Barrett oesophagus (BE) Complication of chronic GERD characterized by columnar / intestinal metaplasia within the oesophageal squamous mucosa. Clinical features: Rising incidence, ~10% of individuals with symptomatic GERD. White males, 40- 60yo. Risk factor for dysplasia (preinvasive change) and oesophageal adenocarcinoma. Presence of dysplasia a/w prolonged symptoms, longer segment length, increased patient age and Caucasian race. Management is controversial, but most currently do periodic endoscopy with biopsy for dysplasia surveillance. Intramucosal or submucosal invasive carcinoma requires treatment. Diagnosis requires endoscopy and histology: Endoscopy: tongues / patches of red velvety mucosa extending upward from the GEJ, alternating with the pale smooth squamous oesophageal mucosa and interfacing distally with the light brown columnar gastric mucosa. Long segment = 3cm or more, short segment = less than 3 cm Histology: columnar / intestinal metaplasia (requirement of goblet cells depends on UK/US guidelines). Dysplasia is characterized by architectural and cytologic atypia, and can be low or high grade. Adenocarcinoma Most oesophageal adenocarcinomas arise from Barrett oesophagus → usu. distal 1/3 of oesophagus, may involve the gastric cardia Risk factors: GERD, smoking, radiation, reduced rates of H.pylori infection (because H.pylori causes gastric atrophy which reduces acid secretion and reflux and therefore Barrett oesophagus) Pathogenesis: Progression from BE to adenocarcinoma occurs over an extended period through the stepwise acquisition of genetic and epigenetic changes. Early stages: chromosomal abnormalities, TP53 mutation, downregulation of CDKN2A (p16/INK4a). Later progression: amplification of EGFR, ERBB2, MET, cyclin D1 and cyclin E Clinical features: Caucasian males. Rapid increase in incidence since 1970s. Patients usually present with pain or dysphagia, progressive weight loss, haemetemesis, chest pain or vomiting. Tumour usually has already spread to submucosal lymphatic vessels by the time patients are symptomatic and therefore has poor prognosis due to advanced stage at presentation. Prognosis is much better (5yr survival of 80%) in tumours limited to mucosa or submucosa. Gross: flat/raised patches, ulceration, diffuse infiltration Histology: adjacent BE. Gland formation +/- mucin, often intestinal-type or less commonly signet- ring cell morphology. Squamous cell carcinoma 50% in middle third of oesophagus Risk factors: Alcohol and tobacco use, poverty, caustic oesophageal injury, achalasia, frequent consumption of very hot beverages, diets deficient in fruits or vegetables, nutritional deficiencies, mutagenic compounds e.g. nitrosamines and polycylic hydrocarbons, HPV infection in high risk areas G.Soon | Pathweb | Department of Pathology, NUHS | 2020 7 Systemic Pathology GASTROINTESTINAL TRACT PATHOLOGY Pathogenesis: Molecular pathogenesis incompletely defined, but recurrent abnormalities include SOX2 amplification, cyclin D1 overexpression and loss of function mutations in tumour suppressors TP53, e-cadherin and NOTCH1 Clinical features: M:F = 4:1, older than 45 years old, African-Americans. Usually insidious onset, presenting with dysphagia, odynophagia or obstruction (with subconscious adjustment of diet from solid to liquid foods), prominent weight loss due to impaired nutrition and effects of tumour itself. Complications: Tumour ulceration causing haemorrhage, iron deficiency anemia and sepsis; local invasion into surrounding structures e.g. trachea-oesophageal fistula resulting in aspiration of food and pneumonia; aorta-oesophageal fistula causing exsanguination. Prognosis: Poor, especially with advanced tumours and LN metastases (which are common - LN drainage = upper 1/3: cervical LN, middle 1/3: mediastinal, paratracheal and tracheobronchial LN, lower 1/3: gastric and celiac LN) Gross: Small grey-white plaque-like thickenings, growing into tumour masses that may be polypoid / exophytic, protruding and obstructing the lumen. Also may be ulcerative or diffusely infiltrative lesions, causing thickening, rigidity and luminal narrowing. Rich lymphatic network promotes circumferential and longitudinal spread; tumour nodules may present several cm away from the principal mass Histology: Begins as in-situ lesion (squamous dysplasia → carcinoma in-situ). Most SqCC are well to moderately differentiated. III. STOMACH 4 major anatomic regions: Cardia, fundus, body, antrum. o Cardia and antrum: mucin-secreting foveolar cells that form small glands. Antral glands also contain endocrine G cells that release gastrin to stimulate luminal acid secretion by parietal cells in the body and fundus o Body and fundus: acid-secreting parietal cells (also secretes intrinsic factor) and digestive enzymes-secreting chief cells (oxyntic mucosa) Normal gastric lumen is extremely acidic (pH close to 1), which contributes to digestion but has potential to damage mucosa Clinical presentations: asymptomatic, epigastric pain, nausea, vomiting, haematemesis, melena Gastropathy and acute gastritis Gastritis = mucosal inflammation. Acute gastritis = neutrophils present Gastropathy = gastric dysfunction or injury with rare or absent inflammatory cells. Causes: NSAIDs, alcohol, bile, stress-induced, portal hypertension. o Hypertrophic gastropathy: specific group of diseases including Menetrier disease and Zollinger-Ellison syndrome Causes: Chemical e.g. alcohol, bile reflux (post-gastrectomy), corrosives, chemotherapy; radiation therapy; NSAIDs; corticosteroids. Contributory factors: Smoking, elderly age (?due to reduced mucin and bicarbonate secretion), high altitudes (decreased oxygen) G.Soon | Pathweb | Department of Pathology, NUHS | 2020 8 Systemic Pathology GASTROINTESTINAL TRACT PATHOLOGY Pathogenesis: Disruption of the normal protective mechanisms in the stomach – (i) Mucus barrier: mucin secretion by surface foveolar cells forms a thin layer of mucus and phospholipids that prevents large food particles from directly touching the epithelium (ii) Bicarbonate secretion: the mucus layer has a neutral pH as a result of bicarbonate ion secretion by surface epithelial cells (iii) Epithelial barrier: the gastric epithelial cells beneath the mucus layer has intercellular tight junctions, forming a physical barrier that limits back-diffusion of acid and leakage of other luminal materials, including pepsin, into the lamina propria. The epithelial layer is maintained by complete replacement of the surface foveolar cells every 3 to 7 days (iv) Rich mucosal blood flow: delivers bicarbonate, oxygen and nutrients to epithelial cells while washing away acid that has back-diffused into the lamina propria. In acid-secreting parts of the stomach, a capillary ‘alkaline tide’ is generated as parietal cells secrete hydrochloride acid into the gastric lumen and bicarbonate into the vessels NSAIDs: inhibit cyclooxygenase (COX)-dependent synthesis of prostaglandins E2 and I2, which stimulate nearly all of the above defense mechanisms while reducing acid secretion. Both COX1 and 2 isoenzymes contribute to mucosal protection, so even selective COX2 inhibitors e.g. celecoxib can result in gastropathy or gastritis Uremic patients and urease-secreting H.pylori: inhibition of gastric bicarbonate transporters by ammonium ions Chemicals/alcohol/chemoradiotherapy: Direct mucosal damage to both epithelial and stromal cells. Chemotherapy agents that inhibit DNA synthesis or the mitotic apparatus also cause generalized mucosal damage by insufficient epithelial renewal Clinical presentation: depends on etiology e.g. NSAID-induced gastropathy may be asymptomatic, or persistent epigastric pain that responds to antacids or PPIs, while pain associated with bile reflux is refractory to such therapies and may be accompanied by occasional bilious vomiting Histology: foveolar hyperplasia, lamina propria oedema and vascular congestion. Neutrophils seen in acute gastritis (vs ‘gastropathy’). Acute erosive haemorrhagic gastritis = erosions (superficial mucosal defect due to loss of epithelium) in more severe mucosal damage +/- haemorrhage. Extensive erosions may progress to ulcers Chronic gastritis Chronic mucosal inflammation that can lead to mucosal atrophy and intestinal metaplasia (IM) Causes: Most common - Helicobacter pylori infection (longstanding can result in atrophic, usually multifocal, gastritis). Others - autoimmune gastritis (most common cause of diffuse atrophic gastritis), radiation injury, chronic bile reflux, mechanical injury, involvement by systemic diseases e.g. Crohn disease, amyloidosis, graft vs host disease Clinical presentation: Symptoms usually less severe but more persistent compared to acute gastritis. Nausea, abdominal pain, +/- vomiting. Haematemesis is uncommon. Complications: Peptic ulcer disease, mucosal atrophy which is associated with intestinal metaplasia (IM) and a risk factor to gastric adenocarcinoma (greatest in autoimmune gastritis, possibly because achlorhydia of gastric mucosal atrophy permits overgrowth of bacteria that G.Soon | Pathweb | Department of Pathology, NUHS | 2020 9 Systemic Pathology GASTROINTESTINAL TRACT PATHOLOGY produce carcinogenic nitrosamines. IM in chronic H.pylori gastritis may regress after clearance of the organisms) Helicobacter pylori gastritis Spiral-shaped or curved bacilli that causes predominantly antral gastritis with normal or increased (local) gastrin production Pathogenesis: Pattern of H.pylori gastritis is a result of interplay between gastroduodenal mucosal defenses, host inflammatory responses and bacterial virulence factors. There is an inverse relationship between risk of duodenal ulcer and gastric adenocarcinoma depending on the pattern: 1. Antral-limited: Greater risk of duodenal peptic ulcer due to the increased acid production (due to stimulation of gastrin release by cytokines released or specific products of H.pylori) 2. Pangastritis: Body and fundus progressively involved, resulting in multifocal atrophic gastritis associated with reduced parietal cell mass and acid secretion, IM and increased risk of gastric adenocarcinoma Virulence of H.pylori is linked to several factors: Flagella: allows the bacteria to be motile in viscous mucus Urease: generates ammonia from endogenous urea and thereby elevates local gastric pH and enhances bacterial survival Adhesins: enhance bacterial adherence to surface foveolar cells Toxins: cytotoxin-associated gene A (CagA) and the associated 20 gene pathogenicity islands that are present in 50% of H.pylori isolates overall but 90% in populations with elevated gastric cancer risk and therefore may be involved in disease progression, partly because CagA expressing strains can effectively colonize the gastric body and cause multifocal atrophic gastritis Host factors: Genetic polymorphisms that lead to increased expression of proinflammatory cytokines tumour necrosis factor (TNF) and interleukin IL-1b or decreased expression of the anti- inflammatory cytokine IL-10 are associated with development of pangastritis, atrophy and gastric cancer. Iron deficiency may also be risk factor of H.pylori associated gastric cancer Clinical features: Fecal-oral transmission → higher rates in areas of poverty, household crowding. Infection typically acquired in childhood and persists for life without treatment. Mostly asymptomatic; symptoms usually only in chronic infection. Complications: Peptic ulcer, gastric adenocarcinoma, gastric lymphoma. Treatment: combination of antibiotics (triple therapy) and proton pump inhibitor. Relapses can occur after incomplete eradication or reinfection, which is common in regions with high endemic colonization rates Endoscopy: erythematous mucosa +/- coarse nodular appearance Histology: H.pylori organisms within the superficial mucus overlying the epithelial cells in the surface and neck regions (has tropism for gastric epithelia, not found in areas of IM or duodenal epithelium). Can be demonstrated with special stains G.Soon | Pathweb | Department of Pathology, NUHS | 2020 10 Systemic Pathology GASTROINTESTINAL TRACT PATHOLOGY 1. Antral-limited (usually): +/- cardia → antral biopsies performed for evaluation of H.pylori. Mucosa shows mixed inflammatory infiltrate: neutrophils (activity), plasma cells, lymphocytes (+/- lymphoid aggregates) and macrophages 2. Pangastritis (if long standing): In addition to inflammation, body and fundus show patchy mucosal atrophy (loss of chief and parietal cells → looks like antral mucosa) (vs. diffuse atrophy in autoimmune gastritis), typically associated with IM and increased risk of gastric adenocarcinoma Other diagnostic tests: (Non-invasive) Serologic test for H.pylori antibodies, fecal bacterial detection, urea breath test (based on conversion of urea into ammonia and CO2 by bacterial urease). (Invasive) Gastric biopsy specimens can also be analyzed by rapid urease test, bacterial culture or PCR detection of bacterial DNA Autoimmune (AI) gastritis (less than 10% of chronic gastritis) Body-predominant gastritis characterized by antibodies to parietal cells and intrinsic factor (IF) (can be detected in serum and gastric secretions), resulting in defective gastric acid secretion (achlorhydria), endocrine cell hyperplasia (hypergastrinemia), decreased ileal vitamin B12 absorption (leading to deficiency and pernicious anaemia) and reduced serum pepsinogen I secretion (from chief cells) Pathogenesis: Autoimmune destruction of parietal cells (which secretes gastric acid and IF) causes: o Absence of acid production (achlorhydria), stimulating increased gastrin secretion (hypergastrinemia), hyperplasia of the antral gastrin-producing G cells and hyperplasia of enterochromaffin-like cells in the gastric body (neuroendocrine cell hyperplasia, which can progress to form small multicentric low grade neuroendocrine tumours). Achlorhydria also decreased iron absorption (iron deficiency anaemia) o Lack of intrinsic factor, disabling ileal vitamin B12 absorption, leading to vitamin B12 deficiency and slow-onset megaloblastic anaemia (pernicious anaemia) Chief cell destruction also occurs (through general gastric gland destruction during the autoimmune attack on the parietal cells), resulting in reduced serum pepsinogen I concentration Note: H.pylori chronic gastritis doesn’t have achlorhydria or pernicious anaemia despite gastric atrophy because it is usually patchy / multifocal with residual patches of parietal and chief cells vs diffuse atrophy of AI gastritis The principal agent of injury is actually CD4+ T cells directed against parietal cell components, including the H+, K+-ATPase proton pump. Autoantibodies against parietal cell components (including the proton pump) and intrinsic factor are present in 80% of patients with AI gastritis but are NOT thought to be pathogenic - neither secreted IF nor the luminally oriented proton pump are accessible to the circulating antibodies, and passive transfer of the antibodies does not produce gastritis in experimental animals. Hence they are important mainly for diagnosis only Clinical features: slow onset disease with variable progression to gastric atrophy over 2-3 decades – median age at diagnosis is 60, and anaemia is only seen in a few patients. Patients may present with symptoms of anaemia or vitamin B12 deficiency (atrophic glossitis, malabsorptive diarrhoea, peripheral neuropathy with numbness or paraesthesias, cerebral dysfunction e.g. memory loss, G.Soon | Pathweb | Department of Pathology, NUHS | 2020 11 Systemic Pathology GASTROINTESTINAL TRACT PATHOLOGY personality changes, subacute combined degeneration of the spinal cord). Slightly more F>M; a/w other autoimmune diseases e.g. Hashimoto thyroiditis, but little evidence of linkage to specific HLA alleles so far. Treatment: Prevention/treatment of vitamin B12 and iron deficiencies (prevention is important because unlike anaemia, neurologic changes are not reversed by vitamin B12 therapy) Histology: diffuse mucosal atrophy of the oxyntic glands (chief and parietal cells) within body and fundus +/- intestinal metaplasia, with no/minimal damage to antrum and cardia. Mainly chronic inflammation (lymphocytes, macrophages, plasma cells with lymphoid aggregates) +/- neutrophils, deep in the lamina propria and centered on the gastric glands. Also varying degrees of neuroendocrine cell hyperplasia +/- neuroendocrine tumours H.pylori associated gastritis Autoimmune gastritis Location Antrum Body Inflammation Neutrophils, subepithelial plasma cells Lymphocytes, macrophages, plasma cells +/- neutrophils Acid production Increased to slightly decreased Decreased Gastrin Normal to decreased Increased Complications Peptic ulcer, adenocarcinoma, MALT Atrophy, pernicious and iron deficiency anaemia, lymphoma adenocarcinoma, neuroendocrine tumours Eosinophilic gastritis Tissue damage associated with dense infiltrates of eosinophils in the mucosa and muscularis, usually antral or pyloric region. May be caused by allergic reactions e.g. cow’s milk allergy, in association with some immune disorders e.g. systemic sclerosis, parasitic infections and H.pylori infection May affect other GI sites, a/w peripheral eosinophilia and raised serum IgE levels Lymphocytic gastritis Idiopathic but 40% associated with celiac disease, suggesting an immune-mediated pathogenesis. Typically affects entire stomach F>M, presents with non-specific abdominal symptoms Endoscopy: thickened gastric folds covered by small nodules with central aphthous ulceration on endoscopy (varioliform gastritis). Histology: Marked increase in intraepithelial T lymphocytes Granulomatous gastritis Descriptive term for any gastritis that contains granulomas / aggregates of epithelioid macrophages. E.g. Idiopathic, gastric involvement by Crohn disease, sarcoidosis, infections Peptic ulcer disease (PUD) Chronic mucosal ulceration affecting the duodenum or stomach, usually due to H.pylori infection o Antrum/proximal duodenum (most common location): usually due to chronic H.pylori induced antral gastritis, which is associated with increased acid secretion and decreased duodenal bicarbonate secretion G.Soon | Pathweb | Department of Pathology, NUHS | 2020 12 Systemic Pathology GASTROINTESTINAL TRACT PATHOLOGY o Body/fundus: usually due to some H.pylori gastritis or AI gastritis, resulting in mucosal atrophy and lesser acid secretion. Therefore protects from antral/duodenal ulcers o Oesophagus (rare): due to GERD or acid secretion by ectopic gastric mucosa (can occur occur in duodenum or Meckel diverticulum) Pathogenesis: Imbalance between mucosal defenses and damaging factors of chronic gastritis (PUD therefore generally develops on a background of chronic gastritis). Likely host and bacterial factors determine why some people develop only chronic gastritis and others get PUD Clinical features: Most due to H.pylori infection, NSAIDs (potentiated by steroids) or cigarette smoking (synergizes with H.pylori for gastric PUD). Rare causes e.g. Zollinger-Ellison syndrome Presentation: Epigastric burning or aching pain (can be chronic/recurring, occurring 1-3hrs after meals, worse at night and relieved by alkali or food). With penetrating ulcers, pain may be referred to the back, left upper quadrant or chest, mimicking cardiac chest pain. Nausea/vomiting, bloating/belching, weight loss. May also be symptomatic from complications e.g. iron deficiency anaemia, haemorrhage or perforation. Complications: Bleeding (most frequent - 15-20% of patients; may be life threatening or first presentation); Perforation (5%; accounts for 2/3 of ulcer deaths – surgical emergency!); Obstruction (2%; mostly in chronic ulcers, secondary to oedema or scarring usually in pyloric channel ulcers +/- duodenal ulcers). Malignant transformation occurs rarely, if ever. Treatment: H.pylori eradication, neutralization of gastric acid (primarily with proton pump inhibitors (PPI)), and withdrawal of offending agents e.g. NSAIDs. Surgery for treatment of bleeding or perforated ulcers (previously, antrectomy and vagotomy to prevent the acid-stimulatory effects mediated by the vagus nerve, but now not necessary with medical treatment) Gross: Solitary (>80%), round to oval, sharply punched-out defect with a smooth clean ulcer base as a result of peptic digestion of exudate. The mucosal margin may overhang the base slightly, but is usually level with surrounding mucosa vs. heaped up margins characteristic of cancers. (Note: Size and location do not differentiate between benign and malignant ulcers) Histology: thin surface layer of fibrinopurulent exudate, underlying suppurative necrosis, granulation tissue with mononuclear leukocytes, and a fibrocollagenous scar forming the ulcer base. Vessel walls are thickened and possibly thrombosed within the scarred area – bleeding from these damaged vessels from the ulcer base may cause life-threatening haemorrhage. Stress-related mucosal disease Occurs in patients with severe physiologic stress, usually during the 1st 3 days (acute) o Stress ulcers: shock, sepsis, severe trauma, post-myocardial infarction o Curling ulcers: severe burns or trauma. Proximal duodenum o Cushing ulcers: intracranial disease. Duodenum and oesophagus. High incidence of perforation G.Soon | Pathweb | Department of Pathology, NUHS | 2020 13 Systemic Pathology GASTROINTESTINAL TRACT PATHOLOGY Healing with complete re-epithelisation occurs within days to several weeks after correction of the underlying condition Pathogenesis: Local ischaemia from systemic hypotension or stress-induced splanchnic vasoconstriction, upregulation of inducible nitric oxide synthase and increased release of vasoconstrictor endothelin-1. Other contributing factors: systemic acidosis, gastric acid hypersecretion from vagal nuclei stimulation in intracranial injuries Gross: shallow erosions to deeper ulcers anywhere in stomach, usually multiple, rounded and less than 1 cm in size. Ulcer base frequently stained brown to black by acid digestion of extravasated blood Histology: erosion/ulcer sharply demarcated with adjacent normal mucosa. No scarring or blood vessel thickening seen in peptic ulcers (which arise in the setting of chronic injury). Non-stress related causes of gastric bleeding Dieulafoy lesion: submucosal artery that does not branch properly within the wall of the stomach, resulting in a mucosal artery 10x the size of mucosal capillaries. Usually lesser curvature near the GEJ. Erosion of the overlying mucosal epithelium can cause self-limited but copious gastric bleeding. Bleeding often associated with NSAID use and can be recurrent Gastric antral vascular lesion (GAVE): Mostly idiopathic but can also be associated with cirrhosis and systemic sclerosis. Endoscopy - longitudinal stripes of oedematous erythematous mucosa created by ectatic mucosal vessels alternates with less severely injured, paler mucosa (‘watermelon stomach’). Histology - antrum shows reactive gastropathy with dilated capillaries containing fibrin thrombi Other miscellaneous non-neoplastic conditions Gastritis cystica: Exuberant reactive epithelial proliferation associated with entrapment of epithelial- lined cysts within the submucosa (gastritis cystica polyposa) or deeper layers of the gastric wall (gastritis cystica profunda). Mimics invasive adenocarcinoma Hypertrophic gastropathies: Characterized by giant ‘cerebriform’ enlargement of the rugal folds due to epithelial hyperplasia without inflammation, linked to excessive growth factor release Menetrier disease: rare disorder caused by excessive secretion of TGFa characterized by diffuse foveolar hyperplasia of the gastric body and fundus, and hypoproteinaemia due to protein-losing enteropathy. A/w weight loss, diarrhoea. Risk of gastric adenocarcinoma increased in adults. Treatment is supportive Zollinger-Ellison syndrome: Caused by gastrin-secreting tumours (‘gastrinomas’) commonly found in small intestine or pancreas. Can be sporadic (75%) or syndromic (MEN1). Gastrinomas cause parietal cell hyperplasia and acid hypersecretion → often present with peptic ulcers. Histology: Marked thickening of oxyntic mucosa due to marked increase in parietal cells, hyperplasia of mucous neck cells, mucin hyperproduction and proliferation of endocrine cells within the oxyntic mucosa G.Soon | Pathweb | Department of Pathology, NUHS | 2020 14 Systemic Pathology GASTROINTESTINAL TRACT PATHOLOGY (neuroendocrine cell hyperplasia → tumour). Treatment: blockade of acid hypersecretion usu. with PPIs, and treatment of the gastrinoma. Dysplasia Preinvasive in-situ lesion with architectural and cytologic atypia Often arises in background of chronic gastritis, which exposes the epithelium to inflammation- related free radical damage and proliferative stimuli that lead to the accumulation of genetic alterations over time that result in carcinoma Polyps Develop due to epithelial or stromal cell hyperplasia, inflammation, ectopia or neoplasia. Inflammatory and hyperplastic polyps: 75% of all gastric polyps. Reactive lesions, usually in a/w chronic gastritis which initiates the injury that leads to reactive hyperplasia and polyp growth. Risk of dysplasia correlates with polyp size Fundic gland polyps: sporadic or in patients with familial adenomatous polyposis (FAP). Increasing incidence with use of PPI therapy, which inhibits acid production, thereby increasing gastrin secretion which stimulates oxyntic gland growth. Sporadic polyps have no cancer risk, while FAP- associated polyps may develop dysplasia and cancer Gastric adenoma: 10% of all gastric polyps. Frequency increases with age; prevalence varies and parallels incidence of gastric adenocarcinoma. M:F = 3:1. Incidence also increased in FAP patients. Similar to dysplasia, it occurs on a background of chronic gastritis with atrophy and intestinal metaplasia. Significant risk of adenocarcinoma (up to 30% of adenomas; related to size of lesion) → requires more aggressive therapy than colonic adenomas Gastric adenocarcinoma - More than 90% of all gastric cancers. Malignant epithelial neoplasm with glandular differentiation - Two main (Lauren) histologic subtypes: Intestinal-type and diffuse-type o Intestinal-type: Predominates in high-risk areas (e.g. Japan, East Europe). Precursor lesions include flat dysplasia and adenoma. M:F = 2:1 o Diffuse-type: Incidence is relatively uniform across countries, with no clearly identified precursor lesions. M=F. - Risk factors: Lower socioeconomic status, multifocal mucosal atrophy, intestinal metaplasia. PUD is not a risk factor (although patients with partial gastrectomies for PUD have a slightly higher risk of developing cancer in the residual gastric stump, possibly due to hypochlorhydria, bile reflux and chronic gastritis) - Pathogenesis: Majority are sporadic; familial gastric cancers tend to be diffuse-type. o Diffuse-type: Loss of expression of cell adhesion protein E-cadherin is a key step. This may occur via loss of function mutations in the tumour suppressor gene CDH1 which encodes E- cadherin (germline loss is strongly associated in familial gastric cancer, but loss of function is also seen in ~50% of sporadic diffuse-type tumours). Other mechanisms of decreased E- G.Soon | Pathweb | Department of Pathology, NUHS | 2020 15 Systemic Pathology GASTROINTESTINAL TRACT PATHOLOGY cadherin expression in sporadic tumours include hypermethylation and silencing of the CDH1 promoter. CDH1 mutations are also common in sporadic and familial breast lobular carcinoma. Individuals with BRCA2 mutations are also at increased risk of developing diffuse gastric cancer o Intestinal-type: Strongly associated with mutations that result in increased signaling via the Wnt pathway, including loss-of-function mutations in the adenomatous polyposis coli (APC) tumour suppressor gene and gain-of-function mutations in the gene encoding b-catenin. FAP patients (who carry germline APC mutations) thus have increased risk of intestinal-type gastric cancer. Loss of function mutations or silencing of a number of other tumour suppressor genes including those involved in TGF-b signaling, regulation of apoptosis (BAX) and cell cycle control (CDKN2A) o TP53 mutations are also found in the majority of sporadic gastric cancers of both diffuse and intestinal types o Chronic inflammation promotes gastric neoplasia: Genetic variants of proinflammatory and immune response genes, including those that encode IL-1b, TNF, IL-10, IL-8 and Toll-like receptor 4 (TLR4), are associated with elevated risk of gastric cancer when accompanied by H.pylori infection. Environmental factors also affect risk - Clinical features: Overall incidence falling due to decrease in intestinal-type gastric carcinoma, paralleling the decrease in H.pylori prevalence and decreased consumption of dietary carcinogens (found in preserved foods), although cancer of the gastric cardia is increasing (whose profile is similar to distal oesophageal adenocarcinomas). Early symptoms are usually non-specific (e.g. dyspepsia, nausea, dysphagia). Tumours are therefore often diagnosed at late stage with weight loss, anorexia and haemorrhage. Treatment: Surgical resection (preferred); if not, chemotherapy, radiotherapy and palliative care. Prognosis: depends on depth of tumour invasion (e.g. into adjacent organs), extent of nodal and distant metastases. Favourite sites of metastases: supraclavicular LN (Virchow node), periumbilical LN (Sister Mary Joseph nodule), ovary (Krukenberg tumour), pouch of Douglas (Blumer shelf). Also suggested that diffuse histologic type may have worse prognosis than intestinal type. 5 yr survival rate can exceed 90% in early gastric cancer (i.e. tumour with no deeper than submucosal invasion irrespective of LN mets), but is overall low because of advanced stage at presentation → screening is important - Gross: mostly antrum (lesser curve > greater curve) o Intestinal-type: usually bulky exophytic masses or ulcers/excavated o Diffuse-type: usually flat/depressed, widely infiltrative, inducing stromal desmoplasia that thickens and stiffens the gastric wall and causes rugal flattening, imparting a leather bottle appearance (‘linitis plastica’), rather than forming a discrete tumour mass - Histology: o Intestinal-type: glandular structures with apical and luminal mucin o Diffuse / poorly cohesive-type: discohesive cells that infiltrate singly or in small clusters and do not form glands; may have ‘signet-ring cell’ appearance (i.e. large intracytoplasmic mucin vacuole that pushes the nucleus to the periphery G.Soon | Pathweb | Department of Pathology, NUHS | 2020 16 Systemic Pathology GASTROINTESTINAL TRACT PATHOLOGY Lymphoma Extranodal lymphomas arise commonly in the GI tract, especially the stomach. ~5% of all gastric malignancies are primary lymphomas, most commonly extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma). MALT lymphoma can transform into more aggressive tumours that are histologically identical to diffuse large B-cell lymphoma (DLBCL), often in association with additional genetic changes Pathogenesis: MALToma usually arises at sites of chronic inflammation - H.pylori infection is the most common inducer of MALT lymphoma in the stomach, possibly via NF-KB dysregulation. NF-KB is a transcription factor that promotes B-cell growth and survival. The 3 chromosomal translocations associated with gastric MALT lymphoma t(11;18), t(1;14) and t(14;18) also result in constitutive activation of NF-KB Clinical presentation: dyspepsia, epigastric pain +/- haematemesis, melena and constitutional symptoms. Treatment: H.pylori eradication (results in durable remission with low rates of recurrence in most patients). Radiation/chemotherapy may be required with failure of H.pylori eradication e.g. tumours with translocations (due to constitutive activation of NF-KB), tumours invading to the muscularis propria or beyond, lymph node involvement, or transformation to DLBCL Histology: dense lymphoid infiltrate in the lamina propria, which infiltrates gastric glands to form lymphoepithelial lesions. Expresses B cell marker CD20, negative for CD5 and CD10. Well-differentiated Neuroendocrine Tumours (NET) Previously known as carcinoid or ‘carcinoma-like’ tumours as they have a more indolent clinical course than GI carcinomas; more than 40% of GI NET occur in the small intestine Risk factors / associations: Neuroendocrine cell hyperplasia, autoimmune chronic atrophic gastritis, MEN1 and Zollinger-Ellison syndrome. PPI therapy may be associated with NE cell hyperplasia but the risk of progression to a NET is extremely low Clinical presentation: Asymptomatic or symptomatic depending on the hormones produced e.g. gastrin-secreting tumours may cause Zollinger-Ellison syndrome, while ileal tumours may cause carcinoid syndrome (cutaneous flushing, sweating, bronchospasm, diarrhoea etc. due to released substances including serotonin) especially in the presence of metastatic liver disease (whereby the bioactive products are directly released into the systemic circulation without the ‘first-pass effect’) or with a large enough tumour burden. The clinical course of NET is quite variable; even low grade NET can metastasize. Most important prognostic factor is location (midgut most aggressive and often multiple > hindgut/foregut). Gross: Intramural or submucosal masses that create small polypoid yellow-tan lesions. Often firm (due to desmoplastic reaction) → can cause kinking and small bowel obstruction Histology: Islands, trabeculae, strands, glands or sheets of uniform cells with round to oval nucleus, ‘salt and pepper’ chromatin and scant pink cytoplasm. Positive with immunohistochemical stains for neuroendocrine granule markers e.g. Synaptophysin and Chromogranin A G.Soon | Pathweb | Department of Pathology, NUHS | 2020 17 Systemic Pathology GASTROINTESTINAL TRACT PATHOLOGY Gastrointestinal stromal tumour (GIST) Most common mesenchymal tumour of the abdomen arising from interstitial cells of Cajal of the muscularis propria; more than 50% occur in the stomach Pathogenesis: ~75-80% have oncogenic gain-of-function mutations in the tyrosine kinase receptor (TKR) KIT, while ~8% have activating mutations in a closely related TKR, platelet-derived growth factor receptor α (PDGFRA). KIT and PDGFRA gene mutations are mutually exclusive since they act within the same signal transduction pathway to promote tumour cell proliferation and survival. Both sporadic and germline mutations result in constitutively active KIT or PDGFRA TKR. Mutation of KIT or PDGFRA is an early event in sporadic GISTs and alone are insufficient for tumorigenesis. GISTs without KIT or PDGFRA mutations have mutations in other genes that function in these pathways (NF1, BRAF, HRAS, NRAS). Patients may also have germline loss of function mutations in genes encoding components of the mitochondrial succinate dehydrogenase complex (SDHA/B/C/D), which confer an increased risk for GIST and paraganglioma (Carney-Stratakis syndrome) Clinical features: Usually in adults ~60 yo, uncommonly in children (some of which are related to Carney triad, a nonhereditary syndrome seen primarily in young females that includes gastric GIST, paraganglioma and pulmonary chondroma, or Neurofibromatosis (NF) type 1). Patients can be asymptomatic or symptomatic related to mass effect or mucosal ulceration causing blood loss/anemia. Treatment: if resectable → complete surgical resection. If not resectable, those with KIT or PDGRFA mutations often respond to tyrosine kinase inhibitor imatinib. Development of imatinib-resistance can occur due to secondary KIT or PDGFRA mutations. Prognosis: correlates with tumour size, mitotic index and location. Metastasis usually to liver or as multiple peritoneal nodules Gross: usually solitary, well-circumscribed fleshy mass covered by ulcerated or intact mucosa; may also bulge out towards serosa. Cut surface has a whorled appearance Histology: Spindle cell or epithelioid type or mixed. Immunohistochemical expression of KIT/CD117 (detectable even for those without the mutation) or DOG1 IV. SMALL INTESTINE AND COLON Main functions: Nutrient and water transport → dysfunction causes malabsorption and diarrhoea Immune system interfaces with a diverse array of antigens present in food and gut microbes → infectious and inflammatory disorders Colon is also a frequent site of gastrointestinal tumours Intestinal obstruction Can occur at any level, but frequently small intestine because of its relatively narrow lumen Causes: Hernias (most frequent cause worldwide), intestinal adhesions, intussusception, volvulus, and more rarely, tumours, infarction and other causes of strictures e.g. Crohn disease Clinical presentation: abdominal pain and distension, vomiting and constipation. May be complicated by bowel perforation → surgical emergency G.Soon | Pathweb | Department of Pathology, NUHS | 2020 18 Systemic Pathology GASTROINTESTINAL TRACT PATHOLOGY Hernia sac: protrusion of a serosa-lined pouch of peritoneum through any weakness or defect in the abdominal wall e.g. inguinal/femoral canal, umbilicus or surgical scar site (‘external herniation’). The pouch may contain viscera that may become entrapped, causing obstruction. Pressure at neck of the pouch may further impair venous drainage of the entrapped viscus, resulting in stasis and oedema, increasing the bulk of the herniated loop, leading to permanent entrapment (incarceration), arterial and venous compromise (strangulation) and infarction Adhesions: fibrous bridges that can develop between bowel segments, abdominal wall or other sites. Usually acquired (e.g. due to previous surgery, infection or other causes of peritoneal inflammation e.g. endometriosis) but can rarely be congenital. Adhesions can cause bowel kinking or form closed loops through which other viscera may slide and become entrapped (‘internal herniation’) Volvulus: twisting of a loop of bowel about its mesenteric point of attachment, resulting in both luminal and vascular compromise (i.e. obstruction and infarction). Most often occurs in large redundant loops of the sigmoid colon, followed by caecum, small bowel, stomach or transverse colon Intussusception: when a segment of intestine, constricted by a wave of peristalsis, telescopes into the immediately distal segment. Once trapped, the invaginated segment is further propelled by peristalsis and pulls the mesentery along. May progress to intestinal obstruction as well as compression of mesenteric vessels (infarction). Most common cause of IO in children M: present with chronic diarrhoea, bloating, chronic fatigue, anaemia (due to iron and vitamin malabsorption). May have atypical or asymptomatic presentation (‘silent’ celiac disease = positive serology and villous atrophy without symptoms, or ‘latent’ celiac disease = positive serology without villous atrophy) o Children, M=F: classically symptoms occur after introduction of gluten to diet between 6-24 months of age, manifesting as irritability, abdominal distension, anorexia, chronic diarrhoea, failure to thrive, weight loss or muscle wasting. Extraintestinal complaints include arthritis or joint pain, aphthous stomatitis, iron deficiency anemia, delayed puberty and short stature. 10% of patients may have dermatitis herpetiformis, an itchy blistering skin lesion Diagnostic noninvasive serologic tests (generally performed prior to biopsy): IgA antibodies against tissue transglutaminase (most sensitive), anti-endomysial antibodies. Presence of HLA-DQ2 and DQ8 does not confirm diagnosis, but useful if absent for its negative predictive value Diagnostic biopsies: usually taken from the 2nd duodenal segment or proximal jejunum, which are exposed to the highest concentrations of dietary gluten Complications: Risk of malignancy - enteropathy-associated T cell lymphoma (an aggressive lymphoma of intraepithelial T cells), small intestinal adenocarcinoma. Thus, when symptoms of abdominal pain, diarrhoea and weight loss develop despite a strict gluten-free diet, cancer or refractory sprue (in which response to a gluten-free diet is lost) must be considered. G.Soon | Pathweb | Department of Pathology, NUHS | 2020 22 Systemic Pathology GASTROINTESTINAL TRACT PATHOLOGY Treatment: gluten-free diet → resolution of symptoms, decreasing titers of anti-tissue transglutaminase antibodies and restoration of mucosal histology within 6-24 months. May also reduce the risk of long-term complications e.g. anaemia and cancer Histology: Intraepithelial lymphocytosis, crypt hyperplasia and villous atrophy (but not specific: can be seen in other diseases e.g. viral enteritis – correlation with serology is important) Environmental enteropathy (aka tropical enteropathy / tropical sprue): disorder prevalent in areas and populations with poor sanitation and hygiene, and may contribute to a large number of childhood deaths. Presently no accepted clinical, lab or histopathologic criteria that allows diagnosis. Reported histologic features are more similar to severe celiac disease than infectious enteritis Autoimmune enteropathy: X-linked disorder characterized by severe persistent diarrhoea and autoimmune disease that occurs most often in young children, caused by FOXP3 gene mutation, resulting in defective function of regulatory T cells Lactase (disaccharidase) deficiency: Osmotic diarrhoea due to inability to break down or absorb lactase. Can be congenital (rare autosomal recessive disorder caused by mutation in gene encoding lactase) or acquired (common in adults, caused by down-regulation of lactase gene expression, which can develop following enteric viral or bacterial infections and may resolve over time). Defect is biochemical so histology is generally unremarkable Infectious enterocolitis Aetiology varies with age, nutrition, and host immune status as well as environmental influences. Paediatic infectious diarrhoea is often caused by enteric viruses, while cholera is common in areas with poor sanitation. Enterocolitis can present with a broad range of symptoms including diarrhoea, abdominal pain, urgency, perianal discomfort, incontinence and dysentery Bacterial Cholera: Vibrio cholerae (comma-shaped gram-negative bacteria, non-invasive) - Endemic in India and Bangladesh, with several epidemics in other countries. Primarily water-borne infection (can also be present in food) - Cholera toxin released by the organism causes accumulation of chloride, bicarbonate and sodium within the intestinal lumen, creating an osmotic driving force (secretory diarrhoea) - Most individuals asymptomatic / mild diarrhoea. Severe disease: abrupt onset of watery diarrhoea and vomiting following an incubation period of 1-5 days (voluminous ‘rice-water’ stools) - Complications: dehydration, hypotension, shock and death (usually within first 24 hours). Treatment: timely fluid replacement (oral rehydration often sufficient) Campylobacter enterocolitis: Campylobacter jejuni (comma-shaped flagellated gram negative) - Most common bacterial enteric pathogen in developed countries, cause of traveler’s diarrhoea. Usually a/w contaminated chicken, also unpasteurized milk or contaminated water Bacteria produces toxin and a minority also invade (latter associated with dysentery) Most patients have watery diarrhoea, either acute or following an influenza-like prodrome after an incubation period of up to 8 days. Dysentery in 15% of adults and more than 50% in children Complications: Reactive arthritis (primarily in patients with HLA-B27), erythema nodosum, Guillain- Barre syndrome. Treatment: Supportive (antibiotics generally not required) G.Soon | Pathweb | Department of Pathology, NUHS | 2020 23 Systemic Pathology GASTROINTESTINAL TRACT PATHOLOGY Shigellosis: Shigella sp. (gram negative facultative anaerobe, belongs to Enterobacteriaceae family) One of the most common causes of bloody diarrhoea. Extremely low infective dose → highly transmissible via fecal-oral route (contaminated water/ food). Usually in children Yersinia pseudotuberculosis Ingestion of pork, raw milk and contaminated water. Preferentially involves ileum, appendix and right colon with Peyer patchy and regional lymph node hyperplasia, mimicking acute appendicitis. Pseudomembranous colitis: morphologic diagnosis (can also be seen in ischaemia or necrotizing infections) but usually caused by Clostridium difficile (anaerobe) Risk factors are advanced age, hospitalization and antibiotic treatment (almost any antibiotic may be responsible). Antibiotics disrupt normal colonic microbiota, allowing C.difficile overgrowth, which releases toxins that lead to epithelial damage. Diagnosis of C.difficile-associated colitis is via detection of the toxin rather than culture. Treatment: Metronidazole or vancomycin. Pseudomembranes are an adherent layer of inflammatory cells and debris at sites of colonic mucosal injury, that are seen endoscopically as a tan-grey-white coating. Histologically, there is surface epithelial denudation of the colonic mucosa with distension of the superficial portions of the crypts by a mucopurulent exudate (‘volcanic eruption’) that coaelesce to form pseudomembranes Mycobacterial: Mycobacterium tuberculosis, Mycobacterium bovis Intestinal tuberculosis: (primary involvement) drinking of contaminated milk in countries where bovine tuberculosis is present and milk is not pasteurized; or (secondary involvement) caused by swallowing of coughed-up infective material in patients with advanced pulmonary disease Organisms are seeded to mucosal lymphoid aggregates of small and large bowel, which undergo granulomatous inflammation that can lead to ulceration of the overlying mucosa, esp. ileocaecal region. Healing can cause strictures. Mimics Crohn’s disease Viral Norovirus: ~50% of all gasteroenteritis outbreaks worldwide, usually related to contaminated food or water. Sporadic cases usually due to person-person transmission. Self-limiting disease Rotavirus: common cause of severe childhood diarrhoea and diarrhoeal mortality (esp. 6-24 mths age) Adenovirus: common cause of paediatric diarrhoea and in immunocompromised patients HSV, CMV: systemic infections that can also infect the GIT Parasitic Nematodes (roundworms Ascaris and Strongyloides, hookworms and pinworms), cestodes (flatworms and tapeworms), trematodes (flukes) Protozoa: Entamoeba histolytica (amebiasis) G.Soon | Pathweb | Department of Pathology, NUHS | 2020 24 Systemic Pathology GASTROINTESTINAL TRACT PATHOLOGY Fecal-oral transmission. Mostly affects the caecum and ascending colon. Causes dysentery Amoeba attach to the colonic epithelium, induce apoptosis, invade crypts and burrow laterally creating a ‘flask-shaped’ ulcer. Parasites can also penetrate splanchnic vessels and embolize to the liver to produce abscesses in ~40% of patients Protozoa: Giardia lamblia (giardiasis) Most common parasitic pathogen in humans; spread by fecally contaminated water or food. Presentation can be subclinical or acute/chronic diarrhoea, malabsorption and weight loss Identified in duodenal biopsies as pear-shaped organisms tightly bound to the brush border of villous enterocytes. No invasion. Protozoa: Cryptosporidium parvum (cryptosporidiosis) First discovered as a cause of chronic diarrhoea in AIDS patients; also a cause of acute self-limited diarrhoea or persistent diarrhoea in immunocompetent hosts. Usu. via contaminated drinking water Usually identified in terminal ileum and proximal colon. Intracellular, epithelial apical membrane Fungal Candida, Aspergillus, Mucormycosis, Histoplasma: systemic infections that can affect the GIT Irritable bowel syndrome (IBS) Chronic relapsing abdominal pain, bloating and changes in bowel habits, but normal gross and microscopic evaluation – diagnosis depends on clinical symptoms and functional testing. Pathogenesis is poorly defined, with interplay between psychological stressors, diet, perturbation of the gut microbiome, increased enteric sensory responses to gastrointestinal stimuli and abnormal GI motility. Not associated with serious long-term sequelae; prognosis is most closely related to symptom duration, with longer duration correlating with reduced likelihood of improvement Inflammatory bowel disease (IBD) Chronic inflammation of the GI tract resulting from inappropriate mucosal immune activation, usually referring to either Ulcerative Colitis (UC) or Crohn Disease (CD) Pathogenesis: Likely due to combined effects of alterations in host interactions with intestinal microbiota, intestinal epithelial dysfunction, aberrant mucosal immune responses and altered composition of the gut microbiome o Genetics: risk of disease is increased when there is an affected family member. Over 160 IBD-associated genes have been identified, with each gene conferring only a small increase in risk e.g. NOD2 (for CD) which is involved in recognition and response to intracellular pathogens (supporting the hypothesis that inappropriate immune reactions to luminal bacteria are an important component of IBD pathogenesis) o Mucosal immune responses: T helper cells are activated in Crohn disease (response polarized to the TH1 type; TH17 cells most likely contribute to disease pathogenesis). Many other pro-inflammatory cytokines including TNF and immunoregulatory molecules e.g. IL-10 also appear to play a role. Immunosuppressive agents remain the mainstay of treatment G.Soon | Pathweb | Department of Pathology, NUHS | 2020 25 Systemic Pathology GASTROINTESTINAL TRACT PATHOLOGY o Epithelial defects: defects in intestinal epithelial tight junction barrier function in CD (a/w specific disease-associated NOD2 polymorphisms); inhibition of matrix metalloproteinase 9 in UC (a/w polymorphisms involving ECM1) o Microbiota: as mentioned earlier, linkage to NOD2 points to the involvement of microbes in the causation of CD. The presence of antibodies against bacterial progetin flagellin are also seen in CD. Clinical trials suggest that probiotic bacteria or even fecal microbial transplants from healthy individuals may benefit IBD patients It has been theorized that IBD is a result of a self-amplifying cycle that gives rise to maladaptive and injurious immune responses, by which transepithelial flux of luminal bacterial components activates innate and adaptive immune responses. In a genetically susceptible host, the subsequent release of TNF and other immune-mediated signals direct the epithelium to increase tight junction permeability, causing further increase in the influx of luminal material, resulting in a vicious cycle. The hygiene hypothesis suggests improved food storage conditions, decreased food contamination and changes in gut microbiome composition results in inadequate development of regulatory processes that limit mucosal immune responses. This in turn allows some mucosa-associated microbial organisms to trigger persistent and chronic inflammation in susceptible hosts Clinical features: Teens and young adults. Caucasians but increasing incidence in other regions e.g. Africa, South America and Asia. Distinction between CD and UC is based largely on the distribution of affected sites and morphologic expression of disease at these sites. Extraintestinal manifestations may also be present. Crohn disease Ulcerative colitis Recurrent granulomatous, fibrosing inflammatory Recurrent acute-on-chronic ulcero-inflammatory disorder affecting terminal ileum (or colon) +/- other disease affecting mainly rectum and distal colon systemic manifestations Clinical features Relapsing disorder: intermittent attacks of (bloody) diarrhoea with stringy mucoid material, lower abdominal pain, cramps that are temporarily relieved by defecation +/- fever; can also present acutely. Asymptomatic periods may last for weeks to months Disease re-activation by triggers include physical or Triggers may include episode of infectious emotional stress, specific dietary items and cigarette enteritis, psychological stress, after smoking smoking (a strong exogenous risk factor for cessation development of Crohn disease; initiation of smoking may be associated with disease onset but smoking cessation does not result in disease remission) Extraintestinal manifestations: uveitis, ankylosing Similar; also primary sclerosing cholangitis (PSC) spondylitis, migratory polyarthritis Saccharomyces cerevisiae antibodies positive pANCA+ (75%) Complications Fistulae between bowel loops and with other organs Nil e.g. bladder, vagina, skin (esp. perianal); perforations and peritoneal abscesses Fibrosing strictures (particularly of the terminal Nil ileum; require surgical resection) G.Soon | Pathweb | Department of Pathology, NUHS | 2020 26 Systemic Pathology GASTROINTESTINAL TRACT PATHOLOGY Common recurrence after surgery No. Colectomy cures intestinal disease (although extraintestinal manifestations may persist) Fat/vitamin malabsorption, iron deficiency and Nil hypoalbuminaemia (in extensive small bowel disease) Increased malignancy risk (in colonic disease) Yes No toxic megacolon Toxic megacolon occurs due to damage of the muscularis propria by inflammatory mediators, and disturbance of neuromuscular function. Significant risk of perforation Gross and microscopy Skip lesions (i.e. separate sharply delineated areas Diffuse continuous involvement. Rarely ‘caecal of disease) patch’ in L-sided UC Frequently ileum; any other area of the GI tract Disease limited to Rectum +/- part or all of colon. Small intestine normal apart from mild mucosal inflammation of the distal ileum (‘backwash ileitis’) in severe pancolitis Transmural inflammation and oedema – thickened Mucosa +/- submucosa – usually thin wall, mild wall with marked fibrosis +/- strictures. In extensive or no fibrosis / serositis; strictures are rare transmural disease, serositis and mesenteric fat extending around the serosal surface (‘creeping fat’) ‘Cobblestone’ appearance of mucosa (due to patchy Slightly red granular friable mucosa; Frequent sparing of mucosa interspersed with deep ulcers) mucosal pseudopolyps (isolated islands of regenerating mucosa that bulge into lumen amongst broad-based ulcers). Mucosal atrophy in chronic disease with a flat and smooth mucosal surface that lacks normal folds Aphthous ulcer (earliest lesion) → coalesce into Superficial broad-based ulcers along the long elongated serpentine ulcers oriented along the axis axis of the colon; no fistula/sinuses of the bowel. Deep fissuring ulcers between mucosal folds, with fistulae/sinuses/perforation Microscopy: Active chronic colitis Activity: cryptitis, crypt abscesses (clusters of neutrophils within crypts), erosions, ulceration Chronicity: distortion of mucosal architecture due to repeated cycles of crypt destruction and regeneration, epithelial metaplasia (pseudopyloric metaplasia and (in the left colon) Paneth cell metaplasia), crypt atrophy/shortening Non-caseating granulomas (~35% of cases) is the Nil hallmark – may occur in areas of active disease, or uninvolved regions in any layer of the intestinal wall or mesenteric lymph nodes Indeterminate colitis: ~10% of IBD patients without definitive features of either UC or CD. Serologic studies for p-ANCA (UC) and antibodies to Saccharomyces cerevisiae (CD) may help differentiate, but despite diagnostic uncertainty, patients with indeterminate colitis often still can be treated effectively due to extensive overlap in medical management of UC and CD G.Soon | Pathweb | Department of Pathology, NUHS | 2020 27 Systemic Pathology GASTROINTESTINAL TRACT PATHOLOGY Colitis-associated neoplasia One of the most feared long-term complications of UC and colonic CD Risk of dysplasia is related to: (i) duration of disease (risk increases sharply 8-10 years after disease onset); (ii) extent of disease (patients with pancolitis are at greater risk than those with only L-sided disease); (iii) nature of the inflammatory response (greater frequency and severity of active inflammation confers increased risk) To facilitate early detection of neoplasia, patients usually undergo frequent endoscopic surveillance approximately 8 years after diagnosis of IBD (earlier for patients with both IBD and PSC who have even greater risk of developing cancer). The goal of surveillance biopsies is to identify dysplastic epithelium, which is a precursor to colitis-associated carcinoma. Dysplasia can occur in flat areas of mucosa that are not grossly recognized as abnormal. Dysplasia can be low grade or high grade, and may be multifocal. Sporadic colonic adenomas can also occur in IBD patients and may be difficult to distinguish from polypoid foci of IBD-associated dysplasia. Treatment depends on the distinction as IBD-associated dysplasia may prompt colectomy due to association with invasive carcinoma while sporadic adenomas can be excised via polypectomy. Diversion colitis Inflammation developing in a segment of colon diverted away from the normal faecal flow e.g. in surgical treatment of intestinal disorders (like UC) which may require creation of a temporary or permanent ostomy and a blind distal segment of colon Pathogenesis: Not well understood; possibly due to changes in the luminal microbiota and diversion of the fecal stream that provides nutrients to colonic epithelial cells. Treatment: enemas containing short-chain fatty acids, a product of bacterial digestion in the colon and an important energy source for colonic epithelial cells, can promote mucosal recovery in some cases. Ultimate cure is re- anastomosis of the diverted segment. Histology: Numerous mucosal lymphoid follicles. In severe cases, may mimic IBD (crypt abscesses, mucosal architectural distortion or rarely granulomas) Microscopic colitis Idiopathic disease, presenting with chronic non-bloody watery diarrhoea and with normal radiologic and endoscopic findings. Encompasses 2 entities: collagenous colitis and lymphocytic colitis Collagenous colitis: middle-aged and older women; characterized by a dense subepithelial collagen layer +/- increased numbers of intraepithelial lymphocytes Lymphocytic colitis: strong association with celiac disease and autoimmune disease; increased intraepithelial lymphocytes (>20 T-cells per 100 colonocytes) Graft vs host disease Occurs following haematopoietic stem cell transplantation, usually involving small bowel and colon. Presents as watery diarrhoea but may become bloody in severe cases G.Soon | Pathweb | Department of Pathology, NUHS | 2020 28 Systemic Pathology GASTROINTESTINAL TRACT PATHOLOGY Occurs secondary to donor T cells targeting antigens on the recipient’s GI epithelial cells. Histology shows epithelial apoptosis (particularly of the crypt cells) with sparse inflammation in the lamina propria. Rarely, total gland destruction occurs Diverticular disease Acquired pseudodiverticular outpouchings of colonic mucosa and submucosa (unlike true diverticula e.g. Meckel diverticulum, which includes all 3 layers of the colonic wall). Usually multiple (diverticulosis) Pathogenesis: results from the elevated intraluminal pressure usually in the sigmoid colon (probably due to exaggerated peristaltic contractions with spasmodic sequestrations of bowel segments, which may be enhanced by diets low in fiber which reduce stool bulk, particularly in the sigmoid colon). This causes outpouchings in the focal discontinuities in the colonic muscle wall where nerves, arterial vasa recta and their connective tissue sheaths penetrate the inner circular muscular coat. The external longitudinal layer of the MP is unable to reinforce these gaps as they are gathered into the 3 bands (taenia coli) in the colon Clinical features: Prevalence increases with age (common in those over 60yo); less common in Japan and developing countries ? dietary differences. R-sided disease more common in Asia but uncommon in Western countries. Most individuals are asymptomatic, but ~20% present with intermittent cramping, continuous lower abdominal discomfort, constipation, distension, sensation of incomplete defecation or occasionally chronic / intermittent per rectal bleeding (with erosion into blood vessels). Complications: Obstruction of diverticula leads to inflammation, resulting in diverticulitis and peri-diverticulitis, which can lead to perforation, pericolonic abscesses, sinus tracts, fistulae and occasionally peritonitis. Diverticulitis may also cause segmental diverticular disease-associated colitis (SCAD), fibrotic thickening in and around the colonic wall or stricture formation. Treatment: Increased dietary fiber may help symptoms. Even when diverticulitis occurs, it most often resolves spontaneously; relatively few patients require surgical intervention Gross: small flask-like outpouchings ~0.5-1 cm in diameter that occur alongside the taenia coli Histology: thin wall composed of flattened / atrophic mucosa, compressed submucosa and attenuated or totally absent muscularis propria. Hypertrophy of the circular layer of the muscularis propria in the affected bowel segment is common Polyps Gross morphology: sessile (broad-based) vs pedunculated (narrow base +/- stalk) Non-neoplastic (inflammatory, hamartomatous or hyperplastic) vs neoplastic (usually adenoma) Non-neoplastic polyps Hyperplastic: benign epithelial proliferations, usually in left colon, often multiple. Serrated surface architecture (serrations restricted to upper third of the crypt) Inflammatory: can form as part of the solitary rectal ulcer syndrome due to impaired relaxation of the anorectal sphincter, leading to recurrent abrasion and ulceration of the overlying rectal mucosa; an inflammatory polyp develops as a result of the chronic cycles of injury and healing. Entrapment of G.Soon | Pathweb | Department of Pathology, NUHS | 2020 29 Systemic Pathology GASTROINTESTINAL TRACT PATHOLOGY the polyp in the fecal stream subsequently leads to mucosal prolapse. Histology = mixed inflammatory infiltrates, surface erosion, and epithelial hyperplasia +/- lamina propria fibromuscular hyperplasia (in mucosal prolapse) Hamartomatous: occur sporadically or as part of various genetically determined or acquired syndromes (some of which are associated with increased cancer risk either within the polyps or at other intestinal or extra-intestinal sites) o Juvenile polyps: morphology of sporadic vs syndromic forms are indistinguishable. Usually in children