GI Pathology Flashcards
Basic Histology of GI tract
Mucosa, Submucosa, Muscularis Propria and Serosa/Adventitia depending on peritoneal covering
Anatomical disorders of oesophagus: definitions (2), common sites, pathogenesis (1), presentations (3)
Atresia = congenital absence of lumen (most commonly at or near tracheal bifurcation) Fistula = abnormal connection between 2 structures (most tracheoesophageal fistula are congenital -- type III MC: connection of lower oesophagus to trachea)
- failure of foregut division (partitioning) in 4th week of gestation (1/3000 pregnancies, slight male predominance)
- atresia is a/w fistula
Presentation:
- aspiration
- regurgitation
- electrolyte or fluid imbalances
Motor disorder of oesophagus: definition and characteristics (3), aetiologies (2), presentations (3), complications (4)
Achalasia = rare neuromotor disease characterised by triad of:
- aperistalsis
- increased resting tone of LES
- incomplete LES relaxation during swallowing
Aetiologies:
- primary - idiopathic (failure of inhibitory neurons)
- secondary - Chagas disease (trypanosoma cruzi cause destruction of myenteric plexus; endemic in SA)
Presentations:
- progressive dysphagia
- nocturnal regurgitation
- aspiration
- Barium swallow: bird beak with proximal dilation at LES
Complications:
- candida oesophagitis
- lower oesophageal diverticulum
- aspiration pneumonia
- ESOPHAGEAL SCC
Mallory Weiss Syndrome: definition, aetiology, pathogenesis, prognosis, complication
= Longitudinal MUCOSAL tears of distal oesophagus +/- proximal stomach
- 5-10% UGIB, usually self-limiting
Aetiology:
- severe retching associated with excessive alcohol intake
Pathogenesis:
- failed reflex relaxation of gastro-oesophageal musculature during prolonged vomiting –> reflux of gastric contents –> stretch oesophageal wall and tear
Prognosis
- superficial tears heal quickly without surgical intervention
Boerhaave Syndrome = severe transmural form of MWS involving oesophageal rupture (leading to mediastinitis)
Oesophageal varices: definition, aetiology, presentation/prognosis, pathogenesis, pathology (2)
= dilated tortuous submucosal veins in lower oesophagus due to portal hypertension
- second most common cause is hepatic schistosomiasis
65-90% of cirrhotic patients (commonly AFLD)
- asymptomatic until rupture –> life-threatening massive UGIB (40% mortality; 50% rebleed within 1 year)
- death due to direct haemorrhage and hypovolemic shock or hepatic coma from massive protein load in bleeding
Pathogenesis:
- portal HT induces back flow of portal blood into caval system (via portosystemic shunts) –> enlargement of submucosal venous plexus in distal oesophagus –> massive haematemesis
Pathology:
- tortuous dilated veins within submucosa seen on endoscopy
- intact or ulcerated and necrotic overlying mucosa (especially if ruptured)
Oesophagitis: definition, aetiologies, most common?, manifestations of chemical esophagitis, clues to agent in viral esophagitis
= inflammation of the oesophagus
Wide variety of aetiologies:
(VITAMINCD)
- infection e.g. HSV, CMV, Candida (immunosuppressed)
- autoimmune (eosinophilic oesophagitis)
- metabolic e.g. renal failure
- iatrogenic e.g. doxycycline, bisphosphonates, chemo/RT
- chemical —> GASTROESOPHAGEAL REFLUX (MC cause), corrosive agents (alcohol, hot drinks, acids
Chemical oesophagitis usually causing odynophagia
- ulceration and acute inflammation
Viral esophagitis endoscopic/histological appearance gives clue for agent
- punched out ulcers with nuclear viral inclusions and rim of degenerating epithelial cells – HSV
- shallower ulcers with nuclear and cytoplasmic inclusions – CMV
Reflux oesophagitis (GERD): cause, prevalence, presentation (3), complications (3), risk factors (4), histology (3)
Most common type of oesophagitis affecting 3-4% of general population
- due to reflux of gastric contents into lower oesophagus
Presentation:
- heartburn
- dysphagia
- regurgitation
Complications:
- minor UGIB (haematemesis, melena)
- stricture
- BARRETT OESOPHAGUS
Risk factors:
- conditions that decrease LES tone or increase abdominal pressure
- — alcohol, smoking, obesity, CNS depressants, pregnancy, hiatal hernia etc.
- cause not identified in most cases
Histology:
- doesn’t correlate with clinical symptoms
- unremarkable in mild cases
- basal zone hyperplasia (>20% full thickness)
- elongation of lamina propria papillae (>2/3 full thickness)
- leukocytic (neutrophilic, eosinophilic) exocytosis
Treatment with PPI
Barrett Oesophagus: definition, prevalence, appearance, histology, complications (2)
= replacement of distal oesophageal squamous epithelium with metaplastic columnar epithelium at least 1 cm above OGJ
- affecting 5-15% of patients with reflux oesophagitis
identified in:
- endoscopic exam - tongues/patches of “salmon-coloured” mucosa extending upward 1cm above OGJ alternating with pale areas of squamous mucosa
- histological exam - presence of goblet cells with distinct mucous vacuoles (intestinal metaplasia) and columnar cells
- presence of these 2 are required for diagnosis
Complications:
- risk factor (precursor lesion) for oesophageal glandular dysplasia and adenocarcinoma (30-100x); 0.5% dysplasia/year – but most don’t develop adenoCA
Management:
- surveillance endoscopy with biopsy for dysplasia –> early detection of cancer = better prognosis
Dysplasia: definition
Dysplasia = precursor of malignancy i.e. premalignant lesion with architectural and cytological abnormality but no stromal invasion
- can be classified into high grade or low grade depending on differentiation
Benign vs Malignant Neoplasms (4)
Recall features to distinguish (BAP)
- differentiation
- rapidness of growth (circumscription vs. necrosis/ haemorrhage)
- invasiveness (stromal/ desmoplastic, lymphovascular, perineural; adj organ, capsular invasion)
- distant metastases (LN, distant organs)
Oesophageal carcinoma: types, epidemiology, risk factors, common site of malignancy, presentations (6)
Malignant epithelial neoplasm
- SCC most common (90%), AdenoCA (10%)
- M:F 4:1
- 60-70 years old
Risk factors:
SCC
– lifestyle - tobacco smoking, alchohol, hot drinks, nutritional deficiency, nitrosamines
– oesophageal disease - achalasia, plummer-vinson syndrome (oesophageal web, anemia, atrophic gastritis)
– tylosis (hyperkeratosis of palms and soles)
AdenoCA
– Barrett oesophagus (30-100x) and GERD
Presentation:
- **SCC mostly in middle third, AdenoCA at distal third
- dysphagia (solid then liquid), odynophagia
- LOW
- dry cough, haemoptysis, pneumonia: tracheal invasion
- hoarseness: RLN invasion
- hyperCa (PTHrp in lung SCLC)
–> Sx usually appear at late stage with submucosal lymphatic invasion –> poor prognosis (5 year survival <25% for ADC and 9% for SCC)
Pathogenesis:
- AdenoCA –> chromosomal abnormalities and TP53 mutation
- SCC unclear
Oesophageal carcinoma pathology full details: gross appearance, histology, LN metastasis sites
Pathology:
- gross
- – SCC: whitish small plaque-like thickenings –> polypoid mass (may ulcerate, diffusely infiltrate - INTRAMURAL GROWTH in 11-17%, invade surrounding structures)
- – ADC: flat or raised patches –> large exophytic masses that infiltrate/ulcerate/invade
- histology
— architecturally, composed of proliferation of tumour cells with squamous/ glandular differentiation in a desmoplastic stroma
with tumour cells in sheets and nests with keratinisation for SCC
or infiltrative irregular and complex glands for ADC
— cytologically, malignant with hyperchromasia, high N:C ratio, prominent nucleoli, pleomorphism and frequent mitosis
with intercellular bridging for SCC
or
mucin secretion for ADC
– may also comment: infiltration into muscularis propria, lymphovascular invasion
- LN metastasis
- middle third –> mediastinal, paratracheal, tracheobronchial nodes
- lower third –> gastric and celiac nodes
Important elements of pathology report (3)
Diagnosis
Prognosis
- stage, grade, resection margin clearance, lymphovascular/perineural invasion, background tissue status
Therapeutic prediction
- e.g. HER2 over expression in 15% patients with gastric adenoCA using IHC and FISH techniques
Basic anatomy and physiology of the stomach
Cardia - mucus secreting glands lined by foveolar cells
Fundus - parietal and chief cells
Body - mucus secreting glands, parietal cells (acid), chief cells (pepsin)
Antrum - mucus secreting glands, endocrine cells (G cells produce gastrin)
Balance of destruction (acid, peptic enzymes) and protection (mucus layer, bicarbonate, rich blood flow, PGs, regenerative capacity)
Other structures include inflammatory cells, stromal and soft tissue cells
- Gastropathy = cell injury and regeneration but inflammatory cells rare/ absent
Acute Gastritis: definition, consequences (3), manifestations (6), aetiology (5), Cushing vs Curling ulcer, pathogenesis of common causes (3)
= Transient mucosal inflammation (destruction>protection)
- may lead to mucosal erosion (epithelium of mucosa), ulceration (breach whole mucosa and extend deeper) and haemorrhage
Clinical manifestations:
- asymptomatic in mild cases
- epigastric pain, nausea, vomiting
- bleeding –> haematemesis, melon, massive blood loss (rare)
- acute gastric ulcers (Curling or Cushing)
- —> Curling in proximal duodenum
- —> Cushing in stomach, duodenum or oesophagus; higher risk of perforation
Aetiology:
- Drug - NSAID (most common), aspirin, chemotherapy
- Metabolic - alcohol, chemical, uraemia
- Traumatic e.g. NG tube
- Severe stress e.g. severe burns, trauma (Curling ulcer)
- CNS injury (Cushing ulcer with high incidence of perforation) – direct stimulation of vagal nucleus increasing acid secretion
Pathogenesis:
- NSAID –> inhibit COX dependent synthesis of PG E2 and I2 –> loss of stimulation of all defence mechanisms of stomach (mucus, bicarbonate, blood flow, regeneration) — COX-1 larger role than COX-2 but both involved (higher risk with aspirin/ ibuprofen but celecoxib also has risk)
- uremia –> inhibition of gastric bicarbonate transportors by ammonium ions
- chemicals/ alcohol/ radiation/ NSAID –> direct cellular damage
- chemo –> insufficient epithelial renewal
- stress related mucosal injury –> local ischemia (hypotension, vasoconstriction)
Pathology: acute/active!! neutrophils!!
- moderate edema and slight vascular congestion
- hyperplasia of foveolar mucous cells
- may have erosions and haemorrhage in severe cases (acute erosive haemorrhagic gastritis)
- stress ulcers (brown to black base with sharply demarcated margins)
Chronic Gastritis: definition, clinical severity, aetiology (3)
Chronic inflammation of the gastric mucosa
- clinically usually less severe but more persistent than acute gastritis
Aetiology;
- H.pylori (>80%)
- Autoimmune (<10%)
- NSAID
H. Pylori-associated Chronic Gastritis: pattern of gastritis, pathogenesis (4), associated diseases, complications, histopathology (3), diagnosis, treatment
Major cause of chronic gastritis
Pattern of gastritis:
- antral predominant with increased acid secretion
- pangastritis affecting both antrum and body if severe (reduced parietal cell mass and reduced acid secretion)
Pathogenesis:
Features of virulence
– flagella: motility
– urease: break down urea and generate ammonia to neutralise gastric acid
– adhesins: enhance adherence to foveolar cells of gastric mucosa
– toxins (CagA): carcinogenesis
Associated diseases:
- gastric ulcer
- duodenal ulcer (account for almost 100% of cases)
Complications:
- increase risk of gastric adenoCA and gastric lymphoma
Histopathology:
- HP concentrated within overlying mucus layer with tropism for gastric foveolar epithelium (antrum)
- chronic +/- active inflammation –> lymphoplasmacytic + macrophages +/- neutrophils at superficial lamina propria
- glandular atrophy
- intestinal metaplasia –> may progress to glandular dysplasia and adenoCA
- may see lymphoid aggregates with induced MALT
Diagnosis:
- serological, stool, urea breath test
- specimens –> rapid urease, culture, PCR
Treatment: triple therapy (amoxicillin, clarithromycin + PPI)
Autoimmune Gastritis: pattern of gastritis, pathogenesis (2), associated disease, complication, histopathology (4)
Slight female predominance, median 60yrs old
Accounts for <10% gastritis
Pattern:
- body (parietal and chief cells) predominant
Pathogenesis:
- antibodies to parietal cells –> loss of H+/K+ ATPase (atrophic gastritis) –> defective gastric acid secretion (achlorydia) –> hypergastrinemia with antral G cell hyperplasia
- antibodies to intrinsic factor –> disable ileal vitamin B12 absorption –> B12 deficiency –> pernicious anaemia (megaloblastic)
- chief cell damage can cause increase in serum pepsinogen I levels
Associated diseases:
- pernicious anemia (minority of patients)
- neurological changes
Complications:
- risk of gastric adenoCA
Histopathology:
- chronic inflammation (lymphoplasmacytic and macrophages) –> deep and centred on gastric glands
- diffuse gastric glandular atrophy (of oxyntic acid producing mucosa in body and fundus) –> parietal and chief cell loss –> intestinal metaplasia
- endocrine G cell hyperplasia
NSAID-associated gastritis
Chronic use suppresses mucosal prostaglandin synthesis
Histopathology:
- reactive gastritis
- foveolar hyperplasia, proliferation of smooth muscle cells in lamina propria, lamina propria oedema, vascular ectasia
–> ulcer
Peptic Ulcer Disease: risk factors (5), pathogenesis (5), locations, gross morphology (4), histology (4)
Risk factors for injury:
- increase damage – H.pylori (MC, >70%), NSAID (MC), Aspirin, smoking (decrease blood flow and impair healing), alcohol
- decrease defence – ischemia, shock, high dose steroids (decrease PGs and impair healing)
Pathogenesis:
- imbalance of mucosal defences (mucus, bicarbonate, blood flow, PGs, regenerative capacity) and damaging forces –> chronic gastritis background –> peptic ulcer
- hyperacidity from H. pylori, parietal cell hyperplasia, excessive secretion, insufficient inhibition of gastrin, gastrin releasing tumour/ hyperCa stimulate gastrin production
- decreased blood flow and impaired healing due to smoking
- steroid suppress PGs and regeneration
Locations:
- can occur at any part of the GIT that is exposed to acid injury
- —> H. Pylori: gastric antrum and D1 of duodenum (MC)
- —> GERD: lower oesophagus
- —> Gastric heterotopia: Meckel diverticulum
- —> Zollinger Ellison syndrome (gastrin tumour): multiple ulcers
Gross morphology:
- round to oval solitary lesions
- sharply punched out
- fibrosis causing puckering of surrounding mucosal folds
- clear and smooth base (peptic digestion of exudate); bleeding possible
Histology: 4 layers
- necrotic debris
- acute inflammation
- granulation tissue (richly vascular)
- fibrosis
Gastric vs Duodenal ulcer: % of ulcer cases, location, risk of malignancy, clinical presentation, complications
Gastric ulcer -25%
- lesser curvature of stomach; interface of body and antrum
- small risk of malignancy –> need biopsy
- epigastric pain exacerbated by food, worse at night
Complications -
- bleeding (left gastric artery) – may cause Fe def anemia or acute bleed
- perforation
Duodenal ulcer - 75%
- D1 of duodenum (anterior wall then posterior)
- no risk of malignancy (no need biopsy)
- epigastric pain relieved by food, worse at night
Complications -
- bleeding (gastroduodenal artery)
- perforation
- gastric outlet obstruction/ pancreatitis if posterior ulcer (scarring and stenosis)
Treatment: HP eradication and neutralisation of gastric acid
Gastric polyps
small proliferations on mucosal surface
- often incidental finding on endoscopy, 5%
Non-neoplastic (>90%)
- hyperplastic/inflammatory polyp (in chronic inflammation –> injury with reactive hyperplasia)
- fundic gland polyps (decreased acid –> increase gastrin –> glandular hyperplasia)
Neoplastic (pre-malignant/dysplasia)
- adenomatous polyp – risk of CA related to size – higher risk if >2cm; high malignant potential up to 30% (background chronic gastritis with atrophy and intestinal metaplasia)
Gastric adenocarcinoma: incidence, common location, risk factors (6), clinical presentations
HK 2016, 6th incidence of CA, 4th in mortality – decreasing trend of incidence but generally higher in Asia
- 85-90% malignant neoplasms of stomach
- more commonly found at lesser curvature and antrum
Risk factors:
- environmental – smoking, diet (nitrosamines, low fruit and veg, smoked food)
- host factors – HP infection, chronic gastritis with intestinal metaplasia (c.f. chronic inflammatory states in tumourigensis), gastric adenoma, EBV
- genetics – APC, Lynch syndrome
Clinical presentations:
- cachexia, weight loss (60%)
- epigastric pain (50%)
- vomiting +/- melena
- metastasis e.g. Virchow’s node, Sister Mary Joseph nodule (umbilicus), distant organs such as ovaries (Krukenburg tumour)
Gastric adenoCA histopathology: gross classification, microscopic classification (causes, histology, HER2 status, prognosis) overall prognosis and staging
Gross classification (Borrmann) - rarely used now
- Type 1: polypoid
- Type 2: fungating mass with sharp raised margins
- Type 3: ulceration with poorly defined margins
- Type 4 (linitis plastica): diffuse infiltration due to desmoplastic reaction that stiffens gastric wall
Microscopic classification (Lauren)
- Intestinal type (most common)
- — mostly environmental risk factors (diet, smoking) and pre-exisitng disease e.g. HP infection, chronic gastritis, FAP with APC mutation
- — histology: cohesive, gland formation, apical mucin vacuoles with abundant mucin in lumen
- — grossly: bulky tumour
- — 10-15% HER2 amplified
- — better prognosis
- Diffuse type
- — uncertain association with env risks; hereditary diffuse gastric cancer syndrome with inherited E-cadherin mutation
- — histology: discohesive mucinous cells with infiltrative growth pattern, SIGNET RING CELLS (large mucin vacuoles push nucleus to periphery), desmoplastic reactions
- — grossly: mass may be difficult to appreciate, linitis plastica (diffuse rugal flattening and rigid wall due to desmoplastic reaction)
- — <1% HER2 amplified
- — worse prognosis
- Mixed type
Prognosis:
- TNM staging
- early = limited to mucosa and submucosa = good prognosis
- advanced = invaded muscularis propria = poor prognosis
Gastric Lymphoma: most common type, classification, MALToma features and associations, histology
5-10% of malignant neoplasms of stomach
- most common extra-nodal lymphoma
Mostly non-Hodgkin B cell type
- associated with HP or EBV infection
Classification:
- low grade = MALToma, related to HP
- high grade = transformation from MALToma to diffuse large B cell lymphoma
MALToma is the commonest gastric non-Hodgkin lymphoma (extra nodal marginal zone lymphoma of MALT)
- accounts for >50% cases
- strong association with HP infection (eradication of HP treats 70% cases)
- “homing” = tend to home back to stomach and presents at early stage
(Histology:)
- expansile lymphoid infiltrate in lamina propria
- lymphoepithelial lesions characterised by destruction and infiltration of glandular structure by lymphoid infiltrate
Gastrointestinal Stromal Tumour: most common sites, pathogenesis (2), pathology (2)
- commonest GI mesenchymal tumour accounting for 0.2% of GI malignancy
- 40-70 males
Site: stomach (50-70%) > small intestine > colon > others
Pathogenesis:
- originate from interstitial cells of Cajal in muscularis propria
- activation mutation of c-KIT/CD117 (75-85%) or PDGRFA (10%)
Pathology:
- IHC of c-KIT/CD117 (diagnostic marker)
- tumour cells arranged in fascicles and exhibit bland elongated nuclei (spindle cells) or plumper epithelioid cells
- solitary well circumscribed mass
Primary treatment is complete resection
Imatinib (TKI) therapy for life in unresectable or metastatic tumour (usually >10cm)
Carcinoid: origin, common sites in body, types in stomach (3), carcinoid syndrome features (5) and cause, pathology (3), prognosis (2)
Neuroendocrine cell tumour (0.3% of gastric neoplasms) derived from APUD cells of neural crest origin
- 75% in GI tract, 25% in lung
3 types in stomach:
- Type I - associated with autoimmune chronic atrophic gastritis (decreased acid –> increase gastrin –> G cells hyperplasia)
- Type II - MEN1 and Zollinger-Ellison syndrome
- Type III - sporadic
Carcinoid syndrome: flushing, diarrhoea, SOB, wheezing, tachycardia due to 5HT secretion – implies liver metastasis
Pathology:
- uniform round cells with centrally located stippled nuclei and scant eosinophilic granular cytoplasm in organoid pattern
- small polypoid, yellow/tan appearance
- IHC of neuroendocrine markers e.g. synaptophysin, chromogranin
High grade NET are called NEC and resemble small cell carcinoma of lung –> in GI tract, most common at jejunum
Prognosis of NET:
- Grading - Ki67 IHC stain for proliferation
- Location -
- foregut –> rarely metastasise and cured by resection
- midgut –> metastatise, multiple and aggressive – MC small bowel tumour
- hindgut –> benign course
Ischemic Bowel Disease: definition, pathogenesis (2), areas most prone to damage (3), aetiology (4 categories and examples)
Ischaemia = insufficient blood supply (Infarction = necrosis due to ischaemia)
Pathogenesis:
- hypoxic injury phase - little damage; epithelial cells resistant to transient hypoxia
- reperfusion injury phase - increase O2 = increase ROS; increase WBC and complements = increase inflammation
Areas most prone to damage
- watershed zones – end of arterial supplies
- -> splenic flexure (Griffith’s point) - SMA and IMA
- -> sigmoid colon (Sudeck’s point) - IMA and hypogastric arteries
- superficial portion of mucosa (epithelial lining of villi or crypt) –> farthest away from blood supply
Aetiology: Local circulation problems - Luminal BLOCK --> arterial embolism (MC; 50% cases) e.g. AF; SMA most vulnerable as greatest velocity of flow and most acute angle off aorta --> thrombosis (arterial or venous)
- Mural NARROWING
- -> atherosclerosis
- -> vasoconstriction (secondary to shock, vasoconstrictors)
- -> vasculitis
- Extramural COMPRESSION
- -> adjacent mass lesion
- -> volvulus, hernia
Systemic circulation problems
- shock (systemic hypoperfusion leading to insufficient blood supply to vital organs)
- -> recall 5 types of shock and effects in frank-starling law BP = CO x TPR (CO = SV x HR where SV dependent on contractility and VR)
Ischemic Bowel Disease: types of infarction (causes, manifestations, prognosis)
Mucosal = only mucosal layer Mural = mucosal + submucosal layers
- -> both due to systemic hypoperfusion (shock), localised anatomical defects
- -> manifests as abdominal pain, melena, abdominal distension
- -> progress to transmural if not restored
- -> pathology: mucosal necrosis and submucosal oedema
Transmural = all layers
- -> due to acute occlusion of major mesenteric artery
- -> manifests as sudden onset severe pain, bloody diarrhoea
- -> perforation, sepsis and shock if untreated - high mortality >50%
Pathology:
- atrophy or sloughing of surface epithelium, crypts may be hyper proliferative
Haemorrhoids: definition, risk factors (3), manifestations (4), classification
= variceal dilations of anal and perianal venous plexuses (collateral vessels connecting portocaval systems formed in response to venous hypertension)
Common GI lesion affecting 5% of population
Risk factors:
- persistent elevated venous pressure from chronic constipation
- pregnancy
- portal HT (rare)
Manifests as rectal bleeding, pruritus, prolapse or acute pain (thrombosed haemorrhoids)
Classified into internal and external
- Internal
- -> above dentate/pectinate line – NO PAIN
- -> further divided into grade 1 (no prolapse), 2 (prolapse can be reduced spontaneously), 3 (prolapse can be reduced manually), 4 (irreducible)
- External
- -> below dentate line – PAIN (if thrombosed)
Pathology:
- thin-walled, dilated submucosal vessels beneath anal or rectal mucosa
- may have focal mucosal erosion
- squamous epithelium for external; columnar epithelium for internal
Angiodysplasia (vascular ectasia): definition, prevalence, manifestation, location, pathogenesis (2), associations
= vascular malformation (AVM) characterised by tortuous dilation of submucosal and mucosal veins (+ venules and capillaries)
uncommon, <1% population
but one of the commonest causes of LGIB (20-40% cases)
Manifests as recurrent self-limiting bleeding (but up to 15% massive GI bleeding)
Location
- majority at cecum and ascending colon (80%)
Pathogenesis uncertain
- mechanical: intermittent occlusion of penetrating veins during peristalsis –> lead to dilation and loss of precapillary sphincter function –> AVM)
- degenerative vascular changes
- sometimes associated with ESRD
Infective Enterocolitis: causes, presentation and diagnosis, intestinal TB pathology and diagnosis, pseudomembranous colitis pathology and treatment, general pathology of bacterial infections (4)
Caused by bacteria (Vibrio, gram negatives, C. difficile), virus. (rotavirus, norwalk, enterovirus, CMV) or parasites (nematodes, custodies, hookworms etc.)
- enterotoxigenic E.coli common
- agents vary with host factors e.g. paediatric diarrhoea –> enteric viruses
Presents as diarrhoea, sometimes with ulceration and inflammation of intestine
Specific diagnosis by stool culture
Intestinal tuberculosis
- pathology: necrotising granuloma (necrotic centre, epithelioid histiocytes, langhans giant cells)
- granulomas can be present in all layers of bowel wall and cause transmural disease (cause strictures, fibrosis, perforation)
- Dx: ZN stain, TB culture, TB PCR
Pseudomembranous colitis
- due to toxins of C.difficile (disruption of normal colonic bacteria allow C.diff overgrowth) –> detection of toxin for Dx
- org. particularly prevalent in hospitals
- water diarrhoea, abdominal cramping, fecal leukocytes
- pathology: layer of inflammatory cells (neutrophils) and debris overlying sites of mucosal injury; damaged crypts distended by mucopurulent exudate that “erupts”
- grossly seen as yellow plaques over bowel mucosa
- treatment: antibiotics (metronidazole, vancomycin), fecal microbiota transplantation
Many bacterial infections have similar histology (acute self-limited colitis)
- intraepithelial neutrophil infiltrates, cryptitis (neutrophil infiltration of crypts), crypt abscess
- preservation of crypt architecture (distinguish for chronic inflammation)
Inflammatory Bowel Disease: pathogenesis, risk factors, CD vs UC incidence, presentations, sites (2), gross pathology (5)
Increasing incidence in HK
- normally present in young adults
Pathogenesis uncertain (idiopathic) but proposed ones include:
- NOD2 mutation (not in HK)
- aberrant host mucosal immune response (Th1/2/17 cells) – treatment of IBD with immunomodulation or immunosuppression
- altered gut microbiota
- defective tight junctions of epithelium
Risk factors:
- smoking –> risk for CD but protective for UC
Crohn’s Disease
- 1/100000
- abdominal pain and diarrhoea (+/- mucus if colon/ anus involved), fever
- affects whole GIT, most commonly at cecum and ileum
- SKIP LESIONS
- TRANSMURAL inflammation –> thick wall
- APHTHOUS ULCERS progress and coalesce –> deep linear ulcers and fissures –> COBBLESTONE appearance (coarse textured)
- mural fibrosis, strictures, serositis
Ulcerative Colitis
- 2/100000
- abdominal pain and blood mucoid diarrhoea
- affects RECTUM +/- colon
- continuous lesions
- MURAL inflammation –> thin wall
- superficial broad based ulcers and no fissures
- no fibrosis, strictures or serositis
- isolated islands of regenerating mucosa bulge into lumen –> pseudo polyps
IBD histology (8), complications (6), factors affecting risk of malignancy (3), extracolonic manifestations (4)
Active chronic inflammation
- ACTIVITY shown by erosion, ulceration, cryptitis (neutrophil infiltrate epithelial cells), crypt abscess (neutrophils within crypt lumen)
- CHRONICITY with glandular distortion, branching (evidence of regeneration), atrophy (and fibrosis), epithelial metaplasia (pseudo pyloric; paneth cell metaplasia in left colon)
CD –> NON-CASEATING GRANULOMA
Complications of CD and UC
- CD –> MALABSORPTION (e.g. B12 deficiency), strictures (esp terminal ileum), fistula, perforation
- UC –> IDA, toxic megacolon (infl mediators disturb neuromuscular function and damage muscularis propria)
Both have increased malignant risk and dysplasia (UC>CD)
- risk increases with duration (>8-10 years), extent (pancolitis > proctitis), activity (frequent inflammation)
- need regular endoscopic surveillance (higher risk of dysplasia if have PSC so need earlier check)
Extracolonic manifestations:
- eye: uveitis
- joints: ankylosing spondylitis, enteropathic arthritis
- legs: erythema nodusum, pigmentation
- liver: PSC (more in UC)
- clubbing
Diverticulosis: definitions (true, false, diverticular disease, diverticulitis), pathogenesis (2), presentation (3), complications (6)
Diverticulum = blind pouch protruding from luminal organ
- True = congenital out pouching of all layers of bowel wall e.g. Meckel’s diverticulum
- False = herniation of mucosa and submucosa through muscularis propria into subserosal region e.g. diverticulosis coli
- diverticular disease = symptomatic diverticula
- diverticulitis = infection of diverticulum
Pathogenesis:
- outpouching at focal weakness of wall where arterial vasa recta/ nerves penetrate inner circular muscle coat to create discontinuities in the muscle wall
- increased luminal pressure e.g. constipation, low fibre diet
Pathology:
- thin wall composed of flattened mucosa, compressed submucosa and attenuated muscularis propria
Presentation:
- mostly middle aged/ elderly (80% asymptomatic)
- at sigmoid colon (smaller luminal diameter and increased pressure)
- vague abdominal distension/pain
Complications:
- bleeding from vasa recta (MC cause of LGIB), diverticulitis (due to stasis of contents), perforation and peritonitis/pericolic abscess, stricture (IO), fistula
Solitary Rectal Ulcer (Mucosal Prolapse Syndrome): misnomer?, incidence, presentations (3), gross features
Misnomer
- can be multiple, non-ulcerated, outside rectum (at sigmoid colon)
1/100000 - affecting all ages
Presents as rectal bleed, tenesmus, mucosal discharge
MIMICS CA RECTUM GROSSLY
Polyps: definition, classifications and examples
= lesion which projects into lumen of bowel
- sigmoid colon is the most common site for GI polyps (also diverticula and CA)
Classification of polyps:
- pedunculated vs sessile
- neoplastic vs non-neoplastic
Non-neoplastic:
- hamartomatous, inflammatory and hyperplastic
Neoplastic:
- adenoma, sessile serrated adenoma, traditional serrated adenoma, carcinoma
- all are precursors or pre-malignant lesions for colonic CA
Serrated polyps = histological appearance of sessile serrated adenoma, traditional serrated adenoma and hyper plastic polyp
Hamartomatous Polyps: definition, subtypes, aetiology, common sites, risk of CA, histology, clinical presentations
Hamartomatous polyp
= disorganised overgrowth of tissue indigenous to the site
- mostly sporadic; may be syndromic in familial polyposis syndrome –> need to screen family members
- have extraintestinal manifestations
- subtypes: juvenile/ peutz-jeghers
Juvenile polyps: (MC type)
- children <5
- most common at rectum, with rectal bleed and prolapse through sphincter
- syndromic: 3-100 polyps; higher risk of adenoCA
- histology: <3cm, CYSTIC DILATION of glandular structures (filled with mucin and inflammatory debris) in inflamed stroma
Peutz-Jeghers polyps
- rare AD disorder (LKB1/STK11 gene)
- most common at jejunum/ileum, then colon and stomach
- over entire GI tract
- mucosal pigmentation of buccal mucosa, lips
- small malignant potential but increases risk of CA colon, breast, ovary, pancreas
- histology: network of SMOOTH MUSCLE CORES extend into polyp and surrounding normal looking glands (“Christmas tree”)
Inflammatory polyps: definition, associated conditions, clinical presentation, histology
= mucosal overgrowth secondary to chronic recurrent mucosal injury and regeneration
- associated with IBD, solitary rectal ulcer and other chronic colitis
- clinical triad of rectal bleed, mucus discharge, inflammatory lesion of anterior rectal wall
- histology: markedly inflammed stroma and regenerating glands, inflammed granulation tissue
Colorectal Adenoma: incidence, classification by architecture, classification by dysplasia, advanced adenoma features (3)
Benign neoplasm, well known PRECURSOR of colorectal adenoCA
- incidence increases with age
- characterised by EPITHELIAL DYSPLASIA
Classified by architecture and dysplasia
- tubular MC (>75% tubular glands): MC in sigmoid colon, small pedunculated polyps composed to small, rounded or tubular glands
- tubulovillous: cauliflower like, mixture
- villous (>75% villous): least common, finger-like projection with highly dysplastic cells, large, sessile, covered but slender villi, secrete protein and K rich mucus, more frequent foci of invasion, larger sessile
- low grade dysplasia - simple architecture, mild atypia (preserved nuclear polarity, cigar-shaped nuclei)
- high grade dysplasia - complex architecture, marked atypia (loss of polarity, distinct nucleoli, round vesicular nuclei) –> progress to CA if untreated
Advanced adenoma (higher malignant potential) = SIZE MOST IMPORTANT - >1cm (foci of cancer 40% if >4cm), presence of villous component, high grade dysplasia
Serrated Polyps: definition, 3 types (prevalence, CA risk, common site, morphology - size, sessile or pedunculated, additional histological features)
= serrated (sawtooth) architecture of epithelial component
Hyperplastic polyp
- MC polyp in adult, 75% of hyperplastic polyps
- decreased turnover of epithelium and delayed shedding leading to “pile up” of goblet cells
- NON-MALIGNANT
- common site: left colon (sigmoid)
- morphology: <5mm, sessile, star shaped lumina/ serrated architecture at SURFACE
Sessile serrated adenoma
- 25%
- PRE-MALIGNANT
- right colon
- > 5mm (larger than hyperplastic), serrated architecture throughout the full length of glands, including CRYPT BASE – important to distinguish from hyperplastic
Traditional serrated adenoma
- 1%
- PRE-MALIGNANT
- left colon
- larger than hyperplastic, sessile/pedunculated
Familial Adenomatous Polyposis Syndrome: CRC burden, mutation, phenotype, risk of CRC, histology, extracolonic manifestations (2), diagnosis, screening, treatment, other associated syndromes (3)
<1% of CRC –> typical adenoCA
- AD mutation in APC gene (TSG)
Phenotype: >100 adenomas (usually >1000), 100% risk of CRC by 30 years old
Histology: tubular, villous adenoma
Extracolonic manifestations: multiple gastric fundic polyps, increased risk of CA thyroid, GB and adrenals
Diagnosis: colonoscopy >100 polyps
Screening: flexible sigmoidoscopy Q1y from puberty to 50yrs old
Treatment: prophylactic colectomy (but still have risk of extracolonic manifestations), NASID/COX2 inhibitor to decrease polyp burden
Other syndromes with FAP variants:
- attenuated FAP = <100 polyps, later onset, 10% with MYH gene mutation
- Gardner syndrome = FAP + extracolonic manifestations (sebaceous/epidermoid cyst, osteoma, desmoid tumour - SOD)
- Turcot syndrome = FAP + CNS tumours (medulloblastoma and glioblastoma)
Other polyposis syndromes (5)
All AD
Peutz-Jeghers syndrome - STK11 gene (multiple PJ polyps, mucosal pigmentation, risk of CA in breast, pancreas, ovaries, lung, uterus)
Cowden syndrome - PTEN gene (multiple hamartomatous polyps, oral papillomas, risk of CA breast and thyroid)
Cronk-hite canada syndrome - non hereditary (multiple hamartomatous polyps, nail atrophy, skin pigmentation, alopecia)
Juvenile polyposis syndrome - SMAD4 gene (50-100 juvenile polyps, increased risk of gastric intestinal and pancreatic adenoCA)
Serrated polyposis syndrome - non hereditary (>20 serrated polyps throughout colon/ serrated polyps with +ve hx of serrated polyposis)
Lynch syndrome (HNPCC):CRC burden, mutation, phenotype, risk of CRC, histology, extracolonic manifestations (2), diagnosis, screening (3), treatment,
commonest hereditary disease associated with colorectal cancer – 5-7% CRC
- AD mutation in MMR (mismatch repair) genes (MLH1, MSH2) leading to micro satellite instability
- microsatellite = repetitive, non-coding short DNA sequence –> particularly prone to replication errors
- phenotype: multiple polyps but not polyposis (excessive); predominantly right-sided
- 80% lifetime risk of CRC
Histology: sessile serrated adenoma
Extracolonic manifestations: increased risk of CA endometrium, ovary, small bowel, stomach, bile duct etc.
Diagnosis: genetic analysis of DNA MMR genes
Screening:
- clinical - Amsterdam criteria (>3 relatives with CRC or Lynch associated CA; >2 successive generations, >1 tumour before 50 yrs old)
- pathological - IHC of MMR protein in nucleus (MLH1-PMS2; MSH2-MSH6 –> further genetic test to see which gene in the pair is involved once there is loss of nuclear IHC staining), detection of micro satellite instability (Q1y)
Treatment: genetic counselling, consider prophylactic colectomy/hysterectomy
Colorectal Carcinoma: incidence, aetiology, risk factors (6), histology (3), morphology (left vs right colon), presentation (general, left tumour, right tumour, metastasis sites)
Most common cancer and 2nd in mortality in HK
- 85-90% sporadic, 10% familial syndromes
Risk factors:
- lifestyle - high fat and refined carb diet, low fibres and vitamins A/C/E, smoking, alcohol, obesity
- IBD - UC>CD
- genetics: Lynch syndrome, polyposis syndrome
Prolonged aspirin or NSAID use is a protective factor
Histology: adenocarcinoma (recall classical description of a tumour - architecturally… cytologically…); tall columnar epithelial cells; mucinous histology (signet ring cells) associated with poor prognosis
Morphology:
- distributed equally along entire length of colon (but rectosigmoid>ascending colon and ceum>transverse colon>descending colon)
- right sided tumours grow as POLYPOID EXOPHYTIC masses that extend along on wall –> rarely cause obstruction (large caliber lumen), tend to bleed
- left sided tumours are ANNULAR/CIRCUMFERENTIAL and produce “napkin ring” constrictions and luminal narrowing –> tend to obstruct – pencil stool, tenesmus, IO
Presentation:
- general: change of bowel habit, rectal bleeding, anemia, abdominal pain, tenesmus, weight loss
- right sided tumour –> fatigue, weakness due to Fe def anemia
- left sided tumour –> obstructive symptoms (altered bowel habit), occult bleed
- metastasis to distant organs - esp liver due to drainage of venous return via portal venous system; also lungs
CRC Molecular Pathogenesis
Many different molecular pathways: Chromosomal Instability (CIN), Microsatellite Instability (MSI), CpG island methylation phenotype (CIMP)
Carcinogenesis:
- stepwise accumulation of genetic and epigenetic abnormalities
- Classical adenoma-carcinoma sequence in chromosomal instability - 80% of sporadic CRC
- – APC mutation (both inactivated) –> accumulation of beta catenin (promote proliferation) –> KRAS mutation, DNA hypomethylation –> SMAD2/4 and TP53 mutations –> adenoCA –> PRL3 activation –> metastasis
- – tubular/villous adenoma –> typical adenoCA
- – predominantly left-sided
- – FAP (no predominant side)
- microsatellite instability pathway - 10-15% sporadic CRC
- – DNA MMR gene deficiency - MLH1 and MSH2 mutations –> accumulation of sequences at coding or promoter regions of genes involved in regulation of cell growth e.g. pro-apoptotic BAX, type II TGF-beta receptor (inhibits cell cycle) –> adenoCA
- – serrated pathway: sessile serrated adenoma –> mucinous adenoCA
- – predominantly right sided
- – Lynch (genetic testing using IHC of DNA MMR genes)
- CIMP (activation of BRAF oncogene) - serrated pathway
CRC Prognosis
Grading: G1-G3 (well - moderate - poorly differentiated)
Staging: MOST IMPORTANT PROGNOSTIC FACTOR - depth of invasion and metastasis
- AJCC TNM staging
Tis = CIS (intraepithelial/ invade lamina propria) - 100% 5 year survival
T1 = invade submucosa - 95% survival
T2 = invade muscularis propria - 70-90% survival
T3 = invade subserosa/ pericolic tissues
T4 = perforate visceral peritoneum or other organs
- Dukes staging (A = invade into but not through bowel wall, B = invade through bowel wall but no LN, C = spread to LN, D = distant metastasis
N0-N2 (N0 = stage IIC)
M1 (stage IV, <15% survival)
CRC Biomarkers: potential for targeted therapy and molecular tests required, use of CEA, screening tests and recommendation for screening
EGFR over expression in 80% patients with metastasis –> potential for anti-EGFR monoclonal Ab treatment
–> need to check for downstream KRAS and NRAS mutations (45% patients) which renders patient unresponsive to anti-EGFR therapy (negative predictor)
(c.f. EGFR mutation in lung ADC used TKI therapy and screens for patients with mutation)
Serum CEA - detect recurrence, monitor response
Screening:
- fecal occult blood test - not sensitive/specific (can’t differentiate Hb or myoglobin)
- fecal immunochemical test: test for Hb
- fecal DNA test - more sensitive
- colonscopy - most sensitive
Recommendations: start at 50, Q10yrs if normal, Q3-5yrs if polyps removed
GIST and Carcinoid of Bowels
Refer to flashcards for stomach
Acute appendicitis: pathogenesis (3 steps), aetiology (4), pathology (4), diagnostic requirement in pathology, gross changes, presentation (3)
Appendix is normal true diverticulum of cecum
Acute appendicitis MC in young adults
- M>F
- diagnosis can be difficult to establish pre-operatively
- may be confused with mesenteric lymphadenitis, acute salpingitis, meckel diverticulitis, ectopic pregnancy
Pathogenesis:
- progressive increase in intraluminal pressure that compromises venous outflow –> ischemic injury and stasis of luminal contents –> bacterial proliferation and inflammation
Usually due to overt lumen obstruction by small stone-like mass of stool (fecalith); less commonly by gallstone, tumour, mass of worms
Pathology:
- subserosal vessel congestion, perivascular neutrophilic infiltrate in all layers of wall
- diagnosis requires neutrophilic infiltration of muscular propria
- severe cases –> focal abscesses (acute suppurative appendicitis) –> haemorrhagic ulceration and gangrenous necrosis (acute gangrenous appendicitis)
Grossly: inflammatory reaction causes serosa to become dull, granular appearing erythematous
Presentation: (often not distinctive)
- periumbilical pain that localised to RLQ
- nausea, vomiting, low grade fever
- mildly elevated WBC
- McBurney’s sign (deep tenderness at 2/3 distance from umbilicus to right ASIS)
Tumours of the appendix
Carcinoid is most common
- incidental finding
- distal tip of appendix – solid bulbous swelling 2-3 cm
- nodal metastasis infrequent
Non-mucin-producing adenoCA/ conventional adenoma
- obstruct and enlarge appendix mimicking acute appendicitis
Mucocele (dilated appendix filled with mucin)
- may be due to obstruction
- may be due to mucinous cystadenoCA – intraperitoneal seeding and spread –> may lead to pseudomyxoma peritonei in most advanced cases (abdomen filled with semi-solid mucin)
Intestinal Obstruction: most common causes, classical presentation, causes of intussusception/ Hirschsprung disease/ abdominal hernia
Hernia, intestinal adhesions, intussusception and volvulus account for 80% cases; remaining 20% by tumours/ infarction
Present as
- pain, distention, vomiting, constipation
Intussusception: segment of intestine (constricted by peristalsis) telescopes into immediately distal segment – pulls mesentery along
- may progress to IO, compressed mesenteric vessels and infarction
- MC case of IO in children <2 yrs old
- no underlying anatomic defect
Hirschprung Disease: congenital defect of colonic innervation
- aka congenital aganglionic megacolon – always affects the colon
- neonates with failure to pass meconium in immediate postnatal period followed by obstructive constipation
- may cause enterocolitis, electrolyte disturbances, perforation, peritonitis
Abdominal Hernia: defect in wall of peritoneal cavity permitting protrusion of serosa-lined pouch of peritoneum
- inguinal, femoral, umbilical, surgical
- SB loops most common
- pressure at neck may impair venous drainage –> stasis and edema
- permanent entrapment = incarceration
- arterial and venous compromising over time = strangulation
