Pathology of the Upper GIT PDF

Pathology of the Upper GIT Part 1: Introduction Dr Marcus Dabner [email protected] Outline • • • • Introduction; overview of upper GIT pathology Oesophagus Stomach (Small bowel, pancreas, GB, liver) DISEASE AETIOLOGY: “VITAMIN CD” VASCULAR INFLAMMATORY/ INFECTIVE TRAUMA AUTOIMMUNE METAB...

Pathology of the Upper GIT Part 1: Introduction Dr Marcus Dabner [email protected] Outline • • • • Introduction; overview of upper GIT pathology Oesophagus Stomach (Small bowel, pancreas, GB, liver) DISEASE AETIOLOGY: “VITAMIN CD” VASCULAR INFLAMMATORY/ INFECTIVE TRAUMA AUTOIMMUNE METABOLIC/ENDOCRINE IATROGENIC/ IDIOPATHIC NEOPLASTIC / OTHER GROWTH DISORDERS CONGENITAL / GENETIC DEGENERATIVE “Upper GI” Symptoms and Signs • Dyspepsia (Pain/discomfort in upper abdomen): ‘heartburn’ and ‘indigestion’; early satiety, postprandial fullness, gnawing or burning pain; Recurrent hiccups/burping • Dysphagia (difficulty swallowing) • Odynophagia (pain on swallowing) • Vomiting: gastric contents, blood • Nausea Pattern of symptoms is important, with some ‘classic’ presentations. Important Complications of Upper GI Disease • Mechanical / chemical injury caused by chronic inflammation +/acidic gastric contents: – – – – Mucosal ulceration: pain, bleeding, secondary infection Erosion of wall with extravasation of gastro-oesophageal contents Erosion of large vessels -> major haemorrhage Aspiration of gastric contents into lungs • Recurrent damage over time may lead to: – Adaptation (muscle hyperplasia, epithelial metaplasia) – Scarring, fistulae between organs, formation of strictures / webs – Development of mutations leading to malignancy Haematemesis • Vomiting of blood – Fresh blood = bright red – Coagulated/altered blood = thicker, granular, brown ‘coffee ground’ • • • Many different causes, but most are due to gastric or oesophageal pathology Most pathology in the oesophagus and stomach may cause haematemesis, but usually only in advanced disease; these disease often have other symptoms (pain, heartburn etc). Generally considered a medical emergency; either large enough to be haemodynamically significant or a sentinel event of a more significant problem Oesophageal Causes *Lacerations (Mallory-Weiss syndrome) *Perforation (cancer or Boerhaave syndrome) *Varices (cirrhosis) *Carcinoma Chemical and pill oesophagitis Infectious oesophagitis (Candida, herpes) Benign strictures Reflux oesophagitis (erosive) Eosinophilic oesophagitis Oesophageal ulcers (many aetiologies) Barrett oesophagus Hiatus hernia *Iatrogenic injury *Oesophageal-aortic fistula (usually caused by cancer) Gastric Causes *Peptic ulcer (gastric or duodenal) Gastritis Gastroenteritis (severe) Gastric cancer Zollinger-Ellison syndrome *Iatrogenic injury Other Swallowed blood (epistaxis, oral bleeding) Radiation injury Chemical injury Batteries! *more commonly cause major haematemesis In General: GI Tumours • Benign: – Polyps (different common ones in each anatomical site) • Pre-malignant: – Dysplasia (similar features in each site, but different context) • Malignant: – – – – – Carcinoma Lymphoma GIST Neuroendocrine tumours Other mesenchymal tumours (leiomyoma, schwannoma, granular cell tumour etc) Part 2: Pathology of the Oesophagus Dr Marcus Dabner [email protected] Learning Outcomes Discuss the pathological features (aetiology, pathogenesis, macroscopic and microscopic features and sequelae) and understand the clinical relevance of the following conditions: • Gastro-oesophageal reflux disease (including hiatal hernia) • Oesophagitis (reflux, viral, fungal, and eosinophilic oesophagitis) • Barrett's oesophagus/metaplasia • Carcinoma of the oesophagus • Oesophageal varices • Be aware of congenital oesophageal disorders, functional disorders DISEASE AETIOLOGY: “VITAMIN CD” VASCULAR INFLAMMATORY/ INFECTIVE TRAUMA AUTOIMMUNE METABOLIC/ENDOCRINE IATROGENIC/ IDIOPATHIC NEOPLASTIC CONGENITAL / GENETIC DEGENERATIVE Oesophageal varices GORD/Reflux oesophagitis/Infections/EE Lacerations/Tears/Perforation Barrett Oesophagus / Dysplasia / Cancer Tracheo-oesophageal fistula, stricture Mechanical Obstruction and Functional Disorders • Mechanical obstruction – Benign mucosal webs or Schatzki rings (associated with chronic iron deficiency or GORD) • Achalasia – Incomplete LOS relaxation, increased sphincter tone and aperistalsis. – Dysphagia, belching. – Range of infectious and non-infectious causes (especially Chagas disease, diabetic autonomic polyneuropathy, Trisomy 21). Oesophageal Varices • Tortuous, dilated veins caused by portal hypertension, usually due to increased pressure and resistance to blood flow through the portal venous system and liver. • Usually occurs in the context of cirrhosis of the liver (present in 30% of people with cirrhosis). Collateral vessels develop at sites where the portal and caval systems communicate. • This results in congestion and dilation of subepithelial and submucosal venous plexuses within the distal oesophagus and proximal stomach. • Most varices never bleed, however when they do they lead to catastrophic exsanguination. Gastro-oesophageal reflux disease (GORD) • GORD: Reflux symptoms that occur at least once a week – Acid reflux: Sensation/taste of acid in oesophagus/mouth, dyspepsia (mild to severe), often worse after eating or when lying down, burning retrosternal sensation moving upwards towards oral cavity – Made worse by being overweight, pregnancy, some foods (mint, curry, citrus, chocolate, fried foods, carbonated drinks), alcohol, caffeine, smoking, NSAIDS, gastritis – May also have: chronic cough/laryngitis, asthma, sleep disorder, dysphagia • Reflux in young children (especially babies) doesn’t tend to cause heartburn but does cause vomiting instead • Affects 5-10% of adults, variable severity of symptoms, complications are uncommon by significant https://doi.org/10.1016/j.cgh.2018.02.014 Causes of reflux • Inadequacy of lower oesophageal sphincter: functional or mechanical or both – Transient lower oesophageal sphincter relaxation • Mediated by vagal pathways, can be triggered by gastric distension or abrupt increase in intra-abdominal pressure – Hiatal hernia – Functional causes: increased gastric filling, lower pH, delayed gastric emptying For details see Tack and Pandolfino (2017), DOI: https://doi.org/10.1053/j.gastro.2017.09.047 Hiatal hernia o Oesophagus passes through the hiatus in the crural part of the diaphragm o The hiatus is approximately 2cm in length and consists of the musculotendinous parts of the left and right crura; size is not fixed and narrows when intra-abdominal pressure rises o Lower oesophageal sphincter is 2-5cm in length and is area of thickened smooth muscle between oesophagus and stomach. Upper part of sphincter lies within hiatus and rest is therefore usually intraabdominal. o If sphincter moves superiorly through the hiatus this tends to lead to reflux: o Gastric mucosa can prolapse into oesophageal lumen o Part of stomach can be present in thorax o Most are ‘sliding’ type, minority are ‘para-oesophageal/rolling’, usually due to a defect in the diaphragm that needs to be surgically corrected Note: hernia = gap in wall/tissue that normally constrains the organ, allowing tissue to protrude through the gap https://www.msdmanuals.com/en-au/professional/multimedia/figure/gi_hiatus_hernia https://emedicine.medscape.com/article/178393-overview Consequences of GORD • The major complication of reflux is acute on chronic inflammation, i.e. reflux oesophagitis – Can lead to ulceration and reactive changes in oesophagus including formation of strictures (narrowing) • Chronic inflammation and exposure to low pH from acid gastric contents leads to chronic cellular injury and adaptation. – Important consequences include intestinal metaplasia (Barrett oesophagus), dysplasia and carcinoma Morphology of GORD Macroscopic Microscopic Mild Hyperaemia/redness of mucosa Minimal inflammation, very mild hyperplasia Moderate Small erosions, more significant redness More significant basal hyperplasia, papillary elongation, intraepithelial inflammatory cells including neutrophils and small numbers of eosinophils Severe Active inflammation, ulceration or Barrett metaplasia Inflammatory cells more prominent, ulceration, intestinal metaplasia in areas of Barrett’s. “Endoscopic view of reflux oesophagitis with multiple erosions within the squamous-lined esophagus, a metaplastic zone and distal gastric mucosa. Note the tan islands of metaplastic epithelium within the white squamous mucosa.” From Kumar et al, Robbins and Cotran Pathologic Basis of Disease 10th ed, chapter 17 Barrett’s Ulcer Squamous LOS T62M3615(4): Extensive Barrett’s oesophagus (intestinal metaplasia = raised, reddish areas, squamous mucosa = pale areas), Stricture at GOJ due to hiatus hernia, Ulceration Stomach Stricture (probably healed ulcer) Barrett Oesophagus • Barrett oesophagus refers to a complication of chronic oesophagitis where oesophageal squamous mucosa undergoes metaplasia to intestinal type columnar epithelium • 10% of people with GORD, 2% of general population • Typically 40-60 year olds • Increases risk of oesophageal adenocarcinoma. – Metaplasia associated with chronic inflammation, increases risk of mutations within cells at GOJ, which increases risk of dysplasia, which increases risk of adenocarcinoma • Short segment: <3cm, Long segment: >3cm. Risk of dysplasia /adenocarcinoma increases with increasing length/area. • Morphology: – Macroscopic: Tongues of red, velvety mucosa extending proximally from GOJ, within residual islands of pale squamous lined mucosa, usually contiguous with gastric mucosa at the distal end. – Microscopic: Intestinal metaplasia, characterized by columnar cells with prominent intestinal type goblet cells (mucin vacuole above the nucleus), usually moderate to severe inflammation, may have dysplasia or no dysplasia. If dysplasia is present, may be low or high grade. Barrett esophagus. (A) Normal gastroesophageal junction. (B) Barrett esophagus. Note the small islands of residual pale squamous mucosa within the Barrett mucosa. (C) Histologic appearance of the gastroesophageal junction in Barrett esophagus. Note the transition between esophageal squamous mucosa (left) and Barrett metaplasia, with abundant metaplastic goblet cells (right). From Kumar et al, Robbins and Cotran Pathologic Basis of Disease 10th ed, chapter 17 Other causes of oesophagitis • Eosinophilic oesophagitis – Characteristic form of inflammation with numerous eosinophils, often associated with atopic disease (atopic dermatitis, allergic rhinitis, asthma, or peripheral eosinophilia). – As with other atopic disease, mast cells may also be important in pathogenesis. – Food allergens include milk, eggs, soy, legumes, wheat. – Incidence appears to be increasing. – In addition to GORD-like symptoms, patients have food impaction, dysphagia, and vomiting. – Can present in children; Infants may have feeding intolerance and failure to thrive. – Typically develop rings/webs: stacked circular rings (referred to as feline oesophagus because of endoscopic resemblance to a striped cat’s tail), strictures, and linear furrows/ulcers – Histologically, large numbers of intraepithelial eosinophils (15-20 per HPF). – Not associated with increased risk of Barrett esophagus. From Kumar et al, Robbins and Cotran Pathologic Basis of Disease 10th ed, • Chemical (accidental or deliberate ingestion) • Radiation (e.g. radiotherapy for lung or H&N tumours) Other causes of oesophagitis • Infective: Fungal (Candida), Viral (HSV, CMV) – Often causes ulcerative oesophagitis: extensive ulceration without typical reflux changes (usually quite welldefined ulcers, often multiple) – Fungal infection often causes pseudomembranes – Mild disease is common, severe disease tends to be seen in immunocompromised patients (chemotherapy, steroid Rx, AIDS) – Viral inclusions or fungal organisms identifiable histologically B. HSV inclusions. C. CMV inclusions. From Kumar et al, Robbins and Cotran Pathologic Basis of Disease 10th ed, chapter 17 Candida oesophagitis Immunocompromised (also tongue involvement) Varicella oesophagitis Important • Not everyone with GORD has macroscopic/microscopic changes of reflux oesophagitis; many people have subclinical disease • Not everyone with chronic oesophagitis has GORD develops Barrett’s • Not everyone with a hiatal hernia has symptoms of GORD • Not everyone with GORD has gastritis The spectrum of changes within and between patients can be highly variable Severe dysplasia -> Carcinoma in Situ o Atypia (large nuclei, hyperchromatic nuclei, irregular nuclei, coarse chromatin) o Abnormal maturation, full thickness in CIS, nearly full thickness in HGD (disorderly, no clear demarcation from basal to superficial layers) o Suprabasal mitoses, including abnormal forms o THESE FEATURES ARE BROADLY APPLICABLE TO DYSPLASIA OF SQUAMOUS EPITHELIUM AT OTHER SITES (e.g. oral cavity, oesophagus, tongue, cervix, anus, skin) Barrett’s oesophagus (intestinal metaplasia) with dysplasia. Note the transition from basal nuclei with mucin vacuoles to disorderly, large nuclei with mitoses. Also note associated acute on chronic inflammation www.pathologyoutlines.com Contributed by Mark Wick MD Oesophageal Cancer • Although the full spectrum of benign and malignant tumours of different tissue types in the GIT can be seen in the oesophagus, in practice the vast majority of tumours are carcinomas – Adenocarcinoma (gland forming) – Squamous cell carcinoma • Compared to other GIT sites, Oesophageal Ca is relatively uncommon, however the risk factors and potential precursors are common so it is something we have to consider from a prevention/early detection perspective • Natural Hx is of a rapidly growing tumour that often presents late with advanced disease: local invasion, nodal spread and metastases are common due to location (rich lymphatic and venous drainage and multiple closely related anatomical structures). • If not detected during surveillance for GORD or Barrett’s, usually presents with difficulty swallowing, rapid weight loss, haematemesis, chest pain or vomiting. https://www.aihw.gov.au/reports/cancer/can cer-data-in-australia/contents/cancerrankings-data-visualisation Smyth, E.C., Lagergren, J., Fitzgerald, R.C., Lordick, F., Shah, M.A., Lagergren, P., Cunningham, D., 2017. Oesophageal cancer. Nature Reviews Disease Primers 3.. doi:10.1038/nrdp.2017.48 Oesophageal Adenocarcinoma • Almost always in background of chronic GORD and Barrett’s • Gastric atrophy is protective (reduced acid) • Tobacco use, radiation, obesity all increase risk (developed countries more common; about 50% of oesophageal cancers in these countries) • M:F ratio 7:1, some unusual geographic and racial variation, more common in Caucasians, increasing in incidence in USA but not really in Australia • Usually occurs in distal third of the oesophagus and may extend into stomach. • Morphology: • Macroscopic: Flat or raised patches which develop into large, ulcerating and fungating masses. May diffusely infiltrate or invade deeply. • Microscopic: Form glands, produce mucin, often have intestinal phenotype but may also have gastric signet ring phenotype. • Molecular: Often TP53 and CDKN2A mutations, but tend to accumulate high mutation burdens with progression. • Usually present relatively late and have <25% 5 year survival From: Short et al, Am Fam Physician. 2017 Jan 1;95(1):22-28. From Kumar et al, Robbins and Cotran Pathologic Basis of Disease 10th ed, chapter 17 Oesophageal Squamous Cell Cancer • • • • • Most arise due to alcohol and tobacco use, also associated with frequent consumption of hot beverages, caustic injury, achalasia, radiation, chronic iron deficiency (Plummer-Vinson syndrome), nitrosamine containing carcinogens, small proportion with HPV association (high risk types). Age 40 onwards, M:F ratio 4:1, also unusual geographic and variations (e.g. very common in Iran, China, Brazil, Southern Africa, some other countries). Usually occurs in middle third of the oesophagus. Often arises via squamous dysplasia. Morphology: https://librepathology.org/wiki/Squamous_cell _carcinoma_of_the_esophagus – Macroscopic: Pale white plaque-like thickenings (in situ SCC) grow to polypoid or ulcerating masses that infiltrate the wall and narrow the lumen. Often invades through wall and causes fistulas (trachea or other adjacent organs). – Microscopic: Squamous differentiation (sheets and tongues of cells with dense cytoplasm, marked nuclear atypia, intercellular bridges). • • Molecular genetics: Variable, but often RB, CDKN2A and TP53 abnormalities Patients usually present late and survival depends on stage at presentation. However, overall <20% 5 year survival. Kumar et al, Robbins and Cotran Pathologic Basis of Disease 10th ed, chapter 17 Ulcerated squamous cell carcinoma Squamous cell carcinoma with tracheo-oesophageal fistula. Died of aspiration pneumonia Good articles if you want to know more • Peters, Y., Al-Kaabi, A., Shaheen, N.J., Chak, A., Blum, A., Souza, R.F., Di Pietro, M., Iyer, P.G., Pech, O., Fitzgerald, R.C., Siersema, P.D., 2019. Barrett oesophagus. Nature Reviews Disease Primers 5.. doi:10.1038/s41572-019-0086-z • Smyth, E.C., Lagergren, J., Fitzgerald, R.C., Lordick, F., Shah, M.A., Lagergren, P., Cunningham, D., 2017. Oesophageal cancer. Nature Reviews Disease Primers 3.. doi:10.1038/nrdp.2017.48 Summary • Relatively limited range of common diseases in oesophagus. • Know details of GORD, hiatal hernia, oesophagitis, Barrett’s, SCC, adenoCa and varices. • Understand links between GORD, oesophagitis, intestinal metaplasia, dysplasia and adenocarcinoma • Be aware of non-GORD causes of oesophagitis and functional causes of oesophagitis.