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Goitre: enlargement of the gland, diffuse or multinodular (iodine deficiency, hormone synthesis defects). Graves disease: diffuse hyperplasia with tall columnar cells and scalloped colloid; autoantibodies to the TSH receptor cause hyperthyroidism, ophthalmopathy and dermopathy. Hashimoto thyroiditis: lymphocytic infiltrate with germinal centres and Hurthle (oxyphil) cells, gland destruction and hypothyroidism; risk of lymphoma. Subacute (De Quervain) thyroiditis: granulomatous inflammation with giant cells after a viral infection, with painful gland.

Follicular adenoma (encapsulated, solitary). Carcinomas: papillary carcinoma (commonest; nuclear features of ground-glass nuclei, grooves and pseudo-inclusions, psammoma bodies; lymph node spread; BRAF mutations; excellent prognosis), follicular carcinoma (capsular and vascular invasion; haematogenous spread; diagnosis needs the whole capsule examined), medullary carcinoma (from C cells, calcitonin, amyloid stroma, RET mutations; MEN 2), and anaplastic carcinoma (very aggressive, older patients). Fine needle aspiration with Bethesda cytology categories guides management.

Parathyroid: primary hyperparathyroidism from a single adenoma (80-85 percent), hyperplasia or, rarely, carcinoma; hypercalcaemia (stones, bones, groans); secondary hyperparathyroidism in chronic kidney disease. Adrenal: cortical adenoma (Conn syndrome: aldosterone; Cushing syndrome: cortisol), adrenocortical carcinoma (rare, large, aggressive), phaeochromocytoma (medulla, catecholamines; rule of 10s; hypertensive crises), neuroblastoma in children. Adrenal insufficiency: autoimmune adrenalitis (Addison disease) and acute haemorrhage (Waterhouse-Friderichsen syndrome in meningococcal sepsis).

Pituitary adenomas: functioning (prolactinoma, the commonest; growth hormone adenoma causing acromegaly or gigantism; ACTH adenoma causing Cushing disease) or non-functioning; classified by immunohistochemistry of hormones and transcription factors. Microadenomas are under 1 cm; macroadenomas compress the optic chiasm (bitemporal hemianopia) and cause hypopituitarism. Pituitary apoplexy is haemorrhage into an adenoma. Sheehan syndrome is postpartum pituitary necrosis.

1. Describe the nuclear features of papillary thyroid carcinoma. 2. Compare Graves disease and Hashimoto thyroiditis. 3. What causes primary hyperparathyroidism most often? 4. Which visual field defect occurs in a pituitary macroadenoma?

1. Ground-glass (optically clear) nuclei, nuclear grooves and pseudo-inclusions, with psammoma bodies. 2. Graves: TSH-receptor stimulating antibodies, hyperplasia, hyperthyroidism. Hashimoto: lymphocytic destruction, Hurthle cells, hypothyroidism. 3. A single parathyroid adenoma. 4. Bitemporal hemianopia.

Gastro-oesophageal reflux disease: oesophagitis, ulcers and strictures. Barrett oesophagus: intestinal metaplasia with goblet cells replacing squamous epithelium in the distal oesophagus; precursor of adenocarcinoma via dysplasia. Adenocarcinoma: distal oesophagus, associated with Barrett and obesity. Squamous cell carcinoma: mid-oesophagus; alcohol, smoking, hot drinks, achalasia. Varices in portal hypertension can bleed massively.

Acute gastritis (NSAIDs, alcohol, stress). Chronic gastritis: autoimmune (body and fundus; parietal cell antibodies, pernicious anaemia, intestinal metaplasia) and H. pylori-associated (antrum; lymphoid follicles; risk of ulcer, MALT lymphoma and adenocarcinoma). Peptic ulcer: punched-out lesion with a clean base, in the first part of the duodenum or gastric antrum and lesser curvature. Gastric adenocarcinoma: intestinal type (glandular, from metaplasia; H. pylori, diet) and diffuse type (signet ring cells, linitis plastica; CDH1 mutations). Other tumours: MALT lymphoma, gastrointestinal stromal tumour (KIT), neuroendocrine tumours.

Coeliac disease: gluten-induced villous atrophy, crypt hyperplasia and intraepithelial lymphocytes; anti-tissue transglutaminase antibodies. Inflammatory bowel disease: Crohn (transmural, skip lesions, granulomas, fissures) and ulcerative colitis (mucosal, continuous from rectum, crypt abscesses, pseudopolyps). Ischaemic colitis, infectious colitis and diverticular disease. Appendicitis: neutrophils in the muscularis propria.

Polyps: hyperplastic (benign), adenomas (tubular, villous, tubulovillous; dysplasia; villous and large adenomas have higher risk) and serrated lesions. Adenoma-carcinoma sequence: APC mutation, then KRAS, then SMAD4 and TP53 loss over years. Hereditary syndromes: familial adenomatous polyposis (APC, hundreds of polyps, prophylactic colectomy) and Lynch syndrome (mismatch repair deficiency, microsatellite instability). Adenocarcinoma: left colon (obstruction, change in bowel habit) and right colon (iron deficiency anaemia, occult bleeding); staging by depth of invasion and nodal status (TNM), which is the main prognostic factor; spread to liver via the portal vein. Screening by faecal occult blood test and colonoscopy reduces mortality.

1. What is Barrett oesophagus and what is its risk? 2. Compare the two types of gastric adenocarcinoma. 3. Describe the histology of coeliac disease. 4. Outline the adenoma-carcinoma sequence.

1. Intestinal metaplasia of the distal oesophagus; predisposes to adenocarcinoma. 2. Intestinal type: glandular, arises from metaplasia. Diffuse type: signet ring cells and linitis plastica, CDH1 mutations. 3. Villous atrophy, crypt hyperplasia and increased intraepithelial lymphocytes. 4. APC mutation, then KRAS, then SMAD4 and TP53 loss, from adenoma to carcinoma.

Acute hepatitis: hepatocyte swelling and necrosis with lobular inflammation (viral A-E, drugs, autoimmune). Chronic hepatitis: portal inflammation, interface hepatitis and fibrosis, graded and staged (viral B and C, autoimmune, metabolic). Steatotic liver disease: alcohol-related and metabolic dysfunction-associated (macrovesicular steatosis, ballooning, Mallory-Denk bodies in steatohepatitis). Cirrhosis: diffuse nodular regeneration surrounded by fibrous septa; complications portal hypertension and hepatocellular carcinoma. Other: haemochromatosis (iron), Wilson disease (copper), primary biliary cholangitis, primary sclerosing cholangitis, alpha-1 antitrypsin deficiency.

Acute pancreatitis: fat necrosis and haemorrhage (gallstones, alcohol); chronic pancreatitis: fibrosis and loss of acini with calcification. Cystic lesions: pseudocysts, serous cystadenoma, mucinous cystic neoplasm and intraductal papillary mucinous neoplasm (IPMN; pre-malignant). Pancreatic ductal adenocarcinoma: two thirds in the head; precursor PanIN; KRAS, CDKN2A, TP53 and SMAD4 mutations; desmoplastic stroma; perineural invasion; presents late with painless jaundice (head), weight loss, migratory thrombophlebitis (Trousseau); poor prognosis; only about 15-20 percent are resectable (Whipple procedure). Neuroendocrine tumours (insulinoma, gastrinoma) form the other main group.

1. What are the histological features of steatohepatitis? 2. Name the stages of the pancreatic cancer precursor and its genes. 3. Which pancreatic cystic lesion is pre-malignant? 4. Why do head-of-pancreas tumours cause jaundice?

1. Steatosis with hepatocyte ballooning, lobular inflammation and Mallory-Denk bodies. 2. PanIN progressing to ductal adenocarcinoma with KRAS, CDKN2A, TP53 and SMAD4 alterations. 3. Intraductal papillary mucinous neoplasm (and mucinous cystic neoplasm). 4. They compress the common bile duct as it runs through the pancreatic head.