For education and revision only. Not individual medical advice; check current NICE/BNF and local guidance before clinical use. Clinical safety and terms.
🔬 Organ-system histology. Each organ has a characteristic microscopic architecture that reflects its function, and most diseases are recognised by how they disturb it - villous atrophy in coeliac disease, interface hepatitis, crescents in the glomerulus, alveolar wall thickening in fibrosis, or the loss of normal layers in invasive cancer. This chapter works through the organ systems, highlighting the normal features and the classic pathological changes examiners expect you to know. Your four questions for an organ biopsy: What is the normal architecture of this organ? Which layer or compartment is affected? What is the pattern of injury (inflammation, atrophy, fibrosis, deposits, neoplasia)? How does it match the clinical picture?
Melanocytes - neural crest-derived, in the basal layer (about 1 in 10 basal cells); transfer melanin to keratinocytes - number similar in all skin colours; difference lies in melanin amount and distribution. Absent in vitiligo; malignant in melanoma.
Disease
Histology
Psoriasis
Regular epidermal hyperplasia (acanthosis), parakeratosis (nuclei retained in stratum corneum), loss of granular layer, Munro microabscesses (neutrophils), dilated papillary vessels (Auspitz sign)
Eczema
Spongiosis (intercellular oedema in the epidermis), lymphocytic infiltrate
Conducting airways: nasal cavity, trachea and bronchi lined by pseudostratified ciliated columnar epithelium with goblet cells, with submucosal glands and cartilage (C-shaped rings in the trachea; plates in bronchi). Bronchioles (<1 mm) - no cartilage or glands, simple ciliated columnar to cuboidal epithelium, club (Clara) cells (secretory, protective), relatively more smooth muscle (bronchospasm in asthma).
Respiratory portion: respiratory bronchioles → alveolar ducts → alveoli. Type I pneumocytes (95% of surface area - thin, gas exchange; easily damaged), type II pneumocytes (cuboidal, surfactant production - lamellar bodies; stem cells for repair; deficient in premature neonates → respiratory distress syndrome; antenatal steroids accelerate maturation), alveolar macrophages (dust cells). Blood–air barrier about 0.5 µm (type I cell, fused basement membranes, endothelium).
Disease
Histology
Asthma
Goblet cell hyperplasia, thickened basement membrane, smooth muscle hypertrophy, eosinophils, mucus plugs with Curschmann spirals and Charcot–Leyden crystals
Chronic bronchitis
Mucous gland hyperplasia (Reid index >0.4), squamous metaplasia
Emphysema
Destruction of alveolar walls - centriacinar (smoking, upper lobes) or panacinar (α1-antitrypsin deficiency, lower lobes)
ARDS
Diffuse alveolar damage - hyaline membranes, then type II cell hyperplasia and fibrosis
The GI Tract - General Plan, Oesophagus and Stomach
General plan (four layers):mucosa (epithelium, lamina propria, muscularis mucosae), submucosa (vessels, glands in oesophagus and duodenum, Meissner's submucosal plexus), muscularis propria (inner circular and outer longitudinal with Auerbach's myenteric plexus between), serosa (mesothelium) or adventitia (oesophagus, retroperitoneal parts - no serosa, which allows early spread of oesophageal cancer).
Oesophagus - stratified squamous non-keratinised epithelium; muscularis propria skeletal in the upper third, mixed in the middle, smooth in the lower third. Reflux oesophagitis (basal cell hyperplasia, elongated papillae, intraepithelial eosinophils), eosinophilic oesophagitis (>15 eosinophils per high-power field - dysphagia and food bolus obstruction in atopic young men; rings on endoscopy), Barrett's (columnar with goblet cells), achalasia (loss of myenteric ganglion cells).
Stomach - simple columnar mucus-secreting surface epithelium with gastric pits; fundus and body glands contain parietal cells (acid, intrinsic factor - eosinophilic "fried egg" cells; target of autoimmune gastritis), chief cells (pepsinogen - basophilic) and enterochromaffin-like cells (histamine); antral glands - mucous and G cells (gastrin).
Gastritis:H. pylori (antral, chronic active - neutrophils and lymphoid follicles; organisms on the surface - Giemsa), autoimmune (body and fundus - parietal cell loss, intestinal metaplasia, ECL hyperplasia - pernicious anaemia, carcinoid risk), chemical/reactive (NSAIDs, bile reflux - foveolar hyperplasia, few inflammatory cells).
Gastric adenocarcinoma - intestinal type (glandular - H. pylori, intestinal metaplasia) and diffuse type (signet ring cells - linitis plastica, CDH1).
Small intestine - villi (finger-like, absorptive) and crypts of Lieberkühn (stem cells, Paneth cells - antimicrobial granules); enterocytes with microvilli, goblet cells, enteroendocrine cells, intraepithelial lymphocytes. Villus:crypt ratio about 3:1. Duodenum - Brunner's glands (submucosal, alkaline mucus); jejunum - prominent plicae circulares; ileum - Peyer's patches.
Large intestine - no villi; straight test-tube crypts with abundant goblet cells; outer longitudinal muscle forms taeniae coli (absent in the rectum and appendix).
Liver lobule - hexagonal, with a central vein at the centre and portal tracts (hepatic artery, portal vein, bile duct - the portal triad) at the corners. Acinus (Rappaport) - functional unit: zone 1 (periportal) - best oxygenated, gluconeogenesis, first to receive toxins (e.g. some viral hepatitis); zone 3 (centrilobular) - least oxygen, highest CYP450 activity → most vulnerable to ischaemia, paracetamol (NAPQI) and alcohol, right heart failure (nutmeg liver).
Hepatocytes in plates one cell thick, separated by sinusoids (fenestrated endothelium, Kupffer cells); space of Disse contains hepatic stellate (Ito) cells - store vitamin A; activated to myofibroblasts → fibrosis and cirrhosis. Bile canaliculi between hepatocytes drain to canals of Hering and bile ducts.
Nephron:glomerulus (fenestrated endothelium, glomerular basement membrane, podocytes with foot processes and slit diaphragms - nephrin - the filtration barrier; mesangial cells support and phagocytose) within Bowman's capsule → proximal convoluted tubule (cuboidal with brush border, many mitochondria - reabsorbs about 65% of filtrate; most vulnerable to ischaemia and toxins - acute tubular necrosis) → loop of Henle → distal tubule (macula densa - juxtaglomerular apparatus with renin-secreting juxtaglomerular cells) → collecting duct (principal cells - ENaC, aquaporin-2; intercalated cells - acid–base).
Ureter and bladder - urothelium; bladder muscularis propria (detrusor) - muscle invasion defines staging of bladder cancer (T2), so biopsies must include detrusor.
Glomerular disease
Light microscopy
Immunofluorescence / EM
Minimal change disease
Normal
Podocyte foot process effacement on EM only; children; steroid-responsive
Pituitary - anterior (adenohypophysis) - from Rathke's pouch (oral ectoderm): acidophils (GH, prolactin), basophils (ACTH, TSH, FSH, LH), chromophobes; posterior (neurohypophysis) - neural tissue with axons from the hypothalamus (supraoptic and paraventricular nuclei) storing ADH and oxytocin (Herring bodies). Adenomas (pituitary neuroendocrine tumours) - prolactinoma commonest; craniopharyngioma from Rathke's pouch remnants (calcified, children).
Thyroid - follicles lined by cuboidal follicular cells around colloid (thyroglobulin); flat cells with abundant colloid when inactive, tall cells with scalloped colloid when active (Graves'); parafollicular C cells (calcitonin - neural crest; medullary carcinoma).
Thyroid disease
Histology
Hashimoto's thyroiditis
Lymphocytic infiltrate with germinal centres, Hürthle (oncocytic) cells, fibrosis; risk of thyroid lymphoma
Graves' disease
Hyperplastic tall follicles with scalloped colloid
De Quervain's (subacute) thyroiditis
Granulomatous inflammation with giant cells - painful after viral infection
Undifferentiated, older people, very poor prognosis
Parathyroid - chief cells (PTH) and oxyphil cells; adenoma (85% of primary hyperparathyroidism), hyperplasia (MEN, CKD), carcinoma (rare).
Adrenal gland - cortex ("GFR" from outside in - zona glomerulosa (aldosterone - "salt"), zona fasciculata (cortisol - "sugar"; lipid-laden clear cells), zona reticularis (androgens - "sex")) and medulla (chromaffin cells - neural crest - adrenaline and noradrenaline; phaeochromocytoma). Addison's disease (autoimmune) destroys the cortex; long-term steroids atrophy the fasciculata and reticularis but spare the glomerulosa (aldosterone controlled by renin–angiotensin).
Testis - seminiferous tubules with Sertoli cells (support spermatogenesis, blood–testis barrier, inhibin, anti-Müllerian hormone, androgen-binding protein - respond to FSH) and germ cells (spermatogonia → spermatocytes → spermatids → spermatozoa); Leydig cells in the interstitium (testosterone - respond to LH; Reinke crystals).
Germ cell tumours - arise from germ cell neoplasia in situ: seminoma (sheets of clear cells with lymphocytes - radiosensitive; placental ALP) and non-seminomatous (embryonal carcinoma, yolk sac tumour - AFP, Schiller–Duval bodies; choriocarcinoma - hCG; teratoma); undescended testis is a risk factor; spread to para-aortic nodes.
Epididymis - pseudostratified columnar epithelium with stereocilia (sperm maturation). Vas deferens - thick muscular wall.
Prostate - tubuloalveolar glands with two cell layers (secretory luminal cells - PSA; basal cells) in fibromuscular stroma; zones - peripheral zone (70% - most carcinomas - palpable on DRE), transition zone (BPH), central zone. Prostatic adenocarcinoma - small glands with loss of the basal cell layer (p63/high-molecular-weight keratin negative), prominent nucleoli, perineural invasion; graded by Gleason pattern → ISUP grade group (1–5).
Cervix - ectocervix (stratified squamous non-keratinised) and endocervix (mucus-secreting columnar); the transformation zone between them - CIN 1–3 (dysplasia confined to the epithelium, graded by thickness - lower third, two-thirds, full thickness) → squamous cell carcinoma; koilocytes (HPV cytopathic effect - perinuclear halo, wrinkled nucleus); p16 immunostaining as a marker of high-risk HPV.
Placenta - chorionic villi with cytotrophoblast and syncytiotrophoblast (hCG, hPL) bathed in maternal blood; hydatidiform mole (swollen villi, trophoblast proliferation - complete 46,XX paternal; partial triploid).
Breast - terminal duct lobular unit (TDLU) - origin of most breast cancers; ducts and lobules lined by two layers - luminal epithelial and myoepithelial cells on a basement membrane. Fibroadenoma (commonest benign lump in young women - stromal and epithelial proliferation), fibrocystic change, DCIS (often calcified, myoepithelial layer intact), invasive carcinoma of no special type (ductal) (75%), invasive lobular carcinoma (single-file cells, E-cadherin loss, bilateral and multifocal, metastasises to peritoneum and GI tract), phyllodes tumour (leaf-like, stromal overgrowth, rapid growth). Biomarkers - ER, PR, HER2, Ki-67.
Retina - 10 layers: photoreceptors (rods - night vision, periphery; cones - colour and acuity, concentrated in the fovea which has no rods and no overlying inner layers), bipolar cells, retinal ganglion cells (axons form the optic nerve - glaucoma damages them), retinal pigment epithelium (phagocytoses outer segments; drusen in macular degeneration; Bruch's membrane). Retinoblastoma (Flexner–Wintersteiner rosettes), uveal melanoma (commonest primary intraocular malignancy in adults - liver metastases).
Ear - external ear (elastic cartilage of pinna; keratinised skin of canal with ceruminous glands), middle ear (simple cuboidal/columnar mucosa; cholesteatoma - keratinising squamous epithelium in the middle ear eroding ossicles), inner ear (organ of Corti - inner and outer hair cells with stereocilia on the basilar membrane in the cochlea - damaged by noise, aminoglycosides, cisplatin, age; vestibular apparatus - semicircular canals, utricle and saccule with otoliths - BPPV from displaced otoconia).
Scenario. Why does paracetamol overdose damage the centre of the liver lobule first?
Answer: Zone 3 (centrilobular) hepatocytes have the highest CYP2E1 activity (generating the toxic metabolite NAPQI), the lowest glutathione reserves and the lowest oxygen supply - so they are most susceptible to paracetamol, alcohol and ischaemic injury.
Scenario. A 30-year-old with coeliac disease starts a gluten-free diet before his duodenal biopsy. What effect will this have?
Answer: The mucosa may recover, giving a false-negative biopsy (and serology may become negative). He should eat gluten in more than one meal every day for at least 6 weeks before testing (NICE NG20).
Scenario. Why must a transurethral bladder tumour resection specimen include detrusor muscle?
Answer: Bladder cancer staging and treatment depend on whether the tumour invades the muscularis propria (T2 and above → cystectomy or radical radiotherapy). Without detrusor in the specimen, muscle invasion cannot be excluded, and re-resection is needed.