Membership of the Royal College of Surgeons (MRCS) Pathology, Microbiology and Pharmacology Syllabus

Match these tumour markers to their associated cancers: CEA, CA 19-9, CA 125, AFP, PSA, CA 15-3, hCG.

CEA: colorectal (also other GI). CA 19-9: pancreatic. CA 125: ovarian. AFP: hepatocellular carcinoma and non-seminomatous germ cell tumours. PSA: prostate. CA 15-3: breast. hCG: germ cell tumours, choriocarcinoma, gestational trophoblastic disease.

Name the four main modalities of cancer treatment and give the meaning of neoadjuvant vs adjuvant therapy.

Surgery, radiotherapy, chemotherapy, and biological/targeted/immunotherapy (plus hormonal therapy). Neoadjuvant = given before primary (usually surgical) treatment to downstage/shrink the tumour. Adjuvant = given after primary treatment to eradicate micrometastatic residual disease.

Which radiotherapy modality and which chemotherapy class are cell-cycle phase specific versus non-specific examples?

Radiotherapy is most effective in late G2/M phase (cells are radiosensitive there). Phase-specific chemo: antimetabolites (S phase, e.g. methotrexate, 5-FU), vinca alkaloids/taxanes (M phase). Phase-non-specific: alkylating agents (e.g. cyclophosphamide) and platinums act throughout the cycle.

Name the commonest organisms causing surgical site infections.

Staphylococcus aureus (including MRSA) is the most common overall; coagulase-negative staphylococci (e.g. S. epidermidis) especially with prosthetics; plus E. coli and other Gram-negative bacilli and anaerobes after bowel/contaminated surgery; Enterococcus and Pseudomonas in healthcare settings.

Classify surgical wounds by contamination and give approximate infection risks.

Clean (no viscus opened, ~1-2%), clean-contaminated (controlled opening of a viscus, ~5-10%), contaminated (gross spillage/acute non-purulent inflammation/open trauma, ~15-20%), and dirty (established infection or perforated viscus, >25-40%).

State the key features distinguishing Gram-positive from Gram-negative bacteria.

Gram-positive: thick peptidoglycan cell wall, no outer membrane, stain purple/violet. Gram-negative: thin peptidoglycan with an outer membrane containing lipopolysaccharide (endotoxin), stain pink/red. LPS is a potent trigger of sepsis.

Define a healthcare-associated infection (HCAI) and name the four most clinically important in UK surgery.

An HCAI is an infection acquired as a result of healthcare contact, not present/incubating at admission (often arising 48h+ after admission). Key examples: MRSA, Clostridioides difficile, surgical site infection, and catheter-associated UTI/hospital-acquired pneumonia.

Describe Clostridioides difficile infection: cause, classic risk factor, and first-line treatment.

C. difficile is a Gram-positive spore-forming anaerobe causing toxin-mediated (toxins A and B) pseudomembranous colitis. Classic risk factor: broad-spectrum antibiotics (classically the 4 Cs: clindamycin, cephalosporins, co-amoxiclav, ciprofloxacin/fluoroquinolones). First-line treatment is oral vancomycin (fidaxomicin as alternative).

Give the qSOFA criteria and what defines septic shock.

qSOFA (each scores 1): respiratory rate $\geq 22$/min, altered mentation (GCS < 15), systolic BP $\leq 100$ mmHg. Septic shock = sepsis with persisting hypotension requiring vasopressors to maintain MAP $\geq 65$ mmHg AND serum lactate $> 2$ mmol/L despite adequate fluid resuscitation.

Outline the 'Sepsis Six' bundle.

Three OUT: take blood cultures, measure serum lactate, monitor urine output. Three IN: give high-flow oxygen, give IV broad-spectrum antibiotics, give IV fluids. Ideally delivered within the first hour.

Differentiate bacteriostatic from bactericidal antibiotics with examples.

Bacteriostatic agents inhibit bacterial growth/replication (rely on host immunity), e.g. tetracyclines, macrolides, sulfonamides, trimethoprim, clindamycin, chloramphenicol. Bactericidal agents kill bacteria directly, e.g. beta-lactams (penicillins, cephalosporins), aminoglycosides, vancomycin, metronidazole, fluoroquinolones.

Name the main blood-borne viruses of surgical concern and rank their approximate transmission risk after a needlestick injury from a positive source.

Hepatitis B (HBV), hepatitis C (HCV), and HIV. Approximate transmission risk per percutaneous exposure from a positive source: HBV ~1 in 3 (up to 30%), HCV ~1 in 30 (3%), HIV ~1 in 300 (0.3%).

Outline the immediate management of a sharps/needlestick injury.

Encourage bleeding and wash the wound with soap and running water (do not suck); irrigate exposed mucous membranes/eyes. Report and risk-assess, identify the source and test (with consent), test the recipient, consider HIV post-exposure prophylaxis (ideally within 1 hour, up to 72h) and hepatitis B booster/immunoglobulin as indicated.

Describe the morphological stages of atherosclerotic plaque development.

Endothelial injury, then fatty streak (lipid-laden foam macrophages), progressing to a fibrofatty atheroma with a necrotic lipid core and fibrous cap, then a complicated plaque (calcification, ulceration, haemorrhage, thrombosis or aneurysm).

Classify aneurysms (true vs false) and define a dissection.

A true aneurysm involves all three layers of the vessel wall (intima, media, adventitia), e.g. atherosclerotic AAA. A false (pseudo)aneurysm is a contained breach where blood is held by surrounding tissue, not all wall layers. An aortic dissection is blood tracking into a tear within the media, splitting the wall.

Distinguish the morphology of a transmural (STEMI) from a subendocardial myocardial infarct.

Transmural infarcts involve the full thickness of the ventricular wall, due to complete epicardial coronary occlusion, and correspond to ST elevation (Q-wave) MIs. Subendocardial infarcts spare the outer wall, affecting the inner third (most vulnerable to ischaemia), often with global hypoperfusion or partial occlusion.

Compare ulcerative colitis and Crohn's disease pathologically.

UC: mucosa/submucosa only, continuous from rectum proximally, limited to colon, no granulomas, crypt abscesses, pseudopolyps. Crohn's: transmural inflammation, skip lesions anywhere mouth-to-anus (terminal ileum common), non-caseating granulomas, cobblestoning, fissures, fistulae and strictures.

Define the Barrett's oesophagus metaplasia and its malignant significance.

Barrett's is metaplasia of the lower oesophageal stratified squamous epithelium to columnar (intestinal-type, goblet-cell containing) epithelium due to chronic acid reflux. It is premalignant, predisposing to oesophageal adenocarcinoma via a metaplasia-dysplasia-carcinoma sequence.

Outline the adenoma-carcinoma sequence in colorectal cancer with key gene changes.

Normal mucosa → adenoma → carcinoma, driven by progressive mutations: APC (early adenoma initiation), KRAS (adenoma growth), then loss of TP53 and 18q/DCC/SMAD with carcinoma development. Microsatellite instability (mismatch-repair defects, e.g. Lynch syndrome) is an alternative pathway.

List the histological grades of hepatic injury terms: steatosis, hepatitis, cirrhosis.

Steatosis: reversible fatty change of hepatocytes. Hepatitis: hepatocyte inflammation/injury (with ballooning, Mallory bodies, lobular inflammation). Cirrhosis: irreversible end-stage with diffuse fibrosis and regenerative nodules disrupting the architecture, predisposing to portal hypertension and hepatocellular carcinoma.

Differentiate the common benign and malignant breast lesions and the key receptors assessed in breast cancer.

Benign: fibroadenoma (mobile, young women), fibrocystic change, duct papilloma, phyllodes (can be borderline/malignant). Malignant: invasive ductal (no special type, most common) and invasive lobular carcinoma; DCIS is in situ. Key receptors: oestrogen receptor (ER), progesterone receptor (PR), and HER2 — triple-negative if all absent.

Compare follicular adenoma, papillary and medullary thyroid carcinoma.

Follicular adenoma: benign, encapsulated. Papillary carcinoma: most common thyroid cancer, spreads via lymphatics, Orphan-Annie-eye nuclei and psammoma bodies, good prognosis. Follicular carcinoma: spreads haematogenously, capsular/vascular invasion. Medullary carcinoma: arises from parafollicular C cells, secretes calcitonin, associated with MEN 2.

Distinguish the three commonest skin malignancies by behaviour.

Basal cell carcinoma: commonest, locally invasive, rolled pearly edge, almost never metastasises. Squamous cell carcinoma: can metastasise (low-moderate), arises in sun-damaged skin/scars. Malignant melanoma: most aggressive, metastasises early; prognosis depends on Breslow thickness.

State the prognostic significance of Breslow thickness in melanoma.

Breslow thickness is the vertical depth in millimetres from the granular layer of the epidermis to the deepest tumour cell. It is the single most important prognostic factor: thicker tumours have a worse prognosis and a higher risk of metastasis (it also guides surgical excision margins).

Define pharmacokinetics and its four components (ADME).

Pharmacokinetics is what the body does to the drug. ADME: Absorption (drug entering the bloodstream), Distribution (movement into tissues/compartments), Metabolism (biotransformation, mainly hepatic phase I/II), and Excretion (elimination, mainly renal).

Define pharmacodynamics, and the terms efficacy, potency, agonist and antagonist.

Pharmacodynamics is what the drug does to the body. Efficacy: maximal effect a drug can produce. Potency: amount of drug needed for a given effect (lower dose = more potent). Agonist: binds and activates a receptor. Antagonist: binds but blocks/produces no response (competitive or non-competitive).

Give the equations for volume of distribution and drug clearance.

Volume of distribution: $V_{d} = \dfrac{\text{amount of drug in body}}{\text{plasma concentration}}$. Clearance: $CL = \dfrac{\text{rate of elimination}}{\text{plasma concentration}}$. The elimination half-life links them: $t_{1/2} = \dfrac{0.693 \times V_{d}}{CL}$.

Differentiate zero-order from first-order kinetics and give a drug example of zero-order.

First-order: a constant FRACTION of drug is eliminated per unit time (rate proportional to concentration), giving a constant half-life — most drugs. Zero-order: a constant AMOUNT is eliminated per unit time (saturated enzymes), so half-life rises with dose — e.g. ethanol, phenytoin, high-dose aspirin.

Define first-pass metabolism and bioavailability.

First-pass metabolism is the metabolism of an orally absorbed drug by gut wall and liver (via the portal vein) before reaching the systemic circulation, reducing the amount available. Bioavailability ($F$) is the fraction of an administered dose reaching the systemic circulation unchanged; IV $F = 1$ (100%).

Describe the WHO analgesic ladder.

Step 1: non-opioid (paracetamol $\pm$ NSAID). Step 2: weak opioid (e.g. codeine, tramadol) $\pm$ non-opioid. Step 3: strong opioid (e.g. morphine) $\pm$ non-opioid. Adjuvants (e.g. gabapentinoids, antidepressants, steroids) can be added at any step.

Outline the mechanism, key side effects and reversal of opioids.

Opioids act as agonists at $\mu$ (mu), $\kappa$ and $\delta$ receptors (G-protein coupled), giving analgesia. Side effects: respiratory depression, sedation, miosis, constipation, nausea, pruritus, tolerance/dependence. Reversal: naloxone (a competitive opioid antagonist).

Differentiate the mechanisms of local anaesthetics, and why infected/acidic tissue reduces their effect.

Local anaesthetics reversibly block voltage-gated sodium channels on the internal axonal membrane, preventing depolarisation/action potential propagation. They must cross the membrane in unionised form; in acidic (infected) tissue more drug is ionised, so less crosses and efficacy falls. Max lidocaine dose: 3 mg/kg plain, 7 mg/kg with adrenaline.

State the features of the triad of general anaesthesia and an example agent for induction and maintenance.

The triad is hypnosis (unconsciousness), analgesia, and muscle relaxation (areflexia). Induction commonly with IV propofol (or thiopentone); maintenance with a volatile agent (e.g. sevoflurane, isoflurane) or IV propofol (TIVA); muscle relaxation with neuromuscular blockers (e.g. rocuronium, suxamethonium).

Compare depolarising and non-depolarising neuromuscular blockers.

Depolarising (e.g. suxamethonium): ACh receptor agonist causing persistent depolarisation, rapid onset/short duration, initial fasciculations, NOT reversed by neostigmine (can trigger malignant hyperthermia, hyperkalaemia). Non-depolarising (e.g. rocuronium, atracurium): competitive antagonists, reversed by anticholinesterases (neostigmine) or sugammadex (for rocuronium).

Compare the mechanism, monitoring and reversal of heparin (unfractionated and LMWH) and warfarin.

Unfractionated heparin: potentiates antithrombin III (inhibits thrombin/IIa and Xa), monitored by APTT, reversed by protamine sulfate. LMWH: mainly anti-Xa, monitored by anti-Xa levels if needed, partially reversed by protamine. Warfarin: vitamin K epoxide reductase inhibitor (reduces factors II, VII, IX, X), monitored by INR, reversed by vitamin K $\pm$ prothrombin complex concentrate/FFP.

Describe the mechanisms of the common antiplatelet agents aspirin and clopidogrel.

Aspirin irreversibly inhibits cyclo-oxygenase (COX-1), reducing thromboxane $\text{A}_2$ and platelet aggregation for the platelet's lifespan (~7-10 days). Clopidogrel (and prasugrel/ticagrelor) irreversibly block the platelet ADP receptor $\text{P2Y}_{12}$, reducing aggregation.

Name the main classes of direct oral anticoagulants (DOACs) and their targets/reversal agents.

Direct factor Xa inhibitors: apixaban, rivaroxaban, edoxaban — reversed by andexanet alfa (or PCC). Direct thrombin (factor IIa) inhibitor: dabigatran — reversed by idarucizumab. DOACs need no routine monitoring.

List the major antihypertensive drug classes with one mechanism each.

ACE inhibitors (block angiotensin I→II conversion), ARBs (block AT1 receptor), calcium channel blockers (reduce vascular smooth muscle/cardiac calcium entry), thiazide diuretics (reduce Na+ reabsorption in distal tubule), beta-blockers (reduce heart rate/contractility and renin), and alpha-blockers (vasodilation).

Match these antibiotic classes to their mechanism of action: beta-lactams, aminoglycosides, fluoroquinolones, macrolides, metronidazole.

Beta-lactams (penicillins/cephalosporins): inhibit cell wall peptidoglycan synthesis. Aminoglycosides (gentamicin): bind 30S ribosome, inhibit protein synthesis. Fluoroquinolones (ciprofloxacin): inhibit DNA gyrase/topoisomerase. Macrolides (erythromycin): bind 50S ribosome, inhibit protein synthesis. Metronidazole: produces free radicals damaging DNA (anaerobes).

Outline the mechanisms of bacterial antibiotic resistance.

Enzymatic drug inactivation (e.g. beta-lactamases/ESBLs), modification of the target site (e.g. altered penicillin-binding proteins in MRSA), reduced drug uptake/altered permeability, increased efflux pumps, and development of alternative metabolic pathways. Resistance genes spread via plasmids, transposons and conjugation.