(a) Describe the molecular mechanisms of carcinogenesis of breast carcinoma. Describe the salient histopathological features of…

(a) Breast carcinoma: carcinogenesis and invasive carcinoma NST

Molecular mechanisms (multistep accumulation of genetic and epigenetic changes):

• Hereditary: germline BRCA1/BRCA2 mutations impair homologous-recombination repair of DNA double-strand breaks, causing genomic instability. Others: TP53 (Li-Fraumeni), PTEN (Cowden), CHEK2, PALB2, ATM.
• Hormonal: oestrogen exposure (early menarche, late menopause, nulliparity, HRT, obesity) drives ER-positive epithelial proliferation and DNA damage by its metabolites.
• Oncogenes and pathways: HER2 (ERBB2) amplification, PIK3CA mutation activating PI3K/AKT/mTOR, cyclin D1 amplification, MYC.
• Tumour suppressor loss: TP53, RB, CDH1 (E-cadherin, in lobular cancer).
• Molecular subtypes reflecting these pathways: luminal A and B (ER-positive), HER2-enriched and triple-negative (basal-like, often BRCA1-related), which guide therapy. Invasive carcinoma of no special type (formerly ductal), the commonest type (70–80%):
• Gross: firm, grey-white, gritty mass with irregular, stellate margins (scirrhous).
• Microscopy: malignant cells in nests, cords, glands and single cells infiltrating a desmoplastic stroma, often with associated DCIS. Nottingham grade from tubule formation, nuclear pleomorphism and mitotic count (grade 1–3). Adverse features: high grade, lymphovascular invasion, necrosis. ER, PR, HER2 and Ki-67 are assessed by immunohistochemistry.

(b)(i) IgA: diagram and role in disease

Serum IgA is mostly monomeric (IgA1). Secretory IgA is a dimer joined by a J chain and carrying the secretory component from the polymeric immunoglobulin receptor, which transports it across epithelium and protects it from proteolysis. It is the main antibody of mucosal secretions, colostrum and milk, neutralising microbes and toxins and preventing their adherence. Role in disease: selective IgA deficiency (commonest primary immunodeficiency) with recurrent sinopulmonary and gut infections, giardiasis, coeliac disease and anaphylaxis to blood products. IgA nephropathy (Berger disease) with mesangial IgA deposits and haematuria, and IgA vasculitis (Henoch–Schönlein purpura). IgA anti-tTG antibodies in coeliac disease diagnosis.

(b)(ii) Opportunistic infections in AIDS

Opportunistic infections are caused by organisms of low virulence that produce disease when host defences, especially cell-mediated immunity, are impaired.

• Bacterial: Mycobacterium tuberculosis, Mycobacterium avium complex, recurrent bacterial pneumonia, Salmonella septicaemia.
• Parasitic: Toxoplasma gondii (brain abscess), Cryptosporidium, Cystoisospora (Isospora), Microsporidia, visceral leishmaniasis.
• Viral: cytomegalovirus (retinitis, colitis), herpes simplex, varicella-zoster, JC virus (progressive multifocal leukoencephalopathy), EBV and HHV-8 related tumours.
• Fungal: Pneumocystis jirovecii pneumonia, Candida (oesophageal), Cryptococcus neoformans (meningitis), Histoplasma, Talaromyces marneffei.

(c) ARBs, difference from ACE inhibitors and hypertensive emergency

ARBs (losartan, valsartan, telmisartan, olmesartan) selectively block AT1 receptors, preventing angiotensin II-mediated vasoconstriction, aldosterone release, sodium retention, sympathetic activation and cardiac and vascular remodelling. Uses: hypertension, heart failure, diabetic nephropathy, post-MI. Differences from ACE inhibitors:

• ACE inhibitors block formation of angiotensin II, ARBs block its receptor (so they also block angiotensin II made by non-ACE pathways such as chymase).
• ACE inhibitors raise bradykinin, causing dry cough and angioedema, ARBs do not.
• With ARBs, AT2 receptors remain stimulated by the raised angiotensin II.
• Both cause hyperkalaemia and are contraindicated in pregnancy and bilateral renal artery stenosis, and should not be combined. Hypertensive emergency (severe hypertension with acute end-organ damage): admit to ICU with arterial monitoring and use titratable IV drugs. Reduce mean arterial pressure by no more than 25% in the first hour, then to about 160/100 mm Hg over 2–6 hours and to normal over 24–48 hours. Drugs: labetalol, nicardipine or clevidipine, sodium nitroprusside, nitroglycerin (acute coronary syndrome, pulmonary oedema), esmolol, and phentolamine for catecholamine crisis. Special cases: aortic dissection (systolic below 120 mm Hg within 20 minutes with esmolol plus a vasodilator), eclampsia (magnesium sulphate with labetalol or hydralazine). Avoid sublingual nifedipine.

(d) Granulomatous inflammation

Definition: a distinctive pattern of chronic inflammation in which activated macrophages transform into epithelioid cells forming aggregates (granulomas), often with multinucleate giant cells and a lymphocyte cuff, in response to persistent, poorly degradable agents or T-cell mediated immunity (Th1: IL-12, IFN-γ, TNF-α). Types:

• Immune granulomas: caseating (tuberculosis), non-caseating (sarcoidosis, Crohn disease), leprosy (tuberculoid), syphilis (gumma), fungal infections (histoplasmosis), cat-scratch disease (stellate with neutrophils).
• Foreign-body granulomas: around sutures, talc, silica or keratin, with foreign-body giant cells and visible material, without a specific immune response.
• Other forms: necrotising granulomas of granulomatosis with polyangiitis, palisading granulomas (rheumatoid nodule, granuloma annulare).

(e) Firearm and entry-wound features for range and direction

A firearm is a weapon that discharges a projectile through a barrel by the expansive force of gases from burning propellant (gunpowder). Range:

• Contact: muzzle imprint, cherry-red tissue (carbon monoxide), soot and powder inside the wound, and stellate laceration over bone (skull).
• Close range: burning and singeing of hair (within about 15 cm for black powder), blackening or soot (within about 30 cm), tattooing by unburnt powder (up to about 60–90 cm), with an abrasion collar.
• Distant: round wound with abrasion and grease collar only, no soot or tattooing. For shotguns, the spread of pellets estimates range (single hole up to about 1–2 m, then satellite holes). Direction:
• Circular abrasion collar indicates a perpendicular shot, an eccentric (oval) collar is wider on the side from which the bullet came.
• Bevelling of bone: entry bevels inward (inner table), exit bevels outward.
• Entry is smaller with inverted edges, exit larger with everted edges, and the track joining them gives the trajectory.