(a) (i) Enumerate any five risk factors for oral cancer. Describe its morphology. 5+5=10 (ii) Enumerate five causes of membranous…

(a)(i) Oral cancer: risk factors and morphology

Five risk factors: tobacco in any form (smoking or chewing); areca nut and betel quid (a major cause in India); alcohol, with synergy with tobacco; high-risk HPV, mainly type 16, especially for oropharyngeal cancer; chronic irritation from sharp teeth or poor oral hygiene. Premalignant conditions such as leukoplakia, erythroplakia, oral submucous fibrosis and lichen planus add risk.

Morphology. Gross: it arises most often on the lateral border of the tongue, floor of mouth and buccal mucosa (gingivobuccal in India). It may start as a white (leukoplakia) or red (erythroplakia) patch and becomes a hard, indurated ulcer with raised, rolled, everted edges, or an exophytic fungating growth. Microscopy: over 90% are squamous cell carcinomas. Invasive nests and cords of atypical squamous cells break through the basement membrane into the stroma, with keratin pearls and intercellular bridges in well-differentiated tumours, and nuclear pleomorphism, hyperchromasia and abnormal mitoses; poorly differentiated tumours lose keratin. Field cancerisation explains multiple primaries; p53 mutation and cyclin D1 overexpression are common. Spread is to cervical lymph nodes.

(a)(ii) Membranous glomerulonephritis: causes and morphology

Five causes. Idiopathic (primary, about 75%, with antibodies to the podocyte antigen PLA2R); SLE (class V lupus nephritis); infections (hepatitis B and C, syphilis, malaria); drugs (penicillamine, gold, NSAIDs, captopril); malignancy (carcinoma of lung and colon, melanoma). Thyroiditis is another cause.

Morphology. Light microscopy: diffuse, uniform thickening of the glomerular capillary walls with no hypercellularity. Silver stain shows small projections ("spikes") of basement membrane between deposits, and later "chain-link" appearance. Immunofluorescence: diffuse granular deposits of IgG and C3 along the basement membrane. Electron microscopy: electron-dense subepithelial deposits, with the basement membrane growing between and over them (spike and dome), and effacement of podocyte foot processes; later the deposits are enclosed and resorbed. It presents with nephrotic syndrome and carries a risk of renal vein thrombosis.

(b)(i) Aspirin

Mechanism: irreversible acetylation of COX-1 and COX-2. Indications: pain and fever; anti-inflammatory use in acute rheumatic fever and rheumatoid arthritis; antiplatelet use (75 to 150 mg a day) in acute coronary syndrome, after MI and stent, and in stroke and TIA; Kawasaki disease; low-dose prophylaxis of pre-eclampsia. Drug interactions: warfarin and heparin (bleeding); other NSAIDs and corticosteroids (gastric bleeding); methotrexate (toxicity from reduced renal excretion); ibuprofen (blocks the antiplatelet effect); diuretics and ACE inhibitors (reduced effect); probenecid (loses uricosuric action). Side effects: gastric irritation, ulcer and bleeding; prolonged bleeding time; salicylism (tinnitus, vertigo, deafness) and, in overdose, metabolic acidosis; hypersensitivity and aspirin-exacerbated asthma; Reye syndrome in children with viral illness; renal impairment. It is avoided in children and in late pregnancy.

(b)(ii) Cyclosporine

Mechanism: it binds cyclophilin and the complex inhibits calcineurin, so NFAT cannot activate and IL-2 transcription and T-cell activation fall. Indications: prevention of rejection after kidney, liver, heart and bone marrow transplantation and in graft-versus-host disease; autoimmune disease, such as severe psoriasis, rheumatoid arthritis, steroid-dependent nephrotic syndrome, uveitis and aplastic anaemia. Drug interactions: CYP3A4 and P-glycoprotein inhibitors (ketoconazole, erythromycin, diltiazem, verapamil, grapefruit juice) raise levels; inducers (rifampicin, phenytoin, carbamazepine) lower levels and risk rejection; aminoglycosides, amphotericin and NSAIDs add nephrotoxicity; potassium-sparing diuretics and ACE inhibitors cause hyperkalaemia; live vaccines are contraindicated. Side effects: nephrotoxicity, hypertension, hyperkalaemia, hypomagnesaemia, tremor, hirsutism, gingival hyperplasia, hepatotoxicity, hyperlipidaemia, infections and lymphoma. Trough blood levels and creatinine are monitored.

(c)(i) Asexual life cycle of Plasmodium falciparum, and rapid diagnostic tests

Asexual cycle (in humans). Pre-erythrocytic: the female Anopheles injects sporozoites, which reach hepatocytes within minutes and develop into a tissue schizont, which ruptures in 5 to 7 days to release thousands of merozoites. There is no hypnozoite stage, so no relapse. Erythrocytic: merozoites invade red cells of all ages, develop into ring forms (early trophozoites), then trophozoites and schizonts (8 to 24 merozoites), and the cell ruptures every 48 hours (malignant tertian fever). Mature trophozoites and schizonts stick to capillary endothelium (PfEMP1) and are not seen in peripheral blood; some merozoites become gametocytes.

Rapid diagnostic test. Principle: lateral-flow immunochromatography on a drop of blood; labelled monoclonal antibodies bind parasite antigen (HRP-2 for P. falciparum, pLDH or aldolase for other species), the complex moves along the strip and is captured at a test line, with a control line proving validity; the result is read in 15 to 20 minutes. Advantages: rapid, simple, no electricity or microscopist, suitable for field and village-level use. Disadvantages: cannot quantify parasitaemia or species fully; HRP-2 persists for weeks after cure (false positive); pfhrp2 and pfhrp3 gene deletions and low parasitaemia give false negatives; heat-sensitive kits.

(c)(ii) Human herpesviruses and laboratory diagnosis of HSV

Human herpesviruses and their primary target cells: HHV-1 (HSV-1): mucoepithelial cells; latent in trigeminal ganglion. HHV-2 (HSV-2): mucoepithelial cells; latent in sacral ganglia. HHV-3 (varicella-zoster virus): epithelial cells and T cells; latent in dorsal root ganglia. HHV-4 (Epstein-Barr virus): B lymphocytes and epithelial cells. HHV-5 (cytomegalovirus): monocytes, endothelial and epithelial cells. HHV-6 and HHV-7: CD4⁺ T lymphocytes. HHV-8 (Kaposi sarcoma herpesvirus): B cells and endothelial cells.

Laboratory approach to HSV. Collect fluid or scrapings from the base of a vesicle, CSF in suspected encephalitis, or swabs. PCR for HSV DNA is the most sensitive and specific test and the method of choice, especially on CSF. Direct fluorescent antibody staining on smears gives rapid antigen detection. Culture in Vero or human fibroblast cells gives cytopathic effect in 1 to 3 days (shell vial culture is faster). Tzanck smear (Giemsa or Papanicolaou) shows multinucleated giant cells with Cowdry type A intranuclear inclusions, but is insensitive and cannot separate HSV from varicella-zoster virus. Serology with type-specific IgG to glycoprotein G (gG-1, gG-2) shows past infection and seroconversion in primary infection.