Describe the microscopic features of breast cancer. Enumerate any five major prognostic factors. Enumerate any five differences…

(a)(i) Microscopic features of breast cancer and prognostic factors

Most breast cancers are adenocarcinomas arising from the terminal duct–lobular unit. Microscopy first separates carcinoma in situ from invasive carcinoma.

Microscopic features

• Ductal carcinoma in situ: malignant cells fill the ducts but the myoepithelial layer and basement membrane stay intact. Patterns include solid, cribriform, micropapillary and comedo, the last with central necrosis that often calcifies.

Invasive carcinoma of no special type (ductal), about 70–80% of cases:

• Tumour cells lie in nests, cords, sheets and tubules within a dense desmoplastic stroma, which makes the tumour hard and gritty.
• Nuclear pleomorphism, mitoses and lymphovascular invasion are seen.
• It is graded by the Nottingham (modified Bloom–Richardson) system, which scores tubule formation, nuclear pleomorphism and mitotic count 1–3 each. A total of 3–5 is grade 1, 6–7 grade 2 and 8–9 grade 3.

Invasive lobular carcinoma:

• Small, uniform, discohesive cells infiltrate in single file ("Indian-file") and form targetoid rings around ducts.
• Signet-ring cells may be present.
• The cells have lost E-cadherin.

Special types: mucinous (cells floating in mucin), tubular (open tubules) and medullary pattern (syncytial sheets with lymphoid infiltrate). Paget disease shows large clear cells in the nipple epidermis.

Five major prognostic factors

1. Axillary lymph node status: the most important single factor.
2. Tumour size: larger tumours do worse.
3. Histological grade and type: tubular and mucinous types do better.
4. ER/PR and HER2 status, and molecular subtype: triple-negative disease does worst.
5. Lymphovascular invasion and distant metastasis.

(a)(ii) Primary versus secondary tuberculosis

Primary TB is infection of an unsensitised host; secondary (post-primary) TB arises in a sensitised host by reactivation or reinfection.

• Host and age: primary — Non-sensitised host, mostly children; secondary — Sensitised host, mostly adults.
• Site of lesion: primary — Subpleural Ghon focus in the lower part of the upper lobe or upper part of the lower lobe; secondary — Apex of the upper lobe (Assmann infraclavicular focus; reactivation often from apical Simon foci), where oxygen tension is high.
• Lymph nodes: primary — Prominent hilar lymphadenopathy, forming the Ghon complex (Ranke complex when calcified); secondary — Regional nodes are minimally involved.
• Caseation and cavitation: primary — Limited caseation; cavitation is rare; secondary — Extensive caseation and cavitation.
• Spread: primary — Lymphatic and haematogenous, leading to miliary TB or meningitis; secondary — Bronchogenic, endobronchial and intestinal spread.
• Sputum: primary — Usually smear-negative and paucibacillary; secondary — Often smear-positive and highly infectious.
• Outcome: primary — Mostly heals by fibrosis and calcification, and is often asymptomatic; secondary — Progressive and symptomatic, with fibrocaseous disease.

The differences arise from hypersensitivity. It is absent at first in primary infection, which allows spread to the nodes. It is already present in secondary disease, which localises the lesion but drives tissue destruction.

(b)(i) Primaquine for radical cure of malaria

Radical cure means eliminating the dormant liver stages, the hypnozoites of P. vivax and P. ovale, which otherwise reactivate weeks or months later and cause relapse.

• Why blood schizonticides are not enough: chloroquine and ACTs clear only the erythrocytic parasites. They do not touch the hypnozoites.
• What primaquine does: it is an 8-aminoquinoline and acts as a tissue schizonticide and hypnozoitocide. Its oxidative metabolites generate reactive oxygen species that disrupt parasite mitochondria.
• Standard regimen: it is given after the blood schizonticide, at 0.25 mg/kg/day for 14 days.
• Gametocytocidal action: a single low dose also kills P. falciparum gametocytes and so interrupts transmission.
• Contraindications: it causes haemolysis in G6PD deficiency, so screening is advised. It is avoided in pregnancy and infancy.

(b)(ii) Albendazole as a broad-spectrum oral antihelminthic

Albendazole, a benzimidazole carbamate, is called broad-spectrum because a single, cheap, well-tolerated oral drug kills many classes of helminths.

• Mechanism: it binds parasite β-tubulin far more strongly than host tubulin and blocks microtubule polymerisation. Glucose uptake stops, glycogen and ATP are depleted, and the worm is immobilised and dies. It is also ovicidal and larvicidal.

Spectrum:

• Nematodes: Ascaris, hookworm, Trichuris, Enterobius, Strongyloides, Trichinella and cutaneous larva migrans.
• Cestodes: neurocysticercosis and hydatid disease.
• Protozoa: Giardia.
• Pharmacokinetics: its active metabolite, albendazole sulfoxide, penetrates tissues, cysts and CSF.
• Use in practice: a single 400 mg dose treats most intestinal worms, which is why it is used in mass deworming.

(c)(i) Candidiasis

Definition. Candidiasis is an opportunistic fungal infection caused by Candida species. These are commensal yeasts of the mouth, gut and vagina that become pathogenic when host defences fall.

Presentations

• Mucocutaneous: oral thrush, oesophagitis, vulvovaginitis, balanitis, intertrigo, paronychia and onychomycosis.
• Invasive: candidaemia, endocarditis, endophthalmitis, hepatosplenic candidiasis, peritonitis and urinary infection.

Aetiological causes

• Species: C. albicans is the commonest. Others are C. tropicalis, C. glabrata, C. parapsilosis, C. krusei and the multidrug-resistant C. auris.
• Predisposing factors: diabetes, broad-spectrum antibiotics, steroids, neutropenia, HIV, central venous catheters, TPN, abdominal surgery and prematurity.

Laboratory diagnosis of invasive candidiasis

1. Specimens: blood, CSF, sterile fluids, catheter tip and tissue.
2. Direct microscopy: Gram or KOH mount shows Gram-positive budding yeast cells with pseudohyphae. PAS or GMS stains show tissue invasion.
3. Culture: automated blood culture and Sabouraud dextrose agar, which gives creamy, pasty colonies.
4. Identification:

• The germ-tube test is positive for C. albicans.
• Chlamydospores form on cornmeal agar; CHROMagar or MALDI-TOF identify other species.

5. Non-culture tests: (1,3)-β-D-glucan, mannan antigen with anti-mannan antibody, and PCR.
6. Antifungal susceptibility testing: especially for C. glabrata and C. auris.

(c)(ii) Shigellosis

Definition. Shigellosis, or bacillary dysentery, is an acute invasive infection of the colon caused by Shigella. It presents with fever, tenesmus and small stools containing blood and mucus. It spreads faeco-orally, and an infectious dose of 10–100 bacilli is enough.

Causative organisms Shigella are Gram-negative, non-motile, non-capsulated bacilli. There are four serogroups:

• Group A: S. dysenteriae, whose type 1 causes the most severe disease.
• Group B: S. flexneri.
• Group C: S. boydii.
• Group D: S. sonnei.

Modes of pathogenicity

1. Invasion: bacilli cross the epithelium through M cells, are taken up by macrophages and induce macrophage apoptosis with IL-1β release. The genes for this lie on a large virulence plasmid and encode the type III secretion system and Ipa proteins.
2. Spread: they invade colonocytes from the basolateral side, multiply, and move from cell to cell by actin-based motility (IcsA/VirG). Intense neutrophil inflammation follows, producing mucosal ulcers and dysentery.
3. Toxins: Shiga toxin of S. dysenteriae type 1 inactivates the 60S ribosome and halts protein synthesis. It damages endothelium and can cause haemolytic uraemic syndrome.

Laboratory diagnosis

1. Specimen: fresh stool or a rectal swab with mucus flakes, in buffered glycerol saline if delayed.
2. Microscopy: many pus cells, RBCs and macrophages.
3. Culture: MacConkey agar shows pale non-lactose-fermenting colonies. XLD shows red colonies without black centres, and DCA and SS agar are also used. Selenite F broth serves as enrichment.
4. Biochemistry: non-motile, H₂S-negative, urease-negative and citrate-negative. All except S. dysenteriae ferment mannitol.
5. Serogrouping and confirmation: slide agglutination with group-specific antisera and PCR for ipaH.
6. Antibiotic susceptibility testing: essential given rising resistance.