Content

Specimens: cytology (cells from smears, fine needle aspiration and fluids), biopsy (small sample), and surgical resection specimens. Handling: fixation (formalin), processing, paraffin embedding, cutting sections and haematoxylin-eosin staining. Frozen section gives a rapid intraoperative diagnosis (for example margin status) at the cost of lower quality. Ancillary techniques: immunohistochemistry (antibodies to identify cell lineage and prognostic or predictive markers, such as oestrogen receptor and HER2), special stains, molecular tests (FISH, sequencing) and electron microscopy. The history of pathology runs from Morgagni (organ pathology) and Virchow (cellular pathology) to today's digital and molecular pathology.

Grading: degree of differentiation (well, moderately, poorly differentiated), nuclear atypia and mitotic rate; reflects biological aggressiveness. Staging: anatomical extent, using the TNM system: T (size and local invasion of the primary tumour), N (lymph node involvement) and M (distant metastasis). Stage is usually the strongest predictor of prognosis. The pathology report includes tumour type, grade, margins, lymphovascular invasion, nodal status and biomarkers.

Steps: local invasion (loss of cell adhesion, E-cadherin downregulation, proteases degrade the basement membrane), intravasation into lymphatics or blood vessels, survival in the circulation, arrest at a distant site, extravasation and colonisation (growth). Epithelial-mesenchymal transition helps cells become invasive. Routes: lymphatic (carcinomas; first to regional nodes, the sentinel lymph node), haematogenous (sarcomas and many carcinomas; liver, lung, bone and brain are the commonest sites) and transcoelomic (seeding of body cavities, as in ovarian cancer). Site preference: colorectal to liver, breast and prostate to bone, lung to brain and adrenal. Immunohistochemistry helps to find the primary site of a metastasis.

1. What is a frozen section used for? 2. Define grade and stage. 3. List the steps of the metastatic cascade. 4. Which tumours metastasise to bone?

1. Rapid intraoperative diagnosis, for example to check surgical margins. 2. Grade: degree of differentiation and aggressiveness of tumour cells; stage: extent of spread (TNM). 3. Local invasion, intravasation, circulation, arrest, extravasation, colonisation. 4. Especially breast and prostate cancer.

Benign (reactive) lymphadenopathy: follicular hyperplasia (B cell response; preserved architecture with reactive germinal centres of varying shape), paracortical hyperplasia (viral infections), sinus histiocytosis, and granulomatous lymphadenitis (tuberculosis, sarcoidosis, cat scratch disease). Lymphoma: Hodgkin lymphoma (Reed-Sternberg cells and variants, CD30 and CD15 positive, background of inflammatory cells; subtypes nodular sclerosis, mixed cellularity and others) and non-Hodgkin lymphoma (effacement of architecture; diffuse large B-cell lymphoma with large cells; follicular lymphoma with neoplastic follicles and t(14;18) BCL2). Immunohistochemistry (CD20, CD3, CD30, BCL2, Ki-67) and molecular tests classify the lymphoma.

Normal marrow cellularity is about 100 minus age percent in adults (roughly 50 percent at 50 years). Examination: aspirate (cell morphology) and trephine biopsy (architecture, cellularity, fibrosis, infiltrates). Diseases: acute leukaemias (sheets of blasts, over 20 percent), myelodysplastic syndromes (dysplastic maturation with normal or high cellularity and cytopenias), myeloproliferative neoplasms (hypercellular with proliferation of megakaryocytes, granulocytes or erythroid cells; fibrosis in myelofibrosis), aplastic anaemia (hypocellular marrow replaced by fat), lymphoma and metastatic infiltration (often bone marrow involvement by carcinoma causes leucoerythroblastic anaemia).

1. Distinguish reactive follicular hyperplasia from follicular lymphoma. 2. Which cell characterises Hodgkin lymphoma and what markers? 3. What findings characterise aplastic anaemia in the marrow?

1. Reactive: preserved node architecture with varied germinal centres; lymphoma: effaced architecture with neoplastic follicles (BCL2 positive, t(14;18)). 2. Reed-Sternberg cells, CD30 and CD15 positive. 3. A hypocellular marrow replaced by fat.

Left-to-right shunts (acyanotic; risk of pulmonary hypertension and Eisenmenger syndrome): atrial septal defect, ventricular septal defect (commonest), patent ductus arteriosus, atrioventricular septal defect. Right-to-left shunts (cyanotic): tetralogy of Fallot (pulmonary stenosis, ventricular septal defect, overriding aorta, right ventricular hypertrophy), transposition of the great arteries, tricuspid atresia, truncus arteriosus. Obstructive lesions: coarctation of the aorta, aortic stenosis.

Myocardial infarction: coagulative necrosis. Timeline of morphology: no change at 0-4 hours (electron microscopic changes only), coagulative necrosis with neutrophils from 12-24 hours, macrophage removal at 3-7 days (softening: risk of rupture), granulation tissue at 1-2 weeks, fibrous scar by 6 weeks or more. Subendocardial infarcts follow global hypoperfusion; transmural infarcts follow acute coronary occlusion. Complications: arrhythmia, cardiogenic shock, rupture of free wall, septum or papillary muscle, mural thrombus, pericarditis, aneurysm, and heart failure.

Valve disease: calcific aortic stenosis (degenerative calcification, bicuspid valve), rheumatic heart disease (Aschoff bodies, fibrosis and fusion of mitral commissures; 'fish mouth' stenosis), mitral valve prolapse (myxomatous degeneration), infective endocarditis (vegetations) and non-bacterial thrombotic endocarditis. Cardiomyopathies: dilated (four-chamber dilation), hypertrophic (asymmetric septal hypertrophy, myocyte disarray), restrictive (amyloid, endomyocardial fibrosis) and arrhythmogenic. Myocarditis: lymphocytic inflammation with myocyte necrosis (viral).

1. List the components of tetralogy of Fallot. 2. Describe the morphological time course of myocardial infarction. 3. What are Aschoff bodies? 4. What is the histological hallmark of hypertrophic cardiomyopathy?

1. Ventricular septal defect, pulmonary stenosis, overriding aorta, right ventricular hypertrophy. 2. Coagulative necrosis with neutrophils at 12-24 hours, macrophages at 3-7 days, granulation tissue at 1-2 weeks, scar by 6 weeks. 3. Granulomatous lesions of rheumatic fever in the heart. 4. Myocyte disarray with asymmetric septal hypertrophy.

Obstructive: emphysema (permanent enlargement of airspaces distal to the terminal bronchiole with wall destruction: centriacinar in smokers, panacinar in alpha-1 antitrypsin deficiency), chronic bronchitis (Reid index, mucous gland hyperplasia), asthma (mucus plugs, eosinophils, Curschmann spirals, Charcot-Leyden crystals) and bronchiectasis. Restrictive: idiopathic pulmonary fibrosis (usual interstitial pneumonia pattern with honeycombing), sarcoidosis (non-caseating granulomas), pneumoconioses (coal, silicosis, asbestosis with asbestos bodies) and hypersensitivity pneumonitis. Acute lung injury: diffuse alveolar damage with hyaline membranes (ARDS).

Pneumonia: lobar (consolidation of a lobe: congestion, red hepatisation, grey hepatisation, resolution; Streptococcus pneumoniae) and bronchopneumonia (patchy, around bronchi; often hospital-acquired). Lung abscess. Tuberculosis: primary (Ghon focus and Ghon complex) and secondary reactivation in the upper lobes with caseating granulomas and cavitation. Pulmonary embolism: from deep vein thrombosis; may cause infarction (wedge-shaped haemorrhagic infarct). Pulmonary oedema: cardiogenic (heart failure cells: haemosiderin-laden macrophages) or non-cardiogenic.

Risk factors: smoking (main), radon, asbestos, air pollution. Non-small cell lung cancer (NSCLC): adenocarcinoma (commonest, peripheral, glandular; mutations in EGFR, ALK, KRAS; TTF-1 positive), squamous cell carcinoma (central, keratinisation, p40 positive; associated with hypercalcaemia via PTHrP), large cell carcinoma. Small cell carcinoma: central, small cells with scant cytoplasm and nuclear moulding, neuroendocrine markers (chromogranin, synaptophysin), early metastasis; paraneoplastic syndromes (SIADH, ectopic ACTH). Pancoast tumour: apical tumour causing Horner syndrome. Molecular testing guides targeted therapy and immunotherapy (PD-L1).

1. Distinguish centriacinar from panacinar emphysema. 2. What is the sequence in lobar pneumonia? 3. Which lung cancer types are central and which peripheral? 4. Which mutations are targets in lung adenocarcinoma?

1. Centriacinar: smokers, upper lobes, respiratory bronchioles. Panacinar: alpha-1 antitrypsin deficiency, lower lobes, whole acinus. 2. Congestion, red hepatisation, grey hepatisation, resolution. 3. Squamous and small cell carcinoma are central; adenocarcinoma is usually peripheral. 4. EGFR, ALK (and others such as ROS1 and KRAS).