Systemic Pathology
1. What this chapter covers, and how NEET PG actually tests it
Systemic pathology spans every organ, and no chapter can list all of it. It does not need to.
The exam samples this material through named appearances: a described cell, inclusion body or gross pattern, with the disease as the answer.
Every one of those eponyms is a mechanism made visible. Something specific happened to the tissue, and the appearance is its structural record.
Learning why each appearance forms is what makes it recallable, and it is also what rescues you when the stem describes the appearance without naming it.
| System | The appearances that recur | Usual framing |
|---|---|---|
| Cardiovascular | Aschoff body, onion-skin, myxoid valve | A murmur plus a history |
| Respiratory | Ferruginous body, Charcot-Leyden, honeycomb | An exposure plus imaging |
| Gastrointestinal | Signet ring, skip lesion, crypt abscess | Endoscopy plus biopsy |
| Hepatobiliary | Mallory body, Councilman body, ground glass | Liver function plus serology |
| Endocrine | Orphan Annie nuclei, psammoma body | A nodule plus hormone levels |
| Nervous system | Lewy body, neurofibrillary tangle, Negri body | A clinical syndrome |
2. Cardiovascular pathology
2.1 Atherosclerosis and its complications
The sequence is endothelial injury, lipoprotein accumulation, monocyte recruitment and foam cell formation, smooth muscle migration, and fibrous cap formation.
Plaque rupture, not plaque size, causes acute events, which is why a modestly stenotic plaque with a thin cap is more dangerous than a large stable one.
A thin fibrous cap, a large lipid core and abundant inflammatory cells define the vulnerable plaque.
Statins stabilise plaques partly through effects independent of lipid lowering, which explains benefit appearing before cholesterol falls substantially.
The abdominal aorta below the renal arteries is the commonest site, followed by the coronary and popliteal arteries.
2.2 Rheumatic and infective valve disease
Rheumatic fever follows group A streptococcal pharyngitis by two to four weeks, through molecular mimicry between M protein and cardiac myosin.
The Aschoff body is the pathognomonic lesion, a granuloma containing Anitschkow cells with characteristic caterpillar-shaped nuclei.
The mitral valve is most often affected, and chronic disease produces a fish-mouth or buttonhole stenosis.
Infective endocarditis produces vegetations that are large and destructive in acute Staphylococcus aureus disease, and smaller in subacute viridans streptococcal disease.
Libman-Sacks endocarditis of lupus produces sterile vegetations on both surfaces of the valve, which distinguishes it from infective vegetations on the line of closure.
Marantic endocarditis accompanies malignancy, particularly mucinous adenocarcinoma, and produces small sterile vegetations.
2.3 Cardiomyopathies and vasculitis
Dilated cardiomyopathy gives systolic failure, and its causes include alcohol, doxorubicin, peripartum state, coxsackievirus and haemochromatosis.
Hypertrophic cardiomyopathy is a sarcomeric protein mutation with asymmetrical septal hypertrophy and myofibre disarray, and is a leading cause of sudden death in young athletes.
Restrictive cardiomyopathy follows amyloid, sarcoid, haemochromatosis and endomyocardial fibrosis.
| Vasculitis | Vessel size | Distinguishing feature |
|---|---|---|
| Giant cell arteritis | Large | Jaw claudication, vision loss, skip lesions |
| Takayasu arteritis | Large | Young Asian women, absent pulses |
| Polyarteritis nodosa | Medium | Hepatitis B, spares the lung, rosary beading |
| Kawasaki disease | Medium | Children, coronary aneurysms |
| Granulomatosis with polyangiitis | Small | c-ANCA, upper and lower airway plus kidney |
| Eosinophilic granulomatosis | Small | Asthma, eosinophilia, p-ANCA |
| IgA vasculitis | Small | Palpable purpura, children after infection |
Polyarteritis nodosa spares the pulmonary vessels, which is the single feature separating it most reliably from the ANCA-associated vasculitides.
3. Respiratory pathology
3.1 Obstructive disease
Centriacinar emphysema affects upper lobes and follows smoking; panacinar emphysema affects lower lobes and follows alpha-1 antitrypsin deficiency.
The difference in distribution reflects where the insult acts, since inhaled smoke damages proximal airways first while a circulating protease deficiency acts uniformly and shows first where perfusion is greatest.
Chronic bronchitis is defined clinically by productive cough for three months in two consecutive years, and pathologically by an increased Reid index.
Asthma shows Curschmann spirals of shed epithelium, Charcot-Leyden crystals from eosinophil membrane protein, and basement membrane thickening.
3.2 Restrictive and occupational disease
| Pneumoconiosis | Exposure | Feature |
|---|---|---|
| Coal worker's | Coal dust | Upper lobe, anthracotic macules |
| Silicosis | Foundry, sandblasting | Upper lobe, eggshell calcification, raises tuberculosis risk |
| Asbestosis | Shipyard, insulation | Lower lobe, ferruginous bodies, pleural plaques |
| Berylliosis | Aerospace | Non-caseating granulomas, mimics sarcoidosis |
Silica impairs macrophage function, which is why silicosis specifically increases susceptibility to tuberculosis rather than merely coexisting with it.
Asbestos bodies are fibres coated in iron-protein complex, and their presence proves exposure but not disease.
Idiopathic pulmonary fibrosis shows usual interstitial pneumonia with temporal heterogeneity, fibroblastic foci and honeycomb change, worst in the subpleural lower zones.
3.3 Lung tumours
Adenocarcinoma is now the commonest type overall and the commonest in non-smokers and women, and is peripheral.
Squamous cell carcinoma is central, cavitates, and causes hypercalcaemia through parathyroid hormone-related peptide.
Small cell carcinoma is central, highly aggressive, and causes the endocrine paraneoplastic syndromes.
Pancoast tumours at the apex produce Horner syndrome and brachial plexus involvement.
Carcinoid tumours are neuroendocrine, generally indolent, and cause the carcinoid syndrome only once hepatic metastases allow serotonin to bypass first-pass metabolism.
That requirement explains why a bronchial carcinoid can cause the syndrome without liver involvement, since its venous drainage reaches the systemic circulation directly.
Mesothelioma arises from pleura after asbestos exposure with a latency of decades, encases the lung, and is calretinin positive on staining.
4. Gastrointestinal and hepatobiliary pathology
4.1 Oesophagus and stomach
Barrett oesophagus is intestinal metaplasia with goblet cells replacing squamous epithelium, and predisposes to adenocarcinoma.
Squamous carcinoma affects the upper two-thirds and follows smoking, alcohol and hot beverages; adenocarcinoma affects the lower third and follows Barrett change.
Helicobacter pylori causes antral gastritis with increased acid and duodenal ulceration, or body gastritis with atrophy and gastric ulceration.
Autoimmune gastritis destroys parietal cells in the body and fundus, causing achlorhydria and pernicious anaemia.
Signet ring cells define diffuse gastric carcinoma, and linitis plastica is the resulting rigid leather-bottle stomach.
Virchow node, Sister Mary Joseph nodule and Krukenberg tumour are its characteristic metastatic signatures.
4.2 Inflammatory bowel disease
| Feature | Crohn disease | Ulcerative colitis |
|---|---|---|
| Distribution | Mouth to anus, skip lesions | Rectum extending proximally, continuous |
| Depth | Transmural | Mucosal and submucosal |
| Granulomas | Non-caseating, present | Absent |
| Appearance | Cobblestone, creeping fat | Pseudopolyps, lead-pipe colon |
| Complications | Fistula, stricture, abscess | Toxic megacolon, higher cancer risk |
| Smoking | Worsens | Protective |
Transmural inflammation is what produces fistulae and strictures, so every Crohn complication follows from the depth of involvement rather than from its site.
Crypt abscesses occur in both and are not discriminating; granulomas are.
4.3 Colorectal polyps and the two carcinogenesis pathways
Most colorectal cancer arises from adenomatous polyps, and the risk of a given polyp is predictable from three features.
Size above one centimetre, villous rather than tubular architecture, and the presence of high-grade dysplasia each raise the malignant risk, and villous lesions are the most dangerous.
Hyperplastic polyps are the commonest polyp overall and carry no malignant potential, which is why distinguishing them matters at colonoscopy.
The classical adenoma-carcinoma sequence runs APC, then KRAS, then TP53, and accounts for the majority of sporadic cancers.
Loss of APC is the initiating event, and it is why familial adenomatous polyposis produces hundreds of polyps and near-certain cancer without colectomy.
The second pathway is microsatellite instability from mismatch repair failure, which underlies Lynch syndrome.
Lynch syndrome cancers are typically right-sided, arise from fewer polyps, and occur earlier, which is why surveillance strategies differ between the two syndromes.
Right-sided tumours present with iron deficiency anaemia because the caecum is capacious and stool is liquid, while left-sided tumours present with obstruction and altered bowel habit.
4.4 Liver
Hepatitis B ground glass hepatocytes reflect abundant surface antigen in the endoplasmic reticulum.
Councilman bodies are apoptotic hepatocytes, seen in viral hepatitis and yellow fever.
Mallory bodies are damaged intermediate filaments, seen in alcoholic hepatitis but also in Wilson disease and non-alcoholic steatohepatitis.
Alcoholic liver disease progresses through steatosis, alcoholic hepatitis and cirrhosis, with a characteristic AST to ALT ratio above two.
Wilson disease accumulates copper with low ceruloplasmin and Kayser-Fleischer rings; haemochromatosis accumulates iron with a raised transferrin saturation and a bronze diabetes picture.
Primary biliary cholangitis destroys small bile ducts in middle-aged women with antimitochondrial antibody; primary sclerosing cholangitis affects larger ducts in men with ulcerative colitis and shows onion-skin fibrosis with beading on cholangiography.
4.5 Cirrhosis and portal hypertension
Cirrhosis is diffuse fibrosis with regenerative nodules, and its consequences divide cleanly into two groups.
Failure of hepatocyte function produces jaundice, hypoalbuminaemia, coagulopathy and hyperoestrogenism, the last giving spider naevi, gynaecomastia and palmar erythema.
Portal hypertension produces varices, splenomegaly, ascites and caput medusae, all of which are consequences of pressure rather than of lost synthetic function.
Sorting a clinical feature into one group or the other is usually what the question is testing.
Hepatic encephalopathy reflects failure to clear nitrogenous waste, and is precipitated by gastrointestinal bleeding, infection, constipation and electrolyte disturbance.
Hepatocellular carcinoma arises on a background of cirrhosis in most cases, and hepatitis B is the exception because it can cause cancer without cirrhosis through direct viral integration.
5. Endocrine and nervous system pathology
5.1 Thyroid
Hashimoto thyroiditis shows lymphoid follicles with germinal centres and Hurthle cell change, and carries a raised risk of thyroid lymphoma.
Graves disease shows diffuse hyperplasia with scalloped colloid, driven by thyroid-stimulating immunoglobulin.
| Thyroid carcinoma | Feature |
|---|---|
| Papillary | Commonest, best prognosis, Orphan Annie nuclei, psammoma bodies, lymphatic spread |
| Follicular | Haematogenous spread, diagnosis needs capsular or vascular invasion |
| Medullary | Parafollicular C cells, calcitonin, amyloid stroma, RET in MEN 2 |
| Anaplastic | Elderly, rapidly fatal |
Follicular carcinoma cannot be diagnosed on fine needle aspiration, because the distinguishing feature is invasion through the capsule, which requires the architecture that aspiration destroys.
Papillary carcinoma, by contrast, is diagnosed on nuclear features alone and so is readily identified by aspiration.
5.2 Adrenal and multiple endocrine neoplasia
Cushing syndrome is most often iatrogenic; among endogenous causes, pituitary adenoma is commonest.
Conn syndrome produces hypertension with hypokalaemia and suppressed renin.
Phaeochromocytoma follows the rule of tens and secretes catecholamines, and alpha blockade must precede beta blockade to avoid unopposed alpha stimulation.
MEN 1 involves parathyroid, pancreas and pituitary; MEN 2A involves medullary thyroid carcinoma, phaeochromocytoma and parathyroid; MEN 2B replaces the parathyroid component with mucosal neuromas and a marfanoid habitus.
5.3 Nervous system
Alzheimer disease shows neurofibrillary tangles of hyperphosphorylated tau and amyloid plaques of beta-amyloid, with hippocampal atrophy.
Parkinson disease shows Lewy bodies of alpha-synuclein with depigmentation of the substantia nigra.
Huntington disease shows caudate atrophy with a CAG trinucleotide repeat expansion showing anticipation.
Rabies shows Negri bodies in hippocampal and Purkinje neurons.
Creutzfeldt-Jakob disease shows spongiform change with prion protein misfolding and no inflammation.
| Brain tumour | Feature |
|---|---|
| Glioblastoma | Commonest primary malignant, pseudopalisading necrosis, butterfly lesion |
| Meningioma | Psammoma bodies, whorls, dural attachment |
| Medulloblastoma | Child, cerebellum, small blue cells, drop metastases |
| Schwannoma | Cerebellopontine angle, S-100 positive |
Metastases are commoner than primary brain tumours, are typically multiple and at the grey-white junction.
They lodge there because the calibre of the vessels drops abruptly at that boundary, trapping tumour emboli, which is the same mechanical principle that governs metastasis elsewhere.
Location also predicts age in the paediatric setting: most childhood brain tumours are infratentorial, while most adult tumours are supratentorial.
That single rule resolves a large proportion of paediatric neuro-oncology questions before any histology is considered.
5.4 Bone
Bone pathology is examined through the pairing of age, site and radiological appearance, and the three together are usually sufficient.
| Tumour | Age | Site | Appearance |
|---|---|---|---|
| Osteosarcoma | Adolescent | Metaphysis around the knee | Sunburst, Codman triangle |
| Ewing sarcoma | Child | Diaphysis | Onion-skin periosteal reaction, t(11;22) |
| Giant cell tumour | Young adult | Epiphysis | Soap-bubble, locally aggressive |
| Osteochondroma | Adolescent | Metaphysis | Benign, commonest bone tumour |
| Osteoid osteoma | Young | Cortex | Night pain relieved by aspirin |
Metabolic bone disease is separated by the biochemistry rather than the radiology.
Osteoporosis has normal calcium, phosphate and alkaline phosphatase, since the bone present is normal in composition and merely reduced in quantity.
Osteomalacia has low calcium and phosphate with raised alkaline phosphatase, because mineralisation has failed.
Paget disease has normal calcium and phosphate with a markedly raised alkaline phosphatase, and shows a mosaic pattern of lamellar bone.
Its feared complication is transformation to osteosarcoma in an elderly patient, which is why new pain in known Paget disease is investigated seriously.
6. Worked examples
Example 1
A 50-year-old shipyard worker has progressive breathlessness. Imaging shows lower zone fibrosis and calcified pleural plaques. Sputum contains golden-brown beaded structures.
The occupational history and the lower zone distribution are the first discriminators, since coal and silica affect the upper zones.
Golden-brown beaded structures are ferruginous bodies: asbestos fibres coated in an iron-protein complex by macrophages that cannot digest them.
Their presence proves exposure but does not by itself prove disease, and it is the fibrosis and plaques that establish asbestosis here.
The important further step is recognising that his greatest malignant risk is bronchogenic carcinoma rather than mesothelioma, and that smoking would multiply that risk enormously.
Example 2
A 35-year-old woman has a thyroid nodule. Fine needle aspiration shows follicular cells with overlapping nuclei, nuclear grooves and intranuclear inclusions.
The nuclear features named are those of papillary carcinoma, and this is the type diagnosable on cytology alone.
Orphan Annie nuclei appear empty because chromatin is marginated, and nuclear grooves and pseudoinclusions arise from irregular nuclear membranes.
Had the aspirate shown a bland follicular pattern instead, no diagnosis would have been possible, because follicular carcinoma is defined by capsular or vascular invasion and aspiration destroys that architecture.
Papillary carcinoma spreads by lymphatics and carries an excellent prognosis.
Example 3
A 24-year-old has bloody diarrhoea. Colonoscopy shows continuous inflammation from the rectum to the splenic flexure with pseudopolyps. Biopsy shows mucosal inflammation with crypt abscesses and no granulomas.
Continuity from the rectum proximally is the pattern of ulcerative colitis, since Crohn disease characteristically skips.
Mucosal rather than transmural involvement excludes the depth that produces Crohn fistulae and strictures.
Crypt abscesses appear in both conditions and are not discriminating; the absence of granulomas is what supports ulcerative colitis.
The clinically important consequences are the risk of toxic megacolon and the need for colonoscopic cancer surveillance after eight to ten years of extensive disease.
7. Traps the exam sets repeatedly
Using crypt abscesses to distinguish Crohn disease from ulcerative colitis. They occur in both. Granulomas, transmural involvement and skip lesions are the discriminators.
Attempting to diagnose follicular carcinoma on aspiration cytology. Capsular and vascular invasion cannot be assessed without intact architecture.
Treating Mallory bodies as specific to alcohol. They also appear in Wilson disease and non-alcoholic steatohepatitis.
Assuming polyarteritis nodosa involves the lungs. Pulmonary sparing is its most useful distinguishing feature.
Giving a beta blocker first in phaeochromocytoma. Unopposed alpha stimulation precipitates a hypertensive crisis, so alpha blockade must come first.
Expecting an abnormal calcium in osteoporosis. The biochemistry is entirely normal, because the bone that remains is of normal composition and only its quantity has fallen.
Assuming hepatocellular carcinoma always requires cirrhosis. Hepatitis B is the exception, causing cancer through direct viral integration even in a non-cirrhotic liver.
Summary
Systemic pathology is examined through named appearances, and every appearance is a mechanism made visible.
Plaque rupture rather than plaque size causes acute coronary events, and the vulnerable plaque has a thin cap over a large lipid core.
Aschoff bodies with Anitschkow cells are pathognomonic of rheumatic carditis, which follows streptococcal pharyngitis by molecular mimicry.
Vasculitis is classified by vessel size, and pulmonary sparing separates polyarteritis nodosa from the ANCA-associated diseases.
Emphysema distribution follows the route of the insult: upper lobes for inhaled smoke, lower lobes for alpha-1 antitrypsin deficiency.
Pneumoconioses are separated by zone and by exposure, and silica specifically impairs macrophages and raises tuberculosis risk.
Crohn disease is transmural with skip lesions and granulomas; ulcerative colitis is continuous, mucosal and without granulomas.
Liver inclusion bodies each record a distinct process, and Mallory bodies are not specific to alcohol.
Papillary thyroid carcinoma is diagnosed on nuclear features, while follicular carcinoma requires demonstration of invasion.
Colorectal cancer follows two pathways, the APC-KRAS-TP53 sequence and microsatellite instability, and they differ in polyp burden, site and age.
Cirrhosis produces two separable groups of features, those of lost synthetic function and those of portal pressure.
Bone tumours are identified by the combination of age, site and radiological appearance, while metabolic bone disease is separated by biochemistry.
In the nervous system, each degenerative disease has its own misfolded protein, and metastases outnumber primary tumours.
