Pathology: How Bodies Go Wrong, in Order

You bang your shin on a table. Within minutes it is red, warm and swelling; within days it is yellow-green; within weeks it is gone. Nothing was prescribed. A tiny, ordered programme of damage, response and repair ran by itself, and doctors can name every step.

That programme is the root of most pathology. The same few moves (injury, inflammation, healing, a blocked vessel, a growth that will not stop) explain a surprising share of what medicine treats, from a heart attack to a scar to a tumour. A pathologist looks at a piece of tissue and asks which move happened, and what it did. This piece explains how medicine works and is not medical advice. For a health question, see a clinician; in an emergency, call your local emergency number.

Cell injury and death: reversible, then not

Cells live on a tight budget of oxygen, energy and intact membranes. Hurt them (too little blood, a toxin, an infection, heat, a genetic fault) and they pass through two stages. At first the injury is reversible: the cell swells, its energy pumps slow, fat may build up inside; take the cause away and it recovers. Past a threshold, the injury is irreversible: membranes break, the cell's own enzymes leak, and the cell dies. The idea that matters is the threshold, because the whole of emergency medicine is a race to remove the cause before it is crossed.

Cells die in two main ways. Necrosis is death by accident: the cell bursts or is digested, spills its contents, and the body reacts with inflammation. This is what happens in a heart attack. Apoptosis is death by design, a tidy self-dismantling that leaves no mess. It sculpts the fingers of an embryo and removes damaged cells every day. John Kerr, Andrew Wyllie and Alastair Currie named it in 1972; the 2002 Nobel Prize in Physiology or Medicine went to Sydney Brenner, Robert Horvitz and John Sulston for finding the genes that control it. Too little apoptosis lets damaged cells survive (cancer); too much kills useful ones.

The threshold is different for each tissue because each has a different appetite for oxygen. Brain cells starve in minutes; heart muscle in tens of minutes; resting skeletal muscle can tolerate hours. Restoring blood is not purely good, either: when blood returns to starved tissue it can bring a second wave of damage called reperfusion injury, one reason treatment timing is delicate.

On the cartoon, heart muscle starved for 20 minutes has lost about 12% of its cells; at 30 minutes, half. That steep S-shape is the point: damage is slow, then fast, and the middle is where saving tissue is possible.

Inflammation: the fast response, and what happens when it does not stop

Inflammation is the body's first reply to injury or infection. The Roman writer Celsus listed four signs: redness (rubor), swelling (tumor), heat (calor) and pain (dolor); loss of function is usually added as a fifth. Each has a cause you can follow. Local blood vessels widen (redness, heat) and become leaky, letting fluid and defence cells out (swelling); chemical signals stimulate nerves (pain). It looks like damage but it is defence.

Acute inflammation lasts hours to days. Neutrophils, short-lived cells that arrive first, flood in within hours to kill microbes and eat debris. Macrophages follow within a day or two, clear what is left, and signal that repair should begin. If the cause is removed, the inflammation resolves. If it is not (a persistent infection, an irritant such as silica or tobacco smoke, or the immune system attacking the body's own tissue) it becomes chronic: macrophages and lymphocytes accumulate, tissue is damaged and rebuilt at the same time, and scar slowly replaces working tissue. Chronic inflammation is part of the story of conditions as different as rheumatoid arthritis, hepatitis and atherosclerosis.

The way to remember it: acute inflammation is a fire brigade, chronic inflammation is a fire that was never put out.

Healing and scarring: regenerate or patch

After injury a tissue has two choices. Regeneration replaces like with like. Repair plugs the gap with a quicker, cruder material, collagen, which is scar. Which one you get depends on whether the tissue's cells can divide and whether its framework survived. Skin surface, gut lining and blood cells are replaced constantly. The liver is quiet but can regrow. Heart muscle and most brain neurons almost never do.

Wound healing runs in overlapping phases: bleeding stopped by a clot, inflammation, growth of new tissue and vessels, then months of remodelling. Scar tissue is never quite as good as what it replaces. In skin, collagen strength reaches only around 20% of normal after three weeks and climbs to at most about 80% after a year. A scar does not sweat, grow hair or stretch like skin, and in organs scar can be a disease in itself: cirrhosis of the liver, a scar in a heart after infarction, fibrosis of the lung. In some people scar overgrows its wound (keloid).

Haemodynamics: clots, emboli and infarcts

Haemodynamics asks what happens when blood flow goes wrong. Blood is built to clot at a cut, and the same machinery can fire where it should not. A thrombus is a clot that forms inside an intact vessel. An embolus is a lump (usually a clot) that breaks away and travels until it lodges. An infarct is the area of dead tissue behind a blockage. A clot in a leg vein can travel through the heart to the lungs; a clot on a plaque in a heart artery can starve a patch of heart muscle.

Three conditions favour a clot: slow or turbulent flow, a damaged vessel lining, and blood that clots too easily. They are called Virchow's triad, although the German pathologist Rudolf Virchow never proposed it as a triad: the name was attached to him decades after he died.

How much tissue dies depends on where the block is and what backup exists. A block high in the tree starves everything downstream. A block low in the tree affects a small territory. Tissues with a rich web of side connections (the hand, the gut arcades) survive a blockage that would kill tissue supplied by a single "end" artery.

Block the left branch of an end-artery organ and half the tissue is at risk; with some backup, a quarter dies; with rich backup, 5%. Same clot, very different outcomes: pathology is about location as much as cause.

Neoplasia: how cancers start and grow

A neoplasm (new growth) is a clone: the descendants of a single cell that picked up changes in its DNA allowing it to ignore the normal limits. Cancer genes come in two kinds, oncogenes that jam the accelerator and tumour suppressors that are the brakes. In 1971 Alfred Knudson, studying a childhood eye cancer (retinoblastoma) that occurs in both inherited and non-inherited forms, proposed that a suppressor gene needs both copies to be lost, a "two-hit" idea that explained why inherited cases appear earlier: one hit is already there at birth. In 2000 Douglas Hanahan and Robert Weinberg organised the traits a cancer needs (self-sufficient growth signals, ignoring stop signals, evading cell death, endless replication, a blood supply, and invasion) as the "hallmarks of cancer".

A benign tumour grows in place and stays encapsulated; a malignant tumour invades neighbours and can spread. Benign does not always mean harmless: a benign mass in a skull or against a vessel can do harm by pressure alone. Cancers are common because many steps are needed, and these take time: in 1954 Peter Armitage and Richard Doll noticed that cancer rates climb as a steep power of age, as expected if several separate changes must accumulate. If, say, six steps were needed, the rate at 80 would be 32 times the rate at 40.

The IARC estimated about 20 million new cancer cases and 9.7 million cancer deaths worldwide in 2022, and that roughly one person in five develops cancer in a lifetime.

Tumours also grow on a clock that fools intuition. A tumour that starts as one cell must double about 30 times to reach around a billion cells, roughly a centimetre across and about a gram: the size at which it may first be found. Another 10 doublings would make it about a kilogram. Most of a tumour's life is silent, and the last stretch is quick.

At a doubling time of 100 days, the model takes about 8.2 years to reach a centimetre and just 2.7 years more to reach a kilogram. That is why early detection matters so much, and why growth that "appeared overnight" was usually years in the making.

Spread: invade, travel, settle

The thing that makes cancer lethal is rarely the first lump; it is metastasis, the spread to distant organs, which accounts for most cancer deaths. A cancer cell must break from its neighbours, invade local tissue, enter a lymph channel or blood vessel, survive the journey and the immune system, stop in a distant small vessel, leave it, and then grow in a foreign tissue. Every step is hard, so the great majority of cells that escape die. The few that succeed do not choose randomly: the 19th-century "seed and soil" idea of Stephen Paget, that certain cancers prefer certain organs, still frames the discussion. Lymph nodes, liver, lung, bone and brain are common destinations.

This is why staging exists. The TNM system records the size of the Tumour, spread to lymph Nodes and Metastasis, and tells clinicians (and patients) how far the disease has gone, which tends to predict outcome better than the tumour's appearance alone.

The autopsy and the biopsy: pathology as evidence

Pathology is also a method. In 1761 Giovanni Morgagni, in De sedibus et causis morborum, matched the symptoms his patients had in life with the damage he found after death, and so made disease a matter of places in the body. In 1858 Rudolf Virchow's Cellular Pathology pushed the place of disease down to the cell. Today the same tools run in two forms. An autopsy examines a whole body after death to find out what happened. A biopsy takes a piece of living tissue (with a needle, a punch or surgery), which is cut thin, stained and read under a microscope; more tests then look at proteins and genes.

Both are still revealing. A review projected that a major diagnostic error would be found in roughly 8% to 24% of autopsies at a modern US hospital. Yet autopsy has declined: in the UK in 2013 only 0.7% of adult inpatient deaths were followed by a consented autopsy. And a biopsy has a weakness of its own: it looks at a small piece. A cancer that is patchy can be missed if the needle goes through healthy tissue next to it.

If a fifth of the organ is involved, three samples all miss about half the time (51%); twelve miss under 7% of the time. That is why a "negative" biopsy is read with its limits in mind.

What a graduate just sees

• Injury has a threshold: reversible, then not. Time is the variable.
• Necrosis is accident and apoptosis is design; both are normal words in the clinic.
• Redness, heat, swelling and pain are defence, and chronic inflammation is a fire that never went out.
• Tissues either regenerate or scar, and scar is a patch that never matches the original.
• A clot's damage depends on where it lodges and what backup the tissue has.
• A cancer is a clone, grown by exponential doubling, and is silent for most of its life.
• Metastasis, not the first lump, is usually what kills.
• A biopsy samples a small piece of a large, patchy organ, so a negative one is evidence, not proof.

Where it shows up next

• Immunology (35/57) goes deep into the defence cells that inflammation calls up, and into allergy and autoimmunity.
• Pharmacology (35/56): many drugs work by damping inflammation, preventing clots or attacking dividing cells.
• Clinical Reasoning & Diagnosis (35/59): a diagnosis is a guess about which of these mechanisms is happening.
• In the world: pathologists who read the slides and sign the reports, cancer screening, wound care, and every news story about a "new" cause of cancer or heart disease.

If you want to go deeper

• 📘 Textbook. Vinay Kumar, Abul Abbas and Jon Aster, Robbins & Kumar Basic Pathology (Elsevier). The standard first course; the larger Robbins and Kumar Pathologic Basis of Disease is the full reference.
• 📘 Textbook. Ivan Damjanov, Pathology for the Health Professions (Elsevier). A shorter text for nursing and allied-health programmes.
• 📘 Gentler. Siddhartha Mukherjee, The Emperor of All Maladies: A Biography of Cancer (2010). A history of cancer that reads like a story.
• 🌐 Free course. The US National Cancer Institute's What Is Cancer? and Khan Academy: Health and medicine videos.