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Cancer research: 880 3D models

Cancer cells and hallmarks, tumour microenvironment, metastasis, cancers by organ, models, diagnostics and therapy (real sizes nm–cm). Each one is a ready-made 3D model you can turn, recolour and place in a figure — open BioDiorama and type its name in the Library search.

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Cancer cell types · Features of malignancy · Abnormal mitosis & chromosomes · Oncogenes & tumour suppressors · DNA damage & repair · Telomeres & immortality · Hallmarks of cancer · Clonal evolution · Cancer metabolism · Cell death & its escape · Senescence · Cancer stem cells · Carcinogens & oncogenic microbes · Tumour stroma & fibroblasts · Immune cells in tumours · Tumour blood & lymph vessels · Hypoxia, acidity & metabolism · Immune checkpoints · Immunotherapy at the cell level · Hot & cold tumours, lymphoid structures · Tumour matrix & mechanics · Tumour crosstalk & signals · Metastasis: EMT & plasticity · Metastasis: invasion & migration · Metastasis: basement membrane breach · Metastasis: intravasation · Metastasis: circulating tumour cells · Metastasis: extravasation · Metastasis: pre-metastatic niche & homing · Metastasis: lymphatic spread · Metastasis: bone · Metastasis: liver, lung & brain · Metastasis: peritoneum & other sites · Metastasis: dormancy & colonisation · Metastasis: routes & organotropism · Breast cancers · Grading & pathology scoring · Lung & thoracic cancers · Staging (TNM) · Precancerous lesions · Gastrointestinal cancers · Lymphomas & myeloma · Liver, pancreas & biliary cancers · Urological & testicular cancers · Gynaecological cancers · Leukaemias · Bone & soft-tissue sarcomas · Skin & eye cancers · Childhood cancers · Head, neck & endocrine cancers · Brain & nerve tumours · Cell lines in culture · Spheroids & 3-D culture · Tumour organoids · Tumour-on-chip · In vivo & alternative models · Liquid biopsy · Biopsies & specimens · Imaging read-outs · Chemotherapy at work · Targeted therapy & antibodies · Radiation therapy · Local therapies & nanoparticle delivery · Drug resistance · Drug screening & read-outs · Cancer cell lines (SEM look) · Ablation & interventional oncology · Radiotherapy techniques & radiobiology · Cancer surgery & endoscopy · Cell therapies & cancer vaccines · Resistance mechanisms (more) · Side effects of cancer treatment · Metastasis & microenvironment (more) · Paraneoplastic & oncological emergencies · Cancer models & read-outs (more) · Tumour types (more) · Immune checkpoint blockade · Immunometabolism · Radioligand therapy · Targeted protein degradation · Bispecifics & antibody–drug conjugates · Tertiary lymphoid structures · Cancer — the driver, by site · Cancer — the drug at its target · Cancer — finding it and treating it · Cancer — by site · Cancer — types · Cancer — how it is described

Cancer cell types 45

Adenocarcinoma cell — A gland-forming carcinoma cell: tall and columnar, with stubby, disordered microvilli on top, mucin droplets under the apex and a large, irregular nucleus with a prominent nucleolus that has drifted up from the base as polarity is lost. (≈ 15–25 µm tall)
Squamous cell carcinoma cell — A keratinising squamous carcinoma cell: polygonal, with dense pink cytoplasm full of keratin tonofilament bundles and spiny intercellular bridges (desmosomes) all round; the nucleus is dark, irregular and enlarged. (≈ 20–30 µm)
Keratin pearl (squamous whorl) — The signature of well-differentiated squamous cell carcinoma: tumour cells flatten and keratinise as they spiral inwards, forming concentric onion-skin layers around a core of compact keratin. Cut in half to show the whorl. (≈ 100–300 µm)
Signet ring cell — A carcinoma cell swollen by one huge droplet of mucin that squashes the nucleus into a crescent against the membrane, like a signet ring — the cell of diffuse gastric cancer and some breast, colon and bladder cancers. (≈ 15–20 µm)
Small cell carcinoma cells (nuclear moulding) — A cluster of small cell carcinoma cells: oval nuclei with finely speckled "salt-and-pepper" chromatin and almost no cytoplasm, pressed so tightly that they mould against one another like a stack of tiles. (each cell ≈ 10–15 µm)
Anaplastic large cell (hallmark cell) — The hallmark cell of anaplastic large cell lymphoma: a big cell with a horseshoe- or kidney-shaped nucleus wrapped around a pink, Golgi-rich zone beside it. Many carry the NPM–ALK fusion and stain strongly for CD30. (≈ 25–40 µm)
Melanoma cell — A malignant melanocyte: epithelioid with a few short dendrites, its cytoplasm dusted with brown melanin granules (melanosomes) and its nucleus holding one big, cherry-red macronucleolus. Amelanotic melanomas lose the pigment. (≈ 20–30 µm)
Leiomyosarcoma cell (cigar-shaped nucleus) — A malignant smooth muscle cell: long and spindle-shaped, packed with myofilament bundles, with a blunt-ended "cigar" nucleus capped by small clear vacuoles at its ends — atypical, enlarged and dark compared with normal smooth muscle. (≈ 80–150 µm long)
Rhabdomyoblast (tadpole cell) — The tumour cell of rhabdomyosarcoma, a cancer of developing skeletal muscle: bright pink cytoplasm, sometimes cross-striated, drawn out into a tadpole or strap shape with an eccentric round nucleus. (≈ 30–100 µm)
Lipoblast (scalloped nucleus) — The diagnostic cell of liposarcoma: a fat-forming cell holding several clear lipid vacuoles that press into its dark nucleus from all sides and leave it scalloped. (≈ 20–40 µm)
Reed–Sternberg cell — The malignant cell of classic Hodgkin lymphoma: huge, with two mirror-image nuclei, each holding a large inclusion-like nucleolus — the "owl's eyes". Settings show the mononuclear Hodgkin cell, the lacunar cell and the "popcorn" cell of the nodular lymphocyte-predominant type. (≈ 20–50 µm)
Hairy cell (hairy cell leukaemia) — A malignant B cell of hairy cell leukaemia: a small round cell fringed with fine, irregular, hair-like cytoplasmic projections and holding an oval or bean-shaped nucleus. Almost all carry BRAF V600E. (≈ 12–20 µm)
Leukaemic myeloblast with Auer rods — A myeloblast of acute myeloid leukaemia: a big nucleus with fine chromatin and nucleoli, a rim of cytoplasm and one or more pink, needle-like Auer rods (fused azurophilic granules). The APL setting shows a "faggot cell" with bundles of rods and a bilobed nucleus. (≈ 15–20 µm)
Burkitt lymphoma cell — A Burkitt lymphoma cell: round and medium-sized, with deeply blue (basophilic) cytoplasm punched with clear lipid vacuoles and a round nucleus holding several small nucleoli. Driven by MYC translocated next to an immunoglobulin gene. (≈ 10–25 µm)
Myeloma plasma cell — A malignant plasma cell of multiple myeloma: oval, with an eccentric nucleus whose chromatin sits in "clock-face" clumps, a pale Golgi zone (hof) beside the nucleus and cytoplasm stacked with rough ER making monoclonal antibody. Variants: a Mott cell crammed with Russell bodies, a flame cell and a binucleate cell. (≈ 15–25 µm)
Sézary cell (cerebriform nucleus) — A malignant skin-homing T cell of Sézary syndrome and mycosis fungoides: little cytoplasm around a nucleus folded into deep grooves like the surface of a brain. (≈ 10–20 µm)
CLL cells and smudge cells — Chronic lymphocytic leukaemia: small, mature-looking lymphocytes whose chromatin sits in coarse blocks ("soccer-ball" or cracked-earth pattern), beside smudge cells — fragile CLL cells flattened and smeared open when the blood film was made. (cells ≈ 7–10 µm)
Tumour rosettes (Homer Wright, Flexner–Wintersteiner) — Rings of small tumour cells pointing their tapered ends to a centre: around a tangle of neural processes (Homer Wright rosette of neuroblastoma and medulloblastoma), around a true lumen (Flexner–Wintersteiner rosette of retinoblastoma) or around a blood vessel (perivascular pseudorosette of ependymoma). (≈ 50–100 µm across)
Hepatocellular carcinoma cell — A liver cancer cell that still looks like a hepatocyte: polygonal, with a central nucleus and big nucleolus, a canaliculus plugged with green bile on its face, bile pigment granules and ropy pink Mallory–Denk bodies of tangled keratin. (≈ 20–30 µm)
Clear cell renal carcinoma nest — A nest of clear cell renal cell carcinoma: polygonal cells whose cytoplasm, emptied of glycogen and lipid in processing, looks water-clear, each with a small round nucleus, all wrapped in a delicate "chicken-wire" net of capillaries. VHL loss drives it. (≈ 80–120 µm)
Papillary thyroid carcinoma cell (Orphan Annie nucleus) — The nuclear features that diagnose papillary thyroid carcinoma: an enlarged oval nucleus with clear, "Orphan Annie eye" chromatin pushed to the rim, a lengthwise groove like a coffee bean and an intranuclear pseudo-inclusion — a pocket of cytoplasm poking into the nucleus. (≈ 15–20 µm)
Osteosarcoma cell laying down osteoid — A malignant bone-forming cell of osteosarcoma: pleomorphic, with an angular dark nucleus, wrapped in the lace-like pink osteoid it secretes directly — the defining feature of the tumour. (≈ 20–50 µm)
Oncocytic tumour cell (packed with mitochondria) — An oncocyte, the cell of oncocytomas and Hürthle cell tumours: large and polygonal, its granular pink cytoplasm stuffed with hundreds of swollen mitochondria (often with mitochondrial DNA mutations), around a round central nucleus with a prominent nucleolus. (≈ 20–30 µm)
Chondrosarcoma cells in lacunae — A block of malignant cartilage cut across its top: blue-grey hyaline matrix pitted with crowded lacunae, many holding two atypical chondrocytes or plump, irregular nuclei — the higher the grade, the more cells and the stranger their nuclei. (≈ 150 µm block)
Seminoma cells ("fried egg") — Seminoma, the commonest testicular germ cell tumour: large round cells with crisp borders and clear, glycogen-rich cytoplasm around a central squarish nucleus with a big nucleolus ("fried eggs"), lined up along a fibrous septum crowded with small lymphocytes. (cells ≈ 15–25 µm)
Bizarre tumour giant cell — A bizarre, multinucleated tumour giant cell of an undifferentiated (pleomorphic) sarcoma or anaplastic carcinoma: huge and irregular, with nuclei of wildly different size and shape — the extreme of anaplasia. (≈ 50–150 µm)
Mesothelioma cells on the pleura — Malignant mesothelial cells on the pleural surface: plump polygonal cells covered in a dense brush of very long, slender microvilli — longer and bushier than those of adenocarcinoma, a classic electron-microscopy clue. (≈ 60 µm strip)
Neuroendocrine tumour cell (dense-core granules) — A well-differentiated neuroendocrine (carcinoid) tumour cell: a round nucleus with speckled "salt-and-pepper" chromatin and cytoplasm full of small dense-core secretory granules (each a dark core inside a pale halo), gathered towards the base. (≈ 15–20 µm)
Merkel cell carcinoma cell (paranuclear dot) — A Merkel cell carcinoma cell: small and round with scant cytoplasm, finely dusted chromatin and, beside the nucleus, a tight ball of keratin filaments — the paranuclear "dot" that lights up with CK20 staining. Most carry Merkel cell polyomavirus. (≈ 12–18 µm)
Megakaryoblast (budding blebs) — A leukaemic megakaryoblast of acute megakaryoblastic leukaemia: a blast with a round nucleus and deeply blue cytoplasm that buds into rounded blebs, like platelets trying to form — common in children with Down syndrome. (≈ 15–25 µm)
Cleaved lymphoma cell (centrocyte) — The small cleaved cell of follicular lymphoma: a little cytoplasm around an angular nucleus split by deep clefts and notches. A setting shows the large centroblast beside it, with a round open nucleus and nucleoli on the membrane. (≈ 8–12 µm)
Langerhans cell histiocytosis cell (Birbeck granules) — A neoplastic Langerhans cell: oval, with a pale folded nucleus split by a lengthwise groove like a coffee bean, and cytoplasm holding Birbeck granules — rod-shaped organelles, some with a bulb at one end like a tennis racket. (≈ 15–25 µm)
Granular cell tumour cell — A cell of granular cell tumour (Abrikossoff tumour), of Schwann-cell origin: large and polygonal, its cytoplasm crammed with coarse pink lysosomal granules and a few larger "pustulo-ovoid bodies", around a small dark nucleus. (≈ 25–40 µm)
Rhabdoid tumour cell (filament whorl) — A rhabdoid cell of atypical teratoid/rhabdoid tumour and malignant rhabdoid tumour of the kidney: an eccentric vesicular nucleus with a big nucleolus pushed aside by a glassy pink inclusion — a whorl of intermediate filaments. SMARCB1 (INI1) is lost. (≈ 15–25 µm)
Psammoma body — A psammoma body: a tiny round calcification laid down in concentric layers, like tree rings, around dying tumour cells at the tip of a papilla — typical of papillary thyroid carcinoma, serous ovarian carcinoma and meningioma. (≈ 30–100 µm)
Lobular carcinoma cell (intracytoplasmic lumen) — A small, round invasive lobular breast carcinoma cell that has lost E-cadherin and slips through tissue in single file. Inside, an intracytoplasmic lumen — a little vacuole lined by microvilli with a dot of mucin in the middle — gives it a "targetoid" look, distinct from the giant vacuole of a signet ring cell. (≈ 12–15 µm)
Monoblast (acute monocytic leukaemia) — A leukaemic monoblast of acute monocytic leukaemia: large, with plenty of grey-blue cytoplasm dotted with fine vacuoles and a few granules, and a round or gently folded nucleus with lacy chromatin and one or more prominent nucleoli. The promonocyte setting shows the next step, with a deeply folded nucleus. (≈ 15–25 µm)
Chordoma physaliphorous cells — Chordoma, a rare cancer of notochord remnants in the skull base and spine: cords of large "physaliphorous" (bubble-bearing) cells, their cytoplasm packed with clear vacuoles, lying in a blue-grey myxoid matrix. They express brachyury (TBXT). (≈ 150 µm)
Dysplastic megakaryocytes (MPN and MDS) — Megakaryocytes tell bone-marrow cancers apart: in myeloproliferative neoplasms such as myelofibrosis they are huge, with hyperlobated, cloud-like or "staghorn" nuclei; in myelodysplastic syndromes they shrink to micromegakaryocytes or carry several small, separate round nuclei. (≈ 20–100 µm)
Dysplastic neutrophil (pseudo-Pelger–Huët) — A dysplastic neutrophil of myelodysplastic syndrome: instead of three to five lobes it has a bilobed "pince-nez" nucleus (two round lobes joined by a thin strand) or a single round one, with coarse chromatin and pale, granule-poor cytoplasm. The normal setting shows a segmented, granular neutrophil. (≈ 10–12 µm)
Ring sideroblast — A ring sideroblast, the hallmark of myelodysplastic syndrome with SF3B1 mutation: a red-cell precursor whose mitochondria, choked with iron they cannot use for haem, form a necklace of blue granules (on Prussian blue staining) circling at least a third of the nucleus. (≈ 12–15 µm)
Anatomy of a cancer cell (cutaway) — A carcinoma cell opened up to show everything that sets it apart: an irregular, blebbing surface with microvilli; a large, misshapen nucleus with coarse chromatin and several big nucleoli; crowded ribosomes and rough ER for growth; a Golgi stack; small, fragmented mitochondria; lysosomes, an autophagosome, lipid droplets, secretory vesicles and extra centrosomes. (≈ 20–30 µm)
Cancer cell in an electron-microscope section — A cancer cell as it appears in a transmission electron microscope thin section — a flat, grey-toned slice: an irregular, deeply indented nucleus with clumped heterochromatin at the rim and a big nucleolus, swollen mitochondria with cristae, rough ER profiles, lysosomes, lipid droplets and microvilli along the edge. (≈ 20 µm)
Glioma cells linked by tumour microtubes — Diffuse gliomas wire themselves into a network: their astrocyte-like tumour cells extend long, thick membrane tubes (tumour microtubes) that reach other tumour cells and connect through gap junctions (connexin 43), sharing calcium waves and repairing damage together — which makes them hard to kill with radiation and surgery. (≈ 200 µm)
Neoplastic mast cell (systemic mastocytosis) — The mast cell of systemic mastocytosis, driven by the KIT D816V mutation: unlike a normal round mast cell it is spindle-shaped, with an oval or bilobed nucleus and fewer, unevenly spread purple (metachromatic) granules, and it gathers in clusters in the bone marrow. (≈ 15–30 µm)

Features of malignancy 11

Normal cell vs cancer cell — A normal epithelial cell beside a cancer cell, both cut open: the cancer cell is bigger and irregular, blebbing, with an enlarged, misshapen nucleus, coarse chromatin and several large nucleoli, and more mitochondria and ribosomes for growth. (cells ≈ 10–30 µm)
Rising nuclear–cytoplasmic ratio — Four cells cut in half, from a normal cell to dysplasia to carcinoma: the nucleus swells until it nearly fills the cell, its outline grows irregular, its chromatin coarser and its nucleoli bigger and more numerous. (cells ≈ 15 µm)
Nuclear pleomorphism (grades 1–3) — A field of tumour nuclei with their tops cut off to show chromatin and nucleoli, as a pathologist grades them: grade 1 small and uniform, grade 2 moderately varied, grade 3 large, misshapen and wildly different in size, with coarse chromatin and big nucleoli. (nuclei ≈ 8–30 µm)
Enlarged nucleolus (ribosome factory) — A cancer cell nucleus cut open around its swollen nucleolus, driven by MYC to make ribosomes for growth: pale fibrillar centres, each wrapped in a dense fibrillar shell, sit in the granular component, and new ribosomal subunits stream out through the nuclear pores. (nucleus ≈ 15 µm, nucleolus ≈ 3–5 µm)
Nuclear envelope blebs and rupture — A cancer cell nucleus squeezed and weakened (lamin loss): blebs balloon out where the lamina meshwork thins, one has ruptured, and chromatin spills through the hole into the cytoplasm, where the DNA sensor cGAS latches on. (nucleus ≈ 15 µm)
Loss of polarity and orderly layering — An epithelium going wrong from left to right: tidy columnar cells in one row, nuclei lined up at the base, give way to crowded, piled-up cells of every size whose nuclei float at any height — the loss of polarity seen in dysplasia and carcinoma. (≈ 150 µm strip)
Cell-in-cell (entosis) — One cancer cell inside another: in entosis a living cell invades its neighbour and ends up in a vacuole, pressing the host nucleus into a crescent; the inner cell is usually killed and digested by lysosomes, feeding the host. (≈ 20–40 µm)
Polyploid giant cancer cell (budding) — A polyploid giant cancer cell, made when a stressed cancer cell copies its genome again and again without dividing (often after chemotherapy or radiation). It survives, then buds off small, aggressive daughter cells (neosis) that can repopulate the tumour. (≈ 50–100 µm)
Thick cancer glycocalyx (mucins and sialic acid) — A patch of cancer cell surface: long, bottle-brush mucins such as MUC1 tower over the membrane, studded with short, truncated sugar chains capped by sialic acid (and the Tn and sialyl-Tn antigens) — a bulky coat that shields the cell and helps it spread. Switch to normal to compare. (patch ≈ 0.5 µm (1 unit ≈ 20 nm))
Cytoskeleton of a normal vs a transformed cell — Two cells on a dish: a normal fibroblast spread flat and anchored by straight actin stress fibres ending in focal adhesions, and a RAS-transformed cell that has rounded up, lost its stress fibres and wears only a disordered cortical actin mesh and blebs. (cells ≈ 30–60 µm)
Exosomes and oncosomes from a cancer cell — Cancer cells shower their surroundings with vesicles: small exosomes (30–150 nm) are made inside multivesicular bodies and released when these fuse with the membrane, while large oncosomes (1–10 µm) bud straight from the surface. They carry oncogenic proteins, RNA and DNA to other cells. (cell ≈ 20 µm; vesicles 0.03–10 µm)

Abnormal mitosis & chromosomes 17

Multipolar mitosis — A cancer cell dividing with three (or more) spindle poles, made by extra centrosomes: the chromosomes line up on a Y-shaped plate and will be torn three ways, leaving daughters with the wrong chromosome numbers — a source of aneuploidy that usually ends in death. (cell ≈ 20–30 µm)
Centrosome clustering (pseudo-bipolar spindle) — How cancer cells survive extra centrosomes: they herd them into two clusters so the spindle stays roughly bipolar. The clustered poles are messy, and merotelic attachments leave lagging chromosomes — low-level chromosomal instability. (cell ≈ 20–30 µm)
Lagging chromosome in anaphase — Anaphase in a cancer cell: the sister chromatids are pulled to opposite poles, but one is left behind in the middle, held by microtubules from both poles (a merotelic attachment). It may end up in the wrong daughter or in a micronucleus. (cell ≈ 20 µm)
Anaphase bridge (chromatin bridge) — A strand of chromatin stretched between the two separating sets of chromosomes — from a dicentric chromosome made by fused telomeres or by unresolved DNA. As the cell pinches, the bridge breaks, setting off breakage–fusion–bridge cycles and chromothripsis. (cell ≈ 20 µm)
Micronucleus and its rupture — A cell after a faulty division: beside the main nucleus sit small micronuclei, each holding a lost chromosome or fragment. Their flimsy envelopes rupture easily; the exposed DNA is shattered (chromothripsis) and sensed by cGAS, triggering inflammation. (cell ≈ 15–25 µm)
Chromothripsis (chromosome shattering) — Chromothripsis in two steps: a chromosome trapped in a micronucleus shatters into tens of pieces (left), which are stitched back together in random order and orientation, with some lost (right) — one catastrophic event that can create many cancer-driving rearrangements at once. (chromosome ≈ 5 µm)
Kinetochore attachments (correct and faulty) — A mitotic chromosome close up, with microtubule bundles from the two poles: correct (amphitelic) attachment, or the errors cancer cells make more often — syntelic, merotelic and monotelic — and an unattached kinetochore broadcasting the "wait" signal of the spindle assembly checkpoint (MAD2). (chromosome ≈ 2–5 µm)
Cytokinesis failure (binucleate cell) — Division that fails at the last step: the contractile ring tightens, stalls (blocked by a chromatin bridge or a faulty ring) and relaxes, leaving one tetraploid cell with two nuclei and extra centrosomes — a launch pad for aneuploidy. (cell ≈ 25 µm)
Breakage–fusion–bridge cycle — Four steps of a breakage–fusion–bridge cycle, left to right: a chromosome loses a telomere; after copying, its sister chromatids fuse at the bare ends; in anaphase the two centromeres pull the fused chromosome into a bridge; it snaps unevenly, leaving one daughter with an inverted duplication and the other with a loss — and a fresh broken end to start again. (chromosome ≈ 5 µm)
Chromosomal translocation (Philadelphia chromosome) — A reciprocal translocation: two chromosomes break and swap ends, and the two derivative chromosomes carry a fused cancer gene at the junction. The default is t(9;22), which makes the small Philadelphia chromosome and BCR–ABL1 in chronic myeloid leukaemia; others drive lymphomas, leukaemias and sarcomas. (chromosomes ≈ 2–8 µm)
Aneuploid cancer karyotype (spectral painting) — A metaphase spread from a cancer cell with every chromosome painted its own colour (spectral karyotyping, SKY/M-FISH): far more than 46 chromosomes, extra and missing copies, and multicoloured chromosomes where pieces of different ones have been joined. (spread ≈ 40 µm)
Extrachromosomal DNA (ecDNA, double minutes) — A tumour cell nucleus full of extrachromosomal DNA: small circles of DNA, each carrying copies of an oncogene such as MYC or EGFR, gathered in hubs that are transcribed intensely. They have no centromeres, so they are shared out unevenly at each division — a fast route to amplification and drug resistance. (nucleus ≈ 15 µm; ecDNA ≈ 1–3 Mb circles)
Homogeneously staining region (gene amplification) — Two copies of the same chromosome: a normal one with its banding pattern, and one stretched by a homogeneously staining region — tens of tandem copies of an oncogene (here lit up as if by FISH) inserted into the chromosome, a stable form of amplification seen in many cancers. (chromosome ≈ 5–10 µm)
Chromosome missegregation (aneuploid daughters) — Two daughter cells just after a faulty division, with their chromosomes colour-coded: in a normal division each gets two of every chromosome; after a missegregation one gets three of a chromosome and the other only one — the start of aneuploidy. (cells ≈ 15 µm each)
Chromosome territories in an aneuploid nucleus — An interphase nucleus cut open with each chromosome's territory painted: in a normal cell every colour comes in pairs; this cancer cell has an extra copy of one chromosome (trisomy), a lost copy of another (monosomy) and a rearranged, two-coloured territory. (nucleus ≈ 15 µm)
Centriole amplification (centriole rosette) — Centrioles close up: normally a mother centriole builds a single daughter at right angles each cell cycle. Too much of the kinase PLK4 (or loss of p53 control) makes it build several at once, in a flower-like rosette — the origin of the extra centrosomes found in many cancers. (≈ 0.5–1 µm)
Atypical mitotic figures (ring, dispersed, asymmetric) — Abnormal mitoses that pathologists count as a sign of high-grade cancer: a ring mitosis around a single (monopolar) spindle pole, a dispersed metaphase whose chromosomes never line up, and an asymmetric anaphase that hands one daughter far more chromosomes than the other. (cell ≈ 20–30 µm)

Oncogenes & tumour suppressors 23

RAS switch (GDP off, GTP on, mutant stuck on) — RAS, the most often mutated oncogene, as a switch on the inner face of the membrane, held by its farnesyl anchor. With GDP it is off; SOS swaps in GTP and RAS turns on and grabs RAF. A GAP such as NF1 normally switches it off again — mutations at G12, G13 or Q61 stop that, so RAS stays stuck on. (RAS ≈ 4 nm)
RTK–RAS–RAF–MEK–ERK cascade — The MAPK growth signal relayed from membrane to nucleus: a growth factor dimerises its receptor tyrosine kinase, whose phosphotyrosines recruit GRB2–SOS; SOS switches on RAS, which activates RAF, which phosphorylates MEK, which phosphorylates ERK — and ERK enters the nucleus to switch on growth genes. BRAF V600E and RAS mutations keep it running. (membrane to nucleus ≈ 1 µm (compressed))
PI3K–AKT–mTOR pathway and PTEN — The growth and survival pathway most often switched on in cancer: PI3K turns the membrane lipid PIP2 into PIP3, which docks AKT; activated AKT frees mTORC1 on the lysosome to drive protein synthesis and growth. PTEN erases PIP3 — lose PTEN, or mutate PIK3CA, and PIP3 piles up. (≈ 50 nm scene)
HER2 overexpression on a cancer cell — A breast cancer cell coated in HER2 receptors: normal cells carry a modest number, but ERBB2 gene amplification can put up to a hundred times more on the surface, where they pair up and signal without any ligand. The setting follows the pathology score (IHC 0 to 3+). (cell ≈ 15 µm)
MYC–MAX on its DNA target (E-box) — The MYC oncoprotein at work: MYC pairs with MAX through a zipper of coiled helices, and their basic helices grip the DNA at an E-box (CACGTG), recruiting the machinery that turns on thousands of growth genes. MYC is amplified or overexpressed in most cancers. The MAX–MAX and MXD–MAX settings show its quieter rivals. (≈ 10 nm)
WNT–β-catenin and the APC destruction complex — Why APC is the gatekeeper of colorectal cancer: without a WNT signal, a destruction complex of APC, Axin, CK1 and GSK3 tags β-catenin for the proteasome. When APC is truncated by mutation the complex falls apart, β-catenin floods the cytoplasm and nucleus, and with TCF switches on MYC and cyclin D1. (≈ 60 nm scene (compressed))
Hedgehog signalling at the primary cilium — Hedgehog signalling happens in the primary cilium, the cell's antenna. PTCH1 keeps Smoothened out; when Sonic hedgehog binds PTCH1, SMO moves into the cilium and GLI transcription factors are activated at the tip. Losing PTCH1 or mutating SMO leaves it on — the cause of basal cell carcinoma and some medulloblastomas. (cilium ≈ 3–5 µm (compressed))
VHL and HIF (oxygen sensing) — The VHL tumour suppressor reads oxygen: with oxygen, HIF-1α carries hydroxyl tags that VHL recognises, so it is ubiquitinated and destroyed by the proteasome. With no oxygen — or when VHL is lost, as in clear cell kidney cancer — HIF-1α survives, pairs with HIF-1β on DNA and switches on VEGF, GLUT1 and other genes. (≈ 20 nm scene)
Oncogenes and tumour suppressors: accelerator and brakes — The classic way to explain cancer genes: an oncogene is an accelerator pedal stuck down (here wedged by a brick), a tumour suppressor is a brake whose cable has been cut. Cancer usually needs both — a stuck accelerator and failed brakes. (teaching model)
Driver point mutation in DNA — A single changed base in the DNA that drives a cancer: one base pair in a codon is swapped, so the protein gets the wrong amino acid at a crucial spot — like KRAS G12D, which locks RAS on, or BRAF V600E. The codon is highlighted, the mutated base glows red. (≈ 6 nm of DNA)
Super-enhancer condensate at an oncogene — Cancer cells drive their key oncogenes, such as MYC, from super-enhancers: clusters of enhancers densely loaded with transcription factors, BRD4 and Mediator that gather into a liquid-like droplet (a condensate) around the gene's promoter and fire RNA polymerase II at it. (≈ 300 nm)
Enhancer hijacking (broken TAD boundary) — The genome is folded into loops (TADs) held by cohesin rings at CTCF sites, which keep each gene with its own enhancers. When a deletion or methylation knocks out a boundary, a strong enhancer from the next loop can reach an oncogene and switch it on — as in IDH-mutant glioma (PDGFRA) and T-ALL. (≈ 500 nm)
OncomiR silencing a tumour-suppressor mRNA — An oncogenic microRNA at work: miR-21, made in excess by many cancers, sits in an Argonaute protein and pairs with the tail (3′ UTR) of a tumour-suppressor messenger RNA such as PTEN or PDCD4, so less of the protective protein is made. (≈ 15 nm)
NOTCH signalling between two cells — NOTCH, a receptor activated by touch: a ligand (Delta or Jagged) on a neighbouring cell pulls on NOTCH, which is cut by γ-secretase to free its intracellular domain (NICD) to enter the nucleus. Activating NOTCH1 mutations, as in T-cell leukaemia, free NICD with no ligand at all. (≈ 40 nm across the gap)
p53 guarding the genome (tetramer on DNA) — p53, the most often mutated gene in cancer, binds DNA as a tetramer of four DNA-binding cores held by a central tetramerisation domain, switching on genes that pause the cell cycle (p21), repair DNA or trigger apoptosis. Most cancer mutations hit the DNA-binding core so it unfolds, lets go and clumps. (≈ 15 nm)
MDM2 tagging p53 for destruction — In an unstressed cell, MDM2 keeps p53 low: it grips p53's transactivation helix in a deep cleft and adds a chain of ubiquitins, sending p53 to the proteasome. Many tumours with normal p53 amplify MDM2 instead; the p14ARF setting shows the tumour suppressor that holds MDM2 back when oncogenes fire. (≈ 20 nm scene)
RB–E2F: the G1 restriction point — The restriction point of the cell cycle in one scene: RB clamps the transcription factor E2F on its DNA site; cyclin D–CDK4/6 adds phosphates to RB until it lets go, and E2F switches on the S-phase genes. p16 normally restrains CDK4/6 — lost p16, extra cyclin D or lost RB all push cells into division. (≈ 20 nm)
Cell cycle and its checkpoints — The cell cycle as a wheel — G1, S (DNA copying), G2 and M (mitosis), with G0 rest off to the side — and the three checkpoint gates cancer cells break: the G1/S restriction point (RB, p53–p21), the G2/M DNA damage checkpoint (ATM/ATR, CHK1/2) and the spindle assembly checkpoint in mitosis. (teaching model)
Knudson two-hit hypothesis (loss of heterozygosity) — Why one faulty copy of a tumour suppressor is not enough: three pairs of the same chromosome — both copies working; one inherited or acquired "first hit" (as in hereditary retinoblastoma); and a "second hit" that knocks out the remaining good copy, often by losing that whole stretch (loss of heterozygosity). (chromosomes ≈ 5 µm)
What p53 decides: arrest, repair, senescence or death — Activated p53 (centre) chooses the cell's fate depending on how bad the damage is: pause the cell cycle through p21, switch on DNA repair, lock the cell into permanent senescence, or trigger apoptosis through PUMA, NOXA and BAX — four outcomes, each a barrier to cancer that tumours must break. (teaching model)
XPO1 exporting tumour suppressors through a nuclear pore — A nuclear pore close up: many cancers overproduce the export receptor XPO1 (exportin 1, CRM1), which carries tumour suppressors such as p53, IκB and FOXO out of the nucleus where they cannot act. The pore's eight-fold scaffold, central channel, cytoplasmic filaments and nuclear basket are shown. (pore ≈ 120 nm)
Spliceosome mutation (SF3B1) and mis-splicing — Mutations in the splicing factor SF3B1 (common in myelodysplastic syndrome, CLL and uveal melanoma) make the spliceosome choose the wrong branch point and a cryptic 3′ splice site a little upstream, so a few extra bases stay in the mRNA and many messages are destroyed. The intron is drawn as a lariat about to be cut out. (≈ 40 nm)
SWI/SNF chromatin remodeller on a nucleosome — The SWI/SNF (BAF) complex uses ATP to slide and evict nucleosomes, opening DNA for genes that keep cells differentiated. Its subunits — ARID1A, SMARCA4, SMARCB1, PBRM1 — are mutated in about one cancer in five (ovarian clear cell, rhabdoid tumours, kidney and lung cancers). (≈ 30 nm)

DNA damage & repair 13

Double-strand break on chromatin (γH2AX) — A DNA double-strand break in chromatin and the alarm it raises: the MRN complex grabs and bridges the broken ends, ATM is activated and phosphorylates histone H2AX (γH2AX) for a megabase around the break, and 53BP1 and BRCA1 gather on the marked nucleosomes — the "focus" seen under the microscope. (≈ 100 nm of chromatin)
DNA damage foci in a nucleus — A nucleus after X-rays, cut open: every double-strand break becomes a bright focus of γH2AX (green) and 53BP1 (red) about a micrometre wide — roughly 30–40 per gray of radiation. Counting them is how labs measure DNA damage and repair. (nucleus ≈ 12 µm)
Non-homologous end joining (NHEJ) — The fast, error-prone way cells glue broken DNA back: the Ku70/80 ring slides onto each broken end, recruits the big kinase DNA-PKcs, and the XRCC4–ligase IV complex (with XLF filaments) holds the ends together and seals them — often losing or adding a few bases. (≈ 30 nm)
Homologous recombination (RAD51 filament) — Error-free repair of a broken chromosome using its sister as a template: the broken end is trimmed back to a single-stranded tail, BRCA2 loads RAD51 onto it to form a helical filament, and the filament searches for and invades the matching sister DNA (a D-loop) to copy the lost sequence. BRCA1 and BRCA2 mutations break this pathway. (≈ 50 nm)
Mismatch repair (MutSα clamp) — Proofreading after copying: the MutSα clamp (MSH2–MSH6) slides along new DNA, stops at a mismatched pair (here G·T), and MutLα (MLH1–PMS2) marks the new strand for removal and resynthesis. Losing MLH1, MSH2, MSH6 or PMS2 (Lynch syndrome) makes tumours with microsatellite instability. (≈ 20 nm)
Base excision repair (base flipped out) — Repair of a single damaged base: a DNA glycosylase scans the helix, flips the damaged base (an oxidised 8-oxoguanine, a uracil or a missing base) right out of the stack into its pocket and cuts it off; APE1, polymerase β and ligase then fill and seal the gap. (≈ 10 nm)
Nucleotide excision repair (UV dimer) — Repair of bulky, helix-bending damage such as the thymine dimers made by sunlight: XPC spots the distortion, TFIIH unwinds a bubble of about 25 bases, and the endonucleases XPF–ERCC1 and XPG cut out the damaged stretch for polymerase to refill. People with xeroderma pigmentosum lack it and get many skin cancers. (≈ 20 nm)
Stalled replication fork (replication stress) — Oncogenes such as RAS and MYC push cells to copy DNA too fast, and forks stall at damaged bases or collisions — replication stress. Here the CMG helicase and polymerases are stuck at a lesion; the setting shows the fork reversed into a four-way "chicken foot", a protective state that BRCA proteins guard. (≈ 40 nm)
PARP1 at a single-strand break — PARP1, the first responder to nicks in DNA: it clamps onto a single-strand break and, switched on, builds long branched chains of poly(ADP-ribose) on itself and nearby histones, calling in XRCC1, ligase III and polymerase β to mend the nick. Cancers lacking BRCA depend on it — the basis of PARP-inhibitor therapy. (≈ 20 nm)
Microsatellite slippage (MSI) — How microsatellite instability arises: copying a run of repeats (here A·T pairs), the new strand slips and loops out a repeat unit. Mismatch repair normally fixes the loop; without it the repeat grows or shrinks at every division — the MSI-high pattern of Lynch syndrome cancers, which respond well to immunotherapy. (≈ 15 nm)
R-loop (RNA–DNA hybrid) — An R-loop: newly made RNA anneals back to its DNA template behind RNA polymerase, leaving the other DNA strand looped out and exposed. Oncogene-driven over-transcription makes many of them; they block replication forks and break DNA, a source of genome instability. Enzymes such as RNase H1 and senataxin clear them. (≈ 20 nm)
Interstrand crosslink and the Fanconi anaemia pathway — An interstrand crosslink welds the two strands of DNA together (made by cisplatin, mitomycin C or aldehydes) so they cannot be pulled apart. Two replication forks converge on it, the FANCI–FANCD2 clamp is ubiquitinated onto the DNA and nucleases unhook the link. Faults in this Fanconi anaemia/BRCA pathway cause cancer predisposition. (≈ 40 nm)
APOBEC mutagenesis on single-stranded DNA (kataegis) — One of the commonest sources of mutations in cancer: APOBEC3A/3B enzymes, meant to fight viruses, deaminate cytosines on DNA left single-stranded at the lagging side of replication forks, leaving clusters of C→T and C→G changes in a TCW context — showers of mutations called kataegis. (≈ 30 nm)

Telomeres & immortality 6

Telomere T-loop and shelterin — The protective cap at a chromosome end: thousands of TTAGGG repeats fold back into a T-loop, the single-stranded 3′ overhang tucking into the double helix (a D-loop), all coated by the six-protein shelterin complex — TRF1 and TRF2 on the duplex, POT1–TPP1 on the overhang, TIN2 and RAP1 linking them — so the end is not mistaken for a break. (≈ 100 nm (compressed))
Telomerase extending a telomere — Telomerase, switched back on in about 90% of cancers: the TERT protein uses a short template inside its own RNA (TERC) to add TTAGGG repeats onto the chromosome's 3′ overhang, undoing the shortening that comes with every division. TERT promoter mutations are among the commonest in cancer. (≈ 25 nm)
Telomere shortening and the cancer escape — The same chromosome over successive generations of cells: its telomere caps (yellow) shrink with each round of division until, critically short, they trigger senescence or crisis. The cancer setting shows telomerase keeping the caps long — replicative immortality. (chromosomes ≈ 5 µm)
Telomere crisis (end-to-end fusions) — When cells divide past their limit without telomerase, uncapped chromosome ends are "repaired" by gluing them together: chains of chromosomes fused end to end, with DNA damage marks at every junction. Most cells die; the few that switch on telomerase emerge with scrambled genomes — a key step in many cancers. (chromosomes ≈ 5 µm)
ALT telomeres in PML bodies — About one cancer in ten keeps its telomeres long without telomerase, by Alternative Lengthening of Telomeres: telomeres gather in enlarged PML nuclear bodies (ALT-associated PML bodies) and copy one another by recombination. ALT cancers, often sarcomas and gliomas, have usually lost ATRX or DAXX. (nucleus ≈ 12 µm)
G-quadruplex at a telomere overhang — The guanine-rich telomere overhang can fold on itself: four guanines pair into a flat square (a G-tetrad), and three tetrads stack with potassium ions between them into a G-quadruplex. These knots block telomerase and stall replication, and drugs that stabilise them are studied against cancer. (≈ 3 nm)

Hallmarks of cancer 8

Hallmarks of cancer (wheel) — The hallmarks of cancer as a 3D wheel, after Hanahan and Weinberg: the capabilities cells acquire on the way to cancer, each on its own coloured tile with a symbol, around a tumour cell. Choose the six of 2000, the ten of 2011 or the fourteen of 2022. (teaching model)
Autocrine growth loop — Sustaining its own growth signal: the cancer cell makes a growth factor (such as TGF-α, PDGF or IGF2), secretes it from vesicles and binds it with receptors on its own surface — a loop that needs no signal from outside. (cell ≈ 15 µm)
Loss of contact inhibition (transformed focus) — Normal cells on a dish stop dividing once they touch and form a flat single layer; transformed cells ignore the signal and pile up into a dense, many-layered heap — a focus, the classic sign of oncogenic transformation. (≈ 1 mm of dish)
Bacteria inside a tumour cell (tumour microbiome) — Polymorphic microbiomes, a newer hallmark: tumours carry their own bacteria. Here spindle-shaped Fusobacterium nucleatum, common in colorectal cancer, clings to the cell through its Fap2 adhesin and lives inside vacuoles, where it fuels growth, immune escape and chemoresistance. (cell ≈ 20 µm)
Promoter hypermethylation silencing a tumour suppressor — Silencing without mutation: in many cancers the CpG island at a tumour suppressor's promoter (such as MLH1, CDKN2A or BRCA1) is coated in methyl groups by DNMTs, read by methyl-binding proteins that pack the nucleosomes tight, and the gene is switched off. The open setting shows the same gene active. (≈ 60 nm of chromatin)
Cell competition: a mutant cell extruded — An epithelium polices itself: when a single cell gains an oncogene such as RAS, its normal neighbours often squeeze it out of the sheet (epithelial defence against cancer), tightening a ring of actin around it. The "mutant wins" setting shows the reverse: super-competitor cells (high MYC) expanding while normal neighbours are pushed out and die. (≈ 80 µm of epithelium)
Differentiation block in acute myeloid leukaemia — Unlocking phenotypic plasticity, as in acute myeloid leukaemia: normally a myeloblast matures step by step through promyelocyte, myelocyte, metamyelocyte and band cell to a segmented neutrophil (top row); in AML, mutations jam the process after the blast stage, so blasts pile up and few mature cells are made (bottom row). (cells ≈ 10–20 µm)
Making a human cancer cell (TERT, SV40, RAS) — The classic experiment showing how few changes it takes: a normal human fibroblast becomes immortal with TERT, escapes p53 and RB control with SV40 large T and small t antigens, and with an activated RAS gene becomes a fully transformed cancer cell that piles up and forms tumours. Each added gene arrives as a ring of DNA. (cells ≈ 20–100 µm)

Clonal evolution 6

From one cell to a tumour (doublings) — How fast numbers grow: one transformed cell, then 8 after three doublings, about a thousand after ten (a microscopic cluster), a million after twenty (a 1 mm nodule) and a billion after thirty — a 1 cm tumour, about the smallest a scan can find. Each step is drawn at its own scale. (1 cell to ≈ 1 cm)
Fish plot of clonal evolution — A fish plot: time runs left to right and the height of each coloured band is the share of the tumour belonging to one clone. Subclones arise inside their parents, some sweep to dominance, and treatment (the narrowing) can wipe out most clones while a resistant one survives and returns at relapse. (diagram)
Tumour phylogenetic tree — A tumour's family tree drawn from its mutations: the trunk carries the truncal mutations every cancer cell shares, branches carry mutations of later subclones, and each tip is a living clone. Linear, branching or punctuated (big-bang) evolution give very different trees. (diagram)
Field cancerisation (mutant clones in normal tissue) — Normal-looking tissue is already a patchwork: in the oesophagus, skin or mouth of healthy adults, clones carrying mutations such as NOTCH1 or TP53 spread over large patches. A cancer usually grows out of one of them, and the rest of the "field" stays at risk of a second tumour. (≈ 5 mm of mucosa)
Therapy bottleneck and the resistant clone — Darwinian selection by treatment, in three tumours side by side: a mixed tumour with a rare resistant clone (red) before treatment; after treatment only a few cells, mostly resistant, are left; at relapse the resistant clone has taken over. (tumours ≈ 1 cm)
Mutant stem cell taking over a crypt — How a colorectal cancer starts its takeover, in three colonic crypts cut lengthwise: a normal crypt; a mutant stem cell at the base (such as one with APC loss) sending up a ribbon of mutant cells; a crypt fully converted (monoclonal) that splits in two (crypt fission) to spread the clone. (crypts ≈ 0.1 × 0.4 mm)

Cancer metabolism 10

Warburg effect (aerobic glycolysis) — Why tumours light up on PET scans: a cancer cell crowds its surface with GLUT1 glucose transporters, burns glucose through glycolysis even with oxygen present, and pours out lactate through MCT4, using fewer, smaller mitochondria. The normal setting shows a cell that sends most of its pyruvate into mitochondria instead. (cell ≈ 15 µm)
Glutamine addiction (glutaminolysis) — Many cancer cells, especially MYC-driven ones, depend on glutamine: it is imported by SLC1A5 (ASCT2), turned into glutamate by glutaminase (GLS) and then into α-ketoglutarate, which tops up the TCA cycle inside the mitochondrion to make building blocks for new cells. (mitochondrion ≈ 2 µm)
Lactate shuttle between tumour cells — Metabolic symbiosis in a tumour: a cell far from the blood vessel, starved of oxygen, runs on glycolysis and exports lactate through MCT4; a well-oxygenated cell beside the vessel takes the lactate up through MCT1 and burns it in its mitochondria, sparing glucose for its hypoxic neighbour. (≈ 60 µm)
Lipid droplet-laden cancer cell — A cancer cell storing fat: lipid droplets of every size crowd its cytoplasm, filled from fatty acid synthase (FASN) and fat taken up from its surroundings, and wrapped in ER. They fuel growth and membranes and protect against stress — common in prostate, kidney, breast and ovarian cancers that live next to fat. (cell ≈ 20 µm)
Macropinocytosis (RAS-driven nutrient scavenging) — Starved pancreatic and other KRAS-mutant cancer cells drink their surroundings: big membrane ruffles fold over and close around gulps of fluid full of protein such as albumin, forming macropinosomes that fuse with lysosomes to digest the protein into amino acids. (cell ≈ 20 µm)
Mitochondrial network: fused vs fragmented — Cancer cells reshape their mitochondria: a flat cell cut open shows either a long, branched, fused network (more oxidative metabolism) or, as in many RAS- and MYC-driven tumours, a fragmented swarm of small mitochondria made by DRP1-driven fission, which helps them divide and migrate. (cell ≈ 30 µm)
Tunnelling nanotube between cancer cells — Two cancer cells joined by a tunnelling nanotube, a thin membrane bridge riding on actin that hovers above the dish. Mitochondria, vesicles and even microRNAs travel along it — cancer cells use them to share organelles and spread drug resistance. (≈ 50 µm)
Autophagy in a starving cancer cell — Self-eating to survive: a stressed cancer cell wraps worn-out mitochondria and other cargo in a cup-shaped phagophore, which closes into a double-membraned autophagosome and fuses with lysosomes to recycle the contents. Autophagy restrains early tumours but keeps established ones — like RAS-driven pancreatic cancer — alive. (cell ≈ 20 µm)
Reversed pH gradient of a cancer cell — Cancer cells keep their insides slightly alkaline and the space around them acidic — the reverse of normal cells. Proton pumps and exchangers (NHE1, V-ATPase), lactate–proton export (MCT4) and carbonic anhydrase IX throw acid out, and the acid halo helps the cell invade and blunts immune cells. (cell ≈ 20 µm)
Mutant IDH and the oncometabolite 2-HG — Mutant isocitrate dehydrogenase (IDH1 R132H, IDH2) gains a new job: it turns α-ketoglutarate into 2-hydroxyglutarate (2-HG), which floods the cell and jams α-KG-dependent enzymes such as the TET DNA demethylases, so methylation builds up and cells stop maturing — in gliomas, AML and cholangiocarcinoma. (≈ 40 nm scene (compressed))

Cell death & its escape 10

Mitochondrial apoptosis: BAX pores and BCL-2 — The point of no return of apoptosis: BAX and BAK gather into pores in the outer mitochondrial membrane and cytochrome c pours out to activate caspases. Cancer cells escape by making too much BCL-2, which grabs BAX and BAK before they can open pores — the target of venetoclax. (mitochondrion ≈ 2 µm (pores ≈ 10–100 nm))
Apoptosome (the wheel of death) — The apoptosome: seven APAF1 proteins, each holding a molecule of released cytochrome c at the tip of its spoke, assemble into a wheel whose hub gathers and switches on caspase-9 — which then activates the executioner caspases 3 and 7. XIAP, raised in many cancers, can block it. (≈ 30 nm across)
Death receptor signalling (FAS and the DISC) — The extrinsic route to apoptosis: a trimer of FAS ligand (or TRAIL) on a killer cell clusters FAS (or DR4/5) on the target; inside, the receptors' death domains pull in FADD and procaspase-8 to build the death-inducing signalling complex (DISC), activating caspase-8. Cancer cells resist by making c-FLIP, a dud caspase-8. (≈ 30 nm)
Necroptosis (RIPK3 and MLKL pores) — A back-up, inflammatory way to die when caspases are blocked: RIPK1 and RIPK3 stack into an amyloid-like necrosome fibre, RIPK3 phosphorylates MLKL, and MLKL clusters drive into the plasma membrane and break it, spilling the cell's contents. Many tumours silence RIPK3 to avoid it. (≈ 40 nm)
Pyroptosis (gasdermin pores) — Fiery, inflammatory death: caspase-1 (from an inflammasome) or caspase-3 cuts gasdermin D or E, and the freed N-terminal pieces assemble into huge ring pores in the membrane, letting IL-1β and IL-18 out and water in until the cell swells and bursts. Chemotherapy can trigger it through gasdermin E. (≈ 40 nm)
Ferroptosis (lipid peroxidation) — Death by rusting membranes: iron-driven oxidation turns the polyunsaturated tails of membrane lipids into lipid peroxides that kink and spread until the membrane fails. The enzyme GPX4, using glutathione, repairs them — cancer cells that have switched to a mesenchymal, therapy-resistant state are especially dependent on it. (≈ 10 nm of membrane)
Anoikis (death on detachment) — Normal epithelial cells die when they lose their grip on the matrix — anoikis, "homelessness". An anchored cell (left) holds the matrix with integrins; a detached one rounds up, blebs and dies. Metastatic cancer cells learn to survive detachment, using signals such as TrkB, FAK and SRC. (≈ 50 µm)
Mitotic catastrophe — What happens when a cancer cell with damaged DNA or a poisoned spindle tries to divide anyway: chromosomes fail to separate, the cell ends up huge with many micronuclei and fragments of chromatin, and soon dies — one of the main ways radiotherapy and drugs such as taxanes kill tumour cells. (cell ≈ 30–50 µm)
Stages of apoptosis — Apoptosis as a sequence, left to right: a healthy cell; the cell shrinks and its chromatin condenses against the envelope (pyknosis); the membrane blebs and the nucleus breaks into pieces (karyorrhexis); the cell falls apart into membrane-wrapped apoptotic bodies; and a macrophage engulfs them without any inflammation. (cells ≈ 15 µm)
Immunogenic cell death — Some treatments (anthracyclines, oxaliplatin, radiation) kill cancer cells in a way that alerts the immune system: the dying cell puts calreticulin on its surface ("eat me"), releases ATP ("find me") and HMGB1, and a dendritic cell comes to take up its antigens and prime T cells. (cell ≈ 20 µm)

Senescence 3

Senescence-associated secretory phenotype (SASP) — A senescent cell — big, flat and no longer dividing — is far from silent: it secretes a cocktail of inflammatory cytokines (IL-6, IL-8), growth factors and matrix-cutting enzymes, the SASP. It can call immune cells to clear damaged cells, but over time it can also push neighbouring cells towards cancer. (≈ 100 µm)
Oncogene-induced senescence (heterochromatin foci) — A cell stopped in its tracks by an overactive oncogene: flat and enlarged, with a large nucleus cut open to show senescence-associated heterochromatin foci (SAHF) — each a condensed chromosome that silences growth genes — and patchy loss of the lamin B1 meshwork. Oncogene-induced senescence is a barrier that early tumours must break. (cell ≈ 80 µm)
SA-β-gal stained senescent cells — A culture stained for senescence-associated β-galactosidase at pH 6: senescent cells — huge, flat, with blue-green granules round the nucleus — sit among small, spindle-shaped proliferating cells that stay unstained. Used after chemotherapy, radiation or oncogene activation to count senescent cells. (≈ 400 µm field)

Cancer stem cells 7

Cancer stem cell hierarchy — Two views of who regrows a tumour. In the hierarchical model a few cancer stem cells at the top self-renew and feed progenitors that make the bulk of non-dividing, differentiated tumour cells. In the stochastic (clonal evolution) model any tumour cell can take on stem-like powers, and the hierarchy is fluid. (teaching model)
Asymmetric division of a cancer stem cell — A cancer stem cell dividing asymmetrically: fate determinants such as Numb are sorted to one side of the cell along the spindle, so one daughter stays a stem cell while the other starts down the path to becoming a differentiated tumour cell. (cell ≈ 15–25 µm)
ABC transporters pumping out chemotherapy — One reason cancer stem cells survive chemotherapy: their membranes are packed with ABC transporters such as ABCB1 (P-glycoprotein, MDR1) and ABCG2 (BCRP), which use ATP to grab drug molecules from the membrane and throw them back out of the cell — the "side population" seen by flow cytometry. (≈ 20 nm of membrane)
Cancer stem cell surface markers — The markers used to sort cancer stem cells: CD44 (a hyaluronan receptor with a long stalk), CD133 (prominin-1, which snakes five times through the membrane and gathers on protrusions) and EpCAM, plus high ALDH1 enzyme inside — combinations differ by tumour type, such as CD44⁺CD24⁻ in breast cancer. (cell ≈ 15 µm)
Cancer stem cells surviving chemotherapy — Why tumours come back: chemotherapy kills the fast-dividing bulk of a tumour (here shrunken and grey), but quiescent, drug-pumping cancer stem cells (red) survive and later regrow the tumour. Switch between before, after treatment and relapse. (tumour ≈ 1 mm)
Holoclone, meroclone and paraclone colonies — Single cancer cells grown into colonies reveal who is stem-like: a holoclone is large, round and tightly packed with small cells (stem-like), a paraclone is small and loose with big flat cells that soon stop dividing, and a meroclone is in between. (≈ 5 mm of dish)
Lineage tracing of cancer stem cells (Confetti) — The experiment that proved cancer stem cells exist in intestinal tumours: Lgr5⁺ tumour cells were labelled at random in one of four colours (the Confetti reporter); weeks later each colour runs in a ribbon from the tumour base to its surface — a whole clone made by one stem cell. (adenoma ≈ 1–2 mm)

Carcinogens & oncogenic microbes 7

HPV E6 and E7 disabling p53 and RB — How high-risk human papillomavirus (HPV16, HPV18) causes cervical, anal and throat cancers: its E6 protein recruits the ubiquitin ligase E6AP to destroy p53, and its E7 protein pulls RB off E2F, so infected cells keep dividing without the brakes. The virus particle sits behind. (≈ 50 nm scene)
Viral DNA integrated into a host chromosome — Some cancer viruses leave a permanent mark: a stretch of viral DNA spliced into the host genome. HPV integration breaks its own E2 gene so E6 and E7 run unchecked; hepatitis B DNA lands near TERT or other cancer genes in liver cancer; retroviruses can switch on a neighbouring oncogene (insertional mutagenesis). (≈ 40 nm of DNA)
Epstein–Barr virus in a B cell — Epstein–Barr virus, carried by most adults, hides in B cells as circular episomes in the nucleus. Its LMP1 protein clusters in the cell membrane and mimics a constantly firing CD40 receptor, keeping the cell alive and dividing — a driver of Burkitt and Hodgkin lymphoma and nasopharyngeal carcinoma. (cell ≈ 10 µm)
Helicobacter pylori injecting CagA — Helicobacter pylori, the main cause of stomach cancer: the spiral bacterium clings to gastric cells and, through its type IV secretion "syringe", injects the oncoprotein CagA, which scrambles cell signalling and polarity — the injected cell stretches out into the "hummingbird" shape. (≈ 30 µm)
Koilocyte (HPV-infected squamous cell) — The tell-tale cell of HPV infection in a cervical smear or skin wart: a flat superficial squamous cell whose enlarged, dark, wrinkled ("raisin-like") nucleus sits in a big clear halo of cytoplasm, often with two nuclei. It marks a low-grade squamous intraepithelial lesion that can progress. (≈ 40–60 µm)
Hepatitis B virus in a hepatocyte — Hepatitis B, a leading cause of liver cancer worldwide, in an infected hepatocyte cut open: covalently closed circular DNA (cccDNA) minichromosomes in the nucleus keep the infection going; surface antigen piles up in the ER (the "ground-glass" look); 42 nm Dane particles and empty surface-antigen spheres and filaments leave the cell. (cell ≈ 25 µm)
UV light and the melanin cap — Sunlight's ultraviolet rays reaching basal keratinocytes of the skin: melanocytes hand melanin to their neighbours, which pile it over the nucleus like a parasol (a supranuclear melanin cap). Rays that slip past it — or reach cells with little melanin — weld neighbouring pyrimidines into dimers, the signature mutations of melanoma and other skin cancers. (≈ 60 µm of epidermis)

Tumour stroma & fibroblasts 9

Myofibroblastic CAF (myCAF) — A cancer-associated fibroblast of the contractile kind: spread flat on the collagen it has pulled straight, with α-smooth-muscle actin stress fibres anchored in focal adhesions at its tips. myCAFs sit next to tumour cells and stiffen the stroma. (≈ 50–80 µm long)
Inflammatory CAF (iCAF) — A secretory cancer-associated fibroblast found away from the tumour cells: star-shaped, without stress fibres, releasing a cloud of IL-6, LIF and CXCL12 that feeds tumour growth and keeps T cells out. (≈ 30–40 µm across)
Antigen-presenting CAF (apCAF) — A cancer-associated fibroblast that carries MHC class II on its surface and shows antigen to a CD4 T cell — but without co-stimulation, so it can push the T cell towards anergy or a regulatory fate. Seen in pancreatic and breast cancer. (≈ 30 µm)
Where CAFs come from — Cancer-associated fibroblasts arise from many cells: resident fibroblasts, pericytes leaving vessels, bone-marrow mesenchymal stromal cells, adipocytes, endothelial cells (EndMT), epithelial cells (EMT) and quiescent stellate cells of the liver and pancreas. All are pulled towards the activated CAF in the middle by TGF-β, PDGF and other tumour signals. (schematic, cells ≈ 20–60 µm)
Desmoplastic tumour stroma — The dense, fibrous stroma of pancreatic and many breast cancers: small infiltrating tumour glands lost in thick bundles of collagen laid down by CAFs, with few vessels. The desmoplastic reaction makes the tumour hard (scirrhous), raises pressure and blocks drugs and T cells. (≈ 150 µm block)
Cancer-associated adipocyte — At the invasive edge of breast, ovarian and colon cancers, fat cells hand their lipid over to tumour cells: the adipocyte shrinks (delipidation), releases fatty acids and IL-6, and can turn into a fibroblast-like cell. The tumour cell stores the lipid in droplets and burns it for energy. (≈ 100 µm)
Latent TGF-β activation by integrin pulling — TGF-β is stored in the matrix in a latent "straitjacket": its prodomain (LAP) wraps the growth factor and LTBP tethers it to fibrillin microfibrils. Integrin αvβ6 or αvβ8 on a cell binds the RGD motif in LAP and, pulling against the anchored matrix, opens the cage so mature TGF-β can reach its receptors — a key switch for CAF activation and immune exclusion. (≈ 40 nm)
Nerves growing into a tumour — Tumours recruit nerves (axonogenesis and neurogenesis): fibres sprout from a nearby nerve into the tumour, their varicosities releasing noradrenaline, acetylcholine or neuropeptides that speed tumour growth — part of the emerging field of cancer neuroscience. Tumour cells also invade along nerves (perineural invasion). (≈ 150 µm)
Fibrin and platelets in tumour stroma — Tumour cells display tissue factor, which sets off clotting in the leaky stroma around them: a mesh of fibrin forms and platelets stick to it. The fibrin acts as scaffold for new vessels and immune cells, and with platelets coats tumour cells — part of why cancer patients clot easily (Trousseau syndrome). (≈ 50 µm)

Immune cells in tumours 17

Macrophage polarisation (M1 vs M2) — Two faces of the tumour-associated macrophage. M1-like (left): round, ruffled and spiky, releasing TNF and IL-12 that help kill tumour cells. M2-like (right): elongated with long pseudopods and CD206, releasing IL-10, TGF-β and VEGF that suppress immunity and feed vessels. Real TAMs sit on a spectrum between them. (≈ 20–40 µm each)
Perivascular TAMs on a tumour vessel — TIE2-expressing macrophages wrap their processes around a tumour capillary and release VEGF-A, driving new vessel growth and opening a doorway (the "TMEM" portal) for tumour cells to enter the blood. (≈ 60 µm of vessel)
Exhausted T cell — A CD8 T cell worn down by chronic antigen in the tumour: its surface carries clusters of inhibitory receptors (PD-1, TIM-3, LAG-3, TIGIT), its granules are few and its mitochondria small and fragmented. Progenitor-exhausted cells (TCF1⁺) still respond to PD-1 blockade; terminally exhausted cells do not. (≈ 7 µm)
Dendritic cell cross-priming tumour antigen — A conventional type 1 dendritic cell (cDC1, XCR1⁺ CLEC9A⁺) has swallowed fragments of a dying tumour cell and shows the tumour peptides on MHC class I to CD8 T cells that dock on its veils — the step that starts most anti-tumour T-cell responses. (≈ 40 µm across the veils)
Macrophage eating a tumour cell — A macrophage wraps a tumour cell in a phagocytic cup. Tumour cells normally escape with the "don't eat me" signal CD47; blocking CD47, coating the cell with a therapeutic antibody (antibody-dependent cellular phagocytosis, ADCP), or giving the macrophage a chimeric antigen receptor (CAR-M) lets it engulf them. (≈ 40 µm)
MDSCs suppressing a T cell — Myeloid-derived suppressor cells crowd round a T cell and shut it down: polymorphonuclear MDSCs release reactive oxygen species and peroxynitrite that nitrate the T-cell receptor; monocytic MDSCs make nitric oxide and arginase, starving the T cell of arginine. (≈ 30 µm)
Regulatory T cell at work in a tumour — A FOXP3⁺ regulatory T cell (centre) holds back anti-tumour immunity in several ways at once: its CD25 (IL-2 receptor α) soaks up IL-2 made by an effector T cell (left); its CTLA-4 strips CD80/CD86 from a dendritic cell (right); and it releases TGF-β and IL-10. (≈ 30 µm)
NK cell killing a tumour cell — A natural killer cell, cut open, has docked on a tumour cell and moved its lytic granules to the contact. NK cells attack when the target has lost MHC class I ("missing self", invisible to T cells) or shows stress ligands such as MICA/B and ULBPs that activate NKG2D. (≈ 25 µm)
Neutrophil extracellular traps in a tumour — A tumour-associated neutrophil has burst and thrown out a web of decondensed chromatin studded with histones and granule enzymes (a NET). NETs wrap tumour cells, shield them from T and NK cells, awaken dormant cancer cells and help them spread. (≈ 50 µm)
Mast cell degranulating in a tumour — A mast cell packed with granules releases them next to a tumour vessel: histamine, tryptase, heparin, VEGF and FGF2 loosen the vessel wall, recruit other cells and drive angiogenesis — mast cells cluster at the edges of many tumours. (≈ 30 µm)
Glioma-associated microglia — In the healthy brain microglia are ramified, sampling their surroundings with fine branches. Next to glioma cells they retract their branches and become amoeboid, tumour-supporting cells — together with blood-derived macrophages they can make up a third of a glioblastoma. (≈ 60 µm)
Tumour-associated neutrophils (N1 vs N2) — Neutrophils in tumours come in two broad states. N1-like (left): mature, with a hypersegmented nucleus, they release reactive oxygen species and kill tumour cells. N2-like (right), shaped by TGF-β: immature-looking with a band or ring nucleus, they release MMP-9, VEGF and arginase that feed vessels and suppress T cells. Both are cut open to show the nucleus. (≈ 12 µm each)
Plasma cell making anti-tumour antibodies — A plasma cell in a tumour or its tertiary lymphoid structure, cut open: an eccentric nucleus with "clock-face" chromatin, a pale Golgi zone beside it and the rest packed with rough endoplasmic reticulum turning out thousands of antibodies a second. Antibodies against tumour antigens coat nearby tumour cells and go with better survival. (≈ 15 µm)
Monocytes becoming tumour macrophages — Most tumour-associated macrophages start as blood monocytes. Drawn by CCL2 and CSF-1 from the tumour, a monocyte rolls in a vessel (left), squeezes through the wall, and in the tissue spreads out and matures into a macrophage (right) — CCR2 and CSF1R inhibitors try to cut this supply. (≈ 70 µm)
Bacteria living inside a tumour — Many tumours carry their own microbes. In colorectal cancer, Fusobacterium nucleatum — long spindle-shaped rods — binds tumour cells through its Fap2 and FadA adhesins, lives inside them and inside macrophages, speeds tumour growth, blocks NK cells via TIGIT and travels with metastases. (≈ 40 µm)
Killer T cells attacking tumour cells — A close-up of a tumour being attacked, as in a scanning electron micrograph. Wrinkled, glossy tumour cells hold on to the wet tissue with a skirt of fine retraction fibres; cytotoxic T cells, furred with hundreds of curled microvilli, press onto them. They first make contact, then form a synapse and release cytotoxic granules into it, and finally the tumour cell blebs and dies. Small vesicles drift between the cells. (≈ 60 µm)
Macrophage engulfing a cancer cell — A close-up of phagocytosis, as in a scanning electron micrograph. A macrophage spread on the wet tissue reaches out with ruffled lamellipodia and pseudopods, wraps a wrinkled tumour cell in a phagocytic cup, closes over it, and finally holds it inside a phagosome where lysosomes fuse to digest it. Choose the stage. (≈ 50 µm)

Tumour blood & lymph vessels 12

Tip and stalk cells (sprouting angiogenesis) — A new capillary sprouting from a vessel towards a hypoxic tumour. The tip cell at the front senses VEGF-A with dozens of filopodia; stalk cells behind it divide and hollow out a lumen; pericytes follow late. Dll4–Notch signalling keeps only one tip cell per sprout. (≈ 80 µm)
Leaky tumour vessel — A tumour capillary cut open: the endothelium has wide gaps and fenestrae, pericytes hang loosely off the wall, the basement membrane is patchy, and plasma and red cells leak into the tumour — raising interstitial pressure and letting large drugs and nanoparticles in (the EPR effect). Switch to a normal capillary to compare. (≈ 60 µm)
Tumour vascular network — Normal tissue is fed by an orderly tree: arteriole, evenly spaced parallel capillaries, venule. A tumour network is chaotic — tortuous, dilated, unevenly spaced vessels with blind ends, loops and shunts, leaving hypoxic gaps. Anti-angiogenic therapy can transiently "normalise" it: pruned, straighter and more even. (≈ 0.5 mm block)
Vessel co-option — Instead of growing new vessels, some tumours hijack existing ones: cancer cells crawl along the outside of a normal vessel, in single file or as a sleeve, using it as a road and a supply line. Common in brain, lung and liver metastases, and a way to escape anti-angiogenic drugs. (≈ 80 µm)
Vasculogenic mimicry — Aggressive tumour cells (melanoma, glioblastoma, some breast cancers) build blood channels themselves, without endothelium: a looping network of PAS-positive matrix channels lined by tumour cells carries red cells and joins real vessels. Seen from above with the top layer of cells removed. (≈ 120 µm)
Intussusceptive angiogenesis — A vessel that splits from the inside: opposite walls bulge in until they touch ("kissing contact"), a tissue pillar forms across the lumen, and pillars widen and fuse until one vessel becomes two. Faster and cheaper than sprouting, it remodels tumour vessels during and after therapy. Shown from left to right on one vessel, cut open. (≈ 60 µm)
Glomeruloid microvascular proliferation — A hallmark of glioblastoma: tufts of tangled, tiny capillaries with piled-up endothelial cells and pericytes, looking like a kidney glomerulus. They form where VEGF from hypoxic tumour is highest. (≈ 100 µm)
Tumour lymphangiogenesis — Tumour cells and macrophages release VEGF-C and VEGF-D, making nearby lymphatic capillaries sprout towards them. Lymphatic capillaries are wide, thin-walled and blind-ended, with overlapping "oak-leaf" endothelial cells joined by button junctions and anchoring filaments that hold them open — an easy route to the lymph nodes. (≈ 100 µm)
Angiogenic switch — A small tumour can stay dormant for years at 1–2 mm, fed only by diffusion. When pro-angiogenic signals (VEGF, FGF2, angiopoietins) outweigh inhibitors (thrombospondin-1, angiostatin), the "angiogenic switch" flips: vessels sprout from nearby capillaries into the nodule, and it starts to grow fast. (≈ 1–2 mm nodule)
VEGF-A binding VEGFR2 (and how drugs block it) — A VEGF-A dimer bridges two VEGFR2 receptors on an endothelial cell, pairing them so their kinase domains phosphorylate each other and signal the cell to grow and move. Anti-VEGF antibodies (bevacizumab) and VEGF traps (aflibercept) catch the ligand, ramucirumab blocks the receptor, and tyrosine-kinase inhibitors jam the kinase. (≈ 25 nm)
Solid stress squeezing tumour vessels — Proliferating cancer cells and stiff matrix push on everything around them. Thin-walled tumour vessels are squashed flat or shut, cutting blood flow and drug delivery and adding to hypoxia. Drugs that loosen the matrix (losartan, hyaluronidase) can reopen them. (≈ 100 µm block)
Tumour endothelium blocking T cells — Tumour vessels act as a checkpoint of their own. Under VEGF and prostaglandin E2 the endothelium shows Fas ligand and PD-L1 but few adhesion molecules (endothelial anergy): CD8 T cells that try to cross are killed, while regulatory T cells, which resist FasL, slip through. (≈ 50 µm)

Hypoxia, acidity & metabolism 8

Tumour cord and oxygen gradient — Tumour cells packed around a single capillary, cut across. Oxygen diffuses only about 100–150 µm: cells next to the vessel are well oxygenated and dividing, the next ring is hypoxic (HIF-1α on, pimonidazole-positive), and beyond that cells die and leave a necrotic zone. (≈ 300 µm across)
HIF-1α: how a tumour cell senses low oxygen — With oxygen, prolyl hydroxylases tag HIF-1α with hydroxyl groups, VHL marks it with ubiquitin and proteasomes destroy it within minutes. In hypoxia HIF-1α survives, enters the nucleus, pairs with HIF-1β (ARNT) on hypoxia response elements and switches on VEGF, GLUT1, CAIX and glycolysis genes. The cell is cut open to show both routes. (≈ 20 µm cell)
Acid pumps of a tumour cell — Glycolytic tumour cells keep their insides alkaline by pumping acid out: MCT4 exports lactate with a proton, NHE1 swaps protons for sodium, V-ATPase pumps protons with ATP, and carbonic anhydrase IX on the surface turns CO₂ into bicarbonate and H⁺. The space outside drops to pH 6.5–6.9, which helps invasion and disables T cells. (≈ 40 nm membrane patch)
Lactate shuttle between tumour cells — Tumour cells share fuel. Hypoxic cells far from the vessel burn glucose by glycolysis and export lactate through MCT4; well-oxygenated cells beside the vessel take that lactate up through MCT1 and oxidise it, leaving glucose to reach the hypoxic cells. CAFs can feed lactate in too ("reverse Warburg"). (≈ 80 µm)
Adenosine made by CD39 and CD73 — Dying and stressed cells release ATP. On tumour cells, Tregs and CAFs the ecto-enzymes CD39 (ATP → AMP) and CD73 (AMP → adenosine) turn it into adenosine, which binds A2A receptors on T and NK cells, raises cAMP and shuts them down. Anti-CD73, anti-CD39 and A2AR blockers are in trials. (≈ 40 nm)
Tumour and T cell competing for glucose — A tumour cell bristling with GLUT1 transporters grabs most of the glucose around it, leaving a nearby T cell with too little to fuel glycolysis, interferon-γ production and killing — metabolic competition is one way tumours silence T cells. (≈ 30 µm)
Pseudopalisading necrosis — The signature of glioblastoma: a vessel in the tumour clots, the tissue around it dies, and hypoxic tumour cells flee outwards, piling up as a dense ring (a "pseudopalisade") around the necrotic zone. These cells pump out VEGF, driving new vessels at the rim. (≈ 300 µm)
Interstitial fluid pressure in a tumour — Leaky vessels and no working lymphatics fill a tumour with fluid: pressure inside rises almost to that in the vessels and stays flat across the core, then drops steeply at the rim, where fluid oozes out. With no pressure gradient inside, drugs move only by slow diffusion. Cut open to show the pressure zones. (≈ 1 cm tumour)

Immune checkpoints 5

Immune checkpoint pair at the synapse — The narrow gap between a T cell (top) and a tumour cell or antigen-presenting cell (bottom), with one receptor–ligand pair drawn from its real domain make-up and size. Choose from inhibitory checkpoints (PD-1, CTLA-4, LAG-3, TIM-3, TIGIT, NKG2A, SIRPα–CD47, BTLA, VISTA) and co-stimulatory pairs (CD28, 4-1BB, OX40, CD40, ICOS). (≈ 15 nm gap)
Immunological synapse (bull's-eye) — Where a T cell meets its target the molecules sort into rings: TCR–peptide–MHC and CD28 gather in the centre (cSMAC), LFA-1–ICAM-1 adhesion forms the middle ring (pSMAC), and the bulky phosphatase CD45 is pushed to the edge (dSMAC), under a ring of actin. PD-1 joins the central microclusters and pulls in SHP2. The T cell is lifted away to show the pattern. (≈ 8 µm across)
T cell meeting PD-L1 on a tumour cell — A CD8 T cell attacks a tumour cell and releases interferon-γ. The tumour answers by raising PD-L1 all over its surface ("adaptive resistance"); PD-1 on the T cell gathers at the contact and switches the attack off. This is the brake that anti-PD-1 and anti-PD-L1 antibodies release. (≈ 25 µm)
CTLA-4 stripping CD80 from a dendritic cell — CTLA-4 on a regulatory T cell grips CD80 and CD86 on a dendritic cell so tightly that it tears them out of the DC membrane and swallows them into the Treg (trans-endocytosis), where they are destroyed. The DC is left without the co-stimulatory ligands that CD28 needs to prime new T cells. (≈ 300 nm)
MHC class I antigen presentation (and its loss) — Inside every cell, proteasomes chop proteins into peptides, TAP pumps them into the endoplasmic reticulum, MHC class I with β2-microglobulin loads them, and the Golgi ships the complexes to the surface for CD8 T cells to read. Tumours escape by switching this off: lowering MHC I, losing β2-microglobulin (B2M) or TAP. (≈ 20 µm cell)

Immunotherapy at the cell level 13

CAR-T cell serial killing — One CAR-T cell can kill many tumour cells in a row. Behind it (left) lie the blebbed remains and apoptotic bodies of earlier targets; it is now attached to a third cell, punching perforin pores into it; intact targets with their antigen wait on the right. (≈ 60 µm)
Complement attack on an antibody-coated tumour cell — Complement-dependent cytotoxicity (CDC): therapeutic antibodies (e.g. rituximab on CD20) cluster on the tumour membrane, C1q docks on their Fc tails, C3b is deposited, and membrane attack complexes (C5b–C9) punch ring-shaped pores that kill the cell. (≈ 50 nm)
Antigen escape from CAR-T cells — CAR-T cells kill every tumour cell carrying their target (e.g. CD19 or BCMA) — but cells that have lost or hidden the antigen survive and regrow the tumour. Antigen escape is a leading cause of relapse; dual-target and logic-gated CARs aim to prevent it. (≈ 60 µm)
Bispecific T-cell engagers redirecting T cells — Bispecific engagers hold a T cell (by CD3) against a tumour cell (by a tumour antigen such as CD19, BCMA, DLL3 or gp100–HLA) so any nearby T cell — whatever its own receptor — forms a killing synapse. Several T cells crowd round one target. (≈ 30 µm)
Antibody-dependent killing by an NK cell (ADCC) — Therapeutic antibodies such as trastuzumab (HER2), rituximab (CD20) or cetuximab (EGFR) coat a tumour cell with their Fc tails pointing outwards. An NK cell grips the tails with CD16 (FcγRIIIa) and releases its lytic granules — antibody-dependent cellular cytotoxicity. (≈ 25 µm)
Oncolytic virus spreading through a tumour — An oncolytic virus (such as T-VEC, a modified herpes simplex virus) infects tumour cells, which often lack the antiviral defences of normal cells. Infected cells swell with new virions and burst, releasing them to infect their neighbours — and spilling tumour antigens and danger signals that rouse the immune system. (≈ 60 µm)
Immunogenic cell death — Some chemotherapies (anthracyclines, oxaliplatin), radiotherapy and oncolytic viruses kill tumour cells in a way the immune system notices: the dying cell moves calreticulin to its surface ("eat me"), releases ATP ("find me") and HMGB1, and dendritic cells move in to take up its antigens. (≈ 30 µm)
cGAS–STING in a dendritic cell — DNA from dying tumour cells reaches the cytosol of a dendritic cell, where cGAS binds it and makes the messenger cGAMP. cGAMP activates STING on the endoplasmic reticulum; STING moves towards the Golgi, recruits TBK1 and IRF3, and the cell pours out type I interferon that primes anti-tumour T cells. STING agonists try to switch this on in tumours. (≈ 15 µm cell)
BCG therapy in the bladder — For early bladder cancer, live attenuated Mycobacterium bovis (BCG) is washed into the bladder. The bacilli stick to fibronectin on the urothelium, are taken up by umbrella and tumour cells, and trigger a flood of neutrophils, macrophages and T cells that clears the tumour — the oldest successful cancer immunotherapy. (≈ 60 µm of urothelium)
Cytokine release syndrome — When CAR-T cells or T-cell engagers kill many tumour cells at once, the activated T cells release interferon-γ and GM-CSF, and nearby macrophages answer with a flood of IL-6 and IL-1 — the cytokine storm behind fever and low blood pressure after therapy. Tocilizumab blocks the IL-6 receptor. (≈ 50 µm)
Logic-gated CAR-T (synNotch AND gate) — A two-step CAR-T cell that kills only cells carrying both of two antigens. A synthetic Notch receptor first binds antigen A; that releases a transcription factor which turns on a CAR against antigen B. Cells with A alone (left) are spared; cells with A and B (right) are killed — sparing normal tissue that carries only one of them. (≈ 40 µm)
Perforin pores and granzyme entry — The killing stroke of a cytotoxic T or NK cell, at molecular scale. A lytic granule fuses with the killer's membrane (top) and releases perforin and granzymes into the synapse. Perforin assembles into ring pores, about 15 nm wide, in the target membrane (bottom), and granzyme B passes through them to trigger apoptosis. (≈ 60 nm)
Armoured CAR-T cell remodelling the tumour — An "armoured" CAR-T cell carries an extra gene for a cytokine such as IL-12, IL-18 or IL-15. Released only where it meets its target, the cytokine keeps the CAR-T cell going and re-educates the neighbours — macrophages switch to an M1-like, tumour-killing state — helping it work in cold solid tumours. (≈ 50 µm)

Hot & cold tumours, lymphoid structures 8

Hot, excluded and cold tumours — Three immune patterns of solid tumours. Inflamed ("hot"): T cells fill the tumour nests — these respond best to checkpoint blockade. Immune-excluded: T cells are held in the surrounding stroma by dense collagen and TGF-β. Immune desert ("cold"): almost no T cells at all. (≈ 200 µm block)
Tertiary lymphoid structure — A lymph-node-like cluster that forms inside or beside a tumour: a B-cell follicle (with a germinal centre when mature) wrapped by a T-cell zone, dendritic cells and high endothelial venules that let lymphocytes in. Mature TLSs predict better survival and response to immunotherapy. Cut open to show the zones. (≈ 0.3–1 mm)
High endothelial venule in a tumour — A specialised venule lined by plump, cuboidal endothelial cells (instead of flat ones) that carry the PNAd and MAdCAM-1 addressins. Lymphocytes roll on them, stick and crawl between the cells into the tissue. HEVs in tumours bring naive and central memory T cells in, and go with tertiary lymphoid structures. (≈ 40 µm)
Cancer–immunity cycle — The seven steps of an anti-tumour immune response (Chen and Mellman): 1 tumour antigens released, 2 picked up and presented by dendritic cells, 3 T cells primed in the lymph node, 4 T cells travel in the blood, 5 they enter the tumour, 6 recognise tumour cells, and 7 kill them — releasing more antigen and turning the cycle again. Every step is a target for therapy. (schematic)
Cancer immunoediting: elimination, equilibrium, escape — The immune system shapes a tumour in three phases. Elimination: T and NK cells destroy nascent tumour cells. Equilibrium: a small tumour is held dormant, sometimes for years, while immune pressure edits it. Escape: variants that hide (losing antigens or MHC) or suppress (recruiting Tregs and MDSCs) grow out. (≈ 100 µm)
Tumour-draining lymph node — Lymph from the tumour flows through afferent lymphatics into the draining lymph node, carrying migratory dendritic cells loaded with tumour antigen. In the paracortex they prime tumour-specific T cells, which leave through the efferent lymphatic — the node is where checkpoint blockade often does its work. Cut open to show cortex, paracortex and medulla. (≈ 5 mm node)
Chemokines guiding T cells into a tumour — Tumour and myeloid cells stimulated by interferon-γ release CXCL9 and CXCL10. CXCR3⁺ T cells crawl up the gradient, front-first with their uropod trailing. Tumours with little CXCL9/10 — or CAFs coating themselves in CXCL12 — stay cold. (≈ 100 µm)
Tumour microenvironment (overview) — All the main players in one block of tumour: nests of tumour cells, cancer-associated fibroblasts in collagen, a leaky vessel with pericytes, tumour-associated macrophages, CD8 and regulatory T cells, a dendritic cell, MDSCs and an NK cell. Each kind is its own part so you can recolour or hide it. (≈ 150 µm block)

Tumour matrix & mechanics 7

Tumour-associated collagen signatures (TACS) — Collagen around a breast tumour changes in a set order, seen by second-harmonic imaging. TACS-1: dense, wavy collagen piles up round the small tumour. TACS-2: the fibres are stretched straight and wrap tangentially round the growing mass. TACS-3: fibres turn radial, and tumour cells migrate out along them — a sign of poor prognosis. (≈ 200 µm)
Collagen cross-linking by lysyl oxidase — Lysyl oxidase (LOX), made by hypoxic tumour cells and CAFs, joins neighbouring collagen fibrils with covalent cross-links. The banded fibrils (67 nm D-period) bundle into thick, stiff cables — the stiffened stroma that drives integrin signalling, invasion and metastasis. (≈ 1 µm of fibre bundle)
Matrix stiffness and YAP in a tumour cell — Cells feel how stiff their matrix is. On a soft matrix a cell stays rounded with small adhesions and YAP/TAZ stays in the cytoplasm. On stiff, cross-linked tumour stroma the cell spreads, builds large focal adhesions and thick stress fibres, the nucleus flattens and YAP moves in to switch on growth and invasion genes. (≈ 50 µm)
Hyaluronan coat around tumour cells — Pancreatic and other tumours wrap themselves in hyaluronan: huge sugar chains anchored by CD44 and HAS enzymes that soak up water into a swollen gel, pushing on vessels and keeping drugs and immune cells out. Hyaluronidase (PEGPH20) cuts the chains into short fragments. (≈ 50 µm)
MMP cutting collagen — Matrix metalloproteinases released by tumour cells and CAFs (MMP-1, -8, -13) or held on their surface (MT1-MMP) unwind and cut the collagen triple helix at one site, three-quarters along, giving the classic ¾ and ¼ fragments that then unravel and are cleared — opening paths through the matrix. (≈ 300 nm long helices)
CAF assembling fibronectin fibrils — A CAF pulls on fibronectin through α5β1 integrins, stretching the folded dimers open so they join into a beaded, branching fibril network — a scaffold that collagen is then laid along and that guides tumour cells and vessels. (≈ 60 µm)
Matrix barrier to drug penetration — Drugs leaving a tumour vessel must cross dense matrix and packed cells. Small molecules diffuse far, but antibodies and nanoparticles pile up near the vessel and barely reach tumour cells 50–100 µm away — one reason solid tumours resist large therapeutics. (≈ 150 µm)

Tumour crosstalk & signals 3

Tumour exosomes carrying PD-L1 — Tumour cells release exosomes — 50–150 nm vesicles budded into multivesicular bodies — studded with PD-L1 and loaded with microRNAs. They travel far beyond the tumour and switch off T cells before they ever reach it, and they prepare distant organs for metastasis. Drawn much larger than life so they show. (≈ 25 µm)
Tunnelling nanotubes stealing mitochondria — Thin membrane tubes (tunnelling nanotubes, 50–200 nm wide) can link a cancer cell to an immune cell. Breast and lung cancer cells have been seen pulling mitochondria out of T cells through them — gaining energy while leaving the T cells depleted. (≈ 30 µm)
Macrophage–tumour paracrine loop (CSF-1 / EGF) — Tumour cells make CSF-1, which draws in macrophages and keeps them alive through CSF1R; the macrophages answer with EGF, which makes the tumour cells move and grow through EGFR. The two cells egg each other on and migrate together towards vessels. (≈ 40 µm)

Metastasis: EMT & plasticity 14

EMT spectrum (epithelial to mesenchymal) — Five cells in a row through epithelial–mesenchymal transition: joined cuboidal cells lose their E-cadherin junctions, pass through a hybrid E/M state and end as spindle-shaped migratory cells. (cells ≈ 15–40 µm)
Loss of apical–basal polarity — A columnar epithelium with microvilli, tight-junction belts and basal nuclei (left) gives way to piled-up, rounded cancer cells with large nuclei that no longer know top from bottom (right), one pushing through the basement membrane. (block ≈ 110 µm)
Cadherin switch at a cell junction — Two cell membranes zipped together by cadherins, each with five calcium-bound extracellular domains, anchored through β- and α-catenin to actin. Switch to N-cadherin to see the looser, sparser mesenchymal contacts of EMT. (gap ≈ 25 nm (schematic))
Junctional complex: intact vs EMT — The side-by-side membranes of two epithelial cells with their junctions from top to bottom — tight junctions, the adherens belt on its actin ring, desmosomes holding keratin, and gap junctions. In EMT the cells part, tight junctions vanish and E-cadherin is taken inside in vesicles. (cells ≈ 10 µm wide (schematic))
EMT transcription factors silencing CDH1 — The E-cadherin gene promoter with its E-box sites occupied by SNAIL, ZEB1 and a TWIST1 dimer, which bring in co-repressors so RNA polymerase II cannot transcribe CDH1 — the switch that starts EMT. Shapes are schematic, not atomic structures. (DNA ≈ 2 nm wide (schematic))
TGF-β signalling triggering EMT — TGF-β dimers bring receptor II and receptor I (ALK5) together on the membrane; the receptor phosphorylates SMAD2/3, which pairs with SMAD4 and carries the signal through a nuclear pore to switch on SNAIL and ZEB — the classic EMT trigger in tumours. (membrane patch ≈ 120 nm (schematic))
Cytoskeleton before and after EMT — An epithelial cell with a cortical actin belt and a keratin cage beside a mesenchymal cell with long stress fibres ending in focal adhesions and a vimentin network — the cytoskeletal rebuild that lets cells crawl. (cells ≈ 20–70 µm)
Cell scattering (HGF/MET) — A compact epithelial colony on a dish breaks up after hepatocyte growth factor activates its MET receptors: edge cells loosen first, then the colony disperses as single spindle-shaped migrating cells. (colony ≈ 150 µm)
EMT–MET plasticity cycle — A loop of the metastatic journey: an epithelial tumour cluster undergoes EMT, spindle cells enter the blood, a circulating cell squeezes out of a distant vessel and the reverse transition (MET) rebuilds an epithelial colony. (schematic (cells ≈ 15 µm))
Acinus: hollow, filled or invasive — A mammary acinus cut open. Normally a single layer of polarised cells surrounds a hollow lumen inside an intact basement membrane; transformed cells fill the lumen, and invasive ones breach the membrane and stream out. (acinus ≈ 60–80 µm)
Tumour budding at the invasive front — A malignant gland whose ragged edge sheds single cancer cells and clusters of up to four cells into the desmoplastic stroma — tumour buds, counted per hotspot (Bd1–Bd3) as a sign of aggressive, EMT-like invasion, best known in colorectal cancer. (field ≈ 140 µm)
Basal extrusion of a transformed cell — Neighbouring epithelial cells contract an actomyosin ring to squeeze out a cell. Healthy cells go apically into the lumen and die, but cells with oncogenic KRAS or lost APC are pushed basally, under the sheet and towards the stroma — an early route to invasion. (cells ≈ 8 µm)
Front–rear polarity of a migrating cell — A cancer cell crawling on a surface: a broad lamellipodium and filopodia at the front, new focal adhesions beneath it, the Golgi and centrosome placed ahead of the nucleus, stress fibres pulling and a narrow tail detaching at the rear. (cell ≈ 80 µm long)
E-cadherin endocytosis in EMT — Cells undergoing EMT clear E-cadherin from their surface without changing the gene: clathrin-coated pits pull it into vesicles and early endosomes, from where it is recycled back or, once tagged with ubiquitin by Hakai, sent to the lysosome for destruction. (membrane patch ≈ 1 µm (schematic))

Metastasis: invasion & migration 26

Invadopodia degrading gelatin — An invasive cancer cell spread on a fluorescent gelatin film: actin-rich invadopodia under it secrete proteases that eat dark holes through the matrix, leaving a trail of degradation spots — the standard gelatin degradation assay. (cell ≈ 50 µm)
Invadopodium close-up — A single invadopodium pushing down from a cancer cell into collagen: a bundle of actin filaments with cortactin, Tks5 and N-WASP inside, MT1-MMP clustered at the tip and secreted MMP-2/9 around it cutting the fibres in its path. Proteins are shown as simple shapes. (protrusion ≈ 0.5–2 µm wide (schematic))
Podosome rosettes — The underside of a Src-transformed cell, where dozens of podosomes — dots of actin each ringed by vinculin and paxillin and linked by actin cables — gather into rosettes that grip and digest the surface. (cell ≈ 120 µm)
Mesenchymal migration through collagen — An elongated cancer cell in a 3D collagen mesh, pulling with long front protrusions and cutting a path with surface proteases; behind it lies a tunnel lined with cleaved fibres that other cells can follow. (cell ≈ 60 µm)
Amoeboid (blebbing) migration — A rounded cancer cell that moves without digesting the matrix: Rho/ROCK-driven contraction of its actomyosin cortex pushes out membrane blebs at the front, and it squeezes through gaps in the collagen mesh with a uropod at the rear. (cell ≈ 20 µm)
Nucleus squeezing through a pore — A migrating cancer cell cut open as it passes a pore narrower than its nucleus: the nucleus pinches into an hourglass, its envelope can tear so chromatin herniates out, ESCRT-III patches the hole and DNA damage builds up. (pore ≈ 5 µm)
Collective invasion strands — Cords of cancer cells that stay joined by cell–cell junctions grow out of the tumour edge into collagen; at each tip a leader cell with mesenchymal-like protrusions (often K14-positive) pulls the strand and clears the way for the followers. (field ≈ 140 µm)
Leader cell carving a microtrack — A leader — a cancer-associated fibroblast or a protease-rich cancer cell — digests and pulls the collagen ahead of it into a tunnel; cancer cells follow in single file through this microtrack without needing their own proteases. (track ≈ 15 µm wide)
Spheroid invading collagen — A tumour spheroid embedded in collagen sprouts strands and single cells in every direction, like a sunburst; the invaded area grows day by day and is measured to compare invasiveness or drugs. (spheroid ≈ 400 µm)
Transwell invasion assay — A Boyden-chamber insert in its well, cut in half: cancer cells seeded in serum-free medium on a Matrigel layer digest through it and the 8 µm-pore membrane towards serum below; the cells that reach the underside are stained and counted. Without Matrigel it measures migration. (insert ⌀ 6.5 mm (cells enlarged))
Invasive front: pushing vs infiltrative — A slab across the edge of a tumour. A pushing (expansive) border advances as a smooth bulge behind a compressed fibrous rim, often with lymphocytes; an infiltrative border breaks into irregular tongues, cords and isolated islands that dissect the stroma — a pattern linked to worse outcome. (slab ≈ 1.2 mm)
Perineural invasion — A small nerve cut open with cancer cells wrapped around more than a third of its circumference and creeping inside the perineurium — perineural invasion, a route of spread along nerves typical of pancreatic, prostate, head-and-neck and bile-duct cancers. (nerve ⌀ ≈ 35 µm)
Collagen signatures at the tumour edge (TACS) — Second-harmonic imaging of breast tumours shows three collagen patterns: TACS-1 dense wavy collagen, TACS-2 straightened fibres stretched around the growing tumour, and TACS-3 fibres aligned outwards that cancer cells use as highways — a sign of poor prognosis. (tumour ⌀ ≈ 500 µm)
Tumour cell–macrophage streaming — Seen by intravital imaging in breast tumours: cancer cells and macrophages travel in alternating single file along collagen fibres towards blood vessels, each attracting the other through a paracrine loop — macrophage EGF and tumour CSF-1. (field ≈ 110 µm)
MMP cutting collagen — An interstitial collagenase (MMP-1, or membrane-bound MT1-MMP) grips a collagen triple helix with its hemopexin domain, unwinds it and cuts all three chains at one site, leaving the typical ¾ and ¼ fragments that then melt into gelatin. Shapes are schematic. (collagen molecule ≈ 300 nm long (schematic))
uPA–uPAR–plasmin system at the leading edge — Urokinase (uPA) bound to its GPI-anchored receptor uPAR focuses protease activity at the front of an invading cell: it converts plasminogen to plasmin, which cuts fibrin, laminin and fibronectin and switches on pro-MMPs; PAI-1 can block it. Shapes are schematic. (membrane patch ≈ 120 nm (schematic))
Single-file infiltration (lobular pattern) — Small, uniform cancer cells that have lost E-cadherin invade as single-file lines between thick collagen bundles and wrap in concentric rings around a benign duct (targetoid pattern) — typical of invasive lobular carcinoma of the breast. (field ≈ 120 µm)
Invasion into fat — Cancer cells creeping in cords between large adipocytes at the edge of a breast or colon tumour; adipocytes next to them shrink into cancer-associated adipocytes and hand over fatty acids that fuel the invaders. (field ≈ 200 µm)
Glioma cells invading along white-matter tracts — Diffuse glioma cells rarely leave the brain but spread widely inside it: thin, elongated cells slip between myelinated fibres along white-matter tracts and gather around capillaries (secondary structures of Scherer), far beyond the visible tumour. (field ≈ 120 µm)
Confined migration in microchannels — A microfluidic chip with its lid removed: cancer cells from the seeding chamber squeeze into channels a few micrometres wide, stretching their bodies and nuclei, and spread out again on the far side — a model of migration through tight tissue spaces. (channels ≈ 3–10 µm wide)
Modes of cancer cell invasion — The ways cancer cells move through tissue, side by side: a rounded blebbing amoeboid cell, a spindle-shaped mesenchymal cell, a chain of cells following each other, a detached cluster, and a collective strand still joined to the tumour mass. (cells ≈ 15–40 µm)
Jamming and unjamming of a cell layer — A packed epithelium behaves like a solid: cobblestone cells, each caged by its neighbours (jammed). In the unjamming transition the cells elongate and flow in coordinated swirls like a fluid — a way to invade collectively without full EMT. (field ≈ 120 µm)
Durotaxis up a stiffness gradient — Cancer cells sense how stiff the matrix is and crawl towards stiffer ground: on soft gel they stay rounded, on stiffer gel they spread, build focal adhesions and stress fibres and move up the gradient — one reason stiff, fibrotic tumour stroma promotes invasion. (cells ≈ 20–60 µm)
Organotypic (raft) invasion assay — Cancer cells grown on a collagen gel packed with fibroblasts and lifted on a grid to the air–liquid interface, cut through: over days they form a stratified layer and invade downwards into the gel as strands and single cells, measured as an invasion index. (gel ≈ 1 cm (cells enlarged))
Lobopodium: the nuclear piston — In stiff, cross-linked matrix some cells push forward a blunt cylindrical lobopodium instead of a lamellipodium: actomyosin pulls the nucleus forward through vimentin and nesprin like a piston, raising pressure at the front to drive the protrusion. (cell ≈ 50 µm)
Inside-out micropapillary clusters — Tight balls of cancer cells floating in empty spaces in the stroma, with their apical microvilli and MUC1 turned outwards towards the stroma instead of a lumen — reversed polarity typical of invasive micropapillary carcinoma, which spreads early to lymph nodes. (clusters ≈ 50 µm)

Metastasis: basement membrane breach 3

Basement membrane breach (microinvasion) — A carcinoma in situ seen from below, through the stroma: cancer cells sit on the basement membrane and a layer of myoepithelial cells. At microinvasion a few cells push through a gap; in invasive carcinoma the barrier is broken wide and cells spread into the stroma. (field ≈ 100 µm)
Basement membrane meshwork — The thin sheet that separates an epithelium from the stroma, at molecular scale: a chicken-wire network of collagen IV joined at NC1 and 7S knots, a laminin polymer layer above, linked by nidogen and perlecan. An invadopodium armed with MT1-MMP punches a hole through it. (mesh ≈ 50 nm pores (schematic))
Pericellular proteolysis halo — A cancer cell in a gel of quenched DQ-collagen: wherever its proteases cut the fibres, the fragments light up, so the cell sits in a glowing halo of digested matrix while the collagen further out stays dark. (cell ≈ 20 µm)

Metastasis: intravasation 6

TMEM doorway on a blood vessel — A tumour microenvironment of metastasis (TMEM): a perivascular TIE2-high macrophage, a Mena-high tumour cell and an endothelial cell in direct contact. The macrophage releases VEGF-A, the vessel opens briefly and the tumour cell slips into the blood — counted in breast cancer biopsies as a prognostic score. (vessel ⌀ ≈ 30 µm)
Tumour cell entering a capillary — Close-up of intravasation: a tumour cell pushes a thin protrusion between two endothelial cells, through the vascular basement membrane and past the pericytes, then pours its body and finally its nucleus into the narrow capillary lumen. (capillary ⌀ ≈ 10 µm)
Mosaic tumour vessel shedding clusters — Tumour vessels are dilated, uneven and leaky; in places tumour cells themselves form part of the wall (mosaic vessels), so whole clusters can bud straight into the blood while red cells leak out. (vessel ⌀ ≈ 30–40 µm)
Tumour cells entering an initial lymphatic — A blind-ended initial lymphatic built from overlapping oak-leaf endothelial cells with button junctions and no continuous basement membrane; anchoring filaments tie it to the collagen and pull the flaps open, an easy door for tumour cells on their way to the lymph nodes. (lymphatic ⌀ ≈ 30 µm)
Tumour thrombus in the renal vein and cava — Renal cell carcinoma can grow as a solid finger of tumour inside its draining vein: out of the kidney along the renal vein, up the inferior vena cava past the liver and sometimes into the right atrium (levels 0–IV), a form of venous invasion seen also with liver and adrenal cancers. (kidney ≈ 11 cm)
Vasculogenic mimicry channels — Aggressive tumour cells — classically in uveal and skin melanoma — line blood-carrying channels themselves, with a PAS-positive matrix but no endothelium; joined to host vessels, these channels give tumour cells direct access to the bloodstream. (channels ⌀ ≈ 10–30 µm)

Metastasis: circulating tumour cells 10

CTC cluster passing a capillary in single file — A cluster of circulating tumour cells reaches a capillary narrower than any of its cells — and instead of jamming, it unfolds into a single-file chain that slips through, then can fold back into a cluster (clusters are 20–100× more metastatic than single CTCs). (capillary ⌀ ≈ 7–10 µm)
CTC travelling with neutrophils — A circulating tumour cell escorted by neutrophils (or macrophages or fibroblasts): neutrophils bound through VCAM-1 push the CTC into the cell cycle and protect it, so these heterotypic clusters seed metastases more efficiently. (CTC ≈ 18 µm)
Platelet and fibrin cloak around a CTC — Inside a vessel, a circulating tumour cell is wrapped in activated platelets and fibrin. The cloak hides it from NK cells (platelets even hand over MHC class I), shields it from shear and later helps it stick to the vessel wall. (CTC ≈ 18 µm)
NK cell killing a circulating tumour cell — In the blood, natural killer cells are the main guards against circulating tumour cells: the NK cell forms a lytic synapse, releases perforin to punch pores and granzymes to trigger apoptosis, and the CTC blebs and dies. (cells ≈ 10–18 µm)
CTC under shear in the bloodstream — Blood flows fastest in the centre of a vessel and slowest at the wall (a parabolic profile); circulating tumour cells pushed to the wall are deformed and rolled by shear stress, which kills many of them within hours. (vessel ⌀ ≈ 45 µm)
Microtentacles on a floating cancer cell — Detached from its matrix, a breast cancer cell sprouts long, thin microtentacles built from detyrosinated microtubules and vimentin; they help it re-attach to the vessel wall and to other cells, aiding arrest and cluster formation. (cell ≈ 20 µm)
Anoikis and its escape — Cells cut off from their matrix normally kill themselves (anoikis): they shrink, bleb, condense and fragment their nucleus and fall apart into apoptotic bodies. Metastatic cells survive detachment by keeping survival signals on (TrkB, integrins, Src, EMT programmes). (cells ≈ 15–20 µm)
Tumour–macrophage hybrid in the blood — Some circulating cells carry both cancer and macrophage markers: fusion hybrids of a tumour cell and a macrophage, with two nuclei and ruffled phagocytic edges, and giant multinucleated cancer-associated macrophage-like cells (CAMLs). (hybrid ≈ 30 µm, CAML up to 100 µm)
A CTC among blood cells — A circulating tumour cell to scale among red cells, platelets and white cells. CTCs are larger than almost everything else in blood but very rare — often a few per millilitre among billions of red cells — which is why they are hard to catch. (field ≈ 100 µm)
Lymph protects, blood oxidises — Melanoma cells that travel first in lymph survive better than those put straight into blood: oleic acid from lymph lipids enters their membranes and protects them from ferroptosis, while in the oxidative bloodstream lipid peroxides build up and the cells die. (vessels ⌀ ≈ 35 µm)

Metastasis: extravasation 6

CTC rolling and arrest on endothelium — Like a white cell, a circulating tumour cell can slow down on inflamed endothelium: sialyl-Lewis sugars on its CD44 or PSGL-1 tether to E-selectin so it rolls with the flow, then integrins grip ICAM-1 and VCAM-1 for firm arrest. (cell ≈ 20 µm)
Extravasation step by step — One venule shows three moments: a circulating tumour cell arrested in the lumen, a second squeezing through a gap between endothelial cells and the basement membrane, and a third already migrating into the organ tissue beyond. (vessel ⌀ ≈ 35 µm)
Angiopellosis: a vessel expelling a cluster — A second way out of a vessel: instead of the tumour cells crawling through, the endothelial cells themselves remodel, wrap around a whole cluster and push it out into the tissue, closing the wall behind it — angiopellosis. (vessel ⌀ ≈ 35 µm)
Tumour colony growing inside a vessel — In the lung, some arrested tumour cells do not extravasate at once: attached to the endothelium they divide inside the arteriole, and the growing colony stretches and finally ruptures the vessel to reach the alveolar tissue. (arteriole ⌀ ≈ 25–45 µm)
Neutrophil extracellular traps catching CTCs — Activated neutrophils cast webs of DNA studded with histones, elastase and myeloperoxidase across the vessel; circulating tumour cells get snagged in these NETs, which hold them near the wall and help them escape into the tissue. (vessel ⌀ ≈ 50 µm)
Tumour cell trapped in a lung capillary — The lung’s capillaries, only 5–8 µm wide and woven over each alveolus, are the first bed most venous blood reaches; a 15–20 µm tumour cell simply jams at a narrow junction, stretched like a sausage, with red cells piling up behind it. (capillaries ≈ 5–8 µm)

Metastasis: pre-metastatic niche & homing 6

Pre-metastatic niche in the lung — Before a single tumour cell arrives, factors and exosomes from the primary tumour prepare the lung: fibroblasts lay down fibronectin, VEGFR1+ bone-marrow-derived cells and neutrophils cluster in the alveolar walls, and S100A8/A9 and LOX remodel the tissue so it will welcome the seeds. (alveoli ≈ 200 µm)
Pre-metastatic niche in the liver — Exosomes from a pancreatic tumour carrying MIF are swallowed by Kupffer cells in the liver sinusoids; they signal through TGF-β to hepatic stellate cells, which lay down fibronectin that traps incoming macrophages and, later, tumour cells. (lobule ≈ 1 mm)
Tumour exosome docking by its integrin code — A tumour-derived exosome, cut open to show its microRNA and protein cargo, lands on a cell in a distant organ: integrins α6β4 and α6β1 steer exosomes to the lung, αvβ5 to Kupffer cells in the liver and β1 to the brain, preparing a niche there. (exosome ⌀ ≈ 100 nm (schematic))
CXCR4–CXCL12 chemokine homing — Stromal cells in bone marrow, lung, liver and lymph nodes secrete the chemokine CXCL12; breast and many other cancer cells carry its receptor CXCR4 and crawl up the gradient, which helps explain where they settle (organotropism). (field ≈ 140 µm)
Seed and soil — Stephen Paget’s 1889 idea in one picture: tumour cells (seeds) land in many organs, but they grow only where the soil suits them — here a colony thrives in one tissue while the seeds on the others stay single and dormant. (schematic)
Exosome release from a cancer cell — Inside a cancer cell, multivesicular bodies fill with small intraluminal vesicles and fuse with the plasma membrane, releasing them as exosomes that carry the tumour’s proteins, RNAs and integrins to distant organs. (cell ≈ 20 µm (exosomes enlarged))

Metastasis: lymphatic spread 10

Lymph node metastasis: ITC to extranodal extension — A lymph node cut in half. Tumour cells arrive by the afferent lymphatics into the subcapsular sinus: isolated tumour cells (≤ 0.2 mm), a micrometastasis (≤ 2 mm), a macrometastasis replacing the cortex, or a deposit bursting through the capsule (extranodal extension). (node ≈ 8 mm)
Sentinel lymph node mapping — Blue dye or a radioactive tracer injected at a breast tumour travels in the lymphatic channels to the first draining node in the axilla — the sentinel node — which the surgeon finds by colour or with a gamma probe and removes to check for spread. (breast ≈ 15 cm)
Tumour embolus in a lymphatic (LVI) — A cluster of tumour cells floating inside a thin-walled lymphatic channel just beyond the tumour — lymphovascular invasion, confirmed by D2-40 (podoplanin) staining of the lining and a strong predictor of lymph node metastasis. (channel ⌀ ≈ 50 µm)
Tumour lymphangiogenesis (VEGF-C) — A tumour releasing VEGF-C and VEGF-D calls in lymphatic vessels: nearby lymphatics dilate and sprout through VEGFR3 towards the tumour edge, widening the road to the lymph nodes. (tumour ⌀ ≈ 2 mm)
From node to node into the bloodstream — Lymph from an abdominal tumour passes node after node, collects in the cisterna chyli, climbs the thoracic duct and empties into the left venous angle — so tumour cells can reach the blood, and an enlarged left supraclavicular node (Virchow’s node, Troisier’s sign) can betray a gastric cancer. (duct ≈ 40 cm (schematic))
Lymphangitic carcinomatosis of the lung — A block of lung where tumour cells fill the lymphatics: the interlobular septa and the sheaths around bronchi and vessels thicken into beaded lines — the pattern behind breathlessness and the “beaded septa” on CT in breast, lung, stomach and pancreatic cancers. (block ≈ 2 cm)
In-transit melanoma metastases — A segment of limb cut open: between a primary melanoma and its regional lymph node, dark nodules appear in the skin and fat along the dermal lymphatics — in-transit or satellite metastases, tumour caught on its way to the node. (limb segment ≈ 15 cm)
Axillary lymph node levels — Breast cancer drains to the axillary nodes in levels set by the pectoralis minor muscle: level I lateral to it, level II behind it and level III medial to it below the axillary vein. Spread usually climbs level by level, and the number of positive nodes sets the N stage. (axilla ≈ 12 cm)
Tumour cells landing in the subcapsular sinus — Lymph from the afferent lymphatic pours into the subcapsular sinus under the node’s capsule, where CD169+ macrophages sample it; arriving tumour cells settle here first, above the B-cell follicles, before growing into the cortex. (field ≈ 110 µm)
Leaving a lymph node through a high endothelial venule — Lymph node metastases can seed the rest of the body: in mice, tumour cells in the node squeeze into its high endothelial venules — vessels lined by plump, cuboidal endothelium where lymphocytes normally enter — and travel on in the blood. (venule ⌀ ≈ 30 µm)

Metastasis: bone 5

Osteolytic vicious cycle — On a bone surface in breast-cancer bone metastasis: tumour cells release PTHrP, osteoblasts answer with RANKL, osteoclasts multiply and dig resorption pits, and the dissolving bone frees TGF-β and IGF that make the tumour grow even more. (field ≈ 120 µm)
Osteoblastic (sclerotic) bone metastasis — In prostate cancer, tumour cells in the marrow release endothelin-1, Wnt and BMPs that drive osteoblasts to coat the trabeculae with thick new woven bone — dense, sclerotic metastases that show white on X-ray yet are weaker than normal bone. (field ≈ 1 mm)
Vertebral metastases and cord compression — A lumbar vertebra cut across: metastases hollow out (lytic) or harden (blastic) the vertebral body and pedicle — the spine is the commonest site of bone metastasis — and a mass growing into the epidural space can squeeze the spinal cord, an oncological emergency. (vertebra ≈ 5 cm)
Pathological fracture of the femur — A proximal femur eaten away by a lytic metastasis below the lesser trochanter — the commonest site of long-bone metastasis — and the fracture that runs through the weakened bone under ordinary load; large painful lesions are pinned before they break (Mirels score). (femur top ≈ 15 cm)
Where bone metastases occur — A simplified skeleton showing that bone metastases gather in bones rich in red marrow — the spine above all, then the pelvis, ribs, skull and the upper ends of the femurs and humeri — the pattern seen on bone scans in breast and prostate cancer. (adult skeleton (schematic))

Metastasis: liver, lung & brain 12

Tumour cell arrested in a liver sinusoid — Gut tumour cells carried by the portal vein jam in the narrow liver sinusoids. The sinusoid is lined by sieve-like fenestrated endothelium over the space of Disse and its stellate cells, between plates of hepatocytes; Kupffer cells in the lumen can catch and kill the newcomer. (sinusoid ⌀ ≈ 10–15 µm)
Growth patterns of liver metastases — Where a liver metastasis meets the liver, three patterns are seen: desmoplastic (a fibrous rim with lymphocytes walls it off — best prognosis), replacement (tumour cells take over hepatocyte plates and co-opt sinusoids, keeping the architecture) and pushing (plates squeezed aside). (interface ≈ 1 mm)
Liver slice with colorectal metastases — A slice through a liver resected for colorectal cancer: firm, pale-tan nodules sharply set off from the brown liver, with yellow central necrosis and a dimple (umbilication) where they reach the capsule. (slice ≈ 15 cm)
Portal spread from the colon to the liver — Blood from the bowel drains through the mesenteric veins into the portal vein and straight to the liver, so the liver’s sinusoids are the first capillary bed colon cancer cells meet — and the liver the commonest site of colorectal metastasis. (abdomen ≈ 30 cm (schematic))
Cannonball metastases in the lung — A lung with its front cut away: many round, sharply defined metastases of different sizes, more in the lower lobe where blood flow is greatest — the “cannonball” pattern of blood-borne spread from kidney, bowel, sarcoma, testis or melanoma. (lung ≈ 25 cm)
Malignant pleural effusion — An axial slice of the chest: tumour studding the pleura makes fluid pour into the pleural space, which squeezes the lung on that side — malignant pleural effusion, common in lung, breast and ovarian cancer and in mesothelioma. (chest ≈ 30 cm across)
Brain metastases at the grey–white junction — A coronal slice of the brain with round, well-circumscribed metastases lodged where grey matter meets white — the arterioles narrow there and trap tumour cells — each ringed by vasogenic oedema; melanoma and kidney metastases often bleed. (brain ≈ 14 cm across)
Crossing the blood–brain barrier — A brain capillary sealed by tight junctions, wrapped by pericytes and astrocyte end-feet: a breast or lung cancer cell arrested in the lumen pushes through this blood–brain barrier — the hardest step of brain metastasis — helped by proteases such as cathepsin S. (capillary ⌀ ≈ 8 µm)
Vessel co-option in the brain — Instead of growing new vessels, metastatic cells crawl along the outside of existing capillaries, wrapping them in sleeves (via L1CAM) and spreading through the brain on this scaffold — vessel co-option, also seen in lung and liver metastases and a reason anti-angiogenic drugs can fail. (field ≈ 110 µm)
Glial reaction around a brain metastasis — Reactive astrocytes with thickened GFAP-rich processes and ramified microglia gather around a brain metastasis. At first they attack it, but astrocytes can also link to the cancer cells through connexin-43 gap junctions and pass on signals that protect them. (metastasis ⌀ ≈ 400 µm)
Leptomeningeal metastasis — Tumour cells that reach the cerebrospinal fluid seed the leptomeninges and coat the lower spinal cord and the nerve roots of the cauda equina with small nodules (“sugar coating”), causing root pain, weakness and cranial nerve palsies; common with breast, lung, melanoma and leukaemia. (cord ⌀ ≈ 1 cm)
Cancer cell inside a brain synapse — Breast cancer cells that reach the brain tuck their processes into glutamate synapses between neurons, taking the place an astrocyte normally holds: glutamate released by the presynaptic terminal activates NMDA receptors on the cancer cell and fuels its growth. (synapse ≈ 1 µm (schematic))

Metastasis: peritoneum & other sites 10

Transcoelomic spread of ovarian cancer — Ovarian cancer rarely needs blood vessels to spread: cells and spheroids shed from the tumour float in the peritoneal fluid, carried by its circulation up the paracolic gutters to the omentum, the undersurface of the diaphragm and the bowel surface, where they implant. (abdomen ≈ 35 cm (schematic))
Omental cake — The fatty apron of the greater omentum hanging from the transverse colon, its soft lobules replaced by firm, confluent tumour plaques — the “omental cake” of advanced ovarian, gastric or colorectal cancer, often removed at debulking surgery. (omentum ≈ 35 cm)
Spheroid clearing the mesothelium — An ovarian cancer spheroid lands on the peritoneum, grips the matrix through integrins and myosin-driven force, and shoves the mesothelial cells aside to open a hole through which it spreads and invades — mesothelial clearance. (spheroid ⌀ ≈ 50 µm)
Peritoneal carcinomatosis on the bowel — Loops of small bowel and their mesentery studded with tumour nodules from millimetre grains to confluent plaques; the burden is scored region by region as the peritoneal cancer index (PCI) to decide on cytoreductive surgery and HIPEC. (bowel ⌀ ≈ 3 cm)
Pseudomyxoma peritonei — An axial slice of an abdomen filled with jelly: a ruptured mucinous tumour of the appendix spreads cells that keep secreting mucin, which collects around the organs and scallops the liver surface (“jelly belly”). (abdomen ≈ 30 cm across)
Krukenberg tumours — Both ovaries swollen into firm, pale masses by metastatic mucin-filled signet-ring cells — most often from a diffuse stomach cancer, sometimes from colon or breast — spread across the peritoneum or through lymphatics. (ovaries ≈ 8–10 cm)
Choroidal metastasis in the eye — An eye cut in half: the richly perfused choroid is the commonest site of eye metastases, usually from breast or lung cancer — a flat, creamy-yellow mass at the back of the eye that can lift the retina off with fluid and blur vision. (eye ⌀ ≈ 24 mm)
Adrenal metastasis — The small, Y-shaped adrenal gland on top of the kidney, holding a round metastasis; with their rich blood supply the adrenals are a frequent site of spread from lung cancer, melanoma, breast and kidney cancer, usually found on staging CT. (kidney ≈ 11 cm)
Omental milky spot colonised — In the fat of the omentum, milky spots — clusters of macrophages and lymphocytes around a tuft of capillaries under gaps in the mesothelium — filter the peritoneal fluid; ovarian and gastric cancer cells home to them and grow there first. (milky spot ≈ 200 µm)
Sister Mary Joseph nodule — A firm, reddish nodule in the navel — a metastasis that reached the umbilicus through lymphatics, veins or the peritoneum, usually from a stomach, ovarian, colorectal or pancreatic cancer; named after the nurse who noticed it at the Mayo Clinic. (nodule ≈ 1–3 cm)

Metastasis: dormancy & colonisation 12

Dormant cell in the perivascular niche — A single disseminated tumour cell resting quietly against a mature microvessel, kept asleep by endothelial thrombospondin-1; when the vessel sprouts, the tip cells release periostin and TGF-β1 and the cell wakes up and divides. (cell ≈ 12 µm)
Dormant cells in the bone marrow niche — Disseminated prostate or breast cancer cells home to the endosteal niche of the bone marrow, competing with haematopoietic stem cells for osteoblasts and CXCL12-rich reticular cells; there they can stay dormant for years before relapse. (field ≈ 120 µm)
Angiogenic dormancy of a micrometastasis — A micrometastasis no bigger than a fraction of a millimetre, without its own blood supply: as many cells die as divide, so it stays the same size for years — until it flips the angiogenic switch, vessels sprout in and it grows. (micrometastasis ⌀ ≈ 0.2 mm)
Immune-mediated dormancy (equilibrium) — A small metastasis ringed by CD8 T cells and NK cells: they kill the cells that divide and release IFN-γ that keeps the rest quiescent, an equilibrium that can last for years until immunity weakens and the tumour escapes. (micrometastasis ⌀ ≈ 50 µm)
Metastatic colonisation — The last and least efficient step of metastasis: a single disseminated cell in a foreign organ grows into a micrometastasis, and only a few go on to recruit vessels and become a macrometastasis with a necrotic core. (up to ≈ 1 cm)
FUCCI-labelled micrometastasis — Cells carrying the FUCCI cell-cycle reporter light up red in G1 or dormancy and green in S, G2 and M; imaging a metastasis this way shows at a glance how many cells are cycling and how many sleep. (cluster ≈ 70 µm)
Inflammation waking dormant cells — Lung inflammation (from tobacco smoke or infection) draws in neutrophils whose NETs carry elastase and MMP-9; these cut laminin into a new shape that dormant cancer cells sense through integrin α3β1, and they start dividing again. (field ≈ 100 µm)
From diagnosis to late relapse — A timeline of one patient: a primary tumour is removed, but cells that had already spread lie dormant for years — in oestrogen-receptor-positive breast cancer, relapses keep appearing 5 to 20 years later — before one wakes and grows into a metastasis. (timeline (schematic))
Linear vs parallel metastatic progression — Family trees built from tumour DNA show when metastases left: in linear progression a late, fully evolved subclone of the primary seeds them; in parallel progression cells spread early and evolve separately at the distant site. (diagram)
Tumour self-seeding — Circulating tumour cells can come home: some re-enter their own primary tumour, drawn by IL-6 and IL-8, settle at its edge and make it grow faster and more aggressive — tumour self-seeding. (tumour ⌀ ≈ 1 cm (schematic))
Polyclonal seeding by a CTC cluster — Multicolour lineage tracing shows that many metastases are founded not by one cell but by a cluster of several clones travelling together: the colony that grows is a patchwork of colours, the clones still mixing. (metastasis ⌀ ≈ 0.5 mm)
Metastatic inefficiency — A funnel for the odds of metastasis: a tumour can shed millions of cells into the blood every day, but shear, immune attack, anoikis and hostile tissue kill almost all of them, and only a tiny fraction ever founds a metastasis. (diagram)

Metastasis: routes & organotropism 5

Organotropism: where each cancer spreads — A see-through body with simplified organs: pick a primary cancer and its usual metastatic sites light up with arrows — breast to bone, lung, liver and brain; prostate to bone; colorectal to liver; lung to brain, bone and adrenals; melanoma to nodes, skin and brain. (adult body (schematic))
Routes of cancer spread — One tumour and the four ways it can spread: direct invasion into a neighbouring organ, the lymphatic route to regional nodes, the haematogenous route through veins, and the transcoelomic route across a body cavity. (schematic)
Venous drainage and the first capillary bed — Which organ catches circulating tumour cells first depends on the vein that drains the tumour: caval (kidney, limbs → lungs), portal (bowel → liver), pulmonary (lung → heart → brain, bone, adrenals) or vertebral (pelvis → spine). Pick a pattern to trace it. (torso (schematic))
Batson’s vertebral venous plexus — A network of valveless veins around and inside the spine connects the pelvic veins directly to the vertebrae; when abdominal pressure rises, blood — and prostate cancer cells — can flow backwards into the spine, bypassing the lungs. (lumbar spine ≈ 20 cm)
Needle-tract seeding — A rare way of spreading: cells dragged out along the path of a biopsy or drainage needle can grow into nodules in the muscle, fat and skin along the tract — seen with liver, pleural and some other tumours, and reduced by coaxial needles. (body wall ≈ 6 cm)

Breast cancers 12

DCIS architectural patterns — One breast duct filled by ductal carcinoma in situ, cut across: cribriform (rigid punched-out spaces), solid, comedo (central necrosis with calcification), micropapillary tufts or papillary fronds with fibrovascular cores — still inside an intact myoepithelial layer and basement membrane. Nuclear grade low to high. (duct ≈ 0.5–2 mm)
Invasive breast carcinoma — Nottingham grade — Invasive carcinoma of no special type in desmoplastic stroma, graded as pathologists do: grade 1 mostly forms small angulated tubules with small uniform nuclei; grade 2 mixes tubules, nests and cords; grade 3 grows in solid nests of large pleomorphic nuclei with prominent nucleoli, many mitoses and necrosis. (field ≈ 1–2 mm)
Mucinous (colloid) carcinoma of the breast — A special type of breast cancer: small clusters of bland tumour cells float in large lakes of extracellular mucin separated by thin fibrous septa. Pure mucinous carcinomas grow slowly and carry a good prognosis. (field ≈ 2–4 mm)
Triple-negative (basal-like) breast carcinoma — A triple-negative, basal-like carcinoma: lobulated sheets of large cells with vesicular nuclei and big nucleoli push into the stroma with a rounded border, with geographic necrosis, brisk mitoses and a dense rim of tumour-infiltrating lymphocytes. Often BRCA1-related; ER, PR and HER2 are all negative. (mass ≈ 1–3 cm (field ≈ 4 mm))
Inflammatory breast cancer (skin) — Breast skin in inflammatory breast cancer (T4d): tumour emboli block the dermal lymphatics, the dermis swells with oedema and the skin turns red and pitted like orange peel (peau d’orange) where hair follicles tether it down. (skin ≈ 2–4 mm thick)
Paget disease of the nipple — The nipple cut through its middle: an eczema-like red, crusted and eroded patch over the tip, large pale Paget cells (HER2-positive adenocarcinoma cells) scattered through the epidermis, and the ductal carcinoma in situ in a lactiferous duct beneath from which they spread. (nipple ≈ 1–1.5 cm)
Phyllodes tumour (cut surface) — A phyllodes tumour of the breast cut in half: a large, bulging, well-circumscribed mass whose fleshy cut surface splits into leaf-like lobules (phyllodes = leaf-like) along curved clefts. Borderline and malignant tumours show stromal overgrowth, haemorrhage, necrosis and a pushing to infiltrative edge. (mass ≈ 4–10 cm)
Breast carcinoma in a mastectomy slice — A slice through a mastectomy specimen, as the pathologist sees it at grossing: yellow fat, white fibroglandular strands running to the nipple, and a hard grey-white carcinoma — spiculated (stellate) with chalky streaks, circumscribed, ill-defined lobular or multifocal — over the pectoralis muscle, with an axillary node. (slice ≈ 10–15 cm wide)
Invasive lobular carcinoma — single files & targetoid — Classic invasive lobular carcinoma of the breast: small, bland, discohesive cells (E-cadherin lost) infiltrating dense stroma in single files and in concentric, targetoid rings around a benign duct, some with intracytoplasmic mucin vacuoles — no glands, no mass-forming nests. (field ≈ 1 mm)
Fibroadenoma of the breast — The commonest solid breast lump in a young woman, and benign: a firm, rubbery, sharply bounded mass that shells cleanly out of the tissue round it. On the cut surface the stroma has squeezed the ducts into curved slit-like clefts — the feature that names it. (mass ≈ 1–3 cm)
Breast mass margins (what BI-RADS scores) — The three margins a radiologist is reading when a mammogram is given a BI-RADS category, side by side in the same tissue: a smooth circumscribed oval, a microlobulated edge, and the straight lines of a spiculated mass reaching into the fat — with a cluster of pleomorphic microcalcifications beside it. (masses ≈ 1–2 cm)
Breast reconstruction after mastectomy — The two ways a breast is rebuilt: a silicone implant in a pocket behind the pectoralis major, or a DIEP free flap of the patient’s own lower abdominal fat and skin, with its artery and vein joined to the internal mammary vessels. (implant ≈ 300–500 mL)

Grading & pathology scoring 4

Immunohistochemistry scoring (ER, HER2, Ki-67…) — Tumour nests stained by immunohistochemistry (brown DAB on a blue counterstain), scored as in the clinic: nuclear markers (ER, PR, Ki-67) by the share of brown nuclei, HER2 0 to 3+ by complete membrane rings, PD-L1 on tumour membranes, aberrant p53, and mismatch-repair loss (tumour nuclei blue, stromal nuclei brown as the internal control). (field ≈ 0.5–1 mm)
Gleason patterns & grade groups (prostate) — Prostate tissue graded as pathologists do: benign glands with papillary infoldings and a basal-cell layer beside carcinoma in Gleason pattern 3 (small, separate glands), pattern 4 (fused, ill-formed and cribriform glands) or pattern 5 (solid sheets, cords and comedonecrosis). The mix of patterns sets the ISUP grade group 1–5. (glands ≈ 0.05–0.3 mm)
Nuclear grade (pleomorphism 1–3) — Tumour cells cut open to compare nuclear grades: grade 1 nuclei are small, round and even with fine chromatin; grade 2 are larger with visible nucleoli; grade 3 are large and irregular, with coarse clumped chromatin, prominent (macro)nucleoli and sometimes several nuclei — the nuclear score used in breast (Nottingham) and renal (WHO/ISUP) grading. (cells ≈ 10–30 µm)
Perineural invasion — A nerve with its fascicles cut across and malignant glands wrapping round it in the perineural space — perineural invasion, reported as an adverse feature because tumour can track along nerves, causing pain and recurrence (common in pancreatic, prostate and head and neck cancers). (nerve ≈ 0.5–2 mm)

Lung & thoracic cancers 8

Lung adenocarcinoma growth patterns — Normal alveoli on the left and adenocarcinoma on the right, in one of its five growth patterns: lepidic (tumour cells creeping along intact alveolar walls), acinar (glands in fibrotic stroma), papillary (fronds with cores), micropapillary (floating tufts) or solid sheets. The predominant pattern sets the IASLC grade. (alveoli ≈ 0.2–0.3 mm)
Keratinizing squamous cell carcinoma — Invasive squamous cell carcinoma (lung, head and neck, oesophagus, skin, cervix): nests of pink polygonal cells with a rim of dark basaloid cells, maturing towards central onion-skin keratin pearls, in desmoplastic stroma. Well-differentiated tumours make many large pearls; poorly differentiated ones grow as pleomorphic sheets without keratin. (nests ≈ 0.2–1 mm)
Small cell carcinoma — histology — Small cell carcinoma under the microscope: sheets of small blue cells with scant cytoplasm, finely granular chromatin and nuclei moulded against each other, smeared crush artefact, necrosis with apoptotic bodies, and blue DNA encrusting vessel walls (Azzopardi effect) — beneath intact bronchial mucosa. (cells ≈ 10–15 µm (field ≈ 0.6 mm))
Bronchial carcinoid tumour — A carcinoid tumour in a main bronchus, opened lengthwise: a smooth, red, highly vascular polyp bulging into the lumen under intact mucosa, with its larger part pushing out through the wall between the cartilage plates (an "iceberg" tumour); mucus collects beyond it. Atypical carcinoids show punctate necrosis. (tumour ≈ 1–3 cm)
Pancoast (superior sulcus) tumour — A lung cancer at the very apex of the lung growing into the thoracic inlet: it destroys the first rib, encases the lower trunks of the brachial plexus (shoulder and arm pain, hand weakness) and the sympathetic chain and stellate ganglion (Horner syndrome), close under the subclavian artery and vein. (tumour ≈ 3–7 cm)
Mesothelioma — histology & asbestos bodies — Epithelioid mesothelioma of the pleura under the microscope: tubules and papillae of mesothelial cells invading the thickened pleura and chest-wall fat, with golden, beaded asbestos (ferruginous) bodies — coated fibres that mark the exposure behind most cases. (field ≈ 1 mm)
Lung cancer in a lobe slice (gross) — A slice through a resected lung lobe: a peripheral adenocarcinoma (grey-white, spiculated, round a black anthracotic scar, puckering the pleura) or a central squamous cell carcinoma round a bronchus, cavitating in its centre, with obstructive pneumonia beyond it and black anthracotic nodes at the hilum. (slice ≈ 15 cm)
Malignant pleural effusion (cytology) — Fluid drained from a malignant pleural effusion and spread on a slide: rounded, three-dimensional "cannonball" balls of adenocarcinoma cells, far bigger than the single reactive mesothelial cells, macrophages and lymphocytes around them — a common first diagnosis of metastatic lung, breast or ovarian cancer. (clusters ≈ 50–150 µm)

Staging (TNM) 16

T stage — depth through the gut or bladder wall — A block of hollow-organ wall cut to show its layers, with a carcinoma reaching the depth that defines its T category: in situ (Tis), into the submucosa (T1), the muscularis propria (T2), through it (T3), through the serosa (T4a) or into a neighbouring organ (T4b). Choose colon, stomach, oesophagus or bladder. (wall ≈ 3–8 mm)
T stages around the bowel (Tis → T4b) — A slice across the bowel with six carcinomas, one at each T category around the ring: in situ in the mucosa, into the submucosa (T1), into the muscularis propria (T2), through it into the subserosa (T3), through the serosa (T4a) and into an adjacent organ (T4b). (bowel ≈ 3–5 cm across)
N stage — regional lymph nodes — A colon segment with an annular carcinoma and its mesentery: the lymph nodes along the arterial arcade, paracolic nodes first and the main nodes at the root last. Involved nodes are swollen and purple; the count sets the N category (N0, N1a–c, N2a–b), with tumour deposits as N1c. (segment ≈ 15–20 cm)
T category by tumour size (breast, lung) — Tumours of increasing size lined up on a centimetre board, each labelled with the T category its greatest dimension gives: for breast cancer T1a–c (up to 2 cm), T2 (2–5 cm) and T3 (over 5 cm); for lung cancer T1a–c (up to 3 cm), T2a–b, T3 and T4 (over 7 cm). (tumours ≈ 0.5–8 cm)
FIGO staging of cervical cancer — A coronal view of the pelvis showing how far a cervical cancer has spread: microscopic (IA), confined to the cervix (IB), into the upper vagina (IIA) or parametria (IIB), the lower vagina (IIIA), the pelvic side wall with a blocked, dilated ureter (IIIB), or the bladder or rectum (IVA). (uterus ≈ 8 cm)
FIGO staging of endometrial cancer — A uterus split open to show how deep an endometrial carcinoma goes (the anatomical FIGO stages): less than half the myometrium (IA), half or more (IB), into the cervical stroma (II) or through to the serosa and adnexa (IIIA). A line marks the half-way depth. (uterus ≈ 8 cm)
Ann Arbor / Lugano staging of lymphoma — A body map of lymph-node regions above and below the diaphragm: stage I is one region, stage II two or more on the same side of the diaphragm, stage III nodes on both sides (or the spleen), and stage IV spread outside the lymphatic system, to the liver, lung or bone marrow. (body)
Renal cell carcinoma — venous tumour thrombus (T3) — Clear-cell renal cell carcinoma grows as a solid tumour thrombus along its veins, and how far it reaches sets the stage: into the renal vein (T3a), up the opened inferior vena cava below the diaphragm (T3b), or above it into the right atrium (T3c). (IVC ≈ 2–3 cm)
Prostate cancer T stage (T2 → T4) — A prostate split open with a carcinoma in its peripheral zone (where most arise, next to the rectum): confined inside the capsule (T2), breaking out through it (extraprostatic extension, T3a), into a seminal vesicle (T3b) or into the rectum or bladder neck (T4). (prostate ≈ 4 cm)
Sentinel lymph node biopsy — Sentinel node mapping for breast cancer: blue dye and a radiotracer injected next to the tumour run along a lymphatic channel to the first draining axillary node — the sentinel node, blue and "hot" under the gamma probe. If it is free of cancer, the other nodes can be spared. (breast ≈ 15 cm)
Inked resection margins (R0 / R1) — A lumpectomy specimen at grossing: each face is painted a different ink to keep its orientation, then the specimen is sliced like a loaf. One slice is lifted to show the tumour and how close it comes to the ink — clear (R0) or tumour touching ink (R1, needing re-excision). (specimen ≈ 4–8 cm)
Axillary lymph-node levels I–III — The axillary lymph nodes that drain the breast, grouped by their relation to the pectoralis minor muscle: level I lateral to it, level II behind it and level III medial to it below the clavicle — the levels used to plan and report axillary surgery. (axilla ≈ 10–15 cm)
Neck lymph-node levels I–VI — The side of the neck with its lymph-node levels used in head and neck cancer: Ia submental, Ib submandibular, II–IV along the jugular chain under the sternocleidomastoid (upper, middle, lower), V the posterior triangle and VI the central compartment. (neck ≈ 12 cm)
Rectal cancer — mesorectal fascia & CRM — An axial slice through rectal cancer as MRI stages it: the tumour grows from the rectal wall into the yellow mesorectal fat towards the mesorectal fascia — the plane of total mesorectal excision. Clear, threatened (within 1 mm) or involved circumferential resection margin, nodes and extramural venous invasion decide pre-operative treatment. (slice ≈ 8 cm across)
Lung cancer T stage by invasion — A slice through a lung lobe at the chest wall showing how invasion raises the T category regardless of size: a tumour reaching and puckering the visceral pleura (T2), one growing through the parietal pleura into ribs and intercostal muscle (T3), or a separate nodule in the same lobe (T3). (slice ≈ 8 cm)
Pancreatic cancer resectability (vessel contact) — Whether a pancreatic head cancer can be removed depends on its contact with the big vessels behind it: no contact (resectable), contact with the superior mesenteric or portal vein that can be reconstructed (borderline), or encasing more than half the circumference of the superior mesenteric artery (locally advanced). (pancreas ≈ 15 cm)

Precancerous lesions 13

Oral leukoplakia & erythroplakia — Oral potentially malignant disorders on the lateral tongue: a homogeneous white plaque, a warty (verrucous) one, speckled red-and-white erythroleukoplakia, or a velvety red erythroplakia — the most likely to harbour dysplasia. The cut face shows the thickened epithelium with atypia climbing from the base. (patch ≈ 1–4 cm)
Actinic keratosis → squamous cell carcinoma — Sun-damaged skin with a rough, scaly actinic keratosis over atypical keratinocytes: AK I (lower third), AK II (lower two-thirds), a hypertrophic AK with a cutaneous horn, Bowen disease (full-thickness atypia under a red scaly plaque) and finally invasive squamous cell carcinoma — with solar elastosis in the dermis below. (lesion ≈ 0.3–2 cm)
Melanocytic naevi & dysplastic naevus — Melanocytic naevi in skin, from the surface and on the cut face: junctional (flat, nests at the junction), compound, intradermal (a flesh-coloured dome with nests maturing downwards), a dysplastic naevus (irregular, two-tone, with bridging nests along elongated rete and lamellar fibroplasia) and a pink Spitz naevus. (naevus ≈ 2–10 mm)
Colorectal polyp types — Colonic polyps as seen at colonoscopy: a pedunculated tubular adenoma on its stalk, a carpet-like villous adenoma, a flat pale sessile serrated lesion under a yellow mucus cap, a small hyperplastic polyp, a lobulated Peutz–Jeghers hamartoma with arborising muscle, and a smooth cherry-red juvenile polyp. (polyps ≈ 0.3–4 cm)
Familial adenomatous polyposis (FAP) — An opened colon in familial adenomatous polyposis: a germline APC mutation carpets the mucosa with hundreds to thousands of adenomas, and without colectomy one of them almost always becomes a carcinoma by middle age. (segment ≈ 15 cm)
Lugol chromoendoscopy — oesophageal dysplasia — The oesophageal lining sprayed with Lugol’s iodine: normal glycogen-rich squamous epithelium stains dark brown, while dysplastic and early cancerous areas stay unstained (Lugol-voiding lesions); a high-grade lesion turns pink a few minutes later (the pink-colour sign). (lesions ≈ 0.5–3 cm)
Intraductal papillary mucinous neoplasm (IPMN) — A pancreas cut along its main duct: in main-duct IPMN the duct is dilated, filled with mucin and lined by papillary mucinous epithelium; in branch-duct IPMN side branches swell into mucin-filled cysts. A solid mural nodule is a high-risk sign of cancer. (pancreas ≈ 15 cm)
Pap smear (cervical cytology) — Cervical cells spread on a slide and Pap-stained: normal superficial (pink) and intermediate (blue-green) cells with small nuclei; LSIL with HPV koilocytes (big halo, enlarged wrinkled nuclei, two nuclei); HSIL with small immature cells almost filled by dark nuclei; and squamous cell carcinoma with orange keratinised tadpole cells in a dirty tumour diathesis. (cells ≈ 30–60 µm)
Colposcopy — acetowhite cervix — The cervix as the colposcope sees it after acetic acid: the red columnar epithelium of the transformation zone around the os, and dysplastic epithelium turning white (acetowhite) — faint and thin in LSIL, dense with coarse mosaic and punctation in HSIL, with atypical vessels and an exophytic mass once invasive. (cervix ≈ 3 cm across)
Endometrial hyperplasia → EIN → carcinoma — Endometrium from normal to cancer: evenly spaced tubular glands (normal), dilated, irregular glands with plenty of stroma (hyperplasia without atypia), crowded back-to-back glands with rounded atypical nuclei (atypical hyperplasia / EIN) and confluent glands of endometrioid carcinoma — driven by unopposed oestrogen and PTEN loss. (field ≈ 2 mm)
Serous tubal intraepithelial carcinoma (STIC) — The fimbriated end of a fallopian tube: one fimbria carries a patch of serous tubal intraepithelial carcinoma (STIC), where atypical p53-mutant cells replace the ciliated lining — the precursor of most “ovarian” high-grade serous cancers. (fimbriae ≈ 1–2 cm)
Correa cascade (gastric precancer) — The steps from Helicobacter gastritis to intestinal-type gastric cancer, one at a time on the same stomach lining: normal glands, chronic atrophic gastritis (fewer glands, more inflammation), intestinal metaplasia (goblet cells appear), dysplasia and carcinoma. (field ≈ 1–2 mm)
Germ cell neoplasia in situ (GCNIS) — Seminiferous tubules cut across: normal tubules full of maturing germ cells beside tubules that have lost spermatogenesis and are lined by large, clear, atypical GCNIS cells along the basement membrane — the precursor of almost all adult testicular germ cell tumours. (tubules ≈ 0.2 mm)

Gastrointestinal cancers 7

Signet-ring cell (diffuse) carcinoma — Poorly cohesive (diffuse-type) carcinoma: single tumour cells, each a ball of mucin that pushes its nucleus into a crescent at the edge like a signet ring, infiltrate the stomach wall one by one between surviving glands. Loss of E-cadherin (CDH1) lets them grow without forming glands. (cells ≈ 15–25 µm)
Colorectal adenocarcinoma — histology — Colorectal adenocarcinoma under the microscope: large, irregular "garland" glands lined by tall, crowded cells with elongated pencil-shaped nuclei, their lumens filled with "dirty" necrosis and nuclear debris, invading desmoplastic stroma. (glands ≈ 0.2–0.6 mm)
Gastrointestinal stromal tumour (GIST) — A GIST of the stomach cut through its middle: a well-circumscribed, fleshy tan mass growing from the muscularis propria, bulging into the lumen under stretched mucosa with a central ulcer (umbilication), its cut surface whorled with haemorrhage. It arises from KIT-driven interstitial cells of Cajal. (mass ≈ 2–10 cm)
Advanced gastric cancer — Borrmann types — A patch of stomach lining with an advanced gastric cancer in each Borrmann type: I polypoid, II ulcerated with sharp, heaped-up margins, III ulcerated with ill-defined infiltrating margins, IV diffusely infiltrating — thick, rigid, effaced folds without a discrete mass. (lesion ≈ 3–8 cm)
Paris classification of superficial lesions — Six superficial (type 0) neoplastic lesions side by side, cut in profile through the gut lining as the endoscopic Paris classification describes them: pedunculated (0-Ip), sessile (0-Is), slightly elevated (0-IIa), flat (0-IIb), slightly depressed (0-IIc) and excavated (0-III). (lesions ≈ 0.5–3 cm)
Pseudomyxoma peritonei ("jelly belly") — The opened abdomen in pseudomyxoma peritonei: a ruptured low-grade mucinous neoplasm of the appendix has filled the peritoneal cavity with gelatinous mucin that coats the bowel loops and forms an omental cake. (cavity ≈ 30 cm)
Neuroendocrine tumour of the appendix — An appendix opened lengthwise with a small, firm yellow neuroendocrine tumour (carcinoid) at its tip — usually found by chance after appendicectomy; size and spread into the mesoappendix decide whether more surgery is needed. (appendix ≈ 8 cm; tumour ≈ 0.5–2 cm)

Lymphomas & myeloma 7

Gastric MALT lymphoma — Extranodal marginal-zone (MALT) lymphoma of the stomach: sheets of small centrocyte-like B cells fill the lamina propria around reactive follicles and invade and destroy gastric glands (lymphoepithelial lesions), driven by Helicobacter pylori on the surface — early lesions often regress after eradication. (field ≈ 1 mm)
Reed–Sternberg cell (Hodgkin lymphoma) — The diagnostic cell of classic Hodgkin lymphoma, cut open: a giant B-derived cell with two mirror-image nuclei, each with a huge red nucleolus ("owl eyes"), outnumbered by the reactive small lymphocytes, eosinophils and plasma cells around it. (RS cell ≈ 20–50 µm)
Burkitt lymphoma — "starry sky" — Burkitt lymphoma under the microscope: a "starry sky" of pale tingible-body macrophages, full of the debris of dying cells, scattered through a dark-blue sheet of monotonous, medium-sized B cells. MYC translocation, t(8;14), drives the fastest-growing human tumour (Ki-67 near 100 %). (field ≈ 0.5 mm)
Mycosis fungoides (cutaneous T-cell lymphoma) — A cutaneous T-cell lymphoma in skin: red, scaly patches and plaques (and, later, tumour nodules), with atypical cerebriform CD4 T cells climbing into the epidermis singly and in Pautrier microabscesses above a band-like dermal infiltrate. (plaque ≈ 2–10 cm)
Sézary cell (cerebriform lymphocyte) — A Sézary cell from the blood, cut open: a T lymphocyte whose nucleus is deeply folded and grooved like the surface of a brain (cerebriform). Sézary syndrome is the leukaemic form of cutaneous T-cell lymphoma, with red skin all over (erythroderma). (cell ≈ 8–20 µm)
Multiple myeloma — "pepper-pot" skull — The skull vault in multiple myeloma: dozens of round, sharply punched-out lytic holes with no sclerotic rim ("raindrop" or "pepper-pot" skull), where clonal plasma cells have activated osteoclasts and dissolved the bone. (skull ≈ 18 cm)
Myeloma plasma cell (Mott & flame cells) — A malignant plasma cell from the marrow in myeloma, cut open: an eccentric nucleus with clock-face chromatin, deep-blue cytoplasm packed with immunoglobulin and a pale Golgi zone (hof). Variants store their protein as grape-like Russell bodies (Mott cell), intranuclear Dutcher bodies, or flame-red cytoplasm. (cell ≈ 10–20 µm)

Liver, pancreas & biliary cancers 6

Hepatocellular carcinoma — histology — Hepatocellular carcinoma under the microscope: tumour hepatocytes with large nuclei grow in plates many cells thick (instead of the normal one to two), separated by capillarised sinusoids, sometimes forming pseudoglands with bile plugs or solid sheets. (plates ≈ 50–150 µm)
Fibrolamellar carcinoma (liver) — A liver cancer of adolescents and young adults without cirrhosis: cords of large, pink (oncocytic) tumour cells with big nucleoli and pale bodies, lying between parallel bands of lamellar collagen. It is driven by a DNAJB1–PRKACA fusion. (cells ≈ 30–40 µm)
Pancreatic ductal adenocarcinoma — histology — Pancreatic ductal adenocarcinoma: small, angulated, haphazard and incomplete glands scattered in very dense desmoplastic stroma, with residual acini and an islet nearby, and glands wrapping a nerve (perineural invasion) — one reason this cancer spreads early and hurts. (glands ≈ 0.05–0.2 mm)
Pancreatic cystic neoplasms (cut) — Cystic tumours of the pancreatic tail cut in half: a serous cystadenoma (a sponge of tiny cysts round a calcified central scar, almost always benign), a mucinous cystic neoplasm (a thick-walled cyst full of mucin over ovarian-type stroma, a precursor of cancer) or a solid pseudopapillary neoplasm (solid, haemorrhagic and cystic, in young women). (cyst ≈ 2–10 cm)
Hilar cholangiocarcinoma (Klatskin tumour) — A cholangiocarcinoma at the hilum of the liver, where the right and left hepatic ducts join: it strictures the ducts and the bile ducts upstream dilate (painless jaundice). The Bismuth–Corlette type says how far it reaches — below the confluence (I), at it (II), into the right (IIIa) or left (IIIb) duct, or both (IV). (ducts ≈ 4–10 mm)
Ampullary carcinoma ("double-duct sign") — An opened duodenum with an ulcerated carcinoma at the ampulla of Vater, where the bile duct and pancreatic duct open together: it blocks both, so both dilate behind it (the "double-duct sign") and painless jaundice appears early — which is why these cancers are often caught operable. (tumour ≈ 1–3 cm)

Urological & testicular cancers 5

Renal cell carcinoma subtypes — histology — The three main renal cell carcinomas under the microscope: clear-cell RCC (nests of cells with clear, glycogen-rich cytoplasm in a delicate "chicken-wire" capillary network; VHL loss), papillary RCC (papillae with foamy macrophages in their cores) and chromophobe RCC (sheets of pale cells with crisp, plant-cell-like borders and wrinkled nuclei with halos). (nests ≈ 50–200 µm)
Kidney tumours — cut surface — A kidney bisected at the pathology bench, each tumour with its classic cut surface: clear-cell RCC (golden yellow with haemorrhage, necrosis and cysts), oncocytoma (mahogany brown with a central stellate scar), angiomyolipoma (yellow fat with thick vessels and muscle) and papillary RCC (friable tan-brown). (kidney ≈ 11 cm)
Bladder cancer at cystoscopy — The inside of an opened bladder as the cystoscope sees it: a low-grade papillary urothelial carcinoma waving its fronds like a sea anemone, a solid, ulcerated high-grade tumour, or a flat, red, velvety patch of carcinoma in situ — with the ureteric orifices below. (bladder ≈ 8 cm; tumour ≈ 0.5–3 cm)
Testicular germ cell tumours — histology — Testicular germ cell tumours under the microscope: seminoma (sheets of large clear cells parted by fibrous septa full of lymphocytes), yolk sac tumour (Schiller–Duval bodies with central vessels and hyaline globules; AFP), choriocarcinoma (syncytiotrophoblast capping cytotrophoblast in haemorrhage; hCG) and teratoma (cartilage, glands and keratin cysts). (field ≈ 1 mm)
Testicular tumours — cut surface — A testis bisected after orchidectomy: a seminoma replaces it with a homogeneous, cream, lobulated bulging mass; a mixed non-seminomatous germ cell tumour is variegated, with haemorrhage, necrosis, cysts and cartilage — the brown rim of normal testis, the tunica, epididymis and cord around. (testis ≈ 4–5 cm)

Gynaecological cancers 6

High-grade serous ovarian carcinoma — The commonest and deadliest ovarian cancer under the microscope: solid and papillary masses of cells with large, bizarre nuclei, cut through by slit-like spaces, with laminated calcified psammoma bodies. Nearly all carry TP53 mutations; many start in the fallopian tube. (field ≈ 1 mm)
Mature cystic teratoma (dermoid cyst) — An ovarian dermoid cyst opened: a germ cell tumour lined by skin, filled with greasy yellow sebum and a tangle of hair, with a Rokitansky nodule that may carry teeth, bone or cartilage. Benign; rarely a squamous cell carcinoma arises in it. (cyst ≈ 5–10 cm)
Mucinous ovarian tumour (multiloculated) — An ovarian mucinous tumour cut in half: one of the largest tumours in the body, a smooth-walled mass divided into many locules filled with glistening mucin. Most are benign or borderline; solid areas raise suspicion of carcinoma. (mass ≈ 10–30 cm)
Adult granulosa cell tumour — A sex-cord stromal tumour of the ovary that makes oestrogen: sheets of small cells with pale, oval "coffee-bean" nuclei split by a longitudinal groove, arranged around tiny pink-fluid rosettes (Call–Exner bodies). Driven by a FOXL2 mutation. (field ≈ 0.4 mm)
Hydatidiform mole (molar pregnancy) — A molar pregnancy evacuated from the uterus: grape-like clusters of swollen, fluid-filled (hydropic) villi on fine stalks. A complete mole (all villi swollen, no fetus; paternal genome only) can become invasive or turn into choriocarcinoma; a partial mole mixes normal villi and fetal tissue. (vesicles ≈ 1–20 mm)
Serous borderline tumour (ovarian surface) — An ovary studded with cauliflower-like papillary excrescences on its surface: a serous borderline (atypical proliferative) tumour, which grows slowly without destructive invasion and can progress to low-grade serous carcinoma. (ovary ≈ 4–8 cm)

Leukaemias 8

Myeloblast with Auer rods (AML) — A leukaemic myeloblast cut open: a large nucleus with fine, open chromatin and several nucleoli fills most of the cell; the thin rim of blue cytoplasm holds a few azurophilic granules and needle-like Auer rods — crystallised granules that prove the blast is myeloid (AML). (cell ≈ 15–20 µm)
Faggot cell (acute promyelocytic leukaemia) — The hallmark cell of acute promyelocytic leukaemia (PML–RARA, t(15;17)): an abnormal promyelocyte with a bilobed nucleus, cytoplasm packed with coarse granules and bundles of Auer rods stacked like firewood. Its granules trigger DIC — an emergency treated with all-trans retinoic acid and arsenic. (cell ≈ 15–25 µm)
Hairy cell (hairy cell leukaemia) — A hairy cell: a mature B cell with a pale oval or bean-shaped nucleus and fine hair-like projections all round its pale blue-grey cytoplasm. Hairy cell leukaemia (BRAF V600E) fills the marrow and spleen, causing pancytopenia and a "dry tap". (cell ≈ 12–20 µm)
Leukaemic blasts compared — Four kinds of leukaemic blast cut open side by side: a myeloblast (nucleoli, a few granules), a small lymphoblast with scant cytoplasm and a single small nucleolus (ALL), a large monoblast with a folded nucleus and vacuolated grey-blue cytoplasm, and a megakaryoblast with cytoplasmic blebs. (cells ≈ 10–25 µm)
Ring sideroblast (myelodysplasia) — An erythroblast from the marrow in myelodysplasia, cut open: iron-loaded mitochondria form a ring of blue granules round at least a third of the nucleus on a Perls (Prussian blue) stain. Ring sideroblasts mark MDS with SF3B1 mutation. (cell ≈ 12–18 µm)
Flower cell (adult T-cell leukaemia/lymphoma) — The flower cell of adult T-cell leukaemia/lymphoma: a lymphocyte whose nucleus is divided into petal-like lobes (a clover-leaf), caused by the retrovirus HTLV-1. The disease often brings hypercalcaemia and skin lesions. (cell ≈ 10–15 µm)
Philadelphia chromosome t(9;22) — Chromosomes 9 and 22 and their reciprocal translocation products: ABL1 from 9q34 joins BCR on 22q11, making the short Philadelphia chromosome that carries the BCR–ABL1 fusion — the always-on tyrosine kinase behind chronic myeloid leukaemia and targeted by imatinib. (chromosomes ≈ 2–8 µm)
Leukostasis (hyperleukocytosis) — A small vessel opened lengthwise in hyperleukocytosis: huge numbers of large, stiff leukaemic blasts plug the lumen and squeeze out the red cells, starving the lungs and brain of oxygen — a medical emergency of acute leukaemia. (vessel ≈ 20–50 µm)

Bone & soft-tissue sarcomas 9

Osteosarcoma of the distal femur — An osteosarcoma at the knee end of the femur, split open: tumour fills the metaphysis below the growth plate, breaks through the cortex and forms a soft-tissue mass shot through with sunburst spicules of tumour bone, lifting the periosteum into a Codman triangle at its edge. Mostly teenagers. (tumour ≈ 5–15 cm)
Ewing sarcoma of the femoral shaft — Ewing sarcoma in the shaft of a long bone, split open: small round blue cells permeate the marrow and the cortex, the periosteum lays down layer after layer of new bone ("onion skin") and a large soft-tissue mass bulges out. EWSR1–FLI1, t(11;22); children and young adults. (tumour ≈ 5–15 cm)
Chondrosarcoma — A chondrosarcoma in the end of a long bone, split open: glistening blue-grey lobules of hyaline cartilage fill the marrow, scallop the inside of the cortex and, at higher grades, break out into a lobulated mass with myxoid areas; flecks of "popcorn" calcification run through it. A tumour of adults (often IDH-mutant). (tumour ≈ 5–20 cm)
Giant cell tumour of bone — A giant cell tumour at the end of a long bone, split open: an eccentric, expansile lytic lesion of soft red-brown tissue in the epiphysis, reaching right up to the joint cartilage, ballooning the cortex into a thin shell with "soap-bubble" septa. Driven by RANKL from H3F3A-mutant stromal cells; denosumab blocks it. (lesion ≈ 4–10 cm)
Liposarcoma — histology subtypes — Liposarcoma under the microscope: well-differentiated (mature fat of very uneven cell size with atypical, dark stromal cells in its septa; MDM2-amplified), myxoid (a pale myxoid matrix with delicate branching "chicken-wire" capillaries and small lipoblasts; FUS–DDIT3) and pleomorphic (bizarre multivacuolated lipoblasts). (field ≈ 2 mm)
Leiomyosarcoma — intersecting fascicles — Leiomyosarcoma under the microscope: long fascicles of pink spindle cells with blunt-ended, cigar-shaped atypical nuclei, crossing each other at right angles, with mitoses and tumour necrosis — the features that separate it from a benign leiomyoma. (field ≈ 1 mm)
Kaposi sarcoma (skin) — Kaposi sarcoma of the skin: violaceous (purple) patches, plaques and nodules; on the cut face, slit-like vascular spaces holding red cells between proliferating spindle cells in the dermis. Caused by HHV-8, especially with HIV. (lesions ≈ 0.5–3 cm)
Dermatofibrosarcoma protuberans (storiform) — A dermatofibrosarcoma protuberans under the microscope: uniform spindle cells whorling in a cartwheel (storiform) pattern and threading between fat cells in a honeycomb at its deep edge. A COL1A1–PDGFB fusion drives it, so imatinib works. (field ≈ 1 mm)
Chordoma — physaliphorous cells — A chordoma, a tumour of notochord remnants at the sacrum or skull base: cords and lobules of large "physaliphorous" cells full of bubbly vacuoles in a blue-grey myxoid matrix, parted by fibrous septa. Brachyury (TBXT) marks it. (field ≈ 1–2 mm)

Skin & eye cancers 4

Uveal (choroidal) melanoma — An eye cut through its optic axis with a choroidal melanoma: a brown, dome-shaped tumour from the choroid that becomes mushroom- (collar-stud) shaped once it breaks through Bruch’s membrane, lifting the retina in an exudative detachment. It spreads to the liver (GNAQ/GNA11, BAP1). (eye ≈ 24 mm; tumour ≈ 5–15 mm)
Melanoma — clinical subtypes (ABCDE) — Melanomas as they look on the skin: superficial spreading (asymmetric, irregular border, many colours with red and white regression — the ABCDE warning signs), nodular (a fast-growing blue-black dome that may ulcerate), lentigo maligna (a large, irregular brown stain on sun-damaged skin), acral lentiginous (pigment along the ridges of the sole) and amelanotic (pink). (lesion ≈ 0.5–3 cm)
Basal cell carcinoma — subtypes — The commonest human cancer, from the surface and on the cut face: a nodular BCC (pearly, translucent papule with a rolled edge and branching telangiectasias), an ulcerated "rodent ulcer", a flat superficial BCC, and a scar-like morphoeic BCC — all made of basaloid nests with palisaded edges and retraction clefts (Hedgehog/PTCH1). (lesion ≈ 0.5–3 cm)
Keratoacanthoma (crateriform nodule) — A keratoacanthoma cut through its middle: a dome-shaped, rapidly growing nodule whose glassy squamous epithelium curves up in lips around a central crater plugged with laminated keratin. It may regress on its own, but is treated as a well-differentiated squamous cell carcinoma. (nodule ≈ 1–2.5 cm)

Childhood cancers 7

Retinoblastoma (eye) — An eye cut through its optic axis with retinoblastoma: a chalky white, calcified tumour of the infant retina growing into the vitreous (endophytic, with floating seeds) or under the retina (exophytic, detaching it) — the white pupil (leukocoria) parents notice in photographs. RB1 loss, Knudson’s two hits. (eye ≈ 17–20 mm (infant))
Neuroblastoma — Homer Wright rosettes — Neuroblastoma, a tumour of infant sympathetic nerve cells (often in the adrenal): sheets of small round blue cells arranged in Homer Wright rosettes round a core of pink fibrillary neuropil; differentiating tumours show ganglion cells. MYCN amplification signals high risk. (field ≈ 0.5 mm)
Wilms tumour (nephroblastoma) — triphasic — Wilms tumour, the commonest kidney cancer of children, recapitulates the embryonic kidney in three components: dense nests of small blue blastema, primitive tubules and glomeruloid bodies, and spindle-cell stroma. (field ≈ 1 mm)
Pilocytic astrocytoma (cyst & mural nodule) — The commonest childhood brain tumour, cut across the cerebellum: a large fluid-filled cyst with a small, enhancing mural nodule of tumour in its wall, squeezing the fourth ventricle. A slow, often curable WHO grade 1 glioma (BRAF fusion). (cyst ≈ 3–5 cm)
Botryoid rhabdomyosarcoma — Sarcoma botryoides, a form of embryonal rhabdomyosarcoma in small children: soft, gelatinous, grape-like polypoid masses bulging from the lining of the vagina or bladder, a dense cambium layer of tumour cells under their surface. (cluster ≈ 2–6 cm)
Craniopharyngioma (suprasellar) — A midline cut through the sella: an adamantinomatous craniopharyngioma above the pituitary — a solid-cystic, calcified mass filled with dark "machinery-oil" fluid that lifts the optic chiasm (vision loss) and presses on the pituitary and hypothalamus. Children and teenagers; CTNNB1-mutant. (tumour ≈ 2–5 cm)
Diffuse midline glioma of the pons (DIPG) — A midline cut through a child’s brainstem: a diffuse midline glioma (H3 K27-altered) swells the pons, infiltrating it diffusely, flattening the fourth ventricle and wrapping round the basilar artery in front. It cannot be removed surgically and remains one of the deadliest childhood cancers. (pons ≈ 2.5–4 cm)

Head, neck & endocrine cancers 7

Follicular thyroid carcinoma — capsular & vascular invasion — An encapsulated follicular thyroid tumour among normal colloid-filled follicles: only invasion separates carcinoma from adenoma — a bud of tumour pushing right through the fibrous capsule (capsular invasion) or tumour plugging a vessel in or beyond it (vascular invasion), which lets it spread by blood to bone and lung. (nodule ≈ 1–4 cm)
Medullary thyroid carcinoma — A thyroid cancer of the calcitonin-making C cells: nests of round to spindled neuroendocrine cells with salt-and-pepper chromatin beside pink-orange deposits of amyloid made from calcitonin. Germline RET mutations cause the familial forms (MEN2). (field ≈ 1 mm)
Pleomorphic adenoma (parotid) — The commonest salivary gland tumour, cut through in the parotid: a well-circumscribed, bosselated grey-white mass with glistening blue chondromyxoid islands, and finger-like pseudopods through its thin capsule (why simple shelling-out recurs) — near the facial nerve. A rare carcinoma can arise in it. (tumour ≈ 2–5 cm)
Phaeochromocytoma — zellballen — A catecholamine-making tumour of the adrenal medulla under the microscope: nests ("zellballen") of large chromaffin cells with granular purple cytoplasm and pleomorphic nuclei, each wrapped by thin sustentacular cells and a fine capillary network. Around a third are hereditary (SDH, VHL, RET, NF1). (nests ≈ 50–100 µm)
Thymoma (cut surface) — A thymoma of the anterior mediastinum cut in half: tan lobules of tumour divided by white fibrous bands inside a capsule, with small cysts. Invasion through the capsule into fat and pericardium sets the stage; many patients have myasthenia gravis. (mass ≈ 5–10 cm)
Laryngeal cancer at laryngoscopy — The larynx seen from above as on laryngoscopy: the white vocal cords in a V between the arytenoids and the epiglottis, with a white leukoplakia on one cord, a glottic squamous cell carcinoma (early hoarseness, rarely spreads) or a bulky supraglottic cancer above the cords. (larynx ≈ 4 cm)
Carotid body tumour (paraganglioma) — A paraganglioma of the carotid body: a highly vascular, red-brown mass sitting in the carotid bifurcation and splaying the internal and external carotid arteries apart (the "lyre sign"). The Shamblin class (I–III) says how far it wraps the arteries, which predicts surgical risk; many are SDH-hereditary. (tumour ≈ 2–6 cm)

Brain & nerve tumours 6

Oligodendroglioma — "fried-egg" cells — An oligodendroglioma under the microscope: sheets of uniform cells whose round nuclei sit in clear halos ("fried eggs"), threaded by a branching "chicken-wire" capillary network, with microcalcifications. Defined by IDH mutation and 1p/19q co-deletion. (field ≈ 0.5 mm)
Meningioma — whorls & psammoma bodies — A meningioma under the microscope: syncytial sheets of meningothelial (arachnoid cap) cells wrapping into concentric whorls, some of which calcify at their centre into laminated psammoma bodies. Mostly benign, WHO grade 1; NF2 loss is common. (field ≈ 1 mm)
Schwannoma — Antoni A/B & Verocay bodies — A schwannoma (nerve-sheath tumour, e.g. vestibular schwannoma) under the microscope: dense Antoni A areas where Schwann-cell nuclei line up in palisading rows around nuclear-free zones (Verocay bodies), next to loose, myxoid Antoni B areas with thick hyalinised vessels. (field ≈ 1 mm)
Ependymoma — perivascular pseudorosettes — An ependymoma under the microscope: tumour cells radiate around blood vessels with a nuclear-free halo of fibrillary processes between vessel and nuclei (perivascular pseudorosettes), with occasional true rosettes round tiny lumens. Children (fourth ventricle) and adults (spinal cord). (field ≈ 1 mm)
Diffuse glioma infiltration (Scherer structures) — Why diffuse gliomas can never be fully cut out: single tumour cells spread far through the brain, gathering round neurons (perineuronal satellitosis), round vessels and under the pia, and streaming along white-matter tracts — the secondary structures of Scherer. (field ≈ 1 mm)
1p/19q co-deletion (oligodendroglioma) — The change that defines an oligodendroglioma: a whole-arm translocation leaves one chromosome 1 without its short arm and one chromosome 19 without its long arm. A tumour carrying it, with an IDH mutation, responds far better to chemotherapy — which is why the laboratory runs the FISH probes shown beneath. (chromosomes ≈ 5 µm)

Cell lines in culture 10

Caco-2 monolayer with domes — A confluent colorectal adenocarcinoma monolayer that pumps fluid under itself: patches of cells lift into blisters ("domes"), a sign of polarised, transporting epithelium. (field ≈ 300 µm)
Breast cancer cells in 3-D gel: four growth patterns — Breast cell lines grown on basement-membrane gel form four classic shapes: organised round spheres, tightly packed masses, loose grape-like clusters and invasive stellate colonies. (colonies ≈ 50–150 µm)
Mammary acinus in 3-D culture: hollow, filled or invasive — Non-malignant breast cells form a hollow, polarised sphere around a lumen; oncogenes fill the lumen with surviving cells, and invasive cells break through the basement membrane. (acinus ⌀ ≈ 50–80 µm)
Mycoplasma-contaminated culture (DNA stain) — A DNA stain shows not only the cell nuclei but a haze of tiny specks over the cytoplasm and between cells: mycoplasma, a common hidden contaminant of cancer cell lines. (field ≈ 200 µm)
Organotypic melanoma skin model (raft culture) — Reconstructed skin lifted to an air–liquid interface: a collagen dermis with fibroblasts, a stratified epidermis on top, and melanoma cells forming nests at the junction that invade the dermis. (block ≈ 1 mm wide)
Cancer-cell culture flask (confluence & medium colour) — A T-75 flask of adherent tumour cells. Phenol red in the medium tells the state at a glance: red when fresh, orange-yellow when the cells have overgrown and acidified it, cloudy yellow when contaminated. (≈ 15 × 8 cm)
Suspension lymphoma cells growing in clumps — Many B-cell lymphoma lines (Burkitt-type) grow floating in medium as grape-like clumps of round cells with singles around them — they are split by pipetting, not trypsin. (cells ≈ 10–12 µm)
Cancer cells responding to a cytotoxic drug (dish view) — What a treated culture looks like: survivors stay flat and spread, dying cells round up and bleb, and dead cells detach and float as apoptotic bodies. (field ≈ 250 µm)
Focus formation assay (loss of contact inhibition) — Normal fibroblasts stop dividing when they touch and lie in a flat, aligned sheet; cells transformed by an oncogene keep growing over each other into dense, piled-up foci. (focus ≈ 1–2 mm)
Spectral karyotype of a cancer cell line — Each chromosome pair painted its own colour reveals what cancer genomes are like: far too many chromosomes and many two-coloured ones — pieces swapped between chromosomes by translocations. (spread ≈ 50 µm)

Spheroids & 3-D culture 11

Tumourspheres (cancer stem-cell sphere assay) — Single tumour cells in serum-free medium on a non-stick surface: only self-renewing (stem-like) cells grow into loose floating spheres, so sphere counts estimate their frequency. (well ⌀ ≈ 6.4 mm (96-well))
Tri-culture spheroid (tumour cells, fibroblasts, endothelial cells) — A spheroid seeded with three cell types sorts itself: fibroblasts pack into the core, endothelial cells form vessel-like cords, and tumour cells cover the outside. (⌀ ≈ 400 µm)
Spheroids in a microwell array — Cells spun into hundreds of inverted-pyramid microwells settle to each tip and aggregate, giving many spheroids of nearly the same size at once. (microwell ≈ 400–800 µm)
Magnetic levitation spheroid culture — Cells loaded with magnetic nanoparticles are lifted by a magnet in the lid to the top of the medium, where they gather into a spheroid without any scaffold. (well ⌀ ≈ 6 mm)
Spheroid growth and treatment response over time — The same spheroids imaged on days 0–10: untreated ones keep growing, while treated ones stop, lose their smooth edge, shed dead cells and shrink. (spheroids ≈ 300–700 µm)
Spinner flask culture of tumour spheroids — A glass flask with a slowly turning paddle keeps cells in suspension, where they collide and grow into many spheroids at once. (≈ 12 cm tall)
Cleared spheroid imaged by light-sheet microscopy — Made transparent by optical clearing, a whole spheroid can be imaged cell by cell: each nucleus is a point coloured by depth, and the light sheet picks out one optical section. (⌀ ≈ 500 µm)
Precision-cut tumour slice on a culture insert — A thin living slice of a surgical tumour kept on a porous membrane at the air–liquid interface, with its own stroma, vessels and immune cells — for testing drugs ex vivo. (insert ⌀ ≈ 24 mm)
Tumour cells in alginate microcapsules — Cells encapsulated in soft alginate beads grow into spheroids of a controlled size inside each bead, protected yet fed through the porous gel. (beads ⌀ ≈ 200–400 µm)
3-D bioprinted tumour model — A printer lays down crossing strands of cell-laden bio-ink layer by layer, building a porous tumour construct of set size and stiffness, here with a perfusable vessel-like channel through it. (≈ 1 cm)
Decellularised tumour matrix re-seeded with cells — Washing a tumour (or organ) with detergents removes its cells but keeps the fibrous extracellular matrix; cancer cells seeded back into this scaffold meet the stiffness and proteins of a real tumour. (≈ 5 mm)

Tumour organoids 12

Colorectal cancer organoid — A patient-derived colorectal tumour organoid: a solid, irregular, budding mass of crowded cells with only small scattered lumens — no orderly crypts as in a normal mini-gut. (≈ 200–500 µm)
Pancreatic cancer organoid (PDAC) — Pancreatic ductal adenocarcinoma organoids are typically large, thin-walled, irregular cysts lined by one layer of ductal tumour cells around a fluid-filled lumen. (≈ 200–800 µm)
Breast cancer organoid — Breast tumour organoids often grow as solid, grape-like clusters of cells (here budded into lobules) rather than the hollow acini of normal breast epithelium. (≈ 150–400 µm)
Prostate cancer organoid (cribriform) — Prostate tumour organoids grow as solid spheres pierced by many small, punched-out lumens — the cribriform pattern seen in aggressive prostate cancer. (≈ 200–500 µm)
Glioblastoma organoid (GBO) — Glioblastoma organoids cut straight from surgical tissue grow without gel into dense spheres that keep their stem-like cells, with single tumour cells creeping outwards along fine processes. (≈ 1–2 mm)
Ovarian cancer organoid (papillary) — High-grade serous ovarian cancer organoids form cysts whose walls fold into branching papillary fronds that project into the lumen. (≈ 200–600 µm)
Organoid drug screen (384-well plate close-up) — Patient-derived organoids seeded in small gel drops in a 384-well plate: across the dose series they shrink, fragment and die, and a luminescent ATP read-out measures survival. (wells ≈ 3.5 mm)
Deriving tumour organoids from a biopsy — Four steps from patient to organoid line: a tumour biopsy is minced, digested into small cell clusters, then embedded in gel domes where the clusters grow into organoids. (dishes ≈ 3.5 cm)
Tumour organoid co-cultured with killer lymphocytes — Autologous T cells (or NK / CAR-T cells) added to a patient’s tumour organoids cluster on them and kill: target cells at each contact turn caspase-positive. (organoid ≈ 200 µm)
Air–liquid interface tumour fragment culture — A minced tumour fragment set in collagen on a porous membrane: medium diffuses up from below while the top meets air, keeping the tumour’s own immune cells and stroma alive alongside it. (≈ 1–3 mm)
Engineered colon organoids: normal to cancer (APC, KRAS, TP53, SMAD4) — Editing the four classic colorectal cancer genes one by one into normal colon organoids recreates the adenoma–carcinoma sequence: budding → cystic → thick → solid and invasive, needing fewer growth factors at each step. (organoids ≈ 200–500 µm)
Glioma cells invading a cerebral organoid (GLICO) — Green-labelled patient glioma stem cells placed on a human cerebral organoid home in and invade the neural tissue along thin tumour microtubes, much as they do in the brain. (organoid ≈ 2–4 mm)

Tumour-on-chip 5

Vascularised tumour-on-chip — A three-channel microfluidic chip: medium flows in the side channels, and in the central gel endothelial cells self-assemble into perfusable microvessels around tumour cell clusters. (≈ 25 × 75 mm slide)
Tumour cell extravasating from a microvessel (on-chip close-up) — Inside a perfused microvessel on a chip: one tumour cell arrested in the lumen, one squeezing through the endothelium, and one already spreading in the matrix outside. (vessel ⌀ ≈ 30–50 µm)
Spheroid traps across a drug gradient (microfluidic) — A "Christmas-tree" channel network splits and remixes drug and medium into a stepwise concentration gradient, feeding columns of trapped spheroids — a dose–response on one chip. (≈ 2 × 3 cm chip)
Tumour–liver two-organ chip — Liver and tumour tissues share recirculating medium on one chip: the liver turns a prodrug (yellow) into its active form (red), which then reaches and acts on the tumour. (≈ 25 × 75 mm)
Cancer cells squeezing through confining channels — Cells migrating into ever-narrower microchannels must squeeze their stiff nucleus; in the tightest ones the nuclear envelope can rupture and leak, causing DNA damage. (channels 3–10 µm wide)

In vivo & alternative models 17

Patient-derived xenograft (PDX) passaging — Fragments of a patient’s tumour are implanted under the skin of an immunodeficient mouse (P0); when the tumour grows it is passaged into further mice for expansion and banked frozen. (mice ≈ 9 cm)
Excised xenograft tumours by treatment group — At the end of a study, tumours from each mouse are cut out and laid in rows by treatment arm next to a ruler — the classic picture of a drug or combination shrinking tumours. (tumours ≈ 0.3–1.5 cm)
Chick chorioallantoic membrane (CAM) tumour assay — in the egg — A window cut in a fertilised egg exposes the richly vascular chorioallantoic membrane; tumour cells grafted inside a silicone ring grow within days and draw new vessels towards them. (egg ≈ 6 cm)
Shell-less (ex ovo) CAM culture with tumour grafts — The whole chick embryo grown out of its shell in a dish: the membrane spreads flat over the yolk, so several tumour grafts can be placed, watched and imaged at once. (dish ≈ 10 cm)
Zebrafish larva xenograft — Two days after a few hundred red-labelled human tumour cells are injected into the perivitelline space, a transparent larva shows the tumour mass and cells spread through the green vessels to the tail. (larva ≈ 3–4 mm)
Fruit-fly larva with eye-disc tumours — In Drosophila, cells of the eye-antennal discs made to carry oncogenic Ras and lose polarity genes (e.g. RasV12 scrib⁻) are marked with GFP: they overgrow into large tumours and spread through the larva. (larva ≈ 4–5 mm)
Pancreatic tumour from a KPC mouse (excised) — The KPC genetically engineered mouse (Kras G12D and Trp53 R172H switched on in the pancreas) grows hard, pale, stroma-rich tumours in the pancreatic head, much like human pancreatic cancer. (≈ 3 cm across)
Intestinal polyps in an Apc-mutant mouse (Swiss roll) — Mice with one mutant Apc allele (ApcMin/+) develop dozens of small-intestinal adenomas; the opened gut is rolled mucosa-out into a "Swiss roll" so every polyp can be counted and sectioned. (roll ⌀ ≈ 1–1.5 cm)
Mammary gland whole mount with tumours (MMTV-PyMT) — A mouse mammary fat pad spread on a slide and stained with carmine: the branching duct tree runs past the lymph node, and in MMTV-PyMT mice it fills with hyperplasia, adenomas and carcinomas. (≈ 2 cm)
Mouse lungs with tumour nodules — Mouse lungs (one left lobe, four right lobes) taken to count tumours: Bouin’s fixative turns lungs yellow and India ink turns them black, so white nodules — metastases or Kras-driven adenomas — stand out. (≈ 1.5 cm)
Mouse liver with metastases (intrasplenic model) — Tumour cells injected into the spleen travel by the portal vein to the liver and grow as pale nodules on its dark lobes — a standard model of colorectal and pancreatic liver metastasis. (≈ 2.5 cm)
Bone metastasis in a mouse tibia (micro-CT) — A micro-CT rendering of a mouse tibia after intratibial or intracardiac injection: breast and lung cancer cells punch osteolytic holes through the cortex, while prostate cancer builds dense osteoblastic bone. (tibia ≈ 1.8 cm)
Mouse brain with an orthotopic glioma (fluorescence) — Seen from above after removal, a mouse brain with a fluorescent glioma growing in one hemisphere where the cells were injected by stereotaxis. (≈ 1.5 cm)
Cre–lox switch-on of an oncogene (Lox-Stop-Lox) — Genetically engineered mice carry an oncogene silenced by a STOP cassette between two loxP sites; where Cre recombinase is made (in one tissue, or after a virus or tamoxifen) it cuts the STOP out and the oncogene turns on. (schematic (DNA))
Multicolour clonal tracing in a tumour (Confetti) — A Brainbow-type "Confetti" reporter randomly labels cells in one of four colours; each patch of one colour in the cut tumour is a clone descended from a single labelled cell. (tumour ≈ 2–5 mm)
Hollow-fibre assay — Tumour cells sealed inside thin, porous plastic fibres are implanted under the skin and in the abdomen of a mouse; after dosing, the fibres are pulled out and the surviving cells counted. (fibres ≈ 1 mm ⌀, 2 cm long)
Vascular corrosion cast of a tumour — Resin injected into the circulation and the tissue dissolved away (or a micro-CT of contrast-filled vessels) shows the difference: an orderly tree in normal tissue versus a tangled, dilated, dead-ending mesh in the tumour. (≈ 1–2 cm)

Liquid biopsy 13

Cell-free DNA blood collection tube — Blood for liquid biopsy is drawn into tubes whose preservative stops white cells bursting and diluting tumour DNA; after centrifugation the plasma on top is carefully taken off for cfDNA extraction. (13 × 100 mm)
Circulating tumour DNA among cell-free DNA in plasma — Plasma carries short DNA fragments left by dying cells, mostly still wrapped round a nucleosome (~167 base pairs); tumour-derived fragments are rarer, slightly shorter and carry the tumour’s mutations. (fragments ≈ 50 nm (schematic))
Cell-free DNA fragment-size profile — Sizing all plasma DNA fragments gives a sharp peak at ~167 bp (DNA around one nucleosome) with a 10-bp ripple below it; tumour DNA is shifted to shorter fragments — the basis of "fragmentomics". (chart)
Error-corrected ctDNA sequencing (molecular barcodes) — Each original DNA molecule is tagged with a unique barcode before copying; reads sharing a barcode are collapsed into one consensus, so a real mutation present in the whole family survives while random errors drop out. (schematic)
Immunomagnetic capture of a circulating tumour cell — Nanobeads coated with antibodies against the epithelial marker EpCAM coat a rare tumour cell among billions of blood cells, so a magnet can pull it out of a blood sample. (cell ≈ 15–25 µm)
Calling a CTC by immunofluorescence (CK⁺ CD45⁻ DAPI⁺) — After enrichment, a cell counts as a circulating tumour cell if it has a nucleus (DAPI, blue), epithelial cytokeratin (green) and no leukocyte marker CD45 (red) — the white cells around it are CD45⁺. (field ≈ 100 µm)
Herringbone CTC capture chip (channel close-up) — Chevron grooves in the ceiling of a microchannel stir the flowing blood into swirls, pushing cells against the antibody-coated floor so rare tumour cells stick while blood cells flow on. (channel ≈ 2 mm wide)
Inertial spiral chip separating CTCs from blood — In a curved microchannel, inertial lift and Dean vortices push large tumour cells to the inner wall and small blood cells outwards, so the two streams leave by different outlets — no labels needed. (≈ 3 cm)
Size-based CTC filtration membrane — Blood is pushed through a membrane with 8 µm pores: deformable blood cells squeeze through, while larger, stiffer tumour cells are held back on the surface. (field ≈ 100 µm)
Tumour extracellular vesicles captured on a bead — Tumour cells shed membrane vesicles (exosomes) carrying their proteins and nucleic acids; antibody-coated beads pull them out of plasma for analysis. (bead ≈ 3 µm (vesicles ≈ 100 nm))
Body fluids used for liquid biopsy — Tumour DNA, cells and vesicles can be found in more than blood: urine (bladder and kidney cancers), cerebrospinal fluid (brain tumours) and pleural or ascitic fluid are sampled too. (tubes ≈ 10 cm)
Tracking ctDNA through treatment (molecular relapse) — Serial blood tests after surgery: tumour DNA falls below detection, then rises again months before the relapse shows on a scan — minimal residual disease detected molecularly. (chart)
CEA shed from a tumour cell — Why a blood test can follow a bowel cancer: carcinoembryonic antigen is a heavily sugar-coated protein held on the tumour cell’s surface by a GPI anchor, and the cell keeps cutting it loose into the capillary beneath — where a rising level after surgery means the cancer is back. (cell ≈ 20 µm)

Biopsies & specimens 8

Core needle biopsy (needle tip and cores) — A spring-loaded needle: the stylet shoots into the lesion, tissue falls into its side notch, and the outer cannula slices over it — returning a thin cylinder of tissue for histology. (needle ⌀ ≈ 1.6–2.1 mm (magnified))
Fine-needle aspiration and smear — A thin needle drawn back and forth through a lump collects loose cells; the drop is expelled on a slide and spread into a thin smear for rapid cytology. (slide 75 × 25 mm)
Skin punch biopsy — A circular blade twisted into the skin cuts a cylinder through epidermis, dermis and into fat; the core is lifted out and the small hole closed with a stitch. (punch ⌀ 4 mm (magnified))
Bone marrow aspiration and trephine biopsy — A T-handled needle is screwed into the back of the hip bone: liquid marrow is sucked into a syringe for smears, and a solid core of bone and marrow is taken for histology — key in leukaemia, lymphoma and myeloma. (needle ≈ 10 cm)
Endoscopic forceps biopsy — Passed down an endoscope, a flexible coiled cable ends in two sharp cups that open, close on the edge of a lesion and tear off a few millimetres of mucosa for histology. (jaws ≈ 2–3 mm (magnified))
Lumpectomy specimen with inked margins — Each surface of an excised breast specimen is painted a different ink so the pathologist knows which margin a tumour comes close to; sliced like bread, the cut faces show the firm tumour in the fat. (≈ 6 cm)
Prostate biopsy: needle tracks through a template — Biopsy needles pass through a grid on the perineum into the prostate in a planned pattern; cores that cross the cancer focus (red) map where and how much tumour there is. (prostate ≈ 4–5 cm)
Tumour dissociation into a single-cell suspension — For flow cytometry or single-cell sequencing, a fresh tumour is minced and turned in enzymes by a rotor, then passed through a 70 µm strainer to leave a suspension of single cells. (tubes ≈ 10 cm)

Imaging read-outs 9

PET-CT slice with an FDG-avid lung tumour — One axial slice through the chest: the grey CT shows anatomy and the colour PET overlay shows where radioactive glucose (FDG) piles up — a hot lung tumour, a spread to a mediastinal lymph node, and normal heart uptake. (slice ≈ 35 cm across)
Glioma segmented on MRI (oedema, enhancing rim, necrosis) — A glioblastoma outlined in 3-D from MRI: a necrotic core inside a contrast-enhancing rim, wrapped in a larger zone of swollen (oedematous) brain seen on FLAIR — the regions used in tumour segmentation. (brain ≈ 16 cm)
Spiculated breast mass with microcalcifications — The classic mammographic sign of breast cancer: an irregular mass sending out radiating spicules into the fatty tissue, often with a cluster of tiny, irregular calcium flecks nearby. (mass ≈ 1–2 cm)
Lung nodules on CT: solid, part-solid and ground-glass — Three kinds of lung nodule found on CT screening: a solid one, a hazy ground-glass one, and a part-solid one with a dense core inside the haze — the part-solid type is the most likely to be cancer. (nodules ≈ 5–30 mm)
Fluorescence-guided tumour resection — Patients drink 5-ALA before glioma surgery; tumour cells turn it into a fluorescent pigment, so under blue light the remaining tumour in the cavity glows pink and can be removed more completely. (field ≈ 4 cm)
Sentinel lymph node mapping — Blue dye and a radiotracer injected near the tumour drain along the lymphatics to the first ("sentinel") node; the surgeon finds it by its blue colour and gamma-probe signal and removes only that node. (field ≈ 10 cm)
Intravital microscopy through an imaging window — A glass window implanted over a tumour lets a multiphoton microscope film living cancer cells, leaky tortuous vessels and macrophages in the same animal over days. (window ⌀ ≈ 1 cm)
Radiomics: a segmented tumour as voxels — For radiomics a tumour outlined on CT, MRI or PET is broken into voxels; the spread and texture of their intensities (here colour-binned) become numbers that can predict outcome or mutation status. (tumour ≈ 3–5 cm)
Digital pathology: AI tumour heat map on a slide — A scanned H&E slide is cut into small tiles; a deep-learning model scores each tile, and the colour map shows where it thinks the tumour is, next to the pathologist’s own outline. (slide 75 × 25 mm)

Chemotherapy at work 16

Platinum drug crosslinking DNA (cisplatin adduct) — Cisplatin, carboplatin and oxaliplatin bind two neighbouring guanines on one DNA strand; the crosslink bends the helix sharply, blocking replication and transcription until the cell dies. (DNA ⌀ 2 nm (close-up))
Interstrand crosslink stalling a replication fork — Alkylating drugs such as nitrogen mustards and mitomycin C tie the two DNA strands together; the replication fork cannot unzip past the link and stalls until special repair (the Fanconi pathway) removes it. (schematic)
Doxorubicin intercalating into DNA — Anthracyclines slide their flat ring system between base pairs, stretching and unwinding the helix; this also traps topoisomerase II and makes free radicals — part of why they are both effective and cardiotoxic. (DNA ⌀ 2 nm (schematic))
Topoisomerase poisons (camptothecins, etoposide) — Topoisomerases cut DNA to relieve twisting and must rejoin it. Irinotecan and topotecan freeze topoisomerase I on a nicked strand so an oncoming fork breaks the DNA; etoposide holds topoisomerase II’s double-strand gate open. (schematic)
Antimetabolites jamming the DNA polymerase — Look-alike building blocks — 5-fluorouracil, gemcitabine, cytarabine — are taken up by replicating cells, deplete normal nucleotides or get built into the new strand, and the replication fork stalls; methotrexate blocks folate metabolism upstream. (polymerase ≈ 10 nm (schematic))
Taxane-stabilised microtubules — Paclitaxel and docetaxel bind β-tubulin on the inner face of microtubules and lock them: the tubules stop shrinking, bundle together, and the mitotic spindle cannot work, so dividing cells stall and die. (microtubule ⌀ 25 nm)
Vinca alkaloids peeling a microtubule end — Vincristine and vinblastine bind between tubulin dimers at the growing end, curling the protofilaments outwards like ram’s horns and stopping growth; free tubulin is wrapped into spirals. (microtubule ⌀ 25 nm)
Proteasome inhibitor jamming protein disposal — The 26S proteasome shreds tagged proteins in its barrel; bortezomib and carfilzomib block its cutting sites, so ubiquitin-tagged proteins pile up — myeloma cells, making huge amounts of antibody, die of the stress. (≈ 45 nm long (schematic))
PARP inhibitor trapping and synthetic lethality — PARP inhibitors freeze PARP1 on single-strand breaks (inset); forks crash into it and make double-strand breaks. Normal cells repair them (left), but BRCA-mutant cancer cells cannot, and their chromosomes shatter (right). (nuclei ≈ 10 µm)
Endocrine therapy at the oestrogen receptor — In ER-positive breast cancer, oestradiol-bound receptor recruits coactivators to switch on growth genes; tamoxifen flips helix 12 so corepressors bind instead, and fulvestrant gets the receptor destroyed. (cell ≈ 15 µm (receptor enlarged))
Implanted chemotherapy port — A small reservoir implanted under the chest skin feeds a catheter into a large vein; chemotherapy is given through a bent, non-coring needle pushed through the silicone septum, sparing the arm veins. (port ⌀ ≈ 3 cm)
Elastomeric infusion pump (take-home chemotherapy) — A stretched rubber balloon inside a clear shell squeezes out its drug at a steady rate through a fine flow restrictor — used to give 46-hour 5-fluorouracil infusions at home. (≈ 15 cm long)
Chemo- or radio-embolisation of a liver tumour — Liver tumours draw blood from the hepatic artery; a catheter threaded into it delivers drug-loaded beads (TACE) or radioactive yttrium-90 microspheres (SIRT) that lodge in the tumour’s vessels. (tumour ≈ 3–5 cm)
Ommaya reservoir for drugs into the brain fluid — A dome-shaped reservoir under the scalp with a catheter into a lateral ventricle lets chemotherapy (e.g. methotrexate, cytarabine) be injected straight into the cerebrospinal fluid, past the blood–brain barrier. (head ≈ 20 cm)
Closed-system drug transfer device — Hazardous drugs are drawn up through a vial adaptor with a sealed connector and an expanding bladder that balances pressure, so no droplets or vapour escape to the nurse or pharmacist. (≈ 15 cm tall)
Scalp cooling cap (preventing chemotherapy hair loss) — A tight silicone cap with circulating coolant chills the scalp to about 18 °C during chemotherapy; narrowed blood flow and slower follicle metabolism mean less drug reaches hair roots, reducing hair loss. (head ≈ 20 cm)

Targeted therapy & antibodies 13

EGFR kinase inhibitor blocking a growth signal — Mutant EGFR in lung cancer signals non-stop; small-molecule tyrosine kinase inhibitors sit in the ATP pocket of the inner kinase domains so the receptor can no longer phosphorylate itself and pass the signal on. (receptor ≈ 15 nm (schematic))
Anti-HER2 antibodies on a breast cancer cell — HER2-amplified cancer cells carry a million receptors each; trastuzumab binds near the membrane and pertuzumab blocks the arm used for pairing — together they stop signalling and flag the cell to immune cells. (schematic)
Blocking the MAPK cascade (BRAF and MEK inhibitors) — In BRAF V600E melanoma the RAS→RAF→MEK→ERK relay is jammed on; a BRAF inhibitor plus a MEK inhibitor shut it at two steps, which works better and delays resistance. (schematic)
KRAS G12C locked off by a covalent inhibitor — KRAS was long called "undruggable"; the G12C mutation adds a cysteine next to a hidden pocket, and sotorasib or adagrasib bond to it, trapping KRAS in its inactive GDP state. (KRAS ≈ 4 nm (schematic))
Philadelphia chromosome and BCR-ABL1 inhibitor — Swapping the ends of chromosomes 9 and 22 joins BCR to ABL1, making an always-on kinase that drives chronic myeloid leukaemia; imatinib blocks it — the first great success of targeted therapy. (chromosomes ≈ 5 µm)
PI3K–AKT–mTOR pathway and its inhibitors — A growth signal makes PI3K turn membrane lipids into PIP3, which docks and activates AKT, which in turn switches on mTORC1 on lysosomes to drive growth; drugs now block each step. (schematic)
CDK4/6 inhibitors holding cells in G1 — To pass the G1 restriction point, CDK4/6 with cyclin D must phosphorylate RB to free E2F; palbociclib-type drugs block this, so ER-positive breast cancer cells are held before S phase. (schematic)
Anti-angiogenic therapy normalising tumour vessels — Tumours flood themselves with VEGF and grow dense, twisted, leaky vessels; antibodies such as bevacizumab mop up VEGF, pruning the extra vessels and leaving a more normal network that delivers drugs better. (field ≈ 1 mm)
BH3 mimetic freeing BAX to open mitochondria — Many leukaemias survive by over-making BCL-2, which holds back the death proteins BAX and BAK; venetoclax occupies BCL-2, freeing them to punch pores in mitochondria and release cytochrome c. (mitochondrion ≈ 2 µm)
PROTAC degrader bringing a target to destruction — A PROTAC is a two-headed molecule: one end grabs the cancer protein, the other an E3 ubiquitin ligase; held together, the target is tagged with ubiquitin and shredded by the proteasome — then the PROTAC moves on to the next. (schematic)
Anti-CD20 antibody killing a lymphoma cell with complement — Rituximab coats CD20 on B-cell lymphoma; the antibody tails recruit complement (C1q), which ends in membrane-attack pores that burst the cell, while also calling NK cells and macrophages. (cell ≈ 10 µm)
ADC bystander effect in a mixed tumour — An antibody–drug conjugate delivers its toxin only into cells carrying the target antigen, but a membrane-permeable payload leaks out and also kills neighbouring antigen-negative cells. (field ≈ 100 µm)
Radioligand therapy (lutetium-177 PSMA) — A small molecule that sticks to PSMA carries a lutetium-177 atom to prostate cancer cells wherever they are in the body; its beta particles travel a millimetre or so, hitting neighbouring cells too ("crossfire"). (field ≈ 100 µm)

Radiation therapy 11

Radiation tracks through a nucleus (low vs high LET) — X-ray (photon) radiation acts through scattered electrons that leave sparse ionisations; protons are denser, and alpha particles and carbon ions leave a straight, dense core of ionisations that causes complex, hard-to-repair DNA breaks. (nucleus ≈ 10 µm)
Proton Bragg peak vs X-ray depth dose — X-rays deposit most dose near the surface and keep going through the patient; protons give little dose on the way in, dump it in a sharp Bragg peak, then stop — stacked peaks (SOBP) cover the tumour with nothing behind it. (chart)
Conformal dose cloud (IMRT) sparing the spinal cord — Intensity-modulated radiotherapy shapes the high-dose region (nested isodose surfaces) to hug the tumour, even bending around the spinal cord close behind it. (neck ≈ 12 cm)
Multileaf collimator shaping the beam — Inside the linac head, dozens of thin tungsten leaves slide in from both sides to cut the X-ray beam to the outline of the tumour, changing shape continuously during IMRT and VMAT. (leaves ≈ 5 mm wide)
Thermoplastic immobilisation mask — For head-and-neck and brain radiotherapy, a warm perforated plastic sheet is moulded over the face and clipped to the couch, holding the head in exactly the same position for every treatment. (head ≈ 25 cm)
Stereotactic radiosurgery: beams converging on a target — Many weak beams from different directions cross at one small target: each passes harmlessly through normal brain, but together they give a very high, sharply focused dose — "radiosurgery" without a knife. (head ≈ 20 cm)
LDR brachytherapy seeds (close-up) — Rice-grain titanium capsules containing iodine-125 around a silver marker are pushed through needles, strung with spacers, into the prostate; they stay for good, giving a low dose rate over months. (seed 4.5 × 0.8 mm (magnified))
HDR brachytherapy applicator for cervical cancer — A tandem in the uterus and a ring (or ovoids) against the cervix are connected to an afterloader that steps a tiny iridium-192 source through them, giving a pear-shaped high dose to the cervix in minutes. (uterus ≈ 8 cm)
Cell survival curves (linear-quadratic, fractionation) — Clonogenic survival falls with dose along a curved "shoulder" (the linear-quadratic model); splitting the dose into fractions lets normal cells repair in between, so each fraction repeats the shoulder. (chart)
γH2AX foci after irradiation — Each DNA double-strand break gathers phosphorylated histone H2AX and repair proteins into a bright spot; about 20–40 foci per gray appear within minutes and fade as breaks are repaired over hours. (field ≈ 100 µm)
Proton pencil-beam scanning: spots and energy layers — A thin proton beam is steered by magnets to paint the tumour spot by spot; each beam energy stops at one depth, so the target is filled layer by layer from deep to shallow. (target ≈ 5 cm)

Local therapies & nanoparticle delivery 12

Nanoparticle size and depth of tumour penetration — Particles leaving a leaky tumour vessel travel different distances: large ones (≈ 100 nm) stay close to the vessel, while small ones (≈ 10 nm) diffuse deep into the dense, high-pressure tumour tissue. (field ≈ 200 µm)
Size-switching nanoparticles — Big enough to circulate and leak into the tumour, a 100 nm carrier is cut by tumour enzymes and releases ~10 nm particles that can then diffuse deep into the tissue — trying to get the best of both sizes. (schematic)
Photothermal therapy with gold nanorods — Gold nanorods gathered in a tumour absorb near-infrared laser light, which passes harmlessly through skin, and turn it into heat that cooks the tumour from inside. (tumour ≈ 1 cm)
Gold nanoparticles boosting radiation dose — Heavy gold atoms absorb X-rays far more strongly than tissue and spray out short-range photo- and Auger electrons, raising the local dose (and free radicals) inside tumour cells that took up the particles. (cell ≈ 20 µm)
Boron neutron capture therapy — Tumour cells take up a boron-10 drug; when hit by slow neutrons each boron atom splits into an alpha particle and a lithium nucleus whose tracks are about one cell long, killing the cell but sparing its neighbours. (cell ≈ 20 µm)
Where injected nanoparticles end up — After intravenous injection most nanoparticles are caught by the liver and spleen; on average under 1 % of the injected dose reaches the tumour — a central challenge for nanomedicine. (chart)
Image-guided tumour ablation (RF, microwave or cryo) — A needle-like probe placed through the skin under imaging destroys a small tumour with heat (radiofrequency or microwave) or cold (an ice ball), taking a safety margin of normal tissue around it. (tumour ≈ 2–3 cm)
High-intensity focused ultrasound (HIFU) ablation — A curved transducer focuses ultrasound through the skin into a rice-grain focus that heats to ablation; it is moved spot by spot until rows of small cigar-shaped lesions cover the tumour. (focus ≈ 2 × 10 mm)
Electrochemotherapy with needle electrodes — Short electric pulses through needle electrodes open temporary pores in tumour cell membranes, letting in a drug like bleomycin that normally barely enters — used for skin and soft-tissue tumours. (nodule ≈ 1–3 cm)
Tumour-treating fields (scalp arrays) — For glioblastoma, four adhesive arrays of ceramic discs on the shaved scalp deliver low-intensity alternating electric fields (≈ 200 kHz) that disrupt dividing tumour cells; they are worn most of the day. (head ≈ 20 cm)
Drug wafers lining a glioma resection cavity — After a high-grade glioma is removed, up to eight biodegradable wafers containing carmustine (BCNU) can be laid over the cavity wall; they release the drug locally over two to three weeks. (cavity ≈ 4 cm)
Intravesical BCG for bladder cancer — After superficial bladder tumours are removed, live attenuated BCG bacteria are run into the bladder through a catheter and held for two hours; the local immune reaction they provoke cuts recurrences. (bladder ≈ 8 cm)

Drug resistance 7

Multidrug resistance: efflux pumps — Cancer cells that make many ABC transporters such as P-glycoprotein use ATP to pump drugs like doxorubicin and paclitaxel straight back out, so too little reaches its target. (cell ≈ 20 µm)
Gatekeeper mutation blocking a kinase inhibitor — A single amino-acid change in the drug pocket can make a kinase resistant: EGFR T790M swaps a small threonine for a bulky methionine and raises ATP affinity, so first-generation drugs no longer bind; C797S later removes the anchor osimertinib needs. (kinase ≈ 5 nm (schematic))
Bypass resistance: MET amplification — With EGFR shut down by its drug, some lung cancers amplify the MET gene; the extra MET receptors switch the same downstream pathways back on, going around the block. (schematic)
Drug-tolerant persister cells — Even an excellent targeted drug leaves a few cells alive: slow-cycling "persisters" that tolerate it without a resistance mutation; they can regrow after a drug holiday or evolve true resistance. (field ≈ 1 mm)
Selection of a resistant subclone under therapy — A tumour is a mix of clones; treatment kills the sensitive majority so the tumour shrinks, but a small pre-existing resistant clone survives and regrows into a relapsed tumour made mostly of resistant cells. (tumours ≈ 1–3 cm)
Lysosomal drug trapping — Weakly basic drugs (doxorubicin, sunitinib) become charged in acidic lysosomes and are stuck there; a resistant cell with many lysosomes hoards the drug away from the nucleus (right) unlike a sensitive cell (left). (cells ≈ 20 µm)
Extrachromosomal DNA (ecDNA) amplification — Many aggressive tumours carry extra copies of an oncogene on small circles of DNA outside the chromosomes; they segregate unevenly at division, so copy numbers can shoot up quickly under drug pressure. (nucleus ≈ 10 µm)

Drug screening & read-outs 6

Drug combination matrix (synergy map) — Two drugs tested at every pair of doses: bar height shows the kill achieved, and colour how much it beats what the two drugs alone would predict — the hot region marks a synergistic combination. (chart)
Tumour growth curves by treatment arm — The main read-out of a mouse efficacy study: mean tumour volume over time in each arm (or each mouse as a separate "spider" line), showing how far each treatment slows growth. (chart)
Dose–response curves: IC50 shift in resistant cells — Sigmoid dose–response curves for parental and drug-resistant cells: resistance moves the curve to the right, and the fold change in IC50 measures how much more drug is needed. (chart)
Pooled CRISPR knockout screen in cancer cells — A library of guide RNAs is delivered so each cell loses one gene; after weeks of growth (or drug treatment) sequencing the guides shows which knockouts dropped out — the genes the cancer depends on. (schematic)
Cell Painting for image-based drug profiling — Six dyes paint nuclei, nucleoli and RNA, ER, actin and Golgi, and mitochondria; software measures thousands of features per cell, so a drug’s effect (here enlarged cells with fragmented mitochondria) leaves a fingerprint. (field ≈ 150 µm)
Acoustic droplet dispensing for drug screens — A focused pulse of sound from below a source plate ejects a 2.5-nanolitre droplet of compound straight up into the inverted assay plate — no tips touch, so thousands of drugs and doses can be set up quickly. (plates 128 × 86 mm (corner))

Cancer cell lines (SEM look) 5

HeLa cell (SEM look) — A HeLa cell, a cervical adenocarcinoma line, adherent and well spread on the dish, with membrane ruffles at the edge, many microvilli on top, a large oval nucleus with 2–3 nucleoli, retraction fibres anchoring it. (≈ 20–30 µm)
MDA-MB-231 breast cancer cell migrating — A triple-negative, mesenchymal MDA-MB-231 breast cancer cell in migration mode: elongated spindle shape, a broad ruffled leading edge, a long trailing tail with retraction fibres, irregular nucleus. (≈ 25–35 µm)
MCF-7 cell in amoeboid blebbing — A luminal breast cancer line MCF-7 cell switched to amoeboid movement: a rounded cell covered in large membrane blebs, few microvilli, not spread, round nucleus with prominent nucleolus. (≈ 15–25 µm)
U-87 MG glioblastoma cell — A U-87 MG glioblastoma cell, a highly aggressive type of brain cancer, showing a stellate shape with several long processes, a pleomorphic outline, a large irregular nucleus with multiple nucleoli, and numerous mitochondria. (≈ 20–30 µm)
A549 lung cancer cell rounding up for mitosis — An A549 lung cancer cell in the process of rounding up for mitosis, showing a round shape with chromosomes on the plate, a spindle, many retraction fibres still holding it to the dish, and a few blebs. (≈ 15–25 µm)

Ablation & interventional oncology 9

Cryoablation ice front killing tumour cells — At the edge of a cryoablation ice ball ice forms between cells first, drawing water out so they shrink; deeper in, where it is colder than about −40 °C, ice forms inside cells and kills them. Thawing bursts the cells and clots the capillaries. (cells ≈ 15 µm; scene ≈ 120 µm)
Histotripsy bubble cloud liquefying tumour tissue — Histotripsy fires very short, intense ultrasound pulses that make a cloud of cavitation bubbles at the focus; their violent growth and collapse tear cells into an acellular homogenate with a sharp edge, while collagen-rich vessels and ducts tend to survive. It is non-thermal. (cells ≈ 15 µm; lesion ≈ 0.5–1 mm)
Embolic beads lodged in tumour arterioles — In transarterial chemoembolisation, drug-eluting beads injected into the hepatic artery wedge in the tumour’s feeding arterioles, cutting off flow and releasing doxorubicin; radioembolisation instead lodges tiny yttrium-90 microspheres whose β-particles irradiate the tumour. (nodule ≈ 3 cm; beads 100–300 µm (drawn larger))
Irreversible electroporation around a pancreatic tumour — Irreversible electroporation (NanoKnife) passes short high-voltage pulses between needle electrodes set around a tumour; the field opens permanent nanopores in cell membranes so cells die, while collagen scaffolds, ducts and the encased artery survive — why it is used for locally advanced pancreatic cancer. (probes ≈ 1.5–2 cm apart; tumour ≈ 3 cm)
Laser interstitial thermal therapy of a brain tumour — In laser interstitial thermal therapy (LITT) a cooled laser fibre is passed through a small burr hole into a deep brain tumour under MRI guidance; MR thermometry tracks the heat and the coagulation zone grows until it covers the tumour. (tumour ≈ 2 cm; fibre ≈ 1.6 mm)
Hyperthermic intraperitoneal chemotherapy (HIPEC) — After cytoreductive surgery has removed every visible peritoneal deposit, chemotherapy heated to about 42 °C is circulated through the open or closed abdomen for 30–90 minutes; heat boosts drug uptake and kills the microscopic cells left on the peritoneal surfaces. (abdomen ≈ 35 cm)
Isolated limb perfusion for in-transit melanoma — For many in-transit melanoma or sarcoma deposits on a limb, the limb’s artery and vein are cannulated, a tourniquet seals it off, and a heart–lung style circuit pumps warm, oxygenated perfusate with high-dose melphalan (± TNF-α) through it alone for about an hour — doses the whole body could not tolerate. (leg ≈ 90 cm (shortened))
Photodynamic therapy of a superficial skin cancer — For superficial basal cell carcinoma or actinic keratoses, a cream of 5-aminolaevulinic acid is left on the skin; tumour cells turn it into protoporphyrin IX, which glows red under blue light, and when lit with red light makes singlet oxygen that kills them while sparing normal skin. (block ≈ 1 cm)
Hepatic arterial infusion pump for liver metastases — Liver metastases draw their blood from the hepatic artery, while normal liver relies mostly on the portal vein; a pump implanted under the skin delivers floxuridine through a catheter in the gastroduodenal artery straight to the tumours, at concentrations far higher than the rest of the body sees. (liver ≈ 20 cm)

Radiotherapy techniques & radiobiology 9

Radiotherapy beam arrangements on a pelvic slice — How external beams are arranged around a target: two opposed fields give a wide slab of dose, a four-field box a square, seven intensity-modulated fields or a rotating arc (VMAT) a dose cloud that bends around the bladder and rectum. (axial slice ≈ 36 cm across)
Lattice (spatially fractionated) radiotherapy of a bulky tumour — Lattice radiotherapy places small spheres of very high dose in a 3-D grid inside a bulky tumour, leaving low-dose valleys between them; the steep peaks and valleys shrink large tumours with little harm to the skin and nearby organs. (tumour ≈ 10–15 cm; vertices ≈ 1 cm)
Abscopal effect after radiotherapy — Radiation can turn the tumour it hits into a vaccine: dying cells release antigens that dendritic cells carry to the lymph node, where killer T cells are primed and then travel to shrink tumours outside the beam — rare alone, more common with checkpoint inhibitors. (schematic (tumours ≈ 2–3 cm))
Radiotherapy inside a lumpectomy cavity (balloon or intraoperative) — After a lumpectomy the tumour bed can be treated from inside: a balloon applicator fills the cavity and an iridium-192 source steps through it (accelerated partial-breast brachytherapy), or a spherical X-ray applicator gives one dose in theatre (intraoperative radiotherapy). (breast ≈ 12 cm; applicator ≈ 4 cm)
Eye plaque brachytherapy for uveal melanoma — For a choroidal melanoma a small gold plaque lined with iodine-125 (or ruthenium-106) seeds is sutured to the sclera over the tumour for a few days; the gold shields the orbit while the tumour, from base to apex, receives the dose. (eye ≈ 24 mm; plaque ≈ 14–20 mm)
Prostate seed implant through a perineal template — For low-dose-rate prostate brachytherapy, needles are passed through a grid template on the perineum under transrectal ultrasound and leave rows of iodine-125 seeds that stay for good, spaced to cover the gland while sparing the urethra and rectum. (prostate ≈ 4 cm; seeds 4.5 mm)
Oxygen fixing radiation damage in DNA — Radiation makes radicals on DNA; with oxygen present the radical becomes a peroxide and the damage is “fixed” as a strand break, while in hypoxia a thiol such as glutathione can donate hydrogen and repair it — why hypoxic tumour cells need two to three times the dose (the oxygen enhancement ratio). (DNA ≈ 2 nm wide)
Radium-223 alpha tracks in a bone metastasis — Radium-223 behaves like calcium and is laid down where osteoblasts are making new bone around prostate cancer metastases; its α-particles travel less than 100 µm, so they hit tumour cells next to the bone surface with dense, hard-to-repair DNA damage and spare most of the marrow. (cells ≈ 15 µm; α range ≈ 50–100 µm)
Radioactive iodine treatment of thyroid cancer — Differentiated thyroid cancer cells keep the sodium–iodide symporter, so swallowed iodine-131 is concentrated in them and in any remnant thyroid; its β-particles travel only about a millimetre, destroying the iodine-avid cells while sparing most other tissue, and its γ-rays show where it went. (follicles ≈ 200 µm)

Cancer surgery & endoscopy 10

Mohs micrographic surgery layers — In Mohs surgery a skin cancer is removed as a thin saucer-shaped layer, cut into inked quarters and read on frozen sections of its whole undersurface; wherever tumour reaches the margin another layer is taken from just that spot, until the margins are clear. (defect ≈ 1–3 cm)
Snare polypectomy in the colon — At colonoscopy a wire snare passed through the scope is closed round the stalk of a pedunculated adenoma and the polyp is cut off with diathermy; a flat lesion is first lifted on a cushion of saline injected under it (endoscopic mucosal resection). (colon ≈ 6 cm across; polyp ≈ 1.5 cm)
Transurethral resection of a bladder tumour — A resectoscope passed up the urethra shaves a papillary bladder tumour away in chips with an electric wire loop; the deepest chips must include detrusor muscle so the pathologist can tell whether the cancer has invaded it (T1 versus T2). (bladder ≈ 8 cm; tumour ≈ 2 cm)
Limb-salvage endoprosthesis after distal femur resection — After chemotherapy, an osteosarcoma of the distal femur is removed with a wide margin and the missing bone and knee are rebuilt with a modular metal endoprosthesis — a segmental body on a cemented stem with a rotating-hinge knee — instead of amputating the leg. (construct ≈ 30 cm)
Colostomy or ileostomy through the abdominal wall — After bowel cancer surgery the bowel may be brought out through a trephine in the rectus muscle and turned back on itself as a stoma: a flush end colostomy, or a spouted loop ileostomy that protects a low join; a hydrocolloid baseplate and pouch collect the output. (stoma ≈ 2.5–3.5 cm)
Ovarian tissue cryopreservation before cancer treatment — To protect fertility before sterilising chemotherapy or radiotherapy — including in girls before puberty — one ovary is removed by laparoscopy, its outer cortex, packed with primordial follicles, is cut into thin strips and frozen; after treatment the strips can be grafted back to restore hormones and fertility. (ovary ≈ 3–4 cm; strips ≈ 1 cm)
Self-expanding metal stent through a malignant stricture — When an inoperable cancer narrows the oesophagus, colon or bile duct, a self-expanding metal stent is passed through it endoscopically or under X-ray and springs open, restoring swallowing, bowel passage or bile flow within a day; a covering stops tumour growing through the mesh. (stent ≈ 10 cm long)
Balloon kyphoplasty of a vertebral metastasis — A lytic metastasis or myeloma deposit can collapse a vertebral body and cause severe pain; in kyphoplasty, cannulas are passed through both pedicles, balloons inflated to restore height and create a cavity, and bone cement injected to stabilise the vertebra within minutes. (vertebral body ≈ 4–5 cm)
Endoscopic ultrasound-guided biopsy of a pancreatic mass — An echoendoscope in the duodenum or stomach sits right against the pancreas; under real-time ultrasound a fine needle is passed through the bowel wall into the mass to sample it (EUS-FNA or FNB), often with a cytopathologist checking the material on the spot. (mass ≈ 2–3 cm)
Talc pleurodesis for a malignant pleural effusion — A malignant pleural effusion keeps coming back; after draining it, sterile talc is blown or poured into the pleural space, where it sets off inflammation and fibrin that weld the visceral and parietal pleura together so fluid can no longer collect — the alternative is a long-term tunnelled pleural catheter. (pleural space ≈ mm to cm)

Cell therapies & cancer vaccines 7

Tumour-infiltrating lymphocytes growing out of tumour fragments — TIL therapy starts with small fragments of a resected tumour (often melanoma) cultured in high-dose interleukin-2; the T cells inside crawl out and multiply over two to three weeks, before a rapid expansion to billions of cells that are infused back into the patient. (fragments ≈ 1–2 mm (drawn smaller); T cells ≈ 7 µm)
Neoantigen mRNA vaccine at work in a dendritic cell — A personalised cancer vaccine carries mRNA for the tumour’s own mutant peptides in lipid nanoparticles; dendritic cells take them up, translate the mRNA, cut the proteins into neoantigen peptides and show them on MHC molecules to prime killer T cells. (dendritic cell ≈ 15 µm (molecules enlarged))
What a TCR-T cell and a CAR-T cell recognise — An engineered T-cell receptor (TCR-T) sees a peptide from any protein inside the tumour cell, shown on HLA, so it needs the right HLA type; a chimeric antigen receptor (CAR) uses an antibody fragment to grab an intact surface protein without HLA, and carries its own co-stimulatory domains. (molecules ≈ 10–15 nm tall)
CAR-T trogocytosis stripping antigen from a tumour cell — When a CAR-T cell engages its target it can pull off patches of tumour membrane with the antigen (trogocytosis); tumour cells are left with less antigen and escape, and T cells now carrying the antigen become targets for other CAR-T cells (fratricide) — a cause of relapse. (cells ≈ 8–20 µm)
Differentiation therapy turning leukaemic promyelocytes into neutrophils — In acute promyelocytic leukaemia the PML–RARA fusion blocks maturation; all-trans retinoic acid (with arsenic trioxide) releases the block, and the granule-packed promyelocytes with Auer rods mature over days into band and segmented neutrophils — a cancer cured by differentiating it. (cells ≈ 12–20 µm)
Denosumab or zoledronate stopping bone destruction — In bone metastases tumour cells drive osteoblasts to make RANKL, which forms bone-eating osteoclasts. Denosumab, an antibody, mops up RANKL so no new osteoclasts form; zoledronate binds bone mineral and poisons the osteoclasts that resorb it. (cells ≈ 10–100 µm (antibodies enlarged))
Near-infrared photoimmunotherapy rupturing a tumour cell — In photoimmunotherapy an antibody such as cetuximab carries the dye IR700 to its receptor on cancer cells; near-infrared light (690 nm) changes the dye’s shape so it aggregates and tears the membrane, and the cell swells and bursts within minutes while untargeted neighbours are spared. (cell ≈ 20 µm (antibodies enlarged))

Resistance mechanisms (more) 6

Small-cell transformation of an EGFR-mutant lung adenocarcinoma — Under EGFR inhibitors some lung adenocarcinomas lose RB1 and TP53 and change lineage: the glands give way to sheets of small cells with scant cytoplasm and moulded nuclei, a neuroendocrine cancer the drug no longer touches — so a new biopsy at progression matters. (block ≈ 0.5 mm; small cells ≈ 10 µm)
Melanoma phenotype switching (proliferative to invasive) — Melanoma cells flip between a pigmented, proliferative state with high MITF and a slow, spindle-shaped invasive state with high AXL and low MITF; the invasive, dedifferentiated cells tolerate BRAF/MEK inhibitors and spread, and can switch back. (cells ≈ 20–40 µm long)
Myeloma cells shielded by bone-marrow stroma (adhesion-mediated drug resistance) — Myeloma cells that cling to bone-marrow stromal cells through VLA-4 and VCAM-1, bathed in stromal IL-6, survive drug doses that kill the same cells floating free — cell adhesion-mediated drug resistance, a reason minimal residual disease persists in the marrow niche. (cells ≈ 15 µm)
Loss of interferon-γ signalling (JAK1/2) in immunotherapy resistance — Killer T cells release interferon-γ, which through JAK1, JAK2 and STAT1 makes tumour cells raise MHC class I and stop growing; tumours that lose JAK1 or JAK2 go deaf to the signal and escape PD-1 blockade. (receptors ≈ 10 nm)
EML4–ALK fusion oncogene in lung cancer — In about one in twenty lung adenocarcinomas, mostly in never-smokers, a small inversion on chromosome 2 fuses EML4 to ALK; the EML4 part clusters the ALK kinase domains so they switch each other on without a signal. ALK inhibitors block the ATP pocket, and resistance mutations in the kinase drive the next drug. (protein ≈ 10 nm (chromosome not to scale))
Clonal haematopoiesis (CHIP) in the bone marrow — With age, a blood stem cell that picks up a mutation in DNMT3A, TET2 or ASXL1 can out-compete its neighbours and build a large clone without causing disease; clonal haematopoiesis raises the risk of blood cancers and of heart disease, and chemotherapy or radiotherapy can select clones (TP53, PPM1D) that lead to therapy-related leukaemia. (marrow ≈ 0.5 mm)

Side effects of cancer treatment 13

Chemotherapy mucositis in the small intestine — Chemotherapy and abdominal radiotherapy kill the fast-dividing crypt cells that renew the gut lining: within days crypts fill with apoptotic cells, villi shrink and ulcers open that let bacteria in, causing pain, diarrhoea and infection, before the crypts regrow. (villi ≈ 0.5 mm tall)
Anthracycline damage in heart muscle — Doxorubicin and other anthracyclines poison topoisomerase IIβ in heart muscle cells and generate reactive oxygen species; with rising cumulative dose the cells lose myofibrils, fill with vacuoles and die, and fibrosis replaces them — a dose-dependent cardiomyopathy. (cells ≈ 100 µm long)
Taxane neuropathy: dying-back of sensory nerve endings — Taxanes freeze microtubules into rigid bundles, stalling transport along the longest sensory axons; the nerve endings in the skin of the hands and feet swell and die back first, causing numbness and tingling in a glove-and-stocking pattern. (skin ≈ 1 mm; axon close-up ≈ 1 µm)
Chemotherapy damaging a growing hair follicle — The matrix cells at the base of a growing (anagen) hair follicle divide as fast as tumour cells; chemotherapy kills them, the shaft narrows to a weak point and breaks within weeks (anagen effluvium). Scalp cooling cuts blood flow to the bulbs and spares some follicles. (follicle ≈ 3–4 mm long)
Radiation dermatitis in the treatment field — Skin inside a radiotherapy field reacts in grades: redness from dilated dermal vessels, then dry peeling, then moist desquamation where the basal layer has died and serum seeps out, and rarely ulceration — sharply limited to the shape of the beam. (block ≈ 1 cm)
Lymphoedema of the arm after lymph-node removal — After axillary node dissection or radiotherapy, lymph backs up in the arm: collectors dilate and their valves fail, lymph refluxes into the dermis, protein-rich fluid collects, fat grows and fibrosis sets in, so the limb swells and hardens over the stages. (forearm cross-section ≈ 8–11 cm)
Cisplatin killing outer hair cells in the organ of Corti — Cisplatin lingers in the cochlea and kills the outer hair cells, first in the outermost row and at the high-frequency base, leaving scars; hearing loss starts at high pitches, is permanent, and is a major concern in children (sodium thiosulfate protects). (organ of Corti ≈ 100 µm wide)
Radiation pneumonitis and lung fibrosis — Weeks to months after chest radiotherapy the irradiated lung can become inflamed — leaky capillaries, hyaline membranes and immune cells in thickened alveolar walls (pneumonitis) — and months later scar, with collagen and myofibroblasts collapsing the alveoli (fibrosis). (alveoli ≈ 200 µm)
Checkpoint-inhibitor colitis — Releasing the brakes on T cells with anti-CTLA-4 or anti-PD-1 can turn them on the gut: CD8 T cells crowd the lamina propria and invade the crypts, crypt cells die by apoptosis, neutrophils fill crypts and goblet cells are lost — an immune-related adverse event treated with steroids or infliximab. (crypts ≈ 0.4 mm deep)
Extravasation of a vesicant chemotherapy drug — If a cannula slips out of the vein during an infusion, a vesicant such as doxorubicin leaks into the tissues; it binds DNA in the surrounding cells and keeps killing them, so redness and blistering can progress over weeks to deep necrosis unless the infusion is stopped and dexrazoxane or local measures are used. (block ≈ 3 cm)
Medication-related osteonecrosis of the jaw — High-dose bisphosphonates or denosumab given for bone metastases stop bone turnover in the jaw; after a tooth extraction the socket may not heal, leaving yellow-white dead bone exposed in the mouth for more than eight weeks, often infected — prevented by dental care before treatment. (jaw segment ≈ 5 cm)
Sinusoidal obstruction syndrome after high-dose chemotherapy — Conditioning chemotherapy before stem-cell transplant (busulfan, cyclophosphamide) or drugs such as inotuzumab injure the endothelium of liver sinusoids around the central veins; red cells push into the space of Disse, sinusoids and central veins narrow and zone 3 hepatocytes die — painful liver swelling, jaundice and fluid retention (veno-occlusive disease). (lobule ≈ 1 mm across)
CAR-T neurotoxicity (ICANS) at the blood–brain barrier — Days after CAR-T infusion, cytokines from the expanding T cells and from monocytes activate the brain’s capillary endothelium; pericytes loosen, the blood–brain barrier leaks and cytokines enter the brain, causing confusion, speech loss, seizures or swelling (immune effector cell-associated neurotoxicity syndrome). (capillary ≈ 8 µm)

Metastasis & microenvironment (more) 2

Micrometastasis growing in lung alveoli — A tumour cell that stops in a lung capillary can cross into the alveoli and grow: some colonies creep along the alveolar walls using them as scaffolding (lepidic growth) while others fill the air spaces as solid nests; both start far below the size a scan can see. (alveoli ≈ 200 µm)
Crown-like structures in breast fat — In obesity, enlarged adipocytes die and macrophages gather round each one in a ring — a crown-like structure — releasing inflammatory signals and oestrogen-making aromatase; their number in breast fat goes with a higher risk and worse outcome of breast cancer. (adipocytes ≈ 100 µm)

Paraneoplastic & oncological emergencies 7

Lambert–Eaton antibodies at the neuromuscular junction — In Lambert–Eaton myasthenic syndrome, often caused by small-cell lung cancer, antibodies made against the tumour also attack P/Q-type calcium channels in motor nerve terminals; less calcium enters, fewer vesicles of acetylcholine are released and the muscles weaken, improving briefly with use. (terminal ≈ 5 µm (molecules enlarged))
Crystals blocking a kidney tubule in tumour lysis syndrome — When a bulky, fast-growing cancer such as Burkitt lymphoma or acute leukaemia is killed quickly, its cells spill potassium, phosphate and nucleic acids; uric acid and calcium phosphate crystallise in the renal tubules, block them and injure the lining — acute kidney injury prevented with fluids, allopurinol or rasburicase. (tubule ≈ 50 µm across)
Cancer-associated venous thrombosis (Trousseau) — Cancers, especially of the pancreas, stomach and lung, make the blood clot: tumour cells and the microvesicles they shed carry tissue factor and mucins, activate platelets and draw out neutrophil traps, building fibrin-rich clots in veins — deep vein thrombosis, pulmonary embolism or migratory thrombophlebitis. (vein ≈ 0.4 mm (detail enlarged))
Superior vena cava obstruction by a lung tumour — A right-sided lung cancer or lymphoma with bulky mediastinal nodes can squeeze the thin-walled superior vena cava; blood from the head and arms backs up through the azygos and chest-wall veins, the neck veins bulge and the face swells, relieved quickly by an endovascular stent. (SVC ≈ 2 cm across)
Hyperviscosity from IgM paraprotein (Waldenström) — In Waldenström macroglobulinaemia the lymphoma secretes huge IgM pentamers that thicken the blood, stack red cells into rouleaux and slow flow in small vessels — causing blurred vision, headache, bleeding and confusion, an emergency treated with plasma exchange. (vessel ≈ 25 µm)
Paraneoplastic cerebellar degeneration — An ovarian or breast cancer that expresses a neuronal protein (CDR2, the Yo antigen) can provoke an immune attack on Purkinje cells; killer T cells destroy them, anti-Yo antibodies appear in the blood, and the cerebellum is left with empty baskets and Bergmann gliosis — severe, often permanent ataxia. (cortex ≈ 0.5 mm thick)
Cancer cachexia wasting skeletal muscle — In cancer cachexia, signals from the tumour and the immune system (IL-6, GDF15, activin) switch on protein breakdown in muscle through the ubiquitin–proteasome system; fibres shrink, fat creeps into the muscle and weight is lost that eating cannot restore. (fibres ≈ 50 µm across)

Cancer models & read-outs (more) 12

Matrigel plug angiogenesis assay — Cold liquid Matrigel mixed with angiogenic factors or tumour cells is injected under a mouse’s skin, where it sets into a plug; after one to two weeks the plugs are removed and the new vessels that grew in are scored by their redness, haemoglobin or CD31 staining. (plugs ≈ 0.5–1 cm)
Intracardiac injection model of bone metastasis — Injecting luciferase-labelled cancer cells into the left ventricle of a mouse sends them straight into the arterial circulation, bypassing the lungs; a bright-red pulsing flashback confirms the needle is in place, and weeks later bioluminescence shows metastases in the leg bones, spine and jaw. (mouse ≈ 9 cm)
Measuring a mouse tumour by ultrasound — High-frequency ultrasound measures a mouse tumour more accurately than calipers — in three dimensions and for tumours under the skin or in organs — and power Doppler or microbubble contrast shows its blood flow, all in the same anaesthetised mouse over time. (mouse ≈ 9 cm)
Intraductal injection (MIND) model of breast cancer — In the mouse intraductal (MIND) model, human breast cancer cells are injected through the teat straight into the milk ducts; they first grow inside the ducts like ductal carcinoma in situ and later break out into the fat pad, so progression happens in the right microenvironment. (mouse ≈ 9 cm; duct tree enlarged)
Orthotopic injection into the mouse pancreas — For an orthotopic pancreatic cancer model the anaesthetised mouse’s spleen and pancreatic tail are drawn out through a small left flank incision and a few microlitres of cancer cells are injected under the pancreatic capsule, raising a small bleb; tumours then grow with real stroma and spread to the liver. (mouse ≈ 9 cm)
Multiplex immunofluorescence of a tumour section — Multiplex immunofluorescence or imaging mass cytometry stains one tumour section for many markers at once, so each cell is typed and mapped: tumour nests, killer and regulatory T cells, macrophages and B-cell follicles — and the distances between them predict response to immunotherapy. (section ≈ 1 cm)
Atomic force microscopy stiffness map of a tumour — An atomic force microscope presses a tiny tip into a fresh tumour slice point by point and records how far it sinks, building a map of stiffness: the collagen-rich invasive front is stiff, while the cancer cells themselves are softer than normal cells — a mechanical fingerprint linked to aggressiveness. (slice ≈ 5 mm; grid points ≈ 20 µm)
Breast compressed for a screening mammogram — For a mammogram the breast is pressed flat between a clear paddle and the detector so tissue spreads out, dose falls and blur is reduced; two views per side (cranio-caudal and medio-lateral oblique) look for spiculated masses, clustered fine microcalcifications and distortion within dense tissue. (breast ≈ 12 cm wide)
Dermoscopy of a pigmented skin lesion — A dermatoscope lights and magnifies the skin so structures below the surface show: a benign naevus has a regular brown network, while melanoma shows asymmetry, several colours, a thick irregular network, blue-white veil, irregular dots and streaks at the edge. (lesion ≈ 6–10 mm)
Multi-region sampling of a heterogeneous kidney cancer — Sequencing one biopsy shows only part of a tumour: sampling a clear cell renal carcinoma at many separate regions revealed a shared trunk mutation (VHL) and branches — PBRM1, SETD2, BAP1 and others — found only in some regions, the map of branched evolution behind treatment resistance. (kidney ≈ 11 cm)
Why tumours light up on FDG-PET — The glucose analogue 18F-FDG enters cells through glucose transporters and is phosphorylated by hexokinase, but FDG-6-phosphate cannot go further down glycolysis or leave, so it is trapped; glycolytic tumour cells with many GLUT1 transporters and high hexokinase II pile it up and glow on the PET scan. (cells ≈ 20 µm (molecules enlarged))
Tumour-educated platelets as a liquid biopsy — Platelets take up RNA and proteins from tumour vesicles, and signals from the tumour change how they splice their own pre-mRNA; sequencing the RNA of platelets from a blood sample can therefore reveal cancer and its type — a tumour-educated platelet liquid biopsy. (platelets ≈ 2–3 µm)

Tumour types (more) 15

Gastrointestinal stromal tumour (GIST) of the stomach wall — A GIST grows from the interstitial cells of Cajal in the muscle wall of the stomach as a well-circumscribed, fleshy mass, usually bulging outward under the serosa, sometimes also into the lumen with an ulcer that bleeds; most carry KIT or PDGFRA mutations and respond to imatinib. (tumour ≈ 5 cm)
Desmoid tumour infiltrating skeletal muscle — A desmoid tumour (aggressive fibromatosis) is a firm, white, whorled mass of fibroblasts and collagen with a CTNNB1 or APC mutation; it does not metastasise but its finger-like edges creep between muscle fibres, so it recurs locally — often watched or treated with drugs before surgery. (mass ≈ 5–10 cm)
Ewing sarcoma with onion-skin periosteal reaction — Ewing sarcoma, a small-round-cell tumour of children and young adults with an EWSR1–FLI1 fusion, fills the shaft of a long bone, seeps through the cortex and forms a large soft-tissue mass; the periosteum it lifts lays down layer after layer of new bone, the onion-skin pattern on X-ray. (femur segment ≈ 14 cm)
Hepatoblastoma in a child’s liver (cut surface) — Hepatoblastoma, the commonest liver cancer of young children, is usually one large, well-circumscribed mass in the right lobe; its cut surface is variegated — tan fetal and embryonal epithelium, haemorrhage, bile-stained areas and gritty osteoid in the mixed type — and AFP in the blood is very high. (tumour ≈ 8–12 cm)
Cutaneous angiosarcoma of the scalp — Angiosarcoma of the scalp and face in older people starts as a bruise-like purple patch that will not fade, then grows into plaques and bleeding nodules; under the microscope irregular blood-filled channels lined by atypical endothelial cells dissect the dermis far beyond the visible edge. (block ≈ 3 cm)
Plexiform neurofibroma (“bag of worms”) — In neurofibromatosis type 1, a plexiform neurofibroma grows along a nerve and its branches, swelling every fascicle into a tangle of thick, tortuous, rope-like strands that feel like a bag of worms; it can become a malignant peripheral nerve sheath tumour, and MEK inhibitors such as selumetinib shrink it. (nerve ≈ 10–20 cm long)
Infantile haemangioma (strawberry mark) — An infantile haemangioma appears in the first weeks of life, grows fast for months as a bright-red lobulated “strawberry” of packed GLUT1-positive capillary lobules, then slowly involutes over years into fibrofatty tissue; propranolol speeds its shrinking. (lesion ≈ 1–5 cm)
Pleomorphic adenoma of the parotid gland — The commonest salivary gland tumour is a slow-growing, bosselated, encapsulated mass whose cut surface mixes glistening blue-grey chondromyxoid stroma with cellular epithelial and myoepithelial areas; small pseudopodia through the capsule explain recurrence after simple enucleation, so a cuff of normal parotid is removed with care for the facial nerve. (tumour ≈ 2–4 cm)
Warthin tumour (papillary cystadenoma lymphomatosum) — Warthin tumour of the parotid, strongly linked to smoking, is made of cysts with papillary folds lined by a double layer of pink, mitochondria-packed oncocytes — tall columnar cells on the lumen, cuboidal basal cells beneath — set in lymphoid stroma with germinal centres. (block ≈ 2 mm)
Parathyroid adenoma behind the thyroid — A single enlarged parathyroid gland — an adenoma — causes most primary hyperparathyroidism: it makes too much parathyroid hormone, raising blood calcium. It sits behind the thyroid, often at the lower pole, while the other three glands shrink; removing it cures the disease. (adenoma ≈ 1–3 cm)
Insulinoma in the body of the pancreas — An insulinoma is a small, usually benign neuroendocrine tumour of insulin-making β cells — often under 2 cm, firm and red-brown, anywhere in the pancreas; it causes fasting hypoglycaemia with confusion relieved by glucose (Whipple’s triad), and enucleation cures most. (tumour ≈ 1–2 cm)
Nasopharyngeal carcinoma (lymphoepithelial pattern) — Non-keratinising nasopharyngeal carcinoma, common in southern China and South-East Asia and driven by Epstein–Barr virus, grows as syncytial sheets of large cells with pale vesicular nuclei and big nucleoli mingled with dense lymphocytes; it is very sensitive to chemoradiotherapy, and EBV DNA in plasma tracks it. (block ≈ 0.4 mm)
Synovial sarcoma (biphasic histology) — Synovial sarcoma, a soft-tissue sarcoma of young adults usually near the knee, is defined by the SS18–SSX fusion; under the microscope sheets and fascicles of uniform plump spindle cells surround glands of epithelial cells in the biphasic type, or stand alone in the monophasic type. (block ≈ 0.4 mm)
Medullary thyroid carcinoma with amyloid — Medullary thyroid carcinoma arises from the calcitonin-making C cells: nests and sheets of round to spindle cells with salt-and-pepper nuclei sit in stroma containing amyloid made from calcitonin, among the remaining thyroid follicles; RET mutations underlie hereditary MEN2 cases, and calcitonin and CEA track it. (block ≈ 0.5 mm)
Neuroblastoma of the adrenal gland (cut surface) — Neuroblastoma, the commonest solid cancer outside the brain in young children, usually arises in the adrenal medulla as a large, soft, lobulated grey-tan mass with haemorrhage, necrosis and gritty calcification that pushes the kidney down and wraps around the aorta and its branches; MYCN amplification marks high risk. (tumour ≈ 6–10 cm)

Immune checkpoint blockade 3

Pembrolizumab blocking PD-1 in the synaptic cleft — The full pembrolizumab IgG4 (5DK3) grips PD-1 on the T cell through the face PD-L1 would use (5GGS), so PD-L1 on the tumour cell is left unbound; the other setting shows PD-1 engaged with PD-L1 (4ZQK, 3BIK). (≈ 14 nm cleft; IgG4 ≈ 15 nm)
LAG-3 gripping MHC class II — The checkpoint receptor LAG-3 (domains 1–2) docks on the side of a peptide-loaded MHC class II molecule, away from where the T-cell receptor reads the peptide (mouse LAG-3 on I-Aᵇ, 9CYM). Relatlimab blocks this contact. (≈ 12 nm tall)
Macrophage stripping anti-PD-1 from a T cell — Close-up of the contact: an Fcγ receptor on a tumour-associated macrophage grabs the Fc of anti-PD-1 bound to PD-1 on a CD8⁺ T cell and pulls the antibody, with PD-1 on a membrane tether, off the T cell, which loses its protection (in vivo imaging, Arlauckas 2017). Pembrolizumab IgG4 (5DK3) on PD-1 (5GGS), Fc held by FcγRIII (1E4K). (≈ 12 nm cleft (close-up of the contact))

Immunometabolism 2

IDO1 holding tryptophan over its haem — Indoleamine 2,3-dioxygenase 1 (6E35) clamps L-tryptophan above its haem iron and opens the indole ring to make kynurenine; tumours and tolerogenic dendritic cells use it to starve T cells of tryptophan and feed them kynurenine. (≈ 6 nm)
T-cell mitochondria: fused in memory, fragmented in effector — Memory T cells keep a long, fused mitochondrial network with tightly packed cristae for oxidative phosphorylation and fatty-acid oxidation; effector T cells split theirs into small punctate mitochondria with loose cristae and switch to aerobic glycolysis. Forcing fusion (OPA1) favours memory (Buck 2016). Some mitochondria are cut open to show the cristae. (≈ 10 µm field)

Radioligand therapy 3

PSMA dimer carrying ¹⁷⁷Lu-PSMA-617 — Prostate-specific membrane antigen is a homodimer on the cancer-cell surface; PSMA-617 (8BOW) sits with its glutamate–urea head in each active site and its DOTA cage, holding lutetium-177, out at the funnel mouth. Its β-particles kill the cell and its neighbours (VISION trial). (≈ 12 nm wide)
Somatostatin receptor 2 holding ¹⁷⁷Lu-DOTATATE — The radiopeptide binds deep in the extracellular pocket of somatostatin receptor 2 and the receptor couples to its Gi protein (octreotide–SSTR2–Gi, 7T11); the DOTA cage with lutetium-177 sticks out of the pocket. Receptor-bound drug is internalised, irradiating neuroendocrine tumour cells (NETTER-1). (≈ 13 nm tall)
Radioligand crossfire through a tumour section — PSMA-positive cancer cells hold the radioligand on their membranes; lutetium-177 β-particles wander up to about 2 mm, crossing many cells and reaching PSMA-negative neighbours, while actinium-225 α-particles travel only 50–100 µm in dense, straight tracks that leave clustered double-strand breaks (γH2AX foci) in the nuclei they cross. (≈ 100 µm field)

Targeted protein degradation 2

Cullin-2 ligase tagging BRD4 through the PROTAC MZ1 — MZ1 glues BRD4 to VHL (ternary complex 5T35), which sits on Elongin B/C at the tip of the curved cullin-2 scaffold; RBX1 at the far end brings ubiquitin-loaded E2 (5N4W). The ubiquitin chain marks BRD4 for the proteasome; its placement here is illustrative. (≈ 20 nm across)
Cereblon glue recruiting the IKZF1 zinc finger — Pomalidomide sits in the tri-tryptophan pocket of cereblon and creates a new surface that catches the second zinc finger of Ikaros (IKZF1) on CRL4–DDB1, so the transcription factor is ubiquitinated and destroyed in myeloma cells (6H0F). The other setting leaves the drug out: no zinc finger is caught. (≈ 14 nm across)

Bispecifics & antibody–drug conjugates 3

Trastuzumab deruxtecan bound to HER2 — Trastuzumab grips domain IV of HER2 just above the membrane (1N8Z, grafted on an intact IgG1, 1HZH); deruxtecan carries eight topoisomerase I inhibitor payloads (DXd) on cleavable GGFG linkers at the interchain cysteines. (≈ 20 nm tall)
CD19 × CD3 T-cell engager bridging two cells — A BiTE-type engager is two single-chain antibody fragments on a short linker: one holds CD19 on the B cell, the other CD3ε on the T cell, closing a narrow cytolytic synapse (blinatumomab). Modelled from the FMC63 scFv on CD19 (7URV) and OKT3 on CD3εγ (1SY6). (≈ 14 nm cleft)
Deruxtecan payload killing HER2-negative neighbours — A HER2-positive cell takes up trastuzumab deruxtecan; lysosomal cathepsins cut the GGFG linker and the membrane-permeable DXd diffuses out into adjacent HER2-negative cells, where it traps topoisomerase I on DNA (bystander killing, Ogitani 2016). The charged payload of T-DM1 stays in the target cell. (cells ≈ 12–15 µm)

Tertiary lymphoid structures 2

Mature tertiary lymphoid structure in a tumour section — A tertiary lymphoid structure in tumour stroma: a B-cell follicle with a germinal centre (dark and light zones) sits beside a T-cell zone threaded with high endothelial venules, among tumour nests. Mature TLSs with germinal centres predict response to checkpoint blockade; earlier stages are loose aggregates or primary follicles (Sautès-Fridman 2019). (≈ 0.5 mm field (drawn at 1 unit = 4 µm))
Follicular dendritic cell offering antigen to B cells — In a germinal-centre light zone, a follicular dendritic cell holds intact antigen as clusters of immune complexes (iccosomes) on its thick dendrites; a germinal-centre B cell grips a cluster with its B-cell receptors and pulls the antigen off to present it to T follicular helper cells. TLSs in tumours with these networks make tumour-specific antibodies. (≈ 25 µm)

Cancer — the driver, by site 18

The EGFR mutation that makes a lung cancer — A normal EGFR waits: the two halves of the receptor only pair once a ligand has arrived, and the kinase underneath is held in an inactive fold until they do. An exon 19 deletion shortens the loop in front of the C helix, and L858R puts a bulky charged residue into the activation loop; either way the inactive fold will no longer hold, and the receptor signals with nothing bound to it. Osimertinib goes into the ATP pocket and makes a covalent bond to cysteine 797, which is why it does not come off — and why a serine at 797, the best-known of the on-target escapes, ends its usefulness in an afternoon. (receptor about 20 nm long)
A kinase handed the wrong partner — Four different fusions, one mechanism, and it is worth drawing once. A chromosome breaks and rejoins so that the gene for a kinase ends up behind the gene for a protein that pairs with itself — EML4, CD74, KIF5B, ETV6. The kinase arrives already in a pair and stays in one, so it phosphorylates its partner and itself with nothing switching it on. There is no membrane in it and no ligand: the dimerisation is built into the protein. Which is why one small-molecule inhibitor works across tumours that look nothing like each other, and why these fusions are looked for in a lung biopsy whatever the histology says. (fusion protein 8–12 nm)
MET that is never taken off the surface — A receptor is switched off partly by being removed. Phosphorylated tyrosine 1003, in the stretch of MET that exon 14 encodes, is the handle the ubiquitin ligase Cbl grips; it marks the receptor, the receptor is internalised, and the signal ends. Skipping exon 14 does not change the kinase at all — it deletes the handle. Cbl has nothing to hold, the receptor stays on the surface, and a normal amount of signalling becomes a permanent one. About three in a hundred lung adenocarcinomas, and more in the older patients who have never smoked. (receptor spans 10 nm)
HER2, crowded into pairing — Amplification is a number, so this card is a count. Two copies of HER2 on a patch of membrane sit apart and wait for a partner to be switched on by its own ligand. Twenty copies on the same patch pair with each other by sheer concentration — HER2 has no ligand of its own, and it does not need one once there are enough of them. That is the whole lesion, and it is why the test is a count rather than a sequence: twenty copies behave differently from two without a single base changing in the gene. (patch 15 nm across)
FGFR locked on — A normal FGFR needs an FGF and a heparan sulfate to hold it there. Bladder cancers and bile-duct cancers get round that in two ways, and both are drawn here. A fusion replaces the receptor's tail with a coiled coil — TACC3 is the usual one — so the receptor arrives already paired. A point mutation such as S249C puts a spare cysteine in the linker, and the two receptors simply bolt themselves together with a disulfide. The kinase is untouched in both, which is why the same inhibitor answers both. (receptor spans 9 nm)
JAK2 V617F — JAK2 carries its own brake: a pseudokinase domain that holds the real kinase shut until a cytokine pulls the receptor into shape. Valine 617 sits at the contact between the two. Change it to a phenylalanine and the contact no longer holds, so the kinase runs without erythropoietin, thrombopoietin or G-CSF ever arriving. One mutation, and which of the three myeloproliferative diseases follows depends on what the clone happens to make too much of — red cells, platelets, or a marrow full of scar. (JAK2 spans 12 nm)
FLT3 with a duplication in its hinge — The juxtamembrane stretch of FLT3 folds back into the kinase cleft and keeps it shut between signals. An internal tandem duplication repeats part of that stretch, which makes it too long to reach the place it should block — so the brake is a loop hanging loose, the receptors dimerise, and an immature myeloid cell proliferates without FLT3 ligand. A quarter of acute myeloid leukaemias have it, the ratio of mutant to wild type changes the prognosis, and it can appear at relapse in a leukaemia that did not have it at diagnosis. (receptor spans 10 nm)
The androgen receptor axis, and the three ways out of it — Prostate cancer is a disease of one signal, so blocking it works, and then stops working. Androgen is made, enters the cell, opens the receptor's pocket, and the receptor goes to the DNA and reads the genes a prostate cell grows by. Abiraterone blocks CYP17 and cuts the supply, including the supply the tumour makes for itself; enzalutamide sits in the pocket and holds the receptor in a shape that cannot work. AR-V7 answers both by removing the problem: the message is spliced short, the ligand-binding domain is never made, and what is left is already in the nucleus and already on. (receptor 10 nm; cell 20 µm)
Why a mismatch-repair tumour collects mutations — The polymerase slips when it copies a run of repeats, leaving a loop of extra units in the new strand. MutSα finds the loop, MutLα nicks the strand, and it is cut out before the cell divides. Lose MSH2 or MLH1 and nothing comes: the repeat is a unit longer in every daughter cell, which is what a microsatellite test measures. Where such a repeat sits inside a gene, everything after it is read out of frame — so the tumour makes peptides no T cell has ever met, holds them up on MHC class I, and answers to a checkpoint inhibitor better than almost any other tumour. (microsatellite 20–50 bp)
APC loss in a colon crypt — The first mutation in nearly every colorectal cancer, and it happens in a crypt that still looks normal. β-catenin is normally held by APC against two kinases, phosphorylated four times, ubiquitinated and destroyed within minutes, so there is never any in the nucleus. A truncated APC cannot hold it: β-catenin is never marked, it accumulates, and it walks into the nucleus and sits on TCF, which reads MYC and cyclin D as though a Wnt signal had arrived from outside. Nothing has arrived. The crypt has simply lost the ability to say no. (destruction complex 12 nm)
One phosphate, and the phosphatase that should remove it — The whole signal is the third phosphate on a lipid. PI3K puts it on, turning PIP₂ into PIP₃; AKT has a domain that only sticks to the membrane when PIP₃ is there, and once it is stuck it is phosphorylated and goes off to switch on growth and switch off cell death. PTEN takes the phosphate straight back off, which is why the signal is normally a flicker. Losing PTEN — usually by deletion rather than mutation, in prostate, endometrial and glioblastoma — leaves PIP₃ standing and AKT stuck to the membrane for good. (membrane patch 15 nm)
The G1 brake, and the four ways past it — One card for a set of lesions that are the same lesion. E2F sits on the promoters a cell needs before it copies its DNA, and RB sits on E2F. CDK4/6 with cyclin D phosphorylates RB and lets E2F go; p16 is a wedge that keeps that kinase off. A tumour can delete p16, amplify cyclin D, or delete RB1 — and only the first two can be answered with a CDK4/6 inhibitor. With RB1 gone there is nothing for the kinase to phosphorylate and nothing for the drug to protect, which is why the inhibitor fails in small-cell lung cancer and in the breast cancers that lose RB1 on treatment. (nucleus 6 µm)
An androgen switch wired to the wrong gene — Two genes sit three megabases apart on chromosome 21: TMPRSS2, which a prostate cell switches on whenever androgen arrives, and ERG, a transcription factor a prostate cell has no use for. Delete what is between them and the switch is now in front of the wrong gene. Nothing is mutated and no protein is abnormal — the wiring is. So every day's androgen signal, the ordinary one, makes a transcription factor that then sits on hundreds of promoters and switches on an invasion programme. It is found in about half of all prostate cancers, and it is there already in a high-grade PIN lesion. (genes 3 Mb apart; nucleus 6 µm)
SMAD4, and the brake pancreatic cancer loses — TGF-β should stop an epithelial cell dividing. The receptor phosphorylates SMAD2 and SMAD3, SMAD4 joins them, and only the three of them together can enter the nucleus and switch on p21. Delete SMAD4 — and about half of pancreatic cancers do — and the other two are phosphorylated faithfully and go nowhere. The brake is never pulled. What makes it worse is that the rest of the TGF-β signal still works, and without the brake it drives invasion instead: a tumour with SMAD4 gone is the one that is already everywhere when it is found. (receptor 10 nm; nucleus 6 µm)
STK11 loss, and the cold tumour it makes — This card is half molecule and half tissue, because one causes the other. LKB1 is the kinase that switches on AMPK when a cell runs short of energy; without it mTOR is unrestrained and the cell builds as though food were unlimited. The second half is what an oncologist actually sees: the interferon-driven chemokines that call T cells into a tumour are not made, so the T cells stay in the stroma at the edge and never come in. An STK11-mutant lung adenocarcinoma therefore answers badly to a checkpoint inhibitor, and that is a property of the tumour's edge rather than of its PD-L1 score. (tumour edge 60 µm)
The two neurofibromatoses do two different jobs — The names are consecutive and the proteins have nothing to do with each other. Neurofibromin, the NF1 product, is a GAP: it makes RAS hydrolyse its own GTP a thousand times faster, and without it RAS never switches itself off, so the MAPK cascade runs all day and a Schwann cell becomes a neurofibroma. Merlin, the NF2 product, links the cell junction to the actin beneath it, which is how a cell registers that it has neighbours; without it Hippo is never switched on, YAP goes to the nucleus, and the cell grows as though it were alone — a meningioma, or on both sides a vestibular schwannoma. (RAS 4 nm; junction 20 nm)
What a virus does instead of mutating two genes — Most cancers mutate TP53 and RB1. A cervical or oropharyngeal cancer does not have to, because the virus has brought two small proteins that do the job. E6 does not inhibit p53 — it recruits E6AP, a ubiquitin ligase of the cell's own, points it at p53, and has it destroyed. E7 needs no phosphate: it simply grips RB harder than E2F does and prises the two apart. Which is why HPV-driven tumours carry remarkably few mutations of their own, and why p16 is high in them rather than lost — the cell is making more of a brake that has stopped mattering. (nucleus 7 µm)
EBV's permanently pressed buttons — Epstein–Barr virus does not transform a B cell by mutating it. It gives the cell two proteins that imitate the two signals a B cell normally has to earn. LMP1 is six helices through the membrane that clump together on their own, gathering TRAFs underneath exactly as a triggered CD40 does — so NF-κB is on all the time and the cell behaves as though it had just met a helper T cell. LMP2A is a receptor tail with no receptor on it, its ITAM phosphorylated with no antigen anywhere. A B cell that should have died in the germinal centre for having no useful antibody survives instead. (membrane patch 13 nm)

Cancer — the drug at its target 11

Two antibodies, one receptor, two addresses — HER2 has four ectodomains, and where an antibody lands decides what it does. Trastuzumab binds domain IV, low down against the membrane: it blocks very little, and most of its effect is that an NK cell now has something to grip. Pertuzumab binds domain II, the face a partner receptor has to dock against, so it stops the pairing itself — which is why the two are given together rather than one instead of the other. The same domain IV address carries a payload in trastuzumab deruxtecan: eight molecules of a topoisomerase poison, cut loose inside the cell, in enough quantity to kill the neighbouring cells too. (receptor 10 nm)
A drug that is built into the DNA and then catches the enzyme — A hypomethylating agent does not strip methyl groups off. Azacitidine is taken up as a nucleotide and put straight into the DNA in place of a cytosine; DNMT1 then comes along to copy the methylation pattern on to the new strand, attacks the ring as it always does, and cannot let go — there is a nitrogen where the carbon it needs to finish should be. The enzyme is destroyed along with the strand it is stuck to, and each division dilutes the methylation further until a silenced gene is read again. Nothing in the sequence was ever wrong; it had simply been switched off. (DNA 10 bp)
One methyl group, and the enzyme that can undo it — Temozolomide does nothing more than put a methyl group on the O6 of a guanine — it needs no enzyme to activate it and falls apart at body pH on its own. MGMT takes that methyl group off and onto its own cysteine, and is used up in the process: one enzyme per lesion. If the tumour's MGMT promoter is methylated there is no MGMT to come, so the polymerase puts a thymine opposite the altered guanine, mismatch repair takes the thymine out, another goes back, and the cycle runs until the replication fork breaks. That break is the only thing in the picture that kills the cell — which is why the promoter test predicts the benefit. (DNA 8 bp)
Radioiodine, and the transporter it depends on — This is the oldest targeted therapy there is, and it works because of one protein: the sodium–iodide symporter, which a thyroid cell has and almost nothing else in the body does. Iodide-131 is pulled in, incorporated into thyroglobulin in the follicle lumen, and its beta particles travel a couple of millimetres — far enough to kill this follicle and its neighbour, and no further. It is given after TSH has been pushed up, because TSH is what puts more symporter on the surface. An anaplastic cancer has lost the symporter, so the dose stays in the blood and is passed in the urine; the answer there is to try to make the tumour behave like thyroid again first. (follicle 150–300 µm)
The folate cycle, and the two places a drug stops it — A cell cannot make a thymine without a methyl group, and its only source of one is the folate cycle. Methotrexate sits in dihydrofolate reductase, which keeps the cycle turning — it looks so like folate that it binds a thousand times harder, and everything downstream stops. Pemetrexed sits further round, in thymidylate synthase itself, which is why folate and B12 are given alongside it rather than afterwards. Leucovorin is a folate already in the reduced form, so it rejoins the cycle past the block: a rescue rather than an antidote, and since it rescues the tumour too, the timing is the whole trick. (enzymes 4–6 nm)
An oncometabolite, and a drug in the seam of the enzyme — Mutant IDH1 is not a broken enzyme — it is an enzyme that takes one step too many. Instead of stopping at alpha-ketoglutarate it goes on to 2-hydroxyglutarate, and makes it in millimolar amounts. 2-HG is close enough in shape to alpha-ketoglutarate to sit in the nuclear enzymes that take methyl marks off chromatin and stop them, so the marks pile up and a cell that should have differentiated stays a blast or a glioma cell. Ivosidenib binds in the seam between the two halves of the dimer rather than in the active site, holding it in a shape that cannot take the extra step — and the blasts then differentiate instead of dying, which is why the first sign the drug is working can look like an illness. (IDH1 dimer 8 nm)
The place a RAS pathway is reloaded — A mutant KRAS still has to be loaded with GTP to work, and this is where that happens. SHP2 rests with one of its reader domains folded into its own active site; binding a phosphorylated receptor tail pulls the reader out, the phosphatase switches on, and SOS1 is brought to the membrane to prise the old GDP out of RAS. An allosteric SHP2 inhibitor does nothing to the active site — it sits in a tunnel where all three domains meet and simply holds the resting shape shut. So SOS1 never arrives, RAS is left holding its GDP, and the inhibitor aimed at the mutant protein downstream has far less to do. That is the whole argument for combining them. (SHP2 6 nm)
Why a drug that works everywhere else fails in the brain — Two things keep a drug out of the brain, and neither is a wall. The endothelial cells of a brain capillary are sealed to each other, so the route between cells that a small molecule uses in any other tissue is closed; and P-glycoprotein and BCRP sit in the luminal membrane and put back anything that got in. A large polar antibody is turned round as fast as it arrives, which is why disease can escape in the brain while every other site is still shrinking. A brain-penetrant inhibitor is designed round both: small, lipophilic enough to go through the cell rather than between them, and shaped so the pumps are poor at recognising it. (capillary 6–8 µm)
What a mutation count is actually counting — Tumour mutational burden is a number on a report, and the mechanism behind it fits on one card. Each mutation in coding DNA may change a peptide; some of those peptides are held up on MHC class I; and a few are sequences no healthy cell has ever made, so no T cell was ever taught to ignore them. A tumour with sixteen mutations is likely to have one that fits; a tumour with three is unlikely to. That is all a checkpoint inhibitor does — it lets a recognition that has already happened go through. It also shows why the number is a poor biomarker on its own: it counts mutations, not peptides that fit this particular person's MHC. (cell 10 µm)
Inflamed, excluded, desert — the same tumour three ways — The three immune phenotypes are the same cut of a tumour edge, and the only difference is where the T cells are standing. In an inflamed tumour they are among the tumour cells: everything the immune system had to do has happened, and the drug only has to let it finish. In an excluded tumour they are in the stroma in numbers and not one of them has crossed — they were called, and dense collagen and TGF-β are stopping them. In a desert there are almost none at all, because nothing in the tumour was recognised. Three different problems, and only the first is answered by releasing a brake. (tumour edge 80 µm)
The two brakes no checkpoint antibody touches — PD-1 is not the only thing holding a T cell back, and neither of these is a receptor an anti-PD-1 antibody can reach. ATP leaking out of dying cells is an alarm signal; CD39 and CD73 on the tumour's own surface take all three phosphates off it and leave adenosine, which is the opposite — the molecule a tissue uses to say everyone should calm down. The T cell's A2A receptor reads it, cyclic AMP rises, and the killing stops; and it is strongest exactly where the tumour is most hypoxic. TGF-β works more slowly and lasts longer: it switches the killing programme off at the transcription level, and tells the fibroblasts to lay down the collagen that kept the T cells out to begin with. (synapse 20 µm)

Cancer — finding it and treating it 12

The stains that name an unknown primary — A liver biopsy of a metastasis with no idea where it came from, and the answer is a pattern across several sections rather than one positive stain. CK7 and CK20 sort most of it before any organ-specific stain, because between them they give four answers rather than two. Then the lineage markers, and where each one sits in the cell is as much of the answer as whether it is there: TTF-1 in the nucleus for lung, GATA3 for breast or urothelium, CDX2 with CK20 for colorectum, NKX3-1 for prostate. The negatives carry as much weight as the positive, which is why a panel is read as a whole and a single positive stain in isolation is a trap. (section 4 µm)
Why HER2 testing is a ratio and not a count — Everything in this test happens inside one nucleus. The HER2 probe is counted, and so is a probe for the centromere of the same chromosome — because the alternative explanation is in the picture: a cell with four of everything has extra HER2 and is not amplified, and only the ratio tells the two apart. Two or more is positive; four or more copies on average is positive even below a ratio of two. Where the signals sit in a tight cluster they cannot be counted at all, which is reported as such rather than guessed at. And an equivocal result means twenty nuclei were counted by eye by a person who then had to decide — which is why it is repeated by a second observer. (nucleus 6 µm)
What a sequencing panel physically is — A panel is a set of baits. The patient's DNA is broken into fragments with adapters on the ends, and biotinylated oligonucleotides on a bead — one for every exon of every gene the panel covers, and nothing else — pull out the fragments whose sequence matches. Everything else is washed away, which is ninety-nine per cent of the genome and includes every gene the panel does not carry a bait for. So a negative report means "not found among the genes we looked at": a fusion partner outside the panel, or a gene that entered practice after the panel was designed, was never asked about. And the RNA side is run because a fusion's breakpoint can sit anywhere in a hundred kilobases of intron, where there is nowhere to put a bait — in the messenger RNA the two halves lie directly against each other. (fragments 150–300 bp)
Why a tumour marker is for following and not for finding — Every one of these markers is a protein a gland normally secretes into its own lumen, and the basement membrane is the reason the blood level is low in health — the marker is on the wrong side of it. A tumour has no lumen to put it in and no intact membrane between it and the capillary, so the same protein, made by the same cells, goes into the blood instead. Which is why these measure how much disorganised tissue there is rather than whether a cancer exists: any process that breaks the architecture raises them. Hence prostatitis and BPH raising PSA, endometriosis and a pleural effusion raising CA125, and a tenth of people reading zero for CA19-9 because they lack the enzyme that makes it. (gland 50–200 µm)
One molecule, a picture and a treatment — PSMA is a dimer on the surface of a prostate cancer cell, and there is more of it as the cancer gets worse rather than less. The ligand is three pieces: a group that fits the enzyme's pocket, a linker, and a cage holding a metal — and the cage is what makes it a tool rather than a drug, because what sits in it decides whether you are taking a picture or giving treatment. Gallium-68 makes a positron, which travels a millimetre, meets an electron, and becomes two photons going exactly opposite ways. Lutetium-177 in the same cage makes electrons that travel under two millimetres, so a cell with no PSMA dies beside one that has it. The scan that found the disease is therefore also the proof the dose will land — and PSMA on the salivary glands is why a dry mouth is the dose-limiting effect. (ligand 2 nm; cell 20 µm)
What the prostate MRI is actually measuring — The cut is axial because the zones are the point: the transition zone in the middle is what enlarges with age and is full of nodules that are not cancer, and the peripheral zone round the back holds three quarters of the cancers. What the sequence reads is not a shape but the movement of water: where the glands are gone and the cells are packed together, water molecules have nowhere to go, and that restriction is the dark spot on the map. Against a normal zone where the glands are open and water moves freely. A PI-RADS score is then a number from one to five given by a person judging how focal and how dark the spot is — and the biopsy goes to the spot rather than to a template. (prostate 40 × 30 mm)
The lung screening scan, and what makes it hard — A nodule has first to be told from a vessel or an airway, which branch and taper. Then what matters is what it is made of. A ground-glass component is cells growing along the alveolar walls without filling them, so the air is still there and the tissue only looks hazy; a solid part is where the alveoli have been filled, and that is the invasive component — which is why the staging now measures the solid part rather than the whole nodule. Size in millimetres decides the interval: 4 mm and 9 mm are different problems. The dose is about a fifth of an ordinary CT, which is what makes repeating it annually defensible. And the difficulty is in the picture too: most of what it finds is small and benign, and now needs follow-up, a biopsy or an operation that would never have happened. (nodule 3–20 mm)
Endoscopic ultrasound, and the five layers a CT cannot see — The wall of the gut has five layers that alternate bright and dark on ultrasound, which is why they can be counted — and T stage is simply which of them the tumour has reached. That distinction decides whether an early tumour comes out endoscopically or needs an operation, and no CT can make it. The trade is in the picture: the probe has a few centimetres of reach and extraordinary resolution inside that, which is the opposite of a CT's. And the thing nothing else can do is at the end of it — a needle through the wall into a suspicious node under real-time ultrasound, so the node is sampled rather than described, and the cytology from it changes whether the person has surgery or chemotherapy first. (wall 3–5 mm)
The Whipple, and the anatomy that forces it — Five structures come out for one tumour — the head of the pancreas, the duodenum, the gallbladder, the lower bile duct and the nodes — and the reason is in the picture: the duodenum is wrapped round the head of the pancreas and they share a blood supply, so they cannot be separated. The question before any of it is the vein behind it all: a sheet of tumour against the superior mesenteric vein is resectable, a tumour wrapped round it is not, and that answer is a scan rather than an operation. Then three joins, and they are the operation's whole risk: pancreas to bowel, bile duct to bowel, stomach to bowel — in that order, so juice and bile meet the food downstream of the stomach. The first of the three is the one that leaks, and a soft normal pancreas leaks more readily than a hard obstructed one. (specimen 80–150 mm)
Lumpectomy and mastectomy, as the same decision — A lumpectomy leaves a space rather than a scar: it fills with fluid and then collapses, which is why clips are left in its walls so the radiotherapy boost and any future scan know where the tumour was. Tissue is mobilised to fill it, because an empty cavity in a small breast leaves a dent that radiotherapy then makes permanent. And the radiotherapy to the whole breast is the other half of the operation rather than an addition to it — the two together match a mastectomy for survival. A mastectomy leaves a thin skin flap, because the plane is immediately under it, and a space that fills with serous fluid for weeks whatever is done. Reconstruction is then a series of operations rather than one. (breast 100–150 mm)
Why clearing an axilla swells an arm — The dissection is bounded by things that are kept: the axillary vein as its roof, and the nerves to the serratus and the latissimus found and preserved. What is removed is the fat between them, with every node in it, because a node cannot be told from fat by feel. The arm's lymphatics run through exactly that fat. They were never the target and there is no way to spare them, which is the whole trade — about one in five arms then swells, holding protein-rich fluid, then fat, then fibrous tissue, and the third stage does not reverse. Which is why it is measured and sleeved early rather than watched. The sentinel approach exists for this reason alone: find the first node the breast drains to, take only that, and the rate falls to about one in twenty. (axilla 60–80 mm)
Febrile neutropenia: two defences that fail together — The marrow makes a hundred billion neutrophils a day from cells that divide constantly, and the gut replaces its lining every few days from cells that divide just as fast. One drug hits both, so the count reaches its nadir seven to ten days later at the same moment the barrier thins and breaks. The organism is then the person's own gut flora, which is why the antibiotic is chosen to cover Gram-negative bowel organisms and given within the hour, before any culture is back. And because there are no neutrophils, there is no inflammatory response to raise: no redness, no pus, no sign at the site. That leaves one sign — a temperature — which is why a fever in a neutropenic patient is an emergency on its own with nothing else required. (villus 0.5–1 mm)

Cancer — by site 49

The five things a testicular tumour can be made of — Each element looks like itself on the cut surface, and the report names every one of them because each behaves differently. Seminoma is cream and lobulated with fibrous septa and no haemorrhage. Embryonal carcinoma is grey and soft with haemorrhage and necrosis, and it is the most aggressive. Yolk sac tumour is pale and myxoid and makes AFP. Choriocarcinoma is almost all haemorrhage with a rim of two cell types, and makes hCG. Teratoma is cysts and cartilage, and chemotherapy does nothing at all to it. More than half of these tumours are mixed, which is why the pathologist lists the percentages rather than picking a name. (testis 40 × 25 mm)
The three testicular markers, and the cell each one comes from — These are not a panel — they are three different cells, each secreting its own thing, which is why the pattern names the tumour. AFP comes from yolk sac elements and from nowhere else, so a raised AFP means the tumour is not a pure seminoma whatever the slide shows. hCG comes from syncytiotrophoblast, which a seminoma can contain a little of, so a modestly raised hCG does not rule a seminoma out. LDH comes from any cell dying in quantity, so it measures bulk rather than lineage. And because AFP has a half-life of five to seven days, the markers are a clock as well as a label: a value that does not fall on schedule means disease is still there. (cells 15–30 µm)
Why a testicular cancer goes to the abdomen and not the groin — The testis forms in the abdomen and descends, and it takes its lymphatic drainage with it. So the first nodes are para-aortic — at the level of the left renal vein for a left tumour, precaval and interaortocaval and a little lower for a right one — and the groin is not involved at all. That anatomy is the reason the orchidectomy is done through the groin with the cord clamped first, and never through the scrotum: a scrotal incision opens a drainage field that the disease does not otherwise have, and an inguinal node afterwards means exactly that has happened. (cord 15–20 cm)
The retroperitoneal dissection, and the nerves in it — The template is the fatty tissue between and around the aorta and the vena cava, taken whole, because a node cannot be told from fat by feel. Running obliquely across that same field are the sympathetic chains and the hypogastric plexus, which carry the signal that closes the bladder neck at ejaculation. Take them with the fat and the orgasm is unchanged and the man is dry; find them and keep them and it is antegrade. In a disease of twenty-five-year-olds with a cure rate above ninety per cent that is not a detail, and nerve-sparing is the reason this operation belongs in a few hands rather than many. (field 15 × 12 cm)
The mass that grows while the markers fall — Chemotherapy kills the malignant elements of a germ cell tumour and does nothing at all to mature teratoma, because almost none of it is dividing. So a residual mass can be bigger after treatment than before it while AFP and hCG come down to normal — the one situation in oncology where a growing mass on treatment is good news. It is resected anyway, and for three reasons: it will keep growing, it strangles what it is wrapped around, and about one in twenty undergoes malignant transformation into a sarcoma or a carcinoma years later. Which is why a residual mass over a centimetre comes out rather than being watched. (mass 20–150 mm)
Why Mohs sees the whole margin and a routine excision does not — A routine specimen is bread-loafed: parallel vertical slices a few millimetres apart, which look at a few per cent of the margin and report it as clear. A finger of tumour running between two slices is never seen. Mohs inverts the geometry. The disc is inked in quadrants so a positive edge can be found again on the patient, the edges are pressed flat into the plane of the base, and one horizontal section is cut from underneath — so the entire perimeter and the entire base lie on a single slide. When a finger shows up the quadrant is known, and only that quadrant is taken again: a hundred per cent of the margin examined, and the smallest defect that will do. (disc 10–30 mm)
What makes a skin squamous carcinoma a staging problem — Most cutaneous squamous carcinomas are a lesion you excise and forget. A minority are not, and the features that separate them are all in the cut: more than six millimetres deep, through into the subcutaneous fat, poorly differentiated with little keratin, and — the one that changes management most — tumour wrapped round a dermal nerve. Add the sites that behave badly, the ear and the lip, and the setting that behaves worst, a transplant recipient on immunosuppression, and the lesion moves from an excision to a staged cancer with imaging and a discussion about the draining nodes. (depth 1–10 mm)
The field, not the lesion — Sun-exposed skin is a mosaic of clones, each the descendants of a single keratinocyte that took an ultraviolet hit years ago and carries a TP53 mutation. In an older person they cover most of the surface and not one of them can be seen. An actinic keratosis is simply one clone that has gone further — rough and scaly, with crowded nuclei in the lower epidermis — and a squamous carcinoma is one that has broken the membrane. Which clone, and when, is not predictable. That is why these are treated as a field, with a cream or a light over the whole area, rather than one lesion at a time: freezing the visible one leaves the risk exactly where it was. (epidermis 0.1 mm)
A skin cancer travelling up a nerve — The perineurium is a barrier to almost everything and a corridor to this. Tumour gets inside the sheath and travels back along the nerve towards the skull base, in cuffs with normal nerve between them — and those gaps are the problem, because a margin can be clear while tumour is already centimetres further along. The first sign is not a lump but a symptom, in the nerve's own territory: numbness, burning, or a weak muscle in someone who had a skin cancer removed two years ago. It is found on MRI, as a thickened, enhancing nerve, which is why the scan follows the nerve and not the scar. (nerve 1–3 mm)
The four cut surfaces of a renal tumour — A renal mass can be told apart on the bench more often than most. Clear cell is golden yellow, because the cells are full of lipid and glycogen that the stain washes out, usually with haemorrhage and cysts in it — three quarters of them, and the one that answers to an antiangiogenic drug, because VHL is gone and HIF is driving VEGF. Papillary is brown and friable and often multiple and bilateral. Chromophobe is tan and homogeneous and behaves far better than its grade suggests. Oncocytoma is mahogany with a central stellate scar and is benign — and almost impossible to separate from a chromophobe on a needle, which is why some of them still come out. (kidney 110 mm)
The envelope a renal tumour grows inside — Gerota's fascia is a real envelope round the kidney and its fat, and it is why a renal tumour can reach the size of a grapefruit and still be contained. The staging follows the layers out: inside the capsule is T1 or T2 and a candidate for taking the tumour rather than the kidney; into the perinephric fat but still inside Gerota is T3a, which is why the fat comes out with the kidney; through Gerota is T4 and no longer an operation on the kidney alone. The adrenal sits inside the same envelope, which is why it used to be removed routinely and why it now comes out only when it looks involved. (kidney 110 mm)
Taking the tumour instead of the kidney — Many people with a renal tumour have about one working kidney's worth of function between the two, so a radical nephrectomy is a reliable way to produce chronic kidney disease. A partial takes the tumour with a rim of normal kidney and keeps the rest of the nephrons — but it needs the artery clamped to see the edge and sew the collecting system, and a clock starts: warm ischaemia past about twenty-five minutes costs function in the kidney that is left. That tension is the whole operation. Ablation through the skin avoids both the clamp and the sewing, and suits a small, exophytic, posterior tumour — heat does not stop at the edge of the picture. (tumour 20–40 mm)
The internist's tumour — More than a quarter of renal cancers present with something that is neither a lump nor blood in the urine. Erythropoietin from the tumour — a kidney cell making the hormone it was built to make, but without reference to the oxygen level — gives a high haemoglobin in a disease that usually lowers it, which is why unexplained polycythaemia gets the kidneys scanned. PTHrP gives hypercalcaemia by the same route as a squamous carcinoma. And Stauffer's syndrome is the strangest: the liver tests go off and every scan of the liver is clean, driven by IL-6 from the tumour — and it reverses when the kidney comes out, which is the proof it was never a metastasis. (kidney 110 mm)
One tube, two cancers — Squamous carcinoma and adenocarcinoma of the oesophagus share an operation and almost nothing else. Squamous sits in the upper two thirds, on smoking and spirits together, very hot drinks, and sometimes an achalasia or a caustic stricture from decades before; it is falling where smoking is falling, and it is still the commoner of the two across most of the world. Adenocarcinoma sits at the junction, on reflux and Barrett's and obesity, and it has multiplied several times over in fifty years in the West — faster than any other solid tumour. The line between them on the cut is the squamocolumnar junction, and which side a tumour starts on decides its causes, its epidemiology and much of its treatment. (oesophagus 250 mm)
The oesophagus has no serosa, and the staging shows it — Every other part of the gut has a serosa — a smooth covering that is both a barrier to spread and a plane for the surgeon. The oesophagus has none: outside the muscle there is only loose adventitia. So a tumour that reaches the outside has nothing to stop it and no natural plane to be dissected along, which is why T3 is the commonest stage at presentation and why the margin that matters is the circumferential one, measured in millimetres from the outside of the specimen. It is also why that margin is so often under a millimetre after a technically good operation, and why chemotherapy or chemoradiotherapy goes first. (wall 4 mm)
The lymphatic plexus that runs the length of the oesophagus — Almost nowhere else in the gut drains like this. The oesophageal submucosal lymphatics form a dense network running along the tube rather than out of it segment by segment, so a tumour can seed a deposit centimetres away with entirely normal mucosa between — a skip lesion. That is why the resection is long and the proximal margin is checked on a frozen section. It is also why the nodes are not where the tumour is: a junctional tumour puts nodes in the neck and a mid-oesophageal one puts them in the abdomen. Hence a nodal field that spans three body cavities, and a stage that so often rises after the operation. (plexus along 250 mm)
The stomach as a new oesophagus, and the one artery it lives on — After the oesophagus comes out, the stomach is cut into a tube along its greater curve and brought up through the chest. It then lives on a single artery — the right gastroepiploic, running along the bottom of the tube. There is no second supply, and the last few centimetres at the top are fed only by what seeps through the wall. That is exactly where the join is, which is why an anastomotic leak is the complication this operation is judged by and why it happens there rather than anywhere else. At the other end, a stomach with no vagus will not empty on its own, so the pylorus is widened or stretched before the chest is closed. (conduit 250–300 mm)
Dysphagia, step by step — The lumen is wide and distensible, so by the time food sticks most of the circumference has already gone — which is why the history is short and the disease is not. The sequence is the diagnosis: bread and meat first, then soft food, then liquids, then saliva, over weeks. Dysphagia that progresses in that order is a mechanical story, and in an adult it is cancer until proved otherwise. Trouble with liquids and solids together from the start is a motility story instead. By the time liquids are a problem the patient is usually already losing weight, and nutrition is part of the first consultation rather than the last. (lumen 2–25 mm)
The two endometrial cancers — They sit in opposite settings and behave nothing alike. Type 1 is endometrioid: glands that still look like endometrium, low grade, growing on a thick lining built by years of oestrogen with nothing to oppose it — no ovulation, obesity, tamoxifen, PCOS — with PTEN lost early. It is three quarters of them, it bleeds early, and most are cured by the operation alone. Type 2 is serous: papillary, with nuclei that vary wildly from one cell to the next and TP53 mutated at the very start, growing on an atrophic endometrium in an older woman. It is about one in ten and most of the deaths, and it spreads through the tube into the abdomen like an ovarian cancer rather than growing into the wall. (uterus 80 mm)
One symptom, and the number that acts on it — Postmenopausal bleeding carries roughly a one in ten chance of endometrial cancer — high enough that the symptom alone starts the pathway, with no examination finding required. The commonest cause is still atrophy: a thin fragile lining with bare vessels that bleed from nothing. A polyp is common too, benign, and has to come out to be sure of it. The decision is made on one measurement: an endometrium under about 4 millimetres makes cancer very unlikely, and anything thicker is sampled. It is one of the few numbers in oncology that is a decision all by itself — and the reason this cancer is usually caught early is simply that the uterus is a bag with one exit. (endometrium 1–20 mm)
Depth and LVSI — what the uterus is read for — Once the uterus is out, two findings decide whether anything follows the operation. The first is how far the tumour has gone into the muscle, measured as a fraction of the wall rather than in millimetres, because a uterus can be any thickness; half way is the line. The second is lymphovascular space invasion — tumour inside the thin-walled spaces in the muscle beyond the tumour's own edge. Substantial LVSI changes the treatment on its own, whatever the depth, because it says the disease has already found the route out. Grade and the molecular group sit alongside them, but these are the two a pathologist is measuring on the slide. (wall 15–25 mm)
Why the tracer goes into the cervix — The injection for an endometrial sentinel node goes into the cervix rather than into the tumour, which is counter-intuitive and works because the cervix and the uterine body share their drainage. The usual route runs out through the parametrium and up beside the external iliac vessels, and the first node is in the obturator fossa or on the external iliac vein. But there is a second route, up the infundibulopelvic ligament with the ovarian vessels, straight to the para-aortic nodes and missing the pelvis entirely — which is why a negative pelvic sentinel does not close the question in a high-grade tumour. The node that comes out is then cut thinly and stained for keratin, and that is most of the reason sentinel biopsy upstages people. (pelvis 200 mm)
Three numbers added, and that is the prognosis — A sarcoma is graded by the FNCLCC system, which is three scores added together: how closely the cells resemble the tissue they came from, how many mitoses there are in ten fields, and how much of the tumour is necrotic. Two or three is grade 1, four or five is grade 2, six to eight is grade 3 — and necrosis alone can move a grade 2 to a grade 3. That sum predicts what happens next better than the size, better than the depth, and better than the name of the sarcoma: there are more than seventy named subtypes, and for most treatment decisions the grade matters more than which one it is. (fields 10 × 0.17 mm²)
The biopsy tract comes out with the tumour — A needle through a sarcoma leaves a tract with tumour cells in it. The tract is not sterile and never becomes sterile, so it has to be excised with the tumour — which means the needle must go in along the line the definitive incision will take: longitudinal, through one compartment only, on the side the surgeon will operate from. Done that way, a single ellipse of skin takes the scar, the tract and the tumour together. Put in from the wrong side it crosses a second compartment and often a neurovascular bundle, and everything it passed through is contaminated. More amputations in sarcoma follow a biopsy done in the wrong place than follow the tumour itself. (thigh 170 mm)
The capsule that is not one — A sarcoma is surrounded by a smooth, glistening rim that looks exactly like a capsule, and shelling it out along that plane is easy, bloodless and quick. It is not a capsule: it is normal tissue compressed by the growing tumour, with tumour cells inside it and satellites beyond it. Local recurrence after an unplanned excision of that kind runs well above half, and the re-operation is far bigger than the first one would have been. A wide excision takes a cuff of normal tissue outside the rim, or the whole fascial compartment where that is what is there — and a fascial plane is worth more than a centimetre of muscle, because it is a real barrier and muscle is not. (tumour 50–150 mm)
A sarcoma goes to the lung, not to the nodes — Sarcomas spread by blood. The nodes beside the primary are almost always normal, and taking them achieves nothing — which is the opposite of nearly every carcinoma. The lung is the first capillary bed the blood meets, so that is where the deposits land: round, well defined, at the edges of the lung where the smallest vessels are, and very often the only place in the body involved. And unlike most metastatic disease they are cut out, a wedge of lung at a time. A sarcoma whose only metastases are pulmonary still has a real chance of cure, which is why a CT of the chest is part of staging every one of them. (deposits 5–40 mm)
A sarcoma made by one fusion and almost nothing else — These are not kinase fusions. A chromosome breaks and joins so that a low-complexity stretch from one gene — EWSR1, SS18, PAX3, FUS — ends up bolted to the DNA-binding domain of a transcription factor. The first end binds nothing and gathers the transcription machinery; the second end knows where to go. So the machinery is delivered to hundreds of places it has no business being and a programme runs that no cell in the body runs. The striking thing is what else is there: almost nothing. These genomes carry very few other mutations, which is why these tumours appear in young people — and why there has been so little to aim a drug at. (fusion protein 10 nm)
Four cancers that share an operation and nothing else — "Head and neck cancer" is an administrative category, and the sagittal cut shows why. An oral cavity tumour comes from tobacco and betel, spreads early to levels I–III, and is operated on first. An oropharyngeal one — tonsil or base of tongue — has been split in two by HPV: the virus-driven kind in a younger non-smoker behaves so much better that it is staged on a separate scale. A glottic tumour declares itself at a few millimetres because any change on a vocal cord changes the voice, and the glottis has almost no lymphatics, so it presents small and node-negative. A hypopharyngeal one is silent until it is large, drains richly, and has the worst outcome of the four. (airway 150 mm)
The six levels, and which primary fills which — The neck is divided into six levels against one landmark, the sternocleidomastoid, and the point of the map is that spread is predictable. The oral cavity goes to I, II and III. The oropharynx, larynx and hypopharynx go to II, III and IV. The nasopharynx and scalp reach V. The thyroid, subglottis and cervical oesophagus go to VI, the central compartment. So which levels are cleared follows from where the primary is and nothing else — a selective dissection takes those and leaves the rest, including the muscle, the internal jugular vein and the accessory nerve, which is what a shoulder depends on. (neck 150 mm)
Why head and neck margins are taken from the patient — Mucosa and muscle shrink by about a third the moment they are released, so a 7 mm margin cut on the patient reads as 5 mm on the bench and a 5 mm one reads as close. On top of that, a specimen off the patient has been handled and is no longer oriented to anything the surgeon can find again. So the frozen sections are taken from the edge of the defect rather than from the specimen: the anatomy is still where it was, and a positive edge can be re-excised in the same operation. The numbers that follow are a decision, not a description — over 5 mm clear, 1 to 5 mm close, under 1 mm or on the ink involved — and in the head and neck a close margin changes the radiotherapy. (specimen 30–60 mm)
What a laryngectomy takes, and how the voice comes back — The larynx is where the airway and the food passage cross, and the whole box comes out — which separates the two passages for good. The trachea is brought to the skin as a stoma, so the person breathes through the neck: no filtering, no warming, no smell, no nose-blowing. Swallowing becomes safe, because there is nothing left to inhale into. The voice comes back through a small puncture between the trachea and the oesophagus with a one-way valve in it: cover the stoma, push air through the valve, and the top of the oesophagus vibrates instead of the vocal cords. The sound is low and effortful and it is the person's own, which matters more than it sounds like it should. (larynx 45 mm)
The one layer that splits bladder cancer in two — Everything about this disease turns on whether the tumour is into the detrusor. Above that line it is treated inside the bladder — resection and instillations, with surveillance for years. Below it the bladder comes out. Which means the resection is not only a treatment but the staging specimen, and it has to contain detrusor muscle: after taking the tumour, a second deeper pass at the base goes in specifically to get it. Without muscle in the pot the report cannot say T1; it can only say no muscle was seen, which is a missing answer rather than a stage. In a high-grade tumour that means doing it again within six weeks, because a third turn out deeper than they looked. (wall 3–5 mm)
The whole urinary lining, not the bladder — The urothelium runs continuously from the renal pelvis down the ureter into the bladder and out through the urethra, and every bit of it has seen the same carcinogens from the same blood. So a bladder tumour is a disease of a surface rather than of an organ: a new tumour elsewhere in the tract is a second primary rather than a metastasis, which is why cystoscopic surveillance goes on for years and why the upper tracts get imaged too. When a tumour does invade, the wall is thin and has no serosa over most of it, so it reaches the perivesical fat quickly — and then the obturator and internal iliac nodes, which is why how many nodes were taken at cystectomy predicts survival. (tract 400 mm)
What the urine does after the bladder comes out — Both answers start the same way: a segment of ileum taken out of the food stream with its mesentery and blood supply intact, with the ureters sewn into it. A conduit stops there — the other end comes to the skin, urine arrives at the bag continuously, and there is nothing to hold and nothing to empty. A neobladder opens the segment along its length and folds it into a sphere, which stops it contracting as a tube and lets it hold half a litre at low pressure, joined to the urethra; the person passes urine by relaxing the pelvic floor and pressing, because there is no detrusor to contract. Either way the bowel is still bowel: it makes mucus, chloride goes up and bicarbonate down, and the ileum that was taken no longer absorbs B12. (ileum 150–600 mm)
MGUS, smouldering, myeloma — one disease at three points — The marrow plasma cell percentage and the paraprotein rise along a single line, and the names are cuts across it. Under ten per cent of the marrow is MGUS, present in about three per cent of people over fifty and carrying a risk of roughly one per cent a year for life — which means most people with it die of something else. Ten to sixty per cent with no damage is smouldering, at about one in ten per year, treated now only in the highest-risk group. Over sixty per cent is myeloma on that number alone. But the line that actually defines myeloma is not a percentage: it is damage — calcium up, kidney failing, anaemia, or a lytic lesion — and any one of those makes it myeloma at any percentage. (trephine 10–20 mm)
One clone, one antibody, one band — In health every plasma cell makes a different antibody, so the blood carries millions of sequences with millions of charges and the gel shows a smear. A myeloma is the descendants of a single cell, so every molecule it makes is identical — one heavy chain class, one light chain type, one sequence — and one sequence has one charge, which is what puts a sharp band on the gel. The clone also makes light chains faster than heavy ones, so the excess leaves on its own: small enough to be filtered by the kidney, which is where the damage comes from. And because the paraprotein is made by the tumour, by nothing else, and in proportion to how much of it there is, it is one of the best measures of disease in oncology. (antibody 10 nm)
How light chains block a kidney — The proximal tubule takes back the small amount of light chain that is normally filtered. In myeloma it is overwhelmed, and the excess reaches the distal tubule — where the commonest protein in urine, Tamm–Horsfall, is being secreted and polymerising into a gel. The two bind each other and set: a hard, fractured cast that fills the lumen, stops the nephron behind it and draws a giant-cell reaction round it. This is the commonest kidney lesion in myeloma and it is an emergency, because the nephrons behind the casts die within days. It is also why the free light chain level rather than the paraprotein is what gets followed, and why treatment starts the day it is suspected. (tubule 40–60 µm)
Why myeloma makes a hole that never fills — A myeloma cell cannot live on its own. It holds onto a marrow stromal cell through VLA-4 and VCAM-1, and that contact both keeps it alive and makes it resistant to drugs while it lasts; IL-6 comes back the other way as the growth signal. From that position it pushes the bone balance in two directions at once: RANKL up, so osteoclasts resorb, and DKK1 up, which blocks Wnt and stops osteoblasts replacing what is lost. The result is a hole with no repair at its edge — which is why myeloma lesions are punched out, why they are cold on a bone scan that looks for new bone, and why the skeletal survey is a CT or an MRI instead. (niche 50–100 µm)
A lymph node, and three ways a lymphoma changes it — A normal node has a plan: follicles with pale germinal centres and dark mantles, sitting only in the cortex with spaces between them; a paracortex of T cells between them; medullary cords and sinuses running to the hilum. Follicular lymphoma keeps making follicles, which is the trap — but they are back to back, all through the node including the medulla, all the same size, and the mantle is gone. Diffuse large B-cell lymphoma effaces everything: one sheet of large cells from capsule to capsule and often out into the fat. Hodgkin lymphoma does the opposite — the node fills with reactive cells that are not the tumour, and the tumour is the handful of huge cells among them, often fewer than one in a hundred. (node 10–20 mm)
The lymphoma map is a map of one reaction — A germinal centre is where a B cell divides fast and deliberately mutates its own antibody genes, with AID cutting DNA on purpose in a cell that has switched off some of its checkpoints. It is the most dangerous place in the body for a lymphocyte to be, and most B-cell lymphomas can be placed on the journey through it. Before it, the mantle cell, carrying cyclin D1 from a translocation that happened in the marrow. Inside it, follicular lymphoma, which keeps BCL2 on so the cell is never killed for failing the test, and Burkitt, with MYC joined to an antibody promoter. Leaving it, diffuse large B-cell lymphoma in two kinds that behave differently. At the end of the road, the plasma cell, and myeloma. (germinal centre 200 µm)
Hodgkin goes next door; non-Hodgkin goes everywhere — Hodgkin lymphoma spreads from one node group to the one next along, predictably, and starts in the neck in most people. That orderliness is why it was the first cancer anyone could cure with a radiation field, and why the stage is still described as a journey down the body with the diaphragm as the landmark; the spleen counts as a node group. Non-Hodgkin lymphoma does not behave that way at all. It is in the blood early, so it appears in several places at once with normal nodes between them, and most people are stage III or IV at diagnosis. It also does not need a node: about a third start outside the lymphatic system entirely — stomach, bowel, brain, testis, skin, thyroid, bone — and the marrow above all, which is why it is biopsied. (body 1700 mm)
The adrenal medulla is a ganglion that lost its axons — The adrenal is two organs in one envelope. The cortex makes three steroids in three layers and has nothing to do with what is inside it. The medulla is sympathetic nervous tissue: its chromaffin cells come from the neural crest, store adrenaline and noradrenaline in granules, and secrete into a central vein rather than onto a synapse — a ganglion whose axons never formed. Which is the whole anatomy of neuroblastoma: the same cells build the sympathetic chain beside the spine and the organ of Zuckerkandl at the aortic bifurcation, so the tumour can arise anywhere from neck to pelvis, and about a third of them are not in an adrenal at all. (gland 40 × 20 mm)
Where a neuroblastoma turns up — It goes to bone, and the orbit is thin bone immediately under skin — so deposits there push the eye forward and bruise the lids, and proptosis with periorbital bruising in a toddler is this disease until proved otherwise. It goes to marrow in nests that a film shows as clumps rather than single cells, which is why staging needs two aspirates and two trephines from two sides, and to cortical bone, which hurts: a limp, or a child who will not be put down. And in an infant it does something different again — liver, skin and a little marrow, with a primary that is often small, giving a liver that grows until it embarrasses the breathing and blue-grey nodules in the skin. (child 800 mm)
The stage that goes away on its own — An infant under eighteen months with a small primary, disease in the liver and skin and a little in the marrow — and nothing in cortical bone, which is the whole definition. By any ordinary reading that is widespread disease in a baby. Most of it regresses without treatment: these cells still have working TrkA and still die when the nerve growth factor around them runs out, which is the programme that prunes the sympathetic nervous system in infancy, running late. So the treatment is often to watch, and to give chemotherapy only for a liver big enough to stop the baby breathing. It is one of the few cancers where doing nothing is an evidence-based plan — unless MYCN is amplified, when none of it applies. (infant 700 mm)
MIBG — a molecule that looks like noradrenaline — A neuroblastoma cell is a sympathetic neuroblast with the machinery of one, including the transporter that takes noradrenaline back out of a synapse and the granules that store it. MIBG is built to look like noradrenaline to that transporter and like nothing at all to the enzymes that would break it down, so it is taken in and stays. With iodine-123 on it, it emits a gamma photon that leaves the body: the whole child is imaged at once and every deposit lights up, including marrow a CT cannot see — which is why the response is scored on this scan rather than on the size of the primary. With iodine-131, it emits a beta particle that travels a couple of millimetres and is absorbed inside the deposit. Same molecule, different isotope: theranostics, decades before the word. (cell 15 µm)
Central and lateral — the order thyroid cancer spreads in — The central compartment, level VI, runs between the carotids from the hyoid to the sternum, and that is where a papillary carcinoma goes first. Those nodes are small, numerous and often neither felt nor seen on a scan. The lateral compartments, levels II to V, lie deep to the sternocleidomastoid beside the jugular; those nodes are bigger, often cystic, and are sometimes the thing the person noticed first, with a primary of only a few millimetres behind them. Because the order is predictable, a lateral node with a clear central compartment is uncommon enough to be worth questioning. And the recurrent laryngeal nerve runs up the groove through the middle of level VI, which is where voices are lost. (neck 120 mm)
The only cancer staged by how old you are — Take a papillary carcinoma with nodes in the neck and deposits in both lungs. Under 55 that is stage II, and there is no stage III and no stage IV — however many nodes and however many lung deposits, because the outcome at ten years is still well over ninety per cent. Over 55 the same findings give stage IVB and the staging behaves like every other cancer's. No other cancer does this. It is there because differentiated thyroid cancer in the young behaves like nothing else: a disease that metastasises and then sits there for decades, often taking up iodine and answering to it. The trap is remembering what a stage is for — it says what is likely to kill the person, not how much disease there is or how much treatment it will take. (thyroid 50 mm)
Six categories, each one a decision — A thyroid aspirate is reported in six categories, and the point of the system is that each carries its own risk of cancer and its own next step. Category I is not enough cells to say anything — about one in ten, and the answer is to repeat it with ultrasound guidance. Category II is benign: sixty per cent of aspirates, a few per cent risk, and the end of the matter. Category IV, a follicular neoplasm, is the one cytology cannot answer in principle — the difference between a follicular adenoma and a carcinoma is whether the capsule has been breached, and a needle cannot see a capsule — so it goes to a diagnostic lobectomy. Category VI is malignant: papillary nuclear features are visible on cytology, with a risk near ninety-nine per cent. (aspirate smear)
Lobectomy or total — what the decision costs — The recurrent laryngeal nerve runs in the groove between trachea and oesophagus and is found and followed rather than avoided: a nerve you have not seen is a nerve you may already have divided. Four parathyroid glands the size of a grain of rice sit on threads of their own blood supply. Taking both lobes puts one nerve and two glands at risk twice over, and the calcium that follows is the complication patients actually feel — tingling in the hands and round the mouth the night after. It also commits them to thyroxine for life, and it is what makes radioiodine possible. A lobectomy halves the risk and gives the same survival for a tumour under 4 cm with no extension and no nodes — but the remaining lobe makes thyroglobulin, so that marker cannot be used to follow them. (thyroid 50 mm)

Cancer — types 17

Metaplastic carcinoma of the breast — A triple-negative breast carcinoma in which part of the tumour has turned into another kind of tissue: squamous cells, malignant spindle cells, or tumour that makes its own cartilage or bone. Each element is still carcinoma, which is why the spindle cells stain for keratin. It responds less well to chemotherapy than other triple-negative cancers. (a mass 2–5 cm across; the cells drawn enlarged)
Male breast cancer — Breast cancer in a man is usually a hard lump directly behind the nipple, because that is where the little breast tissue a man has lies. With so little fat around it, it reaches the skin and the pectoral muscle early and often pulls the nipple in. Almost all are ER-positive, and BRCA2 carriers are at the highest risk. Gynaecomastia is the benign look-alike: a soft, symmetrical disc under the areola. (a chest wall about 4 cm deep; the mass 1–3 cm)
Small-bowel adenocarcinoma — A rare cancer of the small intestine, most often in the duodenum around the ampulla, then the jejunum. It grows round the wall as an annular "napkin-ring" with heaped edges and an ulcerated centre, narrowing the lumen so the bowel above it dilates. It presents late, with obstruction, bleeding or jaundice. (bowel about 3 cm across)
Colorectal cancer — consensus molecular subtypes — Colorectal cancers fall into four expression subtypes. CMS1 (about 14%) is microsatellite-unstable and hypermutated, crowded with lymphocytes. CMS2 (37%), the canonical type, is epithelial with WNT and MYC switched on. CMS3 (13%) is metabolic, often KRAS-mutant and mucinous. CMS4 (23%) is mesenchymal: stroma, fibroblasts, TGF-β and new vessels, and the worst prognosis. (a tissue core about 1 cm across)
Anal squamous cell carcinoma — Most anal cancers are squamous cell carcinomas caused by HPV, usually type 16. They start where the glandular lining of the rectum meets the squamous lining of the anus, at the transition zone above the dentate line, through high-grade intraepithelial neoplasia (AIN). Treatment is chemoradiotherapy rather than surgery, which keeps the sphincters. (the anal canal, about 4 cm long)
Gastrinoma (Zollinger–Ellison syndrome) — A gastrin-secreting neuroendocrine tumour, usually a few millimetres across in the wall of the duodenum, less often in the pancreas. Gastrin makes the stomach grow giant folds and pour out acid, so ulcers appear in unusual numbers and places, beyond the duodenal bulb. Most lie in the gastrinoma triangle, and about a quarter are part of MEN1. (stomach and duodenum, about 25 cm)
Penile squamous cell carcinoma — Almost all penile cancers are squamous cell carcinomas of the glans or foreskin, and they come by two roads. Most are HPV-independent: keratinising tumours arising in lichen sclerosus and chronic inflammation behind a tight foreskin. The rest are HPV-associated, warty or basaloid, from HPV-related intraepithelial neoplasia, and the basaloid ones invade deep. Depth into the spongiosum and cavernosum sets the T stage. (the distal penis, cut lengthways, about 6 cm)
Serous carcinoma of the endometrium — An aggressive endometrial cancer of older women, arising not from hyperplasia but on a thin, atrophic lining, often on a polyp. It grows as complex papillae of high-grade cells and is almost always TP53-mutant, so p53 staining is aberrant: every nucleus dark, or none at all. Even a tiny tumour can already have spread to the peritoneum, so it is staged and treated like ovarian high-grade serous carcinoma. (a polyp about 1–2 cm; the cells drawn enlarged)
Uterine carcinosarcoma — A high-grade biphasic tumour, once called malignant mixed Müllerian tumour: malignant glands and malignant sarcoma side by side. It is really a carcinoma that has partly turned mesenchymal, so it behaves like one and spreads through lymph nodes. It forms a bulky, fleshy, bleeding polyp that fills the cavity and often pushes out through the cervix. Cartilage or skeletal muscle in it (heterologous elements) worsens the outlook. (a uterus about 9 cm long; the cells drawn enlarged)
Vulvar squamous cell carcinoma — Vulvar cancer comes by two roads that look different under the microscope. HPV-independent cancers, the majority, arise in older women on lichen sclerosus through differentiated VIN, where only the basal cells are atypical and p53 is abnormal; they keratinise. HPV-associated cancers arise in younger women through HSIL, with atypia from base to surface and block-positive p16; they are warty or basaloid and carry a better prognosis. (skin about 5 mm deep; the cells drawn enlarged)
Mucoepidermoid carcinoma of the parotid — The commonest malignant salivary gland tumour, in adults and children alike. It is made of three cell types round mucin-filled cysts: mucous cells, intermediate cells and epidermoid cells. Most carry a CRTC1–MAML2 (or CRTC3–MAML2) fusion. The grade follows the architecture: low-grade tumours are mostly cystic, high-grade ones solid, necrotic and infiltrative. (a nodule 1–4 cm; the cells drawn enlarged)
Multiple endocrine neoplasia (MEN1, MEN2A, MEN2B) — Inherited syndromes in which several endocrine glands grow tumours. MEN1 (the MEN1 gene, menin) affects the parathyroids, the pancreas and duodenum, and the anterior pituitary. MEN2A and MEN2B are caused by activating RET mutations: medullary thyroid carcinoma in every carrier, phaeochromocytoma in about half, parathyroid disease in MEN2A only, and in MEN2B mucosal neuromas and a marfanoid build. (the head and trunk)
Astrocytoma, IDH-mutant — A diffuse glioma of young adults defined by an IDH1 or IDH2 mutation, almost always with loss of ATRX and a TP53 mutation, and without 1p/19q codeletion. Its cells creep along white-matter tracts far beyond any visible edge, which is why it cannot be cut out completely. It is graded 2 to 4 within one type: mitoses make it grade 3; necrosis, microvascular proliferation or CDKN2A/B deletion make it grade 4. (white matter about 3 mm across; the cells drawn enlarged)
Medulloblastoma — molecular groups — Medulloblastoma, the commonest malignant brain tumour of childhood, is four diseases with different origins, ages and outcomes, and each tends to sit in its own place. WNT tumours arise from the dorsal brainstem at the cerebellar peduncle; SHH tumours from granule-cell precursors in a cerebellar hemisphere; groups 3 and 4 fill the fourth ventricle in the midline, and group 3 has often seeded the meninges by diagnosis. (the posterior fossa of a child, about 8 cm)
Primary CNS lymphoma — A diffuse large B-cell lymphoma confined to the brain, eyes or spinal cord, commonest in older adults and in immunosuppression. It forms deep, homogeneous masses beside the ventricles and across the corpus callosum, often several. Under the microscope the cells gather round vessels in layers, laying down rings of reticulin. Steroids can make it melt away before biopsy, so they are held back until tissue is taken. (a brain slice about 14 cm; the vessel about 0.1 mm)
Nodular lymphocyte-predominant Hodgkin lymphoma — A slow-growing B-cell lymphoma, distinct from classical Hodgkin, now often called nodular lymphocyte-predominant B-cell lymphoma. Large vague nodules of small B cells replace the node, and scattered in them are a few LP or "popcorn" cells with folded, multilobed nuclei. Unlike Reed–Sternberg cells they are CD20-positive and CD30- and CD15-negative, and each is ringed by a rosette of PD-1-positive T cells. (a nodule about 1 mm; the node about 2 cm)
Peripheral T-cell lymphoma (AITL, ALCL) — Lymphomas of mature T cells. Angioimmunoblastic T-cell lymphoma comes from follicular helper T cells: clear cells among arborising high endothelial venules and an expanded dendritic-cell meshwork, with a mixed inflammatory background and an open subcapsular sinus. Anaplastic large cell lymphoma is made of hallmark cells with horseshoe nuclei, strongly CD30-positive, filling the sinuses; ALK-positive cases (NPM1–ALK) are of the young and do better. (a lymph node, about 1 mm shown; the cells drawn enlarged)

Cancer — how it is described 15

Differentiation grade — how much it still looks like a gland — Grade is how far a carcinoma has drifted from the tissue it came from. A well-differentiated (G1) adenocarcinoma still builds round glands with one tidy row of nuclei at their base; a moderately differentiated (G2) one makes crowded, irregular and budding glands beside solid nests; a poorly differentiated (G3) one has stopped making glands and grows as sheets of large, varied nuclei with many mitoses. In the colon the WHO now reports this as low grade (G1–G2) or high grade (G3), because only that split carries prognosis on its own. (gland 0.1–0.3 mm across)
Nottingham grade — three scores added — Invasive breast cancer is graded by scoring three things from 1 to 3 and adding them. Tubule formation: over 75% of the tumour in glands scores 1, 10–75% scores 2, under 10% scores 3. Nuclear pleomorphism: nuclei like normal duct cells score 1, larger and moderately varied score 2, large, vesicular and markedly varied with nucleoli score 3. Mitoses are counted over ten high-power fields, with cut-offs set by the microscope's field area. A total of 3–5 is grade 1, 6–7 grade 2, 8–9 grade 3 — the modified Bloom–Richardson system of Elston and Ellis. (each field about 0.5 mm)
T stage in the colon wall — The T category of a bowel cancer is simply how deep it has gone. Tis is still in the mucosa; T1 has crossed the muscularis mucosae into the submucosa; T2 is in the muscularis propria; T3 is through it into the pericolic fat; T4a has reached the peritoneal surface, and T4b has grown into, or is stuck to, another organ. The layers are drawn here in true order on a colon opened lengthways, and the cut end shows how far the tumour has reached. (wall 2–4 mm thick)
ER and PR — the brown nuclei that are counted — Oestrogen and progesterone receptors work in the nucleus, so a positive stain browns the nucleus and leaves the cytoplasm pale. The pathologist reads two things: what proportion of tumour nuclei are brown and how dark they are. Allred adds a proportion score (0–5) to an intensity score (0–3); the H-score multiplies each intensity by its percentage (0–300). Under 1% is negative and 1–10% is reported as ER-low positive, because the benefit of endocrine therapy there is uncertain; the normal lobule on every slide is the control that proves the stain worked. (nuclei about 10 µm)
HER2 immunohistochemistry — 0, 1+, 2+, 3+ — HER2 sits in the cell membrane, so it is read from the outline of each cell and the nucleus is ignored. A complete, intense ring round more than 10% of the cells — the chicken-wire pattern — is 3+ and positive; weak to moderate complete rings are 2+, equivocal, and go on to in situ hybridisation; faint, incomplete staining in more than 10% is 1+. Since trastuzumab deruxtecan works in tumours without amplification, 1+ and 2+ without amplification are now called HER2-low, and telling 0 from 1+ has become a decision about treatment. (cells 10–20 µm)
PD-L1 — tumour proportion score and combined positive score — PD-L1 is read on the membrane, and the same slide can give two different numbers. The tumour proportion score (TPS) counts only tumour cells with any membrane staining, partial or complete, as a percentage of all viable tumour cells — the score used for pembrolizumab in lung cancer. The combined positive score (CPS) also counts stained lymphocytes and macrophages in the numerator, still divides by the tumour cells, and is capped at 100 — the score used in gastric, oesophageal, head and neck and cervical cancer. So a tumour with almost no stained tumour cells can still have a CPS above 1. (cells 10–20 µm)
Homologous-recombination deficiency — the scars on the chromosomes — A cell that cannot repair double-strand breaks by homologous recombination — most often because both copies of BRCA1 or BRCA2 are gone — mends them with error-prone pathways, and the genome keeps the marks. Three are counted: long stretches where one parent's copy has been lost (LOH), imbalances running out to the telomere (TAI), and arms broken into many blocks of different copy number (LST). Their sum is the HRD score; 42 or more, or a BRCA mutation, predicts response to platinum and PARP inhibitors. (chromosomes 2–10 µm)
Breast cancer intrinsic subtypes — Gene-expression profiling sorts breast cancers into four main intrinsic subtypes, and a panel of stains approximates them. Luminal A is ER-positive, HER2-negative and slow, with few Ki-67-positive cells, still building glands; luminal B is ER-positive but proliferates faster. HER2-enriched tumours overexpress HER2 in every membrane and have usually lost ER. Basal-like tumours lack ER, PR and HER2, fill their cytoplasm with basal keratins, divide fast and often have central necrosis — most are triple-negative and many carry BRCA1 mutations. (cluster about 0.1 mm)
Lung adenocarcinoma — five patterns and the IASLC grade — Invasive non-mucinous lung adenocarcinoma is described by how it uses the alveoli. Lepidic growth creeps along walls that are still intact; acinar makes glands in fibrotic stroma where the alveoli were; papillary covers branching fibrovascular cores; micropapillary floats tufts with no core in the air spaces; solid fills them with sheets. The IASLC grade takes the predominant pattern and the high-grade ones: lepidic-predominant is grade 1, acinar or papillary grade 2, and any tumour with 20% or more solid, micropapillary or complex glands is grade 3. (alveoli about 0.25 mm)
Response after neoadjuvant therapy — pCR and residual cancer burden — When chemotherapy comes before surgery, the specimen is graded for what is left. The tumour bed is a pale fibrous scar, found by the clip placed at biopsy; residual cancer, if any, is scattered through it as islands. No invasive cancer in the breast or the nodes is a pathological complete response (RCB-0). Otherwise the residual cancer burden combines the bed's two dimensions, its cellularity, the in situ fraction, the number of positive nodes and the largest nodal deposit into RCB-I, -II or -III, and RCB-I does nearly as well as a complete response. (slice about 30 × 20 mm)
Two hits — an inherited BRCA mutation and the second one — A tumour suppressor fails only when both copies are lost. Someone who inherits a BRCA1 or BRCA2 mutation already has the first hit in every cell of the body, so a single further event in one cell — usually loss of the remaining working copy, seen as loss of heterozygosity — is enough to start a clone. In everyone else both hits must happen in the same cell by chance, which is why hereditary cancers come earlier, more often and in both breasts. This is Knudson's two-hit hypothesis, first worked out for retinoblastoma. (duct about 0.2 mm across)
Li–Fraumeni syndrome — germline TP53 on its DNA — Li–Fraumeni syndrome is a germline mutation in TP53, and it brings sarcomas, early breast cancer, brain tumours, adrenocortical carcinoma and leukaemia, often in childhood. The structure is the p53 DNA-binding domain gripping its response element (PDB 1TSR), with the hotspot residues marked: some contact the DNA directly (R248, R273), others hold the fold together (R175, G245, R249, R282), and mutation at either kind stops p53 switching on its targets. The R337H setting shows the tetramerisation domain (3SAK): this milder founder mutation, common in southern Brazil, weakens the tetramer and gives mostly adrenocortical tumours. (domain about 5 nm)
Cowden syndrome — the hamartomas — Cowden syndrome, the commonest form of PTEN hamartoma tumour syndrome, is recognised by its tissues before its cancers. On the face, trichilemmomas: lobules of pale glycogen-rich cells growing down round a hair follicle, palisaded at the edge and wrapped in a thick glassy basement membrane. In the gut, many small hamartomatous polyps — normal elements in the wrong arrangement, with splaying smooth muscle and ganglion cells. The lifetime risks that follow are of breast, thyroid, endometrial, kidney and colorectal cancer. (lesion 1–5 mm)
The tobacco adduct — benzo[a]pyrene on guanine — Benzo[a]pyrene from tobacco smoke is turned by CYP1A1 into a diol epoxide that bonds to the N2 of guanine. The major adduct lies along the minor groove, as in this crystal structure of a high-fidelity polymerase stalled on it (PDB 1XC9). When a bypass polymerase copies past it, adenine is put in opposite, and the guanine becomes a thymine at the next replication — the G→T transversion that dominates smokers' lung cancers, concentrated at TP53 codons 157, 248 and 273, exactly where the adducts form most. (DNA 2 nm wide)
Carcinogens at their target — Each named carcinogen leaves its own kind of damage. Ultraviolet B welds neighbouring pyrimidines into cyclobutane dimers, giving the C→T changes of skin cancer. Aflatoxin, from mould on stored grain, is activated in the liver and binds guanine N7, producing the TP53 R249S mutation of liver cancer where it is common. Amphibole asbestos fibres lodge in the pleura, too long to be cleared, and coat themselves into asbestos bodies on the way to mesothelioma. Acetaldehyde from alcohol cross-links the two DNA strands, worst in people who lack ALDH2. (DNA 2 nm wide; pleura 0.1 mm)