7.3 about 24 minDeep Learning viewL7 p.4, 8, 10–12

Invasion and metastasis

To spread, a carcinoma cell must let go of its neighbors, cut through the basement membrane, move through matrix and enter a vessel. Which vessel it enters decides where the metastases appear.

The invasion cascade

L7 p.8, 10

Normal epithelial cells are held to each other by E-cadherin, a calcium-dependent adhesion molecule of the adherens junction, and anchored to the basement membrane by hemidesmosomes. Invasion reverses each of these attachments in turn. The lecture gives the sequence step by step:

  1. Detachment: tumor cells downregulate E-cadherin, so they dissociate from one another.
  2. Attachment to the basement membrane: cells bind laminin through laminin receptors.
  3. Degradation: they secrete proteases, above all matrix metalloproteinases (MMP-2 and MMP-9, the type IV collagenases), which dissolve the type IV collagen of the basement membrane.
  4. Locomotion: cells attach to fibronectin in the extracellular matrix through integrins and pull themselves through the stroma.
  5. Intravasation: they enter lymphatics or venules; in the blood they travel as emboli coated with platelets, which shield them from immune cells.
  6. Extravasation and colonization: they adhere to the endothelium of a distant capillary bed, cross it, and grow if they can recruit vessels (angiogenesis).
L7 p.8, 10

Teaching schematic

basement membrane (type IV collagen)fibronectin, collagenintravasation

  1. 1. Detach

    E-cadherin ↓: cells let go of each other

  2. 2. Attach

    Bind laminin in the basement membrane

  3. 3. Degrade

    MMPs digest type IV collagen

  4. 4. Migrate

    Integrins grip fibronectin in the matrix

  5. 5. Enter a vessel

    Intravasation into a lymphatic or venule

The steps of invasion as a carcinoma cell leaves the epithelium: lose E-cadherin, bind laminin, digest type IV collagen with MMPs, crawl on fibronectin with integrins, enter a vessel.L7 p.8

Lecture slide

Lecture diagram of the metastatic cascade: clonal expansion, a metastatic subclone, adhesion to and invasion of basement membrane, passage through matrix, intravasation, a tumor-cell embolus with platelets, extravasation, a metastatic deposit and angiogenesis.
The lecture's metastatic cascade, from the primary tumor (top) through the basement membrane, matrix and a vessel to a metastatic deposit (bottom). Notice how few cells complete every step: most cells that enter the blood die there.L7 p.10

Core activity · The Missing Arrow

The Missing Arrow

Complete the causal chain. Place the missing step by dragging a card onto a gap, or tap a card and then tap the gap. Some gaps need an event; others need the mechanism that links one event to the next.

A colonic adenocarcinoma cell sits above an intact basement membrane. Complete the chain that takes it to the liver.

Each arrow is a mechanism; each box is an event. Keep them apart.

  1. Malignant cells above an intact basement membrane (carcinoma in situ)
  4. the cells bind laminin through laminin receptors
  5. Tumor cells attached to the basement membrane
  7. The basement membrane is breached: invasive carcinoma
  9. Cells migrate through the stroma and enter a portal venule
  10. the embolus, coated with platelets, travels in the portal vein

Cards

Tap or drag a card. Placing a used card moves it.

Three routes of spread

L7 p.10, 12

Once cells reach a channel, the channel decides the destination. The lecture lists three routes plus perineural invasion.

Teaching schematic

Lymphatic

Most carcinomas

  1. Afferent lymphatic
  2. Sentinel (first draining) node
  3. Further nodes → thoracic duct → blood

Hematogenous

Sarcomas; RCC, HCC, follicular thyroid, choriocarcinoma

  1. Capillary or venule
  2. Portal vein → liver (gut, pancreas)
  3. Caval veins → lung (everything else)

Seeding

Ovarian surface carcinoma; medulloblastoma (CSF)

  1. Cells shed from a serosal surface
  2. Float in peritoneal, pleural fluid or CSF
  3. Implant: omental cake, ascites, drop metastases
Lymphatic spread carries carcinoma cells to the first draining (sentinel) node; hematogenous spread follows venous drainage (portal vein → liver, caval veins → lung); seeding carries cells across a body cavity.L7 p.10

Routes of metastasisL7 p.10

  • Lymphatic

    Typical tumors
    Most carcinomas
    Where it goes
    Regional nodes in the order of drainage; later the thoracic duct and blood
    Notes
    Cells arrive by afferent lymphatics in the subcapsular sinus. The first draining node is the sentinel node.

  • Hematogenous

    Typical tumors
    Sarcomas; carcinoma exceptions: renal cell carcinoma, hepatocellular carcinoma, follicular thyroid carcinoma, choriocarcinoma
    Where it goes
    Portal vein → liver; caval veins → lungs
    Notes
    Veins (thin-walled) are entered far more often than arteries. RCC grows into the renal vein, HCC into the portal and hepatic veins.

  • Seeding (transcoelomic)

    Typical tumors
    Ovarian surface carcinomas (serous cystadenocarcinoma); medulloblastoma
    Where it goes
    Peritoneum, omentum, pleura; CSF pathways
    Notes
    Malignant effusions (ascites); 'drop' metastases along the spinal cord

  • Perineural invasion

    Typical tumors
    Prostate, pancreas, head and neck carcinomas
    Where it goes
    Along nerve sheaths
    Notes
    Painful; hard to excise completely

Two routes follow channels other than vessels. Cerebrospinal fluid works like a body cavity: medulloblastoma, a high-grade cerebellar tumor of children, sheds cells into the CSF that settle on the brainstem and spinal cord ('drop metastases'), which is why the whole neuraxis is imaged and treated. Perineural invasion tracks along the space around nerves; it causes pain and lets tumor reach well beyond the visible edge, so surgeons cannot trust a clean-looking margin. Neither route needs a blood vessel, and neither is stopped by a lymph node.

Lecture image

Operative view: the omentum is replaced by a thick, lumpy, pale sheet of tumor (omental cake).
Seeding: at operation the omentum is replaced by a thick, lumpy sheet of tumor (an 'omental cake'), typical of ovarian serous carcinoma that has exfoliated into the peritoneal cavity.L7 p.12

Case image

Autopsy specimen: serosal surfaces studded with many small, pale tumor nodules; a centimeter scale for size.
At autopsy (Chapter VII case, Q8): small pale tumor nodules stud the serosal surfaces. Many implants of similar size scattered over a surface point to cells shed into the cavity, not to blood-borne spread.Ch. VII cases p.9

Lecture image

Micrograph: a pale nerve bundle in the center, wrapped on both sides by small dark glands of carcinoma.
Perineural invasion: small glands of carcinoma wrap around a nerve (pale, center). Tumors that track along nerves cause pain and recur along the nerve's course.L7 p.12

Why liver and lung: follow the venous drainage

L7 p.10, 12Ch. VII cases p.6

Blood-borne tumor cells lodge in the first capillary bed downstream of the vein they entered. The stomach, intestine, pancreas and spleen drain through the portal vein, so their cancers metastasize first to the liver. Everything drained by the superior and inferior venae cavae (limbs, kidneys, most other organs) passes next through the lungs. That is why the liver and lungs are the organs most often involved by metastases, and why metastatic tumors in the liver far outnumber primary liver cancers.

Lecture image

Liver at autopsy studded with many pale, round tumor nodules of different sizes, some with a central depression.
Liver studded with metastases: many pale, round nodules of different sizes scattered through both lobes. Multiplicity and variable size are the gross signature of metastasis; a primary tumor is usually a single dominant mass. Larger nodules may outgrow their blood supply and become centrally necrotic and depressed (umbilicated).L7 p.12

Case image

Axial contrast CT of the upper abdomen: an enlarged liver with many round, rim-enhancing low-density nodules of different sizes.
The same pattern on CT (Chapter VII case, Q5): an enlarged liver with many rim-enhancing low-density nodules. Biopsy showed mucin-secreting adenocarcinoma.Ch. VII cases p.6

Worked case · Where did it start?

A 60-year-old man has weight loss, fatigue and hepatomegaly. CT shows multiple round nodules throughout the liver; a CT-guided biopsy shows mucin-secreting adenocarcinoma.

Which primary sites fit, and how would you narrow them?

Ch. VII cases p.6

Bone metastases: blastic or lytic

L7 p.11–12

Metastases are the most common malignant tumors of bone. They favor the vertebral column (the most common site), pelvis, ribs and proximal long bones, where red marrow and a rich venous supply are; the valveless vertebral venous plexus offers a direct path from the pelvis to the spine. Breast cancer is the commonest cancer to metastasize to bone, prostate cancer the second. What the tumor cells secrete decides what the bone does.

Teaching schematic

radiodense (white)

Osteoblastic (blastic)

Tumor cytokines stimulate osteoblasts → reactive new bone. Prostate (and breast). Alkaline phosphatase ↑.

radiolucent (dark)

Osteolytic (lytic)

Tumor PGE2, IL-1 and PTHrP (via RANKL) activate osteoclasts → bone destroyed. Lung, renal, breast, myeloma. Fractures, hypercalcemia.

Two ways a metastasis changes bone. Osteoblastic: tumor cytokines stimulate osteoblasts, new bone is laid down, the lesion is dense on X-ray and alkaline phosphatase rises. Osteolytic: tumor products (PGE2, IL-1, PTHrP acting through RANKL) activate osteoclasts, bone is destroyed, the lesion is lucent and calcium may rise.L7 p.11

Osteoblastic (blastic)

  • Tumor cytokines activate osteoblasts → reactive new bone
  • Prostate carcinoma above all; breast can be blastic
  • X-ray: radiodense (sclerotic) lesions
  • Serum alkaline phosphatase ↑ (bone formation)

Osteolytic (lytic)

  • Tumor products (PGE2, IL-1, local PTHrP → RANKL) activate osteoclasts
  • Lung, renal cell, breast carcinoma (and myeloma, a primary bone marrow tumor)
  • X-ray: radiolucent 'punched-out' lesions
  • Pathologic fractures and hypercalcemia
L7 p.11

Lecture image

Three panels: a bone scan with many dark hot spots in spine and ribs; sawn vertebral bodies with many pale tumor nodules; a pelvic radiograph with diffusely dense, mottled bone.
Bone metastases (left to right): a bone scan with many 'hot spots' in the spine and ribs; vertebral bodies studded with pale tumor nodules; and a pelvic radiograph with diffusely dense, mottled bone, the sclerotic pattern that osteoblastic metastases (classically prostate carcinoma) produce.L7 p.12

Knowledge check · 7.3

Answer, read why, and try again whenever you like. Answers are kept in both study modes.

0 of 5 correct
  1. Q1Seeding of body cavitiesCh. VII cases p.9L7 p.10

    A 67-year-old woman was diagnosed with papillary serous cystadenocarcinoma of the ovary 3 years ago. She now has a massively swollen abdomen and dies a month later. At autopsy, the peritoneum is studded with small tumors and there are 4 L of ascites.

    Autopsy specimen: serosal surfaces studded with many small, pale tumor nodules; a centimeter scale for size.

    Which route of metastasis accounts for these findings?

  2. Q2Portal drainage → liver metastasesCh. VII cases p.6L7 p.10

    A 60-year-old man has a 6-month history of weight loss and fatigue, and marked hepatomegaly. CT shows multiple round 'cannonball' nodules in the liver; CT-guided biopsy shows a mucin-secreting adenocarcinoma.

    Axial contrast CT of the upper abdomen: an enlarged liver with many round, rim-enhancing low-density nodules of different sizes.

    Where did this metastatic cancer most likely originate?

  3. Q3Invasion cascade: E-cadherinL7 p.8

    In a colon adenocarcinoma, which change is the first step that allows tumor cells to leave the epithelial sheet?

  4. Q4Blastic bone metastasesL7 p.11–12

    A 74-year-old man has low back pain. His PSA is 86 ng/mL. A bone scan shows many hot spots in the spine and pelvis.

    Which pair of findings is most likely?

  5. Q5Hematogenous spread of sarcomasL7 p.10

    A 15-year-old boy has an osteosarcoma of the distal femur. Staging CT shows three nodules in the lungs; regional lymph nodes are not enlarged.

    How did the tumor most likely reach the lungs?

Previous7.2 Dysplasia and invasionNext7.4 Epidemiology and genes