Describe the routes of spread of malignant tumours. Explain the metastatic cascade and the factors determining the site of metastasis.

Definition

• About 30% of patients have detectable metastases at presentation, and metastasis is responsible for the great majority of cancer deaths
• Exceptions that virtually never metastasise — basal cell carcinoma of the skin and most gliomas, though both are locally invasive and destructive

Routes of Spread

The Metastatic Cascade

• 1. Loss of adhesion — downregulation of E-cadherin loosens cells from one another → 2.
• Attachment to the basement membrane through laminin and fibronectin receptors → 3.
• Degradation of the basement membrane and matrix by matrix metalloproteinases and cathepsins → 4.
• Migration through the defect, guided by autocrine motility factors → 5.
• Intravasation into a vessel or lymphatic → 6.
• Survival in the circulation — most cells die
• platelet aggregation protects the survivors → 7.
• Arrest and extravasation at a distant site → 8.
• Formation of a micrometastasis, angiogenesis and growth
• The process is grossly inefficient — fewer than one in ten thousand circulating tumour cells forms a metastasis; the rate-limiting step is survival and growth at the new site, not escape from the primary

WHY Tumours Metastasise Where They Do

• The spleen and skeletal muscle are the argument for seed and soil — both receive abundant blood yet are almost never sites of metastasis, which no purely mechanical theory explains
• BATSON vertebral venous plexus — a valveless plexus connecting pelvic and vertebral veins, explaining why prostate carcinoma spreads to the lumbar vertebrae without passing through the lungs

Common Sites and Their Primaries

Local Invasion — the First Step

• Invasion precedes metastasis and is itself diagnostic of malignancy
• Malignant cells grow along the lines of least resistance — along fascial planes, perineural spaces and vessel walls
• Some tissues resist invasion — cartilage, elastic arteries and dense fascia are relatively resistant, which is why tumours often spread around rather than through them
• Basement membrane breach is the definitive event, and its demonstration is why histology beats cytology for diagnosis

Applied Aspects

• Sentinel node biopsy identifies the first node draining a tumour; if it is clear, full nodal clearance and its morbidity can be avoided — standard in breast cancer and melanoma
• Metastasis of unknown primary — immunohistochemistry identifies the tissue of origin: cytokeratin for carcinoma, vimentin for sarcoma, S-100 and HMB-45 for melanoma, LCA for lymphoma
• Bone metastases present with pain, pathological fracture, hypercalcaemia or cord compression, and are best detected by isotope bone scan
• Solitary metastases may be resected with curative intent — liver metastases from colorectal cancer are the clearest example
• Staging determines treatment more than histology does, which is why so much effort goes into imaging before any decision is taken
• Anti-angiogenic and anti-metalloproteinase strategies target the cascade directly, though clinical results have been more modest than the biology promised
• Dormancy — micrometastases may remain undetectable for years and then grow, which is why breast cancer can recur two decades after apparently curative treatment
• Adjuvant chemotherapy after "curative" surgery exists precisely to destroy micrometastases that are already present but undetectable
• Circulating tumour cells can be counted in blood and correlate with prognosis, though most never establish a metastasis
• Handling a tumour gently at operation and ligating the venous drainage early are long-standing surgical principles founded on this biology
• The pattern of spread guides the operation — en bloc resection with the draining lymph nodes for carcinoma; wide local excision without nodal clearance for most sarcomas
• Bone metastases from prostate are characteristically osteoblastic, appearing dense on radiographs, whereas most others are lytic — a useful clue to the primary