Metastasis 

                                                                      notes by vivek rao

• ‘Metastases’ are tumour implants discontinuous with the primary tumour 
• Approximately 30% of newly diagnosed patients with solid tumours present with metastases 
• They are the major cause of cancer-related morbidity and mortality

Main Routes of Spread of tumours 

• Direct spread 
• Lymphatics 
• Vascular spread 
• Transcoelomic spread 
• Perineural spread 

Direct invasion

Growth of cancers is accompanied by progressive infiltration, invasion and destruction by the surrounding tissue. 

In general they are poorly demarcate by surrounding normal tissue and well defined cleavage plane is lacking.

Metastasis is mainly by 

Lymphatic spread 

Haematogenous spread 

Transcoelomic spread

Invasion & Metastasis 

For tumour cells to break loose from the primary mass, enter the blood/lymph vessels and produce a secondary growth they must interact with the extracellular matrix (ECM) at several stages: 

                                        Breach the underlying basement membrane 

                                        Transverse the interstitial connective tissue 

                                        Penetrate the vascular basement membrane 

Invasion of the ECM is an active process which involves: 

                                    Detachment of tumour cells from each other 

                                    Attachment to matrix components 

                                    Degradation of the ECM 

                                    Migration of tumour cells

Detachment of Tumour Cells 

                                   Normal cells are adhered to one another via transmembrane glycoproteins (E-cadherins) 

                                   Downregulation of E-cadherin expression in adenocarcinoma of the colon 

                                   Decreased ability for adherence and facilitation of detachment from the primary tumour 

Attachment of Matrix Components 

Expression of integrins by tumour cells serve as receptors for ECM components 

Receptor-mediated attachment of tumour cells to laminin & fibronectin  

Increased density of receptors = increased invasiveness

Degradation of ECM 

1. Secretion of proteolytic enzymes by tumour cells 
2. Induction of host cell protease synthesis (eg. type IV collagenase) 
3. Cleavage of type IV collagen of the epithelial & vascular basement membranes 

Migration of Tumour Cells 

1. Cleavage products of matrix components have growth-promoting, angiogeneic and chemotactic activities 

2. Promotion of migration of tumour cells through loosened ECM, and through the degraded basement  membrane. 

  

Lymph Node Metastasis 

• Motility towards lymphatic capillaries aided by lower interstitial fluid pressures within the ECM, than in the tumour ~ ‘tide of fluid’ 
• Having reached the lymphatic capillaries, tumour cells move along external surface of the endothelium and invade into the lumen via interendothelial gaps 
• The composition of lymphatic vessels makes it easy for fluid, particles and cells to pass into the vessels 
• Having gained access to the capillaries, the tumour cells embolise singly or in clusters towards local lymph nodes
• Some cells do not reach the nodes, but adhere to the lymphatic endothelium and cause ‘in transit’ metastases 
• Tumour cells enter the subcapsular sinus of the lymph node through the afferent lymphatics and may either:

• Invade the cortex of the node
• Bypass the node via lymphpaticovenous connections
• Travel directly into the efferent lymphatics and spread to further local nodes

Lymphangiongenesis  

Until recently lymphatic metastasis was believed to be a ‘passive process’ – it has now become apparent that lymphangiogenesis can contribute actively to tumour metastasis 

Studies describing lymphatic growth and development did not emerge until the late 1990s due to a lack of defined lymphatic endothelial markers 

Widely established lymphatic endothelial markers include: 

                Vascular Endothelial Growth Factor-3 (VEGFR-3)– the first lymphangiogenic growth                             factor identified 

               Podoplanin 

                LYVE-1 

                Prox-1 

                FOXC2 

Current knowledge does not yet provide a full understanding of their exact role in lymphangiogenesis.

While the mechanisms of tumour lymphangiogenesis are not fully understood or defined, multiple studies have established VEGF-C & -D as the main regulator of lymphangiogenesis 

Over-expression of VEGF-C in animal tumour models has demonstrated strong increases in lymphatic vessel formation and significant promotion of lymph node metastases 

Recently VEGF-C has also been shown to promote further metastasis from regional to distal lymph nodes and organs 

It is proposed that tumour lymphangiogenesis increases the lymphatic vascular area within or close to the tumour, and therefore increases contact between tumour cells and the lymphatics ~ facilitating entry of malignant cells into the lymphatic system, thereby promoting metastatic spread 

Colorectal cancer data is conflicting in human models, but it seems likely that both VEGF-C/-D contribute to the disease course  

Therapeutic Strategies 

• Anti-lymphangiogenic therapy is an important area for future research ~ assuming that restriction of lymphatic vessel growth associated with tumours will prevent lymph node metastases 
• Lymph node metastases are a key event in colorectal tumour progression; 
• With lymph node metastases 5-year survival is reduced from 90% to 68% 
• VEGF-C/-D induced stimulation of VEGFR-3 represents a promising target for anti-lymphangiogenic therapy 
• Blocking extracellular ligand-receptor interactions with neutralising monoclonal antibodies to either receptors or ligands ~ demonstrated in some animal models 
• Soluble VEGFR-3-fc fusion protein has also been shown to inhibit lymphangioge 

Skip metastasis :

Local lymph nodes may be bypassed due to venous lymphatic anastomosis or because the inflammation or radiation has obliterated the channels.

Regional nodes act as a barrier to further spread of the tumour, at least for a time. 

The cells, after arrest within the node, may be destroyed. 

Drainage of tumour cell debris or tumour cell antigens, or both can induce reactive changes. 

The enlargement of the nodes may be due to 

• Spread of the cancer cells 
• Reactive hyperplasia 

Vascular spread 

Haematogenous spread s typical of sarcomas but is seen in carcinoma too. Tumour emboli 

          Permeation

Via blood stream spread 

As tumour emboli 

• Osteosarcomas metastatising to the lungs 
• Gastrointestinal malignancies metastatising to the liver

Permeation 

Cords of cells grow along the blood vessels Eg. In renal cell carcinoma the malignant cell cords grow along the vessel walls, renal vein and IVC

Haematogenous spread 

Typical for sarcomas but also used by the carcinomas. 

Arteries: due to thicker walls are less readily penetrated. But is seen when a tumour pass through pulmonary capillary beds or pulmonary arterio-venous shunts or when pulmonary metastasis give rise to tumour emboli. 

Venous invasion follow venous flow draining the site of neoplasm. Eg. Liver and lung.( all portal drainage to the liver and all caval blood flows to the lungs) 

Cancers arising in close proximity to the vertebral column often embolise through the paravertebral plexus. Eg: thyroid and prostate carcinomas 

Certain cancers have a propensity for venous invasion. 

Renal cell carcinoma invades branches of renal vein then renal vein and grow along the IVC in a snake like fashion some times reaching the right side of the heart. 

Hepatocellular carcinoma often penetrate the portal vein 

Such IV growth may not be accompanied by widespread dissemination. 

Secondary carcinoma of lung 

These tan-white nodules are characteristic for metastatic carcinoma. Metastases to the lungs are more common even than primary lung neoplasms simply because so many other primary tumours can metastasise to the lungs. 

Metastatic tumour deposits in solid organs 

Liver, lung, brain, bone marrow 

Certain types of tumours have a characteristic patterns of spread. Eg. Prostatic ca is often spread to bone 

It is thought that the malignant cells and the target organ must express mutually compatible receptors and cell surface adhesion molecules which facilitate cellular anchorage and growth promotion 

Hepatic metastasis: portal circulation 

Pulmonary metastasis: from systemic circulation 

Transcoelomic spread 

• Peritoneal cavity 
• Pleural cavity 
• Pericardial cavity 
• Subarachnoid cavity 
• Joint space 

Krukenberg tumour 

Gastric carcinoma with secondary deposits in the ovary and pouch of Douglas 

Colonic carcinoma with secondary deposits in the ovary and pouch of Douglas 

Tumour cells may remain confined to the surface of the abdominal viscera without penetrating into the substance. 

Some times the mucous secreting tumours of the ovarian or appendiceal carcinoma fill the peritoneal cavity with gelatinous neoplastic mass referred to as pseudomyxoma peritonei.

Breast and lung tumours commonly involve pleural space and cause pleural effusion 

Ovarian and gastric tumours are responsible for peritoneal invovment and cause malignant ascitis. 

There is commonly an inflammatory response in the lining with the accumulation of protein rich fluid and inflammatory cells, proliferation of mesothelial cells and haemorhage 

Transcoelomic spread 

Diagnostic paracentesis of ascitic/ pleural fluid

Spread of lung carcinoma 

Local spread 

Lymphatic spread 

Transcoelomic spread 

Haematogenous spread 

Perineural spread 

Spread along the course of nerve bundles 

Common in prostate carcinoma and some basal cell carcinoma