By Emily Smith
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- To understand what is meant by invasion and metastasis
- To know the different routes of metastasis
- To understand systemic and local effects of tumours
- To understand what tumour markers are, and how they aid in monitoring tumour burden
The ability of a tumour to invade and metastasise are key properties of malignant tumours. These processes increase the tumour burden and lead to a wide range of local and systemic effects.
Invasion is when a tumour grows from its primary site into surrounding structures.
Epithelial to mesenchyme transition (EMT) is a process which allows epithelial cells to undergo multiple changes until it more closely represents a mesenchymal cell, which allows invasion.
For malignant cells to invade in to surrounding tissues they require:
- Altered cellular adhesion
- Decreased expression of E-cadherin reduces the cell-cell adhesion.
- Changes to expression of integrin receptors alters the adhesion between cells and extracellular matrix.
- Increased secretion of proteolytic enzymes.
- Matrix metalloproteinases (MMPs) are enzymes secreted by malignant cells to enable them to breakdown surrounding connective tissue.
- Increased cellular motility
This diagram shows the progression of EMT, which eventually allows cells to cross the basement membrane.
SimpleMed original by Emily Smith
Metastasis is the process in which malignant cells migrate from the primary site of the tumour to a distant secondary site. It is a consequence of growth and invasion at the primary site. In order to metastasise, malignant cells need to:
- Invade through the basement membrane of blood or lymphatic vessels – intravasation.
- Avoid host immune defences.
- Attach to endothelium at a distant location.
- Leave blood or lymphatic vessel to enter surrounding tissue – extravasation.
There are several different routes of metastasis; blood stream, lymphatics and transcoelomic spread (across a body cavity like through the peritoneum). Carcinomas typically spread to the draining lymph nodes first, and then spread via the blood stream. Sarcomas tend to spread by the blood stream.
Many malignant cells can reach a secondary site but might not grow for a number of reasons, including being caught by the immune system, or not being able to invade through local cells. This spread of cancer cells leads to micro-metastases – clinically undetectable groups of malignant cells. These can start to regrow after a period of time, which is what causes an apparently cured patient to relapse. This is also the reason why patients with cancer cannot donate their organs.
Blood Stream Metastasis
Secondary tumours form in organs which are perfused by blood which has drained the tumour. For example, GI malignancies often spread to the liver due to drainage from the portal vein, which takes blood to the liver.
Metastases taking this route often form masses at the liver, lungs, bone and brain.
Bone, as a site for metastases, is commonly favoured by carcinomas originating from lung, breast, thyroid, kidney and prostate. Metastases from the former four organs cause lytic lesions which means they decrease bone mass, whereas metastases from the prostate causes sclerotic lesions - increase bone mass. These changes are visible on x-rays.
Malignant cells enter lymph nodes through the afferent lymph vessels and settle at the periphery. They grow inwards, and groups of affected cells become clumped together by tumour tissue and connective tissue. This can result in lymphadenopathy and blockage of lymph flow leading to lymph oedema in the region drained by the blocked lymph vessels.
This type of metastasis occurs within pleural, pericardial and peritoneal cavities. This results in formation of a protein rich effusion - exudate - within the cavity. This fluid also contains malignant cells causing the exudate, so can therefore by aspirated and used for diagnosis.
Peritoneal effusions (ascites) are commonly caused by ovarian tumours, although can also be caused by any abdominal tumour. Pleural and pericardial tumours are often caused by breast and lung carcinomas.
Local Effects of Tumours
Growth of benign and malignant tumours can lead to compression and obstruction of adjacent structures. For example, growth of a pituitary adenoma can cause compression of the optic chiasm, resulting in a bitemporal hemianopia – loss of peripheral vision. And a colorectal carcinoma can cause constipation due to obstruction of the bowel.
There are some local effects which are more specific to malignant neoplasms. Malignant neoplasms on mucosal surfaces often ulcerate and bleed. This is an important cause of anaemia in patients with GI malignancies, but the bleeding could be occult (not visible to the naked eye). A key feature of malignant neoplasms is their ability to invade into surrounding tissues. For example, at late stages cervical cancer can invade into the bladder and rectum, leading to fistula formation and incontinence as urine or faeces leak out of the vagina.
Systemic Effects of Tumours
A paraneoplastic syndrome is a clinically detectable syndrome caused by a neoplasm, but that causes systemic effects not related to metastases. These signs and symptoms are caused by increasing tumour burden, secretion of hormones and other effects.
An increase in tumour burden, and other factors such as release of cytokines, can lead to cachexia (weight loss), malaise, immunosuppression and thrombosis. Anaemia can also be a complication of tumours through mechanisms such as bleeding (common in GI malignancy) or the failure of bone marrow to produce red blood cells (called aplastic anaemia). There are many other mechanisms which can lead to anaemia.
Tumours which secrete hormones cause a large range of effects. For example, a benign tumour of an endocrine gland may secrete hormones at a higher level than is secreted by healthy tissue. For example, a thyroid adenoma secreting high levels of thyroid hormones results in thyrotoxicosis (hyperthyroidism), and an adenoma of the adrenal cortex can result in Cushing’s syndrome due to excess cortisol secretion.
Some malignant tumours are also able to produce hormones. This is called ectopic hormone secretion as they are not normal sites for hormone production. Examples of this include:
- Bronchial small cell carcinoma (a type of lung cancer) producing ACTH resulting in Cushing’s syndrome.
- Bronchial small cell carcinoma producing ADH resulting in Syndrome of Inappropriate ADH (SIADH).
- Bronchial squamous cell carcinoma producing a PTH related peptide (PTHrP), resulting in hypercalcaemia.
Tumour markers are substances released into circulation by tumour cells. They can be measured in the blood or urine, and their levels can be measured to monitor tumour burden and response to treatment. They are not usually used for diagnosis, but for tracking the established cancer.
This table shows examples of tumour markers, and what they indicate.
SimpleMed Original by Emily Smith
Added by: Maddie Swannack