Cancer is a large group of diseases associated with uncontrolled cell growth and movement, and it has become one of the main causes of death in the UK and the developed world. In 2013 cancer was the most common cause of death in England and Wales, causing 29% of all deaths registered, and this percentage is increasing every year 1. In the UK there were 330,000 new cases of cancer in 2011, and over 160,000 cancer deaths in 2012 2, and with about 2.5 million people currently living with a cancer diagnosis 3 it is important for medics to be aware of cancer and its management, even if they are not specialising in oncology.
What is Cancer?
Cancer is broadly characterised by unregulated cell growth and cells invading and spreading from the primary site to other sites throughout the body, a process termed metastasis. An abnormal growth of cells is called a neoplasm or tumour, and tumours can be classified as benign or malignant. A benign growth is a tumour which never metastasises, and therefore is usually a much less aggressive and dangerous growth; however, this depends on the site of the tumour, as even a benign tumour in the brain can compress vital structures and result in death. A malignant tumour is a growth that does have the ability to metastasise, and so malignant tumours are normally more aggressive and dangerous. When the term ‘cancer’ is used, it normally means a malignant tumour.
Almost every cell type in the body has the capability to produce a tumour if it develops the necessary mutations. Over 100 types of cancer have been identified so far 4, and the broadest way to classify cancers is by the tissue of origin. Cancers are classified as carcinomas when they originate from epithelial tissue (skin, colon), sarcomas when they come from mesodermal tissue (bone, muscle, fat), and adenocarcinomas when the tissue of origin is glandular tissue (e.g. most breast cancers). About 85% of cancers are carcinomas, mainly due to the high levels of cell replication and renewal found in epithelial tissues like the skin and the lining of the gut 4.
As a general rule, benign tumours end in –oma, whilst malignant tumours end in –carcinoma, -sarcoma or –adenocarcinoma. Examples of some benign tumours include fibroma (fibrous tissue), lipoma (fat/adipose tissue) and rhabdomyoma (skeletal muscle), whilst their respective malignant counterparts are fibrosarcoma, liposarcoma and rhabdomyosarcoma. These names may seem complicated, but naming tumours is easier once the basic classification system is understood.
Another way to classify cancers is the type of cell they originate from, particularly with carcinomas. For example, if a tumour originates from the squamous cell layer of the epidermis then it is called a squamous cell carcinoma, and certain lung cancers can be classified as small cell or non-small cell depending on their cell of origin.
Characteristics of Cancer
For a normal cell to become a malignant cancer cell certain changes must occur in the DNA that promote the cells survival and movement and prevent apoptosis (cell death). Whilst the genetic mutations found in different types of cancer may differ widely, 10 characteristics of most, if not all, cancer cells have been suggested. The theory is that as a cell transitions into malignancy it acquires most or all of these characteristics through genetic mutations. These characteristics include proliferating without the need for growth signals, becoming less responsive to growth inhibitory signals, resisting apoptosis, evading the immune system, effectively becoming immortal and replicating indefinitely, undergoing cell changes to enable movement and invasion, stimulating the growth of blood vessels (angiogenesis) to help tumour growth and having an unstable genome with many mutations 5. All of these characteristics are summed up in figure 1 below.
Figure 1: Hanahan and Weinberg’s diagram of the hallmarks of cancer. These 10 traits represent the characteristics of the “perfect” cancer cell 5
It is these 10 qualities that make malignant cells so deadly and often hard to treat. Many cancer cells gain mutations in genes that control the cell replication cycle, some of which are classed as tumour suppressor genes, rendering them ineffective and meaning the cell can divide uncontrollably 6.
Figure 2: a comparison of the appearance of normal cells and cancer cells 7
These genetic mutations can have many causes and triggers, or may even happen spontaneously. Cancer mutations can be classed as acquired or genetic; acquired being when the mutation is caused during life by an external stimulus or ‘carcinogen’, and genetic being a mutation passed down from parent to child that leaves the child more susceptible to developing a certain type of cancer. One example of a genetic cancer mutation is a germline mutation in the RB (retinoblastoma) protein gene which controls and inhibits the cell cycle. A child may inherit one mutated copy of the RB gene, leaving them with only one functional copy on the unaffected chromosome, but if the normal copy should acquire a mutation then the child will develop a retinoblastoma tumour of the retina in the eye. It is a rare cancer that tends to affect children under the age of 5, but because it is usually noticed and treated early over 98% of children are now treated successfully 8.
Another well researched cancer-causing mutation are the genes BRCA1 and BRCA2. These BRCA genes are tumour suppressor genes normally involved in DNA repair, but certain genetic mutations mean they do not function properly, increasing the risk of tumours developing. Women carrying BRCA1 have a 55-65% risk of developing breast cancer as well as a 39% risk of developing ovarian cancer during their lifetime 9. One potential treatment for these women is a prophylactic double mastectomy (removal of both breasts) and oophorectomy (removal of both ovaries). Whilst this reduces their risk of cancer to almost zero, this radical method of management has long term consequences, including leaving these women infertile and causing an early menopause, so it can be devastating news for a patient to be told they are a BRCA gene carrier.
Well known environmental carcinogens which can cause acquired mutations include cigarette smoking in the case of lung and mouth cancer, a high salt diet and processed meat in colorectal and stomach cancers, ultraviolet radiation from the sun in skin cancer and melanoma and asbestos inhalation in another type of lung cancer called mesothelioma. A person’s risk of developing these cancers can often be dramatically reduced by avoiding these environmental factors.
How does Cancer Spread and Kill?
The main mechanism by which cancer causes death is invasion, metastasis and colonisation at secondary sites across the body. Different cancers tend to metastasise to different areas of the body; for example, breast cancer tends to move to the lungs and bones, prostate cancer often metastasises to the vertebrae and pelvic bones, and colorectal cancer normally metastasises to the liver because blood draining from the gut passes first through the portal vein of the liver. However, where a cancer will metastasise to cannot always be explained by directionality of blood flow; about 1/3 of metastases do not make sense in this way, and one certain type of kidney cancer preferentially metastasises to the thyroid gland, a relationship which makes no anatomical sense 10.
Normally cells within organs have well-defined boundaries, with strong basement membranes supporting the cell layers, particularly in epithelial tissue. Cancer is characterised by the spread of cells from a primary site, and cancer cells develop ways to invade past their basement membranes and into surrounding tissues. They can then metastasise to other areas through tissues, via blood vessels or throughout the lymphatic system which drains fluid from tissue and is a part of the immune system 10.
As a cancer spreads and the tumour load increases, the cancer causes physical obstruction, interferes with organ function and competes with normal cells for oxygen and nutrients. Ultimately cancer kills by preventing other organs from functioning and compressing vital structures, especially when there have been brain metastases. It is interesting to note that whilst most cancers do eventually metastasise, only about 1 in 10,000 cells that leave the primary tumour actually survive transport to a secondary site and successfully form a tumour 10.
Staging and Grading
In oncology, tumours are staged and graded to help produce an appropriate treatment plan and give an accurate prognosis for the patient. Staging a tumour is done using the TNM, or Tumour, Node, Metastasis system. There are many ways that different cancers can be sampled to be staged, but the gold-standard is to take a surgical biopsy of the tumour tissue. Histopathologists then use this biopsy to look at the size of the tumour (T), if the cancer has spread to lymph nodes in the lymphatic system (N) and whether the tumour has metastasised to other areas of the body (M) 11.
Tumour grading aims to describe how similar the tumour cells are to normal cells, termed the differentiation of the cell. In general, the more tumour cells resemble normal cells (fully differentiated), the less aggressive the cancer is. When a tumour is completely undifferentiated, or anaplastic, these cells are often the most aggressive and invasive tumour cells. There are different grading systems for different cancers, with some spanning Grade 1-5, but in general the grading system used is as follows:
• Grade I – The cancer cells are well differentiated and dividing slowly
• Grade II – Cells are less well differentiated and dividing faster than normal
• Grade III – Cells are undifferentiated/anaplastic and dividing and invading rapidly 12
Figure 3: basic grading of the cells within a tumour 13
Cancer Management and Treatment
The 3 mainstays of cancer treatment are surgery, radiotherapy and chemotherapy, in order of effectiveness. It is important to understand that cancer treatment can be curative or palliative. Curative treatment tends to be more intense and radical in the aim of causing complete remission of the cancer, whereas palliative treatment is given when a cancer is too widespread to be cured, and aims to reduce pain and increase quality of life for the patient in their last weeks or months.
Surgery is a particularly effective treatment for solid cancers that are easily accessed, such as colorectal, breast, skin, head and neck and mouth cancers. Surgery can be curative if the cancer has not yet spread and a wide excision margin is made around the tumour. Depending on the cancer and its stage the surgery may also involve removing lymph nodes from the surrounding area to prevent spread of the tumour 14.
In radiotherapy, radiation is beamed into the tumour. The radiation causes DNA damage that the faulty cancer cells struggle to repair, and ultimately they undergo apoptosis. About 120,000 cancer patients each year in the UK undergo radiotherapy as part of their cancer management. Radiotherapy also kills normal cells alongside tumour cells, and general side effects of radiotherapy include anaemia which causes tiredness and weakness, loss of hair and sore skin over the treatment area 15.
Chemotherapy uses cytotoxic (cell killing) drugs, usually injected straight into the bloodstream via a vein. There are many different cytotoxic drugs which work in various ways, from drugs which prevent cells from dividing to DNA damaging drugs. Unfortunately, chemotherapeutics are not very specific, and so patients suffer from side-effects caused by the death of cells in their blood, gastrointestinal tract, bone marrow, skin and nails. Hair loss and anaemia are common side-effects, as well as nausea, opportunistic infections, fertility problems and occasionally changes in organ function. Patients undergoing cancer treatment must have regular reviews and be treated appropriately for their side-effects as well as for the cancer, as the side-effects of chemotherapy can severely affect quality of life 16.
A patient’s prognosis depends upon many factors, including their age and the type of cancer they have. Some cancers now have good average survival rates, such as breast cancer (87% 5 year survival) 17, skin melanoma (90%) 18 and testicular cancer (98%) 19. This is mainly due to these cancers being relatively external, and so easier to detect early and more responsive to surgery. NHS screening and public education drives have played an important part in detecting tumours earlier.
Unfortunately these survival rates are not seen in all types of cancer. Certain cancers, such as ovarian and pancreatic cancer, have very low 5 year survival rates as these often present late with indistinct and vague symptoms, so by the time of diagnosis many have already metastasised. On average 46% of ovarian cancer patients, and only 4% of those with pancreatic cancer currently survive 5 years 20, 21. Research is currently being done to try to find ways of detecting these cancers earlier in order to increase survival, and there remains much work to be done to increase early detection and educate the public about cancer signs and symptoms.
1. Office for National Statistics, Deaths in England and Wales 2013 http://www.ons.gov.uk/ons/rel/vsob1/death-reg-sum-tables/2013/info-deaths-2013.html Accessed: 13/07/15
2. Cancer Statistics for the UK http://www.cancerresearchuk.org/health-professional/cancer-statistics Accessed: 13/07/15
3. Key Cancer Statistics http://www.macmillan.org.uk/Aboutus/Ouresearchandevaluation/Researchandevaluation/Keystatistics.aspx Accessed: 13/07/15
4. Pecorino L, Molecular Biology of Cancer, 3rd Edition (2012) Oxford University Press, pp. 2
5. Hanahan, D., & Weinberg, R. A. (2011). Hallmarks of cancer: the next generation. Cell, 144(5), 646-674.
6. Pecorino L, Molecular Biology of Cancer, 3rd Edition (2012) Oxford University Press, pp. 114-115
7. Cell Image http://breastcancer.about.com/od/diagnosis/tp/tumor_grade.htm Accessed: 25/08/15
8. Retinoblastoma http://www.nhs.uk/conditions/retinoblastoma/Pages/Introduction.aspx Accessed: 20/07/15
9. BRCA1 Mutation http://www.cancer.gov/about-cancer/causes-prevention/genetics/brca-fact-sheet Accessed: 22/07/15
10. Pecorino L, Molecular Biology of Cancer, 3rd Edition (2012) Oxford University Press, pp. 197
11. Tumour Staging http://www.cancerresearchuk.org/about-cancer/type/breast-cancer/treatment/tnm-breast-cancer-staging Accessed: 21/07/15
12. Tumour Grading http://www.nhs.uk/chq/Pages/3169.aspx?CategoryID=96 Accessed: 22/07/15
13. Tumour Grading Image http://www.cancer.ie/cancer-information/prostate-cancer/further-tests#sthash.hL20I35J.dpbs Accessed: 25/08/15
14. Cancer Surgery http://www.cancerresearchuk.org/about-cancer/cancers-in-general/treatment/surgery/surgery-to-treat-cancer Accessed: 22/07/15
15. Cancer Radiotherapy http://www.cancerresearchuk.org/about-cancer/cancers-in-general/treatment/radiotherapy/side-effects/general/radiotherapy-reactions Accessed: 22/07/15
16. Chemotherapy http://www.cancerresearchuk.org/about-cancer/cancers-in-general/treatment/chemotherapy/chemotherapy-side-effects#sfx Accessed: 22/07/15
17. Breast Cancer Survival http://www.cancerresearchuk.org/health-professional/cancer-statistics/statistics-by-cancer-type/breast-cancer/survival#heading-Zero Accessed: 22/07/15
18. Melanoma Survival http://www.cancerresearchuk.org/about-cancer/type/melanoma/treatment/melanoma-statistics-and-outlook Accessed: 22/07/15
19. Testicular Cancer Survival http://www.cancerresearchuk.org/health-professional/cancer-statistics/statistics-by-cancer-type/testicular-cancer/survival#heading-Zero Accessed: 22/07/15
20. Ovarian Cancer Survival http://www.cancerresearchuk.org/health-professional/cancer-statistics/statistics-by-cancer-type/ovarian-cancer/survival#heading-Zero Accessed: 22/07/15
21. Pancreatic Cancer Survival http://www.cancerresearchuk.org/health-professional/cancer-statistics/statistics-by-cancer-type/pancreatic-cancer/survival#heading-Zero Accessed: 22/07/15