Basics of cancer
Cancer is one of the most prominent causes of death worldwide (after cardiovascular diseases) having accounted for approximately 12.5% of total deaths (7.1 million people) in 2002 according to the World Health Organisation. Within developed nations such as Australia, this percentage is greater: in 2014, cancer accounted for approximately 30% of registered deaths in Australia (Australian Institute of Health and Welfare, 2017). It is estimated that the incidence of cancer will continue to increase as age-standardised mortality rates decreases.
What is cancer?
The term cancer refers to various diseases characterised by two symptoms: the unregulated proliferation of cells and the spread of these cells through the body by invasion and/or metastasis. Unregulated cell proliferation often results in the development of neoplasms (commonly known as tumours). Without a capability to spread, a tumour is considered non-malignant, or benign (though it is not necessarily harmless). Hanahan & Weinberg (2010; 2011) have described ten cellular-level hallmarks of cancer:
- Self-sufficiency in growth signals.
- Insensitivity to anti-growth signals.
- Evasion of apoptosis (programmed cell death).
- Limitless replicative potential
- Sustained angiogenesis (development of blood vessels).
- Tissue invasion and metastasis.
- Deregulated cellular energetics (or metabolism).
- Evasion of immune response.
- Genomic instability and mutation.
- Tumour-promoting inflammation.
Types of cancer
Cancer can be classified (or coded) on two axes: with a morphological code, which describes the cell type (or histology) of the tumour, and a topographical code, which describes the anatomical site. Classifications are defined in International Classification of Diseases (ICD) lists published by the World Health Organisation, with ICD-O-3.1 containing morphology codes and ICD-10 containing topographical codes. Principal histological categories are summarised below:
- Carcinoma, cancer originating from epithelial cells, the most common histology. The most common sub-types originate in glandular tissue (adenocarcinoma) and skin and lining tissues (squamous cell carcinoma).
- Sarcoma, cancer originating from mesenchymal cells (or connective tissue). Common sub-types originate in bone (osteosarcoma), cartilage (chondrosarcoma), fat (liposarcoma) and muscle (leiomyosarcoma and rhabdomyosarcoma).
- Blastoma, cancer originating from blast cells (unipotent stem cells), generally in children.
- Germinoma, cancer originating from germ cells, generally occurring in the ovaries (dysgerminoma), testes (seminoma), or cranium.
- Leukemia, cancer originating from leukocytes, cells that mature in the bloodstream.
- Lymphoma, cancer originating from lymphocytes, cells that mature in the lymphatic system.
- Myeloma, cancer originating in plasma cells of bone marrow.
Some cancers have a mixed histology, with components from more than one histological category (e.g. carcinosarcoma).
Cancer is more frequently described topographically, and often without acknowledgement of whether the tumour is a primary tumour (i.e. developed locally) or a secondary or metastatic tumour. As an example, “brain cancer” can be used to refer to gliomas that originated in the cerebrum or cerebellum, or to brain metastasis resulting from cancer of the lung. Where the histological type or primary tumour is unknown, it is referred to as a cancer of unknown primary origin.
Cancer incidence and mortality data in Australia is recorded by the Australian Institute of Health and Welfare (AIWH), an agency of the federal government. The Australian Cancer Database contains incidence data, compiled using state and territory registries, and covers all primary cancers with the exception of basal and squamous cell carcinomas of the skin (common non-melanoma skin cancers). The table below presents the mean number of new cases of various cancers (topographically categorised), in addition to the mean age-standardised incidence rates (ASR) per 100,000 persons and risk of diagnosis before the age of 75, for the year 2012, taken from the AIWH. The ASR are hypothetical rates that would have been observed for the same age distribution as the standard population.
|Breast cancer (females)||15050||118.3||9.4%|
|Breast cancer (males)||116||1.0||0.1%|
|Cervical cancer (females)||869||7.4||0.5%|
|Colorectal / bowel cancer||14958||59.0||4.1%|
|Head & neck cancer, including lip||4243||17.0||1.4%|
|Melanoma of the skin||12036||48.7||3.7%|
|Non-melanoma skin cancer, rare types||850||3.3||0.2%|
|Ovarian cancer (females)||1378||10.5||0.8%|
|Prostate cancer (males)||20065||162.7||13.6%|
|Testicular cancer (male)||768||6.9||0.5%|
|Unknown primary site cancer||2745||10.6||0.6%|
|Uterine cancer (females)||2397||18.3||1.7%|
The development of cancer is known as carcinogenesis. Cancer principally develops as a result of genetic abnormalities in, or variations in expression of, proto-oncogenes and tumour suppressor genes, which translate genetic code into proteins that promote and inhibit cell growth respectively. These genetic abnormalities can be the result of a mutagen altering genetic information or spontaneous errors in DNA replication.
Agents responsible for mutations (mutagens) or that otherwise promote the growth of cancers by modification of metabolic behaviours are known as carcinogens. Carcinogens can be categorised as physical (e.g. UV and ionising radiation), chemical (e.g. asbestos, tobacco smoke) or biological (e.g. viral and bacterial infections). Exposures to these are considered risk factors for cancer. Risk factors are generally associated with types of cancer (e.g. tobacco smoke and lung cancer, or meat consumption and colorectal cancer). At least one in three cancers in Australia is attributable to exposure to known modifiable factors (Whiteman et al, 2015). The estimated percentage of cancer cases attributable to cancer risk factors in Australia are presented in table below:
|Lack of fibre||>25-30 g/day||2.3%||2.1%||2.2%|
|Lack of fruits||>300 g/day||1.5%||1.2%||1.3%|
|Lack of vegetables||> 260 g/day||0.3%||0.2%||0.3%|
|Red and processed meats||None||2.7%||1.6%||2.2%|
|Excessive weight||<25 kg/m2||2.5%||4.5%||3.4%|
|Physical exercise||≥ 300 min/week||0.5%||2.9%||1.6%|
|Ultraviolet radiation||UK incidence||7.1%||5.0%||6.2%|
|Breast feeding||> 12 months||-||0.5%||0.2%|
Effects and symptoms
The effects and symptoms of cancer can be systemic or local (i.e. occurring near either the primary site or metastasis) and are the result of disrupted organ function. The presence and intensity of the symptoms of cancer are dependent on the type of cancer, and therefore can, in some cases, serve as useful prognostic indicators.
Most symptoms of cancer are caused by local disruptions of organ function. These disruptions can be caused by pressure from the neighbouring tumour, or the invasion of malignant cells into the organ (by local spread or metastases). Other symptoms are systemic and are seen in many types of cancer. Common cancer symptoms are listed below
- Pain, a common symptom of many cancers, and particularly metastases of the bone and brain.
- Cachexia, a systematic symptom characterised by a loss of apetite, fatigue and weakness, loss of adipose tissue and skeletal muscle mass, etc.
- Swelling of tissue, commonly observed in breast, head & neck, abdominal and superficial cancers.
- Shortness of breath or difficulty breathing, observed in lung and head & neck cancers.
- Presence of blood in urine (haematuria), stool or sputum, for cancer of the bladder, kidney or prostate; bowel; and lung, respectively.
- Loss of neurological functions (reasoning, perception, language comprehension, etc.) with brain cancer.
The symptoms discussed often serve as prognostic indicators of cancer, however they are generally non-specific symptoms (i.e. they don’t indicate a specific disease, in this case cancer). A definitive diagnosis is achieved through the use of various diagnostic procedures, broadly summarised below:
- Anatomical pathology, the biopsy of affected tissue using chemical staining of spectrometric analysis.
- Clinical pathology, the analysis of bodily fluids such as blood or urine (e.g. to detect prostate-specific antigen).
- Diagnostic imaging, the use of medical imaging equipment (e.g. endoscopic examination, magnetic resonance imaging, nuclear medicine (PET, SPECT), radiography (projectional, fluoroscopic, CT) and sonography. CT and MRI are frequently used to determine nodal involvement.
- Physical examination, where the disease is visible or palpable (e.g. superficial disease, breast and testicular cancer, lymphoma and prostate cancer).
Screening programs use diagnostic procedures for large at-risk populations (often defined by age groups). Within Australia, there are 3 national population-based cancer screening programs, listed in table below:
|1991||BreastScreen Australia||Mammograms, to women aged 50 and over|
|1991||National Cervical Screening Program||Papanicolau smear tests, to women aged 20 to 69|
|2006||National Bowel Cancer Screening Program||Faecal occult blood tests, to people aged 50 to 74|
Staging and Grading
The major determinant of treatment and prognosis is the disease extent, or stage. The TNM classification system, published by the Union for International Cancer Control, is the most widely used staging system for solid tumours. The principal classifications of the TNM system are described in table below:
|T||Describing the development of the primary tumour. Possible values include TX (cannot be assessed), T0 (no evidence of primary tumour), Tis (carcinoma in situ), and T1 to T4, describing tumour size or extension into adjacent tissue.|
|N||Describing regional lymph node involvement. Possible values include NX (cannot be assessed), N0 (no regional nodal metastasis), and N1 to N3, describing the extent or number of involved nodes.|
|M||Describing the presence (or otherwise) of distant metastatic spread. Possible values include M0 (no metastasis) and M1 (distant metastasis).|
Each of these categories may include sub-classifications, depending on the cancer type. For example: a T1 classification for lung cancer indicates a tumour ≤3 cm in size, surrounded by lung or visceral pleura, with no evidence of invasion more proximal than the lobar bronchus, but can be sub-categorised as T1a (tumour ≤2 cm in size) or T1b (tumour between 2 and 3 cm in size); while a M1 classification (indicating metastasis) can be sub-categorised as M1a (separate tumour nodules in a contralateral lobe; pleural nodules or malignant pleural effusion) or M1b (distant metastasis, i.e. in extrathoracic organs).
These TNM classifications can be used for anatomic stage or prognostic grouping (described using Roman numerals 0 through IV), to allow a shorthand description of the progression of the cancer. For example, stage IIA for lung cancer corresponds to TNM classifications of either T2b, N0, M0 or T1/T2, N1, M0; while stage IV corresponds to an M1 classification. Survival rates are generally expressed for specific stage groupings and decrease with increasing progression.
The TNM classifications are not the only categorisations used for prognosis prediction. Serum tumour markers, such as prostate-specific antigen (PSA) or human chorionic gonadotropin (hCG) levels can be used for stage grouping in prostate and testicular cancer, respectively. Pathology grading systems describe the level of differentiation in tissue samples; with grades increasing with the loss of differentiation (i.e. high grades mean poor differentiation). The loss of cellular differentiation (anaplasia) can be assessed by comparison against the tissue of origin, and it is an indication of tumour aggressiveness. The Gleason grading system is the most prevalent grading system used.