Session 8, 9, 10 ILOs - Neoplasia 1, 2, 3, 4 and pathology in pictures Flashcards
Understand, explain and define the terms:
- Neoplasm
- Dysplasia
- Tumour
- Cancer
- Metastasis
- Anaplasia
- Pleomorphism
- Progression
- Differentiation
- In situ
Neoplasm = abnormal growth of cells that persists after the initial stimulus is removed (irreversible)
Dysplasia = pre-neoplastic alteration in which cells show a disordered tissue organisation (technically reversible)
Tumour = a swelling i.e. any clinically detectable lump or swelling
Cancer = colloquial term for a malignant neoplasm which is: abnormal growth of cells that persists after the initial stimulus is removed AND invades surrounding tissue with the potential to spread to distant sites
Metastasis = a malignant neoplasm that has spread from its original site to a new, non-continuous site
Anaplasia = cells with no resemblance to any tissue; cells appear primitive and lack specialization along any particular cell line
Pleomorphism = variety in cell size or shape (i.e. a large hyper chromatic nucleus with a high nucleus to cytoplasm ratio)
Progression = process by which a neoplasm arises from monoclonal cells, followed by the accumulation of yet more mutations
Differentiation = the process of becoming different by growth or development
In situ = no invasion through epithelial basement membrane
Describe and understand the difference between in-situ and invasive malignancy
In-situ = no invasion through epithelial basement membrane
Invasive = penetrated through basement membrane
Explain how proto-oncogenes and tumour suppressor genes are involved in the development of neoplasms and explain the concept of clonality
Neoplasms can occur when either proto-oncogenes or tumour suppressor genes are altered:
Proto-oncogenes become abnormally activated (when they are then called oncogenes), favouring neoplasm formation.
Tumour suppressor genes, which normally suppress neoplasm formation, become inactivated.
Clonality: the concept that a collection of cells is monoclonal if they all originated from a single founding cell. Neoplasia is caused by accumulated mutations in somatic cells; mutations are caused by initiators (mutagenic agents) and promoters (cause cell proliferation). Together, initiators and promoters result in an expanded, monoclonal population of mutant cells.
Identify the types of cancers that most commonly arise in certain organs
- Bladder
- Oesophagus
- Stomach/Bowel
- Skin
- Lung
- Breast/Prostate
- Brain
- Thyroid/Pancreas/Uterus
- Cervix
Bladder – transitional cell carcinoma
Oesophagus – squamous cell carcinoma, adenocarcinoma
Stomach/Bowel – adenocarcinoma
Skin – squamous cell carcinoma, malignant melanoma, basal cell carcinoma
Lung – adenocarcinoma, squamous cell carcinoma, small cell carcinoma
Breast/Prostate – adenocarcinoma
Brain - astrocytoma
Thyroid/Pancreas/Uterus – adenocarcinoma
Cervix – squamous cell carcinoma
Describe and understand the processes of invasion and metastasis e.g. growth and invasion at the primary site with breach of the basement membrane, the entrance of a transport system to move to a secondary site and the ability to grow at a secondary site to form a new tumour
To invade and metastasise - the tumour needs to:
- Grow and invade at the primary site
- Invasion requires: altered adhesion, stromal breakdown and motility) - Enter a transport system and lodge at a primary site
- Grow at the secondary site to form a new tumour (colonisation)
Describe the cellular alterations that are required for invasion to occur e.g. altered adhesion, proteolysis and motility
3 cellular adaptations needed for a carcinoma cell:
- Adhesion
- Reduced E-cadherin expression (holds cells together)
- Change integrin expression - Stromal proteolysis
- Altered expression of proteases esp. metalloproteinases
- Leads to a degraded basement membrane and stroma = allows for invasion - Motility
- Requires changes to occur in the actin cytoskeleton
Understand the processes that determine the site of a metastasis e.g. regional drainage and the’ ‘seed and soil’ phenomenon and the transportation routes for malignant cells e.g. lymphatic, blood, transcoelomic.
3 methods by which cancer can metastasise:
- Lymphatic - carcinomas
- Blood - sarcomas
- Transcoelomic
However to be successful, the cancer must colonise the secondary site ‘seed and soil’ phenomenon (i.e. needs to be the right soil for the cancer to grow at the secondary site)
Failure to grow = micrometastasis
Describe the local and systemic effects of neoplasms
Local effects:
- Compression
- Ulceration and bleeding
- Invasion and destruction (LOF)
Systemic effects:
- Hormone production by tumours
- Cachexia (wasting away)
- Malaise
- Immunosuppression
- Hypercalcaemia (osteolytic lesions)
- Anaemia
- DIC and pro-thrombotic effects
Identify the neoplasms that most frequently spread to the bones and the difference between lytic and sclerotic lesions
Cause osteolytic lesions - destruction of bone tissue:
- Breast
- Bronchus
- Kidney
- Thyroid
Cause osteoblastic lesions - increased production of disorganised abnormal bone:
- Prostate
Understand and explain the multifactorial nature of neoplasia pathogenesis e.g. intrinsic and extrinsic factors
Many factors can result in a neoplasm - divided into intrinsic and extrinsic factors
Intrinsic (host factors):
- Heredity
- Age
- Gender (especially hormonal)
Extrinsic factors (related to the environment and behaviour):
- Account for approximately 85% of a population’s cancer risk
- High body mass index
- Low fruit and vegetable intake
- Lack of physical activity
- Smoking/tobacco use (associated with approximately 1/4 of all cancer deaths)
- Alcohol use
- Extrinsic carcinogens (chemicals, radiation and infections)
Much of the increased cancer incidence over the last century is due to prolonged life-span.
About 30% of cancer deaths are due to the five leading behavioural and dietary risks
Describe the geographical variations in the incidence of malignant tumours (e.g., gastric, breast and Burkitt’s lymphoma)
Gastric (stomach)
- Japan has a diet rich in nitrates
- Linked to a high incidence of gastric cancer
- However, on moving to America and changing their diet, they demonstrated lower gastric cancer rates (nitrates linked to high gastric cancer incidence)
Breast:
- Breast cancer is one of the most common and deadly cancer in Iranian women
- Study found that shorter exposure times with higher intensity at low latitudes increased the risk of breast cancer
- Differences in the amount of UV exposure in the United States may be the cause of significant regional differences in breast cancer mortality
Burkitt’s lymphoma:
- Research suggests that Burkitt’s lymphoma is the most common childhood cancer in regions where there is a high incidence of malaria, like Africa.
- In Africa, Burkitt lymphoma is common in young children who also have malaria and EBV that causes infectious mononucleosis
- One mechanism may be that malaria weakens the immune system’s response to Epstein-Barr, allowing it to change infected B-cells into cancerous cells
Understand the mechanisms of action of the following extrinsic carcinogenic agents, including occupational hazards
- Asbestos
- 2-napthylamine
- Radiation - ultraviolet and ionising radiation
- Human papilloma virus (HPV)
- Epstein Barr virus
- Hepatitis B and C viruses
- HIV
- Helicobacter pylori
- Parasites
Extrinsic carcinogenic agents:
Asbestos
- Increases the risk of mesotheliomas (pleural/peritoneum) and lung cancer
- Triggers chronic inflammation and can act as both an imitator and promoter
2-napthylamine
- Increases risk of cholangiomas (kidney cancer)
- Thought to be genotoxic - involves metabolic activation, formation of DNA adducts, and induction of mutagenic and clastogenic effects
Radiation - ultraviolet and ionising radiation
- Radiation can cause DNA damage
- Increases the risk of a mutation occurring, esp. in the skin (basal cell carcinoma - not very malignant but very aggressive locally)
Human papilloma virus (HPV)
- Increases risk of cervical cancer
- Produces E6 that inhibits apoptosis (by proteolytic inactivation of certain pro-apoptotic factors, such as p53)
Epstein Barr virus (EBV)
- Increases the risk of Burkitt’s lymphoma
- EBV infections B cells and promotes cell survival and increases the rate of cell replication
Hepatitis B and C viruses
- Increases risk of liver cell carcinoma
- Chronic inflammation and hepatocyte regeneration increases the risk of neoplasms
Helicobacter pylori
- Increases the risk of gastric adenocarcinoma
- Causes chronic inflammation and can because metaplasia
Parasites
- Malaria can increase the risk of Burkitt’s lymphoma
- Allows EBV to proliferate (risk factor!) and the parasite itself can because B cell proliferation
Understand and describe the functions of proto-oncogenes, tumour suppressor genes and caretaker genes in neoplasia, e.g. oncogenes – ras, c-myc and c-erbB-2 (Her-2); tumour suppressor genes – retinoblastoma (Rb) and p53
Proto-oncogenes e.g. RAS:
- Normal function is to drive cell proliferation
- Cancer involves a gain of function mutation
- Only one allele needs to be damaged
e. g. RAS , mutated in ~15-20% of malignant neoplasms
Tumour suppressor genes e.g. Retinoblastoma and P53:
- Normal function is to stop cell proliferation
- Cancer involves a loss of function mutation
- Needs both alleles to be damaged
e. g. Retinoblastoma, negative regulator of G1/S checkpoint (stops cells passing through)
Caretaker genes e.g. DNA repair genes - subclass of Tumour suppressor genes:
- Involved in preventing accumulation of DNA damage
- Certain familial cancer syndromes that have gremlin mutations of DNA repair genes
e. g. Xeroderma pigmentosa = very sensitive to UV damage and develop cancer at a young age
Understand and describe the stages of carcinogenesis and the alterations in growth control required to achieve this e.g. initiation, promotion and progression.
Animal experiments show that the sequence in which carcinogens are administered is critical.
Initiation
- Some chemical carcinogens (initiators), given first
Promotion - Following initiators, given a second class of carcinogens (promoters)
The Ames test shows that initiators are mutagens, while promoters cause prolonged proliferation in target tissues. This culminates in a monoclonal expansion of mutant cells.
Progression:
- Steady step-wise accumulation of multiple mutations in malignant neoplasms = progression
Identify tumours that can be inherited and describe the understanding behind this e.g. familial adenomatous polyposis and colorectal cancer, hereditary non-polyposis colon cancer syndrome, familial breast cancer, retinoblastoma and the two hit hypothesis.
For familial cancers, the first hit is delivered through the germline and affected all cells in the body. The second hit was a somatic mutation
Familial adenomatous polyposis and colorectal cancer
- Rare autosomal dominant condition characterized by the presence of numerous adenomatous polyps in the gastrointestinal tract and associated with risk for colorectal cancer
- APC gene codes for the APC protein that acts as a tumor suppressor, which means that it keeps cells from growing and dividing too fast or in an uncontrolled way
Hereditary non-polyposis colon cancer syndrome:
- Autosomal dominant associated with colon cancer
- Germline mutation which affects 1 of several DNA mismatch repair genes
Familial breast cancer:
- DNA repair genes are affected (BRCA1/BRCA2)
- These are involved in repairing dsDNA breaks
Retinoblastoma and the two hit hypothesis:
- Knudson came up with a two hit hypothesis to explain the differences between tumours occurring in families and those occurring in the general population
- For familial cancers, the first hit was delivered through the germline and affected all cells in the body. The second hit was a somatic mutation.
- In the case of retinoblastoma this was in one of the 10 million+ retinal cells already carrying the first hit
- In contrast, sporadic retinoblastoma has no germline mutation and so requires both hits to be somatic mutations and to occur in the same cell
