Neoplasia 1-4 Flashcards
What is a neoplasm?
Abnormal growth of cells that persists after the initial stimulus is removed
What is a tumour?
Any clinically detectable lump or swelling
What is cancer?
Any malignant neoplasm
What is a malignant neoplasm?
Abnormal growth of cells which persists after the initial stimulus is removed AND had the ability to invade surround tissues and has the potential to metastasise to distant non-contiguous sites
What is a metastasis?
Malignant neoplasm that has spread from its original primary site to a non-contiguous secondary site
What is anaplasia?
Poor differentiation of cells resulting in cells which have no resemblance to any other cell histologically
Describe 4 changes that occur in pleomorphism
- Increased nuclear size and nuclear:cytoplasmic ratio
- Increased variation in shape/size of cells/nuclei
- Increased mitotic figures
- Increased nuclear staining (hyperchromasia)
What two alterations in DNA must occur for a cell to become neoplastic?
- Activation of proto-oncogenes
- Inactivation of tumour suppressor genes
What two events are required for neoplasia to occur?
- Initiation (by a mutagenic agent)
- Promotion (causes cell proliferation)
Name 3 common initiators of neoplasia (due to extrinsic factors)
- Chemicals
- Radiation
- Infection
Describe a study which provides evidence that suggests neoplasms are monoclonal
- Study of X linked gene for G6PD deficiency in heterozygous women
- Gene has several alleles encoding different isoenzymes
- One of the alleles is inactivated through lyonisation during female embryogenesis
- Heterozygous women possess tissues which are a patchwork of heat stable and heat labile alleles, however neoplastic cells only express one isoenzyme indicating a monoclonal group of cells
What is the name given to a benign tumour of glandular epithelia?
Adenoma
What is the suffix for a malignant epithelial neoplasm?
-carcinoma
What is a sarcoma?
Malignant neoplasm of stromal tissue cells
What is the name given to a malignant neoplasm of bone?
Osteosarcoma
Why are lymphoid and haemopoietic neoplasms always malignant?
Already present in the circulation, so have the potential to metastasise
Give examples of one benign and one malignant germ cell neoplasm
- Benign - ovarian teratoma/dermoid cyst, seminoma
- Malignant - teratoma of the testes
What is a leiomyosarcoma?
Malignant neoplasm of smooth muscle cells
What is a malignant myeloma?
Malignant neoplasm of plasma cells
Give 3 examples of neuronendocrine neoplasms
- Carcinoid
- Bronchial small cell carcinoma
- Pheochromocytoma of adrenal glands
What is the appearance of a benign neoplasm?
- Smooth surface with pushing outer margin
- Tend to grow in a confined local area
- Cells are well differentiated to surrounding tissue
Describe the appearance of a malignant neoplasm
- Irregular, rough surface with possible ulceration and bleeding
- Invasion of surrounding tissue
- Cells range from well to poorly differentiated
What 3 things must malignant neoplasms do in order to metastasise?
- Grow and invade at the primary site
- Enter a transport system and lodge at a secondary non-contiguous site
- Grow and invade at the secondary site (colonisation)
What alterations must occur in order for a neoplasm to grow and invade surrounding tissue? (3)
- Altered adhesion (decreased expression of E-cadherin and changes in integrin expression)
- Stromal proteolysis (production of matrix metalloproteinases MMPs)
- Motility (signalling by integrins causes changes in the actin cytoskeleton)
What 3 transport systems can malignant tumours enter?
- Bloodstream
- Lymphatic system
- Coelemic spaces via transcoelemic spread
By what method do sarcomas usually spread?
Enter bloodstream
By what method do carcinomas usually spread?
Enter lymphatics, which drain to lymph nodes and can enter bloodstream
What is the greatest barrier to successful formation of metastases?
Failed colonisation at the secondary site
What is the name given to surviving microscopic deposits of malignant neoplasms that fail to grow into clinically detectable tumours?
Micrometastases
An apparently disease free person may harbour many micrometastases. What is this phenomenon called?
Tumour dormancy
What is the most likely cause of a relapse after an apparent cure of cancer?
One or more micrometastases begins to grow
Describe the regional drainage of blood, lymph and coelemic fluid
- Blood drains mainly (but not always) into the next available capillary bed, which tends to be the liver or lungs
- Lymph drains into the regional lymph nodes
- Coelemic fluid spreads to other areas of the coelemic space (transcoelemic spread) or to adjacent organs
What is the “seed and soil hypothesis” and what is its significance?
- May explain the unpredictable distribution of blood borne metastases
- Due to interactions between malignant cells and the local tumour environment (cancer niche)
What is a cancer niche?
- Malignant neoplastic cells and the surrounding healthy cells form a cancer niche
- Malignant cells can take advantage of surrounding non-neoplastic cells in order to grow and invade tissue e.g. by using their growth factors or proteases
What is epithelial->mesenchymal transition?
- Occurs when neoplastic cells (mainly carcinoma) undergo various alterations, such as altered adhesion, stromal proteolysis and motility
- Resulting cells resemble mesenchymal cells rather than epithelia
What are the common sites of blood borne metastases?
- Bone
- Lung
- Liver
- Brain
Which cancers are more likely to metastasise to bone?
- Breast
- Kidney
- Prostate
- Thyroid
- Bronchi
What determines the likelihood of a cancer spreading?
Size of the primary neoplasm (basis of cancer staging)
Why do malignant neoplasms have an increased tumour burden compared to benign neoplasms?
- Have the potential to metastasise and spread to other non-contiguous sites, which has a parasitic effect on the host
- Benign tumours do not metastasise
What are the direct local effects of primary/secondary neoplasms on the host? (4)
- Direct invasion and destruction of normal tissue
- Ulceration and surface, causing bleeding (may lead to anaemia)
- Compression of adjacent structures
- Blocking of tubes and orfices
Name 3 paraneoplastic syndromes of cancer that cause indirect systemic effects on the host
- INCREASED TUMOUR BURDEN (has a parasitic effect on the host; secretion of cytokines can cause cachexia, malaise, immunosuppression and thrombosis)
- HORMONE SECRETION (tumours which are well differentiated can produce hormones)
- MISCELLANEOUS EFFECTS (skin problems, fever, neuropathies, clubbing and myositis)
Name 3 tumours which may secrete hormones and cause indirect systemic effects on the host
- Thyroid adenoma (thyroxine)
- Small cell bronchial carcinoma (ACTH and ADH)
- Squamous cell bronchial carcinoma (PTHrp)
How could a benign tumour affect the host?
- Secretion of hormones as the cells are well differentiated (e.g. Thyroid adenoma secretes thyroxine)
- Compression of adjacent structures
Give 3 intrinsic and 3 extrinsic causes of carcinogenesis
- INTRINSIC - age, gender, heredity
- EXTRINSIC - environment, lifestyle, behaviour
Describe an epidemiological study which shows that the majority of cancer risk is due to extrinsic factors
- Japanese migrants to USA immigration act 1924
- Cancer risk for the Japanese for specific cancers tended towards the cancer risk for specific cancers in the Caucasian American population, showing that extrinsic factors are at play
What lessons were learned about the relationship between exposure and cancer risk from the use of 2-napthylamine in the dye industry? (3)
- There is a long delay between initial exposure and malignant neoplasm onset (factory workers did not develop cancer until decades after being exposed)
- Risk of cancer depends on total carcinogen DOSAGE (increased exposure means increased risk)
- Some carcinogens are specific to particular types of cancer (2-napthylamine is specific to bladder cancer)
What sequence of initiation and promotion is required to produce a monoclonal population of mutant cells?
- Initiator (mutagenic agent) is given FIRST
- Promotor given to induce cell proliferation, resulting in a monoclonal population of cells which all have the same mutation
What test can be used to distinguish between initiators and promotors?
Ames test
Why must liver enzymes be added at the start of an Ames test?
Some chemicals are procarcinogens which are converted to carcinogens by the liver enzyme cytochrome P450
How are pro-carcinogens converted to carcinogens in the body?
Cytochrome P450 enzyme in the liver
What is a “complete carcinogen”?
Acts as both an initiator AND promotor e.g. benzo(a)pyrene in cigarette smoke
Name 6 types of chemical carcinogens
- Polycyclic aromatic amines e.g. Benzo(a)pyrene
- Aromatic amines e.g. 2-napthylamine
- N-nitroso compounds e.g. dimethylnitrosamine
- Vinyl chloride e.g. PVC
- Natural products e.g. Aflatoxin B1
- ASBESTOS
Explain how asbestos can lead to the development of mesothelioma
- Used in building materials and particles can be inhaled into lungs
- Particles are needle-like and stick to lungs causing irritation and inflammation
- Regeneration of cells can increased likelihood of mutations occurring
Why is the initiation step bypassed in germline mutations?
All the cells already contain a mutated allele - only one proto-oncogene needs to be activated to favour neoplastic growth
Name 3 types of radiation that may be carcinogenic
- Ionising radiation e.g. alpha, beta, gamma, X rays
- Nuclear radiation e.g. alpha, beta, gamma
- EM radiation e.g. UV, gamma, X rays
In what ways can radiation cause damage to DNA? (2)
- Direct effects on DNA causing mismatching or double stranded DNA breaks
- Indirect effects by the production of free radicals which can cause base mismatching and prelude to mutation
Why is the level of exposure to radiation important in carcinogenesis?
Increased exposure is associated with an increased risk of mutations and developing cancer (shows a DOSE RESPONSE)
In what ways can patients be exposed to radiation that is potentially cancer causing?
- Exposure to UVB from sunlight
- Exposure to X rays in medical tests
- Exposure to radon gas which seeps from the Earth’s crust
Briefly, how do infections cause cancer?
Can directly or indirectly affect genes which control cell growth
Give one example of an infection which can directly affect genes which control cell growth
- HPV associated with development of cervical carcinoma
- Produces E6 and E7 proteins which inhibit p53 and pRB respectively, allowing mutated cells to resist apoptosis and enter the cell cycle and proliferate
Explain how hepatitis B virus can cause liver cell carcinoma
- Virus uses host machinery to replicate and causes damage to many cells
- Stimulates inflammatory response and cell mediated immunity
- Damage to normal parenchymal tissue due to substances produced by inflammatory cells e.g. Free radicals in oxidative burst
- REGENERATION of liver cells increases likelihood of mutation occurring due to replication errors or can act as a promotor for any pre-existing mutations
What pathogen is associated with developing gastric cholanginocarcinoma?
Helicobacter pylori
How can human immunodeficiency virus (HIV) indirectly cause cancer?
Lowers cell immunity, allowing other potentially carcinogenic infections to occur
Why does the development of cancer follow a “two hit hypothesis”? Why do inherited cancers differ form this?
- Requires two mutations in the same cell to inactivate BOTH tumour suppressor genes in order to favour neoplastic growth
- In inherited cancers, the first hit is delivered before birth and affects all cells in the body, so only one somatic mutation is required to cause cancer in postnatal life
When do the mutations occur in sporadic development of cancer?
Both somatic mutations occur in postnatal life
What is a tumour suppressor gene and how is it related to the development of cancer?
- Gene which inhibits neoplastic growth by preventing cell proliferation e.g. RB gene
- If the genes are abnormally inactivated, this can favour neoplastic growth
What can proto-oncogenes code for?
- Growth factors and growth factor receptors e.g. PDGF, HER2
- Plasma membrane signal transducers e.g. RAS
- Intracellular kinases e.g. BRAF
- Transcription factors e.g. MYC
- Cell cycle/apoptosis regulators e.g. Cyclin D1
Give 3 examples of inherited cancer syndromes which affect genes that code for DNA repair proteins
- Xerodema pigmentosum (mutation in gene which affects DNA excision repair)
- Hereditary non-polyposis colon cancer HNPCC (mutation in gene which affects DNA mismatch repair)
- Familial breast carcinoma (mutations in BRCA1/2 genes which code for repair of double strand breaks in DNA)
What can cause genetic instability in cancer cells? (2)
- Mutation in caretaker genes (type of TS gene) which maintain genetic stability
- Mutations in genes which code for DNA repair
Why are multiple mutations required to make a malignant neoplasm?
Requires activation and inactivation of a COMBINATION of multiple proto-oncogenes and tumour suppressor genes
With reference to the colonic adenoma-carcinoma sequence, describe what is meant by “progression” of cancer
- Malignant tumours require alterations in a combination of multiple PO genes and TS genes
- Stepwise accumulation of mutations leads to progressive worsening of neoplasm, until it is malignant
- Early adenoma may progress to an intermediate adenoma, and further mutations may allow it to progress to a carcinoma
Why does it usually take decades for cancer to develop after the initial mutation has occurred?
- Malignant neoplasms require alterations in a combination of multiple PO genes and TS genes
- Requires a stepwise accumulation of mutations to allow progression (cancer evolves from initiation and promotion and progresses until it has the ability to metastasise)
What is the estimated number of mutations required to develop a fully malignant neoplasm?
Approximately 10 or less
What are the 6 “hallmarks of cancer”?
- Divide independently of external growth signals
- Can resist external antigrowth signals
- Grow indefinitely without senescence
- Stimulate sustained angiogenesis
- Resist apoptosis
- Invade tissues and produce metastases
What is the role of proto-oncogenes and tumour suppressor genes?
Control of cell signalling pathways which allow entry into the cell cycle and allow cell proliferation to occur
Describe the progression of cancer (3)
- Stepwise accumulation of mutations in proto-oncogenes and tumour suppressor genes which contribute to genetic instability
- Cell signalling pathways become deregulated
- Leads to a population of cells with an acquired set of mutations that display all the hallmarks of cancer
How may an inflammatory response aid in tumour growth?
- Release of growth factors and cytokines e.g. VEGF which promotes angiogenesis
- Production of free radicals from oxidative burst of neutrophils which can cause direct DNA damage by mismatching of bases
Which carcinomas have the highest incidence rates in the UK? (4)
- Breast
- Lung
- Prostate
- Bowel
What are the most common cancers in children under the age of 14? (3)
- Lymphoma
- Leukaemia
- CNS tumours
Why is lung cancer the largest cause of cancer related deaths in the UK?
High incidence rate but low 5 yr survival rate (~10%)
Name 3 cancers which have low 5yr survival rates
- Lung (10%)
- Pancreatic (3%)
- Oesophageal (15%)
Which cancers have the best 5yr survival rates in the UK? (3)
- Testicular (98%)
- Breast (90%)
- Melanoma (87%)
Why is difficult to determine favourable outcomes of cancer, even if the 5yr survival rate is high?
Dependant on other factors e.g. age and health status (contribute to co-morbidity), tumour stage/grade and the availability of effective treatments
What does a tumour grade measure?
Level of DIFFERENTIATION of tumour cells (low grade is well differentiated; high grade is poorly differentiated or anaplastic)
What does tumour staging measure?
The overall TUMOUR BURDEN of the malignant neoplasm (size, stage of metastasis)
Briefly describe how TNM staging works
- T - size of the primary tumour (T1-4)
- N - extent of regional nodal metastases (N0-3)
- M - extent of distant metastatic spread (M0-1)
- For a given cancer, TNM statuses are converted into STAGE (I-IV)
If a cancer was staged T2:N1:M0, what would be the overall stage?
Stage III - regional metastases present
If a cancer was staged T3:N0:M0, what would be the overall stage?
Stage II - advanced local disease, but no metastasis
If a cancer was staged T3:N2:M1, what would be the overall stage?
Stage IV - distant metastases present
If a cancer was staged T1:N0:M0, what would be the overall stage?
Stage I - early local disease and no metastasis
What staging would be used for lymphomas?
Ann-Arbor staging
Describe Ann-Arbor staging of lymphomas
- Stage I - lymphoma in a single nodal region
- Stage II - lymphoma in two or more nodal regions on the same side of the diaphragm
- Stage III - two or more nodal regions on both sides of the diaphragm
- Stage IV - distant metastases
What is Duke’s staging used for?
Colorectal carcinoma staging
Describe Duke’s staging of colorectal carcinoma
- Duke’s A - invasion but no through the bowel wall
- Duke’s B - invasion through the bowel wall
- Duke’s C - involvement of lymph
- Duke’s D - distant metastases
In general, as staging of a cancer increases, what happens to the 5 year survival rate?
Decreases
Describe, in general terms, the grading of tumours
- Grade 1 - well differentiated
- Grade 2 - moderately differentiated
- Grade 3 - poorly differentiated
- Grade 4 - undifferentiated or anaplastic
Give one example of a tumour in which grading is used
Squamous cell bronchial carcinoma
Which grading system is used for breast cancer?
Bloom-Richardson
Describe the Bloom-Richardson grading of breast carcinomas
- Grade 1 - tubule formation
- Grade 2 - number of mitoses
- Grade 3 - nuclear variation (pleomorphism)
By what mechanisms can cancer be treated? (6)
- Surgery
- Radiotherapy
- Chemotherapy
- Immune therapy
- Hormone therapy
- Treatment targeted to molecular alterations
What is the difference between adjuvant and neoadjuvant treatment and when are these used?
- Adjuvant treatment is given after surgery to eliminate the subclinical disease (remove any remaining micrometastases)
- Neoadjuvant treatment is given prior to surgery in order to shrink the tumour and make it more operable
- Treatment of cancer by surgery usually involves both adjuvant and neoadjuvant interventions
How can the administration of radiotherapy be altered to minimise damage to surrounding tissues?
Given in fractionated doses and is focussed on the tumour (surrounding tissue is shielded)
What type of radiation is usually used in radiotherapy?
Ionising radiation e.g. X rays, gamma rays
At what stage of the cell cycle does radiotherapy have an effect?
End of G2 stage - damages DNA of mutated cells, triggering apoptosis via p53
If a double stranded DNA break occurred, which stage of the cell cycle would be most affected?
M phase - will lead to damage of chromosomes so can interfere with mitosis
Give 4 examples of drugs used in chemotherapy
- Antimetabolites e.g. Fluorouracil, methotrexate
- Antibiotics e.g. Doxorubicin, bleomycin
- Alkylating and platinum-based drugs e.g. Cisplatin
- Plant based derivatives e.g. Vincristine
How are alkylating/platinum-based drugs used in cancer treatment?
Can damage DNA of cancer cells by crosslinking the two strands of the double helix
How are antimetabolites used in cancer treatment?
Mimic normal substrates involved in DNA replication and antagonise the receptors, blocking the pathways
What is the main disadvantage of chemotherapy?
Treatments used are NON-SPECIFIC and NOT LOCALISED so can cause damage to normal non-neoplastic cells, causing adverse side effects
Explain how tamoxifen is used in the hormone therapy treatment of breast cancer. What is the main disadvantage?
- Can bind to and antagonise oestrogen receptors, preventing oestrogen binding (used to treat hormone-positive breast cancer)
- Acts as a PARTIAL AGONIST at the oestrogen receptors, so initial response may be oestrogenic (can cause proliferation of endometrium causing uterine cancer)
Give 2 examples of how oncogenes may be targeted for cancer therapy
- HER2 gene targeted in breast cancer (overexpressed in 25% of cases) can be blocked by HERCEPTIN
- GLEEVEC inhibits the fusion protein BCR-ABL which is abnormally encoded for in chronic myeloid leukaemia
Give 4 examples of tumour markers which can be used in diagnosis of specific cancers
- hCG (testicular cancers)
- alpha feto protein (liver carcinoma, testicular cancers)
- CA-125 (ovarian cancer)
- Prostate specific antigen (prostate cancer)
What are the uses of tumour markers? (2)
- Aid in diagnosis of cancer
- Used to monitor tumour burden and possible recurrence
Name 3 problems associated with cancer screening
- Lead time bias
- Length bias
- Over diagnosis
What is lead time bias?
Earlier detection of cancer by screening may imply that the patient has a longer survival rate, when in fact the survival rate would be the same regardless of when the cancer was diagnosed
What is length bias?
Slow growing tumours which tend to be less fatal are more likely to be detected by screening, giving the impression that detection of cancers through screening makes them less fatal, whereas less fatal cancers are just more likely to be detected by screening
What is over diagnosis?
- Diagnosis of cancers which will probably not progress in the lifetime of the person
- May receive unnecessary treatment when in fact it is not the cancer that will kill them (likely to die from some other cause)
