Oncology Flashcards
Define neoplasia
New growth, the abnormal proliferation of cells. A neoplasm is an abnormal mass of tissue that occurs as a result of abnormal cell proliferation
What is meant by a benign neoplasia?
Nevi or skin moles
What is a malignant neoplasia?
Cancer
What is a pre-mallignant neoplasia?
Carcinoma in situ. Some changes to become abnormal but not quite cancer
What are the 2 potential primary tumour types?
Monoclonal (one cell type) or polyclonal (more than one cell type)
How is neoplasia related to the cell cycle?
Cell division is a basic property of cells, but aberrant cell division is likely to create risk of cancer in any individual
What 2 groups of factors are involved in cancer?
- Genetic factors (predisposition)
- Environmental (epigenetic)
Genetic factors may leadto cancer?
- Chemical and physical carcinogens
- Point mutations
- Chromosomal alterations
Outline what chromosomal alterations may lead to cancer
- Change in composition of a chromosome
- Change in chromosome number
- Can involve all chromosomes (damaged, replaced) and can be inherited
How do epigenetic regulations occur in cells?
Modifications of histones and methylation of DNA in the chromatin
How may epigenetic alterations lead to cancer?
- DNA methylation and histone modification can be altered in cancer
- Do not alter the composition of the DNA, but alter the expression
- e.g. DNA methylation can silence DNA
What is the multiple-hit hypothesis in cancer?
- One mutation (genetic or epigenetic) is not sufficient to produce cancer
- Few forms only arise from 1 genetic modification
- Therefore require multiple alterations to lose cellular control
List the hallmarks of cancer
- Self sufficiency in growth signals
- Insensitivity to anti-growth signals
- Limitless replicative potential
- Evasion of apoptosis
- Sustained angiogenesis
- Tissue invasion and metastasis
Explain the self-sufficiency in growth signals in cancer
- Normally tissues have hormones and growth factors that control proliferation. repair and replacement
- Cancer cells become autonomous and grow/replicate without these
Explain the insensitivity to anti-growth signals in cancer cells
- Normally have mechanisms that halt cell cycle and decide to continue or apoptose
- Cancer cells are non-responsive to these
Explain the sustained angiogenesis in cancer cells
- Secrete factors involved in tissue regeneration
- Induces new blood vessel growth ensuring own blood supply
How do the hallmarks of cancer aid the development of cancer?
- Allows cell survival in an environment unfavourable to other cells
- Continue to develop
- When cellular clones within tumour acquire another modification, allows improved survival and proliferation, and so make up the majority of that tissue/tumour
- Continue to accumulate hallmarks until optimal survival characteristics are acheived
What are oncogenes?
Genes that promote cancer
What are tumour suppressor genes?
Genes that prevent aberrant cell proliferation
What is the relationship between oncogenes and tumour suppressor genes?
Imbalance between these genes leads to neoplasia
How are the oncogenes expressed in mammals?
c-Src, are proto-oncogenes, over-expression and sustained activity (i.e. gain of function) converts proto-oncogenes into oncogenes
How can mammalian proto-oncogenes gain function?
- Mutation
- Translocation
How do proto-oncogenes gain function by mutation?
- Ras and activation of MAPK
- Many tumours
Outline how self-sufficiency in growth signals leads to deregulation of receptor signalling
- Over expression of receptors on the membrane
- Alteration in protein structure (and so signalling without the ligand)
What allows cancer cells to have limitless replicative potential?
- In normal replication, telomere shortens with each replication and undergoes apoptosis when gets too short
- Express telomesase, and so maintain long telomeres
How are tumour suppressor genes involved in cancer and give examples?
- Loss of function induces caners through mutation, deletion or DNA methylation
- E.g. regulators of apoptosis (p53), inhibitors of cell cycle (p16m, p21, Rb), DNA repair genes
What are the 3 main pre-neoplastic changes?
- Hyperplasia
- Metaplasia
- Dysplasia
What histological features are indicative of neoplasia?
- Increased cellularity
- Increased nuclear to cytoplasmic ratio (bigger nucleus)
- Variation in cell and nuclear size between cells
- Nuclear morphology altered
- Necrosis
- Mitotic discs
- Cells separate from stroma (individualised)
- Invasive cells
What are some histological features of benign neoplasms?
- Well differentiated mass
- Good demarcation from surrounding tissue
- Low mitotic rate
- Minimal nuclear or cell pleomorphism (more similar to normal tissue)
- Minimal necrosis
- Low haematotic rate
What are some histological features of a malignant neoplasm?
- Invasive to surrounding tissues incl. blood/lymph vessels
- Disorganisation of tissue
- Increased nuclear or cell pleomorphism
- Large/multiple nuclei
- High mitotic rate
- Necrosis
- High cellularity, minimal stroma
- Scirrhous or desmoplastic region
Compare the growth rate of benign and malignant tumours
- Benign: slow, progressive, rare mitotic figures, normal mitotic figures
- Malignant:slow to rapid growth, many mitotic figures, abnormal mitotic figures
Compare metastasis of benign and malignant neoplasms
- Benign: no metastasis
- Malignant: frequent metastasis
Compare the host consequences of benign and malignant neoplasms
- Benign: space occupying lesion, consequence depends on location (e.g. spine may be dangerous)
- Malignant: life threatening
What is an adenoma?
Benign glandular epithelial neoplasm
What is a papilloma?
Benign protective epithelium (squamous or transitional) neoplasm
What is the suffix for a benign mesenchymal or nervous tissue neoplasm?
- Oma
- Fibrous tissue = fibroma, fat tissue = lipoma
- Astrocytes = astrocytoma
What is an adenocarcinoma?
A malignant tumour of the glandular epithelium
What is a carcinoma?
A malignant tumour of the protective epithelium (squamous or transitional)
What is the suffix for a malignant mesenchymal neoplasm?
- Sarcoma
- Fibrous tissue: fibrosacoma
- Fat tissue: liposarcoma
How are malignant tumours of nervous tissue and round cells named?
Use the word malignant or specific names
What do the letters of TNM staging stand for?
- T: size of primary tumour
- N: degree of lymph node involvement
- M: extent of metastasis
Outline tumour grading
- Indicates how similar/dissimilar a neoplasm is to normal tissue
- Higher grade = more dissimilar
- Linked to prognosis and response to therapy
- Indicates biological behaviour
What is tumour grading affected by?
- Tissue type
- i.e. skin tumour grade 2 does not correspond to glandular tumour type 2
What are the tumour grades?
I: well differentiated
II: moderately differentiated
III: poorly differentiated/anaplastic
What is tumour staging?
- Gives indication of extend of growth and spread
- Guides clinician in developing a therapeutic plan and prognosis
Give the different categories of T in tumour staging
T0-T4, small to large
Give the categories of N in tumour staging
N0: no LN involvement
N1: regional LN involvement
N2: distant LN involvement
Give the categories of M in tumour staging
M0: no detectable metastases
M1: detectable metastases
What diagnostic techniques are required for tumour staging and grading?
- Some imaging
- Macroscopic examination
- Microscopic examination (histopathology, mainly for diagnosis and grading)
- Immunohistochemistry to assess molecular markers (diagnosis and predictive response to treatment)
List some changes associated with neoplastic disease
- Loss of function
- Pain
- Swelling and inflammation
- Necrosis
- Loss of normal morphology
What are metastases?
Spread of the tumour
What is the result of tumour growth?
Space occupying lesion with the possibility of expansion beyond the site of growth, but primary tumours are only responsible for 10% of deaths from cancer
What are the consequences of metastases?
- 90% of deaths are due to metastases
- Changes treatment, other complications
- Long term follow up, may not be apparent for long time after initial diagnosis and treatment of primary tumour
Outline the linear progression model of tumour spread and metastasis
- During local progression, aggressive cells selected, dissemination initiates
- Sequential seeding of metastatic sites
- Each metastatic site produces more seeds as it develops
Outline the early dissemination/parallel progression model of tumour spread
- Dissemination starts early
- Different organs seeded in parallel, not sequentially
- Growth of disseminated tumour cells may need extra factors produced by primary tumour or micro-environment
Outline the metastatic cascade
- Primary tumour formation
- Localised invasion of lymph/blood vessels
- Intravasation
- Transport through circulation
- Arrest in microvessels of various organs
- Extravasation
- Formation of a micrometastasis
- Colonisation and formation of a macrometastasis
Outline the process of invasion and intravasation of metastatic cells
- Breach in basement membrane
- Cells highly invasive through process that changes their phenotype from epithelial to mesenchymal (Epithelial to Mesenchymal transition, EMT)
How does the breach in the basement membrane in metastasis occur?
Secretion from tumour cells of matrix metalloproteinases (MMPs) which degrade components of the ECM
What are the consequences of EMT to cancer cells?
Acquire invasiveness, motility, heightened resistance to apoptosis
What features of epithelial cells are lost in the process of EMT?
- Cytokeratin (intermediate filament) expression
- Epithelil adherens junction protein E-cadherin
- Epithelial cell polarity
What features of mesenchymal cells are acquired in the process of EMT?
- Fibroblast like shape
- Motility
- Invasivness
- Mesenchymal gene expression program
- Mesenchymal adherens junction protein (N-cadherin)
- Protease secretion (MMP-2, MMP-9)
- Vimentir (intermediate filament) expression
- Fibronectin secretion
- PDGF receptor expression
- alphavbeta6 integrin expression
What is EMT stimulated by?
Stimulated factors secreted by the stroma (e.g. TGFbeta, TNFalpha). Normal epithelial cells are not usually sensitive to these, changes in cancer cells make them very sensitive
What is intravasation stimulated by?
Tumour associated macrophages (TAM), recruited by tumour cells to vessels to aid intravasation of tumour cells
Outline the process of transport and extravasation of tumour cells
- Use blood or lymphatic vessels to travel to other areas of the body
- Lodge in vessels of various tissues
- Is a hostile environment for cancer cells and so employ either rapid or slow strategy of extravasation
Outline the slow strategy of extravasation
- Period of days
- Requires proliferation and subsequent destruction of the parenchyma
Outline the rapid strategy of extravasation
- Minutes
- Trigger endothelial vessel wall to retract leaving space for extravasation
- Same method as immune cells
Outline the reversal of EMT (MET)
- After extravasation
- Switch off mesenchymal and switch on epithelial markers
- Establish selves and colonise
What is the consequence of EMT followed by MET?
The secondary tumour (metastasis) resembles the primary tumour from which it originated
What is meant by colonisation with regards to metastases?
Expansion into macroscopic masses (>2mm diameter)
When is EMT normally used in the body?
- Embryogenesis
- Wound healing
What is colonisation of a metastasis dependent on?
Interactions specific to a particular type of metastasising cell and microenvironment
List the pathways of metastasis
- Transcoelomic
- Lymphatic
- Haematogenous
Outline the transcoelomic metastasis pathway
- Cancers arise on surface of abdominal and thoracic structures (mesotheliomas, ovarian adenocarcinomas)
- More similar to invasion, pass across structures
Outline the lymphatic metastasis pathway
- Metastatic cells travel in lymph circulation, lower pressure cf. blood
- Lymph nodes closest to tumour colonised first and develop largest masses
Outline the haematogenous metastasis pathway
- Travel via the blood vessels
- Most commonly veins rather than arteries
- Ultimately enter lungs and liver
- More commonly used by sarcomas cf. carcinomas
What tissues do pancreatic cancers commonly metastasise in?
- Mostly liver
- Some lung
What tissues do colonic cancers commonly metastasis in?
Mostly liver, some bone marrow, some lung
What tissues do mammary and prostate cancers commonly metastasise to?
- Both most commonly bone
- Breast lung, prostate liver
- Both metastasis to lungs, brain, liver
What does metastatic tropism depend on?
- Ability of tumour cells to adapt to microenvironment of distant tissues
- Layout of circulation
- Will not always fit the pattern
What is metastatic tropism?
Cancer cells colonise some metastatic sites more readily than others depending on the primary site
What primary tumours commonly metastasise to the lungs?
- Osteosarcoma
- Haemagiosarcoma
- Melanoma
- Mammary tumours
- Others e.g. thyroid,tonsillar, pancreatic
What primary tumours commonly metastasise to the liver, spleen and/or kidney?
- Mast cell tumours
- Haemagiosarcomas
What primary tumours commonly metastasise to bone?
- Mammary
- Prostate
- Bladder
How do bone metastases develop?
- Cancer cells reach bone via vessel of marrow
- Adhere to specialised stromal cells coating bone facing marrow
- Are attracted by growth factors contained in the ECM
- Aids cancer proliferation
What are the consequences of bone metastases?
- Cancer cells activate osteoclasts and osteoblasts to different extents resulting in osteolytic and osteoblastic metastases
- Lose bone strength (lysis) and get increased mineralisation (large islands of tumour cells, blastic)
What techniques can be used in the detection of metastases?
- Physical examination
- Thoracic radiography
- Ultrasonography
- CT
- MRI
Outline thoracic radiography in the detection of metastases
- Can be used to detect tumour spread via haematogenous route
- Not very sensitive
- Both lateral views required, collapse of lungs can hide metastases
- Can be difficult to interpret
Outline ultrasonography in the detection of metastases
- Sensitive for lesions in liver, spleen, kidneys
- Limited use for determining the nature of the lesion
- Subjective to image quality and interpretation
- Useful for guided biopsy
Outline thoracic CT for in the detection of metastases
More sensitive than radiography
Outline MRI in the detection of metastases
- Good for soft tissues (brain, soft tissue sarcomas, spinal cord)
- Useful for assessing degree of invasion
- Slow, problems with mvoement blur, not good for all anatomical areas
Outline methods for detecting bone metastases
- Radiography: can see areas of bone lysis, production or mixed, commonly at sites typical for bone tumours
- Scintigraphy: very sensitive, good if amputation may be required
What are the implications on treatment due to metastases?
- Surgical procedure must be followed by systemic therapy (chemo/radiotherapy)
- Treatments may not be effective in all secondary sites
- Poor blood flow may mean poor delivery of drugs
- Early detection essential for good prognosis
What are the consequneces of occult micrometastases?
- Challenge for long term survival
- Micrometastasis can be occult, result from slow proliferation and/or dormancy
- May wait until better conditions for survival in unfavourable tissues
- Slow or no proliferation so common anti-cancer treatments may not work
What are the theories of occult metastases?
- Cellular dormancy/quiescence
- Tumour mass dormancy: angiogenic restriction, immunesurveillance
What breeds of dog are particularly predisposed to cancer? (in descending order of prevalence)
- Irish Water Spaniel
- Flat coated retriever
- Hungarian wirehaired viza
- Bernese Mountain dog
- Rottweiler
- Italine spinone
- Boxer
- Staffie
- Welsh terrier
- Giant schnauzer
What are the 3 key points in the approach to cancer cases?
- Establish diagnosis (type and grade of tumour)
- Establish extent/stage of disease
- Investigate complications
Outline the use of FNA and cytology in the diagnosis of cancer
- Quick, simple, in-house
- Distinguish between inflammatory and neoplastic lesions
- Cannot grade as cannot assess architecture
- Not all tumours exfoliate cells
- Good for mast cell tumours and lymphomas
What methods are available for biopsy to diagnose cancer?
- Needle biopsy/TruCut biopsy
- Jamshidi bone biopsy
- Punch biopsy
- Excisional biopsy
- Incisional biopsy
Outline how staging of disease is carried out
- Thorough physical examination, especially palpating LNs
- Radiographs
- Ultrasound
- Advanced imaging
- TMN
- Stages describe the anatomical extent of tumour at a set point in time
What methods may be used to investigate potential complications in cancer?
- Blood biochemistry and haematology
- Urinalysis (paraneoplastic hypercalcaemia, hypoglycaemia, bone marrow infiltration etc.)
What are the options following cancer diagnosis?
- Do nothing
- Euthanasia
- Palliative care
- Chemotherapy
- Surgery
- Radiotherapy
- Anti-cancer vaccines (e.g. melanoma)
- Photodynamic therapy for superficial cancers
- Cryotherapy
What is involved in palliative care of cancer patients?
- Maintain quality of life
- Balance side effects and comfort
- Pain control, especially important with bone tumours
What are the consequences of doing nothing following cancer diagnosis?
- Tumour will grow (rate varies)
- Welfare may be compromised
