Lecture 20 - Neoplasia Review Flashcards
What is a tumour?
A swelling (can be from inflammation)
Any clinically detectable lump or swelling
What is a neoplasm?
An abnormal growth of cells that persists after the initial stimulus is removed
Has autonomous growth
What is a benign neoplasm?
Gross and microscopic appearances are considered to be innocent, implying that it will remain localised and will not spread to other sites
What is Cancer?
A malignant neoplasm
What is a malignant neoplasm?
An abnormal growth of cells that persists after the initial stimulus is removed and invades surrounding tissue with the potential to spread to distant sites
What is a metastasis?
Malignant neoplasm that has spread from its original site to a new non-contiguous site
What is dysplasia?
Pre-neoplastic alteration in which the cells show disordered tissue organisation (altered differentiation)
HAVE NOT YET BREACHED THE BASEMENT MEMBRANE
Is dysplasia reversible?
Yes
How may cells in dysplasia look?
Pleomorphic
Large hyperchromatic nuclei
High nuclear to cytoplasmic ratio
What infection can result in dysplasia in cervical epithelium?
Human Papilloma Virus
HPV
How does the dysplasia progress in the cervical epithelium upon infection by HPV?
Mild dysplasia (CIN1) affects lower 1/3 of epithelium
Moderate dysplasia (CIN2) affects lower 2/3s of epithelium
Full thickness dysplasia (CIN3) affects all of epithelium, also know as carcinoma in situ
Once the atypical cells breach the basement membrane this becomes invasive squamous cell carcinoma
What is the purpose of the cervical screening programme?
Detect dysplasia at an early stage and treat it before it progresses to cancer
Prevent morbidity and mortality from cancer and treatment
What stage of dysplasia is irreversible (no longer reversible back to normal)?
CIN III when its carcinoma in situ or invasive carcinoma
How do benign neoplasms and malignant neoplasms differ in their growth behaviour?
Benign = expansive growth locally with a pushing outer margin
Malignant = expansive and invasive with an infiltrating pattern
How do benign neoplasms and malignant neoplasms differ in their location?
Benign = remain confined to site of origin, don’t produce metastases
Malignant = can metastasis
How do benign neoplasms and malignant neoplasms differ in their function?
Benign = retains function of its cells of origin
Malignant = less likely to retain functions of cells of origin
How do benign neoplasms and malignant neoplasms differ in their histology?
Benign:
-resembles cells of origin
-few mitoses
-normal/mild increase in nuclear : cytoplasmic ratio
-cells uniform
Malignant:
-failure to full differentiate
-many mitoses
-high nuclear : cytoplasmic ratio
-pleomorphism (cells/nuclei vary in size and shape)
What is differentiation?
Process of becoming different by growth or development
What is meant be anaplastic?
Cells have differentiated with no resemblance to any tissue
What are the cytological features of malignancy?
-increasing nuclear size
-increased nuclear:cytoplasmic size
-increased nuclear staining (hyperchromasia)
-increased mitotic figures
-varied size and shape of cells and nuclei (pleomorphism)
As grade of degree of differentiation gets higher, how does the differentiation change?
Higher the grade means the more poorly differentiated
The more likely the outcome will be negative
Why/how does neoplasia occur?
Accumulation of NON-LETHAL mutations in somatic cells
What are some inherited germiline mutations causing neoplasia?
BRCA1
BRCA2
What are initiators?
Mutagenic agents that cause the mutations leading to neoplasia
What are promoters?
Something that results in cell proliferation of a neoplastic clone
What are some common examples of chemical initiators?
Smoking
Alcohol
Diet
Obesity
What is a common infectious agent causing neoplasia?
HPV
What type of cancer does the chemical 2-napthylamine lead to?
Bladder cancer
What type of cancer does UV light often cause?
Malignant melanoma
Briefly describe how a neoplasm develops:
Initiator is supplied to cells
Long periods of promotion (clonal expansion) increases size of neoplastic population
Produces monoclonal population
What are some genes that can be mutated give a “head start/first hit”?
BRCA1/BRCA2
What is progression?
The stepwise accumulation of complimentary mutations the occur over time that provide the cancer cells with a survival advantage
What is the Adenoma-Carcinoma sequence?
What is this process very common for?
The pattern of accumulation of mutations in a certain sequence that happens over time
Wnt pathway activated —> EGFR signalling activated —> TGFB response inactivated —> loss of p53 function
Corresponds to
Early adenoma —> intermediate adenoma —> late adenoma —> carcinoma —> metastasis
Very common in sporadic Colon cancer
What are the 4 classes of normal regulatory genes?
-growth promoting Proto-oncogenes
-growth inhibiting Tumour suppressor genes
-Genes regulating apoptosis
-Genes involved in DNA repair
What is the function of proto-oncogenes?
Drive cell proliferation
What do Proto-oncogenes become when they mutate?
What do these mutated versions do?
Oncogenes
Oncogenes create oncoproteins which promote cell growth in the absence of normal growth promoting signals
How many proto-oncogenes need to be mutated in order for oncogenesis to occur?
1 proto-oncogene mutated since oncogenes are dominant over proto-oncogenes
What is the most common proto—oncogene mutated in a human tumour?
(kRAS)
What type of cancer is RAS mutation very prominent?
Pancreatic adenocarcinoma
What happens when the RAS gene is mutated so its permanently activated?
RAS Phosphorylates Retinoblastoma gene permanently activating it
This allows the cell to constantly progress through the cell cycle
What is the function of a tumour suppressor gene?
Causes loss of function
How many tumour suppressor genes need to be mutated for oncogenesis to occur and why?
Both alleles must be damaged
Mutated tumour suppressor gene is recessive compared to healthy tumour suppressor gene
What is the 2 hit hypothesis?
The need to have both alleles of tumour suppressor genes mutated/inactivated
What is the function of the retinoblastoma gene?
What happens when the Retinoblastoma gene is inhibited?
A key negative regulator G1/S cell cycle checkpoint
Gene allows cells to progress through the cell cycle into phase allowing for continued proliferation
What happens when p53 is disrupted?
What type of gene is this?
Impaired apoptosis
Tumour suppressor gene
What are 3 types of DNA repair whose genes can be mutated?
Mismatch repair
Nucleotide excision
Double strand breaks
What is the definition of invasion?
Breach of the basement membrane with progressive infiltration and destruction of the surrounding tissues
What is the definition of metastasis?
Spread of a tumour to sites that are physically discontinuous from the primary tumour
Marks a tumour as malignant
What is a primary tumour?
The original location of the malignant neoplasm = the primary site
What is a secondary tumour?
The place which a primary tumour has spread/metastasised to = secondary site
What is Tumour Burden?
What happens to tumour burden as amount of cancer increases?
What affect does increasing tumour burden have on the body?
The amount of cancer present in the body
More cancer = more tumour burden
More tumour burden = more fatigue/more draining to patient
What is the process of metastasis?
Tumour must how and invade at primary site
Enter a transport system
Grow at secondary site to form a new tumour
What are the 3 steps to a carcinoma invading?
1.) Altered adhesion
2.) Stromal proteolysis
3.) Motility
What happens in the altered adhesion stage of a carcinoma invasion?
Reduced e-Cadherin expression so epithelial cells less stuck to each other
Integrins expression exchanged (less stuck to basement membrane)
What happens in stromal proteolysis of carcinoma invasion?
Altered expression of proteases such as matrix metalloprteinases
Degradation of the basement membrane and stromatolites so invasion can happen
What happens in the motility stage of carcinoma invasion?
Changes in the actin cytoskeleton
Allows for locomotion of cell to allow them to invade through the basement membrane
What are the 3 ways which a malignant tumour can spread to a distant site?
Blood vessels (Haematogenous spread)
Lymphatic vessels
Transcoelomic spread (fluid in body cavities)
What are the body cavities by which malignant tumours can spread via transcoelomic spread?
Pleural
Peritoneal
Pericardial spaces
Which pathway is the most common pathway by which carcinomas spread to distant sites?
Lymphatic vessels
What can destroy tumour cells in circulation before they reach the secondary site?
Mechanical stress
Apoptosis
Host immune defences
Hostile secondary niche
Fail to grow at secondary site and die
Fail to initiate angiongenesis in order to grow
What is the greatest barrier to a successful metastasis?
Failed colonisation
What are micrometastases?
Clinically undetectable cell clusters that fail to grown into tumours
Howeve they do have th ability, in the right conditions to grow and develop
What are the 5 most common neoplasms the spread/metastasise to bone?
-Breast
-Bronchus
-Kidney
-Thyroid
-Prostate
What should you immediately think of when you see ostesclerotic lesions/metastases?
Why should you think this?
Prostate cancer
Prostate cancer increases production of disorganised abnormal bone
Is small cell carcinoma aggressive?
Very aggressive
What is immunotherapy?
Type of cancer treatment that helps the body’s immune system to recognise and attack cancer cells
What cells do tumour antigens get presented to by MHC molecules?
CD8+ T cells
Cytotoxic T cells
Why can benign neoplasms have significant morbidity and mortality?
Depends on location
For example a benign tumour in the brain can lead to increased intracranial pressure leading to death due to coning
What are some local complications of cancer?
Ulceration at surface leading to bleeding/perforation
Blockage of tubes and orifices
Raised pressure (intracranial pressure then death to coning)
What are some systemic complications of cancer?
Inc tumour burden results in a a parasitic effect on the host
Cachexia (Reduced appetite and weight loss)
Immunosuppression
Malaise
Skin problems
Fever
What are the 6 hallmarks of cancer?
Self sufficiency in growth signals
Resistance to growth stop signals
Cell immortilisation
Angiogenesis
Resistance to apoptosis
Ability to invade and produce metastases
What type of tumours is the TNM staging system used for?
What does the T represent?
What does the N represent?
What does the M represent?
Solid tumours
T = size of primary tumour
N = extent of regional lymph node involvement
M = metastatic spread via the blood
What is Tumour stage used to measure?
What are the stages of Tumour stage?
What do they mean?
The overall burden of the malignant neoplasm
Stage 1 = Early local disease
Stage 2 = Advanced local disease (N0, M0)
Stage 3 = Regional metastasis (N1 or more with M0)
Stage 4 = advanced disease with distant metastasis (M1)
What size is a T1 tumour?
What size is a T2 tumour?
What size is a T3 tumour?
What size is a T4 tumour?
T1 = Less than 2cm
T2 = between 2cm and 5cm
T3 = greater than 5cm
T4 = tumour of any size with direct extension to chest wall or skin
What is the Ann Arbor Staging system used for?
Lymphomas
What are the 4 stages of the Ann Arbor Staging system?
I = lymphoma only affects 1 set of lymph nodes
II = More than 1 set of lymph nodes affected on the same side of the diaphragm
III = lymph nodes affected on different sides of the diaphragm
IV = Non lymph nodes are affected
What cancer is the Dukes Staging System used for?
Bowel cancer
What is grading used to describe?
What are the 4 grades?
The degree of differentiation of a neoplasm
G1 = well differentiated
G2 = moderately differentiated
G3 = poorly differentiated
G4 = undifferentiated or anaplastic
What system is used for prostate cancers?
What does it measure?
Gleasons Pattern
Type of gland formation
How are breast cancers graded?
Grade 1 = Low mitotic count, low pleomorphism, low nuclear to cytoplasmic ratio
Grade 2
Grade 3 = High mitotic count, High pleomorphism, High nuclear to cytoplasmic ratio
What are the types of treatments for cancer?
Surgery
Radiotherapy
Chemotherapy
Hormone therapy
Immunotherapy
What is an adjuvant?
Treatment given AFTER surgical removal of a primary tumour to eliminate sub clinical disease
Wha is a Neoadjuvant?
Treatment given PRIOR to surgical excision to REDUCE size of the primary tumour
How does Radiation Therapy work?
Kills proliferating cells by triggering apoptosis or interfering with mitosis (kills in G2)
Why is radiation therapy give in fractioned doses?
To minimise normal tissue/non cancerous cell damage
What is a hormonal therapy that is used to treat hormone receptor positive (Oestrogen receptor) breast cancer?
How does it work?
Tamoxifen
It prevents oestrogen from binding to the oestrogen. This prevents proliferation of the cells in the breast cancer
What are some potential complications of using Tamoxifen to treat oestrogen receptor positive breast cancer?
Why?
Increased risk of endometrial cancer
In the uterus tamoxifen has opposite effect then in the breasts
It stimulates proliferation of the endometrium increasing likelihood of endometrial cancer
What is the point of cancer screening?
What are the 3 main screening programmes in the UK?
To detect cancers as early as possible when the chance of the cure is the highest
Breast screening
Cervical screening
Bowel screening
What age do women get screened for breast cancer?
How frequently do they get screened?
47 - 73 years old
Every 3 years
What age do women get screened for cervical cancer?
How frequently do they get screened?
25 - 64 years old
25 - 49 years old every 3 years
50 - 64 years old every 5 years
What age are men an women screened for bowel cancer?
How frequently are they screened?
60 - 74 yrs
Every 2 years via Home Testing
What is being checked for when a person is screened for bowel cancer?
Fecal occult blood testing
Basically looking for blood in faeces due to tumours ulcerating leading to bleeding
What are the 3 problems with screening?
Overdiagnosis
Lead time bias
Length time bias
What is overdiagnosis?
The diagnosis of cancers that did not actually have the potential to progress during the lifetime of the patient
What is lead time bias?
Basically the course of the disease process is not altered and the patient lives for the same amount of time as they would have done but they have knowledge of the disease for longer
There is a longer perceived survival time with screening even if the course of the disease is not altered
What is length time bias?
Screening more likely to detect slower growing tumours
Aggressive tumours tend to grow rapidly and present in gaps between scheduled screening
Screen detected cases are usually slowly progressive cases that have a better prognosis than non-screen detected cases
What are the 2 main types of tumours of the testis?
Germ cell tumour
Non-germ cell tumour
What molecular markers are of value in diagnosis of testicular tumours?
HCG (Human Chorionic Gonadotrophin) secreted by choriocarcinoma
Alpha fetoprotein (produced yolk sac tumour)
What is a seminoma?
Cancer of the testes which is a germ cell tumour
Does not secrete tumour markers
What is a characteristic cell present in Hodgkin lymphoma?
Reed Sternberg cells
What is the function of Reed Sternberg cells in Hodgkin’s lymphoma?
Attract eosinophils in the lymph node
What are B symptoms in Hodgkins Lymphoma?
Drenching night sweats
Weight loss
Fever
What is HER-2?
A growth factor receptor
If a breast cancer tumour is HER-2 positive, what is happening at the cellular level?
More proliferation signals and more anti apoptosis signals
What drug can be given to treat a HER-2 positive breast cancer?
Herceptin (trasuzumab)
What genes can be inherited mutated which predisposes a patient to breast cancer?
What type of genes are these?
What is their normal function?
BRCA1 or BRCA2
Tumour suppressor genes
Doing double stranded DNA breaks
What is a triple negative breast cancer?
What can they not be treated by?
A breast cancer that is negative for:
-Oestrogen receptors
-HER-2 receptors
-Progesterone receptors
Cant use Tamoxifen
What is the name of a malignant tumour of glandular epithelium?
Adenocarcinoma
Why may a patient with blood in his stools suspected of an adenocarcinoma of the large intestine have fatigue and tiredness?
Ulceration from the tumour leads to bleeding
Bleeding leads to anaemia becoming tired and fatigued (iron deficiency anaemia)
How can colorectal cancer present as an emergency?
Perforation of the large intestine can lead to sepsis
What tumour marker can indicate colorectal cancer?
CEA = Carcinoembryonic antigen
What is the significance of an elevated PSA?
Indicative of a problem with the prostate
Why do prostate tumours often present without any symptoms ?
Arises in peripheral aspect of the gland so only blocks urethra once its very advanced
Why is back pain commonly associated with prostate cancer?
Venous drainage of prostate near to the spine
If you get metastasis it can go to the bone of the spine
How does infection by HPV lead to cervical cancer?
Leads to dysplasia
Which progresses eventually to invasive carcinoma
How is cervical cancer graded?
What does these mean?
CIN I - mild dysplasia (bottom 1/3 affected)
CIN II - moderate dysplasia (bottoms 2/3s affected)
CIN III - full thickness (hasn’t breached basement membrane)
Invasive carcinoma
What cell is elevated in Hodgkins Lymphoma?
Eosinophils
