Tumour Pathology Flashcards
A tumour (or neoplasm) is
an abnormal growing mass of tissue
Its growth is uncoordinated with that of surrounding normal tissue
Its growth continues after the removal of any stimulus which may have caused the tumour
It is an irreversible change
two types of tumours:
Benign
Malignant = Cancer
A fundamental property of cancer (or malignant tumour) is:
its ability to invade into adjacent tissue and to metastasise (spread)
grow at other sites within the body (secondary tumours)
Secondary sites of a tumour is where
the original tumour spreads and leads to the growth at other sites within the body.
If there are multiple tumours at multiple sites its not feasible to remove all of the tumours even if they are benign.
what can cause cancer
genetic and environmental factors.
males are more likely to get cancer than women.
cancer has a multi-step process of
progression and development
sarcoma =
cancer of connective tissue
features of benign tumours:
- Non-invasive growth pattern
- Usually encapsulated
- No evidence of invasion
- No metastases
- Cells similar to normal
- Benign tumours are “well-differentiated”
- Function similar to normal tissue
- Rarely cause death
Most common types of cancers in the UK:
- Overall
Breast Lung Prostate Colon Melanoma (skin cancer)
highest cancer survival rate after 5 years is
melanoma with 90%.
followed by breast and prostate by 85%
lowest cancer survival rate after 5 years is
lung cancer with 10%.
followed by kidney and colon cancer at 60%
uterus cancer survival rate after 5 years is
80%
classification of tumours are useful for:
- Understanding tumour behaviour
- Determining outcome (prognosis)
- Selecting therapy.
Adeno-
= gland
-oma
= abnormal growth (tumour)
Carcinoma =
cancer in epithelial tissue of skin or lining of internal organs.
Squamous
= very thin flattened cells
epithelial tumour in glandular tissue
benign = adenoma malignant = adenocarcinoma
epithelial tumour in squamous tissue
benign = squamous papilloma
epithelial tumour in squamous tissue
benign = squamous papilloma malignant = squamous carcinoma
connective tissue tumour in bone tissue
benign = osteoma malignant = osteo sarcoma
connective tissue tumour in fat tissue
benign = lipoma malignant = lipo-sarcoma
connective tissue tumour in fibrous tissue
benign = fibroma malignant = fibro- sarcoma
malignant tumours=
cancer
malignant tumours=
cancerous tumours
neural tumour of the central nervous system
only malignant = astrocytoma
neural tumour of the central nervous system
only malignant = astrocytoma
neural tumour of the peripheral nervous system
only benign = Schwannoma
tumour of white blood cell
only malignant = leukaemia
tumour of lymphoid tissue
only malignant = lymphoma
tumour of melanocytes
benign = naevus malignant = melanoma
tumour of germ cells - various tissue
benign = ovarian teratomas (usually) malignant = testicular teratomas (usually)
features of malignant tumours:
- Invasive growth pattern
- No capsule or capsule breached by tumour cells
- Cell appears abnormal
- Cancer cell is often poorly differentiated
- Loss of normal function
- Often evidence of spread of cancer
- Frequently causes death
Lymphoid tissue includes
white blood cells, spleen, bone marrow, thymus and lymph nodes
describe the properties of cancer cells
- Loss of tumour suppressor genes
- Gain of function of oncogenes
- Altered cellular function
- Abnormal morphology
- Cells capable of independent growth
- But no single feature is unique to cancer cells
- Tumour biomarkers
Tumour suppressor genes include:
Adenomatous polyposis (APC)
Retinoblastma (Rb)
BRCA1
oncogenes include:
B-raf Cyclin D1 ErbB2 c-Myc K-ras and N-ras
loss if cellular function includes:
- loss of cell-to-cell function
- altered cell-to-matrix function
- production of tumour-related proteins (tumour biomarkers)
tumour biomarkers include:
- onco-fetal protein
- oncogenes
- growth factors and receptors
- immune checkpoint inhibitors
tumour biomarkers include:
- onco-fetal protein
- oncogenes
- growth factors and receptors
- immune checkpoint inhibitors (slide 7)
Clinical Utility of Tumour Biomarkers include:
- Screening
- Diagnosis
- Prognostic
- Identifying patients with a specific outcome
- Predictive
- Identifying patients who will respond to a particular therapy
Clinical Utility of Tumour Biomarkers:
Alpha-fetoprotein is used for
- Teratoma of testis
- Hepatocellular carcinoma
Clinical Utility of Tumour Biomarkers:
Carcino-embryonic antigen (CEA) is used for
- Colorectal cancer
Clinical Utility of Tumour Biomarkers:
Oestrogen receptor is used for
- Breast cancer
Clinical Utility of Tumour Biomarkers:
Prostate specific antigen is used for
- Prostate cancer
Biomarker Kras
Colorectal cancer
Biomarker Braf
Melanoma
Biomarker PD-L1
Lung cancer
Biomarker EGFR
Lung cancer
Biomarker Her2
- Breast cancer
- Gastric cancer
Morphology Of Cancer Cells
Cellular and nuclear pleomorphism
- Marked variation in size and shape
Mitoses present and often abnormal
Tumour growth is
the imbalance between cell growth and cell death
- Angiogenesis (new blood vessel formation)
- Apoptosis
Tumour Angiogenesis is
- New blood vessel formation by tumours
- Required to sustain tumour growth
- Provides route for release of tumour cells into circulation
- More blood vessels in a tumour = poorer prognosis
Apoptosis is
- Mechanism of programmed single cell death
- Active cell process
- Regulates tumour growth
- Involved in response to chemotherapy and radiotherapy
Fundamental property of cancer is
Invasion and metastasis
- Multi-step process
- Increased matrix degradation by proteolytic enzymes
- Altered cell-to-cell and cell-to- matrix adhesion
Clinical Significance Of Spread Of Cancer
- Major clinical problem of cancer is formation of metastatic (secondary) tumours
- Prognosis depends on extent of cancer spread
Modes Of Spread Of Cancer
- Local spread
- Lymphatic spread
- Blood spread
- Trans-coelomic (across the peritoneal cavity) spread
Tumour Metastasis Via Lymphatics
- Adherence of tumour cells to lymph vessels
- Invasion from lymphatics
- Invasion into lymph node
- Formation of metastasis in lymph node
- Clinical evidence of metastasis
Tumour Metastasis Via Blood
- Adherence of tumour cells to blood vessels
- Invasion from blood vessels
- Invasion into tissue
- Formation of metastasis
- Clinical evidence of metastasis
Trans-coelomic Spread
- Special form of local spread
- Spread of tumour cells across body cavities e.g. pleural or peritoneal cavities
What tumours show trans-coelomic spread
lung, stomach, colon and ovary
Sites of metastasis not related to
tissue blood flow
Metastatic niche depends on
tumour and tissue related factors
Common Sites Of Metastasis
- Liver
- Lung
- Brain
- Bone
- Axial skeleton
- Adrenal gland
- Omentum/ peritoneum
Uncommon Sites Of Metastasis
Spleen
Kidney
Skeletal muscle
Heart
where does a tumour on the breast usually spread to?
bone
where does a tumour on the prostate usually spread to?
bone
where does a tumour on the colorectal usually spread to?
liver
where does a tumour on the ovary usually spread to?
Omentum(sheet of fatty tissue that stretches over the abdomen)/peritoneum
loss of cell to cell adhesion means
the cells can move to another site in the body (metastasis)
Local effects of malignant tumours (cancer)
Pressure Obstruction Tissue destruction Bleeding Pain Effects of treatment
Systemic effects of cancer
- Weight loss-cancer cachexia (weakness and wasting of body)
- Secretion of hormones
- Paraneoplastic syndromes
- Effects of treatment
why is early detection of cancer important
- Reduce/prevent morbidity/mortality
- Detection at pre-invasive stage
example of tissue destruction in malignant tumours
Ulceration/infection
example of bleeding in malignant tumours
Anaemia
Haemorrhage
causes of pain by malignant tumours
- Pressure on nerves
- Perineural infiltration (tumour extends along perineurium of nerve)
- Bone pain from pathological fractures (easier to get fractures with cancer)
what negative effects can treatment of malignant tumours cause
killing off the tumour may lead to tissues around it swelling due to inflammation.
production of hormones that is:
“Abnormal”/inappropriate
happens when organs that are not supposed to produce those hormones produce the hormones
Hormone Production that is considered “Normal” in malignant tumours are
produced by tumours of endocrine organ
But they have abnormal control of hormone production/secretion.
This is usually less common
InappropriateHormone Secretion of:
ATCH and ADH are early signs of
lung cancer
both relate to pituitary gland
Hormone Production that is considered “Normal” in malignant tumours are
produced by tumours of endocrine organ.
But they have abnormal control of hormone production/secretion.
This is usually less common
Hormone Production that is considered Abnormal”/inappropriate in malignant tumours are
produced by a tumour from an organ that does not normally produce the hormone.
Paraneoplastic Syndromes and malignant tumours
- Cannot be explained by local or metastatic effects of tumours e.g. neuropathy, myopathy
- unknown Immune mechanism
- unknown Production of hormone/growth factor
detection of tumours at pre-invasive stage allows
Identification of dysplasia (abnormal growth usually benign)/intraepithelial neoplasia (abnormal growth usually cancer)
Dysplasia is
- Pre-malignant change
- Earliest change in the process of malignancy that can be visualised
- Identified in epithelium
- No invasion
- Can progress to cancer
Features Of Dysplasia
- Disorganisation of cells
- Grading of dysplasia
- High grade
- Low grade
No invasion
disorganisation of cells in dysplasia include:
Increased nuclear size
Increased mitotic activity
Abnormal mitoses
early detection of cancer requires:
Requires effective test
- Sensitive/specific
- Acceptable
Cervical cancer screening
Cervical Cancer Screening:
Established NHS program
Aims to reduce incidence of squamous carcinoma of cervix
Detection of dysplastic cells from squamous epithelium of cervix
Woman aged 58 4 week history of rectal bleeding Colonoscopy - 15 mm polyp in rectum Polyp submitted for pathological examination - Adenoma with low grade dysplasia
Benign tumour of glandular epithelium
adenoma is benign
Follow-up = Regular colonoscopy
Man, 70
Six week history of constipation/diarrhoea
One stone weight loss (unplanned)
Tiredness
- Iron deficiency anaemia
Colonoscopy
- Lesion in caecum
- Biopsied
- Pathology
- AdenocarcinomaMalignant tumour of glandular epithelium
Pathology
- Ulcerated mass in caecum
- Irregular, invasive margin
- Cells pleomorphic, abnormal mitoses
- Poorly differentiated adenocarcinoma of colon
- Several mesenteric lymph nodes contain metastatic tumour
2 years later has increasing tumour biomarker
Which biomarker?
Carcinoembryonic antigen
tumour biomarker alpha-feto protein is used for
liver cancer
tumour biomarker Oestrogen receptor is used for
breast cancer
tumour biomarker Prostate specific antigen is used for
prostate cancer
how to tell if two tumours are linked
through histology.
if its the same tumour then it will have the same histology as the primary. if not then they are two seperate tumours.
Describe the cell cycle of normal cells.
The cell cycle is a series of events leading to division and replication of cell type in which a cells chromosomes are divided between two daughter cells,
- mechanism of cellular replication
- Involves nuclear division plus cytokinesis
- Generates two genetically identical daughter cells
1 chromosome pair is
sex determining
each turn of the cell cycle divides the chromosomes in
a cell nucleus
cell cycle can be divided into
3 phases
- Interphase
- Mitosis
- Cytokinesis
interphase includes
G1, S, G2
Interphase is when
the cell grows and accumulates nutrients needed for mitosis;
- The cell is synthesising RNA
- Producing protein
- Growing in size.
The molecular events that regulate the cycle are ordered and directional- it is impossible to reverse the cycle
Mitosis is when
the cell splits itself into two distinct cells
Cytokinesis is when
new cell is completely divided
what cells become post mitotic when they reach maturity.
terminally differentiated
nerve and heart muscle cells
Regulation of the cell cycle means
- Detection and repair of genetic damage (mutations in DNA sequences must not pass on)
- Prevention of uncontrolled cell division
- Each daughter cell must receive a full chromosome complement
errors in mitosis can
- cause mutations
- kill a cell
DNA synthesis and mitosis must occur
sequentially
control in cell cycle is achieved by
checkpoints in the cycle.
What happens to cells that pass the restriction point
Cells are committed to enter S phase.
Prior to restriction point progress through G1 depends on
external stimuli after restriction point progression becomes autonomous.
Progress can be arrested if certain molecular events are incomplete; The cell cannot proceed to the next phase until checkpoint requirements have been met.
Several checkpoints are designed to ensure that
damaged or incomplete DNA is not passed on to daughter cells.
Two main checkpoints exist:
- G1/S checkpoint
- G2/M checkpoint.
G1 arrest happens when there is
- Inadequate nutrient supply
- External stimulus lacking - not favourable
- includes hormones, growth factors, cytokinesis
G1/S transition is a
rate-limiting step in the cell cycle and is also known as Restriction point;
Abnormal cell size causes
G1 or G2 arrest (near end)
DNA damage detected causes
G1 or G2 arrest (near end)
Chromosome misalignment causes
M-phase arrest (near end)
DNA not replicated or damaged causes
S arrest (middle)
Intrinsic factors
- critical checkpoints
Restriction point (R) in G1
Cell cycle checkpoint activators
- System of cyclically active and inactive enzyme switches
- Catalytic sub-unit cyclin-dependent kinases (CDKs)
activated by a regulatory sub-unit cyclins - The active enzyme complex = CDK/cyclin complex
Two key classes of regulatory molecules, cyclins and cyclin-dependent kinases (CDKs) determine
a cell’s progress through the cell cycle
CDKs are inactive in the
absence of a partner cyclin
Cyclins form the regulatory subunits and have have
no catalytic activity.
CDKs are the catalytic subunits of an activated heterodimer catalytic subunits - constitutively expressed as inactive form
Different CDK/cyclin complexes operate at
sequential stages of the cycle
Active CDK/cyclin complexes
phosphorylate target proteins.
Phosphorylation results in activation/inactivation of target proteins.
Substrates regulate events in the next cycle phase
Inhibitor molecules binding to cyclin/CDK complexes
INK4A gene family
- p16
CIP/KIP gene family
- p21
- p27
- p57
They prevent cell cycle progression.
p16INK4a inhibitor binds to
CDK4 and arrests the cell cycle in G1 phase.
p14 which prevents p53 degradation
Inhibitor molecules binding to cyclin/CDK complexes
INK4A gene family
- p16
CIP/KIP gene family
- p21
- p27
- p57
They prevent cell cycle progression if something is wrong - good.
p16INK4a inhibitor binds to
CDK4 and arrests the cell cycle in G1 phase.
p14 which prevents p53 degradation
In the hypophosphorylated state, pRb is
active and carries out its role as tumour suppressor by inhibiting cell cycle progression.
Phosphorylation inactivates pRb
Carcinogenesis: Failure of cell cycle control
- Balance between proliferation and apoptosis disrupted
- Mutations in genes regulating cell division, apoptosis, and DNA repair cause a cell to lose control of proliferation
- Uncontrolled proliferation of cells forms tumours
- Two frequently disrupted regulatory pathways -
- The cyclin D-pRb-E2F pathway
- p53 pathway
p53 maintains
the integrity of the genome
Carcinogenesis: Failure of cell cycle control
- Balance between proliferation and apoptosis disrupted
- Mutations in genes regulating cell division, apoptosis, and DNA repair cause a cell to lose control of proliferation
- Uncontrolled proliferation of cells forms tumours
- Two frequently disrupted regulatory pathways:
- The cyclin D-pRb-E2F pathway
- p53 pathway
Activation of normal p53 by DNA-damaging agents (or by hypoxia) leads to
cell-cycle arrest in G1 and induction of DNA repair through transcriptional up-regulation of:
- cyclin-dependent kinase inhibitor p21
- GADD45(Growth Arrest & Dna Damage) genes
- if repair fails then apoptosis occurs
if DNA repair fails, p53-induced activation of
BAXgene promotes apoptosis
In cells with loss or mutations of p53, DNA damage
does not induce cell-cycle arrest or DNA repair, and hence genetically damaged cells proliferate, giving rise eventually to malignant neoplasms.
Virtually all cancers are dysregulated at
G1-S
mutated cell cycle regulating genes that can cause cancer:
- cyclin D
- CDK4
- p16
- Rb
aetiological =
causing or contributing to the development of a disease or condition.
The likelihood of developing cancer can be increased through:
Environmental agents
- Chemicals
- Radiation
- Oncogenic viruses
Inherited factors
Genotoxins cause
irreversible genetic damage or mutations by binding to DNA.
Genotoxins include
Chemical agents - N-nitroso-N-methylurea (MNU) Non-chemical agents - ultraviolet light - ionizing radiation. Certain viruses can also act as carcinogens by interacting with DNA.
What is the “TWO-HIT HYPOTHESIS” of oncogenesis
- study was looking at patients with retinoblastoma
There are two forms of the disease; a heritable form and non-heritable form
Suggests that multiple “hits” to DNA were necessary to cause cancer. In the children with inherited retinoblastoma, the first DNA insult was inherited - underlying predisposition.
Any second insult would rapidly lead to cancer.
In non-inherited retinoblastoma, two “hits” had to take place before a tumour could develop, explaining the age difference.
Tumour suppressor genes (anti-oncogenes) often function to
- Restrain inappropriate cell growth and division
- Stimulate cell death to keep our cells in proper balance.
- temporarily halt cell division enabling DNA repair.
In addition, some of these genes are involved in DNA repair processes, which help prevent the accumulation of mutations in cancer-related genes.
Tumor suppressor genes act as “brakes” to stop cells in their tracks before they can form cancers.
Tumour suppressor genes generally follow the “two-hit hypothesis” as
- Tumour suppressor alleles are usually recessive
- Loss of both normal allelic copies gives rise to cancer
Retinoblastoma gene: a tumour suppressor gene
- pRb inhibits the cell cycle
- Rb gene mutations favour cell proliferation
- Mutations in other genes controlling pRb phosphorylation mimic the effect of pRb loss
- Mutational activation of cyclin D or CDK4
- Mutational inactivation of CDKIs also drive proliferation
Normal growth-inhibiting genes:
Genes negatively regulating mitosis – Rb, INK4A family
Genes regulating apoptosis – p53
Inherited cancer syndromes
- account for 5-10% of all cancers
- genetic predisposition to develop cancer
- have early onset of multiple tumours
Individuals who inherit one of these gene changes will have a higher likelihood of developing cancer within their lifetime.
Heredity =
passing of traits to offspring from its parent or ancestors.
In inherited cancer syndromes three types of genes may be affected:
- tumor suppressor genes
- mismatch repair genes
- protooncogenes.
Cancer syndromes often manifest in relatives and show development of independent multiple tumours, early onset and typical phenotypical combinations.
Inherited Predisposition to cancer:
Familial retinoblastoma
Carriers have 10000x risk of bilateral retinoblastoma
Increased risk of second cancers eg bone sarcomas
Inherited Predisposition to cancer:
Familial adenomatous polyposis of colon
- Thousands of polyps at early age
- 100% risk of colon cancer by age 50 years
Hereditary Breast & Ovarian Cancer Syndrome
Hereditary Non-polyposis Colorectal Cancer Syndrome
- Germline mutations in DNA mismatch repair genes
- hMSH2, hMLH1, MSH6
Other inherited predisposition to cancer:
Li-Fraumeni Syndrome
Multiple Endocrine Neoplasia
Von Hippel-Lindau Syndrome
Most common types of cancer that can be genetically transmitted include
- breast
- colorectal
- gynecologic
- endocrine
One of the parents may often have the disease.
VHL a multi-system disorder characterized by
abnormal growth of blood vessels (hemangioblastomas or angiomas).
Hemangioblastomas may develop in the
- retina
- certain areas of the brain
- spinal cord
- parts of the nervous system.
Other types of tumours can develop in:
- adrenal gland
- kidney
- pancreas.
Individuals with VHL also have a higher risk to develop
certain types of cancer, especially kidney cancer.
Nearly all individuals with VHL are found to have mutations in the VHL gene.
APC allows signal transduction but a mutation can cause
FAP colon cancer
p53 allows cell cycle/apoptosis after DNA damage but a mutation can cause
Li-Fraumeni Syndrome:
multiple carcinomas, sarcomas
Rb allows cell cycle regulation but a mutation can cause
retinoblastoma, osteosarcoma
p16(INK4a) inhibits CDKs but a mutation can cause
malignant melanoma
Proto-oncogenes
Normal genes coding for normal growth regulating proteins:
- Growth factors
- Growth factor receptors
- Signal transduction
Cancer Causing Genes:
ONCOGENES are activated by
- Alteration of proto-oncogene structure
- point mutation
- chromosome rearrangements + translocations
- Dysregulation of proto-oncogene expression
- gene amplification
- over-expression
Oncogene activation
Chromosomal rearrangements: translocations
Overexpression
- Burkitt lymphoma - c-myc moves close to IgH gene - Mantle cell lymphoma cyclin D1 gene-IgH
Recombination to form chimeric proteins
- Chronic myeloid leukaemia
Chemical carcinogenesis
- Purine and pyrimidine bases in DNA are critically damaged by oxidizing and alkylating agents
- Chemical carcinogens react with DNA forming covalently bound products (DNA adducts)
- Adduct formation can lead to activation of oncogenes and loss of anti-oncogenes
A purine is
a heterocyclic aromatic organic compound,
adenine and guanine , are purines
complementary pyrimidines are
thymine and cytosine
Radiation carcinogenesis
- Purine and pyrimidine bases in DNA are critical targets for radiation damage
- High-energy radiation is carcinogenic if received in sufficient doses
- ultraviolet radiation (UV-B present in sunlight)
- X-rays
- Gamma radiation
Direct DNA damage can occur when
DNA directly absorbs the UV-B-photon.
UVB light causes thymine base pairs next to each other in genetic sequences to bond together into thymine dimers, a disruption in the strand which reproductive enzymes cannot copy.
Viral carcinogenes:
ONCOVIRUSES
- virus genome inserts near a host proto-oncogene
- viral promoter causes proto-oncogene over-expression
- virus directly inserts an oncogene into host DNA causing cell division
Viruses known to cause cancer in humans:
HPV (genital, throat and anal cancers)
Hepatitis B (liver cancer)
EBV (lymphoma)
It is thought that when the virus infects a cell, it inserts a part of its own DNA near the cell growth genes, causing cell division.
The group of changed cells that are formed from the first cell dividing all have the same viral DNA near the cell growth genes.
Multistep Carcinogenesis
- All sporadic cancers harbour multiple genetic aberrations
- Mutations accumulate with time
- Activation of several oncogenes and loss of two or more anti-oncogenes occurs in most cancers
The incidence of cancer rises dramatically with age due to
build up of risks that increase with age.
The overall risk accumulation is combined with the tendency for cellular repair mechanisms to be less effective as a person grows older.
Typically a series of several mutations to genes regulating cell growth is required before
a normal cell transforms into a cancer cell.
The protein made by the APC gene plays a critical role in several cellular processes by helping control
- how often a cell divides
- how it attaches to other cells within a tissue
- whether a cell moves within or away from a tissue.
- helps ensure chromosome number in cells produced through cell division is correct.
If this protein cannot suppress the cellular overgrowth that leads to the formation of polyps.
mutations in proteins can make it become
abnormal and non-functional
Loss of cell cycle control is key to
malignant transformation
Anti-oncogenes ________ are mutated in the majority of cancers
- p16
- cyclin D
- CDK4
- Rb
Loss or mutations of p53 allow
genetically damaged cells to proliferate forming malignant neoplasms
Loss or mutations of p53 allow
genetically damaged cells to proliferate forming malignant neoplasms (cancers).
