Tumour Pathology Flashcards
What is a tumour (neoplasm)
Abnormal growing mass of tissue
It has uncoordinated growth when compared to surrounding tissue
How will the removal of a stimulus causing the tumour affect its growth
It may continue to grow due to the irreversible change caused
What two groups of tumours are there
Benign
Malignant (cancer)
What are malignant tumours
Tumours that can invade into adjacent tissue and metastasise (spread) and grow at other sites with the body
State two factors which can cause cancer
Genetics
Environmental factors
What are the 5 most common types of cancer
Breast Lung Prostate Colon Melanoma
Why is tumour classification important
So we can understand tumour behaviour
So we can determine the probable outcome (prognosis)
For treatment
What is tumour classification based on
Tissue of origin
Whether the tumour is benign or malignant
Which type of tissues can tumours originate from
Epithelium Connective tissue (mesenchyme) Blood Lymphoid tissue Melanocytes Neural tissue Germ cells (ovary/testis)
What are the two main types of epithelial tumours
Glandular
Squamous
What are benign and malignant glandular epithelial tumours known as
Benign - Adenoma
Malignant - Adenocarcinoma
What are benign and malignant squamous epithelial tumours known as
Benign - Squamous papilloma
Malignant - Squamous carcinoma
In epithelial tumour nomenclature what do the benign and malignant tumours normally end in
Benign - oma
Malignant - carcinoma
What type of connective tissue tumours can occur
Bone
Fat
Fibrous tissue
What is a benign and malignant bone tumour known as
Benign - Osteoma
Malignant - Osteo-sarcoma
What is a benign and malignant fat tumour known as
Benign - Lipoma
Malignant - Lipo-sarcoma
What is a benign and malignant fibrous tissue tumour known as
Benign - Fibroma
Malignant - Fibro-sarcoma
In connective tissue tumour nomenclature what do malignant tumours normally end in
Sarcoma
What is a malignant WBC tumour known as
Leukaemia
What is a malignant lymphoid tissue tumour known as
Lymphoma
What is a benign melanocyte tumour known as
Naevus
What is a malignant melanocyte tumour known as
Melanoma
What is a tumour in the central nervous system known as
Astrocytoma
What is a tumour in the peripheral nervous tissue known as
Schwannoma
What are germ cell tumours known as
Teratomas
What is a teratoma composed of
Various tissues
Develops in ovaries/testies
Where are teratomas normally benign and where are they malignant
Benign - Ovaries
Malignant - Testies
What are the features of benign tumours
Non-invasive growth pattern Normally encapsulated No evidence of invasion No metastases Cells similar to normal Function similar to normal tissue Rarely cause death Are well-differentiated
What are the features of malignant tumours
Invasive growth patterns No capsule (or capsule breached by tumour cells) Abnormal cells Loss of normal function Often evidence of spread of cancer Cancers often poorly differentiated Frequently cause death
State some properties of cancer cells
Loss of tumour suppressor genes Gain the function of oncogenes Altered cellular function Abnormal morphology Cells capable of independent growth
Give examples of tumour suppressor genes
Adenomatous polyposis
Retinoblastoma
BRCA1
Give examples of oncogenes
B-raf Cyclin D1 ErbB2 Myc K-ras N-ras
What does the loss of cellular function cause
It causes the loss of cell-to-cell adhesion
Altered cell-to-matrix adhesion
Production of tumour related proteins (tumour biomarkers)
Give examples of types of tumour biomarkers
Onco-fetal proteins
Oncogenes
Growth factors and receptors
Immune checkpoint inhibitors
How can tumour biomarkers be benefical in the clinical setting
For:
Screening
Diagnosis
Prognostic (to identify patients with a specific outcome)
Predictive (to identify patients who will respond to a particular therapy)
Give examples of some tumour biomarkers
Kras - Colorectal cancer Braf - Melanoma EGFR - Lung cancer PD-L1 - Lung cancer Her2 - Breast cancer, Gastric cancer
Describe the morphology of cancer cells
The show cellular and nuclear pleomorphism (variation in size and shape)
Abnormal mitoses will often be present
What is tumour growth
A balance between cell growth and cell death
What is tumour angiogensis
Formation of new blood vessels by tumours which are required to sustain tumour growth
What is apoptosis
A mechanism of programmed single cell death in an active cell process
What is the role of apoptosis in tumour growth
Regulates tumour growth
Involved in the response to chemo and radiotherapy
What do blood vessels provide for tumours
A route for release of tumour cells into circulation
The more blood vessels that are present in a tumour equal a poorer prognosis
What is the fundamental property of cancer
Invasion
Metastasis
Why is the spread of cancer a major clinical problem
It can cause the formation of metastatic (secondary) tumours
A patients prognosis is dependent on the extent of the spread
How does the conversion from invasion to metastasis occur
Multi-step process
Involves increased matrix degradation by proteolytic enzymes
Altered cell-to-cell and cell-to-matrix adhesion
How can cancer spread
Locally
Lymphatic
Through blood
Trans-coelomic
How does local cancer spread occur
Malignant tumour invades connective tissue
Then invasion of lymph/blood vessels
How does lymphatic cancer spread occur
Adherence of tumour cells to lymph vessels Invasion from lymphatics Invasion to the lymph nodes Metastasis forms in lymph nodes Clinical evidence of metastasis produced
How does blood cancer spread occur
Adherence of tumour cells to blood vessels
Invasion from blood vessels to tissues
Metastasis froms
Clinical evidence of metastasis produced
What is trans-coelomic spread
Special form of local spread
Tumours spread across body cavities (e.g. pleural or peritoneal)
Which type of tumours show trans-coelomic spread
Lung
Stomach
Colon
Ovary
What are the sites of metastasis related to
Not to tissue blood flow
Dependent on tumour and tissue releated factors (metastatic niche)
State some common sites of metastasis
Liver Lung Brain Bone (axial skeleton) Adrenal gland Omentum
State some uncommon sites of metastasis
Spleen
Kidney
Skeletal muscle
Heart
Where does breast cancer commonly metastasise to
Bone
Where does prostate cancer commonly metastasise to
Bone
Where does colorectal cancer commonly metastasise to
Liver
Where does ovarian cancer commonly metastasise to
Omentum
What type of cancer can the alpha-fetoprotein be a tumour biomarker for
Testicular teratoma
Hepatocellular carcinoma
What type of cancer can the carcino-embryonic antigen (CEA) be a tumour biomarker for
Colorectal cancer
What type of cancer can the oestrogen receptor be a tumour biomarker for
Breast cancer
What type of cancer can the prostate specific antigen be a tumour biomarker for
Prostate cancer
What are the local effects of benign tumours
Pressure
Obstruction
What are the local effects of malignant tumours
Pressure
Obstruction
Tissue destruction (ulceration/infection) Bleeding (anaemia and haemorrhage)
Pain (from pressure on nerves, perineural infiltration, bone pain from pathological fractures)
Effects of treatment
What are the systemic effects of cancer
Weight loss (cancer cachexia)
Secretion of hormones (normal and abnormal/inappropriate)
Paraneoplastic syndromes
Effects of treatment
When are ‘normal’ hormones produced by tumours
They are produced by tumours of the endocrine organ however there may be abnormal control of hormone production/secretion
When are ‘abnormal’/inappropriate hormones produced by tumours
They are produced by a tumour from an organ which doesn’t normally produce hormones
Paraneoplastic syndromes…
cannot be explained by local or metastatic effects of tumours (e.g. neuropathy or myopathy)
Why is it better for cancer to be detected at an early stage
It reduces/prevents morbidity/mortality
How can cancer be detected at the pre-invasive stage
Through the identification of dysplasia/intraepithelial neoplasia
What is dysplasia
A pre-malignant change
The earliest change in the process of malignancy which can be visualised
Where can dysplasia be identified
Epithelium
Can progress to cancer
State the features of dysplasia
Disorganisation of cells - increase nuclear size, increases mitotic activity, abnormal mitoses
Grading of dysplasia - high grade, low grade
No invasion
What is required for the early detection of cancer
Effective test which is sensitive/specific and acceptable
Give an example of a screening programme which helps to detect cancer early
Cervical screening programme
What is the aim of the cervical screening programme
To reduce the incidence of squamous carcinoma of the cervix
What does the cervical screening programme aim to detect
Dysplastic cells from squamous epithelium of the cervix
What can cause disorders or cell growth to occur
Normal and abnormal cell cycles
Chemical carcinogenesis
Radiation carcinogenesis
What does the normal cell cycle involve
Mitosis to cause mitotic divison
What is mitosis
Mechanism of cellular replication which causes nuclear division plus cytokinesis
What does mitotic divison produce
Two genetically identical daughter cells
What is the cell cycle
The time interval between mitotic divisions
What should the cell cycle be coordinated with
The body’s needs
Production of cell numbers and cell types is tightly controlled
What must occur for a viable progeny to be produced
The cell must progress through cycle phases (DNA synthesis and mitosis) in the correct sequence
What does quality control ensure
Each daughter cell receives a full chromosome complement
Mutations in DNA sequences do not pass on
What external factors influence the cell cycle control
Hormones
Growth factors
Cytokines
Stroma
What internal factors influence the cell cycle control
Critical checkpoints - Restriction point (R)
What occurs prior to reaching the restriction point
Progress through G1 depends on external stimuli
What occurs after the restirction point
Progression becomes autonomous
What are the phases of the cell cycle
Quiescent, G0
Interphase (G1, S, G2)
Cell division (mitosis)
What is the quiescent phase
The resting phase: cell has left the cycle and stopped dividing
What occurs in G1
Cells increase in size
G1 checkpoint control mechanism ensures everything is ready for DNA synthesis
What occurs in S phase
DNA replication occurs
What occurs in G2
Gap between DNA synthesis and mitosis
Cell continues to grow
G2 checkpoint control mechanism ensures that everything is ready to enter the M phase
What occurs in mitosis
Cell growth ceases
Metaphase checkpoint ensures cell is ready to complete division
Where are checkpoints present in the cell cycle
At the end of G1
End of G2
At metaphase
What happens if the cell size is inadequate
G1 or G2 arrest
What happens if the nutrient supply is inadequate
G1 arrest
What happens if essential external stimulus is lacking
G1 arrest
What happens if the DNA is not replicated
S arrest
What happens if DNA damage is detected
G1 or G2 arrest
What happens if there is chromosome misalignment
M-phase arrest
What are checkpoints
System of cyclically active and inactive enzymes
Catalytic sub-units activated by a regulatory sub-unit
What is a catalytic subunit called
Cyclin-dependent kinases (CDKs)
What is a regulatory sub-unit called
Cyclins
What is the active catalytic subunits and regulatory sub-unit called
CDK/cyclin complex
What do acitve CDK/cyclin complexes do
Phosphorylate target proteins
What does the phosphorylation target proteins cause
The activation/inactivation of that substrate which regulate events in the next cycle phase
How are CDKs constitutively expressed
In an inactive form
How is CDK activity regulated
The cyclins accumulate and are destroyed as cycle progresses CDK inhibitors (CKIs)
What CDK inhibitors (CKIs) families are there and how do they work
INK4A
CIP/KIP
Bind to cyclin/CDK complexes
Describe the INK4A family
They bind to CDK4 and 6 to prevent association of these CDKs with their cyclin regulatory proteins
How is the cell cycle regulated
An extracellular growth signal activates cyclin D
This combines with CDK4 to form a cyclin D-CDK4 complex
The complex inhibits p21 and activates E2F
The activation of E2F responsive genes occurs through phosphorylation and deactivation of RB
This causes Cyclin E to combine with CDK2 to form cyclin E-CDK2 complex
And cyclin A to combine with CDK2 to form cyclin A-CDK2 complex
What does the cyclin E-CDK2 control
G1/S checkpoint
What does the cyclin A-CDK2 control
G2/M checkpoint
Describe the retinoblastoma gene
It encodes a 110 kDa phosphoprotein (pRb) expressed in almost every cell of the human body
pRb is hypophosphorylated and phosphorylation increases as cells progress through the cell cycle
Active cyclin D/CDK complexes will phosphorylate pRb
What is the function of hypophosphorylated/active Rb
Inactivates E2F so puts a brake to the cell cycle
What is the function of phosphorylated/inactive pRb
Loses affinity for E2F
What is the main target for pRb
E2F transcription factor as E2F is a potent stimulator of cell cycle entry
What will free E2F transcription factors do
Activate vital target genes
What causes carcinogenesis
Mutation of genetic material that upsets the normal balance between proliferation and apoptosis (cell death)
What leads to tumours
Uncontrolled proliferation of cells
What types of mutations can cause a cell to lose control of proliferation
Mutations in genes regulating cell division, apoptosis and DNA repair
What can lead to carcinogenesis
Non-lethal genetic damage
Where can non-lethal genetic damage arise from
Environmental agents (e.g. chemicals, radiation and oncogenic viruses) Inherited
Describe chemical carcinogenesis
Purine and pyrimidine bases in DNA are critically damaged by various oxidizing and alkylating agents
The chemical carcinogens or their active metabolites react with DNA forming covalently bound products (DNA adducts)
Adduct formation at particular chromosome sites causes cancer
What is a critical cellular target for radiation damage
Purine and pyrimidine bases in DNA
When is radiation carcinogenic
High-energy radiation if received in sufficient doses (e.g. from ultraviolet radiation, X-rays, Gamma radiation)
Which type of genes are mutated in cancer
Genes that regulate the cell cycle
Which regulatory pathways tend to be disrupted in cancer
The cyclin D-pRb-E2F pathway
p53 pathway
What happens when pRB is inactive or absent
It causes the cell cycle break to be released
Where are cancers most likely to be dysregulated
G1-S
Which genes tend to have mutations that cause dysregulation at G1-S
Rb
CDK4
cyclin D
p16
What is the function of p53
To maintains genomic integrity
What does increased levels of p53 in damaged cells cause
Induces cell cycle arrest at G1
Facilitates DNA repair
If damage is severe it causes p53-induced apoptosis
What occurs in cells with mutated p53
They do not G1 arrest or repair damaged DNA
Genetically damaged cells will proliferate and form malignant neoplasms
State some factors which affect carcinogenesis
Geographic and environmental factors
Age
Heredity
What are proto-oncogenes
Normal genes that promote normal cell growth and mitosis
Normal genes coding for normal proteins that regulate growth
What are tumour suppressor genes
Genes that discourage cell growth, or temporarily halt cell division to carry out DNA repair
What type of genes are classed as tumour-suppressor genes
Genes negatively regulating mitosis - Rb
Genes regulating apoptosis
Genes regulating DNA repair
What is the key event in tumour formation
Uncontrolled cell proliferation via cell cycle dysregulation via loss of tumour suppressor gene function
What types of mutations can mimic the effect of pRB loss
Mutational activation of cyclin D or CDK4
Mutational inactivation of CDKIs also drive proliferation
How can mutations of anti-oncogenes occur
From:
Sporadic mutations
Inherited mutations
How do inherited anti-oncogene mutations arise
One defective inherited copy of pRb
Somatic point mutation of other copy
How do sporadic anti-oncogene mutations arise
2 mutations occur in a single cell
How many allelic copies must be mutated to give rise to cancer
Both
What types of syndromes can be involved in causing cancer
Heredity - accounts for 5-10% of all cancers
Inherited cancer syndromes
Familial cancers
Autosomal recessive syndromes of defective DNA repair
What are inherited cancer syndromes
A strong family history of uncommon site-specific cancers
An autosomal dominant inheritance of a single mutant gene
Give examples of inherited cancer syndromes
Familial retinoblastoma Familial adenomatous polyposis of colon Multiple Endocrine Neoplasia Neurofibromatosis Von Hippel-Lindau Syndrome
What is the risk with familial retinoblastoma
Carriers have 10000x risk of bilateral retinoblastoma
Increased risk of second cancers (e.g. bone sarcomas)
What is the risk with familial adenomatous polyposis of colon
100% risk of colon cancer by age 50 years
What are the signs of familial cancers
Family clustering of cancers but individual predisposition unclear
Multifactorial inheritance
Early age of onset
Multiple/bilateral tumours
Give examples of familial cancers
Some Breast cancers
Some Ovarian cancers
Non-FAP colon cancers
Describe the APC gene
Function: signal transduction
Somatic mutation causes: gastric, colon, pancreas, melanoma
Inherited mutation causes: FAP colon cancer
Describe the p53 gene
Function: cell cycle/apoptosis
Somatic mutation causes: most cancers
Inherited mutation causes: li-fraumeni syndrome (multiple carcinomas and sarcomas)
Describe the Rb gene
Function: cell cycle regulation
Somatic mutation causes: retinoblastoma, colon, lung and breast carcinomas
Inherited mutation causes: retinoblastoma and osteosarcoma
Describe the p16 (INK4a) gene
Function: Inhibits CDKs
Somatic mutation causes: pancreatic, oesophageal carcinomas
Inherited mutation causes: maligant melanomas
Describe BRCA 1/2
Function: DNA repair
Inherited mutation causes: breast and ovarian cancer
What are oncogenes derived from
Proto-oncogenes
How can oncogenes be activated
By:
Alteration of proto-oncogene structure
Dysregulation of proto-oncogene expression
What does the dysregulation of proto-oncogene expression cause
Gene amplification
Overexpression
What does the alteration of proto-oncogene structure cause
Point mutations
Chromosome rearrangements + translocations
What can oncogenes produce
Active oncoprotein products
What type of oncoprotein products are there
Growth Factors Growth Factor Receptors Proteins involved in Signal Transduction Nuclear Regulatory Proteins Cell Cycle Regulators
What does the proto-oncogene sis activate
PDGF causing overexpression
Cancers caused: astrocytoma, osteosarcoma
What does the proto-oncogene erb-B2 activate
EGF-receptors family causing amplification
Cancers caused: breast, ovarian, lung, stomach
What does the proto-oncogene ras activate
GTP-binding causing point mutation
Cancers caused: lung, colon, pancreas, leukaemia
What does the proto-oncogene myc activate
Transcriptional activators causing translocation
Cancer caused: Burkitt’s lymphoma
What does the proto-oncogene cyclin D activate
Cyclins causing translocation and amplification
Cancers caused: mantle cell lymphom, breast, liver, oesophageal
What does the proto-oncogene CDK4 activate
CDK causing amplification
Cancers caused: melanoma, sarcoma
What mechanisms can be used for viral carcinogenesis
Virus genome inserts near a host proto-oncogene
Viral promoter or other transcription regulation elements cause proto-oncogene over-expression
Retroviruses insert an oncogene into host DNA causing cell division
Which DNA viruses are known to cause cancer in humans
HPV (cervical cancer)
Hepatitis B (liver cancer)
EBV (Burkitt lymphoma)
How many genetic aberrations do sporadic cancers obtain
Multiple
The abnormalities accumulate with time
