Brainscape's Knowledge GenomeTM

Browse over 1 million classes created by top students, professors, publishers, and experts.


See full index

1. Essential Medical Science > Tumours > Flashcards

Tumours Flashcards

You may prefer our related Brainscape-certified flashcards:
Biology 101 flashcards USMLE® Step 1 flashcards
1
Q

What is adaptation in terms of cells?

A

■Adaptations are cellular changes in response to changes in environment or demand
cells can increase/ decrease Size, Number, Phenotype, Metabolic Activity, Function.
It is often reversible

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
2
Q

Why do cells adapt?

A

■Acquire new, steady state of metabolism and structure
■Better equips cells to survive in a new environment
Failure of adaptation may lead to sub-lethal or lethal cell injury

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
3
Q

What is Physiological Cellular adaptation?

A

Responding to normal changes in physiology or demand

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
4
Q

What is Pathological Cellular adaptation?

A

Responding to disease related changes

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
5
Q

What is a Fibroblasts susceptibility to environmental change?

A

Survive severe metabolic stress without harm. e.g absence of oxygen

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
6
Q

What is a Epithelial cells susceptibility to environmental change?

A

Labile cell population
Active stem cell compartment
Highly adaptive in number and function

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
7
Q

What is a Cerebral neurons susceptibility to environmental change?

A

Terminally differentiated and permanent cell population

Highly specialised function and easily damaged

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
8
Q

What is a cellular response to increased demand?

A

hypertrophy (increase in size of cells) and hyperplasia (increase in number of cells)

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
9
Q

What is hypertrophy?

A

■Increase in size of existing cells
■Increase in functional capacity
■Particularly seen in permanent cell populations esp cardiac and skeletal muscle
Increased synthesis of structural components and increased meatbolism

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
10
Q

What is Subcellular hypertrophy and hyperplasia?

A
  • Increase in size and number of subcellular organelles

* eg smooth ER hypertrophy in hepatocytes with barbiturates

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
11
Q

What is Hyperplasia?

A
  • Increase in number of cells caused by cell division

* Possible in labile and stable cell populations

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
12
Q

What is atrophy? What are the two different types?

A

Reduction in size of organ or tissue by decrease in cell size and number
Physiological
•Pathological

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
13
Q

What results in pathological atrophy?

A
  • Decreased workload (disuse atrophy)
  • Loss of innervation (denervation atrophy)
  • Diminished blood supply
  • Inadequate nutrition (e.g. cachexia)
  • Loss of endocrine stimulation
  • Pressure
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
14
Q

What are the mechanisms of atrophy?

A

■Reduction in volume of individual cells

■Death of individual cells

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
15
Q

What is metaplasia?

A
  • Transformation of one differentiated cell type into another
  • Trans-differentiation of stem cells
  • Better adaptation to new environment
  • Can affect epithelium and mesenchymal tissues
  • Physiological or pathological
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
16
Q

What can adaptations lead to?

A

neoplasia

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
17
Q

What are examples of neoplasia?

A
  • Glandular metaplasia in oesophagus= Adenocarcinoma
  • Squamous Metaplasia in Cervix= CIN and squamous cell carcinoma
  • Endometrial hyperplasia due to increased oestrogens= Adenocarcinoma
  • Squamous metaplasia in bronchus= dysplasia and squamous cell carcinoma
  • Squamous metaplasia in bladder= Squamous cell carcinoma
  • Parathyroid hyperplasia due to chronic renal failure= adenoma
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
18
Q

What is Dysplasia?

A
  • Earliest morphological manifestation of multistage process of neoplasia (hence irreversible)
  • In-situ disease; non-invasive
  • Shows cytological features of malignancy, but no invasion
  • commonly – abnormality indicating precursor change of malignancy
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
19
Q

What is the definition of cancer?

A

“Cancer is the uncontrolled growth of cells, which can invade and spread to distant sites of the body”

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
20
Q

What is the definition of tumour?

A

TUMOUR
Historically: “an abnormal swelling”
Now synonymous with…
NEOPLASM
“ abnormal and excessive growth of tissue”
- exceeds and is uncoordinated with that of normal tissue
- persists in abnormal growth in the absence of initiating stimulus

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
21
Q

What is the definition of histogenesis?

A

“The differentiation of cells into specialised tissues and organs during growth from undifferentiated cells”

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
22
Q

Which cancers are common in the UK?

A
  1. Breast
  2. Prostate
  3. Lung
  4. Bowel
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
23
Q

Which cancers are common in females in the UK?

A
  1. Breast
  2. Lung
  3. Bowel
  4. Uterus
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
24
Q

Which cancers are common in males in the UK?

A
  1. Prostate
  2. Lung
  3. Bowel
  4. Head & Neck
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
25
Q

How many cancers are linked to tobacco?

A

Worldwide 33% of cancers are linked to tobacco

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
26
Q

What are the most common causes of cancer-mortality?

A 
Incidence:
1.Breast
2.Prostate
3.Lung
4.Bowel
Mortality:
1.Lung
2.Bowel
3.Breast
4.Prostate
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
27
Q

Why are the Characteristics of Tumours Important?

A

‘ Nothing is more important to the individual with a tumour than being told their tumour is “benign” `
* BENIGN VS. MALIGNANT *

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
28
Q

How do you characterise tumours?

A

Benign vs. Malignant:

  1. Rate of Growth
  2. Differentiation
  3. Local Invasion
  4. Metastasis
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
29
Q

What determines the rate of growth of a tumour?

A

Doubling time of tumour cells
Rate at which cells are shed or die

Fast growing tumours = excess of cell production over cell death

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
30
Q

What is the rate of growth of a benign tumour?

A

Slow growing

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
31
Q

What is the rate of growth of a malignant tumour?

A
  • Grow rapidly
  • Growth is often linked to differentiation
  • Exceptions to the rule

Different malignancies show varied growth rates
•Slow-growing tumours associated with long survival
Rapidly-growing tumours lethal within a short time

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
32
Q

What type of cancer is Small cell lung cancer?

A
  • Aggressive and fast growing

- Median life expectancy 6-12 months

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
33
Q

What is differentiation?

A

“The extent that neoplastic cells histologically resemble its cell or tissue of origin”
Graded into:
•Well differentiated- Cells closely resemble those of normal tissue
•Moderately differentiated
Poorly differentiated- Cells hardly resemble those of normal tissue

Mentioned that rate of growth is often closely linked to differentiation

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
34
Q

What type of differentiation do benign/malignant tumours have?

A

Benign: Well differentiated
Malignant: Range of differentiation

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
35
Q

What is Anaplasia?

A

•Neoplasms comprised of such poorly differentiated cells, that they show no resemblance to the normal tissue
failure to differentiate = malignany
•Can be very difficult to tell what tissue these tumours derived from- may require molecular tests
•Hallmark of malignancy

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
36
Q

What is Pleomorphism?

A

Variation of cells and nuclei in:
•Size
•Shape

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
37
Q

What is Abnormal nuclear morphology differentiation?

A
  • Nuclei appear too large for the cell that they are in- High nuclear to cytoplasmic ratio
  • Variability in nuclear outline- Irregular
  • Hyperchromatism – Nuclei look dark compared to normal
  • Abnormally large nucleoli
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
38
Q

What is Mitoses differentiation?

A
  • An indication of proliferation
  • Anaplastic tumours often contain lots of mitoses
  • But mitoses can be seen in normal tissue therefore do not indicate malignancy.
  • Atypical, bizarre mitotic figures seen in malignancy e.g: Tripolar, Quadripolar, Multipolar spindles
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
39
Q

What is loss of polarity differentiation?

A
  • Orientation of cells disturbed

* Disorganised growth

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
40
Q

What is grading of tumours?

A

GRADE
•Related to differentiation
•Closely linked to how aggressive tumour is

  • Well differentiated = low grade / grade 1
  • Moderately differentiated = intermediate / grade 2
  • Poorly differentiated = high grade / grade 3

This is different to STAGE of disease which is a measure of extent of disease and guides treatment and prognostic decisions.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
41
Q

Do benign turmours invade?

A

•Cohesive expansile mass
•Slow growing
•Localised to site of origin
No capacity to infiltrate, invade or metastasise

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
42
Q

Do malignant turmours invade?

A
  • Infiltrate
  • Invade
  • Destroy surrounding tissue
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
43
Q

What is Local Invasion?

A
  • Hallmark of malignancy
  • Malignant tumours won’t respect anatomic boundaries
  • Invasion and destruction of adjacent tissue = tumour penetrates vessel walls and lymphatics = metastases
  • Penetration of organ surfaces and skin
  • Surgical resection difficult- requires resection of adjacent macroscopically normal tissue
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
44
Q

What is Metastasis?

A

“Spread of a tumour to sites physically discontinuous with the primary tumour”

•Pathognomic of malignancy
•Reduces life expectancy significantly
•30% of non-skin malignancies at diagnosis have metastasised
•Generally correlated with aggressive, fast growing, and large neoplasms there are exceptions
Secondary tumour burden is often greater than that of the primary site
Occurs at different stages in natural history in different tumours
May be early or more commonly a late relapse
Unknown primary site
Metastasis is often the presenting tumour

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
45
Q

What are the routes of metastasis?

A
  1. Direct seeding
  2. Lymphatic spread
  3. Haematogenous spread
  4. (Implantation) – accidental spillage of tumour cells during surgery
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
46
Q

What is direct seeding?

A
  • Malignant neoplasm penetrates into a natural body cavities- Most commonly the peritoneal cavity, also pleura, pericardium, joint spaces etc.
  • Particularly common in ovarian cancer = seeding to peritoneum
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
47
Q

What is Lymphatic spread?

A
  • Most common pathway for carcinomas (cancers of epithelial origin)
  • Pattern of lymph node involvement follows the routes of lymphatic drainage
  • Sentinel lymph node biopsy- First node in a regional lymphatic basin that receives lymph flow from primary tumour, Breast, melanoma and other cancers
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
48
Q

What is Haematogenous spread?

A
  • Invasion of tumour into blood vessels
  • Typical of sarcomas (cancers of connective tissue origin)
  • But also seen in carcinomas
  • Bloodborne cells follow the venous flow draining site of the neoplasm
  • Often come to rest in first encountered capillary bed, Liver and lungs most frequently involved
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
49
Q

What is stroma? What is its function?

A

Stroma = connective tissue framework that supports cells
Provides: Mechanical support, Intercellular signalling, Nutrition
•Essential in supporting neoplastic cells
•Around tumours, stroma shows a desmoplastic reaction- Fibrous stroma

Stroma surrounding tumour contains:
•Cancer-associated fibroblasts
•Blood vessels – essential for growth
•Lymphocytic infiltrate
•Myofibroblasts
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
50
Q

What are the Clinical Complications of Tumours?

A 
•Occur in both benign and malignant tumours
•Dependent on:
•  Location
•  Cell of origin
•  Behaviour
•Effects of the tumour can be:
1.Local
2.Metabolic
3.Due to metastases
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
51
Q

What are Local effects of tumours?

A

Compression and displacement
•Benign: e.g. Pituitary adenoma = vision loss
•Malignant: Pancoast tumour in lung = Horner’s Syndrome
Destruction (in malignant tumours)
•Invade and destroy local structures
•Can be rapidly fatal
•E.g. Pulmonary tumour invading into the pulmonary artery

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
52
Q

What are metabolic effects of tumours?

A

Non-specific
Malignant tumours:
•Cachexia – tumour derived factors that interfere with protein metabolism.
Tumour type-specific
•Benign tumours – endocrine e.g. thyroid adenoma = thyrotoxicosis
•Malignant tumours – e.g. small cell lung cancer
•Endocrine - secrete ADH = SIADH (low sodium)
•Neurological - Lambert-Eaton myasthenic syndrome (caused by a autoimmune antibodies to voltage gated calcium channels)

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
53
Q

What are Soft Tissue Tumours?

A

•Tumours of non-bony mesenchymal structures
•Connective tissue, muscle, fat, blood vessels
•Benign tumours – common
•Malignant tumours – rare, accounting for approximately 1% of malignancy
Occur in all age groups – paediatric – young adults- old
•Can occur at any site in the body
•Malignant ones, commonest site; thigh and retroperitoneum. These 2 sites account for > 50%.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
54
Q

What is the presentation of soft tissue tumours?

A

•Most present with a lump
•Lumps are common; sarcomas are rare
Ones to worry about
•Painful/ Deep [to deep fascia]/ >5 cm in size/ Recurrent/ Enlarging

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
55
Q

What is the benign/ malignant classification name suffix?

A

Benign- “Oma”

Malignant- “Sarcoma”

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
56
Q

What is the benign/ malignant classification name of fat tumours?

A

Benign- Lipoma

Malignant- Liposarcoma

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
57
Q

What is the benign/ malignant classification name of Smooth muscle tumours?

A

Benign- Leiomyoma

Malignant- Leiomyosarcoma

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
58
Q

What is the benign/ malignant classification name of Skeletal muscle tumours?

A

Benign- Rhabdomyoma

Malignant- Rhabdomyosarcoma

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
59
Q

What is the benign/ malignant classification name of Neural tumours?

A

Benign- Schwannoma & Neurofibroma

Malignant- MPNST

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
60
Q

What is the benign/ malignant classification name of Blood vessel tumours?

A

Benign- Haemangioma

Malignant- Angiosarcoma

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
61
Q

What is the benign/ malignant classification name of skin tumours?

A

Benign- Dermatofibroma

Malignant- DFSP

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
62
Q

What is the benign/ malignant classification name of fibrous tumours?

A

Benign- Fibroma

Malignant- Fibrosarcoma

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
63
Q

What lab tests are used for tumour diagnosis?

A
  • Immunohistochemistry
  • Cytogenetics – need fresh tissue to culture.
  • Molecular Pathology – FISH, PCR, NGS
  • Many soft tissue tumours have characteristic chromosomal changes
  • These can be used diagnostically
  • Methods: cytogenetics, molecular biology – these look for functional mRNA using FISH, PCR
  • Can look for chromosomal abnormality, Fusion RNA or protein expression
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
64
Q

What is Myositis ossificans?

A

Reactive lesions
occur in young adults
rapidly growing lump on limb
often mistaken for sarcoma

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
65
Q

What is the prognosis and treatment for sarcomas

A 
Prognosis; 50% alive at 5 years, 
Treatment
•Surgery, main treatment option: radical excision, limb sparing surgery
•Radiotherapy
•Chemotherapy
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
66
Q

What is the function of pre and post operative adjuvant radiotherapy? What are potential complictions?

A

•Preoperative- downstage size and extent of tumour
•Post operative- prevent local recurrence
Complications
•fibrosis
•fracture
•radiation induced tumours [usually sarcoma’s]

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
67
Q

What is the function of pre and post operative adjuvant chemotherapy?

A
  • Pre- or Post- surgery
  • Shrink tumour
  • Systemic disease
  • Paediatric sarcomas- e.g. small blue cell tumours are chemoresponsive
  • GIST- Imatinib – a synthetic tyrosine kinase inhibitor
68
Q

What is GIST?

A
  • Tumour of modified smooth muscle of bowel wall
  • Most have a cell membrane receptor CD117.
  • Type of tyrosine kinase receptor - controls cell proliferation and differentiation.
  • Can be detected using immunohistochemistry
  • Now carry out mutational analysis on GISTs in Leeds to see if have a Tyrosine Kinase mutation
  • Indicates whether tumour would respond to Imatinib [Glivec]
  • Newer Tyrosine kinase inhibitors now available
69
Q

What is a papilloma?

A

•Benign tumour of surface (non-glandular /

non-secretory) epithelium

70
Q

What is a adenoma?

A

•Benign tumour of glandular /

secretory epithelium

71
Q

What does further classification of surface epithelium tumors include?

A

–If surface epithelium: Then name CELL TYPE of origin

i.e SQUAMOUS CELL papilloma

72
Q

What does further classification of glandular/secretory epithelium tumors include?

A

GLANDULAR TISSUE of origin

e.g. COLONIC adenome

73
Q

What are malignant epithelial tumours called?

A

carcinomas
•Named by prefixing ‘carcinoma’ with epithelial cell of origin- e.g. BASAL CELL CARCINOMA
•Those derived from secretory epithelium = ADENOCARCINOMAS

•Refer to degree of differentiation - e.g. MODERATELY DIFFERENTIATED
squamous cell carcinoma

74
Q

What is lentigo?

A

Benign melanocytic lesions

75
Q

What is melanocytic naevi?

A

Benign melanocytic lesions

76
Q

Name some CNS tumours? How are they graded?

A

•Many types:
–Meningioma (meninges)
–Astrocytoma/glioblastoma multiforme (astrocytes)
–Oligoendroglioma (oligodendroglial cells)
–Ependymoma (ependymal cells)
–Medulloblastoma (neurones)
–Pituitary tumours and more!

  • WHO Grading (I-IV)
  • Remember that many cancers metastasise to the brain but generally not vice versa
77
Q

What are Germ cell tumours?

A

•Arise from germ cells, so found in

  • Gonads (ovary, testis)
  • Midline

Not all malignant
•Nomenclature based on gonad:
dysgerminoma vs. seminom
•Nomenclature based on differentiation: yolk sac tumour, teratoma, choriocarcinoma, embryonal carcinoma, mixed germ cell tumours

78
Q

What are Haematological malignancies?

A

•Leukaemias
–Acute vs chronic; lymphocytic/lymphoblastic (lymphocytes) vs myeloid/myelogenous (other haematological cells); mainly marrow/blood

•Lymphoma (lymphocytes)
–Many types; mainly nodes/other solid tissues; clumsy distinction e.g. adult T cell lymphoma

•Myeloma = plasma cells

79
Q

What are Embryonal tumours?

A 
•Paediatric tumours
•Histological resemblance to
  embryonic cells of that organ
•Retinoblastoma, nephroblastoma (Wilm’s
     tumour), neuroblastoma, hepatoblastoma,
     etc.
•Awkward term - many now
    ‘small round blue cell tumours’
80
Q

What are Hamartomas & choristomas?

A

•Named as per site of origin

Hamartoma
•Benign, non-neoplastic tissue overgrowth;
‘incidentaloma’
•Indigenous to site but disorganised mass
- e.g. lung hamartoma = bronchial epithelium and cartilage
A hamartoma is a tumour-like lesion, which exhibits uncoordinated growth. Hamartomas are benign and usually consists of at least 2 mature cell types normally found in the organ in which the lesion lies, eg. Lung hamartoma contains cartilage and bronchial epithelium.
Hamartomas are clinically relevant because they can be mistaken for malignant neoplasms on imaging, and they can be associated with genetic syndromes eg. In tuberous sclerosis.

Choristoma
•Heterotopic, non-neoplastic tissue
–e.g. ocular choristoma

81
Q

Why do some tumours have compound names? What are the rules?

A

Tumours not always composed of one cell type. Same rules apply
•Benign tumour - blood vessels and fat
- vessels = angio-; fat = lipo-; benign = -oma
this is called Angiolipoma
•Malignant tumour - epithelial and stromal components - malignant epithelial = carcinoma; malignant
stromal = sarcoma therefore called Carcinosarcoma

•Some tumours have a cystic component
= Cystadenoma, cystadenocarcinoma

82
Q

What are Primary vs. secondary/metastatic tumours?

A

•Primary cancer = at site of origin
•Secondary cancer = metastatic - links with staging; still designated as cancer of origin
–Can be of different grade
•But… there are cancers of unknown primary
–Occult primary
–Migrating pre-/malignant stem cells
–Regressed primary= Examination, imaging and immunohistochemistry may help

83
Q

What are the names of some malignant tumours that have benign names?

A

Melanoma
Mesothelioma
Myeloma
Lymphoma

if they have benign names but are actually malignant

84
Q

What do you call a benign tumour originating fron the Stratified squamous epithelium?

A

Squamous cell papilloma

85
Q

What do you call a benign tumour originating fron the Basal cells of the skin?

A

Basal cell papilloma

86
Q

What do you call a benign tumour originating fron the Transitional epithelium of the bladder?

A

Transitional cell papilloma

87
Q

What do you call a benign tumour originating fron the Glandular epithelium of liver?

A

Liver cell adenoma

88
Q

What do you call a benign tumour originating fron the Glandular epithelium of thyroid?

A

Follicular adenoma

89
Q

What do you call a malignant tumour originating fron the Stratified squamous tissue?

A

Squamous cell carcinoma

90
Q

What do you call a malignant tumour originating from the Basal cells of the skin?

A

Basal cell carcinoma

91
Q

What do you call a malignant tumour originating from the Transitional epithelium of the bladder?

A

Urothelial carcinoma

92
Q

What do you call a malignant tumour originating from the Glandular epithelium of colon?

A

Colonic adenocarcinoma

93
Q

What do you call a malignant tumour originating from the Glandular epithelium of breast?

A

Breast adenocarcinoma

94
Q

What are the risk factors for CRC?

A 
•Male
•Right age range
–Obesity and sedentary lifestyle
–Smoking and drinking alcohol
–Eating too much red meat
–Eating too little fruit / vegetables
–Idiopathic inflammatory bowel disease (UC 18% risk over 30 years)
–Previous polyps / cancers in the bowel
- FH
How to reduce the risk?
•Eat fruit / vegetables
•Increase fibre intake
•Aspirin
•Screening every two years in men & women aged 60-74 years (50-74 in Scotland)- England will now expand to 50
•Faecal occult blood (FOB) test kit
95
Q

CRC FH?

A 
•Sporadic CRC (90 - 95%)
–No evidence of a hereditary syndrome
–May be a familial component
•Hereditary CRC (5 - 10%)
–Familial adenomatous polyposis (FAP)
–Lynch syndrome (previously called hereditary non-polyposis colorectal cancer or HNPCC)
–Others
–
•Investigation led to the discovery of some of the genes responsible for CRC
96
Q

What is FAP?

A
  • Autosomal dominant inheritance
  • Adenomatous Polyposis Coli (APC) gene
  • Tumours develop very early (2nd decade)
  • Bowel literally covered with polyps (minimum 100)
  • Carcinomas inevitably occur by 40 years
  • Prophylactic colectomy performed in early 20’s
97
Q

What is lynch syndrome?

A

Lynch syndrome (HNPCC)
•Microsatellite instability pathway – mutations in one of six DNA mismatch repair genes
•Microsatellites are non-encoding repeat regions of DNA
•Alternative pathway for CRC development outside of the Vogelstein sequence (~15% cases)

98
Q

What are polyps? What is the treatment?

A

•What is a polyp ?–Tissue mass that protrudes into the bowel lumen
•Are they always neoplastic in the colon ?
–No they can be inflammatory, hyperplastic etc.
•What is the definition of an adenoma ?
–Benign neoplasm of glandular epithelium
•How are colonic adenomas classified ?
–Architecture (tubular, villous or tubulovillous)
–Degree of dysplasia (low-grade or high-grade)

•Why are polyps clinically significant ?
–Precursors to CRC
–Majority of CRC evolve through polyps
•Risk of malignant transformation depends on three factors
–Size (> 1cm = high risk)
–Histological architecture (villous adenomas = high risk)
–Severity of dysplasia (high-grade dysplasia = high risk)

•Polypectomy
–Snare
–Endoscopic mucosal resection (EMR)
•Repeat colonoscopy
–New polyps developed in 30% within 26 months

99
Q

How is the treatment for CRC determined?

A

•Staging determines if patients get additional chemotherapy
•Why not give it to everyone?
–Minimal disease = don’t need it (and get side effects)
–Severe disease = need to decide benefit
•Who do we treat?
–High-risk stage II (e.g. pT4, vascular invasion etc.)
–Stage III (node +ve)

•Ultimately around 50% of CRC patients will die from their disease

100
Q

What is the EPIC study?

A

Big epidemiological survey
•The European Prospective Investigation into Cancer and Nutrition (EPIC) study is one of the largest cohort studies in the world, with more than half a million (521 000) participants recruited across 10 European countries and followed for almost 15 years. EPIC was designed to investigate the relationships between diet, nutritional status, lifestyle and environmental factors, and the incidence of cancer and other chronic diseases.

  • The incidence of specific cancers varies enormously from one part of the world to another, suggesting that the environment can play a very significant role in the rates of cancer occurrence. Migrants have been observed to gradually adopt the pattern of cancer incidence of the country to which they emigrate
  • The World Health Organisation have identified numerous occupations as carrying a significant cancer risk through simple epidemiological studies and this has allowed us to identify many new and specific types of carcinogenic agent that workers are exposed to
  • Workers are exposed to heavy metals, such as cadmium and nickel, in aluminium production, coal gasification, coke production, iron and steel industries
  • Mining of hematite and uranium exposes workers to radon
  • Painters and furniture makers are exposed to various solvents and preservatives. Many cases of cancer of the sinonasal cavities and paranasal sinuses have been reported among woodworkers
  • Workers in rubber industry exposed to ß-napthylamine and 4-aminobiphenyl
  • Nasal adenocarcinoma is associated with employment in boot and shoe manufacture and repair, particularly where there is exposure to leather dust. Tannins are an interesting link between furniture workers and leather footwear manufacture. Tannins from oak are used for tanning leather.
101
Q

What are different types of carcinogens?

A
  • Chemicals e.g. PAHs, nitrosamines
  • Infectious agents e.g. human papilloma virus, Helicobacter pylori
  • Radiation e.g. UV light, radon
  • Minerals e.g. asbestos, heavy metals
  • Physiological e.g. oestrogen, androgens

Prolonged exposure to each of these agents (or combinations) can lead to the accumulation of genetic alterations in clonal populations of cells

102
Q

What is PAH?

A 
Chemical carcinogen
•PAH stands for polycyclic aromatic hydrocarbons. These are a class of chemical agents that are produced whenever organic material is burnt e.g. toast, meat, fossil fuels, tobacco
103
Q

What are Nitrosamines?

A

Chemical carcinogen

•Nitrosamines are a class of chemical agent that are produced in the diet when amino acids have nitrogen groups attached to them. Nitrites added as a preservative to processed foods are able to nitrosate amino acids in our diet and convert them into carcinogenic agents.

104
Q

What is a carcinogen?

A
  • Any agent that significantly increases the risk of developing cancer
  • Carcinogens are often genotoxic i.e. can chemically modify or damage DNA - INITIATORS
  • BUT often non-genotoxic e.g. induce proliferation and DNA replication - PROMOTERS
  • “complete” carcinogens can initiate and promote e.g. UV light

•Some non-genotoxic carcinogens induce proliferation as part of their normal physiological function, e.g. oestrogen, while others are cytotoxic and hence lead to proliferation through the replacement of dead or damaged cells, e.g. free radicals such as reactive oxygen species (ROS)

105
Q

How do Initiators and promoters work together to form mutations?

A

Mutation induction (initiation) requires:
• Chemical modification of DNA
Replication of modified DNA and mis-incorporation by DNA polymerase

  • DNA replication is somewhat dangerous as it is not completely error-free. It it were then we would not have had the evolution of species.
  • DNA polymerases make mistakes at a very low but significant rate. This results in the accumulation of genetic variation or polymorphisms in coding and non-coding sequences in the genome. Some of these changes are deleterious and are known as mutations
  • The presence of chemical modifications (miscoding or non-coding adducts or lesions) in the DNA exacerbates the tendency of polymerases to make mistakes (point mutations) by misincorporation, or can cause the polymerase to stall leaving a break in the DNA strand that can end up as a double stranded DNA break – a substrate for deletions, insertions or translocations
  • Chemical modification of the nucleotides involved in base-pairing can occur through environmental insult or through the action of endogenous reactive molecules such as free radicals produced by normal physiological processes
106
Q

What are promotors?

A
  • DNA replication is somewhat dangerous as it is not completely error-free. It it were then we would not have had the evolution of species.
  • DNA polymerases make mistakes at a very low but significant rate. This results in the accumulation of genetic variation or polymorphisms in coding and non-coding sequences in the genome. Some of these changes are deleterious and are known as mutations
  • The presence of chemical modifications (miscoding or non-coding adducts or lesions) in the DNA exacerbates the tendency of polymerases to make mistakes (point mutations) by misincorporation, or can cause the polymerase to stall leaving a break in the DNA strand that can end up as a double stranded DNA break – a substrate for deletions, insertions or translocations
  • Chemical modification of the nucleotides involved in base-pairing can occur through environmental insult or through the action of endogenous reactive molecules such as free radicals produced by normal physiological processes
107
Q

How do Initiation, promotion and progression work together to cause tumors?

A
  • Mouse skin tumour model
  • Genotoxic initiating agent damages DNA
  • Promoting agent fixes damage as a mutation and converts normal cell into mutant cell (initiation)
  • Promotion stimulates clonal expansion of initiated cell to produce papillomas
  • Further rounds of mutation and clonal expansion allows progression of papilloma to carcinoma
  • This slide illustrates how we can define the concepts of intiation, promotion and progression (sometimes also called persistance) that are useful for understanding the roles of different causative agents in carcinogenesis.
  • Some agents are good at initiating cancer; that is, they are good at inducing mutations, which when they occur in certain genes, like RAS, make the cell more susceptible to promotion, which can be thought of as a clonal expansion in response to various types of chemical or physiological insult.
  • In the mouse skin tumour model system we can initiate cells using well-understood mutagens - genotoxic agents that interact directly or indirectly with DNA to cause damage that sometimes results in permanent changes in DNA sequence that are passed on to daughter cells - mutations.
  • Promotion, or clonal expansion, of these initiated cells, can be achieved in the mouse skin using various non-genotoxic agents. These promoting agents often turn out to cytotoxic; that is, they result in cell death, inflammation, and stimulation of cell division in surviving cells. This cell division turns out to be vitally important in the generation of mutations - DNA replication in the presence of DNA damage is an error-prone process that can result in permanent changes in DNA sequence.
  • Repeated treatments with promoting agents can allow the gradual accumulation of mutations occurring as the result of exposure to exogenous (environmental) mutagens or endogenous (occurring naturally within cells) mutagens. The latter include things such as oxygen radicals or lipid metabolism byproducts.
108
Q

Is cancer risk related to cell division?

A

Cancer risk is directly related to
levels of cell division

  • For some tissues in the human body we have an accurate measure of how many stem cell divisions take place in those tissues throughout the lifetime of an individual
  • When you plot the lifetime risk of cancer arising in these tissues with the number of stem cell divisions that take place in those tissues we see a very strong correlation
  • This would support a hypothesis that cell division, and by inference DNA replication, is a significant risk factor for the development of cancer
109
Q

What are common types of genetic abnormalities?

A
  • point mutations (or base pair substitutions) are the smallest change in DNA sequence that can give rise to a change in gene function. They can result in an amino acid substitution (missense) or can introduce a stop codon (non-sense) into the coding sequence of a gene resulting in a truncated protein product. Point mutations can make protein products more active (gain of function) or less active (loss of function)
  • Gain or loss of one to several base pairs that results in a shift in the reading frame of a gene transcript is called a frameshift mutation. This changes the amino-acid sequence downstream of the frameshift, which usually inactivates the protein product
  • Deletions or insertions of DNA fragments from or into a gene will usually disrupt the amino acid sequence and lead to a loss of function
  • Gene amplification can result in a cell having anything up to a hundred copies of a gene, which it would normally only have two copies of. This results in excessive amounts of protein, which represents a gain of function for the cell
  • Chromosomal painting illustrates that some chromosomes are present in inappropriate numbers or show evidence of exchange of material, known as translocations. The one shown is a specific chr 9:22 exchange, known as the Philadelphia chromosome, which is responsible for chronic myeloid leukaemia
  • Chromosomal translocations can result in genes being moved to a more transcriptionally active region of the chromosome, or can result in genes being recombined into new gene fusions. The inversion shown is one that was observed in chromosome 5 of a worker who had been exposed to plutonium in the former Soviet Union
  • Aneuploidy is any departure from the normal structure or number of chromosomes.
  • about 300 of the 570 known cancer genes have been found to be affected by translocations, and around 100 each with frameshift, nonsense and missense mutations
110
Q

How can mutations can lead to a gain of function?

A

•Mutations can lead to a gain of function (activation of proto-oncogenes):
–Base pair substitutions, amplification, translocations, inversions

  • When we observe that a gain of function mutation in a gene confers a particular tumour characteristic to a cell we call the mutant gene an oncogene. The non-mutated version of the gene is referred to as a proto-oncogene. We can introduce oncogenes into normal human cells and observe a change, or transformation, to a more neoplastic form
  • A key concept regarding this terminology is that oncogenes are mutated versions of normal genes, whereas tumour suppressor genes are normal version of genes. However, in both cases a malignant phenotype is only achieved through mutation of the normal gene
111
Q

How can mutations can lead to a loss of function?

A

•Mutations can lead to a loss of function (inactivation of tumour suppressor genes):
–Base pair substitutions, frameshifts, deletions, insertions, chromosomal rearrangements, chromosome loss, promoter methylation

112
Q

How are tumour suppressor genes commonly inactivated?

A

Inactivation of TSGs through methylation of gene promoters – epigenetic change
lGene promoters can be aberrantly methylated in tumours
lMost common TSG inactivation event!!!

  • Approx. 70% of our genes have CpG “islands” associated with their promoter sequences. CpG methylation is only effective at shutting down the expression of a gene if it occurs within the promoter sequence of the gene
  • In cancer cells it is clear that the mechanisms controlling the proper methylation of the genome can be highjacked and used to inactivate TSGs, but the mechanisms by which this occurs are poorly understood at present
  • Promoter methylation appears to be more important in the inactivation of TSGs than somatic mutation. More than half of the TSGs that are involved in familial cancer syndromes due to germline mutations have been found to be silenced in sporadic (non-familial) cancers by promoter methylation
113
Q

What is Metabolic activation?

A

Direct acting
•interact directly with DNA, e.g. oxygen radicals, nitrosamines, UV light, ionising radiation
Procarcinogens
•require enzymatic (metabolic) activation before they react with DNA, e.g. aromatic amines, polycyclic aromatic hydrocarbons (PAHs)

• The majority of carcinogens that we ingest require metabolic activation by enzymes that normally function in the detoxification and excretion of toxic chemicals. This introduces a genetic influence on the extent to which we are sensitive to genotoxic attack by different agents. For example, people who activate a particular chemical more efficiently are more likely to get cancer, while those that excrete the activated chemical less efficiently are also more likely to get cancer

114
Q

How is benzopyrene activated?

A
  • benzopyrene, which can be generated through the combustion of most organic material such as meat, tobacco and fuel, is a classic example of a pro-carcinogen that requires metabolic activation before it becomes able to react with DNA
  • hotspots of DNA damage, formed by reaction of BPDE with the TP53 gene in laboratory experiments, match the hotspots of mutation seen in this gene in the lung tumours of smokers. A smoking gun indeed.
115
Q

How are DNA damage and repair related to cancers?

A
  • Different genotoxic agents (mutagens) can modify DNA in lots of different ways, and this can result in lots of different mutational outcomes ranging in size and severity from single nucleotide substitutions all the way up to chromosome breaks
  • Various DNA repair processes protect the integrity of the genome. Mutational defects in several of these processes can lead to cancer predisposition
  • Inherited defects in the NER repair pathway can lead to Xeroderma pigmentosum (XP), a group of rare autosomal-recessive inherited disorders characterized by extreme skin sensitivity to ultraviolet (UV) light, abnormal skin pigmentation, and high frequency of skin cancers, especially on sun-exposed skin. Dermatologic changes are the most conspicuous findings and are mandatory for the diagnosis
  • Inherited defects in the ATM gene involved in recombinational repair pathway gives rise to Ataxia telangiectasia (A-T), an autosomal recessive disorder. These patients have an elevated incidence of cancers, approximately 100-fold in comparison to the general population. In children, more than 85% of neoplasm cases are acute lymphocytic leukaemia or lymphoma. In adults with A-T, solid tumours are more frequent
  • One basic defect associated with the malady is the abnormal sensitivity of A-T cells to x-rays and certain radiomimetic chemicals, which lead to chromosome and chromatid breaks
  • The ATM gene product interacts with the products of tumour suppressor genes such as TP53 and BRCA1, both of which play an important role in the predisposition to breast cancer. Studies of A-T families have consistently reported an increased risk of breast cancer in women with one mutated ATM gene.
  • Hereditary non-polyposis colorectal cancer (HNPCC) is also known as Lynch syndrome. It is an autosomal dominant disorder. The majority of HNPCC is caused by mutations in one of several mismatch-repair genes: MSH2, MSH6, and PMS1 on chromosome 2, MLH1 on chromosome 3, MSH3 on chromosome 5, and PMS2 on chromosome 7. MSH2 and MLH1 account for the majority of mutations in HNPCC families. Mutations in any one of these genes confers an increased lifetime risk of developing colorectal cancer, as well as cancers of the endometrium, stomach, small intestine, liver and biliary tract, brain, ovary, ureters, and renal pelvis. Specifically, there is a 70 percent to 82 percent lifetime risk of developing colorectal cancer, a 12 percent chance of developing ovarian cancer, and up to a 60 percent chance of developing endometrial cancer.
116
Q

How are genetics and environment linked?

A

• Genetic polymorphisms in genes encoding metabolic activation, detoxifying, or DNA repair enzymes may confer greater or lesser susceptibility to the effects of carcinogenic exposure. This may in part explain why groups of people suffering the same levels of exposure may display a wide range of responses.

117
Q

What can defend against carcinogenesis?

A

•Exposure to variety of carcinogenic agents
•Many levels of defence:
–Dietary antioxidants
–Detoxification mechanisms
–DNA repair enzymes
–Apoptotic response to unrepaired genetic damage
–Immune response to infection and abnormal cells

  • it is important to realise that mutation is an extremely rare process in cells
  • many things have to go wrong or be avoided before a heritable genetic alteration occurs and is expressed in a stable cell lineage
  • as a result cancer is an extremely rare disease at the cellular level – consider how many cells there are in the human body and the fact that tumours arise from single cells
118
Q

What is the link between tobacco smoke and cancer?

A

•33 carcinogens identified in tobacco smoke
–Polycyclic aromatic hydrocarbons e.g. benzopyrene, require metabolic activation
–Acrolein - acrid smell, potent direct-acting mutagen
–Nitrosamines - formed during curing of leaves
–Radioactive lead and polonium
–Heavy metals - cadmium, chromium
•In combination with promotion by alcohol leads to 100-fold increased risk for head & neck cancer

exposure to tobacco smoke is associated with most forms of human cancer, and it’s not surprising when you consider how many dangerous compounds and agents are present in this material

Smoking a pack a day causes 150 mutations in lung cells

119
Q

What is the link between Alcohol and cancer?

A
  • linked to e.g. oral, oesophageal, bowel and liver
  • converted into acetaldehyde - can cause DNA damage
  • increases levels of oestrogen and testosterone
  • increases uptake of carcinogenic chemicals into cells within the upper GI
  • reduces levels of folate, needed for accurate DNA replication
  • can kill surface epithelium leading to unscheduled proliferation

•Alcohol causes at least seven types of cancer, including cancers of the mouth, oesophagus, pharynx, larynx, breast, bowel and liver. There is also increasing evidence linking alcohol to pancreatic cancer.

120
Q

What is the role of oestrogen in breast cancer?

A

All of the strongest risk factors are associated with increased exposure to oestrogen, which can both stimulate cell division and induce DNA damage

  • Breast cancer risk decreases 20% for each year that menarche is delayed
  • In identical twins the one whose menarche begins 1st has 5.4x chance of being 1st to develop breast cancer
  • Oopherectomy leads to 90% decrease in risk of breast cancer
  • Orchiectomy reduces incidence of prostate cancer
121
Q

What is the link between Chronic inflammation and cancer?

A

•Chronic inflammation plays important role in cancer
•Association with many types of cancer e.g. colitis, hepatitis, Barrett’s metaplasia, gastritis, gallstones
•Inflammatory response results in double whammy:
–DNA damage from release of free radicals by immune cells - initiation
–Growth factor induced cell division to repair tissue damage - promotion

  • Virchow first noticed that cancer often arose at sites of chronic inflammation in 1863
  • You may notice that the cause of tumour-associated chronic inflammation maybe due to both microbial infection or noninfective mechanisms
  • one of the key cells in the link between inflammation and cancer are the tumour-associated macrophages (TAMs)
  • these cells are recruited by cytokines released by tumour cells and produce tumour necrosis factor-alpha (TNF-α), a cytokine that induces and maintains the inflammatory response
  • TAMs also release reactive oxygen and nitrogen species (ROS and RNS) that can act as complete carcinogens, resulting in mutation by damaging DNA and stimulating proliferative through induction of growth factors
  • ROS secreted by TAMs and tumour cells can also induce fibroblasts to undergo autophagy, which releases important nutrients that tumour cells can “feed” on
122
Q

What are the Proportion of cancer deaths attributable to environmental or behavioural factors?

A

• Diet is a very complex factor in cancer incidence. In some cases exposure to carcinogens in e.g. red meat, burnt food, heavy metals can raise incidence. In others it can be absence of protective factors such as fibre and antioxidants. In most cases it will be a combination of the two.

123
Q

What is leukaemia?

A

•Tumours of the blood and the haematopoietic lineages
–Myeloid (ML) (granulocytes, monocytes, erthyrocytes, platelets)
–Lymphoid (LL) (B cells, T cells, NK cells)

•Defined as acute or chronic (e.g. ALL vs AML, AML vs CML)

124
Q

What is Lymphomas?

A

Tumours of lymphocytes & the immune or lymphatic systems (e.g. Burkitt lymphoma, Diffuse Large B Cell Lymphoma, Marginal Zone Lymphoma, Follicular Lymphoma)

125
Q

What is CML?

A

Chronic myelogenous leukemia
Philadelphia chromosome: In this translocation, parts of two chromosomes (the 9th and 22nd) switch places. As a result, part of the BCR (“breakpoint cluster region”) gene from chromosome 22 is fused with the ABLgene on chromosome 9.

•Rare (1/100,000)
•Male or female (ratio 1.5:1)
•Middle aged (median age 55-60, <10% under 20)
•Abdominal discomfort or pain
–Splenomegaly
–Splenic infarction 
•Fatigue
–Anaemia 
•Gout 
–Hyperuricaemia 
•Full Blood Count - Leukocytosis and anaemia

Imantinib

126
Q

What is B-Cell chronic lymphocytic leukaemia/lymphoma (B-CLL)

A

Chronic lymphocytic leukemia (CLL)

Common around 3400 cases of clinical CLL a year in UK
•Subclinical disease related to CLL is even more common (MBL)
•Elderly male
–male:female 2:1
–median age 72, majority >50
•Asymptomatic or
–Fatigue
–Autoimmune anaemia
–Splenomegally
–Lymphadenopathy
•Full Blood Count: –Lymphocytosis
127
Q

What is Somatic hypermutation?

A

Somatic hypermutation (SHM) occurs in a special micro-environment (Germinal Centre)
SHM acts on immunoglobulin genes in B-cells
SHM loads are high (2-8% relative to 1/109 elsewhere in genome)
B-cells with mutations that improve recognition of antigen are selected

128
Q

How do cancers cells evade growth suppressors?

A

Rb protein is a key regulator of cell cycle by preventing progression from G1 to S phase.
-ve GFs inhibit progression of cell cycle by activating Rb protein.

Inactivation of Rb gene is common event in tumours and results in resistance to -ve GF growth regulation (lost the gatekeeper between G1 and S phase

129
Q

How do cancers cells avoid immune destruction?

A

No longer is recognised by immune system- stops T cell bimdimg

130
Q

How do cancers cells enable replicative immortality?

A

The activate telomerase

131
Q

How do some cancer cells resist cell death?

A

BCL2- overexpressed in cancer- anti apoptotic gene

132
Q

What is a Proto-oncogene?

A

Normal genes that promote cell proliferation, survival and angiogenesis

133
Q

What is an oncogene? What are some examples?

A

•Oncogenes – mutated versions/increased expression of proto-oncogenes, causing increased/uncontrolled activity of expressed proteins

  • Examples – RAS, myc, RAF, HER2, EGFR
  • RAS family of proteins – 3 genes KRAS, NRAS, HRAS
134
Q

Do one or 2 copies of an oncogene need to be mutated to have an effect?

A

Oncogenes are dominant gain-of-function: 1 mutant copy of the gene acts dominantly to the remaining normal parental gene

135
Q

What are the mechanisms of oncogene activation? (4)

A

Translocation of an oncogene from a low to an active transcriptional site - aberrant expression of the oncogene
Point mutation - substitution of a single base within the amino acid sequence produces a hyperactive oncoprotein
Amplification by insertion of multiple copies of an oncogene – increased expression
Insertion of a promoter or enhancing gene (by retroviruses) near an oncogene – increased expression

136
Q

What are Tumour Suppressor Genes? Give some examples

A

Inhibitory genes- there are two categories
•APC- stops growth (if lose function cell can grow even without growth signals)
•P53
•RB
•BRCA1 BRCA2
•hMLH1, hMSH2- repain and scan for mistakes in genome

137
Q

What are the 2 categories of Tumour Suppressor Genes?

A
  • Antioncogenes / gatekeepers; negative regulators of the cell cycle and proliferation and positive regulators of apoptosis
  • Maintain genetic stability; caretakers
138
Q

Do one or 2 copies of an Tumour Suppressor Genes need to be mutated to have an effect?

A

•Mutation results in loss of their function- need mutation in both copies one copy does enough so need two mutations to have an effect

139
Q

What are the mechanisms of Tumour Suppressor Genes loss? (4)

A

•Carcinogens induce molecular abnormalities in TSGs that cause reduced/lack of protein expression/function:

  • Inactivating point mutations
  • Deletions
  • Translocations
  • Epigenetic silencing (shutdown of gene expression via methylation of CpG sequences in promoter regions
140
Q

TSGs and familial cancer syndromes- common cancers (5)

A

First three (retinoblastoma, li-fraumani, FAP are gatekeepers, last 2 are caretaker genes (BRAC, HNPCC)

•Inheritance of a mutant copy of a TSG or caretaker gene

•Carriers suffer from a risk of developing cancer (70-90% risk depending on the syndrome)
•
•Caretakers – maintain genetic stability. Germline mutations cause genetic instability – individuals predisposed to developing cancer

141
Q

What are the clinical applications of tumour markers?

A

Diagnosis- Identification of type and sub-type
Prognosis- Certain mutations confer worse survival
Therapy
•Predictive markers for therapeutic response
•Development of targeted drugs or gene therapies
Monitoring
•Response to treatment
•Detecting relapse

142
Q

What is the imprtance of serum markers in diagnosis and monitoring

A
  • None have sufficient sensitivity or specificity to be used for general screening
  • Can be used as an adjunct for diagnosis
  • AFP, CA125, hCG, PSA(need to do before examination as eve touching prostate = release of PSA into the bloodstream)
  • Can also be used for monitoring or just monitoring
  • CEA, thyroglobulin
143
Q

Why is testing for HER2 important?

A
  • HER2 overexpressed in 30% of breast cancers
  • Only patients with HER2 overexpression have Herceptin treatment as individuals without overactive HER2 receptors will have no beneficial effect (not driven by HER2)
144
Q

What muation is common in colorectal cancers?

A
  • Approximately 50% of colorectal cancers have a KRAS(oncogene) mutation
  • Cetuximab and Panitumumab block EGFR
  • Licenced for patients who have WT tumours
145
Q

What is Neoplasia?

A

–An autonomous proliferation of cells
–Loss of normal growth control
–Tumour: literally any swelling

146
Q

What does benign mean?

A

–No local invasion; no metastasis

147
Q

What does malignant mean?

A

–Local invasion and metastasis

148
Q

What is Hypertrophy?

A

Enlargement in individual cell size

149
Q

What is Hyperplasia?

A

Increase in number of cells

150
Q

What is Metaplasia?

A

•replacement of mature tissue types

151
Q

What is invasion?

A 
•Invades adjacent normal tissue
•Destroys normal tissue
Still a local disease
•Increased motility
•Decreased adhesion
•Production of proteolytic enzymes
•Mechanical pressure
152
Q

What is metastasis?

A

•Spreads from site of origin to distant sites and forms new tumours in these new areas
Systemic disease

153
Q

Why is there Less adhesion/more motility in invasion?

A

Epithelial – Mesenchymal Transition
•Epithelial cells are tightly connected, polarised and tethered
•Mesenchymal cells loosely connected, able to migrate
In cancer epithelial cells gain mesenchymal properties and can invade and migrate

154
Q

What proteolytic enzymes are produced in invasion

A

•Matrix Metalloproteinases

Degrade extracellular matrix > local invasion

155
Q

What Mechanical Pressure is involved in invasion?

A
  • Uncontrolled proliferation forms mass
  • Pressure occludes vessels
  • Pressure atrophy
  • Spread along lines of least resistance
156
Q

What is Metastatic Disease?

A
  • Half of all adult cancer patients
  • The majority of paediatric patients at presentation
  • The majority of lung cancer patients
  • One third of breast cancer patients
  • Essentially no patients with basal cell carcinoma
157
Q

What are routes of Metastasis?

A
  • Lymphatic - Distant or local lymph nodes
  • Blood- Liver, lungs, bone, brain etc
  • Transcoelomic- Across peritoneal, pleural, pericardial cavities or in CSF
  • Implantation- Spillage of tumour during biopsy/surgery
158
Q

What are the patterns of metastasis?

A

•Carcinomas - Lymphatic spread first
•Sarcomas - Blood spread first
•Bone mets - breast prostate lung kidney thyroid
•Transcoelomic - ovarian
•Brain and adrenal - lung
Bone metastases can be lytic (lung) or sclerotic (prostate)

  • Mechanical hypothesis- Dictated by anatomy eg, lymphatic drainage. Liver mets in GI cancer
  • Seed and Soil hypothesis- “When a plant goes to seed, its seeds are carried in all directions; but they can only live and grow if they fall on congenial soil” Stephen Paget 1889
  • Tissue environment is important – influences organ selectivity for metastases
  • Metastatic cells can remain dormant for years
159
Q

Newborn cancer diagnoses

A

Dx: metastatic congenital adrenal neuroblastoma (undifferentiated), stage IV-S
(placenta, liver, bone marrow, lymph nodes, stomach, mesenteric root, pancreas, spleen, Fallopian tube, skin)

160
Q

What is Angiogenesis?

A
  • New vessel formation (derives from existing vessels)
  • Role of bone marrow derived endothelial stem cells uncertain
  • Role in development, healing
  • Essential if metastases are to grow larger than 1-2mm
161
Q

Why do we Stage and Grade Cancer?

A

•Determine Prognosis – survival time, quality of life
•Decide how to treat the tumour
•Research – compare therapies or prognostic factors
Stage and grade are still the best markers we have for these uses

162
Q

What is the meaning of a cancer stage?

A

•Stage – How advanced is the tumour? Has the cancer spread and if so what is the extent of spread.

163
Q

What is the meaning of a cancer grade?

A

•Grade - how aggressive is the tumour? How different does it look from tissue of origin.

164
Q

Cancer progresses by Invasion and Metastasis

A

Pre-invasive - Early tumour - Locally advanced - Metastases - Death

165
Q

How are tumours staged?

A

Tumours are staged using the TMN system
T = TUMOUR
M = METASTASES
N = NODES
Each organ has an individual TMN system
Stage can be clinical, pathological or radiological
•T = Size +/- extent of primary tumour
•M = Presence and extent of distant metastases
•N = Presence and number of lymph node metastases
TMN can be combined to give an overall stage for the tumour: I to IV

166
Q

What is the staging tool used for CRC?

A

Dukes Staging for Colorectal Cancer
•A = invades into, but not through bowel wall
•B = invades through the bowel wall but with no lymph node metastases
•C = Local lymph nodes involved
•D = Distant metastases

  • A = >90% 5 year survival
  • B = 70% 5 year survival
  • C = 30% 5 year survival
  • D = 5-10% 5 year survival
167
Q

How are tumours graded?

A 
•Differentiation – how much does the tumour resemble tissue it originates from
•Nuclear pleomorphism and size
•Mitotic activity
•Necrosis
Grading performed by histopathologists
It is subjective

1. Essential Medical Science (8 decks)

Brainscape helps you reach your goals faster, through stronger study habits.
© 2024 Bold Learning Solutions. Terms and Conditions