Transcript Neoplasia and cell death peer teaching slides

Neoplasia & Cell Death
Revision
Objectives
• Terminology of Cell change
• Apoptosis vs Necrosis
• Neoplasia
– Benign
– Malignant
• Tumour classification
• Intraepithelial neoplasia
• Tumour grading & staging
• Tumour invasion & metastasis
• Tumour pathogenesis
– Oncogenes
– Tumour suppressor genes
• Cellular mutation
– Germline
– Somatic
• Population-based screening
• Adenocarcinoma sequence
• Clinical complications of
tumours
• Personalised cancer
management
Cell Change - Atrophy
Decrease in cell size
• development (thymus)
• disuse (skeletal muscle)
http://commons.wikimedia.org/wiki/File:Non-
Cell Change - Hypertrophy
Increase in cell size [intracellular
protein]
• physiological (exercise)
• pathophysiological (hypertension)
http://commons.wikimedia.org/wiki/File:Non-
Cell Change - Hyperplasia
Increase in number of cells
• compensatory (bone marrow)
• hormonal (uterus)
• pathophysiological (endometriosis)
http://commons.wikimedia.org/wiki/File:Non-
Cell Change - Metaplasia
Replacement of one well
differentiated cell type by another
• response to irritants (smoking)
http://commons.wikimedia.org/wiki/File:Non-
Cell Change - Dysplasia
Abnormal changes in cellular
shape, size or organisation
• atypical hyperplasia (precancerous)
http://commons.wikimedia.org/wiki/File:Non-
Apoptosis
Programmed death of individual cells
• Usually physiological stimuli (development)
• Controlled process mediated by cellular
signals
Associated with
• No inflammation or secondary tissue
damage
• Integrity of cellular structures retained
• Cell death pathway activated (ATPdependent)
Long-term
• Generally no consequences – part of cell
cycle
• Example – embryological development
http://quizlet.com/13850708/cell-injury-adaptation-and-death-flash-
Necrosis
Premature destruction of cell groups
• Pathophysiological stimuli (injury/disease)
• Process mediated by extracellular factors
Associated with
• Inflammation + secondary tissue damage
• Swelling & disintegration of cellular
structures
• Abnormal pathway (non-ATP dependent)
Longterm
•Inflammation and decreasing blood supply
result in tissue death (gangrene) → death
• Example – cerebral/ myocardial infarction
http://quizlet.com/13850708/cell-injury-adaptation-and-death-flash-
Define Neoplasia
‘A lesion resulting from new and abnormal tissue
growth which persists independent of it’s initiating
stimulus’
• Lesion due to
– Tissue growth: new + abnormal + autonomous
– Persists after initiating stimulus has been removed
Caused by carcinogens
• chemicals
• viruses
• radiation
• hormones
• bacteria, fungi &
parasites
Types of Neoplasia - Benign
Slow-growing
• have a low mitotic rate of division
Often well circumscribed
• no invasion of surrounding lymph/tissue
• no metastasis to other areas
Longterm
• pressure on adjacent tissues
• obstruction of ducts/ hollow
organs
• produce hormones
• can be pre-malignant (causes
anxiety)
Resemble cell of origin
• rarely necrotic
• rarely ulcerate
http://medical-
Types of Neoplasia - Malignant
Fast-growing
• have a high mitotic rate of division
Poorly defined, irregular, infiltrative borders
• invasion of surrounding lymph/tissue
• can metastasise to other areas
Variable resemblance to cell of origin
• commonly necrotic
• commonly ulcerate
http://medical-
Tumour Classification
•
Based on ‘behaviour’ of the tumour e.g. Benign or malignant presentation
OR
•
Based on histogenetic origin
– Degree of histological resemblance between cell of origin & tumour cell
– Allows for tumour grading
CELL OF ORIGIN
BENIGN
MALIGNANT
Epithelial
Papilloma or Adenoma
Carcinoma
Connective tissue
-oma
Sarcoma
Lymphoid
-
Lymphoma
Haemopoietic
-
Leukaemia
Intraepithelial Neoplasia
•
Potentially premalignant dysplasia
– Abnormal growth and transformation of cells
– Confined to the epithelium (in situ)
– May superficially penetrate accessory organ structures
http://www.nature.com/nrc/journal/v7/n7/fig_tab/nrc2154_F1.ht
Tumour Grading & Staging
• Utilised for malignant tumours only – have generally good prognostic value
• Staging
– Histopathological & clinical tumour assessment
– Measures level of tumour spread throughout body
– Example: TNM (Tumour, Node, Metastasis) staging
• Grading
– Histopathological tumour assessment
– Measures degree of histological differentiation
– Example: Gleason grading for prostate cancer
Objectives
• Terminology of Cell change
• Apoptosis vs Necrosis
• Neoplasia
– Benign
– Malignant
• Tumour classification
• Intraepithelial neoplasia
• Tumour grading & staging
• Tumour invasion & metastasis
• Tumour pathogenesis
– Oncogenes
– Tumour suppressor genes
• Cellular mutation
– Germline
– Somatic
• Population-based screening
• Adenocarcinoma sequence
• Clinical complications of
tumours
• Personalised cancer
management
Phase 2a
Lucy Faulkner Phase 3a
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Aims
•
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Oncogenes and tumour suppressor genes
Germ line and somatic mutations
Population based screening
Adenoma-carcinoma sequence in the colorectum
Complications of tumours
The future of personalized medicine
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Onco- and tumour suppressor
genes
• A proto-oncogene is a normal gene that can
become an oncogene due to mutations or
increased expression.
• An oncogene is a genes that drives the
neoplastic behavior of cells
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Onco- and tumour suppressor
genes
• A tumour suppressor gene is a gene which
inhibits the transformation of a cell into a
neoplastic state
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Onco- and tumour suppressor genes
• Mutations in proto-oncogenes and tumour
suppressor genes leads to neoplasia
• Mutations in proto-oncogenes leads to
excessive cell division or prevent apoptosis
from occurring
• Mutation in tumour suppressor genes
prevents DNA repair leading to mutations,
leads to excessive cellular proliferation or
prevents apoptosis from occurring
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Germline and somatic mutations
• Germline mutation: A mutation occurring in
gametes.
• They are passed on to offspring and are
present every cell in the offspring.
• Somatic mutation: acquired mutations
occurring in any of the cells of the body except
the germ cells.
• They cannot be passed on to offspring.
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Population based screening
• Screening: checking apparently
healthy people with no symptoms to
identify those who may be at
increased risk of a disease or
condition
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Population based screening
Why screen for cancer?
• Early detection gives a better prognosis
• Tumours are found at a curable stage and
before they have metastasized
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Population based screening
Problems with screening
• Lead time bias
• Early abnormalities detected by screening may
not have progressed to malignant neoplasms
• Some people are reluctant to be screened
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Population based screening
• Cancer screening tests in the UK: breast
cancer, cervical cancer, bowel cancer
screening
• Screening also offered to those at high risk
(BRCA1, BRCA2, FAP)
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Adenoma-carcinoma sequence
• Stepwise progression from benign to
malignant neoplasms due to an accumulation
of mutations
• The mutations occurring in this sequence are
well defined in colorectal cancer
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Adenoma-carcinoma sequence
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Adenoma-carcinoma sequence
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Complication of tumours
• Why do cancers cause a problem?
• Local effects
• Metastases
• Paraneoplastic/metabolic effects
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Complication of tumours
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Personalized medicine
• Cancer treatments targeted to the genetics of
a patients cancer
• May enable more effective treatments of
cancer in the future
• Examples: Trastuzumab, Imatinib
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Questions
• Give some examples of a tumour suppressor
gene?
• P53, RB1, APC, BRCA1, BRCA2, MSH2, MLH1
• Give some examples of inherited cancer
syndromes
• Multiple endocrine neoplasia syndrome (MENS),
Xeroderma pigmentosum, familial polyposis coli,
von Hippel-Lindau syndrome, Li-Fraumeni
syndrome, retinoblastoma, familial breast cancer
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Questions
• Name the hormone/substance produced
which causes the following paraneoplastic
syndromes:
Cushing’s, SIADH, Carcinoid syndrome,
Lambert-Eaton myasthenic syndrome,
hypoglycaemia
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Questions
• Name the hormone/substance produced which causes
the following paraneoplastic syndromes:
• Cushing’s, SIADH, Carcinoid syndrome, Lambert-Eaton
myasthenic syndrome, hypoglycaemia
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Cushings: ACTH and ACTH-like substance
SIADH: ADH
Carcinoid syndrome: serotonin
Lambert-Eaton myasthenic syndrome: antibodies against
presynaptic voltage-gated calcium channels
• Hypoglycaemia: Insulin or insulin-like substance[7] or "big" IGF-II
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Questions
• A patient has previously been diagnosed with a
squamous cell lung cancer. They come to you
complaining of polydipsia, polyuria, constipation and
muscle weakness. On questioning they admit to
being depressed recently
– Which paraneoplastic syndrome are they likely to
have developed?
– What substance produced by the tumour causes this
effect?
– What change would you see on ECG if this is not
corrected?
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Questions
– What paraneoplastic syndrome are they likely to
have developed?
– Hypercalcaemia of malignancy
– Which substance produced by the tumour causes
this effect?
– Parathyroid hormone like peptide
– What change would you see on ECG?
– Short QT interval
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References/ useful resources
• General and Systematic Pathology
• NHS cancer screening website:
http://www.cancerscreening.nhs.uk/index.html
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Questions
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Questions
[email protected]
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Thank you
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