Neoplasia

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Neoplasia Cell Death

• Revision

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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

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Cell Change - Atrophy

• Decrease in cell size
• development (thymus)
• disuse (skeletal muscle)

http//commons.wikimedia.org/wiki/FileNon-neoplas
tic_changes.svg
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Cell Change - Hypertrophy

• Increase in cell size intracellular protein
• physiological (exercise)
• pathophysiological (hypertension)

http//commons.wikimedia.org/wiki/FileNon-neoplas
tic_changes.svg
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Cell Change - Hyperplasia

• Increase in number of cells
• compensatory (bone marrow)
• hormonal (uterus)
• pathophysiological (endometriosis)

http//commons.wikimedia.org/wiki/FileNon-neoplas
tic_changes.svg
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Cell Change - Metaplasia

• Replacement of one well differentiated cell type
  by another
• response to irritants (smoking)

http//commons.wikimedia.org/wiki/FileNon-neoplas
tic_changes.svg
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Cell Change - Dysplasia

• Abnormal changes in cellular shape, size or
  organisation
• atypical hyperplasia (pre-cancerous)

http//commons.wikimedia.org/wiki/FileNon-neoplas
tic_changes.svg
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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 (ATP-dependent)

• Long-term
• Generally no consequences part of cell cycle
• Example embryological development

http//quizlet.com/13850708/cell-injury-adaptation
-and-death-flash-cards/
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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-cards/
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Define Neoplasia
A lesion resulting from new and abnormal tissue
growth which persists independent of its
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

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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

• Resemble cell of origin
• rarely necrotic
• rarely ulcerate

• Longterm
• pressure on adjacent tissues
• obstruction of ducts/ hollow organs
• produce hormones
• can be pre-malignant (causes anxiety)

http//medical-dictionary.thefreedictionary.com/tu
mor
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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-dictionary.thefreedictionary.com/tu
mor
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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
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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/nr
c2154_F1.html
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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

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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

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Neoplasia and Cell Death

• Phase 2a
• Lucy Faulkner Phase 3a

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Aims

• 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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22
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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23
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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32
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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33
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 syndromesCushings,
  SIADH, Carcinoid syndrome, Lambert-Eaton
  myasthenic syndrome, hypoglycaemia

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Questions

• Name the hormone/substance produced which causes
  the following paraneoplastic syndromes
• Cushings, SIADH, Carcinoid syndrome,
  Lambert-Eaton myasthenic syndrome, hypoglycaemia
• 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
  substance7 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

• lgfaulkner1_at_Sheffield.ac.uk

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Thank you

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