Neoplasia & Cell Death Revision. Objectives Terminology of Cell change Apoptosis vs Necrosis...

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

http://commons.wikimedia.org/wiki/File:Non-neoplastic_changes.svg

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

Cell Change - Hypertrophy


Increase in cell size [intracellular protein]

• physiological (exercise)• pathophysiological (hypertension)

Cell Change - Hyperplasia


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

Cell Change - Metaplasia


Replacement of one well differentiated cell type by another

• response to irritants (smoking)

Cell Change - Dysplasia


Abnormal changes in cellular shape, size or organisation

• atypical hyperplasia (pre-cancerous)

ApoptosisProgrammed 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/

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/

Define Neoplasia

• Lesion due to– Tissue growth: new + abnormal + autonomous– Persists after initiating stimulus has been removed

‘A lesion resulting from new and abnormal tissue growth which persists independent of it’s initiating stimulus’

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

Resemble cell of origin• rarely necrotic• rarely ulcerate

http://medical-dictionary.thefreedictionary.com/tumor

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

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/tumor

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.html

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

The Peer Teaching Society is not liable for false or misleading information…

• 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


Aims

• 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


Onco- and tumour suppressor genes

• A tumour suppressor gene is a gene which inhibits the transformation of a cell into a neoplastic state



• 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



• 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.The Peer Teaching Society is not liable for false or misleading information…

Germline and somatic mutations

• Screening: checking apparently healthy people with no symptoms to identify those who may be at increased risk of a disease or condition


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



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



• Cancer screening tests in the UK: breast cancer, cervical cancer, bowel cancer screening

• Screening also offered to those at high risk (BRCA1, BRCA2, FAP)




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


Adenoma-carcinoma sequence

Normal Mjepithelium Mj

Small Mjadenoma Mj

Large Mjadenoma Mj

Invasive Mjadenocarcinoma Mj Metastases Mj

APC mutation MjMCC Mj mutation Mj

5q deletion Mjc-myc Mj Mj

activation Mj' Mjsusceptibilty Mj Mjgene' 8q24 Mj k-ras Mj mutation Mj

Chromosome Mj17q, 18q Mjdeletion Mj

Tp53 mutation Mj nm23 mutation Mj


Adenoma-carcinoma sequence

• Why do cancers cause a problem?• Local effects • Metastases• Paraneoplastic/metabolic effects


Complication of tumours


Complication of tumours

Complications Mjof tumours Mj

Local effects MjMetabolic effects Mj

Metastases Mj

Local invasion Mj

Ulceration Mj

Destruction of adjacent structures Mj

Compression MjTumour specific Mj

Non-specific Mj

Gastointestinal Mj blood loss MjAnaemia Mj

Airway obstruction Mj

Bowel obstruction Mj

Cachexia Mj

Dysphagia Mj

Lethargy Mj

Malaise Mj

Finger clubbing Mj

Tumour produces a hormone Mj

Hypertrophic Mjosteoarthropathy Mj

Thyrotoxicosis Mj

Cushing's Mj

Hyperparathyroidism Mj

Infection Mj

Hypercalcaemia Mj of malignancy Mj

SIADH Mj

Lambert-Eaton Mjmyasthenic Mj syndrome Mj

Carcinoid Mj syndrome Mj

Haematongenous Mj spread Mj

Lymphatic spread Mj

Transcoelomic Mj spread Mj

Implantation Mj

Complications Mjof tumours Mj

• Cancer treatments targeted to the genetics of a patients cancer

• May enable more effective treatments of cancer in the future

• Examples: Trastuzumab, Imatinib


Personalized medicine

• 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


Questions

• Name the hormone/substance produced which causes the following paraneoplastic syndromes:Cushing’s, SIADH, Carcinoid syndrome, Lambert-Eaton myasthenic syndrome, hypoglycaemia


Questions

• Name the hormone/substance produced which causes the following paraneoplastic syndromes:

• Cushing’s, 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 substance[7] or "big" IGF-II


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?The Peer Teaching Society is not liable for false or misleading information…

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


Questions

• General and Systematic Pathology


References/ useful resources

• NHS cancer screening website: http://www.cancerscreening.nhs.uk/index.html

http://www.cancerscreening.nhs.uk/index.html


Questions


Questions

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Thank you

Neoplasia & Cell Death Revision. Objectives Terminology of Cell change Apoptosis vs Necrosis...

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