Flashcards in Tumour Pathology Deck (36)
Describe the main differences between benign and malignant tumours
Both differ in various ways:
• Growth pattern
• Presence of capsule
• Presence of metastases
• Appearance of tumour cells
Describe the properties of benign cancer cells
• Non-invasive growth pattern
• Usually encapsulated
• No evidence of invasion
• No metastases
• Cells similar to normal in function and appearance
• Benign tumours are “well-differentiated”
• Rarely cause death
Describe the systemic effects of cancer
• Secretion of hormones
• Weight loss-cachexia – unwanted, though can also be due to obstruction etc.
• Paraneoplastic syndromes
• Effects of treatment
Describe the local effects of cancer
Tissue destruction during invasion
Bleeding due to damage of vessels during invasion
Pain due to pressure on nerves
Effects of treatments e.g. IV infusion reactions
Identify the concepts of neoplasia and intraepithelial dysplasia
Dysplastic = abnormal growth or development of existing tissue.
Neoplastic = relates to a new growth or tumor.
Describe the cell cycle of normal cells
• Mechanism of cellular replication
• Nuclear division plus cytokinesis
• Generates two identical diploid daughter cells
Cell Cycle = time interval between mitotic divisions. Called interphase where the chromosomes and cellular contents are duplicated.
Outline the process of carcinogenesis and describe its effects on the cell cycle.
• Cancer is a genetic disease
• Carcinogenesis is caused by mutation of genetic material that upsets the normal balance between proliferation and apoptosis (cell death)
• Uncontrolled proliferation of cells leads to tumours
• Only mutations in genes regulating cell division, apoptosis, and DNA repair cause a cell to lose control of proliferation via cell cycle dysregulation
List the major aetiological agents of cancer.
• Non-lethal genetic damage - Environmental agents e.g. Chemicals, Radiation, Oncogenic viruses
• Geographic and environmental factors
Describe the properties of a cancer cell
• Altered genetics
– Loss of tumour suppressor genes
– Gain of function of oncogenes
• Altered cellular function
– Tumour-related proteins
• Abnormal morphology
• Cells capable of independent growth
• But no single feature is unique to cancer cells
What is the clinical significance of cancer biomarkers?
• Prognostic- Identifying patients specific outcome
• Predictive - who will respond to a particular therapy
Give some examples of cancer biomarkers
• Teratoma of testis
• Hepatocellular carcinoma
Carcino-embryonic antigen (CEA)
• Colorectal cancer
• Breast cancer
Prostate specific antigen
• Prostate cancer
Describe some clinically useful predictive biomarkers
– Colorectal cancer
EGFR (epidermal growth factor receptor)
– Lung cancer
Her2 (neu in rodents, EGFR associated with aggressive breast cancers)
– Breast cancer
– Gastric cancer
Braf (protooncogene that helps direct cell growth)
How can we identify cancer cells by appearance alone?
• Cellular and nuclear pleomorphism
– Marked variation in size and shape
• Mitoses (dividing cells) present and often abnormal
What usually worsens the prognosis of cancer?
High degree of angiogenesis, invasion and cancer spread
Describe the different modes of cancer spread
• Local spread
• Lymphatic spread
• Blood spread
• Trans-coelomic spread
Describe some common sites of metastases
• Bone - Axial skeleton e.g. vertebrae, pelvis
• Adrenal gland
Where do breast cancers commonly metastasise?
Where do prostate cancers commonly metastasise?
Where do colorectal cancers commonly metastasise?
Describe two hormones that are abnormally produced in certain cancers
ACTH - lung cancer
ADH - lung cancer
Define paraneoplastic syndromes
Syndromes or symptoms that cannot be explained by local or metastatic effects of tumours, caused by humoral factors e.g. neuropathy, myopathy. Thought they may be caused due to immune or hormonal factors
Describe the importance of cyclins, cycling dependent kinases and cyclin dependent kinase inhibitors in cancer
Many genes mutated in cancer regulate the cell cycle
Two regulatory pathways frequently disrupted -
1. The cyclin D-pRb-E2F pathway
2. p53 pathway
Active CDK/cyclin complexes phosphorylate target proteins which results in activation/inactivation of that substrate, which regulate events in the next cycle phase.
pRb is hypophosphorylated, and is phosphorylated by CDK/cyclin complexes as cells progress through the cell cycle. Hypophosphorylated/active Rb inactivates E2F, while phosphorylated/inactive pRb loses affinity for E2F. Free E2F transcription factor activates vital target genes and is a potent stimulator of cell cycle entry. If this system is not regulated, uncontrolled progression through the cell cycle occurs.
Where in the cell cycle are cancer cells usually dysregulated and why?
Virtually all cancers are dysregulated at G1-S because of mutation in one of four genes:
o Rb, CDK4, cyclin D and p16
What is p53, its function and its role in cancer development?
•p53 is a gene that codes for a protein that regulates the cell cycle and hence functions as a tumor suppressor gene. Maintains genomic integrity
• p53 levels increase in damaged cells and induces cell cycle arrest at G1 to allow DNA repair
• Severe damage: p53-induced apoptosis (programmed cell death)
• Cells with mutated p53 do not G1 arrest or repair damaged DNA and these genetically damaged cells proliferate and form malignant neoplasms
Define tumour suppressor genes
Normal growth-inhibiting genes that discourage cell growth or temporarily halt cell division to carry out DNA repair. Huge role in carcinogenesis
• Genes negatively regulating mitosis - Rb
• Genes regulating apoptosis
• Genes regulating DNA repair
Normal genes that promote normal cell growth and mitosis
Describe the two hit hypothesis
The Knudson hypothesis, also known as the two-hit hypothesis or multiple-hit hypothesis, is the hypothesis that cancer is the result of accumulated mutations to a cell's DNA
What % of cancers are inherited?
Whats the difference between inherited cancer and familial cancer?
Inherited cancer syndromes
• Strong family history of uncommon site-specific cancers
• Autosomal dominant inheritance of a single mutant gene
– Increased risk of second cancers eg bone sarcomas
• Family clustering of cancers but individual predisposition unclear
• Multifactorial inheritance
• Early age of onset
• Multiple/bilateral tumours
Name some inherited cancer syndromes
Familial adenomatous polyposis
Multiple endocrine neoplasia
Von Hippel-Lindau syndrome
Name some familial cancers
• Some Breast cancers
• Some Ovarian cancers
• Non-FAP colon cancers
How do oncogenes arise from protooncogenes?
Oncogenes are derived from proto-oncogenes, which are activated by:
o Alteration of proto-oncogene structure
• Point mutation
• Chromosome rearrangements + translocations
o Dysregulation of proto-oncogene expression
• Gene amplification
Name some cancers caused by the over expression of some proto-oncogenes
Burkitt lymphome - over expressed c-myc in IgH gene
Mantle cell lymphoma - over expressed cyclin D1 in IgH gene
Name some cancers caused by recombination of proto-oncogenes to form chimaeric proteins
Chronic myeloid leukaemia
Describe how aetiological factors of cancer disrupt the cell cycle
Viruses - insert genomes near protozoans-oncogenes and viral promoter causes over expression or they can insert oncogenes into genome
Chemical - Adduct formation at particular chromosome sites lead to activation of oncogenes and suppression of anti-oncogenes e.g. benzopyrene