Neoplasia and Oncology Basics

Neoplasia Basics

• Neoplasia refers to the abnormal, uncontrolled growth of cells that leads to tumor formation.
• A neoplasm is an abnormal mass or colony of cells due to autonomous new tissue growth.
• Neoplasia describes the cellular process in the body, while neoplasm describes the mass created.
• Neoplasms may be benign (non-cancerous) or malignant (cancerous).
• "Cancer" refers to malignant neoplasms in which abnormal cell division and spread invades and destroys normal tissues.
• Spread of malignant neoplasms can be rapid.

Cancer & Oncology

• Oncology involves the study of neoplasms, including their causes and progression.
• Oncologists sometimes deal with benign neoplasms if they have the potential to become cancerous.
• Deaths from cancer in the UK were 167,142 between 2017-2019.
• Almost half of all UK cancer deaths in 2018 were from lung, bowel, breast, or prostate cancer.
• Cancer caused over 24% of all UK deaths in 2020.
• Cancer is caused by damage to genes, which can be inherited or acquired.

History of Cancer Genetics, Research and Epidemiology

• 1800s: Early observations of cell differentiation were made.
• Early 1900s: Eugenics and environmental factors were noted.
• 1950-1960s: Carcinogenic research and awareness increased.
• 1970s: The molecular revolution in cancer research occurred.
• 1980s: Advancement in oncogenes and tumor suppressors was made.
• 1990s: The genomic era began.
• 2000s-Present: Genomics, personalized medicine, and immunotherapy are used.

Terminology Review

• Important pathological terminology: Aplasia, hypoplasia, atrophy, hypertrophy, hyperplasia, metaplasia, dysplasia, and neoplasia.

Neoplasm & Tumor

• New cells often form a mass of new tissue, also called a tumor (swelling).
• Abnormal cells may arise from precursor cells in the bone marrow and enter the bloodstream, as in leukemia.
• A tumor is a swelling of any type, but now generally denotes a neoplasm.
• Histogenesis is the method used for classifying neoplasms.
• The suffix "-oma" indicates a tumor and often a benign neoplasm.
• Suffix examples: Fibroma, lipoma
• "-oma" can imply a malignant neoplasm.
• Malignant examples: Melanoma, hepatoma, and seminoma
• "-oma" can also imply a non-neoplastic lesion.
• Non-neoplastic examples: Haematoma or granuloma

Neoplastic Cells

• Most neoplasms arise from the clonal expansion of a single cell.
• Clone expansion happens due to chemical, physical or biological agents that alter the cell genome.
• Neoplastic cells lose specialized functions and gain autonomous growth.
• Neoplastic cells pass on heritable biological characteristics to progeny cells.

Cellular Basis of Neoplasms

• Neoplasms comes from a single target cell which experiences genetic mutations.
• Mutation changes the genetic make-up (genotype) of a cell.
• Heritable mutations occur in cells that form gametes, are transmitted to offspring, and are present in every cell.
• Somatic mutations are not inherited they cause genetic differences between cells of the same organism and can contribute to cancer risk.

Mutation

• Mutation may occur spontaneously or be induced by environmental factors and exposure to chemicals/radiation.
• Most mutations impair cell survival and result in cell death, but some mutations give the cell a growth advantage.
• Oncogenes are mutations of genes that stimulate cell division.
• Tumour suppressor genes are mutations of genes that inhibit cell division.

Defining a Neoplasm

• Distinguishing benign from malignant neoplasia is important for diagnosis, treatment, and prognosis.
• A malignant neoplasm autonomy, is capable of invasion and metastatic spread, and may be resistant to treatment.
• Malignant neoplasm may cause death.
• A benign neoplasm has a lesser autonomy, is not invasive, does not metastasize, and can have great harm if not treated.

Benign Neoplasm vs. Malignant Neoplasm

• Benign Neoplasm: slow growth, expansive mass, may cease growing, few mitoses, well-differentiated, resemble normal cells, regular surface structure, often encapsulated, localized, does not invade or metastasize.
• Malignant Neoplasm: rapid growth, invasive mass, rarely ceases growing, relatively common, poorly differentiated, does not resemble normal cells, irregular surface structure, non-encapsulated, infiltrates, invades and destroys surrounding tissue, metastasizes.

Cellular Proliferation

• Hyperplasia is an increase in cell number per unit of tissue, initiated/regulated by hormones, can be useful to the host.
• Metaplasia is a change from one type of adult cell to another, usually in response to an abnormal stimulus, and can be reversible.
• Dysplasia is an abnormal atypical cellular proliferation, usually reversible with an atypical structure/shape, is not a tumor but may be a precursor.
• Metastasis is establishment and growth of a second tumor in a different site from the primary tumor, without direct contact between the tumors.

Malignant Metastatic Spread

• Direct spread may occur via interstitial, lymphatic, venous/capillary, coelomic (across a body cavity), CSF, or epithelial spread.

Environmental Aetiology

• Radiation: X-rays, solar (UV)
• Chemicals: Vaping, aniline dye, tobacco smoke, asbestos.
• Hormones: Oestrogen.
• Environmental factors: Genetic.
• Biological: Epstein-Barr, HPV

Further Aetiology

• Infectious agents
• Hormonal factors
• Genetic factors
• Chemicals
• Radiation

Infectious Agents - Biological

• Human T-cell leukemia viruses (HTLV) types 1 and 2 are associated with human leukemia.
• Human immunodeficiency virus (HIV) increases risk of infections from tumor-related viruses like Kaposi's sarcoma and other herpes viruses.

Infectious Agents

• Kaposi's sarcoma is caused by HHV (Human herpes virus) type 8 or KSHV (Kaposi sarcoma-associated herpes virus).

Infectious Agents-Papillomaviruses

• Papillomaviruses cause wart infections.
• Sexually transmitted human papilloma viruses (HPV) are associated with cervical cancer.
• HPV types 16 and 18 leads to precursor lesions and invasive cervical squamous cell carcinoma (SCC).
• Viral DNA is integrated into cancer cells but require factors for the progression to invasive SCC.

Infectious Agents-Hepatitis

• Hepatitis B & C viruses are also linked to cancer.
• Hepatitis B virus (HBV) causes primary hepatocellular carcinoma (common cancer in Asia).
• Viral DNA integrates into cancer cells.
• Hepatitis C virus (HCV) is involved in hepatic carcinogenesis.

Infectious Agents-Epstein-Barr virus

• Epstein-Barr Virus is a type of herpes virus.
• Epstein-Barr Virus causes infectious mononucleosis and Burkitt's lymphoma, (solid tumor of B-lymphocytes).
• The virius s associated with nasopharyngeal carcinoma where, viral DNA and various EBV-determined antigens are detectable in the tumor cells.

Infectious Agents : Helicobacter pylori

• Helicobacter pylori is a common bacterial pathogen that causes gastric ulcers.
• Helicobacter pylori can cause gastric cancer and lymphoma.
• Helicobacter pylori should be treated even though if most people will not develop cancer.

Hormonal Factors

• Hormones and growth factors control cell proliferation, differentiation, and apoptosis, playing key roles in tumor promotion and growth.
• Alterations in sex steroid metabolism may increase risk of cancers of the breast, endometrium, ovary, and prostate.
• Precise relationships of cancer risk are inconclusive.

Hormonal Factors - Menopause

• Late menopause increases cancer the risk of breast cancers.
• Breasts contain fat cells which produce aromatase (oestrogen).
• Fat cells produce more aromatase during aging, increasing local oestrogen levels (trigger breast cancer in older women)
• The tumour further increases oestrogen levels.
• Immune cells that gather in the tumour site boost oestrogen production.

Hormonal Factors – Breast Cancer

• Medications like tamoxifen block oestrogen action and prevent breast cancer cell stimulation.
• HRT eases menopause symptoms by boosting sex hormone levels, reducing osteoporosis/heart disease risk.
• Prolonged HRT (>5 years) increases breast cancer risk by 30%.
• Shorter HRT exposure (e.g. 2 years) has same breast cancer risk as women who haven't used HRT.
• The health benefits of HRT ought to be weighed against the dangers to justify the treatment.

Genetic Factors

• Retinoblastoma is an inherited malignancy.
• Retinoblastoma is a tumor of the retina inherited as an autosomal dominant disorder.
• This involves an inherited mutation in retinoblastoma gene.
• Retinoblastoma allows uncontrolled growth of the retinal cells.

Genetic Factors - BRCA 1 and 2

• Breast cancer can be genetic.
• Inheritance of mutation in BRCA-1 or 2 gene increases breast cancer development.
• Mutation is 5x likelier
• BRCA genes repair radiation-induced breaks in double-stranded DNA.
• Mutations in BRCA1 or BRCA2 disable repair, leading to errors in DNA replication and cancerous growth.
• It is currently impossible to "repair" BRCA mutation.

Genetic Factors - BRCA 1 and 2 Aetiology

• BRCA1 gene mutates on chromosome 17
• DNA repair mechanism is impaired
• Errors occur in DNA replication, resulting in the development of cancer

Genetic Factors – Molecular Basis

• Some genes can cause cancer in response to stimuli, e.g. oncogenes.
• Oncogenesis converts normal cells into cancer cells.
• Proto-oncogenes promote the normal growth and division of cells.
• Oncogenes are mutated forms of proto-oncogenes and excessive cell multiplication.
• There are approximately 100 known oncogenes.

Genetic Factors - Oncogenes and Proto-oncogenes

• Mutation of proto-oncogenes into oncogenes cause changes in cells.
• The cell changes can include overproduction of growth factors.
• Flooding of the cell with replication signals.
• Uncontrolled stimulation in the intermediary pathways.
• Unrestrained cell growth is also possible.
• this occurs from elevated levels of transcription factors.

Genetic Factors

• The activation of a proto-oncogene can occur by point mutation.
• Point mutation Occurs from changes in the base sequence is changed within a codon.
• A triplet of three nucleotides encodes genetic information within a codon.
• Activation can also occur with Chromosome rearrangement.
• Another cause is Gene amplification resulting in increased copies of a proto-oncogene within a cell.
• Viral insertion is another factor. This results in the control of a proto-oncogene by a active promoter

Role of Growth Factors

• Polypeptides are produced and secreted by cells locally.
• GFs can stimulate cell proliferation, receptors can bind to cell-surface or neighbouring cells
• Uncontrolled auto stimulation may result to the creation of a neoplastic state.
• Ras-encoded proteins function as post-receptor signal transducers for growth stimulation.
• Ras proteins mediate passage of growth signals and in cell nucleus (initiate cell cycle and DNA synthesis)
• Mutations in Ras proteins causes in a continuous growth signal, which is approximately 30% of human cancers.

Genetic Factors - Oncogenes

• The Ras gene (present in normal cells) is responsible for cell growth
• Receptors on the cell surface can respond to a stimulus by activating Ras
• Transformed Ras activation is permanent despite a stimulus being present.
• The altered gene (now called an ONCOGENE) causes hyperactive cell proliferation.

Genetic Factors – P53

• The p53 gene is a transcription factor stimulates expression of several other genes, including a key promoter of apoptosis.
• The p53 gene exists on chromosome 17 and suppress tumour growth.
• Abnormalities in this gene have been detected in many common cancers including colon, breast and lung.

Oncogenes and Cancer

• MYC: Solid tumors and hematologic malignancies
• N-MYC: Neuroblastoma and lung cancers
• L-MYC: Small cell lung cancer
• RAS: Solid tumors
• P53: Sporadic malignancies, Li-Fraumeni familial cancer syndrome
• BRCA1: Breast cancer, ovarian cancer, prostate cancer
• BRCA2: Breast and ovarian cancer
• APC: Colon familial polyposis
• MSH, MLH: Mismatch repair genes associated with hereditary nonpolyposis colon cancer (HNPCC)
• DCC: Colon cancer
• RB: Retinoblastoma and some other tumors
• NF1, NF2: Neurofibroma
• C-ERB-B2: Breast cancer, other tumors
• ABL: Chronic myeloid leukemia
• WT1: Wilms' tumor ATM: Ataxia telangiectasia associated with multiple cancers
• MEN: Multiple endocrine neoplasia syndrome
• HPC1: Prostate cancer
• VHL: Renal and some other cancers
• PTCH: Basal cell cancers (Gorlin syndrome), Melanoma
• BCL-2: Non-Hodgkin's lymphoma

Chemical Factors

• Chemicals and carcinogenic factors, smoking, Aflatoxins are linked
• Aflatoxins are fungal toxins from mold that contaminate cereal and groundnut crops
• Alkylating agents such as mustard gas - cause lung cancer in factory workers who made mustard gas
• Chemical dyes causes lung cancer, for example aniline dye - is an oily poisonous liquid amine used in the rubber and cable industry

Chemical Factors Include Polycyclic Aromatic Hydrocarbons Like:

• Benzanthracene (first pure carcinogen)
• 3,4-benzpyrene (isolated from coal tar)
• 3-methylcholanthrene steroid
• 7,12-dimethylbenzanthracene (most potent carcinogen)
• Also, nitrosamine, some insecticides, some metals (chromium and nickel), and carbon tetrachloride.

Occupational Cancers And Latency

• Occupational cancers exposure to the carcinogen which doesn't cause immediate symptoms due to latency.
• During this time, cells exist and may not manifest into a neoplasm.
• Asbestos exposure has a latency of 25–35 years before causing bronchogenic carcinoma.

Radiation

• Ionising radiation is a specific intensity that ionises the organisms cells.
• Radiation can cause heritable mutations via DNA damage
• Exposure to radiation may cause sickness in hours or days and death within 60 days of exposure.
• Extreme cases causes death within a few hours of exposure.

Radiation – Low Dose (Non Ionising)

• There are unknown genetic and environmental factors involved in radiation.
• Non-Ionising radiations don't have the energy to cause ionisation in tissue, but may cause other adverse effects.
• Non-ionising example: Ultraviolet (UV) radiation

Radiation – Sources

• Sources include alpha, beta particles, gamma rays, and x rays.
• Can come from natural origin or are technologically produced.

Radiation – Sources and Therapies

• At high doses radiation is used to treat cancer, normal x-ray omit high doses.
• High doses of radiation can kill cells or prevent them from dividing (treatments)
• Radiation will affect some normal cells though the treatment is limited to a specific area to affect tissue

Recap and Overview: Tumours

• Benign tumors: Usually slow rate of growth and capsule ensures demarcation.
• Malignant tumors: Imbalanced cell death by apoptosis and expansive growth.

Tumour Considerations

• Complications for a benign neoplasm causes, pressure, obstruction, ulceration, haemorrhage and malignant changes
• Complications for a benign neoplasm causes, Infarction, Infection and Rupture

Management of Neoplasms

• Benign neoplasm is monitored and may have surgery.
• Malignant neoplasms are managed with curative or palliative methods.
• Methods involved are: surgery, radiotherapy, chemotherapy or hormonal manipulation.

Post Lecture Consolodation

• Post-lecture consolidation: Review and recap lecture, consider key terminology.
• Attempt the MCQ quiz and test your knowledge.