Neoplasia – Comprehensive Exam Notes

Introduction to Neoplasia

• Definition: Neoplasia literally means “new growth” (Greek: neos = new, plasia = growth).

  • Growth of tissue/cell proliferation without physiological purpose.

  • Forms an abnormal mass of tissue whose excessive, uncoordinated growth persists even after the original growth-stimulus has ceased.

• Normal controls on proliferation (lost in neoplasia):

  • Intrinsic genetic program of each cell.

  • Extrinsic signals (hormones, growth factors) that initiate or halt division.

  • Apoptosis pathways that eliminate aberrant cells.

  • Senescence: progressive telomere shortening limiting replicative lifespan.

Normal Cell Development & Homeostasis

• Cell cycle = orderly sequence of phases G0 \rightarrow G1 \rightarrow S \rightarrow G_2 \rightarrow M.

  • Alternates between mitotic division of stem cells and resting states.

• Regulation depends on:

  • Surface-area : volume ratio.

  • Availability of nutrients/space & paracrine chemical signals.

  • Differentiation state (specialised cells often permanently in G_0).

• Telomeres safeguard chromosomal integrity; progressive shortening → senescence.

• Apoptosis acts as quality-control: DNA damage that cannot be repaired triggers programmed death.

Breakdown of Control → Cancer Cells

• Cancer cells ignore apoptotic signals and often re-activate telomerase, restoring telomeres → cellular “immortality”.

• Key morphological & biochemical hallmarks:

  • Unrestrained growth; encroachment on neighbours.

  • Anaplasia (loss of differentiation) & pleomorphism (variable size/shape).

  • Production of altered proteins → measurable tumour markers.

  • Underlying driver = DNA mutation or replication error.

Carcinogenesis (Tumourigenesis)

• Definition: multistep process by which normal cells become cancerous.

  1. Initiation – first irreversible genetic hit by a carcinogen.

  2. Promotion – additional exposures enhance proliferation of initiated clone.

  3. Progression – accumulation of further changes → fully malignant phenotype.

• Generic molecular sequence:

  • Genetic predisposition or environmental carcinogen damages DNA.

  • Mutation alters proto-oncogene or tumour-suppressor gene.

  • Cell gains autonomy over growth signals; apoptosis disabled.

  • Telomerase re-expression preserves telomeres → unlimited divisions.

Gene Classes Involved

• Proto-oncogenes: code for normal growth-promoting proteins.

  • Mutation/over-expression → oncogene → unchecked proliferation.

• Tumour-suppressor genes (TSGs): encode brakes on cell cycle or promote DNA repair (e.g., TP53, RB1).

  • Both alleles must be inactivated ("two-hit" hypothesis) for effect.

• DNA repair genes: maintain genomic integrity; loss increases mutation rate.

Oncogene Activation Mechanisms

• Point mutation: small DNA change ⇒ hyper-active protein.

• Chromosome amplification: multiple gene copies ⇒ excess oncogenic product.

• Chromosomal translocation: gene relocated near active promoter or fusion protein (e.g., t(9;22) BCR-ABL in CML).

Tumour-Suppressor Gene Inactivation

• First allele hit commonly via point mutation; second via deletion, methylation, or LOH.

• Familial cancer syndromes: BRCA1/BRCA2 (breast), APC (colorectal), p16 (melanoma).

• Example: p53 pathway

  • Normal p53 arrests cell at G_1 for repair or triggers apoptosis.

  • Loss/mutation ⇒ damaged cells progress through S phase, propagating mutations.

Tumour Classification

• Nomenclature

  • Benign: tissue of origin + “-oma” (osteoma, neuroma).

  • Malignant:

  • Mesenchymal origin → “-sarcoma” (osteosarcoma).

  • Epithelial origin → “-carcinoma” (hepatocellular carcinoma).

  • Exceptions: malignant melanoma, Hodgkin’s disease.

Benign vs Malignant

Invasion & Metastasis

• Metastasis: spread of malignant cells from primary to distant site.

  • Routes: local tissue invasion, lymphatic drainage, haematogenous spread, body cavity seeding.

  • Not every malignant cell can metastasise; additional mutations required.

• Steps of metastatic cascade:

  1. Autonomous proliferation → primary solid tumour.

  2. Loss of contact inhibition; degradation of ECM.

  3. Intravasation into vessels; survival in circulation.

  4. Extravasation at distant capillary bed.

  5. Colonisation & secondary tumour growth.

• Angiogenesis: tumour-secreted VEGF stimulates neovascularisation, delivering O_2 & nutrients.

• Common metastatic patterns:

  • Breast → axillary nodes, bone, brain, liver, lung.

  • Colon → liver, lung, peritoneum.

  • Prostate → bone.

  • Others listed in Table (see transcript p.31).

Risk Factors (Carcinogens)

• Genetic: inherited oncogene/TSG mutations (e.g., BRCA).

• Viruses: HPV → cervix, HBV/HCV → liver.

• Radiation: UV (skin), ionising (leukaemia, thyroid).

• Chemicals: asbestos (lung), benzene (leukaemia), amines (bladder).

• Biologic chronic inflammation: ulcerative colitis → colon ca.

• Lifestyle / Environmental:

  • Cigarette smoke (>50 carcinogens), alcohol metabolites, high-fat diet, obesity (↑ growth factors), physical inactivity.

  • Occupational exposures: pesticides, nickel, asbestos.

  • Ionising/electromagnetic fields, pollution.

• Age & Hormones: increasing age, unopposed oestrogen → endometrial ca.

Clinical Manifestations of Tumours

• Local effects:

  • Pain (pressure, nerve/bone invasion, infection).

  • Obstruction of ducts/tubes (bowel, bronchus) → organ dysfunction.

  • Tissue necrosis/ulceration → secondary infection, bleeding.

• Systemic effects:

  • Cachexia: weight loss, muscle wasting; multifactorial (tumour metabolism, cytokines).

  • Anaemia: chronic bleeding, marrow suppression, nutritional deficit.

  • Fatigue: inflammatory mediators, anaemia, stress, therapies.

  • Infections: immunosuppression.

  • Bleeding / bruising: vessel erosion, thrombocytopenia.

• Paraneoplastic syndromes: remote effects not attributable to local tumour or metastases (e.g., SIADH, Cushing’s).

• Typical initial presentations by site:

  • Lung: chronic cough.

  • Breast: palpable lump.

  • Colon: blood in stool.

  • Cervix/Uterus: abnormal vaginal bleeding.

  • Prostate: dysuria.

Connections & Ethical / Practical Implications

• Early detection hinges on understanding risk factors and recognising subtle clinical manifestations.

• Genetic counselling crucial where familial TSG mutations exist (e.g., BRCA screening).

• Lifestyle modification (tobacco cessation, diet, weight control) can prevent substantial cancer burden.

• Ethical duty to address environmental/occupational carcinogens through policy and workplace safety.

• Targeted therapies now exploit molecular knowledge (e.g., tyrosine-kinase inhibitors for BCR-ABL). Precision medicine requires genetic profiling.

Quick‐Reference Formulae / Concepts

• Two-hit requirement for TSG inactivation: \text{Cancer risk} \propto \text{loss of both alleles of TSG}.

• Mutation accumulation model: \text{Normal} \xrightarrow{\text{Initiation}} \text{Preneoplastic} \xrightarrow{\text{Promotion}} \text{Benign} \xrightarrow{\text{Progression}} \text{Malignant}.

• Telomere length maintenance by telomerase \Rightarrow unlimited divisions.

Study Tips

• Master the vocabulary (-oma, ‑carcinoma, ‑sarcoma) → rapid tumour identification.

• Link each risk factor to its mechanism (e.g., UV → thymine dimers → mutation).

• Use flowcharts to memorise steps of carcinogenesis & metastasis.

• Relate gene classes to clinical examples (e.g., TP53 mutation frequency in solid tumours ≈ 50\%).

• Practice explaining differences between benign vs malignant to reinforce histologic concepts.

Introduction to Neoplasia

Neoplasia, literally meaning “new growth” from Greek neos (new) and plasia (growth), refers to the uncontrolled proliferation of tissue and cells without a physiological purpose. This process leads to the formation of an abnormal mass of tissue, whose excessive and uncoordinated growth continues even after the original growth-stimulus has ceased.

Normal cellular proliferation is tightly controlled by several mechanisms, which are lost in neoplasia. These controls include the intrinsic genetic program of each cell, extrinsic signals like hormones and growth factors that regulate cell division, apoptosis pathways that eliminate aberrant cells, and senescence, a process involving progressive telomere shortening that limits a cell's replicative lifespan.

Normal Cell Development & Homeostasis

The cell cycle is an orderly sequence of phases: G0 \rightarrow G1 \rightarrow S \rightarrow G_2 \rightarrow M. Cells alternate between mitotic division, primarily for stem cells, and resting states. Regulation of the cell cycle is dependent on factors such as the surface-area to volume ratio of the cell, the availability of nutrients and space, and paracrine chemical signals. Additionally, the differentiation state of a cell plays a role, as specialised cells often reside permanently in the G_0 (quiescent) phase.

Telomeres are critical structures that safeguard chromosomal integrity, and their progressive shortening typically leads to cellular senescence. Apoptosis, or programmed cell death, functions as a vital quality-control mechanism, triggering the death of cells when DNA damage cannot be repaired.

Breakdown of Control \rightarrow Cancer Cells

Cancer cells exhibit a profound breakdown in these normal controls, often ignoring apoptotic signals and reactivating telomerase, which restores telomeres and grants them cellular “immortality.” They display several key morphological and biochemical hallmarks, including unrestrained growth which leads to encroachment on neighbouring tissues. Other hallmarks are anaplasia (loss of differentiation) and pleomorphism (variable size and shape among cells). These altered characteristics often result in the production of altered proteins, which can serve as measurable tumour markers. The fundamental underlying driver of these changes is a DNA mutation or replication error.

Carcinogenesis (Tumourigenesis)

Carcinogenesis, also known as tumourigenesis, is a multistep process through which normal cells transform into cancerous cells. This process typically involves three stages: Initiation, which is the first irreversible genetic hit caused by a carcinogen; Promotion, where additional exposures to promoting agents enhance the proliferation of the initiated cell clone; and Progression, where the accumulation of further genetic and epigenetic changes leads to a fully malignant phenotype. This generic molecular sequence begins with genetic predisposition or an environmental carcinogen damaging DNA, resulting in a mutation that alters a proto-oncogene or a tumour-suppressor gene. Consequently, the cell gains autonomy over growth signals, apoptosis pathways are disabled, and telomerase re-expression occurs, preserving telomeres and allowing for unlimited cell divisions.

Gene Classes Involved

Three main classes of genes are involved in carcinogenesis. Proto-oncogenes code for normal proteins that promote cell growth; a mutation or over-expression of these genes converts them into oncogenes, leading to unchecked cellular proliferation. Tumour-suppressor genes (TSGs), such as TP53 and RB1, encode proteins that act as brakes on the cell cycle or promote DNA repair. For a TSG to lose its function and contribute to cancer, both alleles must be inactivated, a concept known as the “two-hit” hypothesis. Lastly, DNA repair genes are responsible for maintaining genomic integrity; their loss or dysfunction increases the overall mutation rate within cells.

Oncogene Activation Mechanisms

Oncogene activation can occur through several mechanisms. A point mutation, which is a small change in the DNA sequence, can result in a hyper-active protein. Chromosome amplification involves the presence of multiple copies of a gene, leading to an excess of the oncogenic product. Chromosomal translocation occurs when a gene is relocated near an active promoter or when two genes fuse to form a fusion protein, such as t(9;22) BCR-ABL observed in Chronic Myeloid Leukemia (CML).

Tumour-Suppressor Gene Inactivation

Inactivation of tumour-suppressor genes typically involves an initial hit to one allele, commonly via a point mutation, followed by a second hit to the other allele through mechanisms such as deletion, methylation, or Loss of Heterozygosity (LOH). Many familial cancer syndromes are linked to inherited mutations in TSGs, including BRCA1/BRCA2 (associated with breast and ovarian cancer), APC (colorectal cancer), and p16 (melanoma). A key example is the p53 pathway: normal p53 protein typically arrests the cell cycle at G_1 phase to allow for DNA repair or triggers apoptosis if damage is irreparable. However, loss or mutation of p53 allows damaged cells to progress through the S phase, propagating mutations and increasing cancer risk.

Tumour Classification

Tumours are classified based on their origin and behaviour, following specific nomenclature. Benign tumours are typically named by adding the suffix “-oma” to the tissue of origin (e.g., osteoma for bone tumours, neuroma for nerve tumours). Malignant tumours, however, have distinct naming conventions based on their origin: those of mesenchymal origin are called “-sarcomas” (e.g., osteosarcoma), while those of epithelial origin are called “-carcinomas” (e.g., hepatocellular carcinoma). There are also exceptions to these rules, such as malignant melanoma and Hodgkin’s disease.

Benign vs Malignant

The crucial distinctions between benign and malignant tumours are typically presented in a comparative table, highlighting differences in growth rate, differentiation, local invasion, and metastatic potential. Benign tumours usually grow slowly, are well-differentiated, remain localised, and do not metastasise. Malignant tumours, in contrast, often grow rapidly, show poor differentiation (anaplasia), are locally invasive, and possess the ability to spread to distant sites through metastasis.

Invasion & Metastasis

Metastasis is the critical process by which malignant cells spread from the primary tumour site to distant parts of the body. This spread can occur via several routes, including local tissue invasion, lymphatic drainage, haematogenous spread through the bloodstream, and seeding within body cavities. It is important to note that not every malignant cell can metastasise; additional specific mutations or adaptations are required for a cell to successfully complete the metastatic cascade.

The steps of the metastatic cascade involve several key stages: first, autonomous proliferation leads to the formation of a primary solid tumour. Second, tumour cells exhibit a loss of contact inhibition and degrade the extracellular matrix (ECM), allowing them to invade surrounding tissues. Third, they undergo intravasation, entering blood or lymphatic vessels, followed by survival in circulation. Fourth, they extravasate at a distant capillary bed, exiting the vessels. Finally, they undergo colonisation and growth, establishing a secondary tumour. Angiogenesis, the formation of new blood vessels, is crucial for tumour growth and metastasis, as tumours secrete VEGF (Vascular Endothelial Growth Factor) to stimulate neovascularisation, ensuring a supply of O_2 and nutrients. Common metastatic patterns include breast cancer spreading to axillary nodes, bone, brain, liver, and lung; colon cancer most frequently metastasising to the liver, lung, and peritoneum; and prostate cancer often spreading to bone.

Risk Factors (Carcinogens)

Numerous risk factors, or carcinogens, contribute to the development of cancer. Genetic factors include inherited mutations in oncogenes or tumour-suppressor genes (e.g., BRCA mutations). Certain viruses are oncogenic, such as HPV leading to cervical cancer and HBV/HCV contributing to liver cancer. Radiation exposure, both UV radiation (causing skin cancer) and ionising radiation (linked to leukaemia and thyroid cancer), is a significant risk factor. Various chemicals are known carcinogens, including asbestos (lung cancer), benzene (leukaemia), and aromatic amines (bladder cancer). Biologic chronic inflammation, as seen in ulcerative colitis, can increase the risk of colon cancer. Lifestyle and environmental factors play a substantial role, including cigarette smoke (containing over 50 carcinogens), alcohol metabolites, high-fat diet, obesity (which increases growth factors), and physical inactivity. Occupational exposures to substances like pesticides, nickel, and asbestos also contribute. Environmental factors further include ionising/electromagnetic fields and general pollution. Finally, increasing age is a significant risk factor, and certain hormones, such as unopposed oestrogen, can increase the risk of endometrial cancer.

Clinical Manifestations of Tumours

Tumours manifest clinically through both local and systemic effects. Local effects arise from the tumour's physical presence and include pain due to pressure, nerve or bone invasion, or infection; obstruction of ducts or tubes (e.g., bowel, bronchus), leading to organ dysfunction; and tissue necrosis or ulceration, which can result in secondary infection and bleeding. Systemic effects are those that affect the entire body. Cachexia, characterised by severe weight loss and muscle wasting, is a multifactorial systemic effect influenced by tumour metabolism and inflammatory cytokines. Anaemia can result from chronic bleeding, bone marrow suppression, or nutritional deficit. Persistent fatigue is common, driven by inflammatory mediators, anaemia, psychological stress, and cancer therapies. Patients are also prone to infections due to immunosuppression. Bleeding and bruising can occur due to vessel erosion or thrombocytopenia. Beyond these, paraneoplastic syndromes are remote effects not directly attributable to the local tumour or metastases, such as SIADH or Cushing’s syndrome.

Initial presentations often vary by site: lung cancer may present with a chronic cough; breast cancer, a palpable lump; colon cancer, blood in stool; cervical/uterine cancer, abnormal vaginal bleeding; and prostate cancer, dysuria.

Connections & Ethical / Practical Implications

Early detection of cancer relies heavily on understanding the associated risk factors and recognising subtle clinical manifestations. Genetic counselling becomes crucial for individuals with familial tumour-suppressor gene mutations, such as BRCA, to guide screening and preventative measures. Lifestyle modifications, including tobacco cessation, a healthy diet, and weight control, can prevent a substantial cancer burden at the population level. Furthermore, there is an ethical duty to address environmental and occupational carcinogens through policy interventions and workplace safety regulations. Advances in molecular knowledge have facilitated the development of targeted therapies, such as tyrosine-kinase inhibitors for BCR-ABL positive leukaemias, highlighting that precision medicine increasingly requires detailed genetic profiling of tumours.

Quick-Reference Formulae / Concepts

Key concepts in neoplasia include the two-hit requirement for TSG inactivation, where cancer risk is proportional to the loss of both alleles of a tumour-suppressor gene. The mutation accumulation model describes the progression from normal cells to preneoplastic, then benign, and finally malignant states through initiation, promotion, and progression. Another fundamental concept is that telomere length maintenance by telomerase enables unlimited cellular divisions, contributing to the immortalisation of cancer cells.

Study Tips

To effectively study neoplasia, it is important to master the vocabulary, distinguishing terms like “-oma,” “-carcinoma,” and “-sarcoma” for rapid tumour identification. Linking each risk factor to its specific mechanism, for example, understanding that UV radiation leads to thymine dimers and subsequent mutations, enhances comprehension. Utilising flowcharts can aid in memorising the complex steps of carcinogenesis and metastasis. It is also beneficial to relate gene classes to clinical examples, such as noting that TP53 mutations are found in approximately 50\% of solid tumours. Finally, practicing explaining the differences between benign and malignant conditions can reinforce crucial histologic concepts.