Hallmarks of Cancer Overview
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Which of the following are considered hallmarks of cancer? (Select all that apply)

  • Learning ability
  • Resisting apoptosis (correct)
  • Avoiding immune destruction (correct)
  • Sustained proliferative signaling (correct)

    • Tumor suppressor genes regulate cell growth and division.

    True

    What is the role of TP53 in cancer biology?

    Regulates genes involved in growth arrest and apoptosis.

    Cancer cells exhibit the ______ effect, which is a form of aerobic glycolysis.

    <p>Warburg</p> Signup and view all the answers

    Match the following cancer types with their categories:

    <p>Small Cell Carcinoma = Highly aggressive lung cancer Acute Lymphoblastic Leukaemia = Common in children Invasive Ductal Carcinoma = Majority of breast cancers Melanoma = Malignant tumor from melanocytes</p> Signup and view all the answers

    What is a common characteristic of invasive breast cancer?

    <p>Malignant cells invade beyond the basement membrane</p> Signup and view all the answers

    What is the main treatment approach for acute leukaemia?

    <p>Chemotherapy and stem cell transplants.</p> Signup and view all the answers

    BRCA1 mutations are associated with non-hereditary cancers only.

    <p>False</p> Signup and view all the answers

    The ______ is often referred to as the 'guardian of the genome.'

    <p>TP53</p> Signup and view all the answers

    What is Chronic Myeloid Leukaemia (CML) commonly associated with?

    <p>Philadelphia chromosome (t(9;22), BCR-ABL1 fusion)</p> Signup and view all the answers

    What are typical markers for Chronic Lymphocytic Leukaemia (CLL)?

    <p>CD19</p> Signup and view all the answers

    The 5-year survival rate for patients treated with Tyrosine Kinase Inhibitors (TKIs) for CML has decreased from 90% to 45%.

    <p>False</p> Signup and view all the answers

    What is the primary cancer type associated with plasma cell dyscrasias?

    <p>Multiple Myeloma</p> Signup and view all the answers

    What is a key characteristic of the SLiM CRAB criteria for diagnosing Multiple Myeloma?

    <p>Light chain ratio abnormalities</p> Signup and view all the answers

    Bowel cancer is also known as __________.

    <p>colorectal cancer</p> Signup and view all the answers

    Familial Adenomatous Polyposis (FAP) leads to a 50% risk of cancer by age 40.

    <p>False</p> Signup and view all the answers

    What is the most common form of bowel cancer?

    <p>Colorectal carcinoma</p> Signup and view all the answers

    Which of the following are risk factors for prostate cancer?

    <p>All of the above</p> Signup and view all the answers

    What type of prostate cancer is most common?

    <p>Prostatic adenocarcinoma</p> Signup and view all the answers

    The Gleason Score for prostate cancer is based on __________.

    <p>glandular patterning</p> Signup and view all the answers

    What are typical symptoms of advanced prostate cancer?

    <p>Haematuria</p> Signup and view all the answers

    The diagnosis of lymphoma can be based on immunophenotyping.

    <p>True</p> Signup and view all the answers

    Which of the following are hallmarks of cancer? (Select all that apply)

    <p>Sustained proliferative signaling</p> Signup and view all the answers

    What role does TP53 play in cancer?

    <p>Regulates genes involved in growth arrest and apoptosis.</p> Signup and view all the answers

    Cancer cells can evade apoptosis by increasing expression of __________ regulators.

    <p>antiapoptotic</p> Signup and view all the answers

    Telomerase activation in cancer cells contributes to finite cell division.

    <p>False</p> Signup and view all the answers

    What is the Warburg effect in cancer cells?

    <p>Increased use of aerobic glycolysis</p> Signup and view all the answers

    What is the significance of BRCA1 mutations in breast cancer?

    <p>Increases risk of breast cancer and other cancers.</p> Signup and view all the answers

    Match the following cancers with their characteristics:

    <p>Melanoma = Originates from melanocytes and often arises in the skin Lung Cancer = Can be categorized into small cell and non-small cell carcinoma Leukaemia = Cancer of white blood cells, categorized by progression rate</p> Signup and view all the answers

    Tumor cells often create an immunosuppressive tumor microenvironment using factors like __________.

    <p>TGF-β</p> Signup and view all the answers

    What are two risk factors for breast cancer?

    <p>Estrogen exposure and family history.</p> Signup and view all the answers

    Which type of chronic leukaemia is common in adults aged 30-60 and linked to the Philadelphia chromosome?

    <p>Chronic Myeloid Leukaemia (CML)</p> Signup and view all the answers

    What is the common treatment for Chronic Myeloid Leukaemia (CML)?

    <p>Tyrosine Kinase Inhibitors (TKIs) like Imatinib</p> Signup and view all the answers

    Chronic Lymphocytic Leukaemia (CLL) primarily affects younger adults.

    <p>False</p> Signup and view all the answers

    Which of the following symptoms is NOT associated with Chronic Lymphocytic Leukaemia (CLL)?

    <p>Bone pain</p> Signup and view all the answers

    The typical genetic marker for Chronic Lymphocytic Leukaemia (CLL) is ______.

    <p>CD19, CD5, and CD23</p> Signup and view all the answers

    What is the primary type of cancer in Multiple Myeloma?

    <p>Plasma cell cancer</p> Signup and view all the answers

    What does the acronym SLiM CRAB stand for in Multiple Myeloma diagnostics?

    <p>Plasma cells ≥60% in marrow, light chain ratio abnormalities, MRI bone lesions, and CRAB (Calcium elevation, Renal failure, Anemia, Bone lesions)</p> Signup and view all the answers

    The 5-year survival rate for Multiple Myeloma is approximately 55%.

    <p>True</p> Signup and view all the answers

    Match the following types of bowel cancer to their definitions:

    <p>Colorectal carcinoma = Most common form of bowel cancer Benign polyps = Non-cancerous growths that can progress to cancer Lymphomas = A type of cancer affecting the lymphatic system Neuroendocrine tumors = Tumors that can arise in the bowel and produce hormones</p> Signup and view all the answers

    What is the most common risk factor for bowel cancer?

    <p>Age</p> Signup and view all the answers

    What is the function of PSA testing in prostate cancer diagnosis?

    <p>To identify elevated levels of Prostate-Specific Antigen in the blood</p> Signup and view all the answers

    What is the most common type of prostate cancer?

    <p>Prostatic adenocarcinoma</p> Signup and view all the answers

    Prostate cancer screening is recommended for all men over the age of 50.

    <p>False</p> Signup and view all the answers

    What is the Gleason Score used for in prostate cancer?

    <p>To determine the aggressiveness of the cancer based on glandular patterns</p> Signup and view all the answers

    Which of the following are hallmarks of cancer? (Select all that apply)

    <p>Evading growth suppressors</p> Signup and view all the answers

    What is the role of TP53 in cancer?

    <p>Regulates growth arrest and plays a role in apoptosis, senescence, autophagy, and metabolic changes.</p> Signup and view all the answers

    Cancer cells gain immunity to destruction by enhancing immune responses.

    <p>False</p> Signup and view all the answers

    The process of cancer cells avoiding apoptosis is often due to the loss of __________ function.

    <p>TP53</p> Signup and view all the answers

    The Warburg effect describes a metabolic shift in cancer cells towards anaerobic glycolysis even in the presence of oxygen.

    <p>True</p> Signup and view all the answers

    What factors contribute to the risk of breast cancer? (Select all that apply)

    <p>Age</p> Signup and view all the answers

    Which genetic mutations are commonly associated with hereditary breast cancer?

    <p>BRCA1 and BRCA2 mutations</p> Signup and view all the answers

    Which of the following features characterize melanoma? (Select all that apply)

    <p>Color variation</p> Signup and view all the answers

    What is the primary treatment for small cell lung carcinoma?

    <p>Chemoradiotherapy</p> Signup and view all the answers

    Acute leukaemia is characterized by rapid growth of immature __________ cells.

    <p>blast</p> Signup and view all the answers

    What are common types of leukaemia? (Select all that apply)

    <p>Acute Lymphoblastic Leukaemia</p> Signup and view all the answers

    What is Chronic Myeloid Leukaemia (CML) commonly linked to?

    <p>Philadelphia chromosome</p> Signup and view all the answers

    Which treatment significantly improved the 5-year survival rates for CML?

    <p>Imatinib</p> Signup and view all the answers

    Chronic Lymphocytic Leukaemia (CLL) typically presents in younger adults.

    <p>False</p> Signup and view all the answers

    Which markers are typical for Chronic Lymphocytic Leukaemia (CLL)?

    <p>CD19, CD5, CD23</p> Signup and view all the answers

    What does SLiM CRAB criteria refer to in the context of Multiple Myeloma diagnosis?

    <p>Plasma cells ≥60% in marrow, light chain ratio abnormalities, MRI bone lesions, and CRAB (Calcium elevation, Renal failure, Anemia, Bone lesions).</p> Signup and view all the answers

    What is the most common form of bowel cancer?

    <p>Colorectal carcinoma</p> Signup and view all the answers

    Which of the following is a significant risk factor for Bowel cancer?

    <p>Age</p> Signup and view all the answers

    In which population is prostate cancer prevalence highest?

    <p>Black males</p> Signup and view all the answers

    What does PSA stand for in the context of prostate cancer screening?

    <p>Prostate-Specific Antigen</p> Signup and view all the answers

    What is the Gleason Score used for in prostate cancer diagnosis?

    <p>Prognosis</p> Signup and view all the answers

    Bowel cancer is rarely asymptomatic in early stages.

    <p>True</p> Signup and view all the answers

    How do tumor cells manage to resist apoptosis?

    <p>Tumor cells resist apoptosis by losing TP53 function, increasing antiapoptotic factors, and downregulating proapoptotic factors.</p> Signup and view all the answers

    What role does autophagy play in cancer cell survival?

    <p>Autophagy helps cancer cells survive under stress by allowing them to degrade and recycle components, contributing to their resilience.</p> Signup and view all the answers

    Describe the necrotic pathway associated with uncontrolled cell death.

    <p>The necrotic pathway involves cell enlargement, loss of membrane integrity, leakage of cell contents, and subsequent inflammation.</p> Signup and view all the answers

    How does telomerase contribute to replicative immortality in cancer cells?

    <p>Telomerase activation maintains telomere length, allowing cancer cells to undergo unlimited divisions without aging.</p> Signup and view all the answers

    What are the roles of VEGF-A and TSP-1 in angiogenesis?

    <p>VEGF-A is a pro-angiogenic factor that promotes blood vessel formation, while TSP-1 acts as an anti-angiogenic factor, inhibiting vessel formation.</p> Signup and view all the answers

    What is the significance of the pro-tumor effects associated with necrosis?

    <p>Pro-tumor effects of necrosis include promoting angiogenesis, extracellular matrix remodeling, and immune evasion.</p> Signup and view all the answers

    In what ways can cancer cells short-circuit the extrinsic apoptotic pathway?

    <p>Cancer cells can bypass the extrinsic apoptotic pathway by altering the expression of death receptors and ligands or modulating downstream signaling.</p> Signup and view all the answers

    How does increased expression of antiapoptotic regulators affect cancer progression?

    <p>Increased expression of antiapoptotic regulators enhances cell survival, allowing tumors to grow and resist treatment.</p> Signup and view all the answers

    What is the significance of hormone receptor positivity in invasive breast cancer?

    <p>It indicates responsiveness to hormonal therapy and a better prognosis.</p> Signup and view all the answers

    How can melanoma be identified in its early stages?

    <p>Melanoma can be identified by asymmetry, irregular borders, color variation, and size over 6mm.</p> Signup and view all the answers

    What role does HER2 play in breast cancer prognosis?

    <p>HER2 overexpression is linked to aggressive cancer behavior but is targetable with therapies like trastuzumab.</p> Signup and view all the answers

    Describe the development model of a dysplastic naevus.

    <p>A dysplastic naevus is larger with irregular borders and varied colors, indicating a higher risk for melanoma.</p> Signup and view all the answers

    What are the main surgical options for treating invasive breast cancer?

    <p>The main surgical options include lumpectomy or mastectomy, often with lymph node assessment.</p> Signup and view all the answers

    Why is early detection critical in the context of melanoma?

    <p>Early detection significantly improves survival rates compared to late-stage melanoma.</p> Signup and view all the answers

    What distinguishes invasive ductal carcinoma from invasive lobular carcinoma?

    <p>Invasive ductal carcinoma constitutes about 80% of breast cancer cases, while invasive lobular carcinoma accounts for 10%.</p> Signup and view all the answers

    Identify two major risk factors for developing melanoma.

    <p>Fair skin and a high number of atypical moles are major risk factors.</p> Signup and view all the answers

    What is the significance of the Epithelial-Mesenchymal Transition (EMT) in tumor progression?

    <p>EMT facilitates the mobility and invasiveness of tumor cells, allowing them to invade surrounding tissues and metastasize.</p> Signup and view all the answers

    How does the loss of E-cadherin contribute to cancer invasion?

    <p>Loss of E-cadherin deregulates contact inhibition, allowing cells to continue proliferating and enhancing invasiveness.</p> Signup and view all the answers

    Describe how the Warburg effect aids cancer cell survival and proliferation.

    <p>The Warburg effect allows cancer cells to perform aerobic glycolysis even in the presence of oxygen, supporting rapid growth and energy production.</p> Signup and view all the answers

    What are the key steps involved in the process of metastasis?

    <p>The key steps in metastasis include local invasion, intravasation, extravasation, formation of micro-metastases, and colonization.</p> Signup and view all the answers

    In what ways do tumor cells create an immunosuppressive tumor microenvironment?

    <p>Tumor cells utilize factors like TGF-β to inhibit immune responses, creating an environment that protects them from immune destruction.</p> Signup and view all the answers

    How do mutations in DNA repair genes influence cancer development?

    <p>Mutations in DNA repair genes, such as BRCA1, lead to genome instability and an increased likelihood of tumorigenesis.</p> Signup and view all the answers

    What role do transcription factors like Snail, Slug, and Twist play in cancer biology?

    <p>These transcription factors initiate EMT by inhibiting E-cadherin expression, promoting tumor cell motility and invasiveness.</p> Signup and view all the answers

    Explain how hypoxia influences glucose transporter expression in cancer cells.

    <p>Hypoxia leads to the upregulation of glucose transporters, such as GLUT1, through the action of transcription factors HIF1α and HIF2α.</p> Signup and view all the answers

    What is the standard treatment protocol for Hodgkin Lymphoma?

    <p>ABVD chemotherapy is the standard treatment.</p> Signup and view all the answers

    Differentiate between primary and metastatic brain tumors.

    <p>Primary brain tumors originate in the brain tissue, while metastatic tumors spread from other body parts to the brain.</p> Signup and view all the answers

    What is the significance of DNA methylation-based diagnostics in brain tumor classification?

    <p>DNA methylation-based diagnostics provide accurate tumor classification.</p> Signup and view all the answers

    Name the four grades of brain tumors according to the WHO classification.

    <p>The grades are I, II, III, and IV.</p> Signup and view all the answers

    What role does the cerebellum play in the central nervous system?

    <p>The cerebellum is responsible for balance, coordination, and posture.</p> Signup and view all the answers

    What is the most common primary brain tumor, and what type of cells does it arise from?

    <p>Gliomas are the most common primary brain tumor, arising from glial cells.</p> Signup and view all the answers

    Describe the treatment approach for ependymoma brain tumors.

    <p>Ependymomas are often treated with surgery and radiation.</p> Signup and view all the answers

    What are the molecular subtypes of medulloblastoma?

    <p>The four molecular subtypes are WNT, SHH, Group 3, and Group 4.</p> Signup and view all the answers

    What are the differences between radial growth and vertical growth in melanoma?

    <p>Radial growth is melanoma in situ with limited dermal invasion and no metastatic potential, while vertical growth involves invasive expansion into the dermis, indicating a higher risk of metastasis.</p> Signup and view all the answers

    Identify one key prognostic indicator for melanoma and explain its significance.

    <p>Breslow thickness, which measures tumor thickness, is significant as increased thickness correlates with a worse prognosis.</p> Signup and view all the answers

    What genetic mutation is most commonly associated with melanoma and how does it affect tumor behavior?

    <p>The BRAF mutation, particularly V600E, is present in about 66% of melanomas and activates the MAPK pathway, promoting tumor growth.</p> Signup and view all the answers

    Describe the clinical features of Small Cell Lung Carcinoma (SCLC).

    <p>Small Cell Lung Carcinoma is highly aggressive, typically central in location, and exhibits neuroendocrine differentiation with high metastatic potential.</p> Signup and view all the answers

    What is the significance of markers like CD56 and TTF-1 in the diagnosis of Small Cell Lung Carcinoma?

    <p>Markers such as CD56 and TTF-1 are specific indicators of neuroendocrine tumors, aiding in the diagnosis of Small Cell Lung Carcinoma.</p> Signup and view all the answers

    What role do high mitotic rates play in melanoma prognosis?

    <p>High mitotic rates suggest aggressive tumor behavior, indicating a poorer prognosis for patients with melanoma.</p> Signup and view all the answers

    Explain the importance of detecting TERT promoter mutations in melanoma.

    <p>TERT promoter mutations, present in approximately 70% of melanomas, are associated with increased telomerase activity and contribute to cancer cell immortality.</p> Signup and view all the answers

    How do the characteristics of Non-Small Cell Lung Carcinoma (NSCLC) differ from Small Cell Lung Carcinoma (SCLC)?

    <p>NSCLC is usually resectable and requires detailed subtyping for targeted therapies, while SCLC is aggressive, non-resectable, and primarily treated with chemoradiotherapy.</p> Signup and view all the answers

    Study Notes

    Hallmarks of Cancer

    • Cancer cells continuously stimulate their own growth through deregulating growth-promoting signals.
    • Mechanisms include activation of growth factors, mutations, and disrupted feedback mechanisms.
    • Sustained Proliferative Signalling
      • Autocrine proliferative signaling
      • Signaling to normal cells within the tumor associated stroma (reactive stroma)
      • Elevated levels of receptor proteins on cancer cells make them hyper-responsive to limiting amounts of GF ligands (e.g., epidermal growth factor receptor)
      • GF independence by continual/constitutive activation of downstream signaling pathways
      • Somatic mutations activate additional downstream pathways
      • Disruptions of negative-feedback mechanisms
        • Oncogenic mutations affecting ras genes compromise Ras GTPase activity
        • In normal cells, the Ras GTPase drives negative-feedback
        • In Ras mutations, the Ras GTPase is INACTIVE, and negative-feedback is disrupted.
    • Evading Growth Suppressors
      • Involves inactivation of tumor suppressor genes (TSG), such as RB and TP53.
      • These genes regulate cell growth and division.
      • Retinoblastoma-associated (RB)
        • Integrates signals extracellular and intracellular to progress the cell cycle.
        • Directly or indirectly inactivated in nearly all human cancers.
      • TP53 proteins
        • "Guardian of the genome"
        • Regulates several genes involved in growth arrest.
        • Plays a role in processes such as:
          • Apoptosis (programmed cell death)
          • Senescence (irreversible cell cycle arrest)
          • Autophagy
          • Metabolic changes in the cell
        • P53 is found mutated in over half of cancers, including ovarian, colon, esophageal, and blood cancers.
    • Resisting Cell Death
      • Cancer cells avoid apoptosis by:
        • Loss of TP53 tumor suppressor function.
        • Increasing expression of antiapoptotic regulators (Bcl-2, Bcl-xl)
        • Increasing survival signals (Igf1/2)
        • Downregulating proapoptotic factors (Bax, Bim, Puma)
        • Short-circuiting the extrinsic ligand-induced death pathway
      • Autophagy helps cancer cells survive under stress.
      • Necrosis promotes tumor-supportive inflammation.
      • Necrosis (extrinsic) is uncontrolled cell death in response to stimuli from outside the cell.
      • It is associated with inflammatory responses due to the release of heat shock, cause inflammasome activation and secretion of proinflammatory cytokine interleukin-1 beta (IL1)
      • Necrotic pathway
        • Cell enlargement
        • Loss of membrane integrity
        • Leakage of cell contents
        • Inflammation (recruitment of immune cells)
        • Nuclear degeneration
      • Pro-tumour:
        • Angiogenesis
        • ECM remodeling
        • Immune evasion by TAMs, TANs, DCs
      • Anti-tumour:
        • Recruitment of cytotoxic macrophages and neutrophils, NK cells, and mature DCs results in elimination of tumor cells.
    • Enabling Replicative Immortality
      • Telomerase activation in cancer cells maintains telomere length, enabling unlimited cell division.
      • Telomerase activation also confers resistance to apoptosis and aids in DNA repair.
      • Additional functions of telomerase (TERT) in tumorigenesis:
        • Amplify signalling by the Wnt pathway
        • Enhancement of cell proliferation
        • Resistance to apoptosis
        • Involvement in DNA damage repair
    • Inducing Angiogenesis
      • This is the formation of new blood vessels.
      • Cancer cells continuously form new blood vessels, which leads to abnormal vasculature.
      • Regulators include VEGF-A (pro-angiogenic) and TSP-1 (anti-angiogenic).
      • During angiogenesis, there is migration, growth, and differentiation of endothelial cells.
      • Angiogenesis promotes tumor progression.
      • The angiogenic switch is always ON.
      • This results in distorted and enlarged vessels, erratic blood flow, microhaemorrhaging, and leakiness.
    • Activating Invasion and Metastasis
      • This is a multistep process that allows cancer cells to spread.
      • This includes:
        • Local invasion
        • Intravasation
        • Extravasation
        • Micro-metastases
        • Colonisation
      • The Epithelial-Mesenchymal Transition (EMT) makes tumor cells mobile and invasive.
        • During EMT, cell-cell and cell-extracellular matrix interactions are remodeled.
        • It promotes tumour progression.
      • Loss of E-cadherin and EMT
        • E-cadherin mediates Contact Inhibition of Proliferation (CIP)
          • Normal cells stop proliferating once they reach confluence with homophilic E-cadherin binding
          • When E-cadherin is lost or mutated, cells continue proliferating
        • Loss of E-cadherin is key to EMT and tumor progression
          • Transcription factors (TF), such as Snail, Slug, Twist, Zeb1/2, initiate EMT.
          • These TF inhibit E-cadherin gene expression, activating EMT, which then promotes tumor cell motility and invasiveness.
          • E-cadherin expression can be altered through accumulation of mutations, LOH, and epigenetic regulation.
    • Deregulating Cellular Metabolism
      • Cancer cells exhibit the Warburg effect, which is aerobic glycolysis (lactase) even with oxygen.
      • This metabolic shift supports rapid growth and is facilitated by oncogenes like RAS and MYC, and TSG (TP53).
      • Upregulation of glucose transporters (e.g., GLUT1) to the cytoplasm is mediated by hypoxia and TF such as HIF1α and HIF2α.
    • Avoiding Immune Destruction
      • Cancer cells create an immunosuppressive tumor microenvironment (TME), utilizing factors like TGF-β to inhibit immune responses.

    Enabling Characteristics of Cancer

    • Genome Instability and Mutation
      • Mutations in DNA repair genes like BRCA1.
      • The most common form of genomic instability is chromosomal instability (CIN).
      • In hereditary cancers, the presence of both CIN and non-CIN forms of genomic instability have been linked to mutations in DNA repair genes (e.g., germline mutation in breast cancer susceptibility 1 (BRCA1)).
      • In sporadic (non-hereditary) cancers, genomic instability is not due to mutations in DNA repair genes or mitotic checkpoint genes, at least at early stages of cancer development.
    • Tumor-Promoting Inflammation
      • Inflammatory cells and molecules in the TME support cancer progression by providing growth factors and aiding metastasis.
      • Inflammation promotes immune suppression, creating a pro-tumor environment.
      • Inflammation supports cancer:
        • Transformation
        • Proliferation
        • Angiogenesis
        • Metastasis
      • Inflammatory cells supply bioactive molecules, such as GF and survival factors.
      • Immune cells, through the production of inflammatory mediators such as cytokines, chemokines, transforming growth factors, and adhesion molecules, contribute to the creation of a tumor-promoting environment.
      • The aberrant expression and secretion of proinflammatory and growth factors by the tumor cells result in recruitment of immune cells, creating a mutual crosstalk.

    Overview of Breast Cancer

    • Risk Factors:
      • Gender and Age: Predominantly affects women, risk increases with age.
      • Previous Breast Cancer: History of breast cancer increases risk.
      • Estrogen Exposure: Long-term exposure (early menarche, late menopause, obesity, contraceptives) raises risk.
      • Pregnancy: Nulliparity/late pregnancy increases risk; early pregnancy has protective effects
      • Genetics: Family history, BRCA1/BRCA2 mutations.
      • Breast Density: Higher density correlates with increased risk.
      • Radiation Exposure: Prior exposure increases risk.
    • Hereditary Breast Cancer:
      • Characteristics: Younger onset, bilateral presentation.
      • BRCA1/BRCA2: Tumor suppressor genes (autosomal dominant) involved in DNA repair.
      • Increase risk for other cancers.
      • Other Syndromes: Li-Fraumeni (TP53 mutation), Cowden’s disease (PTEN mutation).
    • Pathology:
      • Benign Lesions: Generally, non-proliferative conditions have minimal risk.
      • Proliferative Conditions: With or without atypia; atypia (e.g., atypical hyperplasia) significantly increases cancer risk.
      • In Situ Breast Cancer:
        • DCIS: Non-invasive; confined to ducts, precursor to invasive cancer. Managed with surgical excision and possibly radiotherapy.
        • LCIS: Non-obligate precursor; associated with increased bilateral risk of future invasive cancer.
    • Invasive Breast Cancer:
      • Characteristics: Malignant cells invade beyond the basement membrane; potential for metastasis.
      • Clinical Signs: Lump, pain, nipple/skin changes, and distant manifestations.
      • Types: Majority are invasive ductal carcinoma (80%); 10% are invasive lobular carcinoma. Others include special subtypes.
      • Staging and Workup: AJCC system; histological type, grade, and stage, assessed via pathology and radiology (MMG, US, MRI).
    • Prognostic and Predictive Biomarkers:
      • ER/PR: Hormone receptor positivity indicates responsiveness to hormonal therapy and better prognosis.
      • HER2: Overexpression linked to aggressive behavior but targetable with drugs like trastuzumab.
      • Molecular Subtypes: Luminal A/B, HER2-enriched, Basal-like; used for prognosis and treatment planning.
    • Treatment:
      • Surgery: Lumpectomy or mastectomy, with potential lymph node assessment.
      • Radiotherapy: Reduces recurrence, particularly post-surgery.
      • Hormonal Therapy: For ER/PR-positive cancers (e.g., tamoxifen).
      • Chemotherapy & Targeted Therapy: For HER2-positive and high-risk patients.

    Overview of Melanoma

    • Definition:
      • Melanoma is a malignant tumor originating from melanocytes, the cells that produce melanin.
      • It most often arises in the skin but can also develop in other organs.
    • Importance of Early Detection:
      • Early detection significantly improves survival rates compared to late-stage melanoma.
    • Risk Factors:
      • Skin Type: Fair skin, higher susceptibility to UV damage.
      • UV Radiation: Exposure from sunlight or tanning beds.
      • Moles (Naevi): High number of benign or atypical moles.
      • Family History: Family melanoma history increases risk.
      • Previous Melanoma: Prior melanoma increases recurrence risk.
      • Immunosuppression: Weakened immune system.
      • Chemical Exposure: Contact with harmful chemicals.
    • Development Model:
      • Benign Naevus: Small, well-defined, even-colored. Histology shows symmetrical structure and maturation of cells in deeper layers.
        • Spitz Naevus: Common in young people; can resemble melanoma.
        • Blue Naevus: Darker due to pigmented cells in the dermis.
      • Dysplastic Naevus: Larger with irregular borders and varied colors. Higher risk of melanoma, especially with family history (Dysplastic Naevus Syndrome).
      • Melanoma: Characterized by asymmetry, irregular borders, color variation, size (>6mm), and evolution over time.
        • Microscopy: Asymmetrical, single-cell patterns, disorganized, with "buckshot" scatter and cytological atypia (nuclear enlargement, hyperchromasia).
    • Growth Phases:
      • Radial Growth: Melanoma in situ with limited dermal invasion, lacks metastatic potential.
      • Vertical Growth: Invasive expansion into dermis, larger nests, mitotic activity, and potential for metastasis.
    • Prognostic Indicators:
      • Tumor Thickness: Measured as Breslow thickness.
      • Invasion Level: Clark level of invasion.
      • Ulceration: Linked to worse outcomes.
      • Mitotic Rate: Higher rate suggests poor prognosis.
      • Lymphovascular/Perineural Invasion: Indicates aggressive cancer.
      • Satellite Lesions: Presence may signal spread.
    • Key Genetic Mutations:
      • BRAF: Present in ~66% of melanomas, especially V600E mutation, activates MAPK pathway. Mutation testing helps identify candidates for BRAF inhibitors in metastatic cases.
      • NRAS: Found in ~15% of melanomas.
      • KIT: Common in melanomas on mucosal sites, nails, or chronically sun-exposed skin.
      • CDKN2A: Encodes tumor suppressors (p16, p14) involved in cell cycle control.
      • TERT Promoter Mutations: Present in ~70% of melanomas, increase telomerase activity, promoting replicative immortality.
    • Clinical Implications:
      • BRAF Testing: Identifies candidates for targeted therapy with BRAF inhibitors, which improves survival in metastatic melanoma.
      • Associated Features: BRAF mutations are associated with multiple naevi, trunk location, intermittently sun-exposed skin, and specific histologic patterns (e.g., nested, heavily pigmented).

    Overview of Lung Cancer

    • Major Categories of Lung Cancer:
      • Small Cell Carcinoma (14%):
        • Highly aggressive and associated with smoking; usually non-resectable and treated with chemoradiotherapy.
        • Central lung location, neuroendocrine differentiation, ectopic hormone production, and high metastatic potential.
        • Cytological features: Small cells, scant cytoplasm, granular chromatin, nuclear molding, frequent mitosis.
        • Markers: CD56, synaptophysin, chromogranin, TTF-1.
        • Typically fatal due to widespread metastases.
      • Non-Small Cell Lung Carcinoma (NSCLC):
        • Resectable when possible; requires detailed subtyping and molecular diagnostics for targeted therapy.
        • Includes:
          • Adenocarcinoma (38%):
            • Common in smokers and non-smokers, peripheral origin, high rate of extrathoracic metastasis (e.g., adrenal, brain).
            • In-situ form: Lepidic growth without invasion, ground-glass appearance on CT.
            • Markers: TTF-1 positive
          • Squamous Cell Carcinoma (20%):
            • Strong link to smoking, centrally located, locally aggressive, prone to necrosis/cavitation.
            • Histology: Keratinization, intercellular bridges.
            • Markers: p40, CK5/6.
          • Large Cell Carcinomas and Variants:
            • Includes rarer subtypes like adenosquamous and sarcomatoid carcinoma.
    • Key Molecular Subtypes:
      • EGFR Mutation (10-50%):
        • More common in non-smokers, especially East Asians; associated with better outcomes using tyrosine kinase inhibitors.
        • Common mutations in exons 19 and 21.
      • ALK Rearrangement (~4%):
        • Found in younger, light or never-smokers; often detected using FISH, IHC, or NGS.
        • Responds well to targeted therapy (e.g., crizotinib).
      • KRAS Mutation:
        • Associated with poorer prognosis, more common in smokers.
    • Immune Checkpoint Inhibitor Therapy:
      • Tumors evade immune detection via the PD-1/PD-L1 pathway.
      • High PD-L1 expression (≥50%) indicates eligibility for pembrolizumab, improving survival in advanced NSCLC.
      • Testing: Routine for guiding immunotherapy.
    • Clinical Importance of Small Biopsy Samples:
      • Vital for diagnosing unresectable NSCLC and conducting molecular tests for actionable mutations.
      • Proper tissue management ensures accurate diagnosis and effective targeted treatment.
    • Conclusion:
      • Understanding risk factors, molecular subtypes, and targeted therapy options is crucial for treating lung cancer, particularly advanced NSCLC.
      • Molecular diagnostics and PD-L1 status play a significant role in determining personalized treatment strategies.

    Overview of Leukaemia

    • Definition and Causes: Leukaemia is a cancer of white blood cells originating in bone marrow due to genetic mutations that cause uncontrolled proliferation of abnormal cells, disrupting normal blood cell production. It is categorized by progression rate (acute vs.chronic) and cell lineage (myeloid vs.lymphoid).
    • Types of Leukaemia:
      • Acute Leukaemia:
        • General Features: Affects all age groups; characterized by rapid growth of immature "blast" cells; without treatment, survival is short. Chemotherapy and stem cell transplants are common treatments.
        • Acute Lymphoblastic Leukaemia (ALL): Common in children; high cure rates in young patients. B-cell lineage (85%) predominates. Markers include CD10, CD19, CD34, and TdT.
        • Cytogenetics of ALL: Prognosis varies with chromosomal changes such as hyperdiploidy and translocations (e.g., t(12;21)).
        • Acute Myeloid Leukaemia (AML): Predominantly affects adults. Involves a variety of subtypes with distinct morphology and genetic markers like t(8;21) and t(15;17). Prognosis informed by cytogenetic studies.
        • Promyelocytic AML Subtype: Notable for clotting issues, treated with retinoic acid and arsenic trioxide. Shows good prognosis.
        • Management: Includes chemotherapy, supportive care (e.g., transfusions), and targeted therapies for specific genetic mutations (e.g., FLT3 inhibitors).
      • Chronic Leukaemia:
        • Chronic Myeloid Leukaemia (CML): Common in adults aged 30-60, linked to the Philadelphia chromosome (t(9;22), BCR-ABL1 fusion). Phases include chronic (long survival) and blast phase (acute). Treated with Tyrosine Kinase Inhibitors (TKIs) like Imatinib, significantly improving 5-year survival rates from 45% to 90%.
        • Chronic Lymphocytic Leukaemia (CLL): Common in older adults, characterized by proliferation of mature B-cells. Symptoms include lymphadenopathy, splenomegaly, and infection susceptibility. CD19, CD5, and CD23 are typical markers. Genetic deletions (e.g., del17p) affect prognosis.
        • Management of CLL: "Watch and wait" strategy, with treatment upon progression using chemotherapy, anti-CD20 antibodies (e.g., Rituximab), or newer inhibitors like Venetoclax.
    • Summary of Key Points:
      • Differentiation between acute and chronic leukaemias and their lineages.
      • Importance of genetic and cytogenetic markers for diagnosis and prognosis.
      • Treatment varies from supportive care to advanced targeted therapies and stem cell transplants.
      • Acute leukaemia presents with rapid progression and marrow failure, while chronic leukaemia may progress slowly and often appears in older adults with milder symptoms.

    Notes on Multiple Myeloma

    • Definition:
      • Plasma cell cancer in bone marrow.
      • Destroys bones, kidneys, possibly heart/nervous system.
      • Part of plasma cell dyscrasias (e.g., MGUS, SMM, plasma cell leukemia, amyloidosis).
    • Epidemiology:
      • Common in ages 60–70.
      • ~13% of blood cancers in Australia, ~2,600 new cases/year.
      • 5-year survival rate ~55%.
      • Risk factors: Age, male, Black race, family history, radiation/chemical exposure, HIV, MGUS history.
    • Pathogenesis:
      • Exhibits cancer hallmarks: unchecked growth, death resistance.
      • Key genetic mutations: TP53, del13, del17p.
      • Notable translocations: t(11;14) (cyclin D1 overexpression, better prognosis).
    • Diagnosis:
      • SLiM CRAB criteria:
        • Plasma cells ≥60% in marrow

    Light Chain Ratio Abnormalities, MRI Bone Lesions, and CRAB Criteria

    • Light chain ratio abnormalities indicate an imbalance between kappa and lambda light chains in serum or urine, a hallmark of multiple myeloma.
    • MRI bone lesions are characteristic findings in multiple myeloma, revealing areas of bone marrow infiltration and destruction.
    • CRAB criteria (Calcium elevation, Renal failure, Anemia, Bone lesions) are used to diagnose multiple myeloma, with at least one criterion needed for a definitive diagnosis.

    Diagnostic Techniques

    • Serum protein electrophoresis (SPEP) detects an M-spike, a distinct band representing monoclonal proteins, a key marker in multiple myeloma.
    • Immunofixation identifies and quantifies specific paraproteins; it helps determine the type of immunoglobulin (e.g., IgG, IgA) involved in the monoclonal gammopathy.
    • Flow cytometry assesses the percentage of plasma cells in the bone marrow and evaluates prognostic markers like CD138, CD38, and CD56.
    • Cytogenetics (FISH/Karyotyping) detects genetic abnormalities, including translocations, deletions, and hyperdiploidy, which influence prognosis and treatment decisions.

    Prognostic Factors

    • Genetic abnormalities like del17p are associated with a poorer prognosis.
    • t(11;14) translocation is linked to better outcomes.

    Treatment Options

    • Chemotherapy (VRD), which combines bortezomib, lenalidomide, and dexamethasone, is a common treatment regimen.
    • Monoclonal antibodies, like Daratumumab, target specific antigens on myeloma cells.
    • Stem cell transplant (autologous) may be used in eligible patients to consolidate remission and enhance long-term survival.
    • Supportive care, including bisphosphonates to prevent bone fractures, blood transfusions, and palliative care, is essential for managing symptoms and improve quality of life.

    Monitoring and Relapse

    • Regular symptom checks, blood tests, and paraprotein monitoring are crucial for assessing treatment response and detecting early relapse.
    • Bone marrow biopsy may be performed if relapse is suspected to confirm the diagnosis and guide further treatment decisions.
    • Alternative treatment strategies, including newer therapies and clinical trials, can be considered in the event of disease progression or relapse.

    Bowel Cancer (Colorectal Cancer - CRC)

    • CRC is a malignant tumor that primarily affects the large bowel or colon.
    • Adenocarcinoma is the most common type, arising from glandular cells lining the bowel.
    • Benign polyps, like hyperplastic polyps, may be pre-malignant.
    • Pre-malignant polyps include adenomas, which have a significant risk of progressing to cancer.

    Prevalence and Impact

    • CRC is a prevalent cancer, particularly in older adults; it is the second most common cancer in Australia.
    • Early detection dramatically improves survival rates, with high cure rates when diagnosed early.

    Risk Factors

    • Age: Primarily affects older individuals, with a small percentage occurring in individuals under 50.
    • Genetics: Family history of CRC, particularly with early-onset disease, and genetic syndromes like Familial Adenomatous Polyposis (FAP) and Lynch syndrome increase the risk.
    • Lifestyle: Diets high in red or processed meat, obesity, and inflammatory bowel disease contribute to increased risk.

    Carcinogenesis and Genetic Pathways

    • CRC develops through the clonal expansion of mutated cells with multiple genetic alterations in regulatory genes.
    • Chromosomal Instability Pathway: Characterized by numerous somatic mutations in genes like APC, TP53, and KRAS, resulting in uncontrolled growth.
    • Microsatellite Instability (MSI) Pathway: Results from defective DNA mismatch repair often involving BRAF mutations and epigenetic changes.
    • POLE Pathway: Involves defective DNA polymerase proofreading, leading to many silent mutations.

    Clinical Presentation

    • Early stages: Often asymptomatic or present with subtle rectal bleeding.
    • Advanced stages: Symptoms may include bowel obstruction, severe hemorrhage, or local complications from tumor invasion.
    • Systemic symptoms: Cachexia (wasting syndrome), paraneoplastic phenomena (symptoms unrelated to the direct effects of the tumor)

    Diagnosis and Staging

    • Screening and Tests
      • Faecal Occult Blood Test (FOBT): Frequently used in national screening programs.
      • Imaging: CT scans, ultrasound, and virtual colonoscopy.
      • Endoscopy: Colonoscopy allows visual inspection of the colon and biopsy for pathological analysis.
    • Pathology: Microscopic analysis and genetic testing to assess the type, grade, and stage of the tumor, determining the best treatment course.
    • Staging System: Uses the TNM (Tumor, Node, Metastasis) system, evaluating tumor size, lymph node involvement, and metastasis.

    Treatment and Prognosis

    • Surgery: Often the primary treatment for localized disease, providing a good chance of cure.
    • Chemotherapy: Used for advanced or metastatic disease, and can be combined with surgery and radiation.
    • Radiation Therapy: Can be used to reduce tumor size, relieve symptoms, or prevent tumor recurrence.
    • Targeted therapies: May be used to block specific molecular pathways involved in the tumor's growth.
    • Five-year survival rates: Have significantly improved due to early detection and advances in treatment.

    Familial Cancer Syndromes

    • Familial Adenomatous Polyposis (FAP): Autosomal dominant disorder caused by mutations in the APC gene, leading to hundreds of adenomas and a near 100% lifetime risk of CRC by age 40.
    • Lynch Syndrome (HNPCC): Associated with fewer polyps but a high risk of CRC and other cancers. It involves mutations in mismatch repair genes (MLH1, MSH2, etc.) and necessitates rigorous screening.

    Prevention and Screening

    • National Bowel Cancer Screening Program: Targets individuals over 50 to detect early signs using FOBT. This initiative has reduced mortality and improved early detection rates.
    • Benefits of Screening: Effective in identifying early cancer or pre-cancerous lesions, cost-effective, and associated with better outcomes.
    • Challenges: Risk of false positives requiring confirmatory colonoscopies.

    Lymphoma Diagnosis

    • Lymphoma: A cancer of the lymphatic system.
    • Categories:
      • B-cell Lymphomas: Many subtypes, including Follicular Lymphoma, Small Lymphocytic Lymphoma (SLL), Diffuse Large B-Cell Lymphoma (DLBCL), Burkitt Lymphoma, Gastric MALT Lymphoma, and Mantle Cell Lymphoma.
      • T-cell Lymphomas
      • Hodgkin Lymphoma
      • Myeloma

    Case Studies and Diagnostic Approach

    • Case 1: Follicular Lymphoma

      • Patient Profile: 81-year-old female with firm, confluent lymph node masses in both groins; no systemic symptoms.
      • Investigation Steps: Lymph node biopsy for histological and immunological studies, flow cytometry, PCR, and FISH for genetic analysis.

    • Fresh Node Triage and Initial Analysis:

      • Smears and H+E staining: Assessing cell morphology.
      • Triage based on findings: Granulomas and necrosis sent to microbiology, anaplastic cells evaluated with electron microscopy, small lymphocytes analyzed by flow cytometry, and high-grade lymphocytes examined via FISH.

    • Diagnostic Findings:

      • Flow Cytometry: Clonal B-cell population (CD19+, CD20+), CD10+, and aberrant BCL2 expression.
      • Histology: Follicular pattern with BCL6 and CD10 positivity.

    • Diagnosis: Follicular lymphoma confirmed.

    • Management: PET scan demonstrated low disease volume, leading to a "watch and wait" strategy.

    • Progression and Transformation:

      • Progression Risk: Approximately 3% annual transformation rate to DLBCL.
      • Genetic Markers: BCL2-IgH fusion common; additional MYC or BCL6 rearrangements indicate higher risk of transformation.
      • Treatment for Transformation: R-CHOP regimen or intensive therapy like HyperCVAD for aggressive types.

    • Case 2: Classical Hodgkin Lymphoma (Nodular Sclerosis Subtype)

      • Patient Profile: 29-year-old male with neck swelling, significant weight loss, night sweats, and fever.
      • Imaging: CT reveals extensive lymphadenopathy.
      • Biopsy Findings: Reed-Sternberg (R-S) cell variants and a fibrotic background.
      • Immunophenotype: CD30+, CD15-, CD45-, weak PAX5 expression. EBER+ indicates EBV association.

    • Diagnosis: Classical Hodgkin Lymphoma, nodular sclerosis subtype.

    • Treatment: Standard ABVD regimen.

    • Prognosis: High cure rate, with PET scans used to monitor treatment response.

    Key Points in Lymphoma Diagnosis and Management

    • Classification: Defined based on B-cell, T-cell, or Hodgkin lymphoma origin, determined by immunophenotyping.
    • Follicular Lymphoma: Diagnosed by the follicular pattern and BCL2 positivity. Managed with observation for indolent cases and R-CHOP for aggressive transformation.
    • Hodgkin Lymphoma: Characterized by R-S cells, CD30+ expression, and EBV association. Treated successfully with the ABVD regimen.
    • Staging and Monitoring: Involves PET scans, bone marrow examination, and organ function assessment to determine optimal treatment.

    Summary of Treatment Protocols

    • Follicular Lymphoma: "Watchful waiting" for indolent cases; R-CHOP for aggressive transformation.
    • Hodgkin Lymphoma: ABVD chemotherapy standard, monitored with PET scans.

    Brain Cancer Lecture Notes

    Learning Objectives

    • Identify various brain tumor types, locations, and incidence patterns.
    • Understand WHO classification criteria for brain tumors.
    • Appreciate the importance of DNA methylation-based diagnostics for accurate tumor classification.

    Overview of the Brain and Central Nervous System (CNS)

    • CNS Structure:
      • Cerebrum: Cognitive functions and voluntary movements.
      • Cerebellum: Balance, coordination, and posture.
      • Diencephalon: Endocrine functions and sensory processing.
      • Brainstem: Vital functions like breathing and heart rate.

    Brain Tumors

    • Definition: Abnormal tissue growth in the brain or spinal cord disrupting CNS function.
    • Tumor Origin:
      • Primary: Originate in brain tissue (infrequently metastasize outside the CNS).
      • Metastatic: Spread to the brain from another primary site.
    • Tumor Types:
      • Benign: Slow-growing, non-cancerous with clear borders.
      • Malignant: Invasive, rapid growth, and high recurrence risk.

    WHO Classification of Brain Tumors

    • Grading System:
      • Grade I: Slow growth; potentially curable with surgery.
      • Grade II: Infiltrative; risk of recurrence.
      • Grade II: Rapidly reproducing, invasive cells.
      • Grade IV: Aggressive, necrotic tumor with high mortality (e.g., Glioblastoma).

    Tumor Locations

    • Supratentorial: Above the cerebellum.
    • Infratentorial: Below the cerebellum.
    • Spinal: Involving the spinal cord.
    • Intra-axial: Within the brain tissue.
    • Extra-axial: Outside the brain tissue.

    Common Brain Tumor Types

    • Gliomas: Most common primary brain tumors, arising from glial cells that support neurons:
      • Astrocytomas: Based on grade, range from low-grade astrocytomas to the highly aggressive glioblastoma multiforme (GBM).
      • Glioblastomas: Fast-growing with a poor prognosis.
      • Ependymomas: Arise in ependymal cells, lining the ventricles.
      • Oligodendrogliomas: Originate from oligodendrocytes, responsible for myelin production.
    • Ependymoma: Originates in ependymal cells; grades I-III. Treatment often involves surgery and radiation.
    • Medulloblastoma: Malignant tumor common in children, occurring in the cerebellum. Classified into four molecular subtypes: WNT, SHH, Group 3, and Group 4.

    Molecular Diagnostics

    • DNA Methylation-Based Diagnostics:
      • Classify tumors based on DNA methylation patterns, improving diagnostic accuracy, treatment decisions, and prognosis.
      • Illumina DNA Methylation Arrays: Used to identify methylation profiles of tumors.
    • Key Molecular Markers:
      • IDH1 Mutation: Found in glioblastomas and associated with a better prognosis.
      • Glioblastoma Subgroups: Divided into RTK I, RTK II, MES, K27, G34, influencing treatment and outcomes.
    • Brain and CNS tumors: Represent ~10% of all cancers.
    • Children: Primarily present with malignant tumors (e.g., medulloblastomas).
    • Adults: Mostly have benign or low-grade tumors, often supratentorial.

    Treatment Approaches

    • Glioblastoma (GBM): Involves surgery, temozolomide chemotherapy, and radiation therapy. Median survival is approximately 14 months.
    • Ependymoma: Surgery followed by focal radiation.
    • Medulloblastoma: Surgery, multi-agent chemotherapy, and craniospinal radiation.

    Prostate Cancer Summary

    1. Normal Prostate Anatomy & Histology

    • Prostate: Composed of basal cells, epithelial cells, and stromal tissue.
    • Androgen Dependence: Relies on androgens (testosterone, androstenedione, and dihydrotestosterone) for growth and survival.
    • Absence of Androgens: Leads to apoptosis (programmed cell death) in glandular cells.

    2. Characteristics of Prostate Cancer

    • Most Common Type: Prostatic adenocarcinoma.
    • Rare Types: Urothelial carcinoma, squamous cell carcinoma, sarcomas, and lymphoma.
    • Prevalence: Highly common among men, a leading cause of cancer-related deaths.
    • Lifetime Risk: Approximately 1 in 6 for diagnosis and 1 in 30 for death.

    3. Risk Factors

    • Age: Risk increases with age.
    • Ethnicity: Higher risk in Black males; lowest in Asian males.
    • Family History: Doubled risk with a first-degree relative diagnosed.
    • Genetics: Mutations in DNA repair genes (e.g., BRCA1/BRCA2).
    • Lifestyle: Obesity and high-fat diets are linked to higher risk.

    4. Clinical Presentation

    • Early Stage: Often asymptomatic.
    • Advanced Symptoms: Urinary issues (frequency, urgency, hesitancy), bone pain, and hematuria.

    5. Screening and PSA Testing

    • PSA (Prostate-Specific Antigen): A protein produced by prostate cells, elevated in cancer, hyperplasia, or inflammation.
    • Screening: Controversial due to false positives and treatment side effects.
    • Guidelines: Recommend discussing screening with physicians between ages 50-70.

    6. Pathology & Gleason Scoring

    • Cancerous Features: Small, crowded, infiltrative glands without basal layers, enlarged nuclei, and prominent nucleoli.
    • Gleason Score: Based on glandular patterning:
      • Pattern 3: Well-formed glands.
      • Pattern 4: Poorly formed, fused glands.
      • Pattern 5: Sheets or necrotic cells.
    • Gleason Score Calculation: Combination of the most prevalent and worst patterns (e.g., 3+4=7).
    • Grade Groups: Range from 1 (least aggressive) to 5 (most aggressive).

    7. Staging and Prognosis

    • Factors: Tumor type, size, Gleason score, TNM stage, lymph node involvement, and metastasis.
    • Disease Heterogeneity: Ranges from indolent to very aggressive forms.

    8. Treatment Options

    • Localized (Stage I/II):
      • Active surveillance: Close monitoring without immediate treatment.
      • Surgery (radical prostatectomy): Removal of the prostate gland.
      • Radiation therapy: Destroying cancer cells with high-energy rays.
    • Locally Advanced (Stage III): Combination of surgery, radiation, and hormone therapy.
    • Metastatic (Stage IV): Hormone therapy, chemotherapy, and palliative radiation.
    • Hormone Therapy: Androgen deprivation therapy (ADT), which blocks androgen production or receptor activation.
    • Castration Resistance: Prostate cancer can adapt and continue growing through genetic changes or pathway alterations.

    9. Androgen Deprivation Therapy (ADT)

    • Mechanism: Blocks androgen production or receptor activation.
    • Castration Resistance: Prostate cancer can become resistant to ADT through various mechanisms like androgen receptor gene mutations, receptor promiscuity, or activation of alternate pathways.

    10. Key Points

    • High Prevalence: A common cancer with a wide spectrum of aggressiveness.
    • Gleason Score: Crucial for determining prognosis and treatment choices.
    • Histological Markers: Crowded, infiltrative glands, absent basal layers, and large nuclei with nucleoli are typical for prostate cancer.

    Hallmarks of Cancer

    • Cancer cells sustain proliferative signaling by deregulating growth-promoting signals. Examples include activation of growth factors, mutations, and disrupted feedback mechanisms, such as in RAS mutations.
    • Cancer cells evade growth suppressors by inactivating tumor suppressor genes (TSGs) like RB and TP53.
    • Cancer cells resist cell death by:
      • Loss of TP53 function
      • Increasing antiapoptotic regulators (Bcl-2, Bcl-xl)
      • Downregulating proapoptotic factors (Bax, Bim, Puma)
      • Short-circuiting extrinsic death pathways.
    • Cancer cells enable replicative immortality by activating telomerase, which maintains telomere length, allowing unlimited division.
    • Cancer cells induce angiogenesis by continuously forming new blood vessels, creating an abnormal vasculature.
    • Cancer cells activate invasion and metastasis by:
      • Undergoing the epithelial-mesenchymal transition (EMT), making the cells more mobile and invasive.
      • Losing E-cadherin expression.
    • Cancer cells deregulate cellular metabolism by exhibiting the Warburg effect (aerobic glycolysis).
    • Cancer cells avoid immune destruction by creating an immunosuppressive tumor microenvironment.
    • Cancer cells have enabling characteristics including:
      • Genome instability and mutation
      • Tumor-promoting inflammation

    Sustained Proliferative Signaling

    • Cancer cells can sustain proliferative signaling through various mechanisms, including:
      • Autocrine proliferative signaling
      • Signaling to normal cells within the tumor associated stroma (reactive stroma)
      • Elevated levels of receptor proteins on cancer cells, making them hyper-responsive to growth factor ligands.
      • Growth factor independence by continual activation of downstream signaling pathways

    Evading Growth Suppressors

    • Two critical tumor suppressor genes are:
      • Retinoblastoma-associated (RB): Integrates signaling to progress the cell cycle
      • TP53: "Guardian of the genome" regulates genes involved in growth arrest, and plays a role in processes including apoptosis, senescence, autophagy, and metabolic changes.

    Resisting Cell Death

    • Necrosis is uncontrolled cell death associated with inflammatory responses, including:

      • Cell enlargement
      • Loss of membrane integrity
      • Leakage of cell contents
      • Inflammation
      • Nuclear degeneration

    • Autophagy helps cancer cells survive under stress, and necrosis promotes tumor-supportive inflammation.

    Enabling Replicative Immortality

    • Telomerase activation in cancer cells maintains telomere length, enabling unlimited cell division.
    • Telomerase has other functions in tumorigenesis:
      • Amplify signalling by the Wnt pathway
      • Enhance cell proliferation
      • Resistance to apoptosis
      • DNA-damage repair involvement.

    Inducing Angiogenesis

    • Regulators such as VEGF-A (pro-angiogenic) and TSP-1 (anti-angiogenic) control angiogenesis, which involves the migration, growth, and differentiation of endothelial cells.
    • Angiogenesis drives tumor progression.

    Activating Invasion and Metastasis

    • EMT allows cancer cells to:
      • Remodel cell-cell interactions
      • Remodel interactions between cells and the extracellular matrix promoting tumor progression.
      • Loss of E-cadherin mediates contact inhibition of proliferation (CIP) in normal cells.
      • Transcription factors (TFs) like Snail, Slug, Twist, Zeb1/2 initiate EMT by inhibiting E-cadherin expression, leading to increased tumor cell motility and invasiveness.

    Deregulating Cellular Metabolism

    • The Warburg effect, aerobic glycolysis even in the presence of oxygen, supports rapid growth in cancer cells.
    • Oncogenes like RAS and MYC, and TSGs like TP53 facilitate the metabolic shift.
    • Upregulation of glucose transporters (e.g., GLUT1) to the cytoplasm is triggered by hypoxia and TFs like HIF1α and HIF2α.

    Avoiding Immune Destruction

    • Cancer cells utilize factors like TGF-β to suppress immune responses, creating an immunosuppressive tumor microenvironment (TME).

    Genome Instability and Mutation

    • Mutations in DNA repair genes, such as BRCA1, contribute to cancer development.
    • Chromosomal instability (CIN) is the most common form of genomic instability.
    • In hereditary cancers, mutations in DNA repair genes like BRCA1 are associated with both CIN and non-CIN forms of genomic instability.
    • In sporadic (non-hereditary) cancers, genomic instability, at least at early stages, is not primarily due to mutations in DNA repair or mitotic checkpoint genes.

    Tumor-Promoting Inflammation

    • Inflammatory cells and molecules in the TME support cancer progression by:
      • Providing growth factors
      • Aiding metastasis
      • Promoting transformation, proliferation, angiogenesis, and metastasis
      • Supplying bioactive molecules like growth factors and survival factors.
    • Immune cells contribute to tumor-promoting inflammation by producing inflammatory mediators like cytokines, chemokines, transforming growth factors, and adhesion molecules.
    • Aberrant expression and secretion of proinflammatory and growth factors by tumor cells attract immune cells, resulting in mutual crosstalk which further promotes cancer development.

    Light Chain Ratio Abnormalities, MRI Bone Lesions, and CRAB Criteria

    • Light chain ratio abnormalities are a hallmark of multiple myeloma (MM), a cancer of plasma cells.
    • Bone lesions are often seen on MRI scans and can be a sign of MM.
    • CRAB criteria are used to diagnose MM and include:
      • Calcium Elevation
      • Renal failure
      • Anemia
      • Bone lesions

    Multiple Myeloma Diagnosis and Prognosis

    • Blood tests are used to check for anemia, calcium levels, and renal function.
    • Bone marrow biopsy is necessary to confirm a diagnosis of MM, with at least 10% plasma cells required.
    • Serum protein electrophoresis (SPEP) identifies an M-spike, indicating the presence of monoclonal proteins.
    • Immunofixation detects and quantifies specific paraproteins, such as IgG and IgA.
    • Flow cytometry assesses plasma cells and prognostic markers like CD138, CD38, and CD56.
    • Cytogenetics (FISH/Karyotyping) detects chromosomal abnormalities like translocations, deletions, and hyperdiploidy.
    • Genetic abnormalities like del17p are associated with a poor prognosis.
    • t(11;14) translocation is linked to better outcomes.

    Multiple Myeloma Treatment Options

    • Chemotherapy is used for MM, often using the VRD regimen (Bortezomib, Lenalidomide, Dexamethasone).
    • Monoclonal antibodies like Daratumumab are increasingly used in MM treatment.
    • Stem cell transplant (autologous) is a treatment option for some patients.
    • Supportive care includes bisphosphonates to prevent bone complications, transfusions for anemia, and palliative care.

    Monitoring and Relapse in Multiple Myeloma

    • Regular monitoring includes symptom assessment, blood tests, and paraprotein checks.
    • Bone marrow biopsy is performed if relapse is suspected.
    • Alternative treatments may be considered in case of relapse or resistance to initial therapies.

    Bowel Cancer: Definition and Types

    • Bowel cancer is a malignant neoplasm (cancerous growth) in the bowel, primarily the large bowel or colon.
    • Carcinoma of the Large Bowel is the most common type and is called colorectal carcinoma. It arises from glandular cells lining the bowel.
    • Other types of bowel cancer are less common and include lymphomas, neuroendocrine tumors, GISTs, sarcomas, and metastases from other sites.
    • Benign polyps are growths that can be neoplastic (hyperplastic) or non-neoplastic (hamartomatous or inflammatory).
    • Pre-malignant polyps are adenomas with the potential to progress to cancer.

    Bowel Cancer: Significance and Risk Factors

    • Prevalence: Bowel cancer is a common cancer, especially in older adults.
    • Impact: It is often less emphasized than other cancers but early detection significantly improves outcomes.
    • Risk factors:
      • Age: Predominantly affects older individuals, but 10% occur in people under 50.
      • Genetics: Family history and genetic syndromes like FAP and Lynch syndrome increase risk.
      • Lifestyle: Diet high in red and processed meats, obesity, and inflammatory bowel disease are associated.
      • Genetic Susceptibility: Increased risk with affected first-degree relatives, especially if they developed cancer at a young age.

    Bowel Cancer: Carcinogenesis and Pathways

    • Mechanism: Bowel cancer develops through the clonal expansion of mutated cells.
    • Multiple genetic mutations in regulatory genes lead to uncontrolled growth.
    • Key pathways:
      • Chromosomal Instability Pathway: Involves many somatic alterations affecting genes like APC, TP53, and KRAS, associated with the adenoma-carcinoma sequence.
      • Microsatellite Instability (MSI) Pathway: Caused by defective DNA mismatch repair, often with BRAF mutations and epigenetic changes.
      • POLE Pathway: Involves defective DNA polymerase proofreading, resulting in many silent mutations.

    Bowel Cancer: Clinical Presentation, Diagnosis, and Treatment

    • Early stages: Usually asymptomatic or present with subtle bleeding (melena).
    • Advanced stages: Symptoms can include bowel obstruction, severe hemorrhage, cachexia, and paraneoplastic phenomena.
    • Diagnosis:
      • Faecal Occult Blood Test (FOBT): Used in national screening programs.
      • Imaging: CT scans, ultrasound, virtual colonoscopy.
      • Endoscopy: Colonoscopy for visual inspection and biopsy.
      • Pathology involves microscopic analysis and genetic testing to assess tumor type, grade, and stage.
    • Staging: Follows the TNM system, based on tumor size, lymph node involvement, and metastasis.
    • Treatment:
      • Surgery is often the primary treatment.
      • Chemotherapy, radiation, and targeted therapies are used for advanced disease.
    • Survival rates have improved significantly with early detection and advanced therapies.

    Familial Cancer Syndromes Associated with Bowel Cancer

    • Familial Adenomatous Polyposis (FAP): Autosomal dominant disorder caused by mutations in the APC gene, leading to hundreds of adenomas and nearly 100% risk of cancer by age 40.
    • Lynch Syndrome (HNPCC): Characterized by fewer polyps but a high risk of CRC and other cancers. Involves mutations in mismatch repair genes (MLH1, MSH2, etc.) and requires intensive screening.

    Bowel Cancer: Prevention and Screening

    • National Bowel Cancer Screening Program: Targets individuals over 50 to detect early signs using FOBT.
    • Benefits of screening: Effective in detecting early cancer or precursor lesions, cost-effective, and associated with better outcomes.

    Lymphoma: Overview and Classification

    • Lymphoma is a cancer of the lymphatic system.
    • Two main categories:
      • B-cell Lymphomas: Include Follicular, Small Lymphocytic Lymphoma (SLL), Diffuse Large B-Cell Lymphoma (DLBCL), Burkitt, Gastric MALT, and Mantle Cell Lymphoma.
      • T-cell Lymphomas: Include Mycosis fungoides and Sézary syndrome.
      • Hodgkin Lymphoma
      • Myeloma

    Case Studies and Diagnostic Approach to Lymphoma

    • Case 1: Follicular Lymphoma
      • Patient: 81-year-old female with longstanding, firm lumps in both groins, no systemic symptoms.
      • Findings: Confluent masses up to 3 cm, normal FBP.
      • Investigation: Lymph node biopsy, fresh node processed for microbiology, flow cytometry, histology, PCR, and FISH if needed.
      • Diagnostic findings:
        • Flow Cytometry: Clonal B-cell population (CD19+, CD20+), CD10+, aberrant BCL2 expression.
        • Histology: Follicular pattern, BCL6, CD10 positivity.
      • Diagnosis: Follicular Lymphoma.
      • Management: PET scan shows low disease volume, "watch and wait" strategy adopted.
    • Progression and transformation in Follicular Lymphoma:
      • Progression risk: ~3% annual transformation rate, often to DLBCL.
      • Genetic markers: BCL2-IgH fusion is common, additional MYC or BCL6 rearrangements indicate higher risk.
      • Treatment for transformation: R-CHOP regimen or intensive therapy like HyperCVAD for aggressive types.
    • Case 2: Classical Hodgkin Lymphoma (Nodular Sclerosis Subtype)
      • Patient: 29-year-old male with neck swelling, significant weight loss, night sweats, and fever.
      • Imaging: CT reveals extensive lymphadenopathy.
      • Biopsy findings: Reed-Sternberg (R-S) cell variants and a fibrotic background.
      • Immunophenotype: CD30+, CD15-, CD45-, weak PAX5 expression; EBER+ indicates EBV association.
      • Diagnosis: Classical Hodgkin Lymphoma, nodular sclerosis subtype.
      • Treatment: Standard ABVD regimen. High cure rate, with PET scans for monitoring treatment response.

    Key Points in Lymphoma Diagnosis and Management

    • Classification: Based on B-cell, T-cell, or Hodgkin origin, identified via immunophenotyping.
    • Follicular Lymphoma: Diagnosed by follicular pattern and BCL2 positivity. Managed with observation for indolent cases, transformed cases require R-CHOP.
    • Hodgkin Lymphoma: Characterized by R-S cells, CD30+, and EBV association. Treated with ABVD, achieving high cure rates.
    • Staging and Monitoring: Involves PET scans, bone marrow examination, and assessing organ function to plan treatment.

    Summary of Treatment Protocols for Lymphoma

    • Follicular Lymphoma: Watchful waiting for indolent cases; R-CHOP for aggressive transformation.
    • Hodgkin Lymphoma: ABVD chemotherapy is the standard treatment, with PET scans to confirm remission.

    Brain and Central Nervous System (CNS) Tumors: Overview

    • CNS structure:
      • Cerebrum: Cognitive functions, voluntary movements.
      • Cerebellum: Balance, coordination, posture.
      • Diencephalon: Endocrine functions, sensory processing.
      • Brain Stem: Vital functions like breathing and heart rate.
    • Brain tumors: Abnormal tissue growth in the brain or spine, disrupting CNS function.
      • Primary: Originate in brain tissue (rarely spread outside the CNS).
      • Metastatic: Originate elsewhere and spread to the brain.
    • Types:
      • Benign: Slow-growing, non-cancerous, clear borders.
      • Malignant: Invasive, rapid growth, high recurrence risk.

    WHO Classification of Brain Tumors

    • Grading system:
      • Grade I: Slow growth, potentially curable with surgery.
      • Grade II: Infiltrative, risk of recurrence.
      • Grade III: Rapidly reproducing, invasive cells.
      • Grade IV: Aggressive, necrotic, high mortality (e.g., Glioblastoma).

    Brain Tumor Locations

    • Supratentorial: Above the cerebellum.
    • Infratentorial: Below the cerebellum.
    • Spinal: Spine.
    • Intra-axial: Within brain tissue.
    • Extra-axial: Outside brain tissue.

    Common Brain Tumor Types

    • Gliomas: Most common primary brain tumor, arising from glial cells. Include astrocytomas, glioblastomas, ependymomas, oligodendrogliomas.
    • Ependymomas: Originate in ependymal cells; grades I-III, treatment involves surgery and radiation.
    • Medulloblastoma: Malignant tumor common in children, occurring in the cerebellum; with four molecular subtypes: WNT, SHH, Group 3, and Group 4.

    Molecular Diagnostics in Brain Tumors

    • DNA Methylation-Based Diagnostics: Classify tumors using DNA methylation patterns, aiding in diagnosis, treatment decisions, and prognosis.
    • Illumina DNA Methylation Arrays: Tools to identify methylation profiles of tumors.
    • Key Molecular Markers:
      • IDH1 Mutation: Found in glioblastomas, associated with better prognosis.
      • Glioblastoma Subgroups: RTK I, RTK II, MES, K27, G34, influencing treatment and outcomes.
    • Brain and CNS tumors account for ~10% of all cancers.
    • Children: Primarily present with malignant tumors (e.g., medulloblastomas).
    • Adults: Mostly have benign or low-grade tumors, often supratentorial.

    Brain Tumor Treatment Approaches

    • Glioblastoma (GBM): Surgery, temozolomide chemotherapy, radiation (median survival ~14 months).
    • Ependymoma: Surgery followed by focal radiation.
    • Medulloblastoma: Surgery, multi-agent chemotherapy, and cranio-spinal radiation.

    Prostate Cancer Summary

    • Normal Prostate Anatomy: Composed of basal cells, epithelial cells, and stromal tissue. Dependent on androgens (testosterone, androstenedione, dihydrotestosterone) for growth and survival. Androgen depletion causes cell apoptosis.
    • Prostate Cancer:
      • Most common: Prostatic adenocarcinoma.
      • Rare types: Urothelial carcinoma, squamous cell carcinoma, sarcomas, lymphoma.
      • Prevalence: Highly common among men, a leading cause of cancer-related deaths. Lifetime risk is 1 in 6 for diagnosis and 1 in 30 for death.

    Prostate Cancer: Risk Factors

    • Age: Risk increases with age.
    • Ethnicity: Higher risk in Black males, lowest in Asian males.
    • Family History: Doubled risk with a first-degree relative diagnosed.
    • Genetics: Mutations in DNA repair genes (e.g., BRCA1/BRCA2).
    • Lifestyle: Obesity and high-fat diets are linked to higher risk.

    Prostate Cancer: Clinical Presentation and Diagnosis

    • Early Stage: Often asymptomatic.
    • Advanced Symptoms: Urinary issues (frequency, urgency, hesitancy), bone pain, hematuria.
    • Diagnosis: Typically follows an elevated PSA test and biopsy.

    Prostate Cancer: Screening and PSA Testing

    • PSA: A protein produced by prostate cells; elevated in cancer, hyperplasia, or inflammation.
    • Screening: Controversial due to false positives and treatment side effects. Guidelines recommend discussing screening between ages 50-70.

    Prostate Cancer: Pathology and Gleason Scoring

    • Cancerous Features: Small, crowded, infiltrative glands without basal layers, enlarged nuclei, and prominent nucleoli.
    • Gleason Score:
      • Pattern 3: Well-formed glands.
      • Pattern 4: Poorly formed, fused glands.
      • Pattern 5: Sheets or necrotic cells.
      • Score: Combination of the most prevalent and worst patterns (e.g., 3+4=7).
      • Grade Groups: Range from 1 (least aggressive) to 5 (most aggressive).

    Prostate Cancer: Staging and Prognosis

    • Factors: Tumor type, size, Gleason score, TNM stage, lymph node involvement, and metastasis.
    • Heterogeneity: Disease can range from indolent to aggressive forms.

    Prostate Cancer: Treatment Options

    • Localized (Stage I/II):
      • Active surveillance: Monitoring disease progression.
      • Surgery: Radical prostatectomy.
      • Radiation.
    • Locally Advanced (Stage III):
      • Surgery:
      • Radiation:
      • Hormone therapy.
    • Metastatic (Stage IV):
      • Hormone therapy:
      • Chemotherapy:
      • Palliative radiation.
    • Hormone Therapy:
      • Androgen deprivation: Blocks androgen production or receptor activation.
      • Castration resistance: Prostate cancer can adapt through genetic changes or pathway alterations to continue growing.
    • Androgen Deprivation Therapy (ADT):
      • Mechanism: Blocks androgen production or receptor activation.
      • Castration Resistance: Prostate cancer can adapt through genetic changes or pathway alterations to continue growing.

    Key Points in Prostate Cancer

    • High prevalence and wide spectrum of disease aggressiveness.
    • Gleason Score: Crucial for prognosis and treatment.
    • Histological markers: Crowded, infiltrative glands, absent basal layers, and large nuclei with nucleoli.

    Hallmarks of Cancer

    • Cancer cells continuously stimulate their own growth by deregulating growth-promoting signals.
    • Mechanisms include activation of growth factors, mutations, and disrupted feedback mechanisms.

    Sustained Proliferative Signaling

    • Ways of sustaining proliferative signalling:
      • Autocrine proliferative signaling
      • Signaling to normal cells within tumour associated stroma (reactive stroma)
      • Elevated levels of receptors proteins on cancer cells making them hyper-responsive to limiting amounts of GF ligands (e.g. epidermal growth factor receptor)
      • GF independence by continual/constitual activation of downstream signalling pathways
    • Somatic mutations activate additional downstream pathways.
    • Disruptions of negative-feedback mechanisms:
      • Oncogenic mutations affecting ras genes compromise Ras GTPase activity
      • In normal cells, Ras GTPase drives negative-feedback
      • Ras mutations cause Ras GTPase INACTIVITY, disrupting negative-feedback

    Evading Growth Suppressors

    • Involves the inactivation of TGS (e.g., RB and TP53) that regulate cell growth and division.
    • Two critical tumour suppressor genes encode:
      • Retinoblastoma-associated (RB)
        • Integrates signals extracellular and intracellular -> progress cell cycle
        • Directly or indirectly inactivated in nearly all human cancers
      • TP53 proteins
        • “Guardian of the genome” Regulates several genes that are involved in growth arrest
        • Plays role in other processes such as:
          • Apoptosis (programmed cell death)
          • Senescence (irreversible cell cycle arrest)
          • Autophagy
          • Metabolic changes in the cell
        • P53 is found to be mutated in over half of cancers including ovarian, colon, oesophageal and blood cancers

    Resisting Cell Death

    • Tumor cells avoid apoptosis by:
      • loss of TP53 tumor suppressor function
      • increasing expression of antiapoptotic regulators (Bcl-2, Bcl-xl) or of survival signals (Igf1/2), by downregulating proapoptotic factors (Bax, Bim, Puma)
      • short-circuiting the extrinsic ligand-induced death pathway
    • Necrosis (extrinsic): Uncontrolled cell death in response to overwhelming noxious stimulus from outside the cell.

    Enabling Replicative Immortality

    • Telomerase activation in cancer cells maintains telomere length, enabling unlimited cell division.

    Inducing Angiogenesis

    • Continuous new blood vessel formation -> abnormal vasculature.
    • This process involves migration, growth and differentiation of endothelial cells.

    Activating Invasion and Metastasis

    • Invasion and metastasis occur in multiple steps:
      • Local invasion
      • Intravasation
      • Extravasation
      • Micro-metastases
      • Colonisation
    • The Epithelial-Mesenchymal Transition (EMT) makes cancer cells mobile and invasive.
    • Loss of E-cadherin and EMT:
      • E-cadherin mediates Contact Inhibition of Proliferation (CIP)
      • Normal cells stop proliferating once they reach confluence upon homophilic E-cadherin binding
      • Cells that lose E-cadherin or have mutated E-cadherin continue proliferating
      • Loss of E-cadherin is key for EMT and tumor progression

    Deregulating Cellular Metabolism

    • Cancer cells exhibit the Warburg effect, aerobic glycolysis (lactase) even with oxygen.
    • Upregulation of glucose transporters (eg GLUT1) to the cytoplasm through Hypoxia and TF such as HIF1α and HIF2α

    Avoiding Immune Destruction

    • Cancer cells create an immunosuppressive tumor microenvironment (TME), utilizing factors like TGF-β to inhibit immune responses.

    Enabling Characteristics

    Genome Instability and Mutation

    • Mutation in DNA repair genes like BRCA1
    • The most common is chromosomal instability (CIN)
    • In hereditary cancers the presence of both CIN and non-CIN forms of genomic instability have been linked to mutations in DNA repair genes, eg germline mutation in breast cancer susceptibility 1 (BRCA1)
    • In sporadic (non-hereditary) cancers, genomic instability, at least at early stages of cancer development, is not due to mutations in DNA repair genes

    Tumor-Promoting Inflammation

    • Inflammatory cells and molecules in TME support cancer progression by providing GF and aiding metastasis.
    • Inflammation -> immune suppression, creating a pro-tumor environment.
    • Immune cells, through the production of inflammatory mediators such as cytokines, chemokines, transforming growth factors, and adhesion molecules can support tumor progression

    Breast Cancer

    Risk Factors

    • Gender & Age: Predominantly affects women; risk increases with age.
    • Previous Breast Cancer: History of breast cancer increases risk.
    • Estrogen Exposure: Long-term exposure (early menarche, late menopause, obesity, contraceptives) raises risk.
    • Pregnancy: Nulliparity/late pregnancy increases risk; early pregnancy has protective effects.
    • Genetics: Family history, BRCA1/BRCA2 mutations.
    • Breast Density: Higher density correlates with increased risk.
    • Radiation Exposure: Prior exposure increases risk.

    Hereditary Breast Cancer

    • Characteristics: Younger onset, bilateral presentation.
    • BRCA1/BRCA2: Tumor suppressor genes (autosomal dominant) involved in DNA repair.
    • Increase risk for other cancers.
    • Other Syndromes: Li-Fraumeni (TP53 mutation), Cowden’s disease (PTEN mutation).

    Pathology

    • Benign Lesions: Generally, non-proliferative conditions have minimal risk.
    • Proliferative Conditions: With or without atypia; atypia (e.g., atypical hyperplasia) significantly increases cancer risk.
    • In Situ Breast Cancer:
      • DCIS: Non-invasive; confined to ducts, precursor to invasive cancer. Managed with surgical excision and possibly radiotherapy.
      • LCIS: Non-obligate precursor; associated with increased bilateral risk of future invasive cancer.

    Invasive Breast Cancer

    • Characteristics: Malignant cells invade beyond the basement membrane; potential for metastasis.
    • Clinical Signs: Lump, pain, nipple/skin changes, and distant manifestations.
    • Types: Majority are invasive ductal carcinoma (80%); 10% are invasive lobular carcinoma. Others include special subtypes.
    • Staging and Workup: AJCC system; histological type, grade, and stage, assessed via pathology and radiology (MMG, US, MRI).

    Prognostic and Predictive Biomarkers

    • ER/PR: Hormone receptor positivity indicates responsiveness to hormonal therapy and better prognosis.
    • HER2: Overexpression linked to aggressive behavior but targetable with drugs like trastuzumab.
    • Molecular Subtypes: Luminal A/B, HER2-enriched, Basal-like; used for prognosis and treatment planning.

    Treatment

    • Surgery: Lumpectomy or mastectomy, with potential lymph node assessment.
    • Radiotherapy: Reduces recurrence, particularly post-surgery.
    • Hormonal Therapy: For ER/PR-positive cancers (e.g., tamoxifen).
    • Chemotherapy & Targeted Therapy: For HER2-positive and high-risk patients.

    Melanoma

    • Melanoma is a malignant tumor originating from melanocytes, the cells that produce melanin.
    • Early detection significantly improves survival rates compared to late-stage melanoma.

    Risk Factors

    • Skin Type: Fair skin, higher susceptibility to UV damage
    • UV Radiation: Exposure from sunlight or tanning beds
    • Moles (Naevi): High number of benign or atypical moles
    • Family History: Family melanoma history increases risk
    • Previous Melanoma: Prior melanoma increases recurrence risk
    • Immunosuppression: Weakened immune system
    • Chemical Exposure: Contact with harmful chemicals

    Development Model

    • Benign Naevus: Small, well-defined, even-colored. Histology shows symmetrical structure and maturation of cells in deeper layers.
    • Spitz Naevus: Common in young people; can resemble melanoma.
    • Blue Naevus: Darker due to pigmented cells in the dermis.
    • Dysplastic Naevus: Larger with irregular borders and varied colors. Higher risk of melanoma, especially with family history (Dysplastic Naevus Syndrome).
    • Melanoma: Characterized by asymmetry, irregular borders, color variation, size (>6mm), and evolution over time.

    Growth Phases

    • Radial Growth: Melanoma in situ with limited dermal invasion, lacks metastatic potential.
    • Vertical Growth: Invasive expansion into dermis, larger nests, mitotic activity, and potential for metastasis.

    Prognostic Indicators

    • Tumor Thickness: Measured as Breslow thickness.
    • Invasion Level: Clark level of invasion
    • Ulceration: Linked to worse outcomes.
    • Mitotic Rate: Higher rate suggests poor prognosis.
    • Lymphovascular/Perineural Invasion: Indicates aggressive cancer.
    • Satellite Lesions: Presence may signal spread.

    Key Genetic Mutations

    • BRAF: Present in ~66% of melanomas, especially V600E mutation, activates MAPK pathway. Mutation testing helps identify candidates for BRAF inhibitors in metastatic cases.
    • NRAS: Found in ~15% of melanomas.
    • KIT: Common in melanomas on mucosal sites, nails, or chronically sun-exposed skin.
    • CDKN2A: Encodes tumor suppressors (p16, p14) involved in cell cycle control.
    • TERT Promoter Mutations: Present in ~70% of melanomas, increase telomerase activity, promoting replicative immortality.

    Clinical Implications

    • BRAF Testing: Identifies candidates for targeted therapy with BRAF inhibitors, which improves survival in metastatic melanoma

    Lung Cancer

    Major Categories of Lung Cancer

    • Small Cell Carcinoma (14%):
      • Highly aggressive and associated with smoking; usually non-resectable and treated with chemoradiotherapy.
      • Central lung location, neuroendocrine differentiation, ectopic hormone production, and high metastatic potential.
    • Non-Small Cell Lung Carcinoma (NSCLC):
      • Resectable when possible; requires detailed subtyping and molecular diagnostics for targeted therapy. Includes:
        • Adenocarcinoma (38%): Common in smokers and non-smokers, peripheral origin, high rate of extrathoracic metastasis. In-situ form: Lepidic growth without invasion, ground-glass appearance on CT.
        • Squamous Cell Carcinoma (20%): Strong link to smoking, centrally located, locally aggressive, prone to necrosis/cavitation. Histology: Keratinization, intercellular bridges.
        • Large Cell Carcinomas and Variants: Includes rarer subtypes like adenosquamous and sarcomatoid carcinoma.

    Key Molecular Subtypes

    • EGFR Mutation (10-50%): More common in non-smokers, especially East Asians; associated with better outcomes using tyrosine kinase inhibitors. Common mutations in exons 19 and 21.
    • ALK Rearrangement (~4%): Found in younger, light or never-smokers; often detected using FISH, IHC, or NGS. Responds well to targeted therapy (e.g., crizotinib).
    • KRAS Mutation: Associated with poorer prognosis, more common in smokers.

    Immune Checkpoint Inhibitor Therapy

    • Tumors evade immune detection via PD-1/PD-L1 pathway.
    • High PD-L1 expression (≥50%) indicates eligibility for pembrolizumab, improving survival in advanced NSCLC.

    Clinical Importance of Small Biopsy Samples

    • Vital for diagnosing unresectable NSCLC and conducting molecular tests for actionable mutations
    • Proper tissue management ensures accurate diagnosis and effective targeted treatment

    Leukaemia

    • Leukaemia is a cancer of white blood cells originating in bone marrow due to genetic mutations.
    • It is categorized by progression rate (acute vs.chronic) and cell lineage (myeloid vs.lymphoid).

    Types of Leukaemia

    Acute Leukaemia

    • General Features: Affects all age groups; characterized by rapid growth of immature "blast" cells; without treatment, survival is short. Chemotherapy and stem cell transplants are common treatments.
    • Acute Lymphoblastic Leukaemia (ALL): Common in children; high cure rates in young patients. B-cell lineage (85%) predominates. Markers include CD10, CD19, CD34, and TdT.
    • Acute Myeloid Leukaemia (AML): Predominantly affects adults. Involves a variety of subtypes with distinct morphology and genetic markers like t(8;21) and t(15;17)

    Chronic Leukaemia

    • Chronic Myeloid Leukaemia (CML): Common in adults aged 30-60, linked to the Philadelphia chromosome (t(9;22), BCR-ABL1 fusion).
    • Chronic Lymphocytic Leukaemia (CLL): Common in older adults, characterized by proliferation of mature B-cells.

    Multiple Myeloma

    • Plasma cell cancer in bone marrow that destroys bones, kidneys, possibly heart/nervous system.
    • Part of plasma cell dyscrasias (e.g., MGUS, SMM, plasma cell leukemia, amyloidosis).

    Epidemiology

    • Common in ages 60–70.
    • 13% of blood cancers in Australia, ~2,600 new cases/year.
    • 5-year survival rate ~55%.
    • Risk factors: Age, male, Black race, family history, radiation/chemical exposure, HIV, MGUS history.

    Pathogenesis

    • Exhibits cancer hallmarks: unchecked growth, death resistance.
    • Key genetic mutations: TP53, del13, del17p.
    • Notable translocations: t(11;14) (cyclin D1 overexpression, better prognosis).

    Diagnosis

    • SLiM CRAB criteria:
      • Plasma cells ≥60% in marrow.
      • Lytic bone lesions on imaging.
      • M protein by serum protein electrophoresis, or monoclonal free light chain (FLC) abnormality.
      • ≥10% clonal plasma cells in bone marrow.
      • Hypercalcemia.

    Treatment

    • Treatment aims to achieve remission and control progression of disease using various approaches:

      • Chemotherapy

      • Immunomodulatory Drugs (e.g., Thalidomide, Lenalidomide, Pomalidomide)

      • Proteasome Inhibitors (e.g., Bortezomib, Carfilzomib)

      • Monoclonal Antibodies (e.g., Daratumumab, Elotuzumab)

      • Stem Cell Transplantation

      • Other supportive therapies including bisphosphonates for bone disease, pain management, and supportive measures for patients with renal insufficiency.### Multiple Myeloma

    •  Key Features: A type of blood cancer affecting plasma cells, characterized by bone lesions, light chain ratio abnormalities, and CRAB criteria (Calcium elevation, Renal failure, Anemia, Bone lesions).

    • Diagnosis: Requires a bone marrow biopsy showing ≥10% plasma cells, along with blood tests (hemoglobin, calcium, renal function).

    • Diagnostic Techniques:

      • Serum Protein Electrophoresis (SPEP): Identifies the M-spike indicating monoclonal proteins.
      • Immunofixation: Detects and quantifies specific paraproteins (IgG, IgA)
      • Flow Cytometry: Assesses plasma cells and prognostic markers (CD138, CD38, CD56).
      • Cytogenetics (FISH/Karyotyping): Detects translocations, deletions, and hyperdiploidy.

    • Prognostic Factors:

      • Genetic abnormalities like del17p: Indicate poor prognosis.
      • t(11;14): Linked to better outcomes.

    • Treatment Options:

      • Chemotherapy: VRD (Bortezomib, Lenalidomide, Dexamethasone).
      • Monoclonal Antibodies: e.g., Daratumumab.
      • Stem Cell Transplant: Autologous.
      • Supportive Care: Bisphosphonates, transfusions, palliative care.

    • Monitoring and Relapse:

      • Regular symptom, blood tests, and paraprotein checks.
      • Bone marrow biopsies if relapse is suspected.
      • Alternative treatments may be necessary.

    Bowel Cancer (Colorectal Cancer- CRC)

    • Definition: Malignant tumor in the bowel, primarily the large bowel or colon.

    • Types:

      • Carcinoma of the Large Bowel (Colorectal Carcinoma): Most common, arising from glandular cells.
      • Other Types: Lymphomas, neuroendocrine tumors, GISTs, sarcomas, and metastatic cancers.

    • Benign and Pre-malignant Lesions:

      • Benign Polyps: Can be neoplastic (hyperplastic) or non-neoplastic (hamartomatous, inflammatory).
      • Pre-malignant Polyps: Adenomas (tubular, villous, or sessile serrated) with a risk of becoming cancerous.

    • Prevalence: Common, particularly in older adults, and the second most common cancer in Australia.

    • Risk Factors:

      • Age: Primarily affects older individuals, but 10% occur under 50.
      • Genetics: Family history and syndromes (FAP, Lynch) increase the risk.
      • Lifestyle Factors: Diet (red/processed meats), obesity, inflammatory bowel disease.
      • Genetic Susceptibility: Increased risk with affected first-degree relatives, especially if cancer occurred at a young age.

    • Carcinogenesis: Develops through clonal expansion of mutated cells. Multiple genetic mutations in regulatory genes lead to uncontrolled growth.

    • Key Pathways:

      • Chromosomal Instability Pathway: High somatic alterations in genes like APC, TP53, and KRAS. Associated with the adenoma-carcinoma sequence.
      • Microsatellite Instability (MSI) Pathway: Defective DNA mismatch repair, often involving BRAF mutations and epigenetic changes.
      • POLE Pathway: Defective DNA polymerase proofreading, with many silent mutations.

    • Clinical Presentation:

      • Early Stages: Asymptomatic or subtle bleeding (melena).
      • Advanced Stages: Bowel obstruction, severe hemorrhage, complications from tumor invasion.
      • Systemic Symptoms: Cachexia, paraneoplastic phenomena.

    • Diagnosis:

      • Screening and Tests:
        • FOBT (Faecal Occult Blood Test): Used in national screening programs.
        • Imaging: CT scans, ultrasound, virtual colonoscopy.
        • Endoscopy: Colonoscopy for visual inspection and biopsy.
      • Pathology: Microscopic analysis and genetic testing to assess tumor type, grade, and stage.

    • Treatment and Prognosis:

      • Staging: TNM system based on tumor size, lymph node involvement, and metastasis.
      • Therapies: Surgery, chemotherapy, radiation, targeted therapies.
      • Early-stage: High cure rate with surgery.
      • Advanced Cases: System treatments.

    • Familial Cancer Syndromes:

      • Familial Adenomatous Polyposis (FAP): Autosomal dominant disorder caused by APC gene mutations, leading to numerous adenomas and a 100% risk of cancer by age 40.
      • Lynch Syndrome (HNPCC): Fewer polyps, but high risk of CRC and other cancers. Involves mutations in mismatch repair genes (MLH1, MSH2) and requires intensive screening.

    • Prevention and Screening:

      • National Bowel Cancer Screening Program: Targets individuals over 50 to detect early signs with FOBT.
      • Benefits: Effective early detection, cost-effective, associated with better outcomes.
      • Challenges: False positives, need for confirmatory colonoscopies.

    Lymphoma Diagnosis

    • Overview: Cancer of the lymphatic system categorized into B-cell, T-cell, Hodgkin Lymphomas, and Myeloma.

    • Case Studies:

      • Case 1: Follicular Lymphoma
        • Patient Profile: 81-year-old female with firm lumps in both groins. No systemic symptoms.
        • Examination: Firm, confluent masses up to 3 cm, FBP normal.
        • Investigation: Lymph node biopsy for histological and immunological studies. Fresh node processed for microbiology, flow cytometry, histology, PCR, and FISH.
        • Triage and Analysis:
          • Smears and H+E staining for cell morphology.
          • Granulomas/Necrosis sent to microbiology.
          • Anaplastic cells evaluated with electron microscopy.
          • Small lymphocytes analyzed by flow cytometry.
          • High-grade lymphocytes examined via FISH.
        • Diagnostic Findings:
          • Flow Cytometry: Clonal B-cell population (CD19+, CD20+), CD10+, aberrant BCL2 expression.
          • Histology: Follicular pattern, BCL6, CD10 positivity.
          • Diagnosis: Follicular lymphoma confirmed.
        • Management: PET scan shows low disease volume, adopts a “watch and wait” strategy.
        • Progression and Transformation:
          • Progression Risk: ~3% annual transformation rate, often to DLBCL.
          • Genetic Markers: BCL2-IgH fusion common; additional MYC or BCL6 rearrangements indicate higher risk.
          • Treatment for Transformation: R-CHOP regimen or intensive therapy like HyperCVAD.
      • Case 2: Classical Hodgkin Lymphoma (Nodular sclerosis subtype)
        • Patient Profile: 29-year-old male with neck swelling, significant weight loss, night sweats, and fever.
        • Imaging: CT reveals extensive lymphadenopathy.
        • Biopsy Findings: Reed-Sternberg (R-S) cell variants and a fibrotic background.
        • Immunophenotype: CD30+, CD15-, CD45-, Weak PAX5 expression; EBER+ indicates EBV association.
        • Diagnosis: Classical Hodgkin Lymphoma, nodular sclerosis subtype.
        • Treatment: Standard ABVD regimen. High cure rate, with PET scans for monitoring treatment response.

    • Key Points in Lymphoma Diagnosis and Management:

      • Classification: Based on B-cell, T-cell, or Hodgkin origin, identified by immunophenotyping.
      • Follicular Lymphoma: Diagnosed by follicular pattern and BCL2 positivity, managed with observation or R-CHOP for aggressive transformation.
      • Hodgkin Lymphoma: Characterized by R-S cells, CD30+, and association with EBV, treated with ABVD, achieving high cure rates.
      • Staging and Monitoring: Involves PET scans, bone marrow examination, and assessing organ function to plan treatment.

    • Treatment Protocols:

      • Follicular Lymphoma: Watchful waiting or R-CHOP.
      • Hodgkin Lymphoma: ABVD chemotherapy, with PET scans to confirm remission.

    Brain Cancer Lecture Notes

    • Learning Objectives:

      • Recognize various brain tumor types, locations, and incidence patterns.
      • Understand WHO classification criteria for brain tumors.
      • Appreciate the importance of DNA methylation-based diagnostics.

    • Overview of Brain and CNS:

      • CNS Structure: Cerebrum, Cerebellum, Diencephalon, Brain Stem.

    • Brain Tumors:

      • Definition: Abnormal tissue growth disrupting CNS function.
      • Primary: Originate in brain tissue (rarely spread outside CNS).
      • Metastatic: Originate elsewhere and spread to the brain.
      • Benign: Slow-growing, non-cancerous, clear borders.
      • Malignant: Invasive, rapid growth, high recurrence risk.

    • WHO Classification of Brain Tumors:

      • Grading System:
        • Grade I: Slow growth, potentially curable with surgery.
        • Grade II: Infiltrative, risk of recurrence.
        • Grade III: Rapidly reproducing, invasive cells.
        • Grade IV: Aggressive, necrotic, high mortality (e.g., Glioblastoma).

    • Tumor Locations:

      • Supratentorial: Above the cerebellum.
      • Infratentorial: Below the cerebellum.
      • Spinal:
      • Intra-axial: Within brain tissue.
      • Extra-axial: Outside brain tissue.

    • Common Brain Tumor Types:

      • Gliomas: Most common primary brain tumor, arising from glial cells. Includes astrocytomas, glioblastomas, ependymomas, oligodendrogliomas.
      • Ependymoma: Originates in ependymal cells, grades I-III, treatment often involves surgery and radiation.
      • Medulloblastoma: Malignant tumor common in children, occurring in the cerebellum, has four molecular subtypes: WNT, SHH, Group 3, and Group 4.

    • Molecular Diagnostics:

      • DNA Methylation-Based Diagnostics: Classify tumors using methylation patterns, improving precision in diagnosis, treatment decisions, and prognosis.
      • Illumina DNA Methylation Arrays: Identify methylation profiles of tumors.

    • Key Molecular Markers:

      • IDH1 Mutation: Found in glioblastomas, associated with better prognosis.
      • Glioblastoma Subgroups: RTK I, RTK II, MES, K27, G34, influencing treatment and outcomes.

    • Age-Related Patterns:

      • Children: Primarily present with malignant tumors (e.g., medulloblastomas).
      • Adults: Mostly have benign or low-grade tumors, often supratentorial.

    • Treatment Approaches:

      • Glioblastoma (GBM): Surgery, temozolomide chemotherapy, radiation (median survival ~14 months).
      • Ependymoma: Surgery followed by focal radiation.
      • Medulloblastoma: Surgery, multi-agent chemotherapy, and cranio-spinal radiation.

    Prostate Cancer Summary

    • Normal Prostate Anatomy & Histology:

      • Composed of basal cells, epithelial cells, and stromal tissue.
      • Depends on androgens for growth and survival.
      • Absence of androgens causes apoptosis in glandular cells.

    • Characteristics of Prostate Cancer:

      • Most Common: Prostatic adenocarcinoma.
      • Rare Types: Urothelial carcinoma, squamous cell carcinoma, sarcomas, lymphoma.
      • Prevalence: Highly common among men, leading cause of cancer-related deaths. Lifetime risk is 1 in 6 for diagnosis, 1 in 30 for death.

    • Risk Factors:

      • Age: Risk increases with age.
      • Ethnicity: Higher risk in Black males, lowest in Asian males.
      • Family History: Doubled risk with a first-degree relative diagnosed.
      • Genetics: Mutations in DNA repair genes (e.g., BRCA1/BRCA2).
      • Lifestyle: Obesity and high-fat diets linked to higher risk.

    • Clinical Presentation:

      • Early Stage: Often asymptomatic.
      • Advanced Symptoms: Urinary issues (frequency, urgency, hesitancy), bone pain, haematuria.

    • Diagnosis: Follows elevated PSA test and biopsy.

    • Screening and PSA Testing:

      • PSA: Protein produced by prostate cells, elevated in cancer, hyperplasia, or inflammation.
      • Screening: Controversial due to false positives and treatment side effects.
      • Guidelines: Recommend discussion of screening between ages 50-70.

    • Pathology & Gleason Scoring:

      • Cancerous Features: Small, crowded, infiltrative glands without basal layers, enlarged nuclei, prominent nucleoli.
      • Gleason Score: Based on glandular patterning, ranging from 3 (well-formed) to 5 (sheets of necrotic cells).
      • Grade Groups: 1 (least aggressive) to 5 (most aggressive).

    • Staging and Prognosis:

      • Factors: Tumor type, size, Gleason score, TNM stage, lymph node involvement, and metastasis.
      • Disease heterogeneity, ranging from indolent to aggressive forms.

    • Treatment Options:

      • Localized (Stage I/II): Active surveillance, surgery (radical prostatectomy), or radiation.
      • Locally Advanced (Stage III): Combination of surgery, radiation, and hormone therapy.
      • Metastatic (Stage IV): Hormone therapy, chemotherapy, palliative radiation.
      • Hormone Therapy: Androgen deprivation, though resistance can develop.

    • Resistance Mechanisms: Androgen receptor gene mutations, receptor promiscuity, or activation of alternate pathways.

    • Androgen Deprivation Therapy (ADT):

      • Mechanism: Blocks androgen production or receptor activation.
      • Castration Resistance: Prostate cancer can adapt to continue growing.

    • Key Points:

      • High prevalence and wide spectrum of disease aggressiveness.
      • Gleason Score is crucial for prognosis and treatment.
      • Histological markers: Crowded, infiltrative glands, absent basal layers, and large nuclei with nucleoli.

    Tumor Suppressor Gene p53

    • Plays a role in apoptosis, senescence, autophagy, and metabolic regulation.
    • Mutated in over half of all cancers, including ovarian, colon, esophageal, and blood cancers.

    Resisting Cell Death

    • Tumor cells can avoid apoptosis by:
      • Loss of TP53 tumor suppressor function.
      • Increasing expression of anti-apoptotic regulators (Bcl-2, Bcl-xl) or of survival signals (Igf1/2), by downregulating proapoptotic factors (Bax, Bim, Puma).
      • Short-circuiting the extrinsic ligand-induced death pathway.
    • Autophagy helps cancer cells survive under stress, and necrosis promotes tumor-supportive inflammation.

    Necrosis (Extrinsic)

    • Uncontrolled cell death in response to overwhelming noxious stimulus from outside the cell.
    • Associated with inflammatory responses due to the release of heat shock, cause inflammasome activation and secretion of proinflammatory cytokine interleukin-1 beta (IL1).
    • Necrosis involves:
      • Cell enlargement.
      • Loss of membrane integrity.
      • Leakage of cell contents.
      • Inflammation (recruitment of immune cells).
      • Nuclear degeneration.
    • Pro-tumor effects of Necrosis: angiogenesis, ECM remodeling, and immune evasion by TAMs, TANs, DCs.
    • Anti-tumor effects of Necrosis: Recruitment of cytotoxic macrophages and neutrophils, NK cells, and mature DCs results in elimination of tumor cells.

    Enabling Replicative Immortality

    • Telomerase activation in cancer cells maintains telomere length, enabling unlimited cell division, resistance to apoptosis and aiding in DNA repair.
    • Additional functions of telomerase (TERT) in tumorigenesis:
      • Amplify signaling by the Wnt pathway.
      • Enhancement of cell proliferation.
      • Resistance to apoptosis.
      • Involvement in DNA-damage repair.

    Inducing Angiogenesis

    • Continuous new blood vessel formation leading to abnormal vasculature.
    • Regulators include VEGF-A (pro-angiogenic) and TSP-1 (anti-angiogenic).
    • This process involves migration, growth and differentiation of endothelial cells.
    • Angiogenic switch is always ON in tumor progression, leading to:
      • Distorted and enlarged vessels.
      • Erratic blood flow.
      • Microhaemorrhaging and leakiness

    Activating Invasion and Metastasis

    • Invasion and metastasis occur in multiple steps:
      • Local invasion.
      • Intravasation.
      • Extravasation.
      • Micro-metastases.
      • Colonisation.
    • The Epithelial-Mesenchymal Transition (EMT) makes cells mobile and invasive.
      • During EMT, cell-cell and cell-extracellular matrix interactions are remodeled.
    • Loss of E-cadherin and EMT:
      • E-cadherin mediates Contact Inhibition of Proliferation (CIP).
        • Normal cells stop proliferating once they reach confluence upon homophilic E-cadherin binding.
        • Cells lacking E-cadherin or with mutated E-cadherin continue proliferating.
      • Loss of E-cadherin is key to EMT and tumor progression.
        • Transcription factors (TF) eg Snail, Slug, Twist, Zeb1/2, initiate EMT.
        • These TF inhibit E-cadherin gene expression, activate EMT -> tumor cell motility and invasiveness.
        • E-cadherin expression can be altered through accumulation of mutations, LOH and epigenetic regulation.

    Deregulating Cellular Metabolism

    • Cancer cells exhibit the Warburg effect: Aerobic glycolysis (lactase) even in the presence of oxygen.
    • This metabolic shift supports rapid growth and is facilitated by oncogenes like RAS and MYC, and tumor suppressor genes (TSG) like TP53.
    • Upregulation of glucose transporters (e.g., GLUT1) to the cytoplasm through Hypoxia and TF such as HIF1α and HIF2α.

    Avoiding Immune Destruction

    • Cancer cells create an immunosuppressive tumor microenvironment (TME) using factors like TGF-β to inhibit immune responses.

    Genome Instability and Mutation

    • Mutations in DNA repair genes like BRCA1.
    • LCIS: Non-obligate precursor; associated with increased bilateral risk of future invasive cancer.

    Invasive Breast Cancer

    • Malignant cells invade beyond the basement membrane; potential for metastasis.
    • Clinical signs: Lump, pain, nipple/skin changes, and distant manifestations.
    • Types: Majority are invasive ductal carcinoma (80%); 10% are invasive lobular carcinoma.
    • Others include special subtypes.
    • Staging and Workup: AJCC system; histological type, grade, and stage, assessed via pathology and radiology (MMG, US, MRI).

    Prognostic and Predictive Biomarkers

    • ER/PR: Hormone receptor positivity indicates responsiveness to hormonal therapy and better prognosis.
    • HER2: Overexpression linked to aggressive behavior but targetable with drugs like trastuzumab.
    • Molecular Subtypes: Luminal A/B, HER2-enriched, Basal-like; used for prognosis and treatment planning.

    Treatment

    • Surgery: Lumpectomy or mastectomy, with potential lymph node assessment.
    • Radiotherapy: Reduces recurrence, particularly post-surgery.
    • Hormonal Therapy: For ER/PR-positive cancers (e.g., tamoxifen).
    • Chemotherapy & Targeted Therapy: For HER2-positive and high-risk patients.

    Melanoma Overview Summary

    • Melanoma is a malignant tumor originating from melanocytes, the cells that produce melanin.
    • Most often arises in the skin but can also develop in other organs.
    • Early detection is crucial for improved survival rates.

    Risk Factors

    • Skin type: Fair skin, higher susceptibility to UV damage.
    • UV Radiation: Exposure from sunlight or tanning beds.
    • Moles (Naevi): High number of benign or atypical moles.
    • Family History: Family melanoma history increases risk.
    • Previous Melanoma: Prior melanoma increases recurrence risk.
    • Immunosuppression: Weakened immune system.
    • Chemical Exposure: Contact with harmful chemicals.

    Development Model

    • Benign Naevus: Small, well-defined, even-colored. Histology shows symmetrical structure and maturation of cells in deeper layers.
    • Spitz Naevus: Common in young people; can resemble melanoma.
    • Blue Naevus: Darker due to pigmented cells in the dermis.
    • Dysplastic Naevus: Larger with irregular borders and varied colors. Higher risk of melanoma, especially with family history (Dysplastic Naevus Syndrome).
    • Melanoma: Characterized by asymmetry, irregular borders, color variation, size (>6mm), and evolution over time.
    • Microscopy: Asymmetrical, single-cell patterns, disorganized, with "buckshot" scatter and cytological atypia (nuclear enlargement, hyperchromasia).

    Growth Phases

    • Radial Growth: Melanoma in situ with limited dermal invasion, lacks metastatic potential.
    • Vertical Growth: Invasive expansion into dermis, larger nests, mitotic activity, and potential for metastasis.

    Prognostic Indicators

     -Tumor Thickness: Measured as Breslow thickness.
- Invasion Level: Clark level of invasion.
- Ulceration: Linked to worse outcomes.
- Mitotic Rate: Higher rate suggests poor prognosis.
- Lymphovascular/Perineural Invasion: Indicates aggressive cancer.
- Satellite Lesions: Presence may signal spread.

    Key Genetic Mutations

    • BRAF: Present in ~66% of melanomas, especially V600E mutation, activates MAPK pathway.
      • Mutation testing helps identify candidates for BRAF inhibitors in metastatic cases.
    • NRAS: Found in ~15% of melanomas.
    • KIT: Common in melanomas on mucosal sites, nails, or chronically sun-exposed skin.
    • CDKN2A: Encodes tumor suppressors (p16, p14) involved in cell cycle control.
    • TERT Promoter Mutations: Present in ~70% of melanomas, increase telomerase activity, promoting replicative immortality.

    Clinical Implications

    • BRAF Testing: Identifies candidates for targeted therapy with BRAF inhibitors, which improves survival in metastatic melanoma.
    • Associated Features: BRAF mutations are associated with multiple naevi, trunk location, intermittently sun-exposed skin, and specific histologic patterns (e.g., nested, heavily pigmented).

    Lung Cancer Overview Summary

    • Major Categories of Lung Cancer:
      • Small Cell Carcinoma (14%): Highly aggressive and associated with smoking; usually non-resectable and treated with chemoradiotherapy.
        • Central lung location, neuroendocrine differentiation, ectopic hormone production, and high metastatic potential.
        • Cytological features: Small cells, scant cytoplasm, granular chromatin, nuclear molding, frequent mitosis.
        • Markers: CD56, synaptophysin, chromogranin, TTF-1.
      • Non-Small Cell Lung Carcinoma (NSCLC): Resectable when possible; requires detailed subtyping and molecular diagnostics for targeted therapy.

    Summary of Treatment Protocols

    • Follicular Lymphoma: Watchful waiting for indolent cases; R-CHOP for aggressive transformation.
    • Hodgkin Lymphoma: ABVD chemotherapy standard, with PET scans to confirm remission.

    Summary of Brain Cancer Lecture Notes

    Learning Objectives:

    • Recognize various brain tumor types, locations, and incidence patterns.
    • Understand WHO classification criteria for brain tumors.
    • Appreciate the importance of DNA methylation-based diagnostics for accurate tumor classification.

    Overview Of Brain and Central Nervous System (CNS)

    • CNS Structure:
      • Cerebrum: Cognitive functions and voluntary movements.
      • Cerebellum: Balance, coordination, posture.
      • Diencephalon: Endocrine functions, sensory processing.
      • Brain Stem: Vital functions like breathing and heart rate.

    Brain Tumors

    • Definition: Abnormal tissue growth in the brain or spine, disrupting CNS function.
    • Tumors can be:
      • Primary: Originate in brain tissue (rarely spread outside CNS).
      • Metastatic: Originate elsewhere and spread to the brain.
    • Types of Primary Tumors:
      • Benign: Slow-growing, non-cancerous, clear borders.
      • Malignant: Invasive, rapid growth, high recurrence risk.

    WHO Classification of Brain Tumors

    • Grading System:
      • Grade I: Slow growth; potentially curable with surgery.
      • Grade II: Infiltrative; risk of recurrence.
      • Grade III: Rapidly reproducing, invasive cells.
      • Grade IV: Aggressive, necrotic, high mortality (e.g., Glioblastoma).

    Tumor Locations

    • Supratentorial (above cerebellum), Infratentorial (below cerebellum), or Spinal.
    • Intra-axial (within brain tissue) vs. Extra-axial (outside brain tissue).

    Common Brain Tumor Types

    • Gliomas: Most common primary brain tumor, arising from glial cells.
      • Includes astrocytomas, glioblastomas, ependymomas, oligodendrogliomas.
    • Ependymoma: Originates in ependymal cells; grades I-III, treatment often involves surgery and radiation.
    • Medulloblastoma: Malignant tumor common in children, occurring in the cerebellum; has four molecular subtypes: WNT, SHH, Group 3, and Group 4.

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