Hallmarks of Cancer PDF

Overview and Learning Outcomes - Hallmarks of cancer (2000) - 1. Sustained proliferative signalling - 2. Evading growth suppressors - 3. Resisting cell death (apoptosis) - 4. Enabling replicative immortality - 5. Inducing angiogenesis (vasculature)...

Overview and Learning Outcomes - Hallmarks of cancer (2000) - 1. Sustained proliferative signalling - 2. Evading growth suppressors - 3. Resisting cell death (apoptosis) - 4. Enabling replicative immortality - 5. Inducing angiogenesis (vasculature) - 6. Activating invasion and metastasis - 7. Deregulating cellular metabolism - 8. Avoiding immune destruction - Enabling Characteristics - 1. Genome instability and mutation - 2. Tumour-promoting inflammation 1. Sustained Proliferative Signaling: Cancer cells continuously stimulate their own growth by deregulating growth-promoting signals. ○ Mechanisms include activation of growth factors, mutations, and disrupted feedback mechanisms, such as in RAS mutations. 1. ii. deregulate these signals 1. ○ Ways of sustaining proliferative signalling i. Autocrine proliferative signaling 1. ii. Signaling to normal cells within tumour associated stroma (reactive stroma) 1.  iii. Elevated levels of receptors proteins on cancer cells making them hyper-responsive to limiting amounts of GF ligands (e.g. epidermal growth factor receptor) iv. GF independence by conntinual/constitual activation of downstream signalling pathways ○ Somatic mutations activate additional downstream pathways ○ Disruptions of negative-feedback mechanisms i. Oncogenic mutations affecting ras genes compromise Ras GTPase activity ii. No mutations: Ras GTPase drives normal negative-feedback iii. Ras mutation: Ras GTPase INACTIVE, negative-feedback disrupted 2. 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 i. Retinoblastoma-associated (RB) 1. Integrates signals extracellular and intracellular -> progress cell cycle 2. Directly or indirectly inactivated in nearly all human cancers ii. TP53 proteins 1. “Guardian of the genome” Regulates several genes that are involved in growth arrest 2. Plays role in other processes such as: a. Apoptosis (programmed cell death) b. Senescence (irreversible cell cycle arrest) c. Autophagy d. Metabolic changes in the cell 3. P53 is found to be mutated in over half of cancers including ovarian, colon, oesophageal and blood cancers 3. Resisting Cell Death ○ Tumor cells avoid apoptosis by: i. loss of TP53 tumor suppressor function  ii. increasing expression of antiapoptotic regulators (Bcl-2, Bcl-xl) or of survival signals (Igf1/2), by downregulating proapoptotic factors (Bax, Bim, Puma) iii. short-circuiting the extrinsic ligand-induced death pathway ○ autophagy help 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) i. Necrotic pathway: 1. Cell enlargement 2. Loss of membrane integrity 3. Leakage of cell contents 4. Inflammation (recruitment of immune cells) 5. Nuclear degeneration ii. Pro-tumour: angiogenesis, ECM remodeling, and immune evasion by TAMs,TANs, DCs iii. Anti-tumour: Recruitment of cytotoxic macrophages and neutrophils, NK cells, and mature DCs results in elimination of tumor cells. 4. 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: i. Amplify signalling by the Wnt pathway ii. Enhancement of cell proliferation and/or iii. Resistance to apoptosis iv. Involvement in DNA-damage repair 5. Inducing Angiogenesis ○ continuous new blood vessel formation -> abnormal vasculature. ○ regulators VEGF-A (pro-angiogenic) and TSP-1 (anti-angiogenic). ○ This process migration, growth and differentiation of endothelial cells ○ Tumour progression. Angiogenic switch is always ON i. distorted and enlarged vessels, erratic blood flow, microhaemorrhaging and leakiness 6. Activating Invasion and Metastasis ○ Invasion and metastasis occur in multiple steps Multistep process: 1. Local invasion 2. Intravasation 3. Extravasation 4. Micro-metastases 5. Colonisation  ○ The Epithelial-Mesenchymal Transition (EMT) mobile and invasive. i. During EMT, cell–cell and cell–extracellular matrix interactions are remodeled ii. Tumour progression ○ Loss of E-cadherin and EMT i. E-cadherin mediates Contact Inhibition of Proliferation (CIP) 1. normal cells stop proliferating once they reach confluence upon homophilic E-cadherin binding 2. lose E-cadherin or E-cadherin is mutated, continue proliferating ii. Loss of E-cadherin is key EMT and tumour progression 1. TF (eg Snail, Slug, Twist, Zeb1/2) -> initiating EMT 2. These TF have been shown to inhibit E-cadherin gene expression, activate EMT -> tumor cell motility and invasiveness 3. E-cadherin expression can be altered through accumulation of mutations, LOH and epigenetic regulation 7. Deregulating Cellular Metabolism ○ Cancer cells exhibit the Warburg effect, aerobic glycolysis (lactase) even w/ oxygen. ○ metabolic shift supports rapid growth and is facilitated by oncogenes like RAS and MYC, TSG (TP53) ○ Upregulation of glucose transporters (eg GLUT1) to the cytoplasm through Hypoxia and TF such as HIF1α and HIF2α 8. Avoiding Immune Destruction ○ creating an immunosuppressive tumor microenvironment (TME), utilizing factors like TGF-β to inhibit immune responses. Enabling Characteristics 1. 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 or mitotic checkpoint genes 2. 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. i. including transformation, proliferation, angiogenesis, and metastasis ii. supplying 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 ○ The aberrant expression and secretion of proinflammatory and growth factors by the tumor cells result in the recruitment of immune cells, thus creating a mutual crosstalk. 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. 2. 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). 3. 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. 4. 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). 5. 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. 6. 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 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: 1. 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. 2. Dysplastic Naevus: Larger with irregular borders and varied colors. Higher risk of melanoma, especially with family history (Dysplastic Naevus Syndrome). 3. 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: 1. 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. 2. 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 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: 1. 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). 2. 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. Multiple Myeloma Notes: 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. CRAB (Calcium elevation, Renal failure, Anemia, Bone lesions). ○ Tests: Blood tests (hemoglobin, calcium, renal function). Bone marrow biopsy (≥10% plasma cells for diagnosis with CRAB). Serum protein electrophoresis (SPEP) & immunofixation (detect M-spike and paraprotein type). Diagnostic Techniques: ○ SPEP: Identifies M-spike indicating monoclonal proteins. ○ Immunofixation: Detects/quantifies specific paraproteins (e.g., IgG, IgA). ○ Flow cytometry: Assesses plasma cells, prognostic markers (CD138, CD38, CD56). ○ Cytogenetics (FISH/Karyotyping): Detects translocations, deletions, hyperdiploidy. Prognostic Factors: ○ Genetic abnormalities like del17p indicate poor prognosis. ○ t(11;14) linked to better outcomes. Treatment Options:  ○ Chemo: VRD (Bortezomib, Lenalidomide, Dexamethasone). ○ Monoclonal antibodies: e.g., Daratumumab. ○ Stem cell transplant: Autologous. ○ Supportive care: Bisphosphonates, transfusions, palliative care. Monitoring & Relapse: ○ Regular symptom, blood test, paraprotein checks. ○ Bone marrow biopsy if relapse suspected. ○ Alternative treatments may be considered. Conclusion: ○ Complex disease, requires personalized treatment. ○ Translational research essential for improving outcomes. ○ Accurate diagnosis enables better prognosis and treatment. Bowel cancer, also known as colorectal cancer (CRC), is a malignant tumor of the bowel, predominantly the large bowel or colon. Here’s a detailed overview: Definition and Types Bowel Cancer: A malignant neoplasm (cancerous growth) in the bowel. The term "malignant" refers to the potential to be life-threatening. Carcinoma of the Large Bowel: The most common form, known as colorectal carcinoma, which usually manifests as an adenocarcinoma. This type arises from glandular cells lining the bowel. Less Common Types: Lymphomas, neuroendocrine tumors, gastrointestinal stromal tumors (GISTs), sarcomas, and metastatic cancers from other sites. Benign and Intermediate Lesions: ○ Benign polyps: These can be neoplastic (like hyperplastic polyps) or non-neoplastic (such as hamartomatous or inflammatory polyps). ○ Pre-malignant polyps: These include adenomas (tubular, villous, or sessile serrated lesions) with a risk of progressing to cancer. Significance Prevalence: Bowel cancer is common, particularly in older adults, and is the second most common cancer in Australia. Impact: Despite its prevalence, it often receives less attention compared to other cancers. Early detection significantly improves outcomes, with a high chance of cure if diagnosed early. Risk Factors 1. Age: Primarily affects older individuals; about 10% occur in people under 50. 2. Genetics: Family history and genetic syndromes like Familial Adenomatous Polyposis (FAP) and Lynch syndrome increase the risk. 3. Lifestyle Factors: Diet high in red or processed meats, obesity, and inflammatory bowel disease also contribute.  4. Genetic Susceptibility: A person’s risk increases with affected first-degree relatives, particularly if the cancer occurred at a young age in the family. Carcinogenesis and Genetic Pathways Mechanism: CRC develops through the clonal expansion of mutated cells. Multiple genetic mutations in regulatory genes lead to uncontrolled growth. ○ Key Pathways: Chromosomal Instability Pathway: High 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 involving BRAF mutations and epigenetic changes. POLE Pathway: Involves defective DNA polymerase proofreading, with many silent mutations. Clinical Presentation Early Stages: Usually asymptomatic or may present with subtle bleeding (melena). Advanced Stages: Symptoms may include bowel obstruction, severe hemorrhage, or complications from tumor invasion into surrounding structures. Systemic symptoms like cachexia and paraneoplastic phenomena may also occur. Diagnosis Screening and Tests: ○ Faecal Occult Blood Test (FOBT): Used in national screening programs. ○ Imaging: CT scans, ultrasound, or virtual colonoscopy. ○ Endoscopy: Colonoscopy for visual inspection and biopsy. Pathology: Microscopic analysis and genetic testing to assess the type, grade, and stage of the tumor. Treatment and Prognosis Staging: Based on tumor size, lymph node involvement, and metastasis (TNM system). Therapies: Surgery, chemotherapy, radiation, and targeted therapies. Early-stage disease has a high cure rate with surgery, while advanced cases may require systemic treatments. Survival Rates: Five-year survival has improved significantly with early detection and advanced therapies. Familial Cancer Syndromes 1. Familial Adenomatous Polyposis (FAP): An autosomal dominant disorder caused by mutations in the APC gene, leading to hundreds of adenomas and a 100% risk of cancer by age 40. 2. Lynch Syndrome (HNPCC): Characterized by fewer polyps and a high risk of CRC and other cancers. It involves mutations in mismatch repair genes (MLH1, MSH2, etc.) and requires intensive screening. Prevention and Screening  National Bowel Cancer Screening Program: Targets individuals over 50 to detect early signs using FOBT. This program has reduced mortality rates and improved early detection. Benefits of Screening: Effective in detecting early cancer or precursor lesions. Cost-effective and associated with better outcomes. Challenges: Risk of false positives and the need for confirmatory colonoscopies. Summary Bowel cancer has a significant impact, with adenomas being the primary precursor lesion. Understanding the genetic and molecular pathways of CRC is crucial for effective treatment and research. National screening programs are essential for early detection and reducing the overall disease burden. Lecture Notes on Lymphoma Diagnosis Overview of Lymphoma Lymphoma is a cancer of the lymphatic system, divided into two major categories: B-cell Lymphomas: Includes Follicular, Small Lymphocytic Lymphoma (SLL), Diffuse Large B-Cell Lymphoma (DLBCL), Burkitt, Gastric MALT, 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 longstanding, firm lumps in both groins. No systemic symptoms like rash or infection. Examination and Findings: Firm, confluent masses up to 3 cm; full blood panel (FBP) normal. Investigation Steps: ○ Lymph node biopsy for histological and immunological studies. ○ Fresh node processed for multiple tests: microbiology, flow cytometry, histology, PCR, and FISH if needed. Fresh Node Triage and Initial Analysis Smears and H+E staining for initial cell morphology. Triage based on findings: ○ 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 for aggressive types. Case 2: Classical Hodgkin Lymphoma (Nodular Sclerosis Subtype) Patient Profile: 29-year-old male with neck swelling, significant weight loss (10 kg), 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 1. Classification: Based on B-cell, T-cell, or Hodgkin origin, identified via immunophenotyping. 2. Follicular Lymphoma: ○ Diagnosed by follicular pattern and BCL2 positivity. ○ Managed with observation for indolent cases; transformed cases require R-CHOP. 3. Hodgkin Lymphoma: ○ Characterized by R-S cells, CD30+, and association with EBV. ○ Treated with ABVD, achieving high cure rates. 4. Staging and Monitoring: Involves PET scans, bone marrow examination, and assessing organ function to plan treatment. 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. These cases emphasize the importance of accurate immunophenotyping, the role of genetic markers in prognosis, and the tailored management approaches based on disease stage and progression. 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 1. Gliomas: Most common primary brain tumor, arising from glial cells. ○ Includes astrocytomas, glioblastomas, ependymomas, oligodendrogliomas. 2. Ependymoma: Originates in ependymal cells; grades I-III, treatment often involves surgery and radiation. 3. 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 DNA methylation patterns, improving precision in diagnosis, treatment decisions, and prognosis. Illumina DNA Methylation Arrays: Aid in identifying 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 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. Treatment Approaches 1. Glioblastoma (GBM): Surgery, temozolomide chemotherapy, radiation (median survival ~14 months). 2. Ependymoma: Surgery followed by focal radiation. 3. Medulloblastoma: Surgery, multi-agent chemotherapy, and cranio-spinal radiation. Prostate Cancer Summary 1. Normal Prostate Anatomy & Histology The prostate is composed of basal cells, epithelial cells, and stromal tissue. It depends on androgens (testosterone, androstenedione, and dihydrotestosterone) for growth and survival. Absence of androgens causes apoptosis in glandular cells. 2. Characteristics of Prostate Cancer Most common: Prostatic adenocarcinoma. Rare types: Urothelial carcinoma, squamous cell carcinoma, sarcomas, lymphoma. Prevalence: Highly common among men and a leading cause of cancer-related deaths. Lifetime risk is 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, haematuria. Diagnosis: Typically follows an elevated Prostate-Specific Antigen (PSA) test and biopsy. 5. 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. 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. 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). 7. Staging and Prognosis  Factors: Tumor type, size, Gleason score, TNM stage, lymph node involvement, and metastasis. Disease is heterogeneous, ranging from indolent to aggressive forms. 8. 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. 9. 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. 10. 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. This summary encapsulates the essential concepts of prostate cancer, including its pathology, risk factors, diagnostic methods, and treatment strategies. 4o