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Oncology- Oncogenes and Tumor Suppressor Genes
I. Oncogenes
A. Definition: Genes whose normal function promotes cell proliferation and inhibits apoptosis (programmed cell death). When mutated or overexpressed, they contribute to uncontrolled cell growth, a hallmark of cancer.

B. Key Examples & Mechanisms of Activation:
  • RAS family (HRAS, KRAS, NRAS): Normally activated by growth factor signaling (e.g., EGFR) through GTP binding. Mutations (codons 12, 13, 61) lock RAS in the active GTP-bound state, leading to constitutive signaling, independent of growth factors.
  • Other Oncogenes: BRAF, RET, SRC, ERBB2/3, MYC.
  • Mechanisms of Overexpression (beyond mutation):
    • Gene amplification: Increased gene copy number leads to higher protein levels (e.g., ERBB2 in breast cancer, SRC in colon cancer).
    • Chromosomal fusions: Oncogene fused to a highly active promoter, resulting in overexpression in specific tissues.
    • Deregulation of signaling pathways: Oncogene expression triggered by activation of pathways like RAS and Wnt (e.g., MYC).
II. Tumor Suppressor Genes
A. Definition: Genes that normally restrain cell proliferation, promote apoptosis, or repair DNA damage. Loss of function contributes to cancer development.
B. Two Main Classes:
  1. Regulators of Cell Growth and Apoptosis: These genes directly inhibit cell proliferation or promote apoptosis. Examples include TP53, APC, and PTEN. Loss of function leads to uncontrolled growth, similar to oncogene activation. Note that APC's role is particularly significant in intestinal homeostasis.
  2. DNA Repair Genes: Genes involved in repairing DNA damage. Loss of function leads to a "mutator phenotype" – increased genomic instability and accumulation of mutations, increasing the likelihood of cancer development. Examples include BRCA1/2 (involved in non-homologous end joining) and mismatch repair genes (e.g., MLH1, MSH2).
C. Tumor Suppressor Gene Inactivation:
  • Two-hit hypothesis (previously dominant view): Both copies of a tumor suppressor gene need to be mutated for a significant effect. This often occurs through somatic mutations in one allele, and inheriting a mutated copy (germline mutation) in the other.
  • Germline mutations: Inherited mutations increase cancer risk; individuals with one mutated copy are predisposed to developing cancer in specific tissues upon loss of the second allele (e.g., Li-Fraumeni syndrome (TP53), FAP (APC), Cowden disease (PTEN)). The specific tissue affected often reflects the gene's role in that tissue.
  • Epigenetic inactivation: Mechanisms like methylation can silence tumor suppressor gene expression without altering the DNA sequence itself (e.g., MLH1 in colorectal cancer).
  • Mutant p53: In addition to loss of p53 function, mutations can create a non-functional but stable protein that exhibits oncogenic activity, interacting with other p53 family members (p63, p73) to disrupt their function and promote metastasis.
D. Key Examples & Functions:
  • TP53: The most frequently mutated tumor suppressor gene. Its role in apoptosis, growth arrest, DNA repair, and genomic stability is vital. Loss of p53 function contributes to multiple aspects of tumor progression.
  • APC: Negative regulator of the Wnt signaling pathway, crucial for intestinal homeostasis. Loss of APC contributes to colorectal cancer.
  • PTEN: Involved in cell growth regulation; loss contributes to several cancers.
  • BRCA1/2: Key roles in DNA repair; mutations increase risk of breast, ovarian, and pancreatic cancers.
  • Mismatch repair genes (MSH2, MLH1): Involved in DNA mismatch repair; mutations predominantly increase colorectal cancer risk. MLH1 inactivation via methylation is common in microsatellite instability (MSI) cancers.
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Oncology- Cancer Phenotype
I. The Genesis of Cancer:
  • Genetic Basis: Cancer arises from the accumulation of DNA mutations. These mutations disrupt normal cellular processes that prevent tumor formation (tumourigenesis).
  • Epithelial Origin: Most cancers originate in epithelial tissues (epithelial cancers). Research heavily focuses on why these tissues are susceptible and the protective mechanisms cancer cells evade.​
II. Key Capabilities Acquired by Cancer Cells:
Cancer cells must acquire several crucial capabilities to survive and thrive. These can be categorized as follows:
  • Evading Tissue-Specific Controls: In rapidly renewing tissues (like the intestinal epithelium), cancer cells must overcome:
    • Cell Sloughing: Escape the normal process of shedding old cells.
    • Terminal Differentiation: Avoid the programmed cell death associated with differentiation.
  • Generic Capabilities Required for Growth and Survival:
    • Immune Evasion: Escape destruction by the immune system.
    • Angiogenesis: Develop a new blood supply (necessary for nutrient and oxygen delivery, waste removal).
    • Growth Factor Independence: Grow and proliferate even without external growth signals.
    • Metabolic Adaptation: Survive under conditions of energetic stress.
    • Resistance to Apoptosis (Programmed Cell Death): Avoid signals triggering cell suicide.
  • Metastasis:
    • Invasion and Intravasation: Invade surrounding tissues and enter the bloodstream or lymphatic system.
    • Extravasation and Colonization: Exit the circulation and establish secondary tumors (metastases) at distant sites (e.g., liver).
III. The Tumor Microenvironment:
Recent research highlights the importance of the tumor microenvironment (stroma) in cancer progression.
  • Stromal Components: Pancreatic ductal adenocarcinoma exemplifies this, with up to 80% of tumor mass consisting of non-cancerous stromal cells, including:
    • Immune cells: (e.g., macrophages)
    • Fibroblasts: Connective tissue cells
    • Endothelial cells: Blood vessel cells
  • Stromal Roles:
    • Tumor Growth Support: Stromal cells actively contribute to tumor growth.
    • Physical Barrier: They can impede drug penetration, limiting the effectiveness of therapies.
    • Survival Factor Provision: They can secrete factors that protect cancer cells from targeted therapies.




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Oncology- Introduction to Cancer Genetics
I. Revolution in Cancer Genetics:
· High-throughput sequencing: This technology has dramatically accelerated cancer genome analysis, enabling complete genome sequencing in a matter of hours. This represents a major advancement from previous methods. Note the significance of the speed increase.
​
· Increased Sensitivity: We can now identify allelic variations (changes in gene versions) that increase cancer risk, even those with subtle effects (e.g., a mere two-fold increase in risk). This highlights the improved resolution of modern techniques.

· Data Explosion & Interpretation Challenge: The massive increase in genomic data necessitates a focus on understanding the functional implications of these variations and their relevance to cancer treatment. This is a crucial point – the data is abundant, but we need to understand its meaning. This is the current frontier of the field.

II. Key Concepts & Questions for Deeper Understanding:
· Allelic Variations: Define "allelic variation" and its relevance to cancer predisposition. Consider different types of allelic variations (e.g., SNPs, insertions, deletions). How do these variations contribute to cancer development at a molecular level?
· High-Throughput Sequencing Technology: Briefly research the underlying principles of high-throughput sequencing. What are its advantages and limitations compared to previous methods?
· Two-Fold Increase in Risk: What does a two-fold increase in cancer risk actually mean in terms of probability? How does this relate to population studies and the identification of risk factors?
· Implications for Cancer Therapy: How might the knowledge gained from genomic analysis be used to improve cancer treatment strategies (e.g., personalized medicine, targeted therapies)? Explore the concept of precision oncology.


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Oncology- Cancer Exposures:

I. Solar Radiation Exposure
  • High Incidence of Skin Cancer: Over 1 million skin cancer cases are diagnosed globally yearly, with over 90% of malignant melanomas attributed to sun exposure. Australians, due to high UV exposure, have the world's highest melanoma incidence.
  • Exposure Sites: Intermittently, but intensely exposed skin areas (e.g., back) are most frequently affected.
  • Childhood Exposure: Sun exposure during childhood is a significant risk factor for melanoma.
  • Non-Melanoma Skin Cancers: Solar radiation is the primary cause of most non-melanoma skin cancers (basal cell carcinoma and squamous cell carcinoma), often affecting maximally exposed areas (face, ears). These are linked to cumulative sun exposure.
II. Other Radiation Exposure
  • Carcinogenesis Mechanism: Radiation-induced carcinogenesis begins with mutations in tumor suppressor genes or proto-oncogenes, leading to aberrant function.
  • High-Dose Exposure (500-2000 mSv): Carcinogenic, potentially causing various malignancies (acute leukemias, thyroid cancer). Data primarily from Nagasaki, Hiroshima, Chernobyl, and secondary cancers in radiotherapy patients.
  • Low-Dose Exposure (Average ~73.4 mSv/year): Most exposure is from natural sources. Data comes from studies of secondary malignancies in radiotherapy survivors and miner populations. Extrapolation suggests 1-3% of all cancers may be due to natural radiation sources.
  • Radiation Sensitivity: 73% of the population shows increased sensitivity to standard radiation doses, even without obvious pre-existing conditions. This highlights the need for personalized radiotherapy. Rare radiosensitivity syndromes (ataxia-telangiectasia, Bloom's syndrome) significantly increase cancer risk and require adjusted treatment.
III. Other Exposures (<5% of cancer burden)< />pan>
  • Industrial Exposures:
    • Dye/Textile workers (naphthylamines): Bladder cancers
    • Chemical/Rubber workers (benzene): Hematological malignancies
    • Asbestos: Lung cancer, mesothelioma (notifiable)
  • Pharmacological Exposures:
    • Chemotherapeutic agents: Many are carcinogenic (e.g., alkylating agents).
    • Diethylstilbestrol (DES): High doses during pregnancy (1960s) led to clear cell carcinoma of the vagina in a small percentage of female offspring.
  • Environmental Exposures:
    • Few firmly established causal links.
    • Estimates suggest 71% of lung cancer deaths (US) are attributable to air pollution.
    • Cancer incidence varies geographically, reflecting complex interactions of genetic, environmental, economic, and behavioral factors. Migration studies show environmental factors often outweigh genetic predisposition (except in familial cases).
    • Socioeconomic status also influences cancer incidence.
IV. Epidemiological Studies
Epidemiological studies are crucial for understanding cancer etiology and developing prevention strategies. They reveal patterns in cancer incidence related to various exposures and lifestyle factors.
Key Concepts to Remember:
  • Cumulative vs. Acute Exposure: Some cancers are linked to cumulative exposure (e.g., sun exposure and non-melanoma skin cancers), while others are associated with acute, high-dose exposures (e.g., high-dose radiation and various malignancies).
  • Genetic Predisposition: While environmental factors are major contributors, genetic predisposition plays a role, especially in rare cases of familial cancers.
  • Personalized Medicine: Understanding individual sensitivities to radiation and other carcinogens is crucial for tailoring effective and safe treatments.
This study guide provides a framework for understanding the material. Review the original text alongside this guide for a comprehensive understanding. Remember to focus on the key terms and their definitions, the major types of exposures, and the importance of epidemiological studies in cancer research.


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Pathology-Infectious Agents and Cancer
I. Overall Prevalence:
  • Infections account for 16% of global cancer incidence. This varies significantly: 9% in developed countries and >20% in developing countries.
II. Viral Infections:
  • Ubiquity and Latency: Most tumor viruses are widespread, but infection doesn't automatically lead to cancer. Tumor development takes many years post-infection.
  • Multifactorial Carcinogenesis: Viral infection initiates carcinogenesis, but additional genetic, immunological, and environmental factors are crucial for tumor formation. Some viruses increase the risk of multiple cancers.
A. Human Papillomavirus (HPV):
  • Prevalence and Transmission: The most common sexually transmitted infection in developed countries, spread through unprotected sex or contact with infected areas.
  • Viral Characteristics: Small, double-stranded DNA virus (Papovaviridae family); infects squamous epithelial cells. Over 100 genotypes exist.
  • Cancer Association: >80% of cervical cancers worldwide are linked to HPV, along with vaginal, vulval, penile, and anal carcinomas. HPV types 16 and 18 are particularly strongly associated with cervical cancer.
  • Prevention: A quadrivalent vaccine is available, and cervical screening programs significantly reduce cervical cancer incidence.
B. Hepatitis B and C Viruses:
  • Hepatocellular Carcinoma (HCC): 81% of HCC cases are attributed to chronic infection. 75% of those with chronic HBV infection develop lifelong hepatic infection, leading to hepatocellular injury and chronic hepatitis.
  • Risk Increase: Chronic HBV infection increases HCC risk 100-fold. Prevalence of HBV carriers is high in South East Asia, China, and sub-Saharan Africa (>20%).
  • Treatment Advancements: Modern antiviral therapies can cure chronic infection, potentially drastically reducing future HCC incidence.
C. Epstein-Barr Virus (EBV):
  • Endemic Herpes Virus: A common herpes virus.
  • Hodgkin's Lymphoma (HL): EBV is implicated in up to 60% of HL cases in developed countries and ≥80% in developing countries.
  • Burkitt's Lymphoma (BL): EBV is considered causative in >90% of BL cases in equatorial Africa (where >90% of children are infected by age 3), but plays a lesser role elsewhere (<25% of cases). malaria is a suspected co-factor in bl development, potentially through b-cell stimulation or t-cell suppression.< />pan>
  • Other Lymphomas and Nasopharyngeal Carcinoma: EBV's role in other non-Hodgkin's lymphomas (NHL) is less certain, but a strong link exists with nasopharyngeal carcinoma (EBV found in every anaplastic cell).
III. Bacterial Infections:
A. Helicobacter pylori:
  • Gastric Cancer Association: Clearly linked to gastric adenocarcinoma; responsible for one-third (developed countries) to 50% (developing countries) of such cases. The exact carcinogenic mechanism is unclear.
  • Gastric Lymphoma: H. pylori is also implicated in gastric lymphoma development. Different strains may vary in carcinogenic potential.
IV. Parasitic Infections:
A. Schistosomiasis haematobium:
  • Bladder Cancer: Associated with bladder hyperplasia, metaplasia, dysplasia, and invasive carcinoma. May account for 8% of bladder cancers in the developing world (mostly squamous cell), but is irrelevant in developed world cases.
V. Key Concepts for Studying:
  • Geographic variation: Cancer rates linked to infection vary dramatically between developed and developing nations.
  • Co-factors: Viral infections often require additional factors (genetic, environmental, immunological) to cause cancer.
  • Latency: The time between infection and cancer development can be very long.
  • Prevention and Treatment: Vaccines and antiviral therapies offer significant opportunities for cancer prevention and treatment.​

    • Fiber: The previously suggested link between high-fiber diets and reduced colon cancer risk might be confounded by factors like folate intake, and needs further confirmation.
    • Fat: Research continues into how different dietary fats influence cancer risk, with saturated and trans fats (in meats and some dairy) being of particular concern.
  • Specific Dietary Risk Factors: Dietary changes can significantly impact cancer incidence:
    • Salt Fish: Reducing intake could reduce nasopharyngeal cancer by 33-50% in developing countries.
    • Aflatoxins: (Mycotoxin found in contaminated food) Halving median daily intake could reduce HCC incidence by up to 40% in Africa and Asia.
IV. Exercise
  • Inactivity & Cancer Risk: Physical inactivity increases the risk of many adult cancers, with the strongest evidence for breast and colon cancers.
  • Benefits of Exercise: The benefits of increased exercise are independent of obesity. Exercise also improves outcomes and reduces recurrence rates in cancer patients (strongest evidence in breast cancer).
Key Concepts to Remember:
  • Synergistic effects: Multiple risk factors multiply, rather than simply add to, the risk.
  • Confounding factors: It is difficult to isolate the independent effect of one risk factor when others are also present (e.g., alcohol and smoking).
  • Limited evidence: While many associations are noted, the mechanisms and strengths of the relationships are not always well-understood. More research is needed.




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Oncology - Cancer Risk Factors
This study guide summarizes external factors contributing to cancer risk, categorized for easier understanding and recall.
I. Smoking
  • The Biggest Culprit: Tobacco smoking is the leading known carcinogen and the most significant preventable cause of premature death in developed nations.​
  • Cancer Types Affected: Responsible for a substantial percentage of global cancer cases (15% overall, >30% in men from developed countries). Strongly linked to lung cancer (790% increase in risk for smokers), but also causes mesothelioma, myeloid leukemia, various gastrointestinal cancers (oral, esophageal, gastric, pancreatic), ENT cancers (pharyngeal, laryngeal, nasopharyngeal, nasal cavity, paranasal sinuses), urinary tract cancers (bladder, renal), liver cancer, and cervical cancer.
  • Synergistic Effects: Smoking amplifies the cancer risk associated with other carcinogens like alcohol and asbestos.
  • Global Impact: Increasing global cigarette consumption, particularly among women and in developing countries, is expected to further increase the cancer burden.
  • Cessation & Passive Smoking: Quitting smoking reduces cancer risk, though cessation programs have limited success. Passive smoking also significantly contributes (15-30% of lung cancer in non-smokers).
II. Alcohol Consumption
  • Cancer Links: Alcohol is a causative factor in several cancers:
    • Head and neck cancer (oropharynx): Risk increases linearly with alcohol intake.
    • Esophageal cancer (squamous cell): Risk strongly related to alcohol consumption, even at low levels.
    • Breast cancer: Moderate to heavy intake (>2 units/day) linked to increased incidence (2-10% of cases potentially alcohol-related). Mechanism unclear, possibly through increased estrogen and androgen levels.
    • Hepatocellular carcinoma (HCC): Moderate to heavy drinking increases risk through alcoholic cirrhosis. The link is less clear in the absence of cirrhosis.
  • Confounding Factor: The strong association between alcohol and tobacco use complicates the assessment of each substance's individual contribution to cancer risk. Their effects are synergistic (multiplicative), not just additive.
III. Diet and Obesity
  • Obesity's Role: Adult obesity is a risk factor for numerous solid tumors, including endometrial, post-menopausal breast, kidney, esophageal, and colorectal cancers. It's also implicated in prostate, liver, ovarian, gastric, and pancreatic cancers, potentially contributing to up to 20% of cancer deaths in developed countries. The mechanisms are not fully understood. The obesity epidemic will likely increase the cancer burden further.
  • General Dietary Factors:
    • Vegetables: High vegetable consumption may reduce colon cancer risk (especially distal tumors), but evidence is not strong for other cancers.
    • Fruits: Consistent evidence linking high fruit intake to reduced cancer risk is lacking.
    • Red Meat: High red meat consumption increases colonic and rectal cancer risk.
    • Fiber: The previously suggested link between high-fiber diets and reduced colon cancer risk might be confounded by factors like folate intake, and needs further confirmation.
    • Fat: Research continues into how different dietary fats influence cancer risk, with saturated and trans fats (in meats and some dairy) being of particular concern.
  • Specific Dietary Risk Factors: Dietary changes can significantly impact cancer incidence:
    • Salt Fish: Reducing intake could reduce nasopharyngeal cancer by 33-50% in developing countries.
    • Aflatoxins: (Mycotoxin found in contaminated food) Halving median daily intake could reduce HCC incidence by up to 40% in Africa and Asia.
IV. Exercise
  • Inactivity & Cancer Risk: Physical inactivity increases the risk of many adult cancers, with the strongest evidence for breast and colon cancers.
  • Benefits of Exercise: The benefits of increased exercise are independent of obesity. Exercise also improves outcomes and reduces recurrence rates in cancer patients (strongest evidence in breast cancer).
Key Concepts to Remember:
  • Synergistic effects: Multiple risk factors multiply, rather than simply add to, the risk.
  • Confounding factors: It is difficult to isolate the independent effect of one risk factor when others are also present (e.g., alcohol and smoking).
  • Limited evidence: While many associations are noted, the mechanisms and strengths of the relationships are not always well-understood. More research is needed.
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Pathology - Systemic Lupus Erythematosus (SLE)
I. Definition & Epidemiology:
  • Definition: SLE is a multisystem autoimmune disease characterized by the production of autoantibodies targeting nuclear and cytoplasmic antigens. This means the body's immune system mistakenly attacks its own cells.
  • Epidemiology:
    • Incidence: 4 per 100,000 people annually.
    • Predominantly affects women of childbearing age.
    • Higher prevalence in individuals of African and Asian descent.
II. Etiology & Pathogenesis:
  • Etiology (Cause): Unknown. A leading hypothesis suggests defective phagocytosis (the process of engulfing and destroying pathogens) of apoptotic bodies (dying cells). This failure to properly clear apoptotic cells exposes intracellular self-antigens, potentially triggering an autoimmune response.
  • Pathogenesis (Mechanism):
    1. Autoreactive B and T cells (immune cells) become activated.
    2. Immune complexes form: Autoantibodies bind to self-antigens.
    3. These circulating immune complexes deposit in various tissues (skin, joints, kidneys).
    4. Tissue inflammation and damage result from the immune complex deposition. (Visualize this process using Fig 18.1 if available).
III. Clinical Presentation (Symptoms):
SLE's wide-ranging symptoms depend on the affected organs. Remember the diverse nature of its presentations:
  • Common Symptoms: Fatigue, weight loss, low-grade fever.
  • Musculoskeletal: Arthralgia (joint pain).
  • Skin: Scaly red lesions (often on sun-exposed areas).
  • Pulmonary: Pleuritis (lung inflammation), pleural effusion (fluid buildup around lungs), pneumonitis (lung inflammation), potentially leading to pulmonary fibrosis (scarring).
  • Renal: Glomerulonephritis (kidney inflammation), leading to chronic kidney disease. This is a serious complication.
  • Hematological: Anemia (low red blood cell count), lymphopenia (low lymphocyte count), thrombocytopenia (low platelet count).
IV. Immunology (Diagnostic Markers):
Specific autoantibodies are key diagnostic indicators. Note the high prevalence of certain markers:
  • Anti-nuclear antibodies (ANA): >95% of SLE patients test positive. This is a common, but non-specific, finding.
  • Anti-double-stranded DNA (dsDNA) antibodies: 60% of patients. More specific to SLE.
  • Anti-Smith antigen antibodies: 20-30% of patients. Very specific to SLE.
  • Anti-phospholipid antibodies: 20-30% of patients. These antibodies cause a hypercoagulable state (increased risk of blood clots).
V. Prognosis:
  • 15-year survival rate: Approximately 80% from the time of diagnosis.
  • Causes of death: Often related to severe renal (kidney) and pulmonary (lung) complications.
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Oncology -Gender and Cancer Incidence
This section explores the relationship between gender and cancer occurrence. A key takeaway is that observed gender disparities in cancer rates are not always indicative of inherent biological differences.
Key Concept: While some cancers show a clear gender bias in incidence (e.g., stomach cancer is twice as common in men), attributing this solely to innate susceptibility is problematic.
Critical Point: Environmental factors and lifestyle choices significantly confound the interpretation of gender-based cancer statistics. The example of bladder carcinoma highlights this:
  • Initial Observation: Bladder cancer was initially believed to be inherently more common in men.
  • Revised Understanding: Studies revealed that when men and women are exposed to the same occupational carcinogens (e.g., certain chemicals in the workplace) and tobacco smoke, women exhibit similar, if not equal, susceptibility to bladder cancer.
Therefore: The higher incidence of bladder cancer in men was not primarily due to innate biological differences, but rather to differences in exposure to risk factors.



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Pathology-Systemic Sclerosis (Scleroderma)

I. Definition & Epidemiology:

  • Definition: Systemic sclerosis (SSc) is a rare, multisystem autoimmune disease characterized by excessive fibrous tissue accumulation in various organs. Crucially, this fibrosis leads to organ dysfunction.
  • Epidemiology:
    • Annual incidence: 2-10 per million.
    • Predominantly affects women (30-40 years old).

II. Aetiology & Pathogenesis:

  • Aetiology: The underlying cause of SSc remains unknown.
  • Pathogenesis: An aberrant immune response to an unidentified trigger leads to cytokine production (e.g., IL-4, TGF-β). These cytokines stimulate fibroblasts, resulting in excessive collagen deposition and fibrosis. This fibrosis affects multiple organ systems.

III. Clinical Presentation:

Two main subtypes exist, differing significantly in presentation and prognosis:

  • A. Limited Systemic Sclerosis (lSSc):
    • Onset: Typically begins with Raynaud's phenomenon (cold-induced vasospasm in fingers and toes).
    • Progression: Gradual thickening and tightening of skin (fingers, face, neck).
    • Late Complications (after 10-15 years): Calcium deposits (calcinosis) in finger pads, small bowel involvement, and pulmonary hypertension.
  • B. Diffuse Systemic Sclerosis (dSSc):
    • Onset: More rapid onset with widespread skin thickening, contractures, and ulcers.
    • Visceral Involvement: Early involvement of internal organs including pulmonary fibrosis (lung scarring).
    • Major Complications: Severe hypertension leading to acute renal failure ("scleroderma renal crisis") is a life-threatening complication.

IV. Immunology:

  • Autoantibodies are frequently present, aiding in diagnosis and subtype classification:
    • Anti-nuclear antibodies (ANA): Present in ~65% of patients. Note: ANA is not specific to SSc.
    • Anti-centromere antibodies: Found in 70-80% of lSSc patients. Suggestive of limited disease.
    • Anti-topoisomerase I (Scl-70) antibodies: Present in ~40% of dSSc patients. Associated with diffuse disease and worse prognosis.

V. Prognosis & Treatment:

  • Prognosis: Currently incurable.
  • Treatment: Immunosuppressive therapies are used to manage organ involvement and progressive skin disease.
  • Causes of Death: Primarily due to renal and lung complications (renal failure and pulmonary fibrosis).

VI. Key Differences between lSSc and dSSc:

Feature

Limited Systemic Sclerosis (lSSc)

Diffuse Systemic Sclerosis (dSSc)

Onset

Gradual

Abrupt

Skin Involvement

Limited (fingers, face, neck)

Widespread

Visceral Involvement

Late (e.g., pulmonary hypertension)

Early (e.g., pulmonary fibrosis)

Major Complications

Calcinosis, small bowel issues

Scleroderma renal crisis, pulmonary fibrosis

Associated Antibody

Anti-centromere antibodies

Anti-topoisomerase I (Scl-70) antibodies
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Pathology- Vasculitis
Definition: Vasculitis encompasses a group of diseases where inflammation and damage to blood vessels are the primary pathology. This damage can affect vessels of varying sizes, leading to diverse clinical presentations.
Types of Vasculitis:
This guide outlines key features to differentiate between the vasculitides discussed. Remember that overlap exists, and accurate diagnosis often requires biopsy and serological testing (ANCA).
1. Giant Cell (Cranial or Temporal) Arteritis:
  • Vessel Size: Medium and large arteries.
  • Location: Primarily head and neck arteries (temporal artery most commonly).
  • Demographics: Adults >50 years old.
  • Presentation: Weeks to months of fever, anorexia, weight loss, headache, scalp tenderness, jaw claudication (pain with chewing).
  • Serious Complications: Ocular involvement (blindness), aortic aneurysm (25% of cases).
  • Diagnosis: Temporal artery biopsy (positive in only 60% due to focal nature of inflammation); shows lymphohistiocytic infiltrate, media disruption, and often giant cell reaction.
2. Polyarteritis Nodosa:
  • Vessel Size: Medium-sized arteries.
  • Presentation: Systemic vasculitis leading to aneurysm formation and vessel narrowing. Relatively rare with strict diagnostic criteria.
  • Organ Involvement: Gastrointestinal tract (abdominal pain), nervous system (peripheral nerve palsies), muscles (muscle aches).
  • Diagnosis: Imaging showing vessel narrowing and aneurysms; biopsy confirming necrotizing vasculitis.
3. Wegener's Granulomatosis (Granulomatosis with Polyangiitis - GPA):
  • Vessel Size: Small vessels.
  • Presentation: Systemic vasculitis with prominent upper respiratory tract, lung, and kidney involvement. Characterized by c-ANCA positivity.
  • Symptoms: Nasal symptoms, acute renal failure, pulmonary symptoms.
  • Diagnosis:
    • Renal biopsy: Focal segmental necrotizing glomerulonephritis with crescent formation (identical to microscopic polyangiitis).
    • Lung biopsy: Large necrotizing granulomatous inflammation and necrotizing vasculitis.
  • Treatment: Aggressive immunosuppression is crucial to prevent death.
4. Microscopic Polyangiitis (MPA):
  • Vessel Size: Small vessels.
  • Presentation: Systemic vasculitis with significant renal and lung involvement. Characterized by p-ANCA positivity.
  • Demographics: Adults, median age 55.
  • Symptoms: Acute renal failure, pulmonary symptoms.
  • Diagnosis:
    • Renal biopsy: Focal segmental necrotizing glomerulonephritis with crescent formation (identical to Wegener's granulomatosis).
    • Lung biopsy: Marked alveolar hemorrhage and necrotizing capillaritis within alveolar septa.
  • Treatment: Aggressive immunosuppression is essential for survival.
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Facts about medicine and its subtopic such as anatomy, physiology, biochemistry, pharmacology, medicine, pediatrics, psychiatry, obstetrics and gynecology and surgery.