Pathology Roadmap PDF

**[Pathology Roadmap: ]** **Disciplines in Pathology:** - Hematopathology: - Diagnose and monitor diseases of blood, bone marrow, lymph nodes - Manage blood transfusion service - HLA typing - Medical microbiology: - Diagnosis of infectious disease - Analyze...

**[Pathology Roadmap: ]** **Disciplines in Pathology:** - Hematopathology: - Diagnose and monitor diseases of blood, bone marrow, lymph nodes - Manage blood transfusion service - HLA typing - Medical microbiology: - Diagnosis of infectious disease - Analyze tissue and body fluids for microorganisms - Testing bacteria for antibiotic susceptibility/resistance - Important in control of infectious diseases - Medical biochemistry: - Diagnose and monitor disease through examination of the body - Anatomical pathology - Clinical application of anatomy, histology, and pathology to make a diagnosis or rule out a particular disease - Gold standard for: - Cancer and cancer precursors - Certain inflammatory diseases **Autopsy pathology:** - Manner suicide, homicide, accidental, natural, unknown - Cause underlying disease resulting in death (precipitated change that caused death - Mechanism physiological derangement that caused cessation of life **Types of autopsy:** - Clinical autopsy: - Usually, the manner of death is natural and the cause and mechanism are known, but there are more questions to answer - Forensic (medico-legal) autopsies: - Determine the cause and manner of death when the death is unexpected, the manner is not natural, or there are suspicious circumstances **Surgical pathology:** - Vast majority of the workload - Involves gross and microscopic evaluation of tissues that were biopsied or resected surgically **Surgical pathology (test process):** - Tissue biopsy - Biopsy goes in formalin for fixation (minimum of 12 hours) - Sample gets delivered to the pathology lab for accessioning - Grossing: makes a description of the specimen and submits it in a cassette for processing - Fixed tissue is embedded in a paraffin wax block, can be stored for 50 years - Use a microtome to cut thin sections to make slices - Paraffin sections floated in water and put on slides; stained with haematoxylin and eosin - Diagnosis at the microscope **Intra-operative consultation/frozen sections:** - Provide rapid diagnosis that assist surgeon in the course of the operation - Identification of disease process - Assessment of surgical resection margins during removal of tumour - Freeze it to make it hard to get sections from it - Hand stained and looked under microscope **Cytopathology:** - Focuses on samples of cells that are exfoliated or in a liquid suspension - No intact tissue in a cytology sample; diagnosis is based entirely on changes in cells and their nuclei, with no assistance from tissue architecture **Molecular pathology:** - Focused on diagnosis of disease through analysis of molecules in organs, tissues, body fluids - Has relevance to all disciplines - Techniques: - PCR - DNA microarray - FISH - DNA-sequencing **[Pathology concepts and principles ]** **Etiology:** - Single etiologic agent - Less common - Multifactorial: - Many contributors and much more common **Pathogenesis** sequence of events that occurs in the response of cells or tissues to the etiologic agent **Morphological changes:** - Structural changes: - Tools physical exam, light microscopy, electron microscopy - Light microscopy **Basics of disease morphology:** - Tissue/cellular responses to injury/stress - Inflammation and tissue repair - Neoplasia **Tissue/cellular response to injury:** - Homeostasis: steady state - Adaptations: reversible structural/functional changes in response to injury or stress - Results in a new steady state - Cell or tissue survives - Cell death: irreversible injury - Necrosis or apoptosis **Adaptations:** - Hypertrophy: - Increase in cell size; due to increased cellular proteins - Physiologic hypertrophy: - Uterus during pregnancy - Pathologic hypertrophy: - Hypertrophy cardiomyopathy - Hyperplasia: - Increase in number of cells - Typically results in increased tissue/organ mass - Physiologic hyperplasia: - Hormonal: breast glandular proliferation at puberty/pregnancy - Compensatory: partial hepatectomy - Pathologic hyperplasia: - Endometrial hyperplasia, benign prostatic hyperplasia - Atrophy: - Reduced size of an organ or tissue resulting from a decrease in cell size and number - Physiologic: - Notochord and thyroglossal duct in fetal development - Uterus post-partum - Pathologic: - Skeletal muscle after spinal cord injury - Causes: - Derceased work - Denervation - Decreased blood supply - Inadequate nutrition - Loss of endocrine stimulation - Pressure **Metaplasia:** - **Reversible change from one differential cell type to another** - **Ex) barrett's esophagus esophageal mucosa (squamous to columnar in response to GERD)** **Cell injury and death:** - **Causes of cell injury:** - **Oxygen deprivation:** - **Ischemia** - **Inadequate oxygenation of blood** - **Decreased oxygen carrying capacity** - **Blood loss** - **Physical agents** - **Trauma, temperature, pressure change, radiation, electricity** - **Chemical agents and drugs** - **Infectious agents** - **Immunologic reactions** - **Genetic derangements** - **Nutritional imbalances** **Cell death:** 1. **Necrosis** a. **Messy, associated with inflammation** b. **Pathologic** 2. **Apoptosis** c. **Neat, no inflammation** d. **Pathologic or physiologic** **Necrosis:** - **Lethally injured cells lose membrane integrity; cell content leak out** - **Lysosomal enzymes denature and digest cellular proteins** - **Leukocytes (inflammatory reaction) release lysosomal enzymes, digest cellular components** - **Patterns:** - **Coagulative necrosis** - **Tissue architecture preserved for some days** - **Eosinophilic, anucleate cells persist following cell death** - **Liquefactive necrosis** - **Tissue digested into amorphous liquid mass** - **Pus=liquefactive necrosis mixed with neutrophils** - **Gangrenous necrosis** - **More of a clinical term** - **Usually a limb with loss of blood supply** - **Caseous necrosis:** - **Cheese-like** - **Refers to tuberculosis** - **Liquefactive** - **Fat necrosis** - **Not a specific pattern (form of coagulative necrosis)** - **Refers to fat destruction in context of acute pancreatitis** - **Fibrinoid necrosis:** - **Refers to BV wall necrosis in vasculitis** - **Immune-complexes deposited in vessel walls look pink under the microscope** **Ischemia-reperfusion injury:** - **After blood flow is restored, reperfusion paradoxically causes cell injury and cell death** - **Causes generation of reactive oxygen species, calcium overload, inflammation, and complement activation, causing cell death** - **Infarct area of necrosis caused by ischemia** **Apoptosis:** - **Programmed cell detah** - **Degrades DNA and nuclear/cytoplasmic proteins** - **Membrane attracts phagocytes** - **Cell is quickly ingested, minimal inflammation** **Pathways:** - **Intrinsic (mitochondrial) pathway:** - **Harm antagonize anti-apoptotic proteins, channels open in mitochondrial membrane, activation of caspases** - **Extrinsic (death receptor) pathway:** - **Fas-Fas ligand, activation of caspases** **Causes:** - **Physiologic:** - **Embryogenesis** - **Hormone withdrawal** - **Elimination of self-reactive lymphocytes** - **Death of inflammatory cells** - **Pathologic:** - **DNA damage** - **Accumulation of misfolded proteins** - **Infection** **Necroptosis:** - **Hybrid form of cell death** - **Morphologically resembles necrosis** - **Mechanism triggered by programmed signal transduction events similar to apoptosis** - **Caused to physiologic and pathologic conditions:** - **Formation of bone growth plate** - **Steatohepatitis, acute pancreatitis, reperfusion injury** **[Inflammation and Tissue Repair: ]** **Inflammation:** - Response of vascularized tissue to infection and damaged tissues - Brins cells and molecules of host defence from circulation to sites where needed - Steps: - Recognition of agent - Recruitment of leukocytes - Removal/inactivation of agent - Regulation of response - Repair - Two components: - Vascular reaction - Cellular response **Acute inflammation:** - Stimuli: infection, necrosis, foreign bodies - Components: - Alteration in vascular caliber cause **increase in blood flow** - **Structural changes** in microvasculature allows plasma proteins and leukocytes to leave circulation (edema) - **Emigration of leukocytes** from microcirculation and activation causes elimination of agent - Blood vessels: - Vasodilation. - Increased permeability of microvasculature - Vascular congestion slowed blood flow and increased RBC concentration and viscosity - Blood leukocytes (neutrophils first) accumulate along vascular epithelium - Leukocytes stick to endothelium, and migrate through vascular wall into the interstitial tissue **Edema:** - **Exudate:** extravascular fluid with high protein concentration and cellular debris - **Indicates inflammation** - **Transudate:** fluid with low protein content (albumin), little to no cellular material (no increased permeability of BVs); - **Increased hydrostatic pressure and decreased colloid osmotic pressure causes composition** - **\*\* Fluid analysis can speak to etiology** **Leukocytes:** - Neutrophils - Arrive first (6-24 hours) - Segmented nucleus - Macrophages - (24-48 hours) - Mononuclear, clear debris, release mediators for repair - Ingest and destroy bacteria and microbes; produce growth factors that help in repair - Mediated and controlled by adhesion molecules and cytokines **chemokines** **Neutrophil killing mechanism:** - Phagocytosis: destruction in phagolysosomes - Degranulation: free radicals generated in activated leukocytes and lysosomal enzymes - NETs: extrude nuclear contents to make extracellular nets that trap and destroy microbes **Cardinal signs of inflammation:** - Redness, heat, swelling, pain - Loss of function (5^th^ sign) **Morphology of acute inflammation:** - **Serous (water) inflammation:** - Migration of cell-poor fluid (clear) into extravascular compartment - No large number of leukocyte - Examples: - Fluid accumulation in body cavities (effusion) - Skin blister from burn or viral infection - Dermis and epidermis separated with serous fluid inbetween - **Fibrinous inflammation:** - Develops when vascular leaks are large or there is a local procoagulant stimulus - Characteristic of inflammation in lining of body cavities (meninges, pericardium, and pleura - Usually resolves by organization - **Purulent (suppurative) inflammation, abscess:** - Exudate abundant neutrophils, liquefied debris of necrotic cells, and edema fluid - May become enclosed by congested BVs and fibrous tissue= **abscess** **Ulcer:** - Defect on surface of an organ or tissue that is produced by sloughing of inflammation necrotic tissue **Outcomes of acute inflammation:** - Complete resolution: short-term with minimal damage - Abscess formation - Scarring or fibrosis: healing by replacement with CT; seen in tissues that cant regenerate/extensive fibrin exudate - Progression to chronic inflammation: persistence of agent or interference with normal healing **Chronic inflammation:** - Response of prolonged duration (weeks to months), - May follow acute inflammation or may begin insidiously - Causes: - Persistent infection - Hypersensitivity diseases: AI disease - Prolonged exposure to toxic agents **Morphological features of chronic inflammation:** - Infiltration with mononuclear cells: macrophages, lymphocytes, and plasma cells - Tissue destruction - Attempts at healing: - Small vessel proliferation (angiogenesis) - Connective tissue replacement (fibrosis) **Granulomatous inflammation:** - Collections of activated macrophages, often with T lymphocytes - Attempt to contain offending agent that is difficult to eradicate - Often causes injury to normal tissue - Granuloma with multinucleated giant cell= Langhans giant cell **Types of granulomas:** - Foreign body: inorganic material cause granuloma - Immune granuloma: when inciting agent is hard to eradicate - multinucleated giant cell - central necrosis - lymphocytes and macrophages - Ex) tuberculosis, leprosy, syphilis, cat-scratch disease, sarcoidosis, crohn's disease **Systemic effects of inflammation** - Called acute phase response. - Fever - Increased pulse and blood pressure; rigours, chills, loss of appetite, malaise - Septic shock - Leukocytosis - Elevated acute phase proteins **Tissue Repair:** - Mechanisms involved: - Regeneration - Connective tissue replacement/scar **Regeneration:** - Some tissues can replace damaged components and essentially return to normal state; ex) mucosal linings, skin, liver, bone marrow - Triggered by cytokines and growth factors - Cardiac and skeletal muscle and neurons have limited capacity to regenerate **Repair by CT (Scar formation):** - Deeper cut injury, therefore tissue cant regenerate the same - Acute and eventually chronic inflammation - Cytokine and chemical mediators are released - New BVs formed (angiogenesis) - Migration and proliferation of fibroblasts - Meshwork of fibroblasts and BVs= granulation tissue - Maturation and remodeling of fibroblasts to form a mature scar **Wound strength:** - 1 week (sutures removed); strength at 10% - Increases over next 4 weeks; reaches 70-80% by 3 months - Collagen synthesis, structural modification (ie cross-linking, increased fiber size) **Healing by first intention:** - Injury involves only epithelial layer - Main mechanism is epithelial regeneration primary union or healing by first intention **Healing by second intention:** - Cell or tissue loss is more extensive (large wounds, abscesses, ulceration, and ischemic necrosis) - Repair involves combination of regeneration and scarring - Reaction is more intense - Development of granulation tissue and formation of large scar and wound contraction by myofibroblasts **Factors that influence healing:** - Ongoing infection - Diabetes - Poor nutritional status - Steroids - Poor perfusion - Impacted foreign bodies - Type, extent, and location of injury **[Neoplasia: ]** **Terminology:** - **Neoplasia process of new growth/cell multiplication** - **Neoplasm new entity; can be benign or malignant** - **Tumour originally applied to a swelling mass; equated with neoplasm** - **Cancer often refers to malignant neoplasm** **Neoplasm and carcinogenesis:** - **Neoplasm results from non-lethal DNA damage that leads to genetic alterations passed to progeny cell** - **Damage leads to unregulated cell proliferation that becomes autonomous (independent of growth stimuli)** - **Entire cell population within tumour arises from a single cell clonal proliferation** **4 key regulatory genes:** 1. **Oncogenes growth promoting** 2. **Tumour supressing genes growth inhibiting** 3. **Genes that regulate apoptosis** 4. **Genes involved in DNA repair** **Essential alterations for malignant transformation:** - **Self-sufficiency in growth signals** - **Insensitivity to growth inhibitory signals** - **Evasion of apoptosis** - **Limitless replicative potential** - **Sustained angiogenesis** - **Ability to invade and metastasize** - **Defects in DNA repair** **Causes of cancer:** - **Radiant energy** - **Chemical carcinogens** - **Oncogenic viruses and other microbes** - **Genetics/hereditary predispositions** - **Chronic inflammation** **Levels of carcinoma:** - **Dysplasia** - **Cells acquired mutations leading to excess growth but haven't gained ability to invade** - **Pre-cancerous cells** - **Mild dysplasia severe dysplasia** - **In-situ carcinoma** - **Malignant transformation but limited by basement membrane** - **Invasive carcinoma** - **Invades beyond basement membrane into adjacent stroma** **Classification and naming of neoplasms:** - **Behaviour** - **Benign or malignant** - **\*\*Exception: low-malignant potential, borderline tumours** - **Tissue of origin** - **Epithelial and secretory tissue** - **Linings and parenchymal organs (liver, kidney, adrenal cortex)** - **Mesenchymal tissue** - **Bone, muscle, BVs** - **Neuroectoderm** - **Brain and nerves** - **Hematopoietic and lymphoid cells** - **Bone marrow and blood cells** - **Germ cells** - **Egg and sperm precursors** **Nomenclature:** - **Adenoma benign epithelial tumour** - **Carcinoma malignant epithelial tumour** - **\_\_oma benign connective tissue tumour** - **Sarcomamalignant connective tissue tumour** **Macroscopic features:** - **Benign:** - **Often smaller** - **Borders are well circumscribed** - **Compressed effect on adjacent tissue** - **Appearance is often homologous** - **Malignant:** - **Often larger** - **Borders are stellate, irregular, ill-defined** - **Invading into other tissues** - **Often heterogenous with areas of hemorrhage and necrosis** **Microscopic features:** - **Benign:** - **Non-invasive** - **Uniform size, shape, polarity** - **Nuclear morphology pval shape, smooth chromatin, thin nuclear membranes, no or small nucleoli** - **Few mitoses** - **Usually no necrosis** - **Doesn't invade fat, nerve, lymphatics or blood vessels** - **Malignant:** - **Destructive invasion** - **Pleomorphic cell size and shape, tumour giant cells, altered polarity** - **Nucleus pleomorphic size and shape, irregular/clumped chromatin, prominent nucleoli** - **Mitoses usually many, with atypical forms** - **Often necrosis** - **Invasion of fat, nerve, lymphatics or blood vessels** **Clinical perspective:** - **Benign** - **Remains localized** - **Usually slow rate of growth** - **Usually cured by local excision** - **Usually no ability to cause death, depending on location** - **Malignant** - **Spreads via lymphatics, blood vessels, serous cavities** - **Usually fast growing** - **Treatment usually requires radical excision and chemo/radiation** - **Usually has ability to cause death** **Invasion and metastasis:** 1. **Cancer cells invade surrounding tissues and blood vessels** 2. **Cells are transported by the circulatory system to distant sites** a. **Metastasis means to change place** b. **Tumour cells disassociate from the primary tumour and lodge elsewhere and grow into a second tumour mass** c. **Paths of spread:** i. **Lymphatics** ii. **Blood stream** iii. **Body cavities** 3. **Cancer cells reinvade and grow at new location** **Prognosis:** - **Tumour stage most important** - **How far the malignancy has spread** - **Better predictor of prognosis** - **Based on:** - **Primary tumour** - **Extent of spread** - **Lymph node involvement** - **Metastases** - **Tumour type** - **Tumour grade** - **Based on the degree of differentiation of the tumour cells; how well the cells resemble the original, benign tissue from which the cancer arose** - **Reflects behaviour** - **Low grade well differentiated** - **High grade poorly differentiated** **Clinical presentation:** - **Symptoms due to impaired function or injury to organ of origin** - **Mass effects on adjacent organs or tissues** - **General:** - **Weight loss, loss of appetite, fever, general malaise** - **Paraneoplastic syndrome:** - **Disease or symptom that is a consequence of the presence of a cancer in the body but not due to the local presence of cancer cells** - **Due to** - **Release of cytokines/hormones by malignant cells** - **An immune response to the malignancy producing antibodies to tumour cells which cross react with normal cells**