Week 2: Pathological Mechanisms

Question 1

Define cell, tissue, organ and system; and describe the body’s organ systems & constituent organs and function

Answer 1

Cell: smallest, functional unit of an organism

Tissue: group of cells that perform the same function e.g. epithelial (squamous, glandular), connective (blood vessels, fat, muscle, bone), haemato-lymphoid

Organ: different tissues which together perform specific function e.g. cardiovascular, respiratory

Question 2

Define pathology and disease; and list and define the broad categories of disease

Answer 2

Pathology: Study of disease Pathology can be divided into general and systemic. General: processes occurring in general e.g. inflammation Systemic: processes occurring in a system e.g. cardiovascular Disease: Abnormality of cell/tissue structure and/or function due to causative agent and body’s response to it Broad categories of disease: VITAMIN CDEF: Vascular, Infective/ Inflammatory, Traumatic, Autoimmune, Metabolic, Iatrogenic/ Idiopathic, Neoplastic, Congenital, Degenerative/ Developmental, Endocrine/ Environmental and Functional Possible causes of disease (Congenital versus acquired) Physical agents (mechanical, heat, radiation (DNA damage)) Chemicals/drugs: damages organelles and processes e.g. plasma membrane, protein folding Infections Hypoxia/ischaemia: Hypoxia (lack of O2). Disrupts oxidative respiration in MT, decreases ATP. Ischaemia (reduced blood supply inc. nutrients and O2) to tissue. Damage more rapid and severe Immunological reactions: Anaphylaxis, Auto-immune reactions Nutritional Endocrine/ metabolic Genetic disease

Question 3

State that disease can be described in terms of epidemiology, aetiology (cause), pathogenesis(mechanism) and sequelae (consequences) and explain these terms with examples

Answer 3

Epidemiology: incidence, distribution, and control of disease in a population

Question 4

Describe what is meant by reversible and non-reversible cell injury

Answer 4

Reversible cell injury: Changes due to stress in environment. Return to normal once stimulus removed

Irreversible cell injury: Permanent, necrosis usually occurs

There is a threshold between reversible and irreversible

Reversible: - Cloudy swelling: osmotic disturbance, loss of ATP dependent Na pump causes Na influx, build up of metabolites

• Cytoplasmic blebs: swollen MT
• Fatty change: accumulation of lipid vacuoles in cytoplasm due to disruption of fatty acid metabolism

Irreversible:

• Disrupted membranes, Pyknotic nucleus (chromatin shrinks in nucleus), Karyorrhexis (fragmentation of nucelus)

Question 5

Give clear definitions of necrosis and apoptosis and describe the circumstances in which they arise

Answer 5

Necrosis: Unprogrammed cell death

• cell death after injury usually necrosis

always pathological - release cell contents (cell lysis) causing damage and inflammation

• cell swelling
• disruption of plasma membrane and organelles
• DNA disruption

Apoptosis: Programmed cell death

• usually physiological
• can be pathological e.g. viral infection, hypoxia
• cell shrinkage, chromatin condensation, membranes of cell and MT intact, cytoplasmic blebs form into apoptotic bodies which are phagocytosed
• doesn’t cause inflammation

Question 6

Types of necrosis

Answer 6

Coagulative: firm, tissue outline retained e.g. haemorrhage, gangrene

Colliquitive: tissue becomes liquid and structure lost e.g. abcess, cerebral infarct

Caseous: combination of coagulative and colliquitive

Looks “cheese like.” Classic for granulotamous inflammation e.g. TB

Fat: due to lipases on fatty tissue

Question 7

Outline the nature, causes and effects of amyloid

Answer 7

Amylois is a general pattern/appearence due to multiple proteins and causes e.g. cirrhosis

Accumulation can be systemic or localised

Due to:

• Accumulation of a normal protein (systemic deposition) - AL amyloid (too many antibody light chains produced, produced in B cell neoplasms e.g. multiple myeloma),

AA myloid (amyloid associated protein produced in liver. Produced in chronic inflammation e.g. RA

• Production of an abnormal protein - folding of soluble protein fibrils into abnormal, insoluble aggregates e.g. Alzheimer’s Amyloid important in systemic pathology especially in kidney, osteo-articular system and brain

Question 8

Outline the nature, causes and effects of pathological pigmentation (deposition)

Answer 8

Deposition of lipid causing steatosis in liver

Lipofuscin - wear and tear, or age pigment in liver. Endogenous breakdown product. Can deposit in heart and other organs.

Iron- excess iron in liver. Can be genetic cause- haemochromotosis

Carbon - lines lung serosal surface, lymphatics. Due to breathing in air.

Question 9

Calcification

Answer 9

Deposition of calcium salts Can be:

Dystrophic: Deposition in abnormal tissue with normal serum Ca2+ e.g. in caeseous necrosis in TB

Metastatic: Deposition in normal tissue but increased serum Ca+. Usually in connective tissue e.g. blood vessels, valves

Causes:

Increased PTH due to primary (pituitary tumour) or secondary (kidney disease)

Question 10

Describe inflammation and its role in pathology/physiology

Answer 10

Response to tissue damage. Function is to stop harmful stimulus, initiate repair and restore function. Can be acute or chronic

Beneficial - dilutes toxins in oedema fluid, increased entry of drugs and antibodies

Not beneficial - digestion of normal tissue, swelling, inappropriate response e.g. hypersensitivity

Question 11

Explain how changes in the vasculature and cells (neutrophils, macrophages and mast cells) occur and how they contribute to clinical signs

Answer 11

Vascular dilatation

• Histamine, NO
• Arterioles dilate, stasis of blood, fluid passes into tissue

Neutrophil activation

• Chemotaxis, margination, rolling, adhesion, migration pass between endothelial cells
• Phagocytosis

Endothelial activation

• Bradykinin, 5-HT
• Activates vascular endothelium
• Increased leakiness of endothelium
• Plasma proteins pass into tissue e.g. immunoglobulins

Clinical signs - red (due to hyperaemia), heat (due to hyperaemia), oedema (due to fluid exudate), pain (release of bradykinin and PGE2), loss of function (combination of everything)

Question 12

Describe various types of exudates

Answer 12

(Exudate - fluid leaking from blood vessel)

Neutrophilic exudate - suppurative/purulent - aggregration of pus

Fibrinous exudate

Serous exudate

Question 13

Describe the main concepts of how infection may spread

Answer 13

Localised infection:

• Remain at initial site
• Spread to local lymph nodes via draining lymphatics

Systemic infection: - Haematogenous – i.e. spread through blood/lymph to cause SYSTEMIC INFLAMMATORY RESPONSE

Question 14

Outline, with examples, how various chemical mediators affect the inflammatory response

Answer 14

Histamine, NO involved in vascular activation

Leukotrienes involved in neutrophil activation

Bradykinin, 5-HT, histamine involved in endothelial activation

Question 15

Describe how the inflammatory response is controlled (at a basic level) including various possible sequelae

Answer 15

Acute inflammation can cause formation of abscess (collection of neutrophil polymorphs).

Can resolve by itself, heal by repair (usually involves fibrosis) or become chronic inflammation

Question 16

Define chronic inflammation and described the circumstances in which it arises

Answer 16

Persisting tissue damage and ongoing acute inflammation

Involves chronic inflammatory cell infiltrate: lymphocytes, macrophages and plasma cells

Often leads to fibrosis or scarring

Granulomatous inflammation (aggregrates of macrophages) a sub-type of chronic inflammation

Question 17

Outline what is meant by granulomatous inflammation

Answer 17

Subtype of chronic inflammation

Defined by the presence of granulomas, collections of epithelioid macrophages and multinucleate giant cells

• Formation of granulomas is due to T cell mediated immune reaction (Delayed Hypersensitivity Reaction)
• The antigen is presented to CD4+ T Cells which produces IFN gamma and other cytokines resulting in macrophage activation (become epithelioid macrophages)

Question 18

Outline histopathological features of chronic inflammation and give examples of diseases with a chronic inflammatory basis

Answer 18

Infiltration of plasma cells, eosonophils and macrophages

Also accompanied by fibrosis, tissue destruction

Granulomatous inflammation is subtype of chronic inflammation

Diseases with chornic inflammatory basis: Pulmonary fibrosis, Cirrhosis

Question 19

Define healing and the different processes involved

Answer 19

Healing: restoration of structure and function of injured/diseased tissue

Resolution - restoring tissue to normal

Two mechanisms:

Regeneration - parenchymal cells divide and replenish lost tissue

Organisation - formation of scar

Question 20

Describe process of organisation

Answer 20

When resolution or regeneration not possible, necrotic parenchymal cells replaced by collagen

• Involves formation of new blood vessels, and influx of fibroblasts occurs which lay down collagen
• Combination of new blood vessels, fibroblasts and granulation tissue
• When granulation tissue forms, chronic inflammation occurs
• Occurs in endothelial cells

Question 21

Describe the various stages in healing of a wound including skin/mucosa and fractures

Answer 21

Skin healing occurs via:

Primary intention: if there is limited tissue damage e.g. simple incision. Wound edges bought together - minimal scar formation

Secondary intention: lots of tissue damage e.g. infected wound. Wound edges not bought in together, granulation tissue fills in defect, and causes contraction of wound, making it smaller and scar formed

A granulomatous reaction includes foreign body multinucleate giant cells. These partly surround the suture material and secrete proteolytic enzymes in an attempt to digest it.

Mucosa heals by regeneration.

Underlying tissue heals by organisation.

Bone heals by regeneration (not repair), and callus formation

Question 22

Discuss factors which may interfere with wound healing

Answer 22

• Infection
• Poor diet (lack of protein)
• Poor blood supply
• Glucocorticoids (delays collagen formation)
• Moisture (promotes bacteria growth)
• Neutrophil disorder

Question 23

Describe and explain the division of the immune system into innate and adaptive.

Answer 23

Innate: Non-specific defense. Includes physical barrier - skin, chemical barriers, macrophages, dendritic cells. Innate can activate adaptive immunity if required.

Adaptive: Antigen-specific defense. Antigen recognised, processed and lymphocytes (T and B cells) produced which specifically attack pathogen. Has “memory” which makes killing pathogen next time more efficient.

Question 24

Further describe and explain the division of the adaptive immune system into humoral and cellular components and their interdependence

Understand the functional divisions of lymphocytes into B and T cells, and their subdivisions

Answer 24

Humoral: Kills extracellular pathogens e.g. bacteria

• Antibodies: opsionise for phagocytosis, activate complement, neutralise toxins
• Memory B cells

Antibodies:

IgM (pentameric) - main antibody of primary immune response, low affinity, activate complement

IgG (monomeric) - main antibody of secondary immune response, high affinity

IgA (dimeric) - “antiseptic” paint. Present in secretions and lines epithelial surfaces. Blocks pathogen binding. Important in nose, lung, gut as on mucosal surfaces

IgE (monomeric) - higher affinity to mast cells. Role in allergy. Parasite infection.

T helper cells activate B cells to:

• become antibody secreting plasma cells
• undergo isotype switching to IgG, IgA, IgE (as IgM at start) - affinity maturation
• become memory B cells

Cellular: CD4 (helper) T cells

• activates B cells, CD8 T cells CD8 (killer) T cells
• kills intracellular pathogens e.g. viruses

T cell receptor recognises only antigen when presented within a MHC molecule on its surface. Recognises short peptide lengths.

MHC I:

Presents to CD8 T cell

On all nucleated cells

Presents intra-cellular antigen

MHC II:

Presents to CD4 T cells

Presents extra-cellular derived (phagocytosed) antigens

Found on APCs (dendritic, macrophages, B cells)

Question 25

List and describe the function of the main molecular components of the immune system including cellular and circulating factors: these include soluble factors, cellular factors, and other immune cell receptors, the major histocompatibility complexes, complement and other circulating factors including cytokines and chemokines

Answer 25

Innate: - Soluble factors: Antibacterial factors, Complement system - Cellular factors: Scavenger phagocytes Antibacterial: lysosome (breaks down gram positive bacterial cell wall), lactoferrin (protein on mucosal surface which chelates iron, inhibits bacterial growth) Complement: Classical (antigen:antibody complexes), MB-lectin (lectin binding to pathogen), alternative (binding directly to pathogen) causes recruitment inflammatory cells, opsionisation, killing pathogens. Scavenger phagocytes (inc. macrophages, dendritic cells, neutrophils): Macrophages can present antigen to T cells in MHCII in lymph node. Produce cytokines e.g. M1 to recruit neutrophils Cytokines are proteins/signalling molecules produced by many cells (B cells, T cells, endothelial cells) in response to an immune stimulus. Involved in cellular communication Chemokines -type of cytokine, induces chemotaxis (cell migration in response to a chemical)

Question 26

Describe the structure and function of cells of the immune system such as neutrophils, macrophages and lymphocytes.

Answer 26

**Neutrophils**: 50-70% WBCs. - Migrates to bacterial products in response to chemokines - Ingest/destroy pathogens by secreting proteases, lysosomes - Release toxic granules extracellularly - Dies locally: forming pus **Eosinophils** - Responds to parasites - Pathogloical role in allergy - Migrate in response to chemokines e.g. eotaxin - Kills parasites by degranulation - releases toxic substances - Produces cytokines which drives inflammation e.g. IL-1, 2, TNF-a **Basophils** (blood), **Mast cells** (tissues): - Mast cells "guards" mucosal surfaces - Involved in allergy - Releases pre-formed granules contain cytokines, histamine - wheal and flare reaction - Cytokine release: stores pre-formed cytokines which are released to drive inflammatory response **Dendritic cells**: Links between innate and adaptive immunity APC - derived from same precursor as macrophage - phagocytoses pathogens, migrates to lymph node, presents antigen to CD4 T cells, initiate adaptive immunity

Question 27

Prevention of autoimmunity

Answer 27

B cells - Develops in bone marrow - If B cell binds strongly to "self" antigen in bone marrow, it will apoptose T cells - Develops in bone marrow, matures in thymus - If T cell receptor binds to "self" antigen in thymus, apoptoses. - Activation of both cell types require "second signals". - If bind without second signal, becomes anergic (no reaction by immune system) e.g. T cells must express CD3 and CD4/CD8 and bind to MHC

Question 28

Describe the structure and function of these organs and cells, including lymph nodes and spleen

Answer 28

Primary organs of adaptive immune system: - Bone marrow - Thymus Secondary - Lymph nodes - Spleen (filters blood of blood borne pathogens and senescent cells) - Mucosal associated lymphoid tissue (MALT) e.g. in GI tract

Question 29

Primary and Secondary B cell response

Answer 29

Primary response: - Naive B cells becomes activated. - IgM\>IgG. - Antibody affinity is low Secondary response: - Memory B cells allows immediate plasma cell proliferation and antibody production. - Antibody affinity is high (lower threshold for activation) and patrol sites of previous pathogen entry - Isotype switching: increase in IgG and if needed IgA and IgE

Question 30

Steps of what happens during infection

Answer 30

- Neutrophils arrive at site of infection and phagocytose - Dendritic cells phagocytose (recognises PAMP on pathogens) and carry antigen, leave via lymphatics - Naive T helper cells enters lymph node from HEV (high endothelial venule) and binds to DC via TCR (requires seocnd signal and MHCII) - Once naive T cell activated, differentiate into CD4 T cells - CD4 T cells activates B cells (by identifying the correct antigen in their MHC II) and providing a second signal. CD4 T cells also release cytokines to promote B cell development - Activated APCs present antigen within an MHC I to CD8 T cell (second signal needed. CD4 cells secrete cytokines to activate CD8 cells) - Activated B cells become antibody secreting plasma cells - B cell enters lymphoid follicle to form germinal centre and undergo affinity maturation (ones with highest affinity, encouraged to proliferate) - B cells with highest affinity selected to become memory B cells

Question 31

Type I hypersensitivity

Answer 31

- Response to challenge occurs immediately - Increase severity upon repeated challenge - Mediated by IgE on mast cells - Involved in most allergies, asthma, eczema Severe, systemic type I hypersensitivity: Anaphylaxis - Widespread degranulation due to systemic exposure to antigen - Increased vascular permeability leading to soft tissue swelling which threatens the airway, loss of circulatory volume causing shock 1. Sensitisation 2. Mast cells primed with IgE 3. Re-exposed to antigen 4. Antigen binds to IgE on mast cells 5. Mast cells degranulate, releasing pro-inflammtory cytokines, histamine 6. Pro-inflammatory process stimulates future repsonses

Question 32

Type II hypersensitivity

Answer 32

- Due to antibodies binding to antigen on own human cells - IgG usual cause - Drug associated haemolysis - Common cause of autoimmune diseaese e.g. pernicious anaemia, myasthenia gravis, autoimmune haemolytic anaemia, bullous pemphigoid 1. Sensitisation 2. Opsionisation of cells 3. Cytoxicity occurs - complement activation - destruction of tissue Type V hypersensitivty: When antibodies bind to receptors on cell

Question 33

Type III hypersensitivity

Answer 33

- Immune complexes (soluble antigens bind to antibodies (IgM or IgG) - Cause of auto immune disease and drug allergy - Can aggregate in blood vessel causing occlusion, complement activation, perivascular activation E.g. hypersensitivity pneumonitis, SLE

Question 34

Type IV hypersensitivity

Answer 34

Delayed type hypersensitivity - e.g. contact dermatitis - Presents days after exposure - Mediated by T cells (CD4 and CD8) infiltrating area

Question 35

Autoimmune disease

Answer 35

Harmful inflammatory response directed against ‘self’ tissue by the adaptive immune response Can be: - Organ specific (TMD1, myasthenia gravis) - Systemic (RA, IBD) Pathogenesis: Genetic predisposition e.g. MHC I and II Environmental factors e.g. infection (molecular mimicry occurs - where foreign and self antigen are similar causing cross reactivity), geographical factors e.g. vit D levels

Question 36

Coagulative necrosis

Answer 36

Firm, tissue outline retained e.g. haemorrhage, gangrene

Question 37

Colliquitive necrosis

Answer 37

Tissue becomes liquid and structure lost e.g. abcess, cerebral infarct

Question 38

Caseous necrosis

Answer 38

Combination of coagulative and colliquitive. Looks "cheese like." Classic for granulotamous inflammation e.g. TB

Question 39

Fat necrosis

Answer 39

Due to lipases on fatty tissue

Question 40

What are depositions?

Answer 40

Abnormal accumulation of substances Can be composed of: Endogenous: - Normal products of metabolism Intracellular: melanin, haemosiderin Extracellular: amyloid Exogenous: Intracellular and extracellular: tattoo pigments, asbestos

Question 42

Antibody structure and function

Answer 42

Fab region - antigen binding region Fc region - binds to Fc receptors on phagocytes. Activates complement Function: Opsionise pathogens Activates complement Neutralise toxins

Question 43

Myasthenia Gravis

Answer 43

Syndrome of fatiguable muscle weakness Affects limbs, head and neck Due to IgG against AchR. Blocks signal transuction.

Question 44

RA

Answer 44

Multisystem autoimmune disease Skin inflammation, small vessel vasculitis, valvular inflammation Rhematoid factor (auto-antibody) against Fc region of IgG. Forms large immune complexes. Anti-citrullinated antibodies common (due to conversion of alanine to citrulline) - Activation of inflammatory cascade leads to release of cytokines (e.g. TNF) which attacts macrophages, neutrophils to synovium - Leads to osteoclast activation, joint destruction, systemic inflammation Treatments Biologics: Infliximab (Anti-TNF) - reduces joint swelling, systemic inflammation However increases risk of infection esp. TB

Question 45

Normal haemostasis

Answer 45

Vessel injury leads to vasoconstruction, platelet release and activation of coagulation cascade Platelets aggregrate and adhere to vascular subenothelium via von Willebrand factor, forming primary haemostatic plug Primary haemostatic plug forms a stable haemostatic plug due to cross-linking of fibrin (produced by thrombin via coagulation cascade)

Question 46

Virchow's triad

Answer 46

3 things that contribute to thrombosis: - Hypercoaguable state e.g. malignancy - Vessel wall injury e.g. trauma - Stasis of blood flow e.g. AF

Question 47

Histopathology of thromosis

Answer 47

Aterial: - White thrombus - Many platelets, small amounts of fibirin Venous: - Red thrombus - Many fibirin with trapped RBCs

Question 48

Differential diagnosis of sore leg

Answer 48

Trauma Non-traumatic e.g OA, RA Skin infections e.g. Cellulitis, Nec fas Venous occlusion e.g. DVT Bilateral leg swelling e.g. heart failure, cirrhosis, malnutrition

Question 49

Deep vein thrombosis

Answer 49

- Thrombosis in deep venous system, usually in legs **Clinical features:** - Pain, swelling in one leg, red skin - Usually superficial femoral vein - 50% DVT cases will have PE **Risk factors:** Vessel wall: age, surgery Blood flow: obesity, immobilisation Composition of blood: thrombophilias, inflammatory conditions **Investigations:** Blood tests: Fibrin D-dimer (fibrin degradation product) Well's Clinical Scoring system (\<2 DVT possible) Imaging: US **Treatment:** **-** Anticoagulation: LMWH, warfarin, DOACs e.g Apixiban (Xa inhibitor), Dabigatran (IIa (thrombin) inhibitor) Remove risk factors Compression (anti-embolism) stockings

Question 50

Necrotising granuloma

Answer 50

Collection of epithelioid macrophages with necrosis in centre – related to TB

Question 51

Non-necrotising granuloma

Answer 51

No necrosis in centre (centre of pink aggregrates - macrophages) - Sarcoidosis, Chron’s

Question 52

Causes of chest pain

Answer 52

Cardiac: Angina, MI Respiratory: Pleuritic chest pain - infection (pneumonia) Vascular: - PE GI: - Acid reflux, hiatus hernia MSK: - Rib fracture

Question 53

PE

Answer 53

Due to thrombus formation in deep vein in body, usually from lower leg (DVT), which travels and blocks blood vessel in lung Symptoms: dyspnoea, chest pain, haemoptysis Leads to: - Lung collapse - Recurrent VTE (venous thromboembolism) - Thromboembolic pulmonary hypertension Management: O2 Anti-coagulation e.g. heparin, fondaparineux, warfarin Thrombolysis e.g. alteplase or catheter directed thrombectomy

Question 54

Coronary artery disease

Answer 54

Atheromatous arterio-vascular disease - Development of plaques in arteries (due to athersclerosis - build up of plaque due to accumulation of cholesterol) - Leads to progressive narrowing and stenosis of artery - Leads to plaque rupture, formation of an acute thrombus, vascular occlusion, ischaemia (reduced blood supply to organ) and infarction (tissue has become necrotic due to reduced blood supply)

Question 55

Arteriosclerotic cardiovascular disease

Answer 55

Arterial wall thickens due to accumulation of cholesterol and triglycerides Risk factors: - Hypetension, smoking, hyperlipidaemia, diabetes Diagnosis of MI - History - Evidence of cardiac dysfunction - ECG findings - Biochemical evidence of ischaemia (elevated troponin) - visualisation of coronary arteries Treatment: - Anti-platelet agents: aspirin - Anti-coagulant agents: heparin - Thrombolytic drugs: tenecteplase, PCI - Widen plaque: balloon angioplasty - Prevent furthur thrombus: anti-platelets, statin Complications: - Arrhythmia, HF, pericarditis, death

Question 56

Causes of limb weakness

Answer 56

MSK: - Myopathy - Arthropathy (disease of joint) Neurological: - Peripheral neuropathy - Spinal lesion - Cerebral lesion

Question 57

Common presentations of thrombosis or thromboembolism

Answer 57

Sore leg - DVT Chest pain - Coronary artery disease Limb weakness - Stroke

Question 58

Treatment of stroke

Answer 58

Thromolysis Remove source of thrombus - Anticoagulation, Cardioversion - revert to sinus rhythm, replace defective heart valve Address other cardiovascular disease risk factors: - Hypertension, hyperlipidaemia

Question 59

What does cellular pathology involve?

Answer 59

Autopsy (post mortem examination), histopathology (tissues) and cytopathology (cells)

Question 60

Describe typical specimens received in a pathology lab, and their range in size from cytology through biopsies to larger resection specimens

Answer 60

Cytology samples : - Fluid cytology - Smear - Fine needle aspirate Small tissue biopsies: - punch biopsies (skin), excision biopsy Larger tissue resections - hysterectomy

Question 62

Describe how specimens are handled in pathology laboratories, from gross examination through tissue processing to microscopy and reporting, and likely timescales involved

Answer 62

- Tissue removed during surgery - Put into formalin - Transported to pathology lab - Specimen examined - Tissue processed: dehydrated with alcohol, cleared with Xylene in preparation for wax - Tissue embedded in wax - Tissue stained by HandE - Tissue examined by pathologist Urgent: \<1 wk Other: \< 4wks

Question 63

Describe common techniques used in pathology, including immunohistochemistry (IHC) and molecular pathology, and briefly explain their applications

Answer 63

H&E is standard Special stains used to identify certain features e.g. despositions - (amyloid, iron) infections - **IHC**: - brown staining - tumour diagnosis and classification **Molecular pathology:** - Studies DNA, RNA, protein - Large scale qualitative changes in DNA e.g. FISH to detect changes in DNA e.g. chromosomal translocation, tumour classification - Large scale quantitaive changes in DNA e.g. PCR - tumour classification - Small scale chanes in DNA e.g. next gen sequencing

Question 64

Describe common congenital and developmental abnormalities of growth including hamartomas and ectopias

Answer 64

Congenital abnormality: anomalies at or before birth 2 types: Functional: how the body works e.g. CF Structural: how it's physically made up Development abnormality: deformity when growth is disturbed Developmental abnormality = congenital structral abnormality

Question 65

Harmatoma

Answer 65

"Harmation" = bodily defect - Malformation that resembles a neoplasm due to faulty growth in organ - Composed of mixture of mature tissue elements normally found at that site Chondroid harmatoma: Lung leision (can look like coin leision on X ray). Composed of epithelium, cartilage, fat. Benign.

Question 66

Ectopia

Answer 66

"Ektopas" = out of place Abnormal location of tissue or organ, can be congenital or due to injury Ectopic cordis: dispalcement of heart outside body Ectopic pregnancy: implantation occuring in fallopian tube, not in endometrium

Question 67

# Define hypertrophy and hyperplasia, atrophy, and metaplasia; give an account of important physiological and pathological factors and stimuli responsible for these changes and illustrate each of these processes with specific examples Relate these processes to altered tissue homeostasis including cell proliferation

Answer 67

**Hypertrophy**: increase in size of cells Physiolgical causes: exercise Physiological causes: cardiac disease **Hyperplasia:** increase in no. of cells Physiolgical causes: hormonal (proliferative endometrium) Pathological: excess hormones e..g obesity, BPH **Atrophy:** decreased size/no. of cells Physiological: menopause Pathological: decreased blood supply - vascular dementia **Metaplasia:** reversible change of one differentiated cell type into another. (So cells are better adapted to withstand environment) Physiogical: in people with gastric reflux, stratified squamous of oesophagus are replaced by gastric columnar Pathological: Can lead to dysplasia - carcinomas Homeostasis: normal cells in a steady state. Injury can induce changed in homeostasis which leads to cell adaption or cell death Adaptions are reversible changes in no./size of cells in repsonse to changes in environment. Can be physiological (response of cells to stimulation) normal or pathological (repsonse of cells to stress, allowing cells to avoid injury)

Question 68

Discuss the effects of mechanical tissue injury including diverticula, intussusception and herniation.

Answer 68

**Diverticula** - small bulges that develop in the lining of intestine Diverticular disease: small bulges herniate/protrude through bowel wall **Merkel's diverticulum** - Congenital - Usually at terminal ileum - Remanant of yolk sac has failed to involute - Contains all layers of intestine, and ectopic tissue (pancreatic) - Complications: inflammation, bleeding, perforation - Can mimic appendictis due to location **Intussusception** - part of the intestine into the section next to it. Usually small intestine. Usually in children. **Herniation -** abnormal protrusion of organ through a defect or opening in a membrane

Question 69

Ventricular septal defect

Answer 69

Hole in the ventricular septum (wall dividing left and right ventricles) Assoc. with Down's syndrome Can lead to increase in pulmonary resistance and eventually cyanosis

Question 70

Spinal bifida

Answer 70

Defect in neural tube (develops into SC and brain) where it fails to close Symptoms: muscle weakness, bowel/bladder problems

Question 71

Offer a definition of a neoplasm, and critically discuss that definition

Answer 71

**Abnormal tissue growth**, which is **excessive** (not physiological) and **uncoordinated** compared to adjacent normal tissue. Persists even after stimuli that cause it has stopped Excessive growth can be: - neoplastic (benign or malignant) (uncontrolled, non reversible) - non neoplastic (controlled, reversible) However. **tumours and neoplasms** are **different** Tumour = swelling/lump Not all swellings are tumours e.g. harmatomas Not all neoplasms cause swelling e.g. leukaemia

Question 72

# Define dysplasia and its synonyms, and its significance for carcinogenesis

Answer 72

Dysplasia - disordered cell growth where cells fail to differentiate properly, but contained by basement memnbrane Alterations in appearence of cell - cell nuclei more hyperchromatic, nuclear to cytoplasmic ratio increases Can regress, persist or progress

Question 73

Differences between benign and malignant neoplasms, and show how some tumours do not fall neatly into either category

Answer 73

Benign : neoplasm that doesn't invade adjacent tissue, usually well circumscribed - Usually ends with -oma - Adenoma (glandular tissue) - Leioma (smooth muscle) Malignant: neoplasm invades surrounding tissue, can metastasise - Carcinoma (epithelial (cells in skin/lining of organs) origin) - Carcnioma in situ (epithelial dysplasia, not beyond BM). No risk of metastasis as no blood vessels or lymphatics in epithelium above BM. - Sarcoma (mesenchymal (connective or non-epithelial tissue) origin) - Melanoma - Lymphoma - Germ cell tumours - Lymphoma

Question 74

Describe the different routes of tumour growth and spread

Answer 74

**Local invasion -** growth into surrounding tissue by expansion - Benign tumours never locally invade - Malignant tumours always locally invade - Can occupy space, locally destructive, uclerate, invade nerves - pain E.g. oeosophagus - difficulty in swallowing, head of pancreas - jaundice **Metastatic -** spread of tumour to distant sites Lymphatic spread - typical of carcinomas Haemotogenous spread - typical of sarcomas. Liver/lungs typically invovled. Transcoloemic spread - malignant neoplasm spreads into a natural opening e.g. gastric carcinoma Presentation of Mets: Skin leisions, CNS symptoms, breatlessness, haematemesis, jaundice

Question 75

Understand the principles of tumour grading and staging and its clinical relevance

Answer 75

Differentiation - extent to which tumour cell resemble normal cell Range of differentiation - well, moderate, poor, undifferentiated (anaplasia) Importance of differentiation: - Prognosis (well differentiated better prognosis) - As tumours becomes poorly differentiated, higher the grade **Stage** TNM staging Tumour - size Nodes - how many involved Metastasis - if tumour has metastasised, then late/stage IV

Question 76

Discuss the techniques by which a neoplastic diagnosis may be established

Answer 76

History, clinical examination Imaging - XR, CT, MRI Bloods - FBC, UandEs, LFTs, tumour markers e.g. Ca 125 (ovarian), Ca 19-9 (pancreas) Cytology - pap smear, FNA Biopsy - histolopathology Molecular - gene detection