Pathology Flashcards

Question

Identify this cellular accumulation ?

Answer 1

Haemosiderin A intracellular storage complex - found mainly in macrophages When do we observe Haemosiderin in pathology * when there is increased RBC red blood cell destruction 'haemolysis' * chronic congestion * iron infections Grossly = see a brownish tinge (eg lungs, bruised skin) Histology = golden brown granules (Perl's Prussian blue)

Answer 2

Cell adaptations **Physiological adaptation** * occur in normal body conditions * usually beneficial * eg pregnancy, building of muscle **Pathological adaptation** * changes occur due to a disease condition * usually detrimental for the host * eg injury

Answer 3

Cell response to an altered steady state is limited **Reversable cell injury** * return to normal function (once stress or injury ceases) * extent and duration of injury is not excessive **Adapt** * to the changed conditions * can occur after sublethal persistant stress or injury **Irreversable cell injury** * leads to cell death * occurs after severe or prolonged injury The cellular response depends upon the extent, duration and cell type

Answer 4

Cell division **Permanent** * terminally differentiated * non dividing cells eg skeletal muscle, cardiac muscle and neurons **Stable** * conditionally dividing cells * liver, kidney, endothelium of blood vessels, fibroblasts **Labile** * constantly having to renew / mutiple via stem cells * skin, intestine, urogenital, lining of exocrine glands

Answer 5

Hypertrophy an increase in the size of cells. * size increases by an increase in the number and size of organelles * occurs in most organs and tissues * more common in permanent and stable cells - which undergo litle replication * eg striated and cardiac muscle

Answer 6

Cellular adaptation Hyperplasia = an increase in the number of cells * increased mitotic division implied * most common in labile cells that routinely proliferate and readily become hyperplastic * eg epithelium, GIT, glands

Answer 7

The cellular adaptation of hypertrophy is stimulated by Hypertrophy can occur in response to several different stimuli * mechanical or demand * pathological eg increased workload * hormonal eg oestrogen and pregnancy * compensatory loss of a paired organ or part of an organ * xenobiotic eg liver cells increase in size after chronic exposure to drugs Xenobiotic = chemical substances which are foreign to animal life

Answer 8

Traditionally hyperplasia is divided into physiological and pathological responses Physiological * hormonal eg pregnancy * compensatory Pathological * excessive hormonal stimulation (endometrial hyperplasia) * chronic irritation

Answer 9

Atrophy Decrease in size or amount of cells, tissue or an organ * occurs after normal growth has been reached * caused by a decrease in size and or number of cells as a result of gradual and continuous injury Physiological atrophy also called 'involution' eg thymus with age, uterus atrophy post partuition

Answer 10

The pathological causes of atrophy * Nutrient deficient - starvation, reduced blood supply * reduced workload - reduced skeletal muscle mass * disuse - limb immobilisation following injury * denervation - forelimb muscle atrophy after radial nerve paralysis * pressure - may cause atrophy of adjacent tissues * loss of hormonal stimulation - eg prolonged corticosteroid treatment

Answer 11

Cell adaptation metaplasia Replacement of one cell type with another * it is not the transformation of individual cells * stem cells differentiate along a different path, and may eventually replace the original cell type * may be reversible in some cases, if the cause is withdrawn * can be preneoplastic - indicating an increased risk of neoplasia

Answer 12

The cause of metaplasia Usually an adaptive change to withstand an adverse environment * eg cigarette smokers, vitamin A deficiency in birds

Answer 13

Hypoplasia Not a true cell adaptation - due to abnormal development Is the failure of an organ to attain its full size eg enamel

Answer 14

Aplasia Not a cellular adaptation as it is due to abnormal development Failure of an organ to develop

Answer 15

Dysplasia Not a true cellular adaptation as it is due to abnormal cellular development * disorderly arrangemnet of cells which can cause abnormal architecture of a tissue/ organ * reflects abnormal cellular organsisation and development eg hip dysplasia, chondrodysplasia (dwarfism)

Answer 16

Terms **Neoplasia =** a new growth * an abnormal mass, composed of cells originally derived from normal tissues * uncoordinated and excessive growth * unresponsive to normal growth controls * persist after cessation of stimuli **Tumor** = original meaning swelling * now associated with neoplasia or cancer * can be benign or malignant

Answer 17

Terms Cancer * common term for malignant tumors * Cancer is a collection of diseases characterised by * uncontrolled growth of cells * leading to an invasion of surrounding tissues and spread (metastasis) to other parts of the body Oncology * study of tumors or neoplasm

Answer 18

Tumors are clonal The entire population of neoplastic cells within an individual tumor arise from a single cell that has acquired a genetic change. clonal expansion - transformation of a normal neoplastic cell can be caused by * chemical, physical or biological agentsthat directly and irreversable alter the cells genome * characterised by the loss of some or all the cells specialised functions * aquisition of new biological functions Tumors remain independant on the host for nutrition and blood supply

Answer 19

A tumor consist of two components 1. proliferating neoplastic cells (paranchyma) 2. supportive stroma * made of blood vessels and connective tissue * tumor - stromal interactions modulate growth and differentiation

Answer 20

Tumor naming depends upon * whether the tumor is malignant or benign * also reflects the cell type of origin Benign * end oma Malignant * mesenchymal end sarcoma * epithelial end in carcinoma Remember there are always exceptions to the rules

Answer 21

carcinoma (produce keratin) * produce central keratin pearls

Answer 22

Mechanism of fatty change * Excessive delivery of free fatty acids to the liver (GIT dietary excess) * Decreased oxidation of FFA (mitochondrial injury) * Impaired protein sysnthesis (apoprotein) More uncommon * impaired ability to combine triglycerides and protein to form apoprotein * impaired release / secretion of lipoproteins from hepatocytes.

Answer 23

Mechanisms of necrosis ## Footnote **1) Denaturation of proteins** due to reduced PH in severely injured and dead cells **2) Enzymatic digestion of cell components** - Autolysis self digestion by lysosomal enzymes of dead cells - Heterolysis lysosomal enzymes from immigrant leukocytes **Necrosis initiates an inflammatory response in adjacent tissues**

Answer 24

Postmortem autolysis Cells that die along with the rest of the animal (somatic death)

Answer 25

Histology of necrosis Cell nucleus * Pyknosis * Karyorrhexis * Karyolysis Cell cytoplasm * increase eosinophilia (increased binding of eosin to denatured proteins) * Pale ghost like appearance (enzymatic digestion of cytoplasmic proteins)

Answer 26

Coagulative necrosis Denaturation of proteins is the prominent process - therefore enzymes are unable to digest cellular components Cell outline and archetecture intact. Cytoplasm is uniformly eosinophilic (pink), nucleus may be pyknotic, karyorrhectic, karyolytic or absent. * often seen in hypoxic injury * often seen in kidney, liver and muscle (not brain)

Answer 27

Morphology of necrosis * requires 24-48 hrs to appear grossly * pale, soft * friable = (easily crumbled) * shrply demarcated from viable tissue by a zone of inflammation (histologically) Necrotic tissue varies widely in appearance both grossly and histologically

Answer 28

Liquifactive necrosis Cells are lysed and necrotic tissue is converted to a fluid phase. * final stages of brain parenchyma (large amounts of lipid and lytic enzymes) * pyogenic pus forming bacterial infections outside the CNS * centre of absesses or other collections of neutrophils

Answer 29

Caseous necrosis Dead cells form friable, granular white/yellow mass : alike cottage cheese * often involve poorly degradable bacterial components * dystrophic calcification (central lesion) * **cell outline is lost (architecture disrupted)** * necrotic debris mostly composed of nuclear and cytoplasmic remnants of dead leukocytes * surrounded by granulomatous inflammation (macrophages) * fibrous connective tissue capsule

Answer 30

Gangrenous necrosis Initial lesionis coagulation necrosis Moist gangrene = contaminated saprophylytic bacteria putrefaction Gas gangrene = tissue becomes infected with anearobic bacteria (Clostridium sp) Dry gangrene = necrotic tissue dries out and becomes mummified extremeties eg frost bite, ergot, fescue toxin

Answer 31

Fat necrosis Enzymatic necrosis of fat * activated pancreatic enzymes released during pancreatis or damage to pancreatic duct * destruction of surrounding tissue by lipases from pancrease * often get dystrophic calcification * traumatic when fat is crushed (pelvic canal in heifers) * idiopathic necrosis (unknown cause)

Answer 32

Dystrophic calcification calcium salts depositied in tissue * deposition occurs locally in damaged, dying or dead tissue * occurs despite normal serum calcium levels * eg heart, skeletal muscle * significance it indicates previous injury * grossly looks white and has a gritty feel when incised Basophilic blue fine granule dumps

Answer 33

Metastatic calcification calcium salts deposited in tissue deposition in otherwise normal tissue * secondary to hypercalcaemia * eg renal failure - calcium deposition * gastric mucosa, kidney, alveolar

Answer 34

Histological differences benign and malignant neoplasm ## Footnote Differentiation Rate of growth Local invasion Metastasis

Answer 35

Differentiation * the extant to which neoplastic cells resemble corresponding cells morphologically and functionally * poorly differentiated cells are a hallmark of malignancy * Anaplasia = lack of differentiation * cells display pleomorphism (marked different size and shape of cells) * large cell, irregular size and shape, hyperchromatic dark nuclei, multinucleated, disorganised

Answer 36

Growth rate differentiation **Benign** * grow slowly * progressive growth * rare mitotic figures **Malignant** * grow rapidly - often outgrow blood supply leading to necrosis * erratic growth (may appear slow) * OFTEN NUMEROUS MITOTIC FIGURES (in the process of division)

Answer 37

Local invasion for differentiation **Benign** * remain localised to site of origin (discrete lesion) * well demarcated * cohesive, expansile growth * fibrous capsule **Malignant** * progressive infiltration invasion and destruction of surrounding tissue * do not recognise anatomical boundaries * typically unencapsulated Invasiveness is a reliable indicator of malignancy

Answer 38

Metastasis Metastasis is the single most reliable hallmark of malignancy M = when colonies of tumor cells take up residence at a distant site from the parent tumor - the neoplasm has migrated to another location

Answer 39

Pathways of metastasis 1. Direct seeding - transcoelomic spread in the body cavities / surfaces 2. Lymphatics - most carcinomas spread via the lymphatic system 3. Blood vessels - typical spread of sarcomas and also seen in carcinomas liver and lungs For metastasis to occur the neoplasm must have the correct gene combination .

Answer 40

The mechanisms of invasion in metastasis 1. Detach - from main tumor mass - reduce cell to cell adhesion 2. Adhere and penetrate basement membrane 3. Invade extracellular matrix - adhere, migrate, degrade and remodel 4. Invade blood vessels lymph nodes (intravasation) 5. evade immune system cells - often form small tumor emboli with platelets 6. excit from vessel (extravasation) 7. colonise new site 8. stimulate new blood vessel growth angiogenesis ( to grow and thrive)

Answer 41

**Tumour stromal interactions** * Successful tumours can co-opt and adapt the environment to their own inferiors means * tumour cell and stroma interact in a variety of ways (wide range of signalling molecules; growth factors, cytokines, hormones and inflammatory mediators * modulate growth rate, differentiation state and behaviour of tumour cells (invasiveness, metastatic capability) **Scirrhous response (PDGF platelet derived factor)** * some tumour cells release PDGF which stimulates proliferation of fibroblast, and increased production of collagen * often seen in epithelial cell tumours **Cytokine production** * Some tumour cells induce stromal cells to produce cytokines which promote tumour proliferation or motility

Answer 42

The immune response to neoplasms Neoplastic cells have antigen on their cell surface. These antigens are able to stimulate a immune response, and in some cases this response may lead to regression of the tumour. However many cells evade the body's immunosurveillance * antigen loss of tumour cell * class one MHC deficient tumour cell * immunosuppressive cytokines

Answer 43

Chemical response preformed vasoactive amines **Histamine** * mast cells, basophils and platelets * increase muscous production and bronchial constriction * vasodilation and vascular permeability **Serotonins** * platelets of mammals * important neurotransmitter * vasodilation and vascular permeability

Answer 44

Newly synthesised eicosenoids - chemical response in inflammation Arachnidonic acid and metabolitesderived from cell membrane lipids - mediate many aspects of acute inflammation **Prostaglandins** * endothelial cells, mast cells = vasodilation * fever, pain and increase in vascular permeability * act upon hypothalamus **Leukotrienes** * vasoconstriction and increase vascular permeability * LTB4 potent chemotactic agent for leukocytes * however, an incrase in conc leads to vasodilation

Answer 45

Compliment cascade Inflammation activates circulating complement proteins * synthesised by liver up of 25 complement proteins * activated by microbes, antibodies, endotoxins and venom Function * form membrane attack complexes - perforate membranes of pathogens * when complement proteins become activated they become activated proteolytic enzymes * promote chemotaxis and opsonisation * enhance histamine release from mast cells * these in turn activate other compliment proteins resulting in powerful **enzymatic amplification** * **the critical step is activation C3 (most abundant compliment protein)**

Answer 46

Activation of the compliment cascade **Classical pathway** * binding of CL to AB-Ag complexes **alternative pathway** * binding of endotoxin or LPS **Lectin pathway** * plasma manose binding lectin binds to CHOS on microbes activation CL

Answer 47

The kinin system Activated by hageman factor 12 * activated by secondary exposure of collagen or basement membrane, when endothelium is damaged **Bradykinin** * vasoactive amine * vasodilation and increase in vascular permeability (endothelial cell contraction) * increases sensitivity to pain * Kallikreins - kininogens - bradykinin Plays a role in blood pressure and inflammation via the production of bradykinin

Answer 48

Acute inflammation is a vasocentric process * characterised by marked vascular changes vasodilation, increased permeability and fluid exudation * exudation of fluid, plasma proteins * emigration of leukocytes What is responsible for this marked vascular response * mast cell degranulation (BK, PGs and FR) causing vasodilation which in turn increases blood flow.

Answer 49

**Genes of oncogenesis** **Proto oncogenes** * help regulate cell growth and differentiation * when modified in a way initiates or promotes neoplasia are then called **oncogenes** (promotors of autonomous cell growth RAS) **Tumour suppressor genes p53 (transcription up regulation)** * the gene initiates cell cycle arrest at checkpoints * allows for time to repair DNA damage * many tumours have a mutation in p53, preventing cell arrest **Genes coding for DNA repair** * tumours can regain the ability to replicate telomeres - immortality **Genes which code for DNA repair proteins** * cells accumulate potentially mutagenic DNA damage The development of neoplastic behaviour in a cell is complex, multi step process “stepwise development neoplasia”

Answer 50

**The three steps of neoplasia development** **Initiation** * cell is primed by a non lethal, irreversible genetic change * appears morphologically normal * may remain quiescent for years **Promotion (high risk)** * initiated cell expands to form a preneoplastic lesion or benign tumour * in response to stimuli called promoting agents * stimulate proliferation of mutated cells eg. hormones or drugs * not mutagenic effects are reversable **Progression** * with further epigenetic or genetic alterations a malignant tumour arises from a sub clone * represents an irreversible change in the nature of the tumour * complex and poorly understood process

Answer 51

Angiogenesis Continued growth of solid tumour cells absolutely depends on adequate blood supply * provides oxygen and nutrients to growing tumours * tumours induce angiogenesis via growth factors and other signalling molecules released from **ECM - VEGF and FGF** * blood vessels in tumours are tortuous, irregularly shaped, disorganised, leaky and unstable

Answer 52

Immune response to neoplasms Neoplastic cell have antigens on the cell surface (proteins, glycoproteins, glycolipids) * These antigen elicit an immune response * the inflammation response dose not in general protect against neoplasia * macrophages, NK cells and cytotoxic T cells **Evasion of the immune response** * antigen loss variant of tumour cell * class one MHC deficient tumour cell * immunosuppressive cytokines

Answer 53

Direct effects of neoplasia A direct effect is when a tumour directly compromises the function of organs in which they arise * replace normal tissue of organs * cause pressure atrophy of adjacent tissue * compress adjacent blood vessels to cause ischaemia (blood restriction) and tissue necrosis * erosion of blood vessels can cause extensive haemorrhage * may rupture hollow organs such as the stomach, intestine or urinary bladder

Answer 54

Indirect effects of a neoplasm Indirect and often remote effects caused by tumour cell products - known as paraneoplastic syndrome (occur in \>70% of human patients) * cachexia * endocrinopathies * skeletal syndromes * vascular and haematologic syndromes * neurological syndromes * cutaneous syndromes

Answer 55

Cachexi Many animals with cancer show notible weight loss and debility * loss of both muscle and fat * Aetiological complex - extra calories do not reverse the catabolic state * anorexia impaired digestion * nutritional demands of neoplastic tissues / nutrient loss of neoplasm * metabolic and endocrine derangements * humoral factor = TNF - alpha, interleukins IL-1 IL-6 and prostaglandins

Answer 56

Endocrinopathies Due to an overproduction of hormones * hyperthyroidism due to thyroid neoplasia * Cushing's disease (hyper-adrenocortism) due to pituitary or adrenal neoplasm There are also a variety of non-endocrine neoplasms which produce hormonally active substances (ectopic hormone production) * hypercalcaemia or hypoglycaemia are frequently observed due to neoplasm * A wide variety of carcinomas/sarcomas result in the production of parathyroid hormone. Parathyroid hormone PTH removes calcium from bones, increases intestinal and kidney absorption causing hypercalcemia * Hypoglycaemia (low blood sugar) is seen with insulinomas - a functional neoplasm of the islet of Langerhans beta cells = results in incoordination, lethargy, weakness and seizures.

Answer 57

Hypertrophic osteopathy Observed in cats and dogs * **extensive periosteal new bone growth** * occurs with a variety of neoplasms but frequently associated with neoplastic and non neoplastic space occupying thoracic lesions * the cause is not known - but presumed to be overproduction of growth hormone

Answer 58

Haematological and vascular syndromes Neoplasia causes a variety of vascular and haematological disorders, cause remains unclear * anaemia * eosinophilia * neutrophilia * thrombocytopaenia (⅓ of all dogs with neoplasia) * disseminated intravascular coagulation (DIC)

Answer 59

How to diagnose neoplasia Clinical signs and symptoms * generalised lymphadenopathy in lymphoma * cachexia * respiratory distress with coughing / pulmonary neoplasm * lameness in dogs with hypertrophic osteopathy Blood analysis * anaemia, leucocytosis (up), DIC * paraneoplastic syndromes (hypercalcemia) * specific markers (prostatic specific antigen in humans) Imaging techniques * radiography, ultrasound and CT scans * can detect primary and metastatic neoplasms A definitive diagnosis is carried out through cytology and histopathology. Classification and naming of a neoplasm requires microscopic examination of cells - techniques which are routinely practised.

Answer 60

Cytology A sample is collected from solid neoplasms, or body fluids for cytology (examination of individual cells) * stain with a simple rapid stain Diff-Quik * may also include skin scrapings or impression smears * in house or sent away to a laboratory

Answer 61

Identifiable features Cell type involved Scrutinise for features of malignancy * degree of cell differentiation * mitotic index * evidence of invasion or metastasis Techniques * Haematoxylin and eosin - histopathology * Toluidin blue - mast cells * Immunohistochemistry - antibodies * molecular methods PCR

Answer 62

Tumour development Step wise tumour development - cumulative effect of multiple genetic (and epigenetic) changes over a long time course that creates a tumour. Many genes are required to direct and control the steps within the normal cell cycle Oncogenesis = is the complex process by which neoplastic cells develop. DNA mutations can occur in one or many of the different genes that normally regulate cell growth and differentiation- * proto oncogenes - regulate cell growth and differentiation * tumour suppressor genes such as p53 - slow * genes which code for DNA repair proteins * telomerases