Pathology Material for First Exam 2024 PDF

Pathology Material for the first exam 2024 CONCEPTS OF HEALTH AND DISEASE Health Disease Etiology Pathogenesis Morphology and Histology Clinical Manifestations Diagnosis Clinical Course  Introduction Pathophysiology is a term that combines the words p...

Pathology Material for the first exam 2024 CONCEPTS OF HEALTH AND DISEASE Health Disease Etiology Pathogenesis Morphology and Histology Clinical Manifestations Diagnosis Clinical Course  Introduction Pathophysiology is a term that combines the words pathology and physiology.  Pathology: Pathos means disease, i.e. is the science which deals with the study of structural and functional changes in cells, tissue and organs of the body that cause or are caused by disease.  Physiology deals with the function of the human body.  Thus pathophysiology deals with the effect of the changes in cells or organs that occur with diseases on total body function. (Example: traumatic injury causes atrophy of the brain and degeneration of neurons in the brain resulting in Alzheimer’s disease)  Or it may be defined as the physiology of altered health  CONCEPTS OF HEALTH AND DISEASE Health: a “state of complete physical, mental, and social well-being and not merely the absence of disease and infirmity”. Disease: an interruption, cessation or disorder in the function of the body organ or system (physiological dysfunction). Each disease is characterized usually by a recognized etiologic agents, an identifiable group of signs and symptoms or consistent anatomic alteration.  There are six aspects for the disease process: 1. Etiology (causes). 2. Pathogenesis (mechanism) (the origination and development of a disease). 3. Morphological changes (changes in the form and structure). 4. Clinical Manifestation (signs and symptoms). 5. Diagnosis (identifying the   Etiology The causes of the disease are known as etiologic factors, among these factors are:  Biological agents (bacteria, viruses).  Physical forces (trauma, burn , radiation).  Chemical agents (poison, alcohol).  Genetic inheritance.  And nutritional excesses or deficit. Most of the disease do not have a single cause, instead the majority are multifactorial, and many different agents can cause a disease for a single organ. some disease-causing agents are nonspecific or unknown (idiopathic).  Etiology (continued) The multiple factors that predispose to a particular disease or increase the risk or susceptibility of a disease are called risk factors Ex: obesity increase the risk of heart diseases. Differentiate between cause and risk factors. Other way to view the factors that cause disease are by grouping them according to whether they are present at birth (Congenital condition) or acquired in later life (Acquired defect).  Etiology (continued) Congenital conditions are defects that are present at birth, although they may not evident till later in life. Ex: sickle cell anemia. Acquired defects are those that are caused by events that occur after birth. Ex: injury, exposure to infection (HBV, inflammation, hepatitis).  Pathogenesis The sequence of cellular and tissue events that take place from time of initial contact with an etiologic agents until the expression of the disease. How the disease process evolves. Differentiate between etiology and pathogenesis. Ex. atheroscelerosis is cited as the cause of the coronary artery disease while the progression of fatty streak to the occlusive vessel lesion seen in people with CAD represents the pathogenesis of the disorder.   Morphology Morphology: refers to the fundamental structure or form of cells or tissues. Morphologic changes are concerned with both the gross anatomic and microscopic changes that are characteristic of the disease. Histology: deals with the study of cells and extracellular matrix of the body tissues. (Histologic sections play an important role in diagnosis of many types of cancer).  Clinical Manifestations Disease can be manifested in a number of ways including signs and symptoms. Sometimes the condition produces manifestations, such as fever, that makes it evident, that the person is sick. Other diseases are silent at the onset and are detected during examination or after the disease is far advanced Symptoms: are subjective complaint that is noted by the person with the disorder.(ex: pain, difficulty in breathing and dizziness). Signs: are objective manifestation that are noted by an observer.(ex: elevated temperature, rash,). Signs and symptoms are used to describe the structural and functional changes that accompany a disease. A syndrome is a compilation of signs and symptoms or is a group of signs and symptoms that occur together and characterize a particular abnormality or condition (e.g., chronic fatigue syndrome and Down syndrome).   Diagnosis (Question: how we can diagnose and purpose of each one and finally what can do?) The process of identifying the cause of the disease. It is done through examination of the patient including: taking patient history, physical examination and findings of lab tests. Purposes of doing lab test: 1. To validate a problem or confirm a diagnosis. 2. To determine other related health problems.   Clinical Course It describes the evolution of the disease, the steps of the disease, how the disease behave over time, which may be acute, subacute and chronic. Acute disease: is relatively sever but self-limiting. It appears suddenly and worsen rapidly. Chronic disease: implies a continuous, long term process: it can present either with exacerbation (aggravation of symptoms and severity of the disease) or remission (a period during which there is a decrease in severity and symptoms). It develops gradually and worsens over an extended period of time. Subacute: it is between acute and chronic it is not as sever as acute and not as prolonged as chronic.  Position Pathophysiology is an important subject bridging Basic sciences and clinical medicine. pathophysiology basic clinical sciences medicine bridge subject   Clinical Course Can also be divided into or the spectrum of disease severity for infectious disease can range from: Clinical disease: is manifested by sign and symptoms. Preclinical stage: a disease not clinically evident (no sign and symptoms) but is destined to progress to clinical disease. And it is possible to transmit the disease during this stage. Subclinical disease: not clinically apparent and not destined to become clinically apparent (primary tuberculosis remains latent). Healthy or passive carrier Status: refers to an individuals who harbors an organism but is not infected, as evidenced by antibody response or clinical manifestations. Active carrier: refers to the infected individual who can transmit the disease to other when he may or may not exhibit signs and symptoms of infection. Perspective on health and disease in population: Epidemiology: is the study of diseases occurrence in population and the extent of spread of infectious disease. Epidemiology is also involved in the study of risk factors (smoking, alcohol) for multifactorial diseases (e.g. heart disease and cancer). It looks for the patterns of people who are affected with particular disorder (such as age, race, life style). Incidence: The number of new cases arises in a population during a specified time. Prevalence: is the number of people (new and pre-existing) in a population who have a particular disease at a given point of time or period. Perspective on health and disease in population: Continued Mortality: statistics provide information about the number of death in a certain disease at a specific period of time. Morbidity: statistics provide information about the functional effect (clinical course) of a certain disease on a person’s life at a specific period of time. CELLULAR ADAPTATION CELL INJURY AND DEATH Causes of Cell Injury Mechanisms of Cell Injury Reversible Cell Injury and Cell Death Necrosis Cellular Aging  OVERVIEW OF CELLULAR RESPONSES TO STRESS Cells normally maintain a steady state called homeostasis. As cells encounter physiologic stresses or pathologic stimuli, they can undergo adaptive changes that permit survival and maintenance of function. Cells are able to adapt to increased work demands or threats to survival by changing their size  Continue 1) Physiologic adaptations include responses of cells to normal stimulation by hormones or endogenous chemical mediators (e.g., the hormone-induced enlargement of the breast and uterus during pregnancy). 2) Pathologic adaptations are responses to stress that allow cells to modulate their structure and function and thus escape injury.  Adaptation forms 1) Hypertrophy: is an increase in the size (not number) of cells resulting in increase in the size of the organ. It occurs in the cells which have a limited capacity to divide like skeletal muscle and cardiac muscle. It can be physiologic (e.g., uterus during pregnancy and skeletal muscle as a result of increasing the workload (weightlifter)) or pathologic that occurs as a result of disease condition. Types of pathologic hypertrophy are: 1. Adaptive (e.g., myocardial hypertrophy due to HTN). 2. Compensatory (e.g., nephrectomy (kidney removal). It is caused by increased functional demand or by growth factor or hormonal stimulation.  The relationship among normal, adapted,.reversibly injured, and dead myocardial cells Cross section of the heart with left A ventricular hypertrop hy. Adaptation or injury (reversible or irreversible changes) are not dependent only on the nature and severity of stress but also on other variables including: 1. Blood supply. 2. Cellular metabolism. 3. Nutritional status.  2) Hyperplasia: refers to an increase in the number of cells in an organ or tissue. It occurs in tissues with cells that are capable of mitotic division, such as the epidermis, intestinal epithelium, and glandular tissue. – It may occur concurrently with hypertrophy and often in response to the same stimuli. – It can be physiologic or pathologic.  – Two types of physiologic hyperplasia 1. Hormonal hyperplasia (e.g., proliferation of glandular epithelium of the female breast at puberty and during pregnancy, and uterine enlargements during pregnancy that results from estrogen stimulation. 2. Compensatory hyperplasia, in which residual tissue grows after removal or loss of part of an organ (e.g Liver). Most forms of pathologic hyperplasia are caused by excessive hormonal or growth factor stimulation (e.g: endometrial hyperplasia causing abnormal menstrual bleeding, fibroblast proliferation aid for wound healing, papilloma viruses caused skin warts and mucosal lesions. The hyperplastic process remains controlled process (differs from cancer); if the signals that initiate it stop, the hyperplasia disappears. 3) Atrophy: is the shrinkage in the size of the cell by the loss of cell substance. The organ size is decreased Atrophied cells may have diminished function but they are not dead Causes of atrophy include: – Decreased workload (e.g., immobilisation of limbs). – Loss of innervation (e.g., paralysed limbs). – Diminished blood supply (ischemia). – Inadequate nutrition (malnutrition). – Loss of endocrine stimulation (e.g. menopause) – Aging The mechanisms of atrophy consist of a combination of decreased protein synthesis and increased protein degradation (by activation of ubiquitin-proteasome pathway) in cells in addition to stimulation of autophagy (“self-eating”) process. 4) Metaplasia: is a reversible change in which one adult cell type (epithelial or mesenchymal) is replaced by another adult cell type that have better ability to withstand the adverse environment. Metaplasia is thought to arise by reprogramming of stem cells to differentiate along a new pathway to produce the new more resistant type of cells. It occurs in response to chronic irritation and inflammation. Exp: Smokers’ trachae and bronchi are lined by stratified squamous epithelial cells in place of normal columnar epithelial cells in order to survive under these harsh circumstances. Metaplastic cells have survival advantages, but they OVERVIEW OF CELLULAR RESPONSES TO STRESS AND NOXIOUS STIMULI  Cell Injury and Death (a) Causes of cell injury Cell damage can occur in many ways. For purposes of discussion, the ways by which cells are injured have been grouped into five categories: 1. Injury from physical agents 2. Radiation injury 3. Chemical injury 4. Injury from biologic agents 5. Injury from nutritional imbalances  Physical injury Mechanical Forces: Injury or trauma due to mechanical forces occurs as the result of body impact with another object. Temperature Extreme: Extremes of heat and cold cause damage to the cell, its organelles, and its enzyme systems. Electrical Forces: Electrical forces can affect the body through extensive tissue injury caused by heat production>>burning and disruption of neural and cardiac impulses. Electrical burn of the skin  Radiation Injury Radiation energy above the ultraviolet (UV) range is called ionizing radiation, while below those of visible light is called nonionizing radiation. Ionizing radiation impacts cells by causing ionization of molecules and atoms in the cell and consequently the production of free radicals that destroy the vital molecules in the cells. Nonionizing radiation includes infrared light, ultrasound, microwaves, and laser energy. They exert their effect by causing vibration and rotation of atoms>>>thermal energy. Ultraviolet radiation causes sun-burn and increases the risk of skin cancers (by damaging DNA, damaging to melanin-producing process in the skin cells and producing ROS).  Chemical injury (chemical burns) Chemical agents can injure the cell membrane and other cell structures, block enzymatic pathways, coagulate cell proteins, and disrupt the osmotic and ionic balance of the cell. Some of the most damaging chemicals exist in our environment, including gases such as carbon monoxide, insecticides, and trace metals such as lead. Irritant or corrosive chemical product  Chemical injury Drugs: many drugs—alcohol, prescription drugs, over the-counter drugs, and street drugs —are capable of directly or indirectly damaging tissues. Ethyl alcohol can harm the gastric mucosa, liver, developing fetus, and other organs. Lead Toxicity: The toxicity of lead is related to its multiple biochemical effects. It has the ability to 1) inactivate enzymes required for hemoglobin synthesis and that leads to RBC hemolysis, 2) compete with calcium for incorporation into bone, 3) and interfere with nerve transmission and brain development. The major targets of lead toxicity are the red blood cells, the gastrointestinal tract, the kidneys, and the nervous system.  Biological injury Biologic agents differ from other injurious agents in that they are able to replicate and can continue to produce their injurious effects. The most common infection-causing bacteria is Staphylococcus aureus and other types of staphylococci >> bacterial colonization Pathogenicity of microorganism depends on: – Invasion and destruction of cells. – Production of toxins. – Production of hypersensitivity reactions. Injury occurs by diverse mechanisms: 1. Enter host cells and become incorporated into DNA synthetic machinery. 2. Elaborate exotoxin that interferes with ATP production. 3. Elaborate endotoxin that causes cell injury and increase capillary permeability.  Nutritional imbalance Vitamin deficiency (as a result of starvation or stomach acid) and hypervitaminosis (as a result of excess nutrition). Diets rich in animal fat are strongly implicated in the development of obesity and consequently atherosclerosis.  Mechanisms of cell injuries )b( The previously mentioned injurious agents exert their effects by different mechanisms resulting in cell injury and death. Of these mechanisms include: 1. Free radical formation. 2. Hypoxia and ATP depletion. 3. Disruption of intracellular calcium homeostasis. (1) Free Radical Formation Free radicals are highly reactive chemical species with an unpaired electron in the outer orbit (valence shell) of the molecule (NO ). The unpaired electron causes free radicals to be unstable and highly reactive, so that they react non-specifically with molecules in surrounding area. The molecules that react with free radicals are in turn converted into new free radicals. These molecules are produced endogenously by normal pathway during mitochondrial respiration and energy generation, and metabolic burst that accompanies phagocytosis (fig 1.18) OR exogenously by ionising radiation that hydrolyses the water in the cells into hydroxyl radicals or by inflammatory leukocytes that produce ROS. However, free radicals are degraded and removed by cellular defense system, including superoxide dismutase (SOD) , and glutathione peroxidase (GXP) in the mitochondria, they convert the O 2 and hydroxyl radical (OH ) respectively to non-radicals such as hydrogen peroxide (H2O2) and (H2O) respectively. Catalase in peroxisome converts H2O2 to H2O+ O2. Free Radical Production normal production......Continue Oxidative stress is a condition that occurs when the generation of ROS (reactive oxygen species) exceeds the ability of the body to neutralize and eliminate ROS or scavenging system are ineffective. In cells and tissues, ROS react with proteins, lipids, and nucleic acid, thereby damaging cell membranes; inactivate enzymes; and damage nucleic acids that make up DNA (fig 1.19). Role of ROS in cell injury  (2) Hypoxia and Depletion of ATP Hypoxia deprives the cell of oxygen and interrupts aerobic oxidative metabolism and the generation of ATP. Hypoxia can result from an inadequate amount of oxygen in the air, respiratory disease or ischemia (which means the decreased blood flow to the cells due to vasoconstriction or vascular obstruction). ATP sources: oxidative phosphorylation (ADP) & glycolysis glucose which is derived from the circulation or from the hydrolysis of intracellular glycogen. Causes of ATP depletion: – Reduced supply of oxygen and nutrients (like in ischemia), – Mitochondrial damage, – Toxins (e.g., cyanide)  Effects of ATP depletion on the cellular system 1. The activity of the plasma membrane sodium pump (Na+/K+ ATPase) is reduced, resulting in intracellular accumulation of sodium and efflux of potassium, that lead to gain of water, causing cell swelling and dilation of the endoplasmic reticulum. 2. Failure of Ca2+ pump leading to influx of Ca2+ with damaging effects on numerous cellular components. 3. Increase in anaerobic glycolysis as a compensatory mechanism to maintain the cell’s energy source, as a result, the intracellular glycogen stores are rapidly decreased, ATP levels are also decreased and lactic acid accumulates, leading to decreased pH that lead to decrease the activity of many enzymes that affect the nuclear chromatin>>cells shrinkage. 4. Reduction in protein synthesis by detachment of ribosomes from the rough endoplasmic reticulum. Depletio n of ATP Disruption of intracellular )3( calcium homeostasis Normally, intracellular Ca+2 levels are kept extremely low compared to extracellular levels by membrane-associated Ca2+ and by storage in vessels. Ischemia and certain toxins lead to an increase in cytosolic calcium because of increased influx across the cell membrane and the release of calcium from intracellular stores. Functions of Ca2+? The increased calcium level may inappropriately activate a number of enzymes with potentially damaging effects. These enzymes include the phospholipases, responsible for damaging the cell membrane; proteases that damage the cytoskeleton and membrane proteins; ATPases that  Effects of increase d cytosoli c calcium in cell injury Forms of cell injuries  MITOCHONDRIAL DAMAGE Mitochondria can be damaged by increases of cytosolic Ca2+, ROS, and hypoxia and ATP depletion. The two major ways of mitochondrial damage: 1. The formation of channels (called mitochondrial permeability transition pores) in the mitochondrial membrane, these pores lead to loss of mitochondrial membrane potential and pH and depletion of ATP that lead to necrosis of the cell. 2. Increasing the permeability of the mitochondrial membrane for cytochrome c, resulting in leakage of these proteins into the cytosol thereby inducing death signal of cells to die by apoptosis.  Role of mitochondr ia in cell injury and death  MEMBRANE DAMAGE :(1) Main causes 2. 3. 1.  Consequences of various membrane )2( damage 1) Mitochondrial membrane damage  Decreased production of ATP  Necrosis 2) Plasma membrane damage  Loss of osmotic balance  Influx of fluids and ions  Loss of cellular contents.  Loss of energy producing metabolites (ADP)  depleting energy stores.  Necrosis 3) Injury to lysosomal membranes  Leakage of lysosomal enzymes into the cytoplasm  Activation of the acid hydrolases (RNases, DNases, proteases, glucosidases, and other enzymes) in the acidic intracellular pH of the injured (e.g., ischemic) cell.  Enzymatic digestion of cell components by the activated enzymes  Necrosis  DAMAGE to DNA and PROTEINS Main causes of excessive DNA damage involve: radiation injury and oxidative stress. Main causes of accumulation of improperly folded proteins are inherited mutations or external triggers (e.g., free radicals). Accumulation of improperly folded proteins and excessive DNA damage trigger cell apoptosis. Cells have mechanisms that repair damage to DNA, but if this damage is too severe to be corrected or the cells are unable to correct DNA damage, the cells initiate its suicide program and dies by apoptosis Examples of cell injury and necrosis 1) Ischemic and Hypoxic Injury: Ischemia injures tissues faster and usually more severely than does hypoxia. Ischemia Inhibition of aerobic glycolysis and oxidative pathways decreased ATP generation, mitochondrial damage, and accumulation of ROS  cell death (mainly by necrosis) 2) Ischemia-Reperfusion Injury: under certain circumstances, the restoration of blood flow to ischemic, but reversibly injured (viable), tissues results in the death of cells. MECHANISMS !!!!!?????  Overproduction of ROS results from damaged mitochondria and subsequently the incomplete reduction of O 2 while compromising of antioxidant mechanisms  additional tissue injury  Increase of the inflammation with reperfusion because of increased influx of leukocytes and plasma proteins, and activation of the complement system  additional tissue injury Examples of cell injury and necrosis 3) Chemical (Toxic) Injury: A) Binding directly to a critical molecular component or cellular organelle (mercury binds to the SH groups of various cell membrane proteins inhibition of ATP- dependent transporters and increased membrane permeability) B) Formation of free radicals. (Exp: carbon tetrachloride (CCl4) is converted to the toxic free radical (CCl3 ) in the liver causing: 1) Membrane phospholipid peroxidation. 2) Breakdown of ER membranes and  Decline in hepatic protein synthesis  Reduced lipid export from the hepatocytes causing fatty liver 3) Mitochondrial injury diminished ATP stores  Defective ion transporter Cell swelling  plasma membranes damage  Calcium influx  Cell death.  OVERVIEW of CELL INJURY and CELL DEATH Cell injury results when cells are stressed so severely, so that they are no longer able to adapt. 1) Reversible cell injury. In early stages or mild forms of injury, the functional and morphologic changes are reversible if the damaging stimulus is removed. At this stage the injury has not progressed to severe membrane damage and nuclear dissolution. 2) Irreversible cell injury occurs when the cell damage is so severe and persistent for long time thereby inducing cell death. There are two types of cell death: A. Necrosis: the major pathway of cell death occurs under pathological conditions such as ischemia, exposure to toxins, various infections, and trauma. B. Apoptosis : not necessarily associated with pathologic cell injury. The cell kills itself when it is deprived of growth factors (physiological), or the cell’s DNA or proteins are damaged beyond repair (pathological). Cellular features of necrosis and apoptosis  Necrosis Vs. Apoptosis Pyknosis>>> nuclear shrinkage due to DNA condenses into shrinking mass. Karyorrhexis>>>nuclear fragmentation. Karyolysis>>>nuclear fading or chromatin dissolution due to action of DNase and RNase.  APOPTOSIS Apoptosis in Physiological Conditions: 1) The programmed destruction of cells during embryogenesis. 2) Involution of hormone-dependent tissues upon hormone deprivation (regression of the lactating breast after weaning) 3) maintain a constant number of cell population in tissue. 4) Elimination of cells that have served their useful purpose (neutrophils after acute inflammatory response) or are deprived of necessarily survival signal. 5) Elimination of potentially harmful self-reactive lymphocytes 6) Defense mechanism against viruses and tumors  :Apoptosis in Pathologic Conditions DNA damage (Radiation, cytotoxic anticancer drugs, extremes of temperature, hypoxia) Accumulation of misfolded proteins. Viral infections Duct Obstruction (pancreas) Mechanisms of Apoptosis Two basic pathways for apoptosis have been described. These are the extrinsic pathway, which is death receptor dependent, and the intrinsic pathway, which is death receptor independent. The execution phase of both pathways is carried out by proteolytic enzymes called caspases, which are present in the cell as procaspases.  The extrinsic pathway The extrinsic pathway involves the activation of receptors such as tumor necrosis factor (TNF) receptors and the Fas ligand (FasL) receptor. When T cells recognize Fas-expressing cell (target) binds to its receptor on the target cells, to form a death- initiating complex. The complex then converts procaspase-8 to caspase-8. Caspase-8 (initiator caspase), in turn, activates a cascade of executioner caspases that execute the process of apoptosis. (Initiator caspases initiate the apoptosis signal while the executioner caspases carry out the mass proteolysis that leads to apoptosis. Caspases will then cleave a range of substrates, including downstream caspases, nuclear proteins, plasma membrane proteins and mitochondrial proteins, ultimately leading to cell death.) The end result includes activation of endonucleases that cause fragmentation of DNA and cell death. Mechanisms of Apoptosis  The intrinsic pathway The intrinsic pathway, or mitochondrion- induced pathway, It involves the opening of mitochondrial membrane permeability pores with release of cytochrome c from the mitochondria into the cytoplasm. Cytoplasmic cytochrome c activates caspases, including caspase-3 (executioner caspase). Caspase-3 activation is a common step to both the extrinsic and intrinsic pathways. The end result includes activation of endonucleases that cause fragmentation of DNA and cell death. Mechanis ms of Apoptosi s  Definitions Neoplasia is the uncontrolled, disorderly proliferation of cells, resulting in the formation of tumour or neoplasm. A tumor : is a swelling that can be caused by a number of conditions, including inflammation and trauma. In addition, the term has been used to define an abnormal mass of cells that arises because of overgrowth. Unlike normal cellular adaptive processes such as hypertrophy and hyperplasia, neoplasms do not obey the laws of normal cell growth. They serve no useful purpose, they do not occur in response to an appropriate stimulus and they continue to grow at the expense of the host. Neoplasms are classified as benign or malignant. Neoplasms that contain well-differentiated cells (Cell differentiation is the process whereby proliferating cells become progressively more specialized cell types) that are clustered together in a single mass are considered to be benign. These tumors usually do not cause death unless their location or size interferes with vital functions. In contrast, malignant neoplasms are less well differentiated and have the ability to break loose, enter the  Continued……. Benign tumours of most tissues (including parenchymal ( or called epithelial) and mesenchymal tissues, (comprising connective tissues, muscle and blood vessel)) are usually simply designated the suffix -oma. For example, a benign tumor of glandular epithelial tissue is called an adenoma, and a benign tumor of bone tissue is called an osteoma. Papillomas are benign epithelial, microscopic or macroscopic finger-like projections that grow on any surface. The term carcinoma is used to designate a malignant tumor of epithelial tissue origin. In the case of a malignant tumor of glandular epithelial tissue, the term adenocarcinoma is used. Malignant tumors of mesenchymal origin are called sarcomas (e.g., if it originated in bone (connective tissue) it is called osteosarcoma).  Nomenclature of Epithelial Neoplasms Epithelial tissues Benign neoplasms Malignant neoplasms Skin & Mucus Papilloma Papillary carcinoma Glandular Epithelium Adenoma AdenoCarcinoma Placental epithelium Hydatidiform Mole Chorion Carcinoma 70  Nomenclature of Connective Tissue Neoplasms Connective tissues Benign neoplasms Malignant neoplasms Fibroma Fibrous tissue Fibrosarcoma Lipoma Fatty tissue Liposarcoma Osteoma Osteosarcoma Osteoid tissue 71  Carcinoma in situ is a localised preinvasive lesion or is an early stage cancer in which tumour is still confined to the site from which it started and has not spread to surrounding tissue or other organs in the body. The most common type of non-invasive breast cancer is breast ductal carcinoma in situ, in which the cells have not crossed the basement membrane. Depending on its location, in situ lesions usually can be removed surgically or treated so that the chance of recurrence are small.  Carcinogenesis Carcinogenesis is a multistage process by which normal cells are *.transformed to malignant cells with invasive traits It comprises of three distinct stages, including initiation, * promotion and.progression Initiation is induced as a result of irreversible, inheritable DNA.1 damage resulting in mutation. Mutation can be defined as an.inheritable/ permanent changes to DNA a) Mutational activation of proto-oncogenes: Proto-oncogenes (e.g. c-Myc) are central to the stimulation of normal cell growth, proliferation and survival. Upon mutational activation, these become oncogenes, leading to uncontrolled cell growth. C-Myc is.linked with oral squamous cell carcinoma b) Mutational inactivation or tumour suppressor genes: Tumour suppressor genes such as retinoblastoma (Rb) and p53 which are central to the inhibition of uncontrolled cell proliferation. Rb prevents cell division while p53 prevents proliferation of cells- containing DNA damage by inducing DNA repair otherwise cell  Carcinogenesis continue...... Promotion occurs when the initiated cells are exposed to external,.2 non-mutagenic stimuli (e.g., growth factors and chemicals) that promote.the clonal expansion and consequent formation of benign colonies Cells that have been irreversibly initiated may be promoted even after long.latency periods Progression of benign tumours to malignant ones requires some.3 additional, heritable changes in the cellular genome that ultimately generate cells with new traits including: a) Independence on exogenous.growth signals for proliferation.b) Unresponsiveness to growth-inhibitory signals.c) Escape from apoptosis.d) Unlimited replicative potential.e) Encouraging the growth of new blood vessels (angiogenesis).f) Inducing the cells invasion and metastasis Over a period of time many tumours become more aggressive and * acquire greater malignant potential. This phenomenon is referred to as tumour progression and is not simply represented by an increase in tumour.size Tumour progression and associated heterogeneity most likely result from *  Causes of gene mutation The mutant gene may be (1) Inherited (some), makes the subject more susceptible to cancer (predisposing gene) e.g. retinoblastoma, Wilms tumor (nephroblastoma), neurofibromatosis (2) Due to exposure to chemical carcinogens (agents capable of causing cancer) such as organic solvent, toothpaste, silicon, asbestos, or due to exposure of physical factors: radiation (ionized and non ionized), X-rays, nuclear radiaton and ultraviolet radiation(skin cancer). (3) Due to infection of the cell by viruses(some). DNA oncogenic viruses are papova viruses, adenoviruses and herpes viruses l; hepatitis B virus (hepatocellular cancer), Epstein-Barr virus (Burkitt lymphoma= is a cancer of the lymphatic system). (4) RNA oncogenic viruses are retroviruses (reverse transcription) e.g. human T-cell leukemia-lymphoma virus. HIV is not oncogenic virus but it leads to decrease the efficiency of the immune system. Decrease in immunity predispose more to cancer. Some chemotherapeutic cytotoxic drugs are carcinogenic because  Pathohistological Characteristics of Tumors 1. Local increase in cell number. 2. Loss of normal arrangement of cells. 3. Variation of cell shape and size. 4. Increase in nuclear size and density of staining. Due to more DNA because more cells are in mitotic stage. 5. Increase of mitotic activity aneuploi 6. Abnormal mitoses and chromosomesdy. Note !!!!! All of the above characteristics is more prominent in malignant than in benign tumor. The cytologic/histologic grading of tumors is based on the degree of differentiation and the number of proliferating cells. The closer the tumor cells resemble comparable normal tissue cells, both morphologically and functionally, the lower the grade. Accordingly,  Characteristics of malignant Invasion, infiltrating and tumors destroying normal tissues surrounding them. Metastases. It is distant spread of the tumor (1)Spread into body cavities:(e.g. cancer in the stomach--- peritoneal cavity, cancer in the lung ----pleural cavity) (2)invasion of lymphatics: first to local lymph nodes then regional lymph nodes)(lymphadenopathy : enlarged hard lymph nodes)then(reticuloendothelial sytem:spleen, thymus, liver) (3)Hematogenous spread : into the blood stream,(depending in the direction of the blood flow and amount of blood) e.g colon cancer spread into liver. Lung,Brain, liver,-- has high blood supply so it is subjected more to metastasis. Tumors may have Tumor cell Markers.(are antigens expressed on the surface of tumor cells or substances released from normal cells in response to the presence of tumor.) These include Hormones e.g. ACTH (oat-cell carcinoma) of the lung : cancer cell of the lung produce hormones !!!! (so tumor cells may change their function). Alpha fetoprotein (AFP) tumor marker liver cancer