Glossary of 3rd year Pathology ESE - important stuff to remember

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Definition of Atrophy
1. Shrinkage in Cell size
2. Loss of function
3. Pathological adaptation of stable or permanent cells
Causes of Atrophy
1. Loss of innervation --> Poliomyolitis
2. Decreased workload --> Casts
Definition of Involution and Causes of involution
1. Physiological Atrophy
2. Combination of Atrophy and Apoptosis
Causes: Decreased Endocrine stimulation, Fetal development, Thymus
3 Forms of Apoptosis
1.Programmed - Embryogenesis
2.Specialized - Keratinization
3. Clonal deletion
Morphology of Apoptosis
1. Chromatin condenses, fragments
2. Cell shrinks
3. Apoptotic bodies are cleared by tissue histiocytes (remember Tingible body Macs)
Define Cellular adaptation
The state between the normal, unstressed cell and the injured, overstressed cell. Can be physiological/Pathological
Features of Hypertrophy, also specify reasons for Physiological hypertrophy
Increase in synthesis of structural proteins and organelles. Nuclei might have more DNA content, but no mitosis occurs.
1. Weight lifting
2. Alpha-adrenergicR in cardiac muscle
Give two causes of Pathological hyperplasia
1. Excessive hormonal production (thyroid, prostate)
2. Excessive GF as in skin warts by Papilloma virus
Why is Hyperplasia non-neoplastic ?
It is dependent on growth factors
Morphological changes in cellular aging
1. Irregular lobed nucleus
2. vacuolated mitochondria
3. Decreased ER
4. Distorted Golgi
5. Lipofuscin accumulation
Define Metaplasia
Reversible change in which one adult cell is replaced by another adult cell.
The change arises from reprogramming of STEM cells
Define dysplasia. Give a few morphological characteristics
Disorderly but non-neoplastic proliferation.
1. Loss of uniformity of cells
2. Loss of polarity
3. Pleomorphism
4. Abundant mitotic figurs
Remember Carcinoma in situ!
Describe the mechanism that leads to reversible cellular injury
Hypoxia --> decrease in ATP :
1. --> Release of Ca2+ from stores --> Activation of 'ases'
2. Loss of osmotic regulation
3. Glycolysis
Morphological changes in reversible injury
1. Membrane alterations (blebbing)
2. Mitochondrial swelling, vacuoles
3. Clumping of chromatin
4. Eosinophilia increaes
5. Cellular swelling and lipid vacuoles
Give 2 exogenous and 2 endogenous mechanisms creating free radicals
Exogenous :
1. Ionizing radiation
2. Chemicals - CCl4
Endogenous :
1. cellular respiration
2. CyP450 reactions
3. NADPH oxidase
Give 3 types of cellular injuries caused by free radicals. Also describe 2 protective mechanisms
1. Lipid peroxidation --> lipofuscin granules
2. SS breaks
3. Protein cross linking

Protection :
1. GSH
2. Superoxide dysmutase
What are the three characteristics of irreversible cellular damage ?
1. Membrane damage
2. Inability to revers mitochondrial dysfunction (even after restoration of blood flow!)
3. Injury of lysosomal membranes
Membrane damage leads to which effects ? (give 4)
1. Massive Ca2+ influx
2. Loss of volume regulation
3. Vacuolization of mitochondria (Ca2+ rich densitie in matrix)
4. Depletion of metabolites escaping thru membrane
5. Leakage of cellular enzymes to blood (markers !)
Morphology of Hypoxic necrosis :
1. Denaturation of proteins --> coagulative necrosis
2. Eosinophilia (denatured proteins)
3. Vacuolated cytoplasm
4. Nuclear changes(lysis,pyknosis,rhexis)
5. Myelin figures (whirled PL masses)
Define necrosis. What are the two main processes mediating necrosis ?
Cell death in a living tissue.
1. Denaturation of proteins
2. Enzymatic digestion of cell (autolysis, heterolysis)
Define granulomatous reaction
Necrotic foci composed of amorphous cellular debris, enclosed by epitheloid cells and giant cell macrophages
How would you recognize Fat necrosis ? What is usually its cause ?
BANDA stain. This stains Ca2+ soaps (chalky white deposits) which are hydrolyzed adipose tissue bound to Ca2. Causes by Acute pancreatitis
What is the appearance of Fibrinoid necrosis ?
Vessel wall appears glandulalr & eosinophilic. Protein deposition in the wall results in thickening and obstruction of lumen
Give an example of hemorrhagic necrosis ? what is the mechanism ?
Nutmeg liver (centrilobular necrosis). Mechanism is acute congestion due to venous outflow obstruciton
Define steatosis. Is it reversible or not ?
Any abnormal accumulation of TAG within parenchymal cells. Usually seen in cells with high metabolic turnover of lipids. It is reversible, except for CCl4.
Give 4 etiologies causing fatty change
1. Anoxia
2. Alcohol
3. Starvation
4. CCl4
How would you stain lipid in cells ?
Sudan IV or Oil-Red-O (red-orange)
Give two examples of fatty change and their morphology
1. Fatty liver :
Enlarges upto 6kg, small fat vacuoles appear in cytoplasm, coalesce and displace the nucleus.
Contigous cells ruptur and produce fatty-cysts.
2. Heart : Tiger heart
What is Xanthoma ?
Clusters of foamy cells (Mac's with lipid debris) in CT
Morphology of Atherosclerosis
1.Endothelial intima accumulates lipid vacuoles + ca2
2. Plaque formation and lumen narrowin
3. Wall becomes rigid and tears
4. Platelets aggregation
5. Chronic inury
3 diseases of PL accumulation. Describe where the deficiencfy is, what is stored, main clinical outcome
1. Tay-Sachs :
Ganglioside Def
Storage of Ganglioside GM2
Mental retard, death 2-3y
2. Neimann-pick :
Sphingomyelinase Def
Sphingomyelin accumuation in phagocytic cells and neurones
Systemic (organs with many mac's) --> death 3y
Gaucher :
Glucocerebrosidase def
RES cells accumulat glucocereberosid and increase in size
Give 2 examples when protein accumulation can occur
1. Russel bodies in ER of plasma cells
2. Leake of proteins across glomeruli BM in golmerulonephritis leading to compensatory pinocytosis and generation of hyaline droplets in proximal tubules
Give two important causes of glycogen accumulation
1. Diabetes mellitus
2. Glycogenoses
What are the main forms of Glyocgenoses ? Give an example to each
1. Hepatic :
Von Gierke, TypeI -Hepatomegaly due to storage of glyocgen, hypoglycemia
2. Myopathic :
Mc'ardle disease, Type V- glycogen phosphorylase def. Muscle cramps.
3. Other :
Pompe's , Type II-def. of lysosomal acid maltase. Deposition in all organs esp. heart
Clinical symptoms of MPS accumulation. Which components are accumulated ?
Clincal - Coarse face, clouding of cornea, joint stiffness, retardation. Substancesa are Dermatan sulfate, Heparin of ground substance
Two examples of MPS :
MPS I - Hurler :
AR, Def. in L-Iduronidase
Skeletal problems, death due to cardiac complications
MPS II - Hunter :
X linked
No clouding of cornea
3 examples of endogenous pigments . How is lipofuscin accumulated
1. Lipofuscin
2. Melanin
3. Hemosiderin

Lipofuscin accumulates in a perniculear fashion.
What is hemosiderin ? Which two pathologies can arise from its accumulation ?
Hemosiderin is a hemoglobin derived granular pigment. It is large aggregates of ferritin micells.
Can result in Hemosiderosis (NO DAMAGE) or in Hemochromatosis (Damge to liver,heart)
How would you see calcium crystals accumulation grossly ?
As fine white granules or clumps
What is the main cause of Dystrophic calcification ? What are two main causes of Metastatic calcification ?
Dystrophic - Cellular injury
Metastatic - Hyper PTH, VitD intoxication, Tumors (MM)
Define Amyloidosis. Define Amyloid.
Amyloidosis - a group of diseases that share abnormal protein like depositions between cells in many organs.
Amyloid : Proteinaceous substance abnormally deposited in tissue interstitium. It has non-branching fibrils in a beta-pleated sheet confirmation + a glyoprotein component
What is the main pathomechanism in Amyloidosis ?
Amyloid deposition in cells leading to cell compression and damage --> Organ dysfunciton
What are the main types of Amyloidosis
1. Immunocytic (Primay, AL)
2. Reactive systemic (Secondary, AA)
3. Heredofamilial (mediterninan, AR)
4. Endocrine (calcitonin, IAPP)
5. Alzheimer's (Beta-amyloid protein, from APP)
Where is the most common and severe deposition in amyloidosis ? What are the two morpholgies of Spleen amyloidosis deposition
Sago spleen (follicles), Lordacious spleen (sinuses and pulp)
What is the pathomechanism of congestive heart failure leading to Edema
CO decreases --> Renal perfusion decreases --> Increased RAS --> Increased sodium reabsorption --> Hypertension and Edema
What are the 3 main forms of Edema ?
1. Dependent edema (in RV failure, gravity)
2. Pitting edema (usually renal failure)
3. Anasarca (generalized, subcutaneous)
What is the definition and hyperemia and congestion ?
Increased volume of blood in a particular tissue
What is the morphology of Acute hepatic congestion and of Chronic one ?
Acute - Centrolobular hemorrhagic necrosis. Peripheral hepatocytes may develop fatty change
Chronic - Central regions are atropihed, they red-brown and are slightly depressed against surrounding uncongeste areas. NUTMEG liver.
What is the morphology of Chronic pulmonary congestion ?
RBCs escape via damaged hypoxic endo, phagocytosed by Macs that become Hemosiderin laiden. Also thickened fibrotic septa --> Browin induration
Define Petechiae, Purpura, Ecchymoses
Petechiae - 1-2mm in skin, Mucous, serosal surfaces
Purpura - 2-6mm in skin, mucuos
Ecchymoses - few cm, subcutaneous hemorrhages
What is the Virchow's Triad of Thrombus formation
1.Endothelial injury
2. Alterations of blood floow
3. Hypercoagulability
What are Lines of Zhan
Microscopic laminations produced by pale layers of platelets and fibrin alternating w/Darker red cell-rich layers.
In heart and Aorta thrombi
What are the Fates of Thrombi ?
Propagation, Embolization, Dissolution, Organization and recanalization
Give 5 causes of DIC
1. Placental rupture
2. Sepsis
3. Release of granules from leukemic cells
4. SLE, immune-complexes
5. Burns
Pathogenesis of Fat Embolism
Fat globules after fracture of long bones --> Microemboli in brain and lung leading to plt and erythrocyte aggregation --> Injury to endothelium and Thrombocytopenia & Anemia
Define Infarction
Area of Ischemic Coagulative Necrosis
4 factors that influence development on an Infarct
1. Blood supply
2. Rate of development of occlusion
3. Vulnerability to Hypoxia
4. Oxygen content of blood
What is the morphology of inarcts ?
Wedge shaped, with the occluded vessel at the apex and. Histologically : Ischemc-coagulative necrosis (Except brain !)
Mostly later replaced by a fibrotic scar or abscess
Define shock
Systemic hypoperfusion due to a reduction in either CO or circulation blood volume
What are the stages of shock ?
Non progressive (compensated) --> Progressive (non compensated) --> Irreversible
Define acute inflammation. What are its two components
Immediate and early response to injury designed to deliver leukocytes to sites of injury. Where they clear invading microbes and breakdown of necrotic tissue.
Two main components : Vascular changes and Cellular events
Give 4 mechanisms of increased vascular permeability in Inflammation
1. Endothelial contraction in venules (ONLY venules)
2. Endothelial retraction
3. Direct endothelial injury (all microcirculation, necrosis and detachment)
4. Leukocyte mediated endotthelial injury
If you get topic 18 - Leukocyte cellular events in acute inflammatory response, what should you talk about ?
1.Margination and rolling
2.Adhesion and transmigration
3. Chemotaxis and activation
4. Phagocytosis and degranulation
5. Leukocyte induced tissue injury
Mention 6 morphological patterns in acute inflammation
1. Serous (low perm)
2. Fibrinous (medium perm)
3. Suppurative (high perm)
4. Hemorrhagic (anthrax)
5. Ulceration
6. Necrotizing (most severe, Liquifactive necrosis)
Define an ulcer
Site of inflammation where epithelial surface has become necrotic and eroded with associated subepithelial acute inflammation
What are the outcomes of acute inflammation ?
Complete resolution, Scarring&Fibrosis, Abscess formation, Progression to chronic
What is an abscess ?
Necrotic foci (with neutrophils, necrotic debris, edema) rimmed by neutrophils
Give 3 occasions when will scarring/fibrosis be the outcome of an acute inflammation ?
1. After substantial tissue destruction
2.In tissues that cannot regenerate (myocardium)
3. When fibrin exudate is massive
Give 3 occasions when a chronic inflammation arises
1. Persisten infections (TB, other bacteria)
2. Prolonged exposure to non-degradable agent
3. autoimmune disease (SLE, RA..)
What are the stages of the M phase in the cell cycle ?
Prophase (2 identical chormatids at centrosome)
Metaphase (on equatorial plane)
Anaphase (seperation of chormatids)
During the cell cycle, cyclins are regulated by which mechanisms ?
Transcriptional regulation
Proteolytic regulaition (ubiquitin)
What are the components of granulation tissue ?
Vascular connective tissue with new capillaries, proliferating fibroblasts and inflammatory cells
What are the components of repair by CT ?
Angiogenesis, Fibrosis, ECM deposition, Scar remodeling
Stages of wound healing
1. Acute inflammatory response
2. Parenchymal cell regeneration
3. Migration and proliferation of parenchymal and CT
4. Synthesis of ECM
5. Remodeling of CT and parenchyma
3 Mechanisms in Type II HS :
1. Complement dependent reactions
3. Antibody mediated cellular dysfunction
Morphology in Type III HS
1.Fibrinoid deposits within vessel wall with neutrophilic infiltrate --> Acute necrotizing vasculitis (fibrinoid necrosis)
2. Microthrombi and ischemic necrosis
3. Acute glomerulonephritis
Arthus reaction is ?
Local immune complex disease (type III HS) with localized tissue necrosis (vasculitis)
In DTH (type IV HS), what are the main cells acting, and what do they secrete ?
Th1 cells.
Secrete :
IFN-gamma : Activate MACs (sustained activation->Fibrosis)
TNF-Alpha : Increase NO and Prostacylcin, increased E-selectin, Incresed IL8
IL-2 : autocrine/paracrine
IL-3 : Monocytes
Give 3 examples of CTL response type of Type IV HS
1. Autoimmune insulin-dependent diabetes (against Beta cells)
RA - CD8 cells against synovial cells
Myocarditis - CD8 cells kill virus infected cells in the myocardium
If you get topic 27 - transplant rejection and GVH. What do you discuss ?
Direct/Indirect presentation, Hyperacute/acute/chornic rejection, GVH disease and increasing graft survival
What is the etiology of SLE ?
Genetic - HLA-DQ & inherited defect of complement (impaired removal of immune complexes).
Non-genetic : Drugs (procaniamid), Sex hormones, UV light
Immunologic -Intrinsic B cell defect leads to hyperactivation
What are LE bodies ?
When cell nuclei are exposed, ANA can bind to them and form these Le (or hematoxylin bodies)
When you get Morphology of SLE, talk about :
Acute necrotizing vasculitis, Kidney, Skin, Joints, CNS, Heart, Spleen
Acute necrotizing vasculitis in SLE has the following features (vessels affected, what is deposited, consequences)
Vessels affeced are small arteries and arterioles. You can find DNA, C3, Ab, Fibrinogen deposition. It leads to fibrous thickening of the wall and luminal narrowing
What is the most severe type of SLE Kidney damage. What are its characteristics ?
Class IV.
Diffuse proliferative GN. Occurs in 40-50% of patients. Hematuria, Proteinuria, Hypertension. Diminished GFR. Wire-loops in subendothelium(immune complexes), scarring.
Libman-sacks endocarditis happens in ? What are its features ?
IT is a vulvular lesion with deposits on the leaflets. Precipiates may become emoblised.
What is the morphology of the spleen in sLE ?
Moderately enlarged
Capsular fibrous thickening
Concentric thickeining of vessel wall --> Onion skin lesion
Define Rheumatoid Arthritis (RA) :
Systemic, Chronic inflammatory disease. Affects principally the joints and sometimes other organs.
Characterized by non-suppurative proliferative synovitis that leads to destruction of articular cartilage.
What is the morphology of RA ?
*Small joints mostly.
*Chronic synovitis
*Formation of Pannus (highly vascularized inflamed synovium that covers the articular joints)
*Increaesd volume and turbidity of synovial fluid
*Might have small arteries vasculitis
What is the pathogenesis of RA ?
1. ACtivation of Th cells by unknown arthrogenic agent
2. Activation of macs --> cytokines, and degradative enzymes
3. Activation of B cells --> RF, Type III HS (in 80%)
4. Cytokines lead to rheumatoid synovitis, synovial cell and fibroblast proliferation (pannus), secretion of proteolytic enzymes from synovial cells
Define Sjorgen syndrome
Autoimmune disease with self-AB against ductal epithelial cells of exocrine glands
Two forms of Sjorgen ?
*Primary form - Sicca syndrome :
SS-A, SS-B auto anti-nuclear Ab (these are RNPs)
HLA-DR3 association
*Secondary form :
Associted with SLE, RA
Pathogenesis of Sjorgen ?
*Injury is initiated by a defect in Th cells reacting to unknown antigen initiating T and B cells infiltration and inflammation.
*B cells hyperactivity leads to SS-A,SS-B and RF
*Lacrimal and salivary glands show ductal epithelial hyperplasia and luminal obstruction.
*Glands become enlarged and firm
Three important outcomes of sjorgen, except obvious ones :
Kidney tubular problems
Primary Billiary cirrhosis
Respiratory tract itis
(May progress to low-grade MALT)
Definition of Systemic Sclerosis
Scleroderma, Autoimmune disease causing excessive systemic fibrosis
What are the two types of SS ?
Diffuse - Widespread cutaneous and early visceral, Rapid progression
Localized - CREST syndrome, relatively benign
What is the pathogenesis of SS ?
Either activation of Th with release of cytokines that activate Mac's etc and cause fibrosis OR endothelial injury with the usual mechanisms and fibrosis
What are the markers of SS ?
Diffuse type - Anti-DNA topoisomerase I, 70% of cases
CREST - Anticentromere, 90%
Morphology of SS (Skin, GI, Musculoskeletal, Kidney, Heart)
Skin : Claw like fingers, Face is a drawn mask
GI : PRogressive atrophy and fibrosis of esophegeal wall
Skeletal : Inflamed joints, myofiber degeneration
Kidney : Vessels 150-500MicroM, renal failure
Heart: Interstitial fibrosis and RV failure due to lung changes
What is the definition of Polymyositis, Dermatomyositis, Mixed CT disease ?
Inflammatory myopathies characterized by immunologically mediated disorders that cause injury to skeletal muscles
What is common and what is different in Polymyositis, Dermatomyosistis, Mixed CT ?
Common : Bilateral symmetrical weakness of trunk, neck, limbs with lymphocytic infiltration, muscle fiber degen and regen

Different :
Dermatomyositis - Ab mediated injury, skin rash in upper eyelids
Polymyositis - CTL damage, muscle necrosis with inflammatory cells inf.
Mixed CT : Features of SLE, SS, Inflammatory myopathies. ANA against U1RNP. No renal disease.
Define primary immunodeficiencies
Develop due to inherited developmental defects of the immune system
Which is the most common primary ID ?
Isolated IgA deficiency (1:600 in caucasians). Also shows susceptibilty to RA and SLE
Which ID is a component of 22q11 deletion syndrome ?
DiGeorge (also lack of PTH and tetany, don't forget)
What is an important cellular change in DiGeorge ?
T-cell dependent, paracortical areas in lymph nods are depleted
ADA and PNP are types of what and what are their inheritance ? Which damages only T cells directly ?
Only T cells directly : PNP
What is a common feature of HIV which you will most likely forget ?
CNS involvement
4 Clinical features of full blown AIDS ?
Decreaesd humoral response - infections
Persistand diarrhea
Neoplasms (Kaposi's sarcoma due to HHV8)
Neurological disorders (peripheral neuropathy)
Define mendelian disorders
Result from mutations in single genes of large effect
Discuss Pleotropism and Genetic heterogenity in mendelian disorders
Pleotropism - single gene mutations result in variable phenotypes
Genetic Heterogenity - Mutations at several loci may produce the same trait
Give the general features of AD disorders.
-Expressed in heterozygotes
-Mutations affect structural or regulatory proteins
-Onset of clinical features is later than AR
-Male/Female equal
Define Marfan + general features
-Disorder of connective tissue that affects Fibrillin-1, an integral part of elastic fibers.
-Gene is on 15q21
-Affects skeletal, ocular, cardiovascular system
What is the most common cause of death in Marfan ?
Fragmentation of elastic fibers in Aorta leads to aortic rupture
Definition of EDS and general features ?
-A group of disorders resulting from defets in collagen.
-Single gene disorders. -X/AD/AR
-12 variants
-Skin hyper-extensibility
-Hypermobile joints
-Internal complications - rupture of colon
Two types of EDS
Type VI :
Reduced activity of lysyl hydroxylase, no cross linking of collagen - retinal detachment
Type IV : Mutations in collagen III. Colon & aorta ruptrue
Neurofibromatosis definition, inheritance, prevalance
Presence of tumros on nerves, usually multiple resulting in pedunculated nodules protruding from the skin.
AD, 1:3000, 90% type I !
Genetics and pathogenesis of Neurofibromatosis (type I)
NF-1 locus on chr 17 encodes neurofibromin - TSG. Regulates RAS. Ras is overactive.
What is the defining characteristic of Type I neurofibromatosis ?
Concurrence of multiple Cafe-Au-lait spots and multiple skin tumors. Lisch nodules may also be present (pigmented iris hamartomas)
Features of AR diseases
-Most inborn errors of metabolism
-Age of onset is early
-Equally affects male/females
What is the most common lethal genetic disease in caucasians ?
CF, 1:25 are carriers, 1:2500 express it
Genetics of CF
CFTR gene on Chr 7 (cystic fibrosis transmembrane conductance regulator) serves as cAMP dependent Cl channel
Morphology of CF (Pancreas, liver, lung, sweat glands, epididymis/VD)
-Pancreas - 90% of cases. Accumulation of mucus leads to total atrophy of exocrine glands. ADEK Avitaminosis, impaired fat absorption
-Liver - Plugging of bile canaliculi results in cirrhosis.
-Sweat glands - Inability to reabsorb chloride results in increased sweat salt
Epididymis/VD : Obstruction, infertility in 95% of males
5 examples of X-linked diseases
Most are recessive
Define muscular dystrophies
Spontaneous progressive degeneration of skeletal muscle fibers. X linked
Dystrophin is a structural proten attaching the sarcomere to cell membrane
What is special about the Dystrophin gene ?
Largest of genome and therefore susceptible to mutations/deletions
Two types of MD
DMD : deletion, no dystrophin. Cardiac failue, Death
BMD : mutation, muscle abnormalities, less severe, affects cardiac muscle more
Morphology of MD
1.Variation in muscle fiber size
2. Fiber splitting, necrosis
3. Increased CT
4. Dg is based on IHC for abnormal dystrophin
5. UNLIKE polymyositis - no cellular infiltrate
Age rule for DMD
Define polygenic inheritance
Multifactorial. Governed by the additive effect of two or more genes combined with environmental factors. Phenotypes show Gaussian distribution.
What are the genetic characteristics of Polygenic inheritance ?
Threshold effect - disorders become manifest only when a certain value is reached. Severity of disease proportional to number and degree of influence of pathological genes.
Risk of recurrence in first degree relatives 2-7%
Risk of occurences in subsequent pregnanices increases with the birth of each affected child
Define gout
Collective term for syndromes characterized by accumulation of excessive amounts of Uric acid - end product of Purine metabolism (in the form of Monosodium Urate crystals)
Two forms of Gout
Primary : 90% idiopathic, 10% HGPRT def.
-Increased nucleic acid turnover, melignancies
-Chronic renal disease
-Lesch-nyhan syndrome
What is Lesch-nyhan syndrome ?
Complete HGPRT Def, X linked. Purine metabolism salvage pathway is blocked, no negative regulation.
Overproduction of uric acid. Symptoms - Neurologic disorders, retardation, self mutilation
Pathogenesis of Gout
Monosodium urate crystals are chemotactic and activate complement.
Macs and neutrophils accumulate in joints and synovial membrane and mediate injury in the usual way
Morphology of Gout
*Acute Arthritis :
Deposition of crystals in synovial tissue(as needle like structure) initiating inflammation, congestion and edema
*Chronic Tophaceous arthritis : Large deposits of chalky-white sodium urate is known as tophi, in the articular cartilage. These provoke a granulmatous reaction. May lead to ankylosis.
*Gouty nephropathy
Define cytogenic disorders
Change in structure or number of chromosomes
Define karyotype
Photographic representation of a stained metaphase spread in which the choomosomes are arranged in order of decreasing length (1->22, XY) - stained by Giemsa stain
What are the two types of Translocations ?
-Reciprocal balanced
-Robertsonian (only 13,14,15,21,22--> acrocentric chromosomes)
What are the general features of Cytogenetic disorders ?
*Loss of DNA is more severe than gain
*Imbalances in sex chromosomes are tolerated more than in autosomal
*Parents are usually normal (except Down !)
What is the most common chromosomal disorder ?
Down, Trisomy 21
What are the two variants of Down syndrome ?
*47,XY+21 -->95%
*Inbheritance of a parental chromosome with t(21;22/14)-> extra 21 data
How is Trisomy 21 formed, and give 5 clinical symptoms
Meiotic non-disjunction in the ovum
Clinical :
*Flat facial profile
*Cardiac malformation
*Predisposition to leukemia
*Serious infections
*Most do not pass 30
Which cytogenic disorders related to sex chromosomes are compatible with life ?
Why are such abnormalities compatible ?
from 45,X to 49,XXXXY
-Due to X inactivation
-Due to little genetic information on the Y
Define Klienfelter syndrome. Give a few clinical signs
Male hypogonadism with two or more X and at least one Y.
Clinical :
Long legs
Sterlity, Low testosterone levels
Define XYY syndrome, give a few clinical signs
Results from non-disjunction of 2nd meiotic division of the sperm.
Clinical :
Normal males, may be taller and may be anti-social
Define Turner syndrome and give a few clinical signs
Female hypogonadism resulting from complete or partial monosomoy of X
45,X - most common
clinical :
Lymphedema of neck
Widely spaced nipples
Coarcation of Aorta
Infantile genitelia
Streak ovaries
Define Neoplasia
"New Growth"
Abnormal mass of tissue, growing faster than normal tissue and in an uncoordinated manner
What is the nomenclature of benign tumors ?
Adenomas - arising in glands or forming glandular pattern
Cystadenoma - hollow, cyst like, often in ovaries
Papillomas - finger like projections
Polpy - tumor projecting from mucosa into lumen of hollow organ
Define Mixed Tumors
Derived from one germ layer, and differentiates into more than one parenchymal cell type
Define Teratoma/Choristoma/Hamartoma
*Teratoma : From more than one germ layer, usually all 3. Found in tests and ovary
*Choristoma: Ectopic nests of mature, non transformed cells
*Hamartoma : Mass of disorganized, immature cells at their usual site (Example, Lisch nodules in Neurofibromatosis)
Rate of growth of tumors depends on :
-Blood supply
-Pressure constraints (?)
-Hormonal influence
-Level of differentiation
-Malignancy (be careful!)
Define Differentiation and Anaplasia
Differentiation :Extent to which parenchymal cells resemble their normal cells of origin morphologically and functionally
Anaplasia : Failure to differentiate from a developing stem cell into a mature one
Characteristics of Anaplasia
Nucleus/cytoplasm ratio 1:1 instead of 1:4
Numerous mitosis, atypical ones also
Loss of functional polarity
Define Dysplasia and give two examples
Disorderly but non-neoplastic growth. Early phase in tumor formation.
Exhibit pleomorphism, loss of polarity
Examples :
Dysplastic squamous epithelium (mitosis outside of the basal layer)
Carcinoma in Situ
When you get topic 47- Biology of Tumor growth, you should mention :
-History of typical malignant tumor
-Kinetics of tumor growth
-Tumor angiogenesis
-Tumor progression&heterogenity
-Clonal expansion
What are the phases and what are the steps of tumor progression ?
Phases :
Steps : Survival->Accelerated growth->Invasion->Metastasis
What are the steps of metastasis ?
Detachment of tumor cells from each other->Attachment to ECM->Degradation of ECM->Migration to vessel->Intraversion->Homing->Extravasation
Give four spreading routes for cancer
Carcinomas - Lymph
Sarcomas - Blood
Intraepithelial (nipple tumor cells to ducts of gland)
What are the 3 hereditary forms of cancer ?
-Inherited cancer syndromes (single mutant genes, AD)
-Familial cancers (clustering)
-AR syndromes of defective DNA repair(xeroderma)
What should you mention if you get topic 49-Heredity in cancer ?
*3 Hereditary forms of cancer
*TSG's (don't forget DCC in colon and BRCA in breast)
*Genes that regulate apoptosis
*DNA repair genes (HNPCC in colon, xeroderma)
What are acquired preneoplastic conditions ? Give 3 examples
Certain clinical conditions that are associated with an increased risk of developing cancers
*Chronic ulcerative colitis -->Colorectal cc
*Liver cirrhosis-->Hepatocellular carcinoma
*Villous adenoma of colon-->Colorectal cc
When you get Tumor immunity, you talk about the following things :
*Immune surviellence
*Anti-tumor mechanisms
*Tumor escape mechanisms
Name 4 anti-tumor effector mechanisms
*NK cells
*Mac's (kill by TNF-alpha)
Name 4 immunotherapies against tumors
*Adaptive cellular therapy(culturing of patient's lymphocytes with IL-2)
*Cytokine therapy
*Ab therapy (immunotoxins, Ricin against B cell lymphomas)
*Angiogenesis inhibitors (Thrombospondin, Angiostatin)
When you get Laboratory diagnosis of cancer (topic 52) you should mention :
*Sampling techniques
*Specimen evaluation*
*Biochemical assays
*Common markers
What do you look for when evaluating a tumor specimen histologically ?
*Edges (pushing,inf)
*Nucleus/Cytoplasm ratio
*IHC for specific CK, CD markers, etc
What do you mention in topic 53 - Clinical features of neoplasms ?
*Hormone production
Definition of Paraneoplastic syndrome ?
Symptoms not directly related to the spread of tumor or hormones released by the tissue from which the tumor arose. Not a result of the tumor itself
What are the 4 most common Paraneoplastic mechanisms?
*Ectopic hormone secretion
*Hematological (Anemia, Thrombocytopenia, thrombosis, DIC)
*CNS&PNS disorders
When in doubt, which cancer should you bet on when asked which cancer caused this or that paraneoplastic syndrome ?
Lung (usually SCC) !
Remember EPO from renal though
Define benign epithelial tumors and mention 3
Common, generally biologically inconsequential lesions deriving from keratinocytes or skin appendeges
*Seborrheic Keratosis
*Verrucae (Warts)
Name and describe a premalignant skin tumor
*Actinic Keratosis :
Dysplastic change, chronic sun exposure, flesh-colored with rough consistency. May have horns, shows cytological atypia and sun-damaged fibroblasts
Name 2 malignant epidermial tumors
What is the morphology of SCC ?
*whole thickness of epi
*Most common in sunexposed skin of old men
*Associated with immunosuppressing agents
*Breaks thru BM
What is the morphology of BCC ?
*Slow growing, rarely metastasize
*Immmunosuppression increases risk
*Grossly appears as pearly papules with telangietasis
*May show nodular growth deep into dermis
Which tumor is seen grossly as pearly papules with Telangiectasias ?
What are the morphologies of Verrucae (Warts) ?
(in children), caused by HPV
*Vulgaris, rough pebbly surface
*Plaque (Face, hand, flat..)
*Condyloma Acuminatum(soft, cauliflower like on genitalia)
Define melanocytes.
Neural crest cells that migrate into the epidermis and donate Melanin to keratinocytes
What is the difference between a nevus and a nevocellular nevi ?
Nevu is congenital. nevocellular nevi is either congenital or acquired
What are the stages of a Nevocellular nevi ?
Junctional, Compound, Dermal
What are the rules of Nevi growth ?
More mature = deeper, smaller cells, produce less melanin, grow in cords
Also more mature means elevated grossly, less mature means flat
Name 3 premalignant melanocytic tumors
Dysplastic nevi, spitz nevus, Lentigo maligna (!!)
What are the markers of Malignant melanoma ? What are its clinical signs ?
MArkers :HMB45, S100, MAGE
Clinical : Enlargement, Itching, New lesion, Change in color
Mention 3 benign tumors of Adipost tissue
Lipoma, Hibernoma, Lipoblastoma
What are the charecteristics of Liposarcoma ? What are its low grade variants ?
Most common in adults
Fast growing
Low-grade : Well diff., Myxoia with t(12;16)
3 benign fibrous soft-tissue tumors
Fibroma, Nodular fasciitis (TLL!), Fibromatoses
What are the markers of Fibrosarcoma ?
Alpha-SMA +
Define fibrohistiocytic tumors
Mixture of fibroblasts and phagocytic lipid laden cells with histiocytic appearance
Name one benign, one intermediate malignancy, and one malignant Fibrohistiocytic tumor
Benign - Fibrous histiocytoma
Inter. - DFSP
Malignant - MFH
What is special about DFSP ?
What's present in Fibrous Histiocytoma and is missing from DFSP ?
DFSP - Fibroblasts in storiform pattern
DFSP has no collagen, Fibrous histiocytoma has collagen.
What is the most common malignant tumor of childhood ? What are its subtypes ? Which subtype has better prognosis ?
Embryonic / Alveolar subtypes
Embryonic is good prognosis.
What are the markers of Embrynoic rhabdomyosarcoma ? What are the markers for Alveolar Rhabdomyosarcoma ?
Embryonic - CD99, Desmin
Avleolar - Vimentin, MyoD1, Myoglobin
What are the features of Leiomyoma, and what are the markers for LEiomyosarcoma ?
Leiomyoma :
Well circuscribed, whitish-grey, either deep or superficial
Leiomyosarcoma - Alpha-SMA, Vimentin, Desmin+
Name 3 peripheral nerve neoplasms and mention an interesting difference between two of them
*Traumatic neuroma (TLL!)
Schawnomma of the Antoni-A type shows verocay bodies of spindle cells and Neurofibroma does not
Name 3 malignant peripheral nerve tumors
MPNST, PNET, Clear cell sarcoma
What is another name for Clear cell sarcoma, and what is its markers ?
Malignant melanoma of soft parts.
Markers :HMB45, Vimentin, CK, S-100
Name one benign and one malignant tumors of synovial cells
Benign - Giant cell tumor of tendon sheath (localized nodular tenosynovial tumor) - shows on hands, feet, has collagen bundles
Malignant - Malignant tenosynovial tumor
What is common to Rickets and Osteomalacia
Excess amounts of unmineralized matrix
Give 2 causes for Rickets, also give morphology for Rickets
Genetic 1-hydrolase (kidney) def
or VitD-R defect

Morphology :
Failure of cartilage to mature leading to irregular masses of it.
Microfractures leading to abnormal overgrowth of capillaries and fibroblasts
Deformations (Pigeon breast, Bowing of legs..)
In osteomalacia, what are the deformities, and what bones are mostly affected ?
There are NO deformities, only weakening of bones.
Mostly Vetebral bodies and femoral necks
Define vasculitis
Any inflammation of a vessel wall in any artery, vein, venule. Can be local or diffuse. May be immune mediated or by infectious agents
What are ANCAs ?
Anti Neutrophilic Cytoplasmic Antibodies. These serve as a diagnostic marker of Different Vasculities. It is not clear if these are mere markers or take part in pathogenesis.
P-ANCA -> against MPO --> PAN & Churg-strauss
C-ANCA -> Against Proteinase 3 --> Wegner's
What is chapel-Hill classification of vasculitis ? give a few examples of each category
Classification for systemic vasculitis based on size of involved lesion, anatomical location, histology, and clinical manifestations.
Small vessel : Leukocytoclastic angiitis, Wegners, Microscopic Polyangiitis
Medium vessels : PAN, Buergers
Large vessel : Temporal Arteritis, Takayasu
What are the features of Leukocytoclastic vasculitis ?
*Small vessels
*Palpable Purpura
*Skin, mucous, lung, heart
*Pauci-immune injury
*Fibrinoid necrosis
Features of Churg-Strauss syndrome ?
Allergic granulomatos angitis that affects small and medium vessels.
Eosinophilia, bronchial asthma, granulomas.
What are the features of Wegener's granulomatosis ?
Medium vessels,
Most common over 40 y
Either limited (no kideny) or widespread (eyes, skin)
What is Wegner's Granulomatosis triad ?
1. Acute necrotizing granulomas of resp. tract
2. Small to medium vessel vasculitis, esp in lung
3. Focal necrotizing glomerulonephritis
Features of PAN
Medium vessels
Features acute necrotizing inflammations that result in aneurysms, vascular obstructions and infarctions.
Lesions are common in bifurcations, does not affect lung and aorta.
Lesions are segmented.
Acute phase of PAN, features. Late phase.
Transmural inflammation of arterial wall with heavy infiltration. Lumen may become thrombotic. Also may lead to fibrinoid necrosis.
Late phase - fibrous thickening of vessel wall with monocellular inf.
Symptoms of PAN
Fever, weakness, Hypertension(renal), Diarrhea, Coronaries involvement
Features of Kawasaki's disease
Immunodef. that results in polyclonal activation of B cells leading to Auto-Ab against endothel.
Necrotizing arteritis that affects young children. Usually not deadly unless affects coronaries. May also present with Fever, conjunctivitis, edema, erythema
Morphology of Buerger's
Acute lesions with neutrophilic inf of arterial wall with mural or occlusive thrombi and a Microabscess.
Vascular insuf. leads to pain and gangrene, and fibrous encasing affects nearby veins and nerves.
What is the most form of vasculitis ? What are its features ?
Temporal arteritis (giant cell).
Focal granlulomatous inflammation, usually of branches of carotid artery.
Fragmented internal elastic lamina with giant cell reaction to the fragments. Intimal fibrosis and narrowing of lumen.
What is the morphology and symptoms of Takayusu dieases ?
A form of granulomatous vasculitis leading to giant cell inf. and fibrosis.
Irregular thicking of aortic wall, leading to narrowing of orificies.
Symptoms : Ocular problems, neurological, diminished upper extremitiy pulses, MI
How to differentiate b/w Giant cell arteritis and Takayusu when both affect the Aorta ?
Usually only age of patient. Young patients = Takayusu
Define anemia
Reduction in oxygen transport capacity of blood, usually as a result of reduced RBC number of Hb concentration
What is the main difference between acute blood loss anemia and chronic ?
In acute - normocytic, normochromic
In chronic - due to iron stores depletion - microcytic, hypochromic
General features of Hemolytic anemia - what to talk about ?
*Intracorpasuclar abnormalities (hereditary-Spherocytosis,G6PD, Thalassemias), acquired (PNH)
*Extracorpuscular abnormalities (AIHA, HDN, DIC, TTP, Malaria)
*Hemolysis may be intravascular or extravascular(in RES)
What will we NOT see in extravascular hemolysis of RBC that we will in Intravascular hemolysis ?
In extravascular hemolysis there will be NO hemoglobinuria, and no hemoglobinemia !
What are the clinical signs of Hereditary spheocytosis ?
Anemia, splenomegaly, Jaundice, Hemosiderosis, Reticulocytosis
What are the factors that influence sickling on HbS ?
*Amount of HbS
*Presence of other Hb chains (neonates do not manifest till 6months due to HbF)
*Legnth of time exposed to low Oxygen. This is why in spleen and BM effect is worse (slow flow)
What is the morphology in HbS ?
Spleen is enlarged and in late stages may undergo autosplenctomy due to scarring (vaso-occlusion).
BM shows hyperplasia - expansion may cause resorption of bone
Tissue damage to to microthrombi
What is the morphology of Thalassemia ? What is its inheritance ?
Inheritance - AD
Morph :
Severe Hemosiderosis
Hypochromic, Microcytic, decreased MCHC
What are Heinz bodies in G6PD Def. ?
Denatured Hb that precipitates in the RBC. It reduced cell membrane flexibility. Occurs during oxidative crisis
What is special about PNH ?
It is the only hemolytic anemia resulting from acquired membrane defect due to a mutation in a Myeloid stem cell. Platelets & Granulocytes also affected
Topic 64, extracorpuscular hemolytic anemias, what do you mention ?
*Ab against normal or altered RBCs
*May be spontaneously or induced
*Warm AIHA, Cold AIHA
*Microangiopathic,valves prosthetic
*Coombs aglutination test
Define Anemias of diminished erythropoiesis
Anemias caused either by inadequate supply to the BM of necessary substrates or by suppression of marrow cells
What is anemia of chronic disease ?
Serum iron levels and TIBC are reduced, but there is abundant iron storage. Major cause is marrow hypoproliferation due to low EPO resulting from action of inflammatory cytokines such as IL-1, TNF, and IFNgamma
What may induce Aplastic Anemia ? Which cells are depressed in the BM ? What can Aplastic anemia evolve to?
Induced by myelotoxic drugs, irradiation, infections(hepatitis).
Causes damage to BM multipotent Myeloid stem cells.
Aplastic anemia can evolve to AML
General features of AML
Adults >50
Cytoplasm contains azurophilic, MPO granules
3-5 nucleoli
CD34/13/14/15, Sudan Black+
General features of Acute Leukemias
Malignant neoplasms of hematopoietic stem cells. Very immature blasts in the BM due to block in differentiation leading to suppression of normal hematopoietic cells
What are the main groups of AML? Which one shows Auer rods, which one shows t(8;21) ? And one which one is worst prognosis ?
M0-M1 defined by maturation
M4-M5 Monoblastic-monocytic
M6 - Erythroblasts
M7 - Megakaryoblasts
Auer Rods : M2-M3
M2 shows t(8;21)
M1 is worst prognosis
What are the features of Myelodysplastic syndrome ?
*Pre-leukemic condition.
*Maturation defect in BM with inefficient hematopoeisis
*Marrow with bizarre cells - either megaloblastic erythroid precursors or micrmegakaryocytes
*Pancytopenia in blood
*May transform to AML
Define chronic myeloproliferative diseases
Characterized as neoplasms originating from Myeloid stem cells
Where is Ph chr. (t(9;22)) common ? and what is the translocation ?
In CML (mostly CGL), BCR-ABL leading to activation of TK
What are the clinical signs of CML ?
*General symptoms
*Extreme splenomegaly
*LEukocytosis of neutrophils, basophils, eisinophils
*Ph chromosome
*Splenic infarcts due to extramedullary hemopoeisis
What is common to CML and Polycthemia vera, and how would you differentiate ?
Common - Basophilia in blood, Hypercellular BM
Different - Ph chromosome in CML, Only slight spleen enlargment in PV
What is the etiology in MMM ?
BM fibroblasts are stimulated to proliferate by PDGF and TGF-beta from neoplastic megakaryocytes
In topic 68 - Thrombocytopenia, mention :
*Decreased platelet production(aplastic anemia..)
*Increaed plt destruction
What are 4 causes for accelerated platelet destruction ?
Autoimmune - SLE/ITP
Isoimmune - blood transfusions
Drugs - heparin
Infections - HIV
What is the most common hereditary bleeding disorder and what is its inheritance ?
Hemophilia A, X-linnked Recessive
Where is vWF usually synthesized and what is the inheritance of vWD ?
vWF synthesized in endothelial cells and megakaryocytes
vWD - usually AD
What is the difference between Type I and type II vWD ? which is more common, and where to do these patients bleed ?
Difference - type I is reduced quantity, type I is assembly of multimers defective.
More common is type I.
These patients bleed from mucous membranes, just like plt problems
What are the features of Sinus Histiocytosis ?
*Chronic, non-specific lymphadenitis
*Distension of lymphatic sinusoids due to hypertrophy of lining endo cells and inf. with histiocytes
*Often in L.N. draining cancer (immune response)
What is the morphology of Sinus histiocytosis with Lymphadenopathy ?
*Lymph nodes enlarged, painless
*Sinuses containing large histiocytes with vacuoles containing lymphocytes
*Medullary cord plasmacytosis
Features of Dermatopathic lymphadenopathy
Widespread lymphadenopathy secondary to skin disorders with exfoliative skin lesions. The histiocytes may contain melanin
What are the features of Langerhans' cell histiocytosis (histiocytosis X)?
*Clonal proliferation of langerhans cell.
*The tumors have vacuolted cytoplasm with oval or indented nuclei
*HX bodies (Birbeck granules) are seen in cytoplasm and have a tennis racket apppearnce in EM
*Prominent infiltrate of reactive cells (macs, eos) are mixsed with neoplastic histiocytes
What are the 3 patterns of Langerhans cell histiocytosis ?
*Unifocal(skeletal system, fractures)
*Multifoca(children, diffuse,involvement of pituitary, hand-schilar-christian triad)
*Acute disseminated (<2y, aggressive in skin, spleen, liver, lung, BM)
Define reactive lymphadenopathy
Infection or nonmicrobial inflammatory stimuli that causes an immune response against foreign antigen, and results in an enlarged lymph node
What are the features of Acute non-specific lymphadenopathy ?
*Inflamed nodes are swollen, gray-red, tender
*Central necrosis with abscess
*Large GC
*Mitotic figures
*Pus formation

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