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The document discusses cell injury, focusing on necrosis, its types, and causes, including coagulative, liquefactive, and fat necrosis. It also defines reversible and irreversible cell injury, gangrene types, pathological calcification, hypertrophy, hyperplasia, atrophy, metaplasia, dysplasia, free radicals, antioxidants, autophagy, and apoptosis. Lastly, it covers wound healing mechanisms and factors affecting healing, differentiating between primary and secondary intention healing.
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0% found this document useful (0 votes)
14 views93 pagesH&e Paper 1
The document discusses cell injury, focusing on necrosis, its types, and causes, including coagulative, liquefactive, and fat necrosis. It also defines reversible and irreversible cell injury, gangrene types, pathological calcification, hypertrophy, hyperplasia, atrophy, metaplasia, dysplasia, free radicals, antioxidants, autophagy, and apoptosis. Lastly, it covers wound healing mechanisms and factors affecting healing, differentiating between primary and secondary intention healing.
Uploaded by
sankarvighneshCopyright
© © All Rights Reserved
We take content rights seriously. If you suspect this is your content, claim it here.
Available Formats
Download as PDF or read online on Scribd
/ 93
Page |5
CHAPTER
01 CELL INJURY
LONG ESSAY
1 NECROSIS(FEB 2020)
Necrosis is defined as a localized area of death of tissues followed later by degradation
of tissues by hydrolytic enzymes liberated by dead cells
Causes: Hypoxia, chemical & physical agents, microbial agents, immunological agents. s
Based on etiology & morphology, divided into 5 types: Coagulative necrosis
sliquefactive necrosis, caseous necrosis ,fat necrosis, fibrinoid necrosis.
melee Seas Lea Caan
TYPES OF NECROSIS
1. Coagulative necrosis: most common type, outline o'
characteristic of infarcts
tissue is preserved ,itis A
Causes: Ischemia caused by obstruction in a vessel.
Morphology:
Gps _| Microscop\ |
Organs affected: ali organs except br. Necrotized cell are swollen and more
mainly in heart, kidney spleen, eosinophilic cytoplasm than normal
Appearance: dry, pale, yellow, firm. Nucleus shows pyknosis, karyolysis,
lee ee karyorthexis |
| wedge shaped in organs like kidney and | Leukocytes are recruited to the site of
spleen ae fecrosis and lysosomal enzymes digest
a u necrotic cells.
2. Liquefactive.necrosis:Dead tissue rapidly undergoes softening&transforms into a liquid
viscous mass due to action of hydrolytic enzymes.
Causes: Ischemic injury to CNS, Bacterial & fungal infections .Eg: Infarct brain ,
Causes: {5
abscesscavity.
3. Gaseous necrosis: Cheese like, Shows combined features of both coagulative and
liquefactive necrosis .
Cause: Tuberculosis-type IV hypersensitivity reaction. Eg: Tuberculosis in lung & lymph
sees GOO Isl pean YRELSen si MULYAREAELOL jolsndet fests lets
node. 4. Fat necrosis: Occurs nfo rich anatomical leatlons in the body Ee Taumayg
necrosis of breast and thigh ee
:Characterised by deposition of fibrin like_mate
jotungstic acid hematoxylin stain .Eg :Autoimmune vasculitis, Pep
“a8 hoiimune “vasculitis?
| Pathological, impairment of cessation of ion
| Homeostasis
y of cell membrane Is lost
jaintained
rend: involves group of cells imal cluster of cells
Kell enlarged
Velen:
is, Karyolysis, karyorchexis
ell reduced
PNA shows smearing effect
1e2d cells are ingested by neutrophil, polymorphs& ighborin
Pesd ssa igested by neutrophil, polymorp! Bv.neighboring cells
Cent inflammatory response :usual
els
ling is negative,
2)DEFINE REVERSIBLE AND IRREVERSIBLE CELL INJURY WRITE THE PATHOGENESIS OF
IRREVERSIBLE CELL INJURY.DEFINE ABOUT TYPES OF GANGRENE (feb 2015)
and functional changes , induced by an injurious stimulus ,can_revert to
eee) euced by an injurious’ stimulu =
on removal of the same,it is called reversible cell injury.lf the structural and
—amesit is called reversible cell injury ioe
functional changes i by at) injurious stimulus, it cannot be reversed even after removal
functional changes : cannotihe reversed even afterremaval
of the same,it is called irreversible cell injury,
Pathogenesis of irreversible cell inj jury:
+ plt—alschemic membrane injury~>intracellular release of lysosomal enzymes —> F
Ribonucleic protein, nuclear changes and loss of cell shape —>Loss of membrane phospholipids
due to phospholipases—>Cytoskeletal alterations due to proteases —>Lipid peroxidation and
RUC IRGS DNC pas ese CEE Lalterations due to proteases—>Lipi
DNA damage due to free radical,
Gangrene Page |7
Gangrene is the massive necrosis with superadded putrefaction.2 Types: Dry gangrene and wet
gangrene.
Features Dry gangrene Wet gangrene
Cause Mainly arterial occlusion More in venous occlusion;
| Distribution
(coagulative necrosis)
imbs
obstruction invariably followed
by secondary bacterial infection
(Liquefactive necrosis)
more common in bowel
Gross appearance
‘Organ is dry, shrunken and
Moist, soft, swollen’
— black
Line of demarcation Present at junction between Not clear
eae healthy and gangrenous parts iy and gangrenous parts
Putrefaction Limited (no infection and less marked
blood supply)
Presence of bacteria
Prognosi
Absent, little or no septicemia
| Sereno sebecerns |
Better
Overwhelming septicemia
poor
SHORT ESSAY
3.RATHOLOGICAL CALCIFICATION (2021) 3.
—
Deposition of ca in tissue except osteoid TYPES,
oaeeCOEOe Tre
(a)dystrophic calcification- Ca deposition on dead tissue& cause are necrotic tissue, atherosclerosis,
parE BICC CICA Cea Ue Ost OnLONIC EaULISsue stoaroscieros
(b) Metastatic calcification-in normal tissue Ca deposition occur & causes are renal dysfunction,
en ele
multiple myeloma, 27
Site-lung, kidney, blood vessel
SS
Morphology
Gross-fine, gritty& gritty granules
aes toe lenens
sarcoidosis
M/S-clumped, granular with basophilic nature
SSS Ea Dasopmilic nature
4. HYPERTROPHY (2613)
——
T Increase in Size of tissue due to increase in size of cell.
Derease Th Size Ob tssuc uestolincre 2seainsizeloncel
Pathological-hypertrophy of cardiac muscle (LVH)
Eathological hypertrophy oficardiacimuscle (LVH
causé& ™
Physiclogical-hypertrophy of smooth muscle(exercise)
Mechanism-due to igcreased synthesis of cellular protein increased workload in
physiological hypertrophy & action of GF & hypertrophy agonist(NO, sonist(NO, bradykinin) Morphology-
Gross-organ enlarged
M/s-cell size and nuclei enlarged
5.HYPERPLASIA (2017,2014)
in number of cells in tissues or organ leading to organ enlargement
Two types
alphysiological-hormonal hyperplasia (in breast) &compensatory hyperplasia (in partial
hepatectomy)
bJoathotoaical- gynecomastia, benign prostatic hyperplasia Mechanism vation ef growth
} factor or hormone result in cell proliferation
MORPHOLOGY-
Gross-size of affected organ increased
M/S -increase no of cells and mitoticfigures
5.ATROPHY (2015
Reduced size of an organ or tissue
Causes
(a)-physiological
4.During fetal development (atrophy oft!
2. During aduit life (atrophy of brain)
(b)-pathologicai
+.Disuse atropy 2. Denervation atropy 3.Ishcemic atropy 4. Pressure atropy
eae atropy 3.\shcerr Set
Decreased pro
MORPHOLOGY
Gross- organ shrunken& small
Coens eameoneunken& smal
M/S- There isa reduction in size of cell organelle
Sere eenelle 6.METAPLASIA (2019)
Reversible change in which one adult type cell is replaced by on another adult type cell
CAUSES
CAUSES
Chronic persistent injury
Tissue damage, repair, regeneration
SS a ee
‘TYPES
(a}-Epithelial Metaplasia
1.Squamous metaplasia-The original epithelium changes to squamous cell.
Eg. Respiratory Tract (chronic smoking)
2.Columnar metaplasia -The original epithelium changes to columnar
gpithelium Eg. Barrett's esophagus
(b)-Connective tissue metaplasia
1.Qsseous metaplasia-formation of new bone at site of injury
2. myositis ossificans -bone formation in muscle
Mechanism
Develops due to reprogramming of precursor epithelium (stem cells)
7.DYSPLASIA (2017)
Cell shows cytological feature of malignancy.
Se ee a er
Common features: Ceitularity increased, Shows pleomrphism Large hyperchromaric
nuclei, N/C ratio increased ,Loss of polarity.
| Don’t involve the entire thickness of epithelium
May become reversible
SSS
the
Itdoesn’t need to progress to cancer alijtime. east &uterit
fefgyare!s) grsiaisia)
4
fofsists|
eeeer es
CIB
Dyspusa
Vorioustypes fcellulsrada ptations
6. PREE RADICLE (2017)
Unstabie chemical compound containing unpaired electron in outer orbit
TYPES
(a) Oxygen derived free radicle.eg; superoxide ion, hydroxyl ion ee
(b) Nitric ovide derived free radicle.eg;ONOO, NO2.
(Q) Free radicle from drug and chemicals.eg; CCLa
janism of production
Mi
I. Superoxide is produced when oxygen is pai
reduced
2. SOD converts superoxide into hydrogen peroxide
3. Hydrogen peroxide undergoes Fenton reaction to form hydroxyl radicle
Factors affecting free radicle production
1.During inflammation and phagocytosis
2.0xidation reduction reaction
3.Radiation injury
4.Drugs and chemical injury
5.Cellular ageing PATHOLOGICAL EFFECTS
—————_——_
1.Lipid peroxidation in membrane...>membrane damage
sree sonication in memurene.-menuarane.cemaas
2.Cross linking & oxidative modification of protein
3.Damages DNA
7. ANTIOXIDANTS (2017)
These are substance which reduces the effect of free _radicle in
tissue Two types,
a)Enzymatic-
SOD, Catalase, Glutathione i
(b)Non enzymatic
1. Exogeneous- Vit€, Vit
2.Endogeneous-
Transferrin feritin
AUTOPHAGY (2017)
* Self eating
* Lysosomal enzyme digests its own components of the cell during stress
ee eS
* By his mechanism, the starved cell can live by eating its own Content & by
recycling content to provide nutrients and energy.
Role in cancer
* Several autophagy gene (Atg gene) that promote autophagy acts as tumor
suppressor gene& are deleted or mutated in many cancer
eee eS oe eee nemand One
© Tumor cell n rocess to provide nutrients for continued
‘umor cells may corrupt the autophagy process to p! i
growth and_ survival
whan, 4
+ Autophagy can also protect cancer cellS{ they are deprived of nutrients or oxygen
because of therapy or poor blood supply 's (2013)
13,PIGI
(a)ENDOGENEOUS. ()EXOGENEOUS
Bilirubin Carbon
Melanin Tattooing
Fiemosiderin Arsenic
Lipofuscin Beta carotene
14,APOPTOSIS (2014,2022) [important]
Apoptosis is a form of genetically programmed cell death designed to eliminate
unwanted host cells through activation of a coordinated series of events. j
Sequence of Morphological Changes in Apoptosis.
1.Cell shrinkage.
2.Chromatin condensation under the nuclear membrane followed by nuclear fragmentatio
3.Formiation of cytoplasmic blebs followed by fragmentation into apoptotic bodies
4. Phagocytosis of apoptotic bodies (ingestion by macrophages followed by lysosomal degra
Mechanism
It involves two phases (1) initiation phase (2) execution phase
Initiation phase involves two pathways: (2) mitochondrial pathway(b)death receptor pathway
(a) Mitochondrial pathway
- Survival of apoptosis cel! is determined by permeability of mitochondria
Activation of BCL-2 sensor proteins (BAD, BiM, Puma, Noxa) by cell injury —>Activation of
proapoptotic proteins (BAX and BAK) which form oligomers that insert into mitochondrial
Broapopts ad BA oligomers that insertinto mit
menibrane —>Formation of pores in inner mitochondrial membrane —>Decreased membral
potential —>iMlitochondrial swelling Increased permeability of outer mitochondrial membrane
>>>Release of cytochrome C and other proapoptotic factors into cytosol —>Cytochrome Cbi
_to *Apaf-t (*Apaf-1 is apoptosis activating factor) —>Formation of cytochrome C-Apaf-1 com! |
tion of initiator caspase-9
(‘apoptosome’) —>Acti
(b)Death receptor patiway
) —>Three or more molecules
Binding of Fas L to Fas (receptor-ligand interactioi
are brought together—>The cytoplasmic domain of three Fas molecules forms a binding site,
an adapter protein FADD (Fas-associated death domain) —>FADD binds ina
2 aaa “ee
>Activation of Caspase-8 and initiation of caspase cascade 2. Execution phase
Both the activated caspase 8 & 9 activates execution caspases 3 and 6—>Mediates final
phase of apoptosis ‘
Eheke of apoptos!
Diagnosis
1. Stepladder pattern on agarose gel electrophoresis
2. H&E, Feulgen anda
‘acridine orange staining of apoptotic cells,
Electron microscopy findings
Dilation and amorphous ao
densities in mitochondiia
Amorphous debris ot
cytoskeleton <>
Pyknotic nucleus +>
Discontinuittes in plasma ag =
‘and organelle membranes
YF oe
Myelin figures 299
Leakage of corients
. LY pa ate CHAPTER
02
LONG ESSAY
1.Enumerate the type of wound healing. Define the mechanism and factors affecting it.agy
on fracture healing (2028)
Primary union is seen in incised wounds with
Healing by primary or first inter
opposed edges (clean and uninfected wound).
ills appears at the
Day 1:Wound->filled with blood clots and inflammatory cells neutroy
of wound,
Day3
Granulation tissue formation begins and infiltrates the incision space.
¥
Collagen fibers form from the margins of the incision and are laid down vertically.
> Thickening of the epithelial layer due to epithelial cell proliferation and migration of epith
an
cells along incised margin.
‘onal spaces filled with granulation tissue
> Neovascularization is at its peak
Collagen fibres become abundant and_bridge the incisional gap
> Epidermis regains its normal thickness.
Day’7
ion of collagen and proliferation of fibroblast
continued accu
essels and blanching
regression of vi
After days
e forms and gradual increase in tensile strength over time
scar tis Page |15
Healing by secondary intention: Secondary union is geen in open wounds with separated edges,
extensive loss of cells and large defects.
Characteristic Features of Healing by Secondary Intention
Associated with large defects filled with blood clots, necrotic debris and exudate.
-Inflammatory reaction is more intense.
-Large amounts of granulation tissue are deposited
There is formation of epithelial spurs from margins of the wound
-Typically demonstrates ‘wound contraction’ whichis mediated by myofibroblasts and aids in
qomonstates wound contraction Sed ated eros on
decreasing the gap between the dermal edges of the large wound.
ER TE Gap Demwrcen the cermal edges of the large wounc
-Substantial scar formation and thinning of the epidermis is seen
eee ——————
Epithelium,
proliferates and
grows across the
wou
_> co?
g
ae SAY;
Proliferating
capillaries
Blood cleat
fils the,
Neutrophils
Blood
vessel
Macrophages
Death of minmal number of |
heli five Hse cells
epihelal and conmecttve Hesuecele Na dave
A. First 24 hours pieruel
Epithelial at
proliferation “| War
complete weak
Ls
Minimal scar with good
fibrous union . 10-1. Ss
D. Weeks to months ©. 10 day:
Healing by peimaxy intention Factors influencing wound healing,
1. Local (a) Reeteased blood supply (b) Denervation (¢)Lacal infection (d) Foreign
Badv(e) Mechanical stress (f) Large amounts rhage and necrosis
ic (a) Old age (b) Malnutrition (c) Anemia (2) Obesity) Drug ter g
‘Systemic infection (g) Geneti c disorders, eg, syndrome and. thlere=pee 4
se (h) Diabetes mellitus (i) Uremia (j) Vita nd trace metal (zinc and Copp
complications of wound healing
1 Deficient scar formation leading to wound dehiscence (rupture) or ulceration
2. Formation of exuberant granulation tissue which protrudes above the level
ofthe surrounding skin and blocks re epithelialization (proud flesh)
Excessive formation of repair components, eg, collagen leading to hypertrophie
scaror keloid formation 3
4. Development of contractures (palmar or Dupuytren contracture and plantareg
5, Development of incisional hernia, neoplasia, pigmentation or implantation
Fracture healing
Fractures can be:
(2) Traumatic or pathological (due to a pre-existing disease)
(b) Complete or incomplete
(©) Simple (overlying tissue is intact), comminuted (bone is splintered or displaced)
compound (fracture site communicates with the skin surface)
(d) Stress fracture (slowly developed fracture, which develops over a period of incre
physical activity)
Fracture healing mechanism :
Hematoma formation and local inflammatory response at the fracture site > Ingrowth of
Je with formation, of soft tissue callus > Formation of procallus composed of.
ees
granulation tis
developed in be in bone marrow cavity)
2)Discuss in detail about major events occurs during acute inflammation . Add a note on
endothelial adhesion molecule?
It isa transient process, which occurs within minutes of injury, lasts for hours or days @
represents the early body reaction. It is usual followed by repair, a process by which”
tissue is restored to its original state as far as possible. ‘Two major components of acute inflammation:
1. Vascular events
(a) Alterations in vascular caliber that lead to an increase in blood flow
(b) Structural changes in microvasculature, which permit plasma proteins and
leukocytes to leave the circulation
their
2. Cellular events: Immigration of leukocytes from microcirculation and their
accumulation in the focus of injury.
SS
Vascular events in acute inflammation
> Immediate transient vasoconstriction of arterioles.
> Persistent progressive vasodilatation of arterioles
> Opening of new capillary beds (Igcal heat and redness)
> Increased blood volume in microcirculation elevating the hydrostatic pressure
> Tfansudation of fluid into the extracellular space
> furtherinjury release Histamine, leukotrienes, PAF, kinins Histamine, prostaglandins,
and NO Increases vascular permeability
> escape of exudate into the interstitium (hallmark of acute inflammation)
> Stasis n
> Leucocytic margination or peripheral orientation of WBCs along the endothelial
surface (neutrophils stick to the endothelium and migrate through vascular Wall into the
ipterstitial tissue.
Cellular events in acute inflammation
(a) In the lumen
Stmargination (peripheral orientation of leukocytes
rolling (weak attachment of leukocytes to endothelium, detachment and binding
veak attachment ofleukocytes to endothelium, eo ne
again, causing a rolling movement)
> pavementing opadhesion
[b]qutside the vessels
Pdiapediasis
phagocytosis [ refer Q.no. 10]
3).Define a granuloma’ Describe the morphology of a classical granuloma.
Discuss about evolution of granulomatous inflammation? (2015)
inflammation characterized by microscopic aggregation
| Itis defined as distinctive type of chron
| of activated macrophages.
__ structure of granuloma
ells: modified macrophages which resemble epithelial cells.
"1. Epithelioid cells: These are mod
| They Rave a pale pink granular cytoplasm with indistinct cell borders, gftenanneating LOmnsias
into one another.
“The qucleus|s oval or elongate, and may show folding of the nuclearmembrane . the nucleus is
less dense than that of a lymphocyte.
2. Giant cells: Epithelioid cells fuse to form giant cells and are found in the periphery or Sometimes
in the center. They have many small nuclei arranged peripherally or haphazardly.
— See en i ral ymatous inflammation .sor
3. Lymphocytes t forms an integral part of granulomatous inflammation some types may,
panied by plasma cells a
ted
Sometimes granulomas are assoc ith central necrosis
mes gran x ith ceptralpectas
cg; Tuberculosis Fibrosis: Granuloma may heal by producing extensive fibrosis.
Evolution of granuloma
Cell injury (M. tuberculosis ) > failure to digest agent > weak acute inflammatory respon
engulfment by macrophages > persistence of injurious agent> Tell mediated immenee
duet poor digestible agents activation of CD + Tell esuts in release of Imphokines
gamma and TNF-alpha > accumulation of tissue macrophages-> macrophages activatey
gamma ~ macrophages transform into epithelioid cell, giant cell and secretion of fibrob
lastie
proliferating cytokines results in granuloma formation
SHORT ESSAY
4.CHEMICAL MEDIATORS(2020)
‘Ans. Chemical mediators of inflammation may be
1.cell derived
[Source Mediators Action
ming Vasodilatation, increased permeability,
vation, itching and pain
Mast cells, basophils and | Histamine
5
latelets and Serotonin. Actions like histamine but less potent
enterochromaffin cells
‘Neutrophils and Lysosomal enzymes | Tissue damage
macrophages
All leukocytes and Platelet activating Increased vascular permeability
endothelial cells, factor
al leukocytes Leukotrienes LTC4, LTD4 and LTE4
‘ c mmmctifiene: nt
+ Increased permeability Ise
Smooth muscle contraction,»
‘RoeeecnencOtTaCtiOn,
Vasoconstriction *
Bronchoconstriction
Allleukocytes, platelets | Prostaglandin PGD2 and PGE2
aoe antostagiandi £GD2 and PGE2
and endothelial cells
‘meee
I Bronchodilatation Page |19
* Vasodilatation
DRE
PGi2
= Inhibition of
i * Increased permeability of vessels ¥
PGF?
+ Bronchoconstriction
= Vasoconstriction
= Bronchoconstriction
| = Platelet aggregation
* Vasodilatation
latelet a;
Lymphocytes, macrophages | Cytokine
and
endothelial cells
Increased leukocyte adherence, thrombosis,
fibroblastic proliferation and acute phase
{gaction (JL8 chemotactic for neutrophils)
Macrophages Nitric oxide Vasodilatation, antiplatelet effect and
eecenaees mon esociiotaton, antiplatelet effect
microbicidal action
‘Neutrophijs and Oxygen-derived free | Endothelial
damage and increased
Mactophages radicals vascular permeability +
derived
Clotting and fibrinolytic system | fibrin split products
Kinin system
Increased vascular permeability |
————
Kinin/bradykinin
Increased vascular permeability |
—HEACeneait
Complement system
oo
Anaphylatoxins, 3a, Ca and C5a
Shopiyetowis Sa, Cha and Cosa
Increased vascular reread |
—— 5.CHEMOTAXIS (2016)
Migration of leukocyte towards Inflammatory stimulus in direction of gradient of eg
produced chemoattract
Chemo attractants (1). Exogenous—bacterial products
(2), Endogenous—C5a, leukotrienes and cytokines
Mechanism
Binding of chemoattractant to specific transmembrane 6 protein—coupleg
receptors (GPCRs) on the surface of leukocytes —> Recruitment of G protein due tog gna
‘kinase PI3K) 3
rom GPCRs—> Activation of phospholipase C (PLC) to phosphoionositol 3
ses (effector molecules) —> PLC+ PI3K act on membrane Phos
id second messengers —> increased Cytosolic calcium —> Activation
protein tyrosine
Generation
GTPases and numerous kinases—> Polymerization of actin —> ‘Locamo
ae
6.Transudate and exudate(2021)
| Characteristics | Transudate
i
| Cause | Non inflammatory Anflammatory process
Itiafitrate of plasma increased vascular permeabili
Exudate
[Mechanism
‘Appearance Cloudy
[Ser
| Specific gravity
Yellow to red
stelow to red,
>1.08
Hi
i
EE
Usually, present
ns
Hieh
Non pitting
Pus
=
[= i
Page |21
7.GRANULATION TISSUE(2018)
t'sa componentof healing and repair and formation occurs with the help of growth factors
like POGF, FGF, TNF ete.
Niemen geass
Gran
ion tissue has following component
+ Newly formed blood vessels (endothelial proliferation or neoangiogenesis)
* hronic infl ry,
matory cells
Proliferating fibroblasts
Extracellular matrix which in comparison to ordinary extracellular matrix ig more cellular
and more vascular
SCARDINAL SIGNS OF INFLAMMATION (2016)
Cardinal signs are,
(1) Bubor -Mainly Increased blood flow and stasis. Mainly occurs due to vasodilation
(2)€alor ~ Mainly increased blood flow.
\Gaurt ~ Malnluincreased blood flow
(3)Tumor-Mainly due to increased vascular permeability resulting in escape of protein rich
{luidfrom Blood vessels
(4)Dolor-Pain occurs mainly due to chemical mediators like prostaglandins and
8, LEUKOCYTE ADHESION MOLECULE (2021)
—TAivis are molecules on the leukocytes and endothelial surfaces, which regulate leukocyte
nace aoe “
adhesion and transmigration. Synthesized by-endothelial cells and leukocytes,
as belong to toucmolaeas famiies—selectins, gamuneglobulin superfamily,
ip alycop ae
tegrins and mucin-like glycoproteins.
Endothelial molecule and complimentary ieukocyte molecule involved in rolling
Se and complimentery sourocyte molecule involved
saa
| Endothelial molecule (selectins)
eon et molecule | (selectins
Complimentary leukocyte molecule for selectins
1 | P-selectin (CD 62P)
Sialyl-Lewis X-modified proteins
2 | E-selectin (CD 62€) Sialyl-Lewis X-modified proteins
3 | GlyCam-1 (CD34)
Lselectin (CD62L) - LAM DEFICIENCY TYPE 1-integrin defect
-LAM deficiency type I! - selectin defect
-LAM deficiency type I!I-
10.PHAGOCYTOSIS
- Phagocytosis is defined as leukocytic engulfment of microorganisms, foreign particles and q
debris
The two most important phagocytic cells are:
1. Polymorphs
2. Circulating monocytes or macrophages
Steps in Piragocytosis
1. Recognition and attachment
(Mannose receptors and scavenger receptors are two important receptors
that function to bind and ingest microbes.
(b) The efficiency of phagocytosis is greatly enhanced by opsonization of bacteria
(or foreign material)
(c) The process of coating of a particle, such as a microbe, to target it for phagocytosis
is called opsonization and the substance that do these are called opsonins.
(4) opsonins are ‘IgG antibodies’, ‘C3b breakdown products of complement’
and plasma carbohydrate-binding lectins called ‘collectins’ .
2. Engulfment
(a) Bacteria are engulfed by pseudopodia (extensions of cytoplasm) and
trapped within phagosomes forming a phagocytic vacuole.
(b) It then fuses with lysosome to form phagolysosome
3. killing and degradation
(a) Neutrophils and monocytes are armed with both ‘oxygen-
dependent’ (MPO system and 02-derived free radicals; as well as ‘oxygen-independent’
(Lysosomal enzymes and reactive nitrogen species, mainly derived from nitric oxide)
(b)Lysozymes
(c) defensins Page \23
‘A Recoantion
and atachinest
Microbes bind to
Phagccyte
B. Engultment
10.GiANT CELLS (2014)
Cells with more than one nucleus
oe
Physictogical
Osteodastic giant cell Syncyhotrophoblast Megekaryocyte
Pathological
SS =
= “@
Reed- Stemberg cet! Tumorgiant cell
Foreign body giant cell
ee
se
Gaanicelis io
Touton giant cell Osteasiastives heneenieton
Various types of giant cells
Langhans giant cell CHAPTER
INFECTION
03
LONG ESSAY
41).A.60 year old male presented with history of fever, cough and weight loss sineg
ESR 120 mig
month. Chest X-ray showed cavitary lesion in the right apical lobe and
Answer the following
a) What is your diagnosis?
Secondary TB %
b) Discuss pathogenesis and morphology of same?
Chronic granulomatous disease caused Tuberculosis
Mode of transthission
inhalation- coughing , sneezing generates respiratory droplets
Ingestion- during drinking non pasteurized milk from infected cows contaminated with
M.bovis
Inoculation- during postmortem examination (extremely rare mode)
Pathogenesis
1) Before activating cell mediated immunity:
~-> Alveolar macrophages engulf organism and jt blocks phagolysosome fusion
> Extensive proliferation of bacilli results in rupture of macrophage and release of baci
> Recruitment of additional macrophages ingest dying macrophage and their content.
—
> Bacteremia and seeding of multiple site
2)After activating cell mediated immunity
ALcog igen’
> Antigen presenting cell credses antigen and present itto TCell
Transformation nko epithelium cells results in granuloma form
Differentiation of CD4 T Cells to TH4 Cells and subsequent activation of macrophages.
Morphology of primary TB
Gross:
- Main sites of primary Tb are lung, intestine, tonsil, and skin
- In lung, usually seen in lower part of upper lobe and upper part of lower lobe
Ghon's focus is the characteristic lesion z
Regional lymphadenitis can be seen
Ghon's complex -> Ghon's focus + regional lymph node invowvement
Microscopy
- Granuloma can be seen (tubercle) which is caseating type
- This granuloma is usually enclosed within fibroblast
. The caseous necrosis is surrounded by epithelioid cells » Secondary TB
TB ip previously sensitized individual
Source? i) feactivation of latent infection
(2) exogenous reinfection
Site: apex of upper lobe of one or both lungs,
Appearance: initially small focus of consolidation, fim», grey white to yellowin colour
Microscopy:
~ Shows caseating granuloma
2).SYPHILIS (2017)
Though a venereal disease, syphilis involves multiple systems. It is often called ‘the
Ereat imitator’ because many of its signs and symptoms show a major overlap with those
of other diseases.
Causative agent - Treponema pallidum :
Stages of syphilis
(a)primary stage
~ The incubation period ranges from 10 to 90 days (average 21 days).
~ The disease starts with a solitary, firm, nontender raised lesion on
Penis, cervix, vagina, arms or as multiple sores (chancres). The chance heals in a few
days (even without therapy),
(b) secondary stage
Secondary stage is denoted by appearance of a rash in the skin and mucous
Membranes,seen as rough, reddish-brown spots, most Prominent on palms of hands and soles.
+ presence of condyloma Lata
(clatent stage
The latent stage can last for years and during this time the infected person continues
to harbor syphilis even though there are no active signs or symptoms.
(d)Tertiary syp!
~ This can happen even 10-20 years after the infection is first acquired and may evolve into
neurovascular(meningovascular,generalparesis,tabesdorsalis), aortitis (aneurysms, aortic regurgita
tion), gumma formation (hepar lobatum, involvement of skin) and other.
Histology all features
1. Obliterative endarteritis
2. mononuciear infiltrates rich plasma cells. Short essay
3) ACTINOMYCOSIS (2015)
= Anaerobic bacterial infection caused by bacteria Actinomycetes Israeli
organism is found in oral cavity, GI tract & Vagina
infection occurs endogenously
Morphology
Cervicofacial actinomycosis-Most common. Initially firm swelling occurs in lower
>breaks down and form abscess or sinus
Thoracic actinomycosis-Infection mainly occur in lung and lesion intially resembleg
pneumonia and finally spread to entire lungs, ribs, pleura etc.
Abdominal actinomycosis- Occurs in appendix, caecum& liver
Pelvic actinomycosis -Develops as 3 complication of IUDs
w/s
Granulomatous reaction with central suppuration
Central abscess can also be seen
Note-special stain of bacteria GMS stain
4) 1.LEPROSY(2022)
| Lepromatous TUBERCULOID
Noncaseating granuloma composed of
epithelioid cells and giant, ‘els
[ CHARACTERISTICS
| Types of Lesions | Nodular or
| diffuse
| j collection of
| lepra cell
I [Wwithin dermis
| Complication [EN
| SKIN LESION Symmetrical,
| multiple, II
defined,
| nodular lesions
Seen, with less_ | Sensory loss is
sensory loss
Sensory disturbance and paralysis
Red, hypopigmented lesion
mon
[ present absent
[nepetive ‘positive
5) RHINOSPORIDIOSIS (2021}
Causative agent- rhinosporidium seeberi
+ Inflammatory disorder
Site-larynx and conjunctiva
M/S-contain spherical cyst called sporangia
~ This sporangium contains basophilic round spores
~ Chronic inflammatory cells are also present CHAPTER
04 HEMODYNAMICS
LONG Essay
1).50 year old female underwent abdominal surgery and was bedridden for 10 days She
suddenly developed dyspnoea and collapsed. She died a few minutes later Answer the
following :(2017)
a) What is the diagnosis?
Ans . Systemic thromboembolism>*
b) What are the post-mortem findings?
c) What is the etiopathogenesis?
OR
A.50 year old male suffered fracture of left femur in road traffic accident and was
treated.10 days later, he suddenly collapsed and died.Answer the following
questions.(2019)
2) What is the diagnosis?
b) What is the etiopathogenesis?
¢)What are the post-mortem and morphelogical finding?
Emboli are classified based on
{a) Physical state of emboli.
* Solid: thromboemboli and tumour emboli
+ Liquid: Fat, Rone marrow and amniotic fluid emboli
+ Gaseous: Air emboli
(b) Site of origin
* Cardiac emboli (left side of heart)
+ Arterial emboli (atheromas )
+ (enous emboli
(c) Presence or absence of secondary infection
* Sterile7bland emboli
! + Septic emboli
(d) Flow
* Paradoxical emboli/crossed emboli -Emboli crossing over from venous circulation to
arterial circulation or vice-versa
* Retrograde emboli: Travel against the direction of blood flow
(4) Pulmonary embolism
Site-Deep vein of leg, pelvic vein, vena cava
Pathogenesis-[hrombiis as a whole, or its loosely attached tail, gets detached from its origin
-carried to larger vascular channels
-to right side of heart—>right ventricle—>enters into pulmonary arterial circulation,
+ -Iflarge enough it blocks
Clinical Features
‘Cough, severe pleuritic pain, shortness of breath, occasionally hemopt Sis ang.
nsion, pulmonary infarction, righ
failure
(2)Fat embolism
Causes includes:
Extensive burns + Pancreatitis + Diabetes mellitus Vigorous casiepulmonary
resuscitation and trauma of long bone
‘Pathogenesis,
(a)Mechanical obstruction
Fat globules—>systemic circulation—>aggregation of RBC and platelet—>)
(b)Biochemical. mechanism r a
Breakdown of fat globules into ree fatty acids—> Toxic injury to endothelium
acids —>Platelet activation and recruitment of granulocytes —>Production of free ri
proteases and eicosanoids —>Vascular damage
Autopsy finding :
~The lung shows changes of ARDS
n brain it shows cerebral edema, small haemorrhages& microinfarcts_
-Fat demonstration is done with the help of Sudan 3& 4, oil red O
Clinical manifestation re
Clinical manifestations appear within 1-3 days of trauma and include * Tachypnoea,
dyspnoea and tachycardia(pulmonary insufficiency) « Irritability, restlessness, delirium am
coma(neurological effects)
{3)Amniotic fluid embolism 3
Amniotic fluid embolism is a cause of maternal morbidity during labour and immediate _
Postpartum period, and has a mortality of up to 20-40%. =a
Pathogenesis oy “be oy
Caused by infusion of amniotic fluid with all its contents (foetal cells and debris) into maternal
circulation due to tears in placental membrane or rupture of uterine Vescels
* Sudden respiratory distress * Deep cyanosis + Hypotensive shock + Seizures, convulsions,
and death —
Microscopic Features 1
+ Pulmonary microcirculation shows fetal skin, squamous cells, lanugo hair and fat from veraix
caseosa, mu m fetal respiratory tract or GIT. a
* There is pulmonary oedema and diffuse alveolar damage and haemorthag:
Cole or ea
+ Mechanical blockage of pulmonary circulation
+ DIC
mniotic fluid emboli consists of squamous cell shed from fetal skin,lanugo hair and mucin
Derived from respiratory tract
-pulmonary edema, diffuse alveolar damage and pIC
P16 inerninabed jy Maw seelt
al . Page |29
(4) Air embolism
WSchemfe Injury caused by air bubbles by arterial blood flow.
Clinical features
~ “Arteriography
Decompression sickness
- Wintuston
- Trauma
Pathogenesis
“During deep sea dive air is inhaled at high atmospheric pressure
-Inert gases get dissolved in blood
~During rapid ascent gas bubbles form in circulation
-obstruct blood vessels
Results tp
(a)reduced blood supply to skeletal muscles result in bends
(b)Nervous system will get affected result in coma and death
coms System will pet affected result in coma and deat
(c)Resuilts in chokes
{5)Systemic thromboembolism
‘Embolr occlude systemic arterial circulation
Sources of emboli includes,
intracardiac mural thrombi
paradoxical emboli
-Atherosclerotic plaques
Consequences
“lodges on vascular bed of lungs
-lodges on bifurcation of arterial trunk
Propagation and obstruction
~ Fragmentation & lysis
Major sites :Brain Kidney, Blood vessels, spleen
i i \osis ,oliguria, weak anc
2) 50 year old male presented with altered sensorium, cyanosis ,oli we id
Rapid pulse tachypnoea, and cold clammy extrenities.(2019)
a) Whatis the diagnosis?
b} Discuss the etiopathogenesis?
©) Mention the organ involved and describe the pathology in the lungs?
ANS;SEPTIC SHOCK 3
Its defined as a clinical state of cardiovascular collapse characterised by the inadequate perfusion of
the cells and tissues resulting in hypotension and cellular hypoxia
Classification
|. Hypovolaemic shock: Characterised by reduction in the circula ng blood volume.
| 2. Cardiogenic shock : Due to failure of the myocardial pump:
3. Neurogenic shock: Occurs due to loss of vascular tone and peri
4
ipheral pooling of blood.
Anaphylactic shock: Occurs when Si aMerge TEPOREe gare eT ISS ST eee eel
mediators in large Quantities a erro ee
5. Septic shock: Occurs when there, iswidespread endothelial injury and activation. Pathogenesis of Hypovolemic Shock
Vasoconstriction Cell hypoxia and energy deficit
Failure of pre capillary sphincter seratereipatn
imulation of lactic
Peripheral pooling of blood
a and fallin bp
4
Hypoxia Failure of Na-K pump
Release of efflux of k
Lysosomal influx of Na
Enzymes’ = and H20
Enter circulati
And damage capillary
Endothelium
Celldeath &
Pathogenesis of Septic Shock
Microbial products. (Pathogen-AssociatedMolecular Patterns or PAMPS
i
@ctivation of 6 protéin-coupled receptors which. Activation of Signal transducing proteins
recognise bacterial peptides and Nucleotide Called TL
Polymerisation Domain proteins (NCD) 1 and 2 ae |
Complement activation Activation of innate immune cells Activation of coagul
eee Cascade
Activation of c3 to c3a__Activation of endothelial cells and leukocytes Release of
ferdlesse of meters =
Release of IL1, 1L6, 1L8, I sTNFR,TNF,NO,PAF,ROS,PAI-1, HMGB1 7
see
Myocardial depression ARDS Coagulation. Increased vascular pe
Low cardiac output Decreased perfusion
Low peripheral resistance Fever ~Vasodilation
Stages of Shock
(a) Attempt is made to maintain adequate cer oronary blood supply by redist
blood so that vital organs (brain and heart) are perfused and oxygenated. Page |31
{b) Activation of neurohumoral mechanisms leads to widespread vasoconstriction and fluid
‘Sonservation bythe kidney: Neurohumoral mechanisms involved ingluge
(i) Activation of baroreceptors and chemoreceptors
(ii) Activation of renin-angiotensin-aldosterone system
(iil) ADH release
(iv) ReTease of catecholamines
(v) Vascular autoregulation—in response to hypoxia and acidosis, regional blood flow to the heart
2. If the underlying cause is not corrected or the patient has pre-existing cardiovascular disease,
5 Pulmonary hypoperfusion and tachypnoea
(b) Tissue anoxla initiating anaerobic gl ort les to lactic acidosis and ineffective vasomotor
fesponse causing peripheral pooling ‘and, Vasodn fatation,
3. Decompensated (irreversible) shock: Widespread cell injury leads to :
2) Progressive decrease in blood pressure due to decrease in cardiac output
_ b) Metabolic acidosis
¢) Adult respiratory distress syndrome (ARDS)
¢) ischemic cell death of brain, heart and kidney
Morphological Changes in Shock
* “Morphologie changes tn shock are due to hypoxia resulting in degeneration and necrosis in
various organs.
* Major organs affected are brain, heart, lungs and Kidneys. Adgenals, GIT. and liver are also
affected. ar a
1. Heart
+ Heart is more vulnerable to the effects of hypoxia than any other organ.
* Subepicardial and subendocardial regions show haemorthage and necrosis.
eamungs
Because of dual blood supply, lungs are generally not affected by hypovolemic shock. In septic
shock, lungs may manifest with ARDS (shock lung) or show the following features
_* Diffuse alveolar damage
* Interstitial lymphocytic infiltrate and oedema
+ Formation of alveolar hyaline membrane, and thickening and fibrosis of alveolar septae
3. “Kidney
+ shock may lead to irreversible renal injury resulting in anuria and death.
+ Kidney is swollen and may show acute tubular necrosis and brown tubullar casts. The latter are
een in cases of extensive muscle damage due to intravascular hemolysis.
4. Liver
+ Liver is usually enlarged and shows a mottled cut surface.
* Sections show focal (centrilobular) necrosis and fatty change.
3) Thrombosis (2020)
) (2020) 44
Thrombosis is the process of formation of a solid mass in the circulation constituted by platelets,
fibrin and other entrapped blood elements. Vessel wall injury induces rapid recruitment of the
circulating platelets to the site of injury, where they initiate formation of a thrombus. There are
three major contributors to thrombus formation: Factors contributing to thrombus formation
1. Endothelial injury, which may be secondany te!
(a) Myocardial infarction. (b) Ylcerated atherosclero'
laques. (c)
Cardiac
Sadiac surgery
(a Myocarditis y
> alteration innormal blood flow (stasis or turbulence): j
Shassistypleally seen tn hypervscosity syndromes and polycythemia; whereas, «
only associated with hypertension Alteration jn. notmal flow result in
{aJbisruption of laminar flow. (b) Decreased hepatic clearance of activated coagulation in
3.Conditions predisposing to hypercoagulability
a) Genetic :
() Deficiency of antithrombotic factors like ATI, proteins C and S, Methylene
oo reductase (MTHFR) gene mutation and defects in fibrinolysis,
{iincreased_ prothrombotic factors as in Factor V mmutation/factorV Leider Tai
protein C resistance) aa
blAcquired
(i) Venous stasis
(ii) Increased platelet activation
{increased hepatic synthesis of coagulation factors or reduced antico:
(iv) Antiphospholipid syndrome
(v) Tissue injury
Morphology of a thrombus
Thrombi are grey-white, friable, tangled strands of fibrin and platelets, which m:
the cardiovascular system, as in cardiac chambers, arteries and veins and capilla
ries,
General Features of Thrombi
Cardiac thrombi q
mostly develop inthe regions of turbulence and at sites of endocardial inury(atral appenda
endocardial surface of a myocardial infarct and cardiac valves).
* Thrombi in cardiac chambers or aorta show the presence of laminations or lines of Zahn (pale
‘ayers of fibrin and platelets alternating with darker layers of R8Cs), SS ——
* Thrombi in smaller arteries or veins do not show lines of Zahn.
* Mural thrombi are attached to one wall of an underlying structure, usually capacious lumi
heart chambers and aortz ze
* Arterial thrombi are usually occlusive when they involve smaller vessels; la
and,common carotid tend to have mural thrombi z
* Venous thrombl (phlebothrombosis) are invariably occlusive and, contain a large RBC com
because these are formed in a relatively static environment. These are also called red or taste
thrombi. Other features of venous thrombi are as follows: 3 a
- Lines of Zahn are not well developed.
* Mostly affect veins of lower extremity (90% cases).
* May be confused with post-mortem clots
Fate of a thrombus
1. Propagation (accumulation of additional platelets and fibrin leading to progression)
2. Embolization (propagating tail fragments give rise to emboli)
3. Dissolution (fibrinolysis usually on the first or second day)™
4. Organization and recanalization (ingrowth of endothelial cells, smooth muscle and fibrob!
0 nel BPO OL Ocouchal cells, smooth muscle
5. Inflammation. and. fibrosis (central liquefaction, bacterial seeding and influx of inflammatol Page |33
Evolution of thrombus
pe iation of thrombu
: Fibrin-rich thrombus
Lysosomal enzymes Organization
From leukocytes Gradual growth of granulation
_—— subendothelial smooth muscle cells and,
fenchymal cells into the fibrin-rich-
Thrombus
Central Softening a \
Secondary bacterial infection Formation of capillary channels within
| The thrombus
Septic emboli ae of thrombus gets covered
‘with endothelial cells and capillary
with endothelial cell
channels begin to anastomose
fecanalization
‘Thrombus converted into
Subendothelialmass of connective tissue
Eventual incorporation into the wall
of vessel
Contraction of mesenchymal cells so
hata fibrous lump mark the site
Localised area of ischemic necrosis.
dares ofischemicnecrosis,
Causes
-gcclusion of lumen ky thrombi or emboli
-External compression of vessels( tumour)
- local vasospasm of vessels a
infarcts are classified on is following:
1. Colour (amount of haemorshage) (a) Red or Remorrhagic infarcts (b) White or anaemic infarcts
colour i ( : esa en oerN infarcts
b. Presence or absance ctateretal infection (a) Septic infarcts (6) Bland infarcts
——nenonnenenennsmninommemmenceno” (a) Septic infarcts {B)Bland infarcts.
White/pale infarcts
-Caused due to Arterial obstruction
-Seen in solid organs with dual blood su iney
Gross: wed ed in appearance with poorly defined and s| morthagic
“Alle d-2.day infarct becomesoft, sharply demarcated and light yellow in colour
COCO, Satply demarcated and light yellow in colour Red/hemorrhagic infarcts
Seen in spongy orpans like lung and gastroin
Causes due to Venous occlusion
Grose-Sharply circumscribed area of necr
testinal tract
si, fizm in.consistency and dark red to
Microscopy of infarcts
cows Fachemic.congulative ne
frank nectosis appears after4.to.12 hrs
‘Acute inflammatory infiltrate can be seen
snulation tissue may replace the infarcted area
5 PATHOGENESIS OF EDEMA (2014)
L.Edema due to reduced osmotic pressure
Loss of albumin from body—>decreased oncoticpressure—>increased fluid content jg
al tssue space—>decreased blood volume and renal perfusion—>activates Rage.
nd water retention—>edema
Edema due to congestive heart failure
CluF—>inereased fluid content in interstitial tissue space—>decreased CO—>decr
ncy—>increased production of aldosterone—> salt and water retention =>,
TURE NEPHROTIC OEDEMA.
e_ ss Nephrotic syndrome
easeq
edema
4
NEPHRITIC OEDEMA
Glomerulonephritis
Heavy Moderate
high Low
Decreased plasma oncotic Na and water retention
pressure
‘Subcutaneous tissue + visceral | Loose tissue
organ
Severe, generalised
CARDIAC EDEMA RENAL EDEMA
| Congestive heart failure Nephritic syndrome
Acute nephritic syndrom
ATN
Proteinuria Absent Present
[Serum albumin Normal Decreased
ihechaniem Decreased cardiac output Hypoalbuminemia, Deer
plasma oncotic pressure,Na
and water retension
Distribution Dependent area Nephrotic : Severe, General
Nephritic: loose tissues
6. VIRCHOWS TRIAD(2014,2018)
It includes three main component
(2) Endothelial injury-most important factor
(b) Alteration in norma! blood flow -stasis or turbulence
(c) Conditions predisposing to hypercoagulability I Page |35
7-CHRONIC VENOUS CONGESTION OF LUNG 0
Congestion sa passive process resulting from reduced venous outflow of blood from tissue.
Gauses- Mital stenosis Right sided heart fallure
Rs Ria sided ear Tatu
Cgnsequences-pulmonary edema , pulmonary hypertension, Fibrosis
eee na cone Pe oe an ere or locos
Morphology
Gross-Lung heavy with firm consistency, rusty brown in.colour
M/S; Dilatation and congestion of septal capillaries
~ Intra-alveolar haemorrhage (occurs due to tupture of congested capillaries)
~ RBC Breakdown produces hemosiderin which is taken up by alveolar macrophages.
| “hemosiderin laden macrophages present in alveolar lumina are called heart failure cells
(siderophages). oka aa
“Thickening and fibrosis of alveolar septae is eventually seen.
8.LINE OF ZAHN(2018)
-Lines of Zahn are a characteristic of thrombi.
“They have layers, with lighter layers of platelets and fibrin, and darker layers of red blood cells.
~ -They are more present on thrombi formed with faster blood flow, more so on thrombi from the
heart and aorta
-They are only seen on thrombi formed before death,
9.DIFFERENCE BETWEEN HYPEREMIA AND CONGESTION
Hyperaemia Congestion
Characterized by increased Characterized by blood pooling
blood flow due to arteriolar} due to impaired
— __| dilatation outflow/drainage from tissue
‘Appearance __[ Red Cyanosed
Edema Absent Present,
Nature of process Active | Passive
Type of blood Oxygenated Deoxygenated
2.0.CHRONIC VENOUS CONGESTION OF LIVER(2021)
Causes
-Right sided heart failure
-pericarditis
Obstruction of inferior vena cava
| Morphology
Gross-Liver increases in size
-cut section show alternate dark and light area( nutmeg appearance)
-Periportal area of lobules appears pale and show fatty changes
M/S-Congestion and hemorrhagic appearance in central vein
Thickening of central vein and fibrosis
- periportal region show ete Ree es en net ae ei
CHAPTER IMMUNITY
05
LONG ESSAY
1), A30 year old female complaining of fever, butterfly rashes on face, pain in
ae
Knee joint ,chest pain and have photosensitivity. Answer the following.
Questions
a)what is your diagnosis
b)discuss the etiopathogenesis
C)write the morphology of kidney in the
Ans Autoimmune disorder due to formation of antinuclear antibodies(SYSTEMIC LUPUS
ERYTHROMATOUS) —
Organs affected-joints, kidney, heart and skin
Pathogens ‘
(a)UV_RAYS
“Exposure to UV rays causes apoptosis resulting in increased formation of antinuclear
Antibody result in inflammation 3
(2)GENETIC FACTORS
Increased risk in family members and concordance in monozygotic twins.
-MHC genes are thought to regulate the production of autoantibodies. ~
(3)DRUGS
-{soniazid, d-Pencillamine increases the risk
(4)CIGARETTES SMOKING
Increased chance to develop SLE
Flow chart 2
Precipitating factors —>increased apoptosis —>increased nuclear Ag and antinuclear Ab
forms—>Immune comple 1tion—> Stimulation of B cells and T cells—>Increased aul
Morphology of kidney
Jesions occurs due to deposition of immune complex
morphological classification includes
(2) Minimal mesangial lupus nephritis
characterised by nmune complex deposition in mesangium.
igial Jupus_glomerulonephritis
Increased intercapillary mesangial mateix and. cells,
(3) focal proliferative ilomerulonephritis
Swelling and proliferation of endothelial and mesang x sal
-Neutrophilic infiltrate; fibrinoid deposits, and int
(4) diffuse proliferative glomerulonephritis
There is proliferation of endothelial, mesangial and epit
Thickening of capillary walls occur.
-wire loop lesion is the prominent feature.
(5) membranous glomerulonephritis widespread thickening of capillary walls
manfests with severe proteinutia
(6) Advanced sclerosing Tupus nephritis
End stage renal disease
20% glomeruli are affected
Clinical features
CHrOnic, CEMiting, telapsing commonly febrile illness
injury to skin,joints, kidneys and serosal_membtanes
females are more commonly affected than males (2:1)
Butterfly rashes appears on body.
May be Scute or insidious in onset; usually arises in the second or third decade
nephrotic syndrome.
2.4 2S year drug abuser came to the hospital with generalised lymphadenopathy, chronic
rrhoea, loss of weight and mucosal candidiasis. There is a fall in CD cell count. Answer the
Following (
2018,2021)
a) Whatis your diagnosis?
b) Discuss pathogen
<)_ Discuss the pathology of organ involved?
4) List four investigation to be done?
alos
#105 is a disease caused by a retrovirus, human immunodeficiency Hiv). Two AIDS genetically
genetically
¢\fferent but related forms of HIV, namely HIV-1 and HIV-2, are implicated, Infection is characterized
iby depletion of C4 T cells (fewer than 200/L in number)
b cells (fewer than 200/C i
Structure of HIV Virus
BV virus is spherical in shape and contains an electron-dense, cone-shaped core which further
egontains: errs.
Bi 2 jor capsid protein p24
s cleocapsid proteins p7/p9
[10 copies of genomic RNA
Tice viral enzymes (protease, reverse transcriptase and integrase)
The viral core is surrounded by a matrix protein called p17.
The viral core is surrounded by a matrix protein called p17, gp120 and gp 41 Pathogenesis of HIV
me sistem: CO4s-Tells, macrophages/monocytes and dj Ndritic
b4+Tiymphocyte.
* CD4+ molecule is
2 high-affinity receptor for Hy
{iN €P220 binds with Coa molecules ;
Conformational changes in gp120 and formation of anew rec
This new site binds to CCRS/
receptors) resultin
change in ep41 with insertion of a fusion peptide Present a
cell membrane = =
* Viral core containin
ing genome enters cytoplasm df cel
2. Macrophages
Lreplic
count is greatly decrease:
2. cns
* Viruses are carried
* Viruses infect macri
to circulation by infected Monocytes,
‘ophages and microglia (
's due to direct effect of
, TNF-, IL-6) produced
Ro
HIV does not infect neurons)
# gp 120 or may be caused indi
by macrophages ; Page |39
Abnormalities of immune functions:
i Lymphoper Selective loss of Cb4 T helper-inducer cells with reversal of CD4:CD8 ratio
2. Altered Tce functions in_ in vitro
(a) g Lymphocyte. proliferative response to mitogens and antigens,
(b) g Specific cytotoxicity
(c) gL helper cell function for B cells (decreased antibody production)
3. Recreased Teelifunctions invivo
tions ‘Dvve
(a) Loss of activated and memory T cells
ie Decreased type IV hypersensitivity
c) Susceptibility fo opportunistic infections and neoplasms
Suscep e e
4 ict nocyte/macrophage functions
(a) g Chemotaxis and phagocytosis
(b)gHlAcllexpression SS
(c) g antigen presentation
5. Polyclonal 6 cell activation
(a) Hypergammaglobulinaemia and circulating immune complexes
i (b) Decreased ability to mount an antibody response toa new ant Yresponse to anew antigen
(c) Loss of control/signals for ® cell function in vitro
-AlDS-defining opportunistic
Protozoal anc and H Helminthic
. Cryptosporidiosis or isosporidiosis (enteritis)
* Toxoplasmosis (pneumonia or CNS infection)
Fungal
infections:
* Candidiasis (esophageal, tracheal and pulmonary infections)
* Cryptococcosis (CNS infection)
* Coccidioidomycosis (disseminated infection) + Histoplasmosis (disseminated infection)
umocystosis (pneumonia or disseminated infection)
Bacterial infections
* Mycobacteriosis (atypical and Mycobacterium tuberculo:
extrapulmonary) ;
* Nocardiosis (pneumonia, meningitis and disseminate
+ Salmonella infection
Viral
+ Cytomepalovirus (pulmonary, intestinal, retinal or CNS infections)
+ Herpes simplex virus (localized or disseminated infection)
+ Varicella zoster virus (localized or disseminated infection)
* Progressive multifocal leukoencephalopathy
AIDS-Defining Neoplasms
* Kaposi sarcoma
* 8 cell non-Hodgkin lymphoma
+ Primary lymphoma of the brain
+ Invasive cancer of the uterine cervix
Laboratory diagnosis of AIDS includes:
1. Nonspecific tests. (a) Decreased TLC (b) Decreased lymphocyte count (2000/mm3)
2. Specific tests ae
(2) Antigen detection
(\) Acute illness/seroconversion stage: p24 antigenaemia and viraemia, also a
IgM thereafter
(ii) Asymptomatic c phase: decreased or absent free p24, but ant
may be demonstrated
(i) Clinical disease: increased free p24 antigen Method: Antigen-capture ELISA In the
few weeks after infection and in terminal phase, the test is uniformly positive’
b)Antibody detection
ies to appear]
(i) Simplest and most widely used method
egative in window period that follows infection (time taken for antibod:
(ii) N B
2ppears first followed by IgG
ii) ELISA: - Sensitive but not 5 1 cd phase antiglobulin ELISA’
(ii) ELISA: - Sensitive but not so specific - Types use solid phase antiglobulin ELISA’
‘Capture ELISA specific for IgM antibody’
(iv) Western blot test: more specific than ELISA
(v) PCR: Now ‘new gold s standard’ test for diagnosis in all stages of HIV
3.Direct virus isolation and culture in neoplastic T cell line
4,AMYLOIDOSI5(2013) )!*
-pathological fibrillar protein deposited in extracellular space in various tissue.
-Mainly due to protein misfortunes
“Associated with number of inherited and Inflammatory conditions.
Physical'nature
~The main ‘physical constituents of amyloid are non-branching fibrils of indefinite len
On X-ray crystallography and infrared spectroscopy show a cfoss™-pleated sheet Co
Chemical nature -About 95% consists of fibril proteins
In addition has proteoglycan, GRG, Serum amyloid P
Biochemical nature
Clinicopathological | Associated, | Major fibril | Precursor
category \conditions _| protein rotein
Primary Multiple AL Ig light_chains
amyloidosis | myeloma
Secondary ‘Chronic AA SAA
amylordosls inflammatory |"
—~___| condition
Haemodialy: Chronic Abeta-2M | Beta
elated Kidney tmicroglobuline
feats ey one
amyloidosis disease
Pathogenesis 5
(a)Production of abnormal amount of pormal protein ‘
~ Monoclonal 8 cell proliferation —>plasma cells—>Excess immunoglobulin light chain—>A light
Chain =— a
-Chronic inflammation —>Macrophage activation —>increased IL 1 and Il 6—>Increased synthesis
OFSAA Protein
(b)Production of norma! amount of mutant protein
-Mutation—>Mutant transthyretin—>Aggregate & resistant to proteolysis— > ATTR protein
Staining Characteristics
(2) Congo red r
+Ordinary light-pink or red colour + Polarized light-apple green birefringence (due to cross—
pleated configuration) SS ea
{b)Metachromatic stzins (Rosaniline dyes):
Examples are methyl violet and crystal violet. rose pink colour with these dyes.
{Fluorescent stains of Thioflavin T and S:
Ip uitraviolet light, amyloid fluoresces yellow.
{d)immunohistochemistry
ntcAA and anti-lambda, anti-kappa antibodies can be used to differentiate between different types
of amyloid. SD
fe) Toluidine blue:
lue colour in ordinary light and dark red, birefringence under polarized microscopy.
anna TEI a Cari Fe, Direfringence under polarized microscopy.
ff) Alcian blue: Blue-green colour.
J ere | ener
orphology:
size of affected organ (ncreases
become firm and waxy
(a)kidney.
Gross: Kidneys are normal or enlarged in early stage.
Shrunken in late stage. a i
M/s: Primarily glomerular deposits,
Thickening of mesangial matrix due to mesangial deposits a fe:
ing to capillary narrowing.
Widening of basement membrane of glomerular capillaries leadi
Distortion of glomerular vase artutt due to confluent masses
myloid, (b)spleen
Gross:Spleen become enlarged
\W/5 “Two patterns can be seen,
© (1)Sago spleen:Deposite occurs on follicle
amyloid replaces the follicle
presence of tapioca like granules.
(2) Lardaceous spleen:No follicular involvement
-Only affects C7 framework & splenic sinuses.
Formation of large map like area
Short essay
S.TRANSPLANT REJECTION
Rejection of transplant occurs in
(a)Hyper acute rejection
-Occurs with in minute to hour
“Type 2 hypersensitive reaction
Rejection occurs by activation of preformed antibodies & by complement activa
hrombosis &necrosis™= ~
Pathological finding-Arterits,t
(2)Acute rejection
-Occurs within days to weeks
curs by two mechanism:
{a}Accute cellular relection-Mainly by mechanism of typed h
Tlymphocytes F
Action o!
Pathological finding: Mononuclear cell infiltration edema endothelitis ;
(b)Accute hum oral rejection-Due to production of antibody’ b complement activation
: ie Sh Sneed nelas compere activation
Pathological finding:Necrotising vasculitis,thrombosis
(3)Chronie Rejection
-Takes month to sometime years to get the graft to reject
“Mainly occurs by immune & non immune mechanism
“Pathological finding:Fibrosis& Scarring
6.LE BODIES
~An LE cell (Lupus Erythematosus cell}, aiso known as Hargraves cell,
-Itis a neutrophil or macrophage fathas phagocytized (engulfed) the. denatured nucle
material of another ceil,
pie denatured material is an absorbed hematoxylin body (also called an LE body).
LE cell test a
“I's adiagnostic test for systemic lupus erythematosus (SLE) that is based on anjy
immunologic reaction between the patient's autoantibodies tohuclear antigens and’
nuclei in the testing medium,
7-ANTINUCLEAR ANTIBODIES,
-Antinuclear antibodies (ANAs) include
a. Antibodies to DNA
b. Antibodies to histones ~
c. Antibodies to nonhistone’ proteins bound to RNA
d. Antibodies to nucleolar antigen” Page | 43
We can demonstrate this antibodies by immunofluorescence method which shows patterns
ike, :
Homogenous/diffuse nuclear staining: Antibodies to chromatin, histones and
Im or peripheral stamnmg patterns: Antibodies to ds DNA
ee ast apecle miter JF duows
ST Sa ee WET ETENE presenceoaP eeodies to
ar TE ee
pattern: Most commonly seen_mn_ systemic sclerosis. [f shows
discrete spots inthe nucleus which indicate antibodies to_nucleolar CHAPTER
06 NEOPLASIA —
LONG ESSAY
A.METASTASIS(2019) *)
Tumor implants discontinuous with the primary tumor, confirm the malignant nature of
are labelled metastases. ll cancers metastasize with afew exceptions, eg. basal cll qr
(rodent ulcer) and gliomas of the central nervous system, which are locally invasive and a
y
metastasize i
Pathways of Spread of the Tumors
1. Direct seeding of body cavities and surfaces: Penetration of a tumor into a natural open
eer, ata
field/space, eg. pleural, pericardial, subarachnoid and synovial. Sometimes mucinous tuntors of
appendix and ov: ) benign and malignant) fill the peritoneal cavity with a gelatino\
pendix and ovary (both benign and malignant) fil he p ry with a g us
‘neoplastic mass called ‘pseudomyxoma peritonei ar
2. Lymphatic spread
(a) There are numerous interconnections between lymphatic and vascular channels; sq
emphasis on differentiating lymphatic and vascular dissemination may be purposeless,
(b) Functional lymphatics are absent in tumors and lymphatic vessels located at the su
are sufficient for lymphatic spread.
(c) Lymphatic spread tends to follow nat lymphatic drainage and is the
route for dissemination of epithelial malignancies ; sarcomas may also use this route.
: inal is emay aisoluse thisiaute
(4), t intigens may induce reactive hyperplasia and th
spread of tumor cells to regional lymph nodes
(e)A ‘sentinel’ lymph node is defined as the firs
receive lymph flow from the primary tumor
in the regional lymphatic chain to
3. Hematogenous spread
(2) Typical of sarcomas but also seen in carcinomas
(b) Arteries have thick walls, are less penetrable than veins
(c) All portal b!ood flows to liver and all caval blood flows to lungs; therefore, ver
are the most frequently involved organs in hematogenous dissemination
(Gd) Cancers in the vicinity of vertebral column, eg, thyroid and prostate, metastasi
vertebrae via paravertebral plexus. a Mechanism of metastasis :
{pvasion-metastatic cascade (Molecular events in invasion and metastasis )
4, Invasion of Extracellular Matrix
A)loosening of tumor cells: Normal cells are attached to each other by adhesion molecules
Namely :E-Cadherins.
2)Local degradation /proteolysis of basement membrane and interstitial connective tissue
-Extra cellular matrix is of two types :
+ Basement membrane
+ Interstitial connective tissue
3.Changes in attachment or adhesion of tumor cells to ECM proteins
+ Generation of new sites ae?
, © Adhesion of tumor cells to ECM.
‘+ Stimulation of tumor cell migration
4.Locomotion /migration of tumor cells through degraded ECM
* Locomotion involves many receptors and signaling proteins
© Migration through interstitial tissues
2. Metastasis(Vascular dissemination and Homing of tumor cells)
1
enetration of
ror lymphatic channels
2.Invasion of the circulation and formation of tumor emboli
3.Transit through the circulation
4.Arrest within circulating blood or lymph
5.£xit from the circulation into a new
sue site
6.Formation of micro-metastases
7.Angiogenesis
8.Local growth of micro-metastases into macroscopic tumor
—_———— eee
JONCOGENESIS (2014) ican aed
jemical Oncogenesis:
—— a
i
Induction of cancer by chemicals depends on:
Dose, duration and mode of administration of the chemical
en ——
Individual susceptibility.
Resoctated predisposing factors
————— ufficient dose of the carcinogen. The ey
Stages of Chemical Carcinogenesis
iation alone, however, is not Sufficient.
+ Initiation: results from exposure of cells to s
stidden and irreversible, and has memory. Init
formation
+ promotion: entails proliferation and clonal expansion of the altered and initiated eq
include phorbol esters, phenols, hormones, artificial sweeteners and henobarbital
thanges resulting from the application of promoters do not affect DNA directly, anq cs
Initiators
4. Direct-acting carcinogens—Do not require metabolic activation and include:
(a) Alkylating agents
(i) Anticancer drugs, eg, cyclophosphamide, chlorambucil, busulfan, melphalan and nitrog
(ii) b-propiolactone
(b) Acylating agents
(i) 1-acetyl imidazole
(ii) Dimethyl carbamyl chloride
2. indirect-acting procarcinogens—
Require metabolic activation and include:
(a) Polycyclic aromatic hydrocarbons (found in tobacco, smoke, fossil, fuel, soot, tar, mine
and smoked animal foods)
(i) Anthracenes (cause lung and skin cancer)
(ii) Benzopyrene (cause cancer of oral cavity)
(b) Aromatic amines and azo dyes
(i) b naphthylamine (associated with carcinoma of urinary bladder)
(ii) Benzidine (role in pathogenesis of hepatocellular carcinoma)
(c) Naturally occurring products
(i) Aflatoyin B1 (role in pathogenesis of hepatocellular carcinoma)
(ii) Cycasin (role in hepatobiliary tumors)
(d) Miscellaneous
() Nitrosamines and amides (role in pathogenesis of gastric carcinoma)
(ii) Vinyl chloride monomer (implicated in the pathogenesis of angiosarcoma of liver)
eee ever rcinogenesis
—$<$<—<——$<—
Procarcinogen ~ biotransformation of procarcinogens in endoplasmic reticulum of
Bt citeon rc py of cytochrome P-450
- Conversion into.electron deficient electrophiles.
-Binding of electrophilesto electron rich portions of the cell
‘Stages of chemical
(DNA,RNA and proteins target molecule chiefly DNA)
-Rermanent DNA damage ,leading to initiation of cell and
Altered cell undergoes at least one cycle of proliferation in order to
transfer the changeto the progeny
onal proliferation olatpredcs!
Promotion Neoplasm
Microbial carcinogens :
Carcinogenic microbiological agents mainly include gncogenic DNA and RNA viruses as welll as
oncogenic DNAs
bacteria like Helicobacter pylori.
eta like Helicobacter pyle
1, Oncogenic PNA viruses: Genomes of oncogenic DNA viruses integrate into and forms stable
comes
associations with host genome, eg, E6 proteins of high-risk HPV types complex with p53 to enhance
genome, €€, (Gproteins of high risk HEV types complex withips3
its degradation. Oncogenic DNA viruses include:
(a) Human papilioma virus (HPV): Squamous cell carcinomas (SCs) of cervix and anogenital
egion, as well as, oraf and laryngeal cancers are associated with HPV 16, 18, 31, 33, 35 and
51 and their precursor lesions; whereas, UPV.6 and 11 cause genital lesions with low-
‘malignant potential. HPY/ genome is present in episomal (nonintegrated) form benign
warts and preneoplastic lesions. In.cancers, the viral genome appears to be integrated into
the host.DNA. HPV proteins have the following effects on the cell cycle:
* £6.and £7 block p53 and RB cell-cycle suppression pathways, respectively.
* &6 proteins of high-risk HPV type complex with p53 to enhance its degradation. £6
Proteins of low-risk HPV types have low affinity for p53 and do not affect its stability.
* Increased p53 degradation causes a block in apoptosis (p53 increases activity of BAX,
which is proapoptotic).
&. fre igh-risk types binds to RB protein, releasing sequestered E2F from the RB-E2F
complex, triggering entry of cells in the S phase.
+ €7 from low-risk types has a lower affinity for RB protein, and is slow in transforming cells. (b) Epstein-Barr virus (EBV):
EBV is implicated in the pathogenesis of
(i) African form of Burkitt lymphoma
(i) cell lymphoma in immunosuppressed individuals
(ii) — Hodgkin lymphoma
(iv) Nasopharyngeal carcinoma
(v) Gastric carcinoma
(vi) NK cell lymphoma
Mechanism of EBV-induced oncogenesis
EBV attaches ‘fates of erepharynx and 8 ymphoeytesy
ag
Linear genome of EBV cicularizes to form an episome in g cells.
Normal immune system
keeps infected cells in check
Latent infection of B cells
Decreased immunity/evasion
of immune system
UMP-1 induces the NEKB apa JAK/STAT signaling pathways and Bela
Activation of NFKB and JAK/STAT indy
Cyclin D activation via CD49
8 Cells
GO SRG] Increased B. f Survival and proliferation
(6) Hepatitis viruses:
It
ae rani liver cell linjury, and ‘egenerative © hyperplasia. HBV also er
"y element called HBX protein, which ds
Pi is
infected liver by transcriptional aL activation o
Hlin-like (4) Human herpes simplex yirus (HHV) 8:
HHV 8 has an established role in Kaposi sarcoma, B,celllymphomas and multicentric
variant of Castleman disease
‘Oncogenic RNA viruses: fi
Retr es are the ont viruses tha have oncogenic potential in humans.
Retroviruses are the only RNA viruses that seem to have 8 ? Tae
They contain ‘reverse transcriptase’, which induces reverse transcription of viral
synthesize viral ONA f
* HTLV-1 causes adult T cell leukemia-lymphoma (ATLL) endemic in Japan and Caribbean
HEELS causes 2¢
i basin.
__*Ithas tropism for CD41 T cells and is transmitted by passage of infected T cells during
sexual intercourse blood product transfusion and breast feeding, om
ee ec bcciensfusion and breast Feecnne
Helicobacter pylori
This bacteria can be demonstrated in 9074 cases of gastritis and 20-30% cases of gastric
ulcer, and is also implicated in the pathogenesis of gastric carcinoma and lymphoma ~
bacter pylori-induced oncogenesis
ae ae ceo oe
e ie
: Chronic gastritis
creased gastric acid secretion
Multifocal atrophy and decreased gas
Intestinal metaplasia
Dysplasia Carcinoma (adenocarcinoma of intestinal type)
gb Tumors are neoplasms, which grow as cohesive expansile masses, which do not invade,
as are Reopen so
filtrate or metastasize. They are ysually encapsulated, (The capsule is made of a rim of compressed
onnective tissue derived largely from the native stroma.)
a ee mom the native stroma.
: Tumors of mesenchymal origin: Designated by adding suffix ‘oma’ to the cell of origin, eg, fibroma,
ma (Fig. 6.1), osteoma and chondroma.
nsicema and’ chondroma
‘ors of epithelial origin are variously classified: (a) Some based on the cell of origin,
§,sauamous cell carcinoma, (b) Others based on the microscopic architecture, eg, adenoma
re af arn ae
Beular pattern), papilloma (finger-like or warty projections), cystadenoma, (gystic masses) and
pilary cyst adenoma (papillary cystic masses) 3. Mixed tumors: Divergent diferentaton ofa single ineef Parenchymal cells egy
comprised more than one cel type; usually derived from one germ cel layer, eg
adenoma of the salivary gland.
. plasms which infiltrate, invade and metastasize. Th 4
Malignant tumors are neoplasms w! 1 They may bg
+ Mesenchymal or connective tissue in origin, eg, sarcoma
+ Epithelial in origin, eg, carcinomas, ustally named after their parent organ or tissug ofa
+ Poorly differentiated or undifferentiated malignant tumors, eg, cancers composed of
undifferentiated cells or cells of unknown origin. —
Features Benign
Gross features
Soundaries Encapsulated
Size ‘Usually small is
Secondary Changes Less frequent More frequent
Surrounding Tissue Compressed invaded
Microscopic features
Pattern Resemibles tissue of origin
origin
Polarity Retained ‘Lost
Anaplasia Absent Present
Mitoses Present, Few Typical
Tumor giant celis Rare , Without Atypia
Cytogenetic changes Rore
Physiolony of cells function | Maintained
Growth rate Low.
Local invasion
4)DIFFERENTIATION AND ANAPLASIA (2018)
Differentiation
{tis the extent to which neoplastic cells resemble comparable normal ce
and functionally,
* The cells in benign tumors are almost always well differentiated an
origin. Cancers, however, vary from being well differentiated to poorly di
* Well differentiated cancers show progressive maturation or specialization of undifferentiate
as they proliferate. Poorly differentiated or undifferentiated cancers show proliferation withou
differentiation or maturation. ¥ Page |S1
jomas of the epidermis elaborate keratin, just
‘well
stiated hepatocellular carcinomas elaborate bile. Highh lastic undifferentiated cells,
heir resemblance to the normal cells fram which they have
————
‘Coarsely clumped chromatin,or clumping of nuclear chromatin along the nuclear membrane
resulting in prominent appearing nucleoli
i yrominent appearing nucle
Ingfeased nucleocytoplasmic ratio (normal from 1:4 to 1:6; may approach 1:1)
las
toses }ormal, atypical, bizarre, tr, quadri and multipolar spindles (abnormal
ses are seen in malignant tumor only.
Tumor markers are product of Malignant tumors that can be detected in cell themselves and in
blot or body fluid
+CA 125-Ovarian cancer
—
«CA 13-9-Colon cancer, pancreatic cancer
.CEA-Carcinomas of colon, lung, pancreas
|: ESE lung, Rancreas
Icitonin-Medullary Carcinoma Thyroid
SPSA-Prostate Carcinoma
COGENES AND THEIR PRODUCTS (2022)
dene a
Rloto oncogenes are pormal cellular gene .They control cell proliferation, differentiation and
survival
Oncogenes produce gene product called qneoprotein
Oncoproteins production is not under normal regulatory control & became autonomous
Different types of oncogenes include (a)Growth factor oncoproteins :
These are polypeptides elaborated by many cells that normalh
cell to stimulate its proliferation (paracrine action), eg. :
in sarcomas
© POGE in glioblastomas, TGF: ai
+ BetaFGF, a member of the fibroblast growth factor family, ig exp
man melanoma but not in normal melanocytes.
+ Hepatocyte growth factor and its receptor cMET are overexpresseq j
carcinoma of thyroid.
(b) Growth factor receptors:
GF binds to growth factor receptor—> Transient dimerization occurs
Mechanism in carcinogenesis é ,
Receptors for growth factors undergo mutations or are overexpressed —>Mutany
proteins deliver continuous signals —>Continuous activation of signal-transducing
{9m the inner leaflet of plasma membrane —>Signal transduced from cytosol to nua
second messengers—> Activation of nuclear regulatory factors —>DNA transerh
Examples:Point mutations in ERB_B1 (EGF receptor) found in_a subset of jung
arcinomas and Squamous cell carcinoma result in constitutive activation of Egy
tyrosine kinase.
(c) Signal transduction proteins:
Normal signal transduction proteins, which transduce signsls from the grow
factor receptors on the cell surface to the nucleus, may get mutated, eg, mi
RAS (rat sarcoma) gene.
Tumors with RAS Mutation
* _ KRAS-Mutation in adenocarcinoma of lung, colon and pancreas
* HRAS-Mutation in bladder and kidney tumors re
‘+ _NRAS-Mutation in melanoma and Hematopoietic Tumors
(d) Nuclear regulatory molecules:
- Overexpression of MYC gene occurs with t(8;14) ~
in Burkitt lymphoma or may be a result of amplification of the gene as seen I
carcinoma of lung, breast and colon.
activation, level fall immediately after the cell enters the cell cycle.
Persistent overexpression of MYC oncogene leads to autunomous cell_prolife Page \53
{f Cell-cycle regulatory. proteins
«Normal cell cycle Is under control of cyclins and COKA,.8, £ and D.
-Checkpoint is G1_S phase. Mutations in cyclins (particularly
cyclin D) and CDKs (in particular CDKA) may aid in induction of cancer
-eg, ‘overexpression of cyclin 0’ is iqnplicated_in carcinoma of breast, liver and mantle,
celllymphoma, and ‘amplification of CDK4’ in multiple eloma, glioblastoma:
Senphony ‘amplification of COK4’ in multiple myeloma, glioblastoma
/-TUMOR SUPPRESSOR GENE(2022)
“Tumor suppressor genes prevent entry of cells in mitotic pool_and_push
lls into the GO_phase.tt includes
{a)Retinoblastoma gene
7 -First discovered tumor suppressor gene
Functions
-RB gene is the governor of cell cycle
Active RB gene regulates G1/S checkpoint of cell cycle
-RB blocks E2F mediated transcription
Knudson's two hit hypothesis
Two mutation in both alleles of tumor suppressor gene are required to
produce the tumor
-In familial cases one mutation occurs in germ line and gther after birth
ar ne mutation occursin germline and gther after birt
- In sporadic oth occurs after birth
activation
-Mutation of RB gene—>Retinoblastoma & Osteosarcoma
a ———————e ee
-Blocking of RB function —>Cervical carcinoma
SRN NR
Situated on the short arm of chromosome 17, it is also called ‘Guardian of the
TT
Se
1ome’ as P53 mutation is present in more than half of ail human cancers,
-It agrests the cell cycle at G1 when DNA damage occurs.
+ -prevention of neoplasticism transformation,
+ -Role in promoting apoptosis
a poe Methods of inactivation
(a)Homozygous loss of p53-
of p53 behaves like an gncogene
Mutated forn
colon and breast.
sarcomas) are caused by damage to both alleles of p53
8. PARANEOPLASTIC SYNOROMES*
Salient features
Paraneoplastic syndromes are seen in. 10-15% patients with cancer and are importa
to recognize because:
* They may be the earliest manifestation of occult or hidden cancer in some cases
+ They may manifest with signs and symptoms due to excessive production of
* They may mimic metastatic disease. =
Paraneoplastic syndromes can he classified into:
+ Endocrinopathies
* Nerve and muscle syndrome
* Dermatological disorders
* Vascular and hematological changes
+ Bone and soft-tissue changes
| Clinical presentation Mechanism Example
| 1.Endocrinopathies
| Hypercalcemia PTH ‘Squamous cell cai
| coflung
| Hypoglycemia Insulin fibrosarcoma 3
| 2.Nerve Muscle syndrome ‘i
| Myasthenia Immunological Bronchogenic carci
| 3.Dermatological disorder 7 3 ermatomyosit immunological Steast carcinomas
4.Vascular & hematological
genous thromboembolism | Tumor product like mucins which Pancreatic carcinoma
activates clotting.
|S. Bone and soft-
tissue changes
——
Hypertrophic Unknown Bronchogenic carcinoma
esrop iu Sronchiogacie carcinetes
| Osteoarthropathy
——
9, PRECANCEROUS LESIONS*
es
"