DR Priyanka Sachdev General Pathology

C e l l A d a p t a ti o n s
Stress
(Physiological or Pathological)
Cellular adaptation
Cell injury
Reversible Cell injury

“Point of no return “ ------------------
Irreversible Cell injury

• Adaptation, reversible injury and irrversible injury & cell death are
stages of progressive impairment of the cell’s normal function and
structure.
CELL ADAPTATIONS
Adaptations 
 Are reversible
Structural responses to physiologic stress (e.g., pregnancy)
and pathologic stress
 During which new but altered steady states are achieved
 Allowing the cell to survive and continue to function
Stress
In order to survive and continue to function
Cells adjust their structure and functions
Cellular adaptation
(reversible on withdrawal of stimulus)
Dr. Priyanka Sachdev

5 TYPES OF ADAPTATIONS
1. Hypertrophy Increase in the size of cells
2. Hyperplasia  Increase in number of cells
3. Atrophy  Decrease in the size of cells / shrinkage of cells
4. Metaplasia Transformation of one adult cell type with another
5. Dysplasia  ‘Disordered cellular development’

HYPERPLASIA HYPERTROPHY ATROPHY METAPLASIA DYSPLASIA
Definition
Diagram
Types with
e.g.

HYPERPLASIA
• Increase in the number of cells , not size of cell, resulting in enlargement

of the organ or tissue.
• May or may not be seen together with hypertrophy

STRESS
Adaptation
Hyperplasia

HYPERPLASIA
Physiological Pathological

Physiologic hyperplasia
1. Hyperplasia of female breast at puberty, pregnancy and lactation

2. Enlarged size of the uterus in pregnancy is an example of
physiologic hypertrophy as well as hyperplasia.
Pregnant Ulcers
Normal Ulcers
3. Compensatory hyperplasia 
• Regeneration of the liver following partial hepatectomy.
• Following nephrectomy on one side, there is hyperplasia of
nephrons of the other kidney.
Pathologic hyperplasia
1. Endometrial hyperplasia following oestrogen excess

2. Benign prostatic hyperplasia due to DHT (dihydrotestosterone)
3. Formation of skin warts from hyperplasia of epidermis due to
human papilloma virus (HPV)
Definition
Diagram
Types with
e.g.

HYPERTROPHY
• Increase in the size of cells, not number of cells, leading to an increase
in the size of the organ
STRESS
Adaptation
Hypertrophy

HYPERTROPHY

Physiologic hypertrophy
1. Enlarged size of the uterus in pregnancy is an example of physiologic
hypertrophy as well as hyperplasia.
Pregnant Ulcers
Normal Ulcers
2. Hypertrophy of skeletal muscle e.g. hypertrophied muscles in
athletes and manual labourers.
Pathologic hypertrophy
1. Hypertrophy of cardiac muscle occurs in Systemic hypertension,
Aortic valve disease
2. Hypertrophy of smooth muscle e.g. Cardiac achalasia (in
oesophagus), Pyloric stenosis (in stomach).
Definition
Diagram
Types with
e.g.

ATROPHY
• Decrease in cell size and number of cells (with or without
accompanying shrinkage of the organ or tissue)
• Atrophied cells are smaller than normal but they are still viable –
they do not necessarily undergo apoptosis or necrosis
STRESS
Adaptation
Atrophy

ATROPHY

Physiologic atrophy
1. Atrophy of thymus in adult life.

2. Atrophy of ovary after menopause.
3. Atrophy of brain with ageing.
4. Decrease in the size of the uterus that occurs shortly after
parturition
Young age- Normal Old age- Atrophy
Uterus
Hypertrophy Atrophy
Hyperplasia
Normal Pregnancy Parturition

Pathologic atrophy
1. Starvation atrophy  general weakness, emaciation and anaemia
known as cachexia seen in cancer and severely ill patients.
2. Ischaemic atrophy  atrophic kidney in atherosclerosis of

renal artery, Atrophy of the brain in cerebral atherosclerosis.
3. Neuropathic atrophy  e.g. Poliomyelitis,Motor neuron

disease
4. Disuse atrophy  e.g. Wasting of muscles of limb

immobilised in cast, Atrophy of the pancreas in obstruction of
pancreatic duct.
Starvation atrophy Ischaemic atrophy
Neuropathic atrophy
Disuse atrophy
5. Endocrine atrophy  eg. Hypopituitarism may lead to atrophy of
thyroid, adrenal and gonads
6.Pressure atrophy  eg. Erosion of the skull by meningioma ,

Erosion of the sternum by aneurysm of arch of aorta.
7. Idiopathic atrophy  where no obvious cause is present

Endocrine atrophy Pressure atrophy

Definition
Diagram
Types with
e.g.

METAPLASIA
• A reversible change in which one mature/adult cell type is

replaced by another mature/adult cell type
• If injury or stress abates, the metaplastic tissue may revert to its

original type
STRESS
Adaptation
Squamous Columnar
STRESS
Adaptation
Columnar
SquamDor.uPsriyanka
METAPLASIA
SQUAMOUS COLUMNAR
(Col Sq) (Sq
Col)

Squamous metaplasia
Normal columnar epithelium  squamous epithelium

EXAMPLES
1. In bronchus (normally lined by pseudostratified columnar ciliated
epithelium) in chronic smokers.
2. In gallbladder (normally lined by simple columnar epithelium) in

cholelithiasis.
3. In prostate (normally lined by simple columnar epithelium) in

chronic prostatitis
4. In uterine endocervix (normally lined by simple columnar

epithelium) in prolapse of the uterus
Smoke
Calcalus
Uterus
Prolapse
Inflammation

Columnar metaplasia
• Normal squamous epithelium  columnar epithelium

EXAMPLES
1. Barrett’s oesophagus  change of normal squamous

epithelium to columnar epithelium due to GERD
2. Cervical erosion  Ectocervix - change of normal squamous

epithelium to columnar epithelium due to increased exposure of the
cervical epithelium to estrogen
GERD
Hcl Hcl
Normal Barrett’s Oesophagus

Cervical erosion (due to
estrogen exposure

Cervix
Ulterus
Prolapse
Cervical
erosion
(due to
estrogen
exposure
Definition
Diagram
Types with
e.g.

DYSPLASIA
• Disordered cellular development
• Characterised by cellular cytologic changes
• On removal of stimulus, the changes may disappear.

Cytological changes
1. Increased number of layers

2. Disorderly arrangement of cells from basal layer to surface layer
3. Loss of basal polarity i.e. nuclei lying away from
basement membrane
4. Cellular and nuclear pleomorphism
5. Increased nucleocytoplasmic (N/C) ratio
6. Nuclear hyperchromatism
7. Increased mitotic activity
‒ No. of layers normal ‒ No. of layers
‒ Ordered arrangement ‒ Disordered arrangement
‒ Basal Polarity + ‒ Basal Polarity –
‒ Pleomorphism – ‒ Pleomorphism +
𝐍
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𝐍𝐨𝐫𝐦𝐚
‒ ‒ �
𝐥Mitosis normal
‒ Hyper chromatism – ‒ H
�yper chromatism +
‒ ‒ Mitosis Dr. Priyanka Sachdev
• Full thickness dysplasia is known as carcinoma in situ (Precurssor of
cancer)
Definition
Diagram
Types with
e.g.

QUICK REVISION

Transformation
Number Disordered
Definition Number Size
Size
one cell ->
development
Another
Diagram
- No. of layers
In cell Reprogramming of - Disordered
Mechanism In GR and GF In cell organelles
organelles Stem Cells arrangement
- Basal Polarity –
- Pleomorphism +
𝐍
-
Types with Physio Physio Physio Epi Sq �
-�Hyper
chromatism +
e.g. Patho Patho Patho Mesen Col - Mitosis
POLLS
B
D
C
B
C
A
Re v e rs i b l e Vs Irreversible C e l l
Injur y
Dr. Priyanka Sachdev , MD

Stress
Cellular adaptation
Cell injury
Reversible Cell injury

“Point of no return “ ------------------
Irreversible Cell injury

Irreversible Injury –
Nuclear Changes
• Pyknosis
• Nuclear shrinkage and increased basophilia
• Karyorrhexis
• Fragmentation of the pyknotic nucleus
• Karyolysis
• Fading of basophilia of chromatin
Reversible injury Irreversible Injury
– Swell
– Intact – Do not swell
Cell – Distrups
membrane – Blebs
ER – Swell – Lysis
Ribosomes – Dispersion – Dispersion
– Swell – Swells
Mitochondria – Small densities – Large densities
Lysosomes – Autophagy – Rupture

– Pyknosis,
Nucleus – Clumping Karyolysis,
Karyorrhexis
POLLS
B
A
D
CELL DEATH
• Apoptosis  Suicide
• Necrosis  Murder
Apoptosis
CELL SUICIDE
Definition
• It is a pathway of cell death that is induced by a tightly regulated
intracellular program in which cells destined to die activate enzymes
(caspase) degrade the cells own nuclear DNA and cytoplasmic proteins.
• The cell is phagoctosed

• There is no leakage outside
• So there is no inflammation
Activates
CASPASE

Activates
CASPASE
Apoptotic bodies

Activates
CASPASE
Apoptotic bodies
Phagocyte
Mechanism
Extrinsic pathway Intrinsic pathway
Initiation Execution Initiation Execution

Extrinsic pathway 
Initiation phase
• It is initiated through specific receptors called death receptors
1. Fas protein (CD95)

2. TNF receptors
Death receptors
(FAS | CD 95 receptor)

Death receptors
(FAS | CD 95 receptor)

FAS (CD- 95)

Fas receptor (Death receptor)
Fas protein (CD95) binds with it
Multiple Fas receptors come together
Cytoplasmic death domain FADD
formed
Activate pro- caspsase 8 and 10 to active

caspase 8 and 10 Dr. Priyanka Sachdev
Mechanism

Intrinsic pathway 
Initiation phase
Stimuli DNA damage (beyod repair)

Cyt. c
DNA

Cyt. c
DNA

Cyt. c
DNA
Damage
Cyt. c
DNA
Damage
Cyt. 6
DNA
Damage
Cyt. 6
DNA Active
Damage Caspase 9
Stimuli (DNA damage)
Anti apoptotic molecules Bcl-2 , Bcl-x ,Mcl -1 are lost
Replaced by pro-apoptotic molecules like Bak, Bax, Bim, Bad
Increased mitochondrial permeability (MPT)
Release to cytochrome C into cytoplasm
Activates Apaf-1 along with procaspase-9
Activated caspase-9
Mechanism

Execution phase
• It is a convergence point for both extrinsic and intrinsic pathways.

Caspase 8 ,10 Caspase 9
Activates caspase 3 ,6, 7
Sequentially activates all other caspase
Caspases cleave cytoskeletal and nuclear matrix proteins
Cell degenerate/ apoptotic bodies formed

Activates
CASPASE

Activates
CASPASE
Apoptotic bodies

Activates
CASPASE
Apoptotic bodies
Phagocyte
Morophological changes in apoptosis
1. Cell shrinkage 3. Pyknosis
6. Phagocytosis 2. Eosinophilia
5. Apoptotic bodies 4. Blebs Karyorrhexis

1. Cellular shrinkage is earliest change
• It is due to damage to cytoskeletal proteins.

Cell Shrinkage
Eosinophilia


3. Nuclear changes
• Pyknosis ie.Chromatin condensation or nuclear compaction
• Karyorrhexis ie. nuclear fragmentation.It is due to activity
of endonuclease and caspases
• It is the most characteristic feature
4. Cytoplasmic membrane shows multiple surface blebs.
• Cell membrane intact thus preventing leaking out of
cellular contents.

5. Nuclear fragments and cytoplasmic organelles form membrane
bound apoptotic bodies
• These are membrane bound round masses of eosinophilic cytoplasm

with tightly packed orgaelles which may contain nuclear debries
6. These apoptotic bodies are recognised by phagocytes and

destroyed
• Characteristically, unlike necrosis, there is no acute inflammatory

reaction around apoptosis.

DIAGNOSIS OF APOPTOSIS
1. Apoptosis markers
• Annexin-V is a recombinant protein with high affinity for

phospholipid like phosphatidylserine.
• Phosphatidylserine is a phospholipid present on inner surface

membrane normally but it is flipped to outer surface during
apoptosis thus become a marker of apoptosis.
2. Agarose gel electrophoresis:
• Fragmented DNA shows Step Ladder Pattern,which is due to

internucleosomal cleavage of DNA by endonuclease
• During karryorrhexis endonuclease activation leaves short DNA

fragments regularly spaced in size.
• This ladderd patteren is characteristic but not specific for

apoptosis.
Apoptosis (Suicide) Necrosis (Murder)
• Single cells or small clusters of cells • Often contiguous cells
• Cell shrinkage • Cell swelling
• Pyknosis and karyorrhexis • Karyolysis, pyknosis,and karyorrhexis
• Intact cell membrane • Disrupted cell membrane
• Cytoplasm retained in apoptotic bodies • Cytoplasm leaked
• Inflammation absent • Inflammation present

POLLS
CD 95 is a marker of -
a) Intrinsic pathway of apoptosis

b) Extrinsic pathway of apoptosis
c) Monocyte
d) Leucocyte
CD 95 is a marker of -
a) Intrinsic pathway of apoptosis

b) Extrinsic pathway of apoptosis
c) Monocyte
d) Leucocyte
In apoptosis, cytochrome C acts through
a) Apaf 1
b) Bcl-2
c) FADD
d) TNF
In apoptosis, cytochrome C acts through
a) Apaf 1
b) Bcl-2
c) FADD
d) TNF
The following is an antiapoptotic gene -
• a) Bax
• b) Bad
• c) Bcl-X
• d) Bim
The following is an antiapoptotic gene -
• a) Bax
• b) Bad
• c) Bcl-X
• d) Bim
The earliest change seen in apoptosis is
• a) Cell shrinkage
• b) Pyknosis
• c) Formation of apoptotic bodies
• d) Fragmentation of cells
The earliest change seen in apoptosis is
• a) Cell shrinkage
• b) Pyknosis
• c) Formation of apoptotic bodies
• d) Fragmentation of cells
Characteristic feature of apoptosis
• a) Cell membrane intact

• b) Cytoplasmic Basophilia
• c) Nuclear moulding
• d) Cell swelling
Characteristic feature of apoptosis
• a) Cell membrane intact

• b) Cytoplasmic Basophilia
• c) Nuclear moulding
• d) Cell swelling
All of the following are features of
apoptosis EXCEPT
• a) Cellular swelling
• b) Nuclear compaction
• c) Intact cell membrane
• d) Cytoplasmic eosiophilia
All of the following are features of
apoptosis EXCEPT
• a) Cellular swelling
• b) Nuclear compaction
• c) Intact cell membrane
• d) Cytoplasmic eosiophilia
Annexin V is a marker of-
• a) Apoptosis
• b) Necrosis
• c) Artherosclerosis
• d) Inflammation
Annexin V is a marker of-
• a) Apoptosis
• b) Necrosis
• c) Artherosclerosis
• d) Inflammation
CELL DEATH
• Apoptosis  Suicide
• Necrosis  Murder
NECROSIS
• Necrosis is death of cells and tissues in the living animal
• Necrosis is defined as a localised area of death of tissue followed later

by degradation of tissue by hydrolytic enzymes liberated from dead
cells
• It is invariably accompanied by inflamatory reaction

REMEMBER
• Necrosis usually affects a group of contigous cells (in contrast to

apoptosis which involves a single cell).
• There are inflammatory changes in the surrounding tissue (in contrast to

apoptosis where there in no inflammatory changes).
COAGULATIVE LIQUIFACTIVE CASSEOUS FAT FIBRINOID
Introduction
Causes
Gross
Microscopy

Architectural detail (outline)
Cytoplasmic detail
Nuclear detail

Coagulative necrosis
• Most common type of necrosis
• Architectural outlines persist but cellular and nuclear details are

lost (Ghost cells / Tombstone)
• Type of tissue can be recognized

Alive Coagulation
Necrosis

Ghost Tombstone
Causes:
1. Ischemia due to thrombosis/ embolism in all organs except brain
(Amongst solid organs brain is the only exception, i.e., it is the only
solid organ in which ischemia leads to liquefactive necrosis and not
coagulative necrosis)
2. Mild burns (thermal injury)
3. Zenker's degeneration necrosis

Grossly
• Focus in the early stage is pale, firm, and slightly swollen
Microscopically
• The hallmark of coagulative necrosis is the conversion of normal cells
into their ‘tomb stones’ i.e. outlines of the cells are retained and the
cell type can still be recognised but their cytoplasmic and nuclear
details are lost
Inflammatory
Viable renal tissue cell infiltrate Necrotic tissue

Introduction
Causes
Gross
Microscopy

Liquefactive (Colliquative) necrosis
• Liquefaction or colliquative necrosis hydrolytic enzymes in

tissue degradation have a dominant role in causing semi-fluid
material
• Their architectural details as well as cytoplasmic and nuclear details

are lost
Alive Coagulation
Necrosis
Alive Liquefaction
Necrosis
Dr. Pr iyanka Sachdev

Causes:
1. Pyogenic bacterial infections attract neutrophils. Bacterial

and leukocytic enzymes liquefy dead cells and tissues.
2. Ischemic necrosis of brain

Gross appearance
• Affected area is soft with liquefied centre containing necrotic debris

with a cyst wall
Microscopic appearance:
1. No architectural or cellular details are visible in the area of

necrosis.
2. The necrotic area usually appears as a cavity containing a mass of

necrotic neutrophils, bacteria and tissue debris
3. The entire necrotic mass is surrounded by a cyst wall formed by

proliferating capillaries and inflammatory cells
Gliosis Granulation tissue Liquefactive necrosis

Introduction
Causes
Gross
Microscopy

Caseous necrosis (cheese like)
• Dead tissue is converted into a homogenous, granular mass

resembling cottage cheese.
• Their architectural details as well as cytoplasmic and nuclear

details are lost
• Accumulation of amorphous (no structure) debris within an area of

necrosis
Alive Coagulation Necrosis
Alive Liquefaction Necrosis
Alive Caseous Necrosis

Cause:
• Mycobacterium tuberculosis
• Syphilis
• Histoplasma
• Coccidioimycosis
Gross appearance
• Foci of caseous necrosis resemble dry cheese and are soft, granular and
yellowish.
• This appearance is partly attributed to the histotoxic effects of

lipopolysaccharides present in the capsule of the tubercle bacilli,
Mycobacterium tuberculosis
Microscopically
• Centre of the necrosed focus contain structureless, eosinophilic
material having scattered granular debris of disintegrated nuclei
• The surrounding tissue shows characteristic granulomatous

inflammatory reaction consisting of epithelioid cells (modified
macrophages having slipper-shaped vesicular nuclei), interspersed
giant cells of Langhans’ and foreign body type and peripheral mantle
of lymphocytes
Viable lymphoid tissue Caseous necrosis
Granulomatous inflammation

Introduction
Causes
Gross
Microscopy

Fat necrosis
• Fat necrosis is a special form of cell death occurring at mainly fat-rich

anatomic locations in the body.
• Death of adipose tissue in a living animal

Causes
• Pancreatic (acute pacreatitis)

• Breast (Traumatic)
• Mesentry (Inflammmation)
Grossly
• Fat necrosis appears as yellowish-white and firm deposits.
• Formation of calcium soaps imparts the necrosed foci firmer and

chalky white appearance
Microscopically
1. The necrosed fat cells have cloudy appearance
2. They are surrounded by an inflammatory reaction.
3. Formation of calcium soaps is identified in the tissue sections as

amorphous, granular and basophilic material
Cloudy appearance Mixed inflammatory cells
H&E, X200
Introduction
Causes
Gross
Microscopy

Fibrinoid Necrosis
• Fibrinoid necrosis is characterized by deposition of fibrin-like

material which has the staining properties of fibrin
• The fibrin like material is deposited in wall of blood vessels

Causes
• Immunologic injury of vessel wall (e.g. in immune complex

vasculitis, autoimmune diseases, Arthus reaction etc), arterioles in
hypertension, peptic ulcer etc.
Microscopically
• Fibrinoid necrosis is identified by brightly eosinophilic, hyaline-

like deposition in the vessel wall.
• Necrotic focus is surrounded by nuclear debris of neutrophils

(leucocytoclasis)
• Local haemorrhage may occur due to rupture of the blood

vessel.
- Arch + - Arch - - Arch -

- Cyto - - Cyto - - Cyto - Blood
Introduction Fat rich locations vessels
- Nucleus - gel debries
- Nucleus - - Nucleus -
- Ischemia of - TB - Breast trauma

all organs - Ischemia Brain - Syphilis - Pancreatitis
Causes (Except - Pyogenic - Histoplasma - Mesentry - Vasculitis
Brain) infection - Coccidiomycosis inflammation
- Liq. Centre - Yellowish

Gross - Pale with Cyst Wall - Dry cheese like white -
Structureless
Tomb- stone Cavity Cont. material with Cloudy Fibrinoid
Microscopy appearance debries granulomatous appearance (ribbon) like
inflammation
POLLS
Necrosis with cell bodies retained as ghost cells is
• a) Coagulative
necrosis
• b) Liquefactive
• c) Caseous
• d) None
Necrosis with cell bodies retained as ghost cells is
• a) Coagulative
necrosis
• b) Liquefactive
• c) Caseous
• d) None
All the following organs likely
undergo coagulative necrosis except
• a)
Spleen
• b)
Heart
• c)
Kidney
• d)
Brain
All the following organs likely
undergo coagulative necrosis except
• a)
Spleen
• b)
Heart
• c)
Kidney
• d)
Brain
Liquefactive necrosis is seen in -
• a)
Heart
• b)
Brain
• c)
Lungs
• d)
Spleen
Liquefactive necrosis is seen in -
• a)
Heart
• b)
Brain
• c)
Lungs
• d)
Spleen
GANGRENE
• Gangrene is necrosis of tissue associated with superadded
putrefaction
GANGRENE = Necrosis + Putrefaction

TYPES
2 main types of gangrene—
1. Dry
2. Wet
3. A variant of wet gangrene called gas gangrene.
1. “Dry” gangrene – less bacterial superinfection; tissue appears dry
2.“Wet” gangrene – abundant bacterial superinfection; tissue

looks wet and liquefactive
FEATURE DRY GANGRENE WET GANGRENE
1. Site Commonly limbs Commonly in bowel
2. Mechanisms Arterial occlusion Blockage of both venous

drainage and arterial obstruction
3. Macroscopy Organ dry, shrunken and black Part moist , soft, swollen, rotten
and dark
4. Putrefaction Limited due to very little blood Marked due to stuffing of organ
supply with blood
5. Line of Present Absent
demarcation
6. Bacteria Bacteria fail to survive Numerous present
7. Prognosis Better due to little septicaemia Poor due to profound toxaemia
Dry, shrivelled
toes
Thrombus Swollen, dark

REMEMBER
• Dry gangrene -> Variant of Coagulative necrosis
• Wet gangrene -> Liquifactive necrosis is superimposed on coagulative

necrosis
GAS GANGRENE
• Special form of wet gangrene caused by gas-forming clostridia

(gram-positive anaerobic bacteria)
• It entres through open contaminated wounds or complication

of operation on colon which normally contains clostridia.
Grossly
• Swollen, oedematous, painful and crepitant due to accumulation of gas
bubbles of carbon dioxide within the tissues formed by fermentation of
sugars by bacterial toxins
Pathologic calcification
Insoluble inorganic calcium salts are a normal constituent of bones and

teeth.
PATHOLOGICAL CALCIFICATION
• Deposition of calcium salts in tissues other than osteoid or enamel

is called pathologic or heterotopic calcification
• It is abnormal deposition of calcium salts, together with smaller

amounts of iron, magnesium and mineral salts in cells and tissues
that are not normally mineralized.
TYPES
2 forms:
1. Dystrophic
2. Metastatic
Calcium normal Hyper Calcemia
.. . . . . …………………..
.
Dead
And Normal
Degenerated tissue
tissue
Dystrophic Metastatic

DYSTROPHIC CALCIFICATION METASTATIC CALCIFICATION
Calcium deposits in dead and dying tissues Calcium deposits in normal tissues
Normal calcium metabolism Deranged calcium metabolism
Normal serum calcium levels Hypercalcemia
Irreversible Reversible upon correction of metabolic

disorder
Occurs due to increased binding of Increased precipitates of

phosphates with necrotic and degenerative calciumphosphate due to hypercalcemia at
tissue — binds to calcium forming calcium certain sites (lungs, stomach, blood
phosphate precipitates vessels, cornea)
Sites of calcification:
Dead tissues
• Caseation eg. Tuberculosis

• Dead parasites like trichinosis, Onchocercosis.
• Fat necrosis
• Infarcts
• Thrombi
• Haematoma
Degenerative tissues
• Atherosclerosis- monckeberg sclerosis
• Damaged heart valves Media (Classification) Intima (uninvolved Lumen Adventitia
• Infected lymph nodes

• Degenerating tumours
H&E, X200
Special stain for calcification
1. Von Kossa gives a black color
2. Alizarin red S that produces red staining

Inflammation
• It is a body defense reaction in order to eliminate or limit the spread of

injurious agent, followed by removal of the necrosed cells and repair of
damaged tissue
• White blood cells or leukocytes are the body’s major infection-fighting

cells.
Inflammation is distinct from infection
• Infection is invasion by harmful microbes (Bacteria, virus, fungi,

parasite) into the body and their resultant ill-effects by toxins.
• Inflammation is a protective response by the body to variety of

etiologic agents (infectious or non-infectious)
Classification
ACUTE CHRONIC
Rapid onset Late onset
Short duration Longer duration
Odema Granuloma formation
Neutrophils Macrophage, lymphocyte

ACUTE INFLAMMATION

CARDINAL SIGNS
Latin English
Rubor : redness
Calor : ↑ed local temperature Celsus
Tumor : swelling
Dolor : pain
Functio laesa: loss of function  Virchow
Acute inflammation
Vascular events Cellular reaction

VASCULAR EVENTS
1. Transient vasoconstriction of arterioles

2. Persistent progressive vasodilatation
3. Elevate the local hydrostatic pressure
4. Increased vascular permeability
5. Slowing or stasis
CELLULAR EVENTS
1. Margination and pavementing

2. Rolling
3. Adhesion
4. Transmigration (diapedes)
5. Chemotaxis
6. Phagocytosis
1.Transient vasoconstriction of arterioles
• Irrespective of the type of cell injury, immediate vascular response is of

transient vasoconstriction of arterioles
• Responsible for blanching seen immediately after injury.
• With mild injury 3-5 seconds

• severe injury 5 minutes
• Vasodilatation results in increased blood volume

redness(rubor)
and warmth (calor) at the site of acute inflammation.
Starling’s hypothesis
• Transudation of fluid into the extracellular space (Oedema
Transudate )
• Swelling at the local site of acute inflammation (tumor)

• Increased vascular permeability is the hallmark of acute
inflammation
• This leads to escape of protein rich fluid (Oedema  Exudate) and

leukocytes in extravascular space.
• Most affected vessels are venules
• It is responsible for swelling (tumor) seen in acute inflammation.

• Increased concentration of red cells  raised blood viscosity

POLLS
Sequence of events in acute
inflammation -
• a) Vasodilatation -> Stasis -> Transient vasoconstriction ->

Increased permeability
• b) Transient vasoconstriction -> Stasis -> Vasodilatation ->
• c) Transient vasoconstriction Vasodilatation -> Stasis ->
• d) Transient vasoconstriction -> Vasodilatation -> Increased
permeability -> Stasis
Sequence of events in acute
inflammation -
• a) Vasodilatation -> Stasis -> Transient vasoconstriction ->

• b) Transient vasoconstriction -> Stasis -> Vasodilatation ->
• c) Transient vasoconstriction Vasodilatation -> Stasis ->
• d) Transient vasoconstriction -> Vasodilatation -> Increased
permeability -> Stasis
First to appear in acute inflammation
a) Vasodilatation
b) Vasoconstriction
c) Increased vascular permeability
d) Decreased vascular permeability
First to appear in acute inflammation
a) Vasodilatation
b) Vasoconstriction
c) Increased vascular permeability
d) Decreased vascular permeability
A
Acute inflammation
Vascular events Cellular reaction

CELLULAR EVENTS

2. Rolling
3. Adhesion
5. Chemotaxis
6. Phagocytosis
Mechanism of rolling and adhesion
Complementary adhesion molecules (CAM)
• The attachment of leukocytes to endothelial cells is mediated by

complementary adhesion molecules (CAM) on the two cell types
Endothelial Molecule Leukocyte Molecule Major Role
1. P-selectin Sialyl-Lewis X Rolling
2. E-selectin Sialyl-Lewis X Rolling and adhesion
3. GlyCam-1 (CD34) L-selectin Rolling
4. ICAM-1 B2 integrins Adhesion
5. VCAM-1 B1 integrins Adhesion
(trasmigration)
6. PECAM-1 (CD-31) PECAM-1 (CD-31) Diapedesis

TRANSMIGRATION (diapedes)
• Escape out into the extravascular space; this is known as

transmigration
• Simultaneous to emigration of leucocytes, escape of red cells through

gaps between the endothelial cells,This is known as diapedesis
• It is a passive phenomenon
• PECAM
CHEMOTAXIS
• Unidirectional oriented along a chemical gradient
Potent chemotactic substance 

• i) Leukotriene B4 (LT-B4)
• ii) Components of complement system (C5a and C3a )
• iii) Cytokines (Interleukins, in particular IL-8)
• C5a is the most powerful chemoattractant (chemokine)

Phagocytosis
The process of engulfment of microbes by the WBC’s (cell-eating)
• Cells performing this function are called phagocytes

Phagocytsis
This sequence was appreciated by Metchnikoff (1880)
1.Recognition and Attachement

2.Engulfment
3.Killing and degradation

SUMMERY
VASCULAR EVENTS
1. Transient vasoconstriction of arterioles

1.Transient vasoconstriction of arterioles
SUMMERY
CELLULAR EVENTS

2. Rolling
3. Adhesion
5. Chemotaxis
6. Phagocytosis
POLLS
Correct sequence in
extravasation of leukocytes is -
• a) Margination - rolling- adhesion - transmigration

• b) Transmigration- margination - rolling- adhesion
• c) Rolling- adhesion- transmigration- margination
• d) Adhesion- transmigration- margination- rolling
Correct sequence in
extravasation of leukocytes is -
• a) Margination - rolling- adhesion - transmigration

• b) Transmigration- margination - rolling- adhesion
• c) Rolling- adhesion- transmigration- margination
• d) Adhesion- transmigration- margination- rolling
Most important for diapedesis ?
• a) PECAM
• b) Selectin
• c) Integrin
• d) Mucin like glycoprotein
Most important for diapedesis ?
• a) PECAM
• b) Selectin
• c) Integrin
• d) Mucin like glycoprotein
All of Which is family of selectin,
except -
• a) P selectin
• b) L selectin
• c) A selectin
• d) E selectin
All of Which is family of selectin,
except -
• a) P selectin
• b) L selectin
• c) A selectin
• d) E selectin
B
B
CHRONIC INFLAMMATION
• Chronic inflammation is a response of prolonged duration (weeks or

months) in which inflammation, tissue injury and attempts at repair
(fibrosis) coexist, in varying combinations.
GRANULOMATOUS INFLAMMATION
• Formation of granuloma is a type IV hypersensitivity reaction
• It is a protective defense reaction by the host but eventually causes

tissue destruction because of persistence of the poorly digestible
antigen
• e.g. Mycobacterium tuberculosis, M. leprae,suture material,

particles of talc etc
Pathogenesis
• 1. Engulfment by macrophages
• 2.Activation of CD4+ T cells
• 3. Release of Cytokines
1. Engulfment by macrophages
Macrophages engulf the antigen
Try to destroy it
But antigen is poorly degradable
These cells fail to digest and degrade the antigen

2.Activation of CD4+ T cells
Macrophages failed to deal with the antigen
Present antigen to CD4+ T lymphocytes
CD4+ T lymphocyte activated
Release lymphokines
IL-1, IL-2, interferon-Y, TNF-α

3. Release of Cytokines
• i) IL-1 and IL-2 stimulate proliferation of more T cells.
• ii) Interferon-γ activates macrophages and transform it into

epitheloid cells
• iii) TNF-α promotes fibroblast proliferation

GRANULOMA  DEFINITION
• A granuloma is a focus of chronic inflammation consisting of a

microscopic aggregation of macrophages that are transformed into
epithelium like cells (epithelioid cells)
• Frequently, these epitheloid cells fuse to form giant cells
• Surrounded by a Collor of mononuclear leukocytes, principally

lymphocytes and plasma cells.
Types of Giant cells
1. Foreign body giant cells

2. Langhans’ giant cells
3. Trouton giant cells
4. Giant cells in tumours
Foreign body giant cells
• These nuclei are scattered throughout the cytoplasm.
• Eg. chronic infective granulomas, leprosy and tuberculosis

Langhans’ giant cells
• Nuclei are arranged either around the periphery in the form of

horseshoe or ring, or are clustered at the two poles of the giant
cell.
• Eg. tuberculosis and sarcoidosis.

Foreign body type giant Langhans giant Cells
cells
Trouton giant cells
• These multinucleated cells have vacuolated cytoplasm due to lipid

content
• e.g. Xanthoma
Giant cells in tumours
Anaplastic cancer giant cells
• These giant cells are not derived from macrophages but are
formed from neoplastic cells
• e.g. carcinoma of the liver, various soft tissue sarcomas etc
Reed-Sternberg cells
• These are also malignant tumour giant cells which are generally
binucleate
• Eg. Hodgkin’s lymphomas
Osteoclastic giant cells of bone tumour

• Eg. Giant cell tumour of the bones or osteoclastoma
EXAMPLES OF GRANULOMATOUS INFLAMMATION
BACTERIAL
1) Tuberculosis Mycobacterium tuberculosis
2) Leprosy Mycobacterium leprae
3) Syphilis Treponema pallidum
4) Granuloma inguinale (Donovanosis) C. donovani
5) Brucellosis (Mediterranean fever) Brucella abortus
6) Cat scratch disease Coccobacillus
7) Tularaemia Francisella tularensis
8) Glanders Actinobacillus mallei
FUNGAL
1. Actinomycosis Actinomycetes israelii
2. Blastomycosis Blastomyces demtitidis
3. Cryptococcosis Cryptococcus neoformans
4. Coccidioidomycosis Coccidioidesimmitis
PARASITIC
1. Schistosomiasis(Bilharziasis) Schistosoma mansoni,

haematobiumjaponicum
MISCELLANEOUS
1.Sarcoidosis Unknown
2.Crohn's disease Unknown
3. Silicosis Silica dust
4.Berylliosis Metallic beryllium
5.foreign body granulomas Talc, suture, oils, wood splinter

etc
Hemodynamics
Oedema
• Oedema is defined as abnormal and excessive accumulation of fluid in

the interstitial tissue space
Effusion
• Effusions is defined as abnormal and excessive accumulation of fluid in
body cavities
Normal fluid exchange
• Hydrostatic pressure in the capillaries, i.e., capillary blood pressure
creats an outward driving force i.e. push water and salts out of
capillaries into the interstitial space
• Osmotic pressure in the capillaries creates an inward driving force, ie.

pull water and salts into vessels

• At the arterial end of capillary - hydrostatic pressure is 38 mmHg
• At the venous end end of capillary - hydrostatic pressure 12 mmHg

is
• Capillary osmotic pressure throughout is 25 mmHg
At arterial end
• Hydrostatic pressure (outward force) > osmotic pressure (inward force)
• Net Outward driving force = 38 - 25 13 mmHg
• =Fluid comes out from capillary into the interstial space.
At venous end 
• Osmotic pressure (inward pressure) > hydrostatic pressure (outward
pressure)
• Net Inward-driving force = 25 -12 13 mmHg
• =Fluid comes back in the capillary from interstitial space.
Under normal circumstances
Cappilary hydrostatic pressure is balanced by colloid osmotic pressure
Small net movement of fluid into the interstitium
Drains into lymphatic vessels
So the tissues is “dry” (no oedema)

Pathogenesis of edema
• 1. Increased capillary hydrostatic pressure

• 2. Decreased plasma oncotic pressure
• 3. Lymphatic obstruction
• 4. Sodium and water retention
• 5. Increased capillary permeability (Inflammation)
1. Increased capillary Hydrostatic pressure
• i) Oedema of cardiac disease e.g. in congestive cardiac failure,

constrictive pericarditis.
• ii) Postural oedema e.g. transient oedema of feet and ankles due to
increased venous pressure seen in individuals Whose job involves
standing for long hours such as traffic constables
2. Decresed plasma oncotic pressure
• The plasma oncotic pressure is exerted by the total amount of plasma

proteins.
• Albumin has four times higher plasma oncotic pressure than

globulin
• Thus it is hypoalbuminaemia that results in oedema.
Edema takes place when
• Total plasma protein is below 5 gm/dl (normal 6-8 gm/dl)
• Albumin is below 2.5 gm/dl (normal 3.5- 5gm/dl)

Examples 
1. Inadequate synthesis of albumin  severe liver diseases

(end- stage cirrhosis)
2. Protein malnutrition
3. Increased loss of albumin  Nephrotic syndrome in

which albumin leaks into the urine through abnormally
permeable glomerular capillaries.
3. LYMPHATIC OBSTRUCTION
• Normally, the interstitial fluid in the tissue spaces escapes by way of

lymphatics.
• Obstruction to outflow of these channels oedema, known as

lymphoedema
Examples 
1. Removal of axillary lymph nodes in radical mastectomy for carcinoma

of the breast causing lymphoedema of the affected arm.
2. Inflammation of the lymphatics as seen in filariasis (elephantiasis)

results in lymphoedema of scrotum and legs known as elephantiasis
3. Milroy’s disease or hereditary lymphoedema is due to

abnormal development of lymphatic channels
4. SODIUM AND WATER RETENTION
• i) Oedema of cardiac disease e.g. in congestive cardiac failure.
• ii) Oedema of renal disease e.g. in nephrotic and nephritic syndrome.

5. Increased capillary permeability
Capillary endothelium is injured
Gaps between the endothelial cells
Leakage of plasma proteins into interstitial fluid
Reduced plasma oncotic pressure and elevated

oncotic pressure of interstitial fluid
Oedema
Examples
• i) Generalised oedema occurring in systemic infections, poisonings,

certain drugs and chemicals, anaphylactic reactions and anoxia.
• ii) Localised oedema due to allergic reactions, insect-bite, irritant drugs

and chemicals.
Causes and examples of oedema
Lymphatic
⬆️Hydrostatic ⬇️Plasma obstruction Sodium retention Inflammation
pressure osmotic pressure (Lymphedema)
• Acute and
• Cardiac failure • Liver cirrhosis • After breast • Cardiac failure chronic
surgery inflammation
• Postural • Malnutrition • Filariasis • Renal failure

oedema
• Renal failure • Milroy disease

(Nephrotic syn)
Dr. P riyanka Sachdev

FEATURE TRANSUDATE EXUDATE
Definition Protein-poor , cell-poor fluid Protein-rich , cell-rich fluid
Character Non-inflammatory oedema Inflammatory oedema
Protein content Low (less than 1 gm/dl) High ( 2.5-3.5 gm/dl)

Glucose content Same as in plasma Low (less than 60 mg/di)
Specific gravity Low (less than 1.015) High (more than 1.018)
pH > 7.3 < 7.3
LDH Low High
Cells Few cells Many cells
Oedema in congestive
Examples cardiac failure Purulent exudate such as pus
Hyperaemia and Congestion
CVC Lung , CVC Liver , CVC Spleen

HYPERAEMIA AND CONGESTION
Localised increase in the volume of blood within dilated vessels of an

organ or tissue.
HYPERAMIA
• Increased volume of blood from arterial dilatation (i.e. increased inflow)

is called hyperaemia (active process)
• Affected tissues turn red (erythema) because of increased delivery of

oxygenated blood.
Examples
• i) Inflammation e.g. congested vessels in the walls of alveoli in
pneumonia
• ii) Blushing i.e. flushing of the skin of face in response to
emotions
• iii) Muscular exercise
• iv) High grade fever
CONGESTION
• Increased volume of blood from impaired venous drainage (i.e.
diminished outflow) is called congestion (passive process )
• Affected tissues turn blue (cyanosis) because of increased delivery

of deoxygenated blood.
HYPEREMIA CONGESTION
1. Active process Passive process
2. Vasodilatation of artery Impaired venous blood flow
3. During exercise & in inflammation Venous obstruction & cardiac failure
4. Oxygenated blood (Red,Erythema) Deoxygenated blood (Blue,Cyanosis)

Congestion
2 types
1. Acute
2. Chronic (chronic venous congestion (CVC)
Congestion
• In left-sided heart failure  pulmonary congestion (CVC

lungs)
• In right-sided heart failure  systemic venous congestion ( CVC of

systemic organs Liver, spleen )
V

CVC Lung CVC Liver CVC Spleen
Gross
Microscopy

CVC Lung
Grossly
• The lungs are heavy and firm in consistency

• Cut surface is dark and rusty brown in colour brown induration
of the lungs.
Microscopically
• The alveolar capillaries are congested.
• Initially, the excess fluid collects in the interstitial lung spaces in the
septal walls (interstitial oedema).
• Later, the fluid fills the alveolar spaces (alveolar oedema).
• There are hemosiderin-containing macrophages in lung alveoli. These

macrophages are called heart failure Cells
Remember
• Heart failure cells are present in the lungs and NOT in the heart.
• These are hemosiderin laden macrophages.

CVC Liver
Grossly
• The liver is enlarged and tender

• Capsule is tense.
• Cut surface shows characteristic nutmeg appearance due to red
and yellow mottled appearance, corresponding to congested centre
of lobules and fatty peripheral zone respectively
Microscopically
• The central veins is distended and filled with blood.
• The centrilobular hepatocytes undergo degenerative changes and

Centrilobular haemorrhagic necrosis occurs.
• The peripheral zone of the lobule is less severely affected by chronic

hypoxia and shows fatty change in the hepatocytes
• So nutmeg appearance
CVC Spleen
Grossly
• Enlarged
• Congested, tense and cyanotic
• Sectioned surface is gray tan
Microscopically
• Red pulp is enlarged due to marked sinusoidal dilatation
• Sinusoids may get converted into capillaries (capillarisation of

sinusoids).
• Some of haemorrhages overlying fibrous tissue get deposits of

haemosiderin pigment  Gamna-Gandy bodies
REMEMBER
• CVC of lung is characterized by presence of heart failure cells

(hemosiderin laden macrophages)
• CVC of liver produces nut-meg liver
• CVC of spleen is characterized by presence of Gamna-Gandy bodies

CVC Lung CVC Liver CVC Spleen
Gross
Microscopy

POLLS
Gandy gamma body is typically seen in chronic
venous congestion of which of the following?
• (a) Lung
• (b)
Kidney
• (c)
Spleen
• (d) Liver
C
Heart failure cells is typically seen in
chronic venous congestion of which of the
following?
• (a) Lung
• (b)
Kidney
• (c)
Spleen
• (d) Liver
A
Nutmeg appearance is typically seen in chronic
venous congestion of which of the following?
• (a) Lung
• (b)
Kidney
• (c)
Spleen
• (d) Liver
D
B
THROMBOSIS
• Thrombosis is the formation of a blood clot (solid mass) in the

unruptured CVS from the constituents of flowing blood , obstructing
the flow of blood through the circulatory system
• It is defined as the pathologic formation of intravascular fibrin-

platelet thrombus
• The mass itself is called a thrombus

• Haemostasis occurs after injury to CVS and is useful as it stop
escape of blood and plasma,
• Thrombosis occurs in the unruptured CVS (without injury)

and has
harmful effects of ischemia
Pathophysiology
• Virchow described three primary events which predispose to thrombus
formation (Virchow’s triad):
1. Endothelial injury
2. Altered blood flow (Stasis or turbulance)
3. Hypercoagulability of blood
Types of Thrombi
3 Types depending on site of origin
1. Cardiac thrombi (vegetations)

2. Arterial thrombi
3. Venous thrombi
Grossly
• Arterial thrombus known as white thrombi as they contains more
platelets and relatively less fibrin
• Venous thrombi known as red thrombi as they contain more enmeshed

red cells and relatively few platelets.
Arterial thrombi
• White
• Mural
• Lines of zahn present alternate layers of light-staining aggregated
platelets admixed with fibrin meshwork and dark-staining layer of red
cells
• Thrombus with lines of Zahn is also called coralline thrombus

Venous thrombi
• Red
• Occlusive
• Lines of zahn absent
Feature Arterial thrombus Venous thrombus
Pathogenesis Endothelial injury or turbulence Stasis
Blood flow Active Sluggish

Sites Coronary, cerebral , femoral arteries Superficial and deep leg veins
Propagation Retrograde manner Antegrade manner
Lines of Zahn Present Absent
Pale platelet layer alternating with dark

Microscopic red cell layer so also called as white RBC mixed with relatively less platelets,
thrombi so also called as red thrombi
Occlusion Incomplete Complete
Complications lschemia and infarction Edema and ulceration

Fate of Thrombus
EMBOLISM
• An embolus is a detached intravascular solid, liquid, or gaseous mass
that is carried by the blood from its point of origin to a distant site,
where it often causes tissue dysfunction or infarction.
• The transported intravascular mass detached from its site of origin

is called an embolus
Classification
A.Depending upon the matter in the emboli

B.Depending upon whether infected or not
C.Depending upon the source of the emboli
D.Depending upon the flow of blood
Depending upon the matter in the emboli
• i) Solid e.g. detached thrombi (thromboemboli), atheromatous

material, tumour cell clumps,parasites, bacterial clumps, foreign
bodies.
• ii) Liquid e.g. fat globules, amniotic fluid
• iii) Gaseous e.g. air

Depending upon whether infected or not:
i) Bland, when sterile
ii) Septic, when infected

Depending upon the source of the emboli
• i) Cardiac emboli from left side of the heart

• ii) Arterial emboli
• iii) Venous emboli
• iv) Lymphatic emboli
Depending upon the flow of blood
i) Paradoxical embolus An embolus which is carried from the venous

side of circulation to the arterial side or vice versa is called paradoxical
or crossed embolus e.g. through patent foramen ovale
ii)Retrograde embolus An embolus which travels against the flow

of blood is called retrograde embolus.
Types
• These may arise in the
Arterial circulation Arterial (systemic) thromboembolism

Venous circulation  Pulmonary Thromboembolism
Effects of arterial emboli
• The effects of arterial emboli depend upon their size, site of lodgement,
and adequacy of collateral circulation
Infarction of the organ

 Gangrene in the lower limbs
Myocardial infarction may occur following coronary embolism.
 Sudden death may result from middle cerebral artery embolism
Effect of venous embolism
• Obstruction of pulmonary arterial circulation leading to
pulmonary embolism
Pulmonary Thromboembolism
• Pulmonary embolism is the most common and fatal form of venous

thromboembolism
• There is occlusion of pulmonary arterial tree by thromboemboli

PATHOGENESIS
Embolus in vein
Flows through venous drainage into the larger veins (SVC and IVC)
Right side of the heart (RA  RV)
Pulmonary artery
Pulmonary embolism
• If the thrombus is large, it is impacted at the bifurcation of the main
pulmonary artery (saddle embolus)
• Multiple small emboli Particularly affecting lower lobes of

lungs
SHOCK
Shock is the clinical syndrome that results from poor tissue perfusion
 In this condition tissues in the body do not receive enough

oxygen and nutrients to allow the cells to function.
This ultimately leads to cellular death
 May progress to organ failure
 Finally, to whole body failure
 Death.
Classification
1. Hypovolumic shock
2. Cardiogenic shock
3. Septic shock
4. Ohers
HYPOVOLUMIC SHOCK CARDIOGENIC SHOCK SEPTIC SHOCK
Causes
Pathogenesis
Symptoms

1. Hypovolaemic shock
• Most common form of shock

• Occurs due to decreased blood volume
Causes
i. Acute haemorrhage
ii. Dehydration from vomiting's, diarrhoea
iii. Burns
iv. Excessive use of diuretics
v. Acute pancreatitis
• Most often due to haemorrhage and, therefore, also called as

haemorrhagic shock
Types
Haemorrhagic shock is divided into 4 types:
• i) < 1000 ml: Compensated

• ii) 1000-1500 ml: Mild
• iii) 1500-2000 ml: Moderate
• iv) >2000 ml: Severe
Pathogenesis
• Occurs from inadequate circulating blood volume due to various
causes,
Symptoms
1. Increased heart rate (tachycardia)

2. Low blood pressure (hypotension)
3. Low urinary output (oliguria to anuria)
4. Alteration in mental state (agitated to confused to lethargic)
3 stages
i)Mild hypovolemia or stage I (< 20% volume loss): Only
mild tachycardia is there with normal BP.
ii)Moderate hypovolemia or stage II (20-40% volume loss):

Tachycardia with normal BP in supine position but hypotension in
erect posture.
iii)Severe hypovolemia or stage III (> 40% volume loss):

Classical signs of shock appear e.g. tachycardia, hypotension,
disorientation etc.
2. Cardiogenic shock
• caused by inadequate pumping action of heart
• Cardiogenic shock occurs when 40% or more of the left ventricle

is destroyed.
Causes
i. Deficient emptying e.g.
a) Myocardial infarction
b) Cardiomyopathies
c) Rupture of the heart, ventricle or papillary muscle
d) cardiac arrhythmias
ii. Deficient filling e.g.

a) Cardiac tamponade from haemopericardium
iii. Obstruction to the outflow e.g.

a) Pulmonary embolism
b) Ball valve thrombus
c) Tension pneumothorax
d) Dissecting aortic aneurysm
Pathogenesis
• There is acute circulatory failure
• sudden fall in cardiac output from acute diseases of the

heart without actual reduction of blood volume
(Normovolaemia)
Symptoms
• Decreased cardiac output has its effects in the form of decreased tissue
perfusion (tissue hypoxia)
• Movement of fluid from pulmonary vascular bed into pulmonary

interstitial space initially (interstitial pulmonary oedema) and later into
alveolar spaces (alveolar pulmonary oedema)
3. Septic (Toxaemic) shock
• Severe bacterial infections or septicaemia induce septic shock

Causes
i. Gram-negative septicaemia (endotoxic shock) e.g.

Infection with E.coli, Proteus, Klebsiella, Pseudomonas and
Bacteroides
ii. Gram-positive septicaemia (exotoxic shock) e.g.

Infection with streptococci, pneumococci

Pathogenesis
Triggering factor 
• Gram positive bacteria  Lipotheichoic acid and superantigens

(staphylococcal TSST, streptococcal pyrogenic exotoxin).
• Gram negative bacteria  Endotoxin (lipopolysaccaride)

Gram positive bacteria Gram positive bacteria
Lipopolysaccharide (LPS) Lipotheicoic acid
LPS binds to CD14 Lipotheicoic acid binds to ILR -2

Macrophages stimulated
Secrete proinflammatory cytokine ( TNF-α and IL-1)
Vasodilatation and increased vascular permeability
Inadequate perfusion of cells and tissues
Septic Shock
• Vasodilatation  hypotension  causes hyperdynamic
circulation in septic shock, in contrast to hypovolaemic and
cardiogenic shock
• Increased vascular permeability Inflammatory oedema

Septic shock has two different stages
1) Early hyperdynamic stage

• It is characterized by vasodilatation (decreased peripheral resistance),
Tachycardia, normal to increased cardiac output, and warm
extrimities.
2) Late hypodynamic stage

• It is characterized by vasoconstriction, decreased output, and oliguria
(renal failure).
HYPOVOLUMIC SHOCK CARDIOGENIC SHOCK SEPTIC SHOCK
Causes
Pathogenesis
Symptoms

Genetic inheritance of Single gene
disorders
• AD
• AR
• XD
• XR
AD Examples
Vo Familial Hypercholesterolemia Autosomal DOMINANT
Vo Hai Disease
Von Willebrand
Familial Familial Adenomatous Polyposis
Hypercholesterolemia Hypercholesterolemia (Familial)
Autosomal Adult polycystic kidney
D Dystrophia myotonica
O Osteogenesis imperfecta
M Marfan syndrome
I Intermittent porphyria
N Neurofibromatosis-1
A Achondroplasia
N Neurofibromatosis – 2
T Tuberous sclerosis
Hai Huntington’s disease; Hereditary spherocytosis
AR Examples
ABCDEFGH SPW
A - Albinism, Alpha 1 Antitrypsin Deficiency
B - Beta Thalassemia
C - Cystic Fibrosis, CGD, CAH
D - Deafness(SNHL), Dubin Johnson
E - Enzyme Deficiencies(Glycogen Storage And Lysosomal Storage)
F - Friedrich's Ataxia, Fanconi Anemia
G - Galactosemia
H - Hemochromatosis, Hurler syndrome
S - Sickle Cell Disease
P - Phenylketonuria
W - Wilson's disease
XD Examples
FAIR
F - Facial (oro) syndrome
A - Alports
I - Incontinenta pigmento
R - Resistant rickets
XR Examples
GRAHAM BELL
G - G6 PD deficency
R - Retinitis pigmentosa
A - Androgen insensitivity
H - Hemophilia A & B, Hydrcephalus
A - Adrenoleucodystrophy
M - Menkes disease
B - Beckers & duchennes musculardystrophy, Blindness (color
E blindness)
L - Emery- Dreifuss dystrophy
L - Lesch nyhan syndrome
- Lowe disease
Normal chromosome complement
a) 46, XX for female

b) 46, XY for male.
2n 2n
Normal Meiosis Anaphase lag or Non disjunction
n , n n+1 , n-1
Normal gametes Abnormal gemetes

When these fuse with normal gametes When these fuse with normal gametes
2n 2n 2n+1 2n-1
Normal diploid cells Trisomy Monosomy

• Cytogenetic disorders involving Autosomes
• Cytogenetic disorders involving Sex chromosomes
Cytogenetic disorders involving Autosomes
• Down Syndrome (Trisomy 21)

• Patau syndrome (Trisomy 13)
• Edwards syndrome (Trisomy 18)
Down Syndrome (Trisomy 21)
• Itis the most common of the chromosomal disorders and

a major cause of mental retardation.
Karyotype
Signs
• Flat facial profile

• Mental retardation
• Microgenia (abnormally small chin)
• Oblique palpebral fissures with epicanthic skin folds (mongoloid
slant)
• Muscle hypotonia (poor muscle tone)
• Flat nasal bridge
• Single palmar fold (Simian crease)
• Curvature of little finger towards other four fingers (Clinodactyly)
• Protruding tongue or macroglossia
• White spots on the iris known as Brushfield spots
• Excessive joint laxity including atlanto-axial instability
• Excessive space between large toe and second toe (Sandle toe)
• A single flexion furrow of the fifth finger
Growth failure
Broad flat face
Mental retardation
Slanting eyes Epicanthic
Flat back of head eyefold Short nose
Abnormal ears Short and broad hands
Many "loops" on finger tips
Palm crease Small and arched palate
Big, wrinkled Tongue
Special skin ridge patterns
Dental anomalies
Unilateral or bilateral
absence of one rib Congenital heart disease
Intestinal blockage
Umbilical hernia Enlarged colon
Diminished muscle tone
Big toes widely
spaced
Complications
• Congenital cardiac defects (Most common is ventricular septal

defect)
• Increased risk of leukemia particularly ALL (more
commonly) and specifically the megakaryoblastic form of
AML (M7-AML)
• Hypothyroidism
• Reduced fertility in females (Males are totally infertile)
• Increased risk of respiratory tract infections
• Virtually all patients with Down syndrome develops Alzheimer
disease after 4th decade.
Patau syndrome (Trisomy 13)
• 1/10,000 births.
• Cleft Lip, flexed fingers with Polydactyly
• Ocular hypotelorism
• Low-set malformed ears
• Cerebral malformation like holoprosencephaly
• Microphthalmia
• Cardiac malformations, scalp defects, hypoplastic or absent ribs.
Karyotype
Edwards syndrome (Trisomy 18)
• Incidence is 1/6,000 births.
• Low birth weight
• Closed fists with index finger overlapping the 3rd digit and the 5th
digit overlapping the 4th
• Narrow hips with limited abduction
• Short sternum
• Rocker-bottom feet
• Microcephaly and prominent occiput.
• Micrognathia
• Cardiac and renal malformations and mental retardation
• 95% of cases are lethal in the 1st year
Karyotype
Low set ears
hypertelorism
Upturned nose
Small jaw
Clenched fist
with digits 2 and 5
overlapping 3 and 4
Rocker bottom feet

Cytogenetic Disorders Involving
Sex Chromosomes
• Klinefelter Syndrome (47 ; XXY)

• Turner Syndrome (45; XO)
Lyon hypothesis (X chromosome
inactivation)
It states that:
1. Only one of the X chromosomes is genetically active
2. Other X of either maternal or paternal origin undergoes
heteropyknosis and is rendered inactive
3. Inactivation of either maternal or paternal X chromosome occurs
at random among all the cells of the blastocyst on or about day 5.5
of embryonic life
4. Inactivation of the same X chromosome persists in all the cells
derived from each precursor cell.
Barr body (X chromatin)
• Inactive X is seen in interphase nucleus as a darkly staining small

mass in contact with the nuclear membrane.
• Molecular basis of X inactivation involves a unique gene called XIST,
whose product is a Long non-coding RNA.
• Used to test genetic femaleness.
• Number of Barr bodies = (N-l) (where N number of X chromosomes)

Examples
Genotype Number of Barr bodies
In normal male (XY) (1 – 1 = O Barr body)
In normal female (XX) (2 - 1 = 1 Barr body)
In turner syndrome (XO) (1 – 1 = 0 Barr body)
In Klinefelter syndrome (XXY) (2 - 1= 1 Barr body)
Superfemale (XXX) (3 – 1 = 2 Barr bodies)

Klinefelter Syndrome
• Best defined as male hypogonadism that occurs when there are two
or more X chromosomes and one or more Y chromosomes.
• Most common causes of hypogonadism in male.
• Incidence is 1 in 660 live male births.
• Karyotype :
• a) 47,XXY is most common (90% of cases)
• b) Mosaics (e.g. 46, XY/47, XXY)
Cinical features
1) Male infertility (most common cause of male sterility)
2) Eunuchoid body habitus
3) Minimal or no mental retardation
4) Failure of male secondary sexual characteristics
5) Gynecomastia with 20-fold increased risk of breast cancer relative to normal
males; female distribution of hair
6) Atrophic testes
7) Elevated follicle-stimulating hormone (FSH) and estrogen.
8) Low testosterone levels.
9) Increased incidence of type 2 diabetes and the metabolic syndrome with insulin
resistance
10) Most common cardiac abnormality is mitral valve prolapse.
11) Increased incidence of osteoporosis and fractures due to sex hormone
imbalance.
Frontal baldness absent
Poor beard growth

Tendency to grow fewer chest hairs
Narrow shoulders
Breast development
Wide hips
Female-type/ pubic hair pattern Small testicular size
Long legs

Turner Syndrome (45; XO)
• Hypogonadism in phenotypic females resulting from monosomy of
X chromosome.
• Karyotype : (45, X)
Clinical features
1. Lymph edema of neck, hands, and feet (short fourth metacarpal)
2. Webbing of neck (due to lymphatic dilation during development)
3. Short stature (due to loss of both copies of the short stature homeobox gene
(SHOX) on the X chromosome)
4. Cubitus valgus (increased carrying angle)
5. Broad chest and widely spaced nipples.
(Note : Breast tissue will be having normal histology)
6. Primary amenorrhea (Turner syndrome is most important cause of primary
amenorrhea)
7. Failure of the development of normal secondary sex characteristics
8. Severely atrophic and fibrous ovaries (streak ovaries)
9. Congenital heart diseases: Bicuspid aortic valve (most common cardiac defect);
preductal coarctation of aorta
Characteristic facial features
Low hairline Fold of skin
Constriction of aorta
Shield-shaped thorax
Poor breast development
Widely spaced nipples
Elbow deformity
Shortened metacarpal IV
Small finger nails Rudimentary ovaries Gonadal
streak (underdeveloped
gonadal
structures)
Brown spots (nevi)
No menstruation
AMYLOIDOSIS
• Amyloidosis refers to a variety of condition in which amyloid proteins
are abnormally deposited extracellularly between the cells in various
organs / tissues.
• Amyloid is a protein that has an alteration in its secondary structure

which imparts it a particular insoluble form
Physical nature
Electron microscopy :
• Nonbranching fibrils with
diameter 7.5-10 nm and
indefinite length
X Ray crystallography / Infrared

spectroscopy:
Cross β pleated sheet
conformation
CHEMICAL NATURE OF AMYLOID
• i) AL (amyloid light chain) protein

• ii) AA (amyloid associated) protein
• iii) Other proteins
AL PROTEIN
• AL amyloid fibril protein is derived from immunoglobulin light chain
• AL fibril protein is derived from the lambda and kappa (k) light
chain .
• AL type of fibril protein is seen in plasma cell dyscrasias (multiple

myeloma)
• It is included in primary systemic amyloidosis

AA PROTEIN
• AA fibril protein is derived from larger precursor protein in the
serum called SAA (serum amyloid associated protein)
• SAA is an acute phase reactant protein synthesised in the liver, in

response to chronic inflammatory conditions
• AA fibril protein is found in secondary amyloidosis
• It is seen in association with several examples of chronic infectious and

a inflammatory diseases and Some tumors like Renal cell carcinoma
(hypernephroma), Hodgkins lymphoma.
Aβ₂m β₂ microglobulin Hemodialysis
AA SAA Familial mediterranean fever

Familial amyloidotic
ATTR Transthyretin polyneuropathies, Senile
cardiomyopathy
Aβ Aβ protein precursor (AβPP) Alzheimer's disease
APrP Prion protein Spongiform encephalopathy
AIAPP Calcitonin Medullary carcinoma of thyroid
A Cal Islet amyloid polypeptide Type II diabetes, Insulinomas
AANF Atrial natriuretic factor Isolated atrial amyloid

DIAGNOSIS OF AMYLOIDOS  Biopsy
• The most definitive investigation for amyloidosis is Biopsy.
• The best sites for biopsy are rectum and abdominal fat pad
(abdominal fat pad aspiration biopsy).
• Other sites of biopsy are salivary glands, gingiva , skin, tongue, bone
marrow and stomach.
STAINING CHARACTERISTICS OF
AMYLOID
STAIN APPEARANCE
1. H&E Pink, hyaline, homogeneous
2. Methyl violet / Crystal violet Metachromasia: rose-pink
Light microscopy: pink-

3. Congo red red Polarising light:
Apple green
birefringence
4. Thioflavin-T/Thioflavin-S Ultraviolet light: fluorescence
5.
Immunoreactivity: Positive
Immunohistochemistry(anti Dr. Priyanka Sachdev
CONGO RED
• Visible light  Pink red colour
• Polarised light  Apple-green birefringence (due to cross-B-pleated

sheet configuration)
• The stain can also be used to distinguish between AL and AA amyloid
(primary and secondary amyloid respectively).
• After prior treatment with permanganate on the section, Congo
red stain is repeated
 Primary amyloid (AL amyloid)  Congo red positivity (congophilia)

persists
Secondary amyloid (AA amyloid) turns negative for Congo red

ORGANS
KIDNEYS
• It is the most common form of systemic amyloidosis.
• It is the most serious form of organ involvement.
• The earliest pathological change seen in renal amyloidosis is thickning

of the glomerular basment membrane.
• Amyloid is primarily deposited in the glomeruli, but interstitial

peritubular tissue, arteries and arterioles are also affected.
• Results in abnormal increase in permeability of the glomerular

capillaries  proteinuria and nephrotic syndrome
Spleen
Two patterns of deposition is seen –
• i) Sago spleen  Amyloid deposition is limited to splenic follicles

(White pulp)  produces topioca like granules
• ii) Lardoceous spleen  Amyloid depositon spares the follicles and

involves the walls of the splenic sinuses (Red pulp)
Hypersensitivity
• Immune response is generally a protective process but it may

sometimes be injurious to the host.
• Hypersensitivity refers to a condition in which immune response

results in excessive reactions leading to tissue damage, disease
or even death in the sensitised host
• Hypersensitivity is defined as an exaggerated state of normal

immune response which results in adverse effects on the
body.
Coomb and Gel classification
1. Type I (Anaphylactic)
2. Type II (Cytotoxic)
3. Type III (Immune complex)
4. Type IV (Delayed or cell mediated)
TYPE I Examples
• Eczema
• Hay fever
• Asthma (atopy)
• Urticaria
• Anaphylactic shock
• Acute dermatitis
• Theobald smith phenomenon
• PK (Prusnitz Kunster) reaction
• Casoni's skin test
• Schultz Dale phenomenon Dr. Priyanka Sachdev
Type 1
All Allergies
Remember PCT (proximal convulated tubule)
P - PK rxn
C - Casoni test
T - Theoblad smith phenomena

Examples
My Myasthenia gravis
Blood Blood transfusion reactions
Group Goodpasture syndrome and Graves' disease
Is Insulin resistant diabetes, ITP
R Rheumatic fever
H Hyperacute graft rejection
Positive Pernicious anemia and Pemphigus vulgaris

Examples
S Serum sickness, Schick test and SLE
H Henoch-Schonlein Purpura
A Arthus reaction
R Reactive arthritis, Raji assay
P Polyarteritis nodosa (PAN) and Post Streptococcal

glomerulonephritis (PSGN)
Examples
John gave TU LIP and Pop Corn
to Hashi
John mote reaction
Tuberculin reaction
LePromin reaction
Pernicious anaemia
Contact dermatitis
Hashimoto thyroiditis

TYPE II
TYPE I TYPE Ill TYPE IV
(ANTIBOD
FEATURE (ANAPHYLAC (IMMUN (DELAYED, T
Y-
TI C) E- CELL-
MEDIATED
COMPLE MEDIATED)
,
X)
CYTOTOXI
C)
Reaction of
Rapidly Results from
humoral
developing deposition of Cell-mediated
antibodies
Definition immune antigen- slow and
that attack
response in a antibody prolonged
cell surface
previously complexes on response
antigens and
sensitised tissues
cause cell
person
lysis
Peak action
15-30 minutes 15-30 minutes Within 6 hours After 24 hours
time
Mediated lgG or lgM
lgE antibodies lgG, lgM antibodies Cell-mediated
by antibodies
Persistence of low Dr. Priyanka Sachdev
HLA-linked,
Genetic basis,
• 1) Autograft (autogenic graft): Graft from self
• 2) Isograft (syngraft): Graft from genetically identical person,

e.g. identical twin
• 3) Allograft (homograft or allogenic graft): Graft from

genetically unrelated member of same species
• 4) Xenograft (heterograft): Graft from different species

NEOPLASIA
• The term ‘neoplasia’ means new growth
• The new growth produced is called ‘neoplasm’ or ‘tumour`
• The branch of science dealing with the study of neoplasms is called

oncology
Neoplasm
An abnormal mass of tissue
 The growth of which exceeds and is uncoordinated

with that of the normal tissues
 Persists in the same excessive manner even after

cessation of the stimuli which evoked the change.
{

NOMENCLATURE
A)Benign tumors
B) Malignant tumors
Benign tumors
• Benign tumors are designed by attaching the suffix –
oma
e.g
1. Tumor of fibroblasts ( fibroma)
2. Tumor of cartilagenous cells (chondroma)
3. Tumor of osteoblasts (osteoma)
Exceptions
• Malignant neoplasms with suffix - Oma –
1. Melanomas
2. Seminoma
3. Hepatoma (hepatocellular Ca)
4. Mesothelioma
5. Lymphoma
TISSUE OF ORIGIN BENIGN MALIGNANT
Epithelial Tumours
1. Squamous epithelium Squamous cell papilloma Squamous cell carcinoma

2. Transitional epithelium Transitional cell papilloma Transitional cell carcinoma
3. Glandular epithelium Adenoma Adenocarcinoma
4. Hepatocytes liver cell adenoma Hepatoma (Hepatocellular
carcinoma)
5. Placenta (Chorionic Hydatidiform mole Choriocarcinoma
epithelium)
6. Neuroectoderm Naevus Melanoma

(Melanocarcinoma)

Mesenchymal Tumours
1. Adipose tissue Lipoma Liposarcoma

2. Adult fibrous tissue Fibroma Fibrosarcoma
3. Embryonic fibrous tissue Myxoma Myxosarcoma
4. Cartilage Chondroma Chondrosarcoma
5. Bone Osteoma Osteosarcoma
6. Synovium Benign synovioma Synovial sarcoma
7. Smooth muscle Leiomyoma Leiomyosarcoma
8. Skeletal muscle Rhabdomyoma Rhabdomyosarcoma
9. Blood vessels Haemangioma Angiosarcoma
10. Lymph vessels Lymphangioma Lymphangiosarcoma
11. Meninges Meningioma Invasive meningioma
12. Lymphoid tissue Pseudo lymphoma Malignant lymphomas
13. Nerve sheath Neurofibroma Neurogenic sarcoma

Malignant tumors
 Malignant tumors arising in Mesenchymal cell origin are

usually called “sarcoma”
- e.g. fibrosarcoma, liposarcoma, leiomyosarcoma, rhabdomyosarcoma
Malignant tumors of Epithelial cell origin are called

“carcinoma”
Carcinoma may be further classified ->
 with glandular growth pattern, i.e. adenocarcinoma
 producing recognizable squamous cells of epithelium, i.e.
squamous cell carcinoma
Malignant tumors
Mesenchymal cell origin Epithelial cell origin
Sarcoma carcinoma
Adenocarcinoma Squamous cell carcinoma

Epithelial Tumours
1. Squamous epithelium Squamous cell papilloma Squamous cell carcinoma

2. Transitional epithelium Transitional cell papilloma Transitional cell carcinoma
3. Glandular epithelium Adenoma Adenocarcinoma
4. Hepatocytes liver cell adenoma Hepatoma (Hepatocellular
carcinoma)
5. Placenta (Chorionic Hydatidiform mole Choriocarcinoma
epithelium)
6. Neuroectoderm Naevus Melanoma

(Melanocarcinoma)

Mesenchymal Tumours
1. Adipose tissue Lipoma Liposarcoma

2. Adult fibrous tissue Fibroma Fibrosarcoma
3. Embryonic fibrous tissue Myxoma Myxosarcoma
4. Cartilage Chondroma Chondrosarcoma
5. Bone Osteoma Osteosarcoma
6. Synovium Benign synovioma Synovial sarcoma
7. Smooth muscle Leiomyoma Leiomyosarcoma
8. Skeletal muscle Rhabdomyoma Rhabdomyosarcoma
9. Blood vessels Haemangioma Angiosarcoma
10. Lymph vessels Lymphangioma Lymphangiosarcoma
11. Meninges Meningioma Invasive meningioma
12. Lymphoid tissue Pseudo lymphoma Malignant lymphomas
13. Nerve sheath Neurofibroma Neurogenic sarcoma

SPECIAL CATEGORIES OF TUMOURS
Tetratoma
• Tumors are composed of cells representative of a single germ layer.
• Teratoma arise from totipotent cells
• Teratomas are germ cell tumors commonly composed of multiple cell

types derived from 3 germ layers  ectoderm, mesoderm and
endoderm
• A teratoma is a rare type of germ cell tumor that may contain immature
or fully formed tissue, including teeth, hair, bone and muscle.
• Teratomas are usually benign but may be malignant

Not actual tumors (neoplasms)
1. Hamartoma
2. Choristoma
• Normally arranged tissue at abnormal (ectopic) site:
Choristoma
• Abnormally arranged tissue at normal site:

Hamartoma

Hamartoma
• It is a focal developmental malformation
• It represents a mass of disorganized but mature

specialized cells indigenous / native to the particular
site
e.g.
a) Hamartoma of lung consists of mature cartilage, mature
smooth muscle and epithelium
b) Hamartoma of spleen consists of red and white pulp
Choristoma
• Ectopic islands of normal tissue.

• Thus, choristoma is heterotopia but is not a true tumour
Eg.
a) Osteocartilaginous choristoma of the tongue
b) Pancreatic tissue in mucosa of stomach
• Normally arranged tissue at abnormal (ectopic)
site: Choristoma
• Abnormally arranged tissue at normal site:

Hamartoma

Lesions with tumor like names but not actual tumors
Normally arranged tissue at a

Abnormally arranged tissue
different anatomical site
present at normal site
(heterotopic rest of cells)
Choristoma Hamartoma

FEATURE BENIGN MALIGNANT
I. CLINICAL AND GROSS FEATURES
1. Boundaries Encapsulated or well- Poorly-circumscribed and
circumscribed irregular
2. Surrounding tissue Compressed Invaded
3. Size Usually small Often larger
4. Secondary changes Occur less often Occur more
often
II.MICROSCOPIC FEATURES
1. Basal polarity Retained Lost

2. Pleomorphism Absent Present
3. N / C ratio Normal Increased
4. Anisonucleosis Absent Present
5. Hyperchromatism Absent Present
6. Mitosis May be present but are always Mitotic figures Increased and are
typical mitoses generally atypical and abnormal

7. Tumour giant cells May be present but without Present with nuclear atypia
nuclear atypia
8. Chromosomal Infrequent Invariably present
abnormalities
III. GROWTH RATE Slow Rapid
IV. LOCAL INVASION Compresses the surrounding Infiltrates and Invades the
tissues without Invading or adjacent tissues
lnfiltrating them
V. METASTASIS Absent Frequently present
VI. PROGNOSIS Local complications Death by local and metastatic

complications

METASTASIS (DISTANT SPREAD)
• Spread of tumour by invasion in such a way that discontinuous

secondary tumour mass/masses are formed at the site of
lodgement away from primary site
• It is the most reliable feature of a malignant tumor

Benign tumours do not metastasise
 All Malignant tumours can metastasise Except
1. Gliomas of CNS
2. Basal cell carcinoma of the skin
Routes of Metastasis
• Cancers may spread to distant sites by following pathway
1. Lymphatic spread
2. Haematogenous spread
3. Transcoelomic spread
• Carcinomas metastasise by lymphatic route
• Sarcomas metastasise by haematogenous route

1. LYMPHATIC SPREAD
• Common route for carcinoma

Pattern of lymph node involvement
• The pattern of lymph node involvement follows the natural routes of
lymphatic drainage producing regional nodal metastasis
• The first node in a regional lymphatics that receives lymph flow
from the primary tumor is called sentinel lymph node.
• Sentinel lymph node is useful in breast cancer, vulvar cancer and
melanoma.
• Term 'sentinel lymph node' was first used by Gould
2. HAEMATOGENOUS SPREAD
• Common route for sarcomas
• Veins are more commonly involved than arteries because veins have
thinner walls that can be penetrated readily (In contrast arteries
have thicker walls)
1. With venous invasion, the tumor cells in blood follow the
venous flow draining the site of neoplasm.
• So liver and lung are the most frequent organs involved

in hematogenous spread because
1. All portal area drainage flows to the liver

2. All caval blood flows to the lung

REMEMBER
• Most common site of metastasis is LIVER

• 2nd most common site of metastasis is LUNG
(i) Direct seeding into body cavities or surface
(ii) Spread via cerebrospinal fluid
(iii) Implantation
(i) Direct seeding into body cavities or surface
• It occurs when a malignant neoplasm penetrates into a natural open

field
• Tumour clusters of tumour cells break off to be carried in the coelomic

fluid and are implanted elsewhere in the body cavity
• Most common cavity involved is peritoneal cavity, but other

cavities may also be involved, e.g., pleural, pericardial, joint space,
subarachnoid.
Eg.
a) Carcinoma of the stomach seeding to both ovaries
(Krukenberg tumour)

• b) Pseudomyxoma peritonei is the gelatinous coating of the peritoneum
from mucin-secreting carcinoma of the ovary or apppendix.
ii) Spread via cerebrospinal fluid
Malignant tumour of the ependyma and leptomeninges may spread
by release of tumour fragments and tumour cells into the CSF and
produce metastases at other sites in the central nervous system.
iii) Implantation
• Spread of some cancers by implantation by surgeon’s scalpel,

needles, sutures, and direct prolonged contact of cancer of the
lower lip causing its implantation to the apposing upper lip.
Routes of Metastasis
• Cancers may spread to distant sites by following pathway
1. Lymphatic spread
2. Haematogenous spread
MECHANISM OF METASTASIS
8 steps
CARCINOGENS AND CARCINOGENESIS
• Carcinogenesis means mechanism of induction of tumours
• Agents which can induce tumours are called carcinogens

3 TYPES
A. Chemical carcinogens
B. Physical carcinogens
C. Biologic carcinogens
ULTRAVIOLET LIGHT IONISING RADIATION
Sunlight
• Source (UV-B is Carcinogenic) X-ray, a-ray, b-ray
Skin Cancers  -All leukaemia's (except

-BCC CLL)
• Cancers -SCC -Thyroid tumours
-Meanoma
Reactive free Radical
• Mechanis Pyrimidine dimers in DNA Formation
m Dr. Priyanka Sachdev
Chemical carcinogens Associated cancer or neoplasm
• Alkylating agents • AML , bladder cancer

• Androgens • Prostate cancer
• Aromatic amines (dyes) (aniline dyes) • Bladder cancer
• Arsenic • Cancer of the lung, skin
• Asbestos • Cancer of the lung, pleura, Peritoneum
• Mesothelioma
• Estrogens • Cancer of the endometrium liver breast
• Ethyl alcohol • Cancer of the liver, esophagus, head and neck
• Tobacco (including smokeless) • Cancer of the upper aerodigestive tract, bladder
• Vinyl chloride • Liver cancer (angiosarcoma)
• Chromium and nickel • Lung cancer
• Benzene • Leukemia, Hodgkin’s lymphoma
• Nitrates • Gartric cancer
• Aflatoxin • Liver cancer

BIOLOGIC CARCINOGENESIS
• Viral Carcinogenesis
• Bacterial Carcinogenesis
• Parasitic Carcinogenesis
Infectious agent Tumors
Virus HPV Cervical, vulvar & penile cancers (squamous cell
carcinoma)
EBV Nasopharyngeal carcinoma, Burkitt’s lymphoma,
Hodgkin’s lymphoma
HBV, HCV Hepatocellular carcinoma
HIV Kaposi sarcoma, NHL, squamous cell carcinoma
HTLV-1 Adult T- cell leukemia
HHV-8 Kaposi sarcoma, primary effusion lymphoma
Bacteria H. Pylori Gastric Cancer
Parasite Schistosomiasis Bladder cancer (squamous cell)
Clonorchis sinensis Liver cancer (HCC), bile duct carcinoma
(cholangiocarcinoma), Pancreatic cancer
Opisthorchis viverrine Bile duct carcinoma (cholangiocarcinoma)
Fasciola hepatica Bile duct carcinoma (cholangiocarcinoma)
Carcinogenic Viruses
RNA viruses DNA viruses

• Human T cell • Hepatitis B virus (HBV)
leukemia virus-1 (HTLV- • Human herpes virus 8 (HHV8)
1) • Human papilloma virus (HPV)
• Hepatitis C virus (HCV) • EpsteinBarr virus (EBV)

TUMOUR LYSIS SYNDROME
• Caused by extensive destruction of a large number of rapidly

proliferating tumour cells
• Characterised by 
1. Hyperuricaemia(due to increased turnover of nucleic

acids).Hyperuricemia can cause uric acid precipitation in the
kidney causing acute renal failure.
2. Hyperkalaemia (due to release of the most abundant intracellular

cation potassium)
3. Hyperphosphataemia (due to release of intracellular phosphate)
4. Hypocalcaemia (due to complexing of calcium with the elevated

phosphate)
TUMOR CELL LYSIS
Hyper
Efflux of K+
Release of nucleic acid phosphatemia
Purine catabolism
Hyperuricemia
Hyperkalemia Calciumphosphate
Precipitation of imbalance
uric acid crystals
Arrythmias
EKG abnormal Acute renal failure
Fluid depletion
Fever, vomiting, diarrhea
poor intake
PARANEOPLASTIC SYNDROME
• A group of conditions developing in patients with advanced cancer
which are neither explained by direct and distant spread of the
tumour
• About 10 to 15% of the patients with advanced cancer develop

paraneoplastic syndromes
• Sometimes PNS may be the earliest manifestation of a latent

cancer.
CLINICAL SYNDROME UNDERLYING CANCER MECHANISM
1. ENDOCRINE SYNDROME
i. Hypercalcaemia -Lung (sq. cell Ca), kidney, breast, -Parathormone-like protein
Adult T-cell leukaemia-lymphoma -Vitamin D
ii. Cushing's syndrome -Lung (small cell carcinoma), -ACTH or ACTH-like substance
pancreas, neural tumours
iii. Inappropriate anti-diuresis -Lung (small cell Ca), -ADH or atrial natriuretic factor
prostate,
intracranial tumour -Insulin or insulin-like substance
iv. Hypoglycaemia -Pancreas (islet cell tumour),
mesothelioma, fibrosarcoma -Serotonin, bradykinin
v. Carcinoid syndrome -Bronchial carcinoid tumour,
carcinoma pancreas, stomach
vi. Polycythaemia -Kidney, liver, cerebellar -Erythropoietin
haemangioma
2. NEUROMUSCULAR SYNDROMES
i. Myasthenia gravis -Thymoma -Immunologic
ii. Neuromuscular disorders -Lung (small cell Ca), breast -Immunologic

3. OSSEOUS, JOINT , SOFT TISSUE
i. Lung Not known

Hypertrophic Lung Not known
osteoarthropathy
ii. Clubbing of
fingers
i. Thrombophlebitis Pancreas, lung, GIT Hypercoagulability
4. HAEMATOLOGIC
(Trousseau's phenomenon)
SYNDROMES
ii. Non-bacterial thrombotic Advanced cancers Hypercoagulability
endocarditis
iii. Disseminated AML, adenocarcinoma Chronic thrombotic phenomena
intravascular coagulation
(DIC)
iv. Anaemia Thymoma Unknown
5. GASTROINTESTINAL SYNDROMES
i. Malabsorption Lymphoma of small bowel Hypoalbuminemia
6. RENAL SYNDROMES
i. Nephrotic syndrome Advanced cancers Renal vein thrombosis, systemic
amyloidosis
7. CUTANEOUS SYNDROMES
i. Acanthosis nigricans Stomach, large bowel Immunologic
ii. Seborrheic dermatitis Bowel Immunologic
iii. Exfoliative dermatitis Lymphoma Immunologic
8. AMYLOIDOSIS
i. Primary Multiple myeloma Immunologic (AL protein)
ii. Secondary Kidney, lymphoma, solid tumours AA protein

• Most common tumor associated with paraneoplastic syndrome is
small cell carcinoma of lung
• Hypercalcemia is the most comon paraneoplastic syndrome. Most

commonly it is caused by parathyroid hormone related peptide
• Cushing’s syndrome is most common endocrinopathy. It is usually

due to production of ectopic ACTH by small cell carcinoma
lung(most common), carcinoid tumor (neuroendocrine tumor),
pancreatic tumor (islet cell tumor), and medullary carcinoma of
thyroid.

Tumor Markers Tumor Types
Hormones
Human chorionic gonadotropin Trophoblastic tumors, nonseminomatous testicular
tumors
Calcitonin Medullary carcinoma of thyroid
Catecholamine and metabolites Pheochromocytoma and related tumors
Oncofoetal Antigens
a-Fetoprotein Liver cell cancer, nonseminomatous germ cell
tumors of testis
Carcinoembryonic antigen Carcinomas of the colon, pancreas, lung, stomach,
and heart
Isoenzymes
Prostatic acid phosphatase Prostate cancer
Neuron-specific enolase Small-cell cancer of lung, neuroblastoma
Specific Proteins
Immunoglobulins Multiple myeloma and other gammopathies
Prostate-specific antigen and prostate- Prostate cancer
specific membrane antigen
Mucins and Other Glycoproteins

CA-125 Ovarian cancer
CA-19-9 Colon cancer, pancreatic cancer
CA-15-3 Breast cancer

Hematology
HAEMATOPOIETIC ORGANS
Age Predominant site for erythropoiesis
2nd- 10th week of gestation (mosoblastic
stage) Yolk sac
10th-24 week of gestation (hepatic stage) Liver
24 weeks -till birth (myeloid stage) Bone marrow throughout skeleton

Birth -upto puberty Bone marrow throughout skeleton
Bone marrow of vertebrae,ribs ,

After puberty (after 16-18 years) sternum , skull, pelvis, and proximal
ends of humerus & femur
HSC
Myeloid (trilineage) stem cells

Lymphoid stem cells
Prolymphocyte
Granulocyte Erythroid p Megakaryocytes
monocyte p
T, B and NK cells Neutrophils RBC Platelet

Eosinophils
Basophils
Monocytes Dr. Priyanka Sachdev
Erythropoiesis
(Hb first Proerythroblast (Large number of erythropoietin receptors)
appears)
Early Normoblast (Basophilic)
(Hb first Intermediate (Polychromatic)

detected by Normoblast
Geimsa Stain)
(Orthochromatic)
(Nucleus Late Normoblast
extruded)
Reticulocyte Requires 1-2 days for maturation
Normal RBC
Stains of Reticulocytes
• Reticulocytes can be stained by Romanowsky stain but it is
nonspecific.
• Reticulocytes specific stains are supravital stains 
1. New methylene blue
2. Brilliant cresyl blue.
• The reticulocytes by either of these staining methods contain

deep blue reticulofilamentous material
Morphology of RBC
VARIATIONS IN SIZE
• RBC of normal size  Normocytic
• When red cell diameter is greater than 9 μm they are referred as

macrocytes
• When red cell diameter is less than 6 μm they are referred as

microcytes
REMEMBER
• On smear size of RBC is compared with small lymphocyte

VARIATIONS IN COLOUR
• RBC with normal hemoglobin content (color) ( Central 1/3rd pallor)

 Normochromic
• When area of central pollar is greater than 50% of diameter, it is

referred as hypochromic
• Variation is size of RBCs is know as anisocytosis
• Variation in shape of RBCs is know as poikilocytosis

• Thalassemia, Hemoglobinopathies
• Post splenectomy
Target cells • Liver disease
• Artefact
• G6PD deficiency
Bite cells • Unstable haemoglobin disorders
• Oxidative drugs
• Sickle cell anemia

Sickle cell • S-beta thalassemia
• Myelofibrosis
Teardrop cell • Underlying marrow infiltrate
• Abetalipoproteinemia
• Liver disease
Spurr cell (Acanthocyte) • Post splenectomy
• McLeod blood group phenotype
• Usdaia
Burr cell (Echinocyte) • Artefact
• Liver disease
• Haemoglobin C disease
Burr cell (Echinocyte) • Haemoglobin SC disease
• Chronic liver disease

• Malignant lymphoma, Multiple
Rouleaux formation myeloma
• Chronic inflammatory disease
• Cold autoimmune haemolytic

anemia
RBC agglutination • Paroxysmal cold
hemoglobinuria
• IgM associated lymphoma
• Multiple myeloma
CLASSIFICATION OF ANAEMIAS
1. MORHOLOGICAL CLASSIFICATION
2. PATHOPHYSIOLOGICAL CLASSIFICATION
MORPHOLOGIC CLASSIFICATION
i. Microcytic, hypochromic
ii. Normocytic, normochromic
iii. Macrocytic, normochromic
PATHOPHYSIOLOGICAL/ ETIOLOGICAL
CLASSIFICATION
Anemia
Blood Loss ↓Production ↑Destruction
Acute Chronic
Cytoplasmic Nuclear Stem cell

defect defect proliferation defect
Heam deficit Globin deficit Megaloblastic Aplastic anemia

Anemia
Iron deficiency anemia Thalassemia
Sideroblastic anemia
Anemia of chronic disease
HEMOLYTIC ANEMIAS
Hereditary Acquired
Ab in RBC membrane Ab in RBC Interior AIHA

- Spherocytosis MANA
PNG
Direct toxin
Defect in enzyme Defect in Hb Splenomegaly
G6PD
Qualitative Quantitative
SCC Thalassemia
Classification of anemias according to MCV
Microcytic Normocytic Macrocytic

S - Sideroblastic L - Liver disease
I - Iron deficiency S – Sickle cell anemia H - Hypothroidism
T - Thalassemia H – Hereditary spherocytosis M - Megalobastic anemia
A - Anemia of A – Autoimmune hemolytic C - Cytotoxic drugs like
chronic disease anemia Methotrexate and other
P – Paroxysmal noctumal drugs like phenytoin
hemoglobinuria
E – Enzyme deficiency
(most important
is G-6PD
deficiency
HAEMOLYTIC ANAEMIAS
• Haemolytic anaemias are defined as anaemias resulting from an

increase in the rate of red cell destruction
RBC destruction
Destruction inside blood Destruction inside mononuclear

Vessels or in the circulation phagocytic system
Intravascular hemolysis Extravascular hemolysis

Intravascular hemolysis
RBC destruction in the blood vessels
↑ Free Hb in serum ↑ Unconjugated bilirubin
Jaundice
↑ Risk of
bilirubin
Hemoglobinemia ↑ Complex ↑ Oxidation of
or pigment
with haptoglobin Hb into
gallstones
↑ Hb excretion which is cleared methemoglobin
in urine in the RES
Methemoglobinuria
↓ Haptoglobin
Hemoglobinuria Methemoglobinemia
↓ Hemopexin Dr. Priyanka Sachdev
Extravascular hemolysis
RBC destruction in reticuloendothelial system
• Anemia ↑ Destruction ↑ Destruction

• Jaundice in spleen in liver No free Hb released in
circulation
• No hemoglobinuria
• No hemoglobinemia
Splenomegaly Hepatomegaly • No methemoglobinuria

FEATURE EXTRAVASCULAR INTRAVASCULAR
HAEMOLYSIS HAEMOLYSIS
1. Frequency More common Less common
2. Location RE system organs (spleen, In peripheral
bone marrow, liver) blood
3. Iron stores Increased Decreased
4. Serum ferritin Normal to high Low
5. Plasma haemoglobin Absent Present
6. Methaemoglobin Absent Present
7. Haemoglobinuria Absent Present
8. Haemosiderinuria Absent Present
9. Unconjugated Markedly elevated Mildly elevated
hyperbilirubinaemia
10. Serum LDH Mildly elevated Markedly elevated
Extravascular Hemolysis Intravascular Hemolysis
• Hereditary spherocytosis • Paroxysmal nocturnal
• Thalassemia hemoglobinuria
• Sickle cell anemia • G-6-PD deficiency
• Autoimmune hemolytic anemia • Clostridial toxin
• Drug induced immune hemolytic • Falciparum malaria
anemia • Mechanical injury to
• G-6-PD deficiency red cells
• Defective cardiac
valves
• Thrombin in
microcirculation
• Sickle cell anemia
(minor)

REMEMBER
• In G-6-PD deficiency both extravascular and intravascular

hemolysis occur
• In Sickle cell anemia, usually there is extravascular hemolysis but

intravasacular hemolysis can also occur
10.10 - Sickle Cell Anaemia
Dr. PRIYANKA SACHDEV , MD

Haemoglobin types in normal Adult
Haemoglobinopathies
• 2 types:
1. Qualitative disorders in which there is structural abnormality in

synthesis of haemoglobin e.g. sickle cell syndrome
2. Quantitative disorders in which there quantitatively decreased

globin chain synthesis of haemoglobin e.g. thalassaemias
Sickle Cell Anaemia
• Sickle cell anaemia (SS) is a homozygous state of HbS in the

red cells
• In this an abnormal gene is inherited from each parent.

Pathogenesis
Haemoglobin
β-globin chain gene mutation (chromosome11)
Single point mutation at sixth position of β-globin chain (mis-

sense mutation)
Substution of a valine residue for a glutamic acid residue
Sickle hemoglobin (HbS) instead of HbA

Consequences of Sickling
1. Vaso occlusion of microcirculation

2. Haemolytic anaemia
3. Increased MCHC
Deoxygenation of HbS-containing RBC
Polymerisation of deoxygenated HbS
Elongated rod-like polymers fibres align
Distort the RBC into classic sickle shape (Sickling)
Express higher levels of adhesion molecules (abnormally sticky)
Vaso occlusion of microcirculation

With repeated episodes of deoxygenation and sickling
Membrane damages permanently
RBC become irreversibly sickled
Difficulty in passing through splenic sinusoids  Spleenic Sequestration
Rapid phagocytosis
Extravascular Haemolysis  Haemolytic anaemia

With membrane damage
Water comes out of the cell
Intracellular dehydration
Increased MCHC

CLINICAL FEATURES
1. Anaemia
2. Vaso-occlusive phenomena
1. Anaemia
• Irreversible sickle cells have difficulty in passing the splenic
sinusoids, sequestration, and rapid phagocytosis.
• Anemia is associated with Jaundice reticulocytosis.

2. Vaso-occlusive phenomena
• Reversible sickle cells express higher levels of adhesion molecules

and are abnormally sticky
• So responsible for occlusion of microcirculation
• Vasoocclusive symptoms are the most common manifestations

of sickle cell anemia.
A. Bone
a) It presents as dactylitis or inflammation of the bones of hands and
feet, so called Hand foot syndrome
b) Avascular necrosis of femoral head
c) Prominent cheek bones
d) Crew cut appearance of skull  due to marrow expansion
causing bone resorption and secondary new bone formation
e) Fish mouth appearance of vertebra  due to vaso occlusive crisis
of vertebral arteries.

B.Lungs  Acute chest syndrome characterized by cough, fever and
chest pain
C. Brain seizures or stroke
D. Skin leg ulcers
E. Penis  stagnation in corpora cavernosa leads to priapism
F. Aplastic crises
• Occurs from the infection of red cell progenitors by
parvovirus B19 sudden worsening of the anemia
G. Spleen
• In the initial stages, there is splenomegaly due to
congestion and trapping of red cells in the vascular sinusoids
• Prolonged hypoxia and infarction can lead to

autosplenectomy which increases susceptibility to infection
with capsulated organisms like Hemophilus influenzae,
Pneumococcus, etc.

Screening
Sickling Test
Method
1. Sample – Venous (from arm)/ Capillary blood (Fingertips, Ear
lobes in adults/ Heel in Infants)
Venous (Arm)
Blood Sample Capillary (Fingertips, Ear lobes in adults/
Heel in Infants)
Mix with
Sodium Metabisulphite (Reducing agent)

Wait for 20 minutes
Microscope
Normal RBC Sickled RBC
Negative test HbA Positive test HbS

Diagnosis
1. Peripheal smear
The blood film shows

1. Sickle cells
2. Target cells
3. Features of splenic atrophy such as presence of Howell-Jolly
bodies
2. ESR
• ESR is usually increased in all anemia except in sickle cell anemia where
ESR is decreased because there is no rouleaux formation.
3. Haemoglobin electrophoresis
• HbS moves Slowly towards Anode.

• HbA moves faster towards Anode
Interpretation
• Formation of 1 band is suggestive of sickle cell anemia
• Formation of 2 bands are suggestive of sickle cell carrier or
trait.
Thalassaemias
• Thalassaemias are quantitative abnormalities of polypeptide

globin chain synthesis
• The thalassaemias are a diverse group of hereditary disorders in

which there is reduced synthesis of one or more of the globin
polypeptide chains.
Classification
• α Thalassaemia Absent or reduced synthesis of α globin chain

(chromosome 16) with normal β -chain synthesis.
• β Thalassaemia Absent or reduced synthesis of β globin chain

(chromosome 11) with normal α -chain synthesis
Classification of -thalassaemias
Clinical
TYPE HB Electrophoresis Genotype
Syndrome
Fatal in utero or
Deletion of
1. Hydrops foetalis 3-10 gm/dl Hb Barts in early infancy
four -genes
Deletion of Haemolytic
2. HbH disease 2-12 gm/dl HbF , HbH
three -genes anaemia
Microcytic
3. -Thalassaemia hypochromic
Deletion of
trait 10-14 gm/dl Almost normal blood
two -genes
picture but no
anaemia
4. -Thalassaemia Deletion of
Carrier Normal Normal Asymptomatic
One -genesDr. Priyanka Sachdev
Classification of �-
TYPE thalassaemias
HB Electrophoresis Genotype Clinical Syndrome
Severe anaemia,
HbA(0-50%),
1. �-Thal <5 gm/dl requires
HbF(50-98%) �thal/ transfusions
major
�thal
Severe anaemia,
Multiple but regular
2. �-Thalintermedia 5-10 gm/dl Variable
mechanisms transfusions not
required
10-12 HbA2(4-9%), Usually

3. �-Thala
minor
gm/dl HbF (1-5%) �A/ asymptomatic
Clinical features of β -Thalassaemia major
� chains not
produced
 chain accumulate
Combine with y chain Destruction of normoblasts in the bone marrow

to form 2 2
Ineffective erythropoiesis
↑HbF
Anemia
Hypoxia in tissues
Repeated ↑EPO secretion by renal cells
blood
transfusion Erythroid hyperplasia in bone marrow
↑Iron absorption Bone changes because of

medullary cavity expansion
Iron overload
Death Dr. Priyanka Sachdev
• 1. Anaemia starts appearing within the first 4-6 months of life
• 2. Marked hepatosplenomegaly  due to extramedullary

haematopoiesis and iron overload.
• 3. Expansion of bones  due to marked erythroid hyperplasia

leading to thalassaemic facies and malocclusion of the jaw.
• 4. Iron overload due to repeated blood transfusions causes

damage to the endocrine organs (slow rate of growth,
delayed puberty, diabetes mellitus) and damage to the liver
and heart.
Thalassaemic facies
Lab Diagnosis of β -Thalassaemia major
1. Perpheral smear
1. Severe microcytic hypochromic RBC

2. Marked anisopoikilocytosis
3. Basophilic stippling
4. Target cells
5. Tear drop cells
6. Nucleated RBCs
2. Bone marrow examination
a) Hypercellular with erythroid hyperplasia

b) Reversal of normal M:E ratio (1:3)
c) Pink inclusions are seen in the normoblasts (caused by a
chain accumulation).
3. Osmotic fragility test
Increased resistance to saline haemolysis i.e. decreased osmotic fragility

4. NESTROF Test
Naked Eye Single Tube Red cell Osmotic Fragility (NESTROF) test
• In this test 2 blood samples (1 of a normal person serving as control and

1 of patient) are added to 2 tubes with 0.35% saline.
• After 30 min a white paper with a black line is placed behind both the
tubes.
• The RBCs in control sample undergo hemolysis so the black line is
visible
• The RBCs in thalassemia trait are resistant so black line is not clearly
visible.
5. Haemoglobin electrophoresis
a) Since β chains are not produced but y chains are synthesized

normally  increased amounts of HbF (90%).
b) Increased amount of HbA2
c) Almost complete absence of HbA
6. Skull X-ray
Widening of the diploe gives rise to 
Crew cut appearance on skull X-ray
Hair on end appearance
 thalassemia
Normal Silent  Thalassemia - -

  carrier trait chain deletion chain deletion
 -  - -  - ----
↑� ↑
 cis Trans-
100%  chain - -   -  -
 chain chain
• 70%  chain Tetramer of
• Asymptomatic  chain
Tetramer of
� chain
Asians • Africans 
• American Barts hemoglobin

� • Hydrops fetalis
HbH
Dr. P•riLyeanthkaaSl
-chains not produced
Formation of � and  chains is
normal
�-chains forms tetramers  - chains forms
�4 or HbH) tetramers (4 or
Barts Hb)
Ineffective erythropoiesis Not able to transport
oxygen properly
HbH inclusion in red cells not
able to release oxygen to tissue
Fetus develops
Trapping of these cells in spleen intrauterine hypoxia
Extravascular hemolytic anemia Fetal death or Still birth

Iron deficiency anaemia
Dr. PRIYANKA SACHDEV , MD

Factors of Iron absorption
Factors increasing absorption Factors decreasing absorption
• Ferrous form (Fe2+) • Ferric form (Fe3+)
• Acid (HCI) in the stomach • Achlorhydria (absence of HCI secretion)
• Ascorbic acid • Alkaline food (pancreatic secretions)
• Amino acid and sugars in the food • Phytates, tannates and phosphates in
diet
• Iron deficiency • Iron overload
• Physiological conditions (pregnancy • Tetracyclines and EDTA
and hypoxia) • Inflammatory disorders
CLINICAL FEATURES
1. Anaemia
• Weakness
• Fatigue
• Dyspnoea on exertion
• Palpitations
• Pallor of the skin, mucous membranes and sclerae.
• Older patients may develop angina and congestive cardiac failure.
2. Epithelial tissue changes
a) Nails (koilonychias or spoon-shaped nails)
b) Tongue (atrophic glossitis)
c) Mouth (angular stomatitis)

3. Plummer-Vinson syndrome
Iron
Deficiency
Anemia
Esophageal
Dysphagia
Webs
Plummer-
Vinson
Syndrome
Sideroblastic anaemia
Mitochondrial Enzymes defect activity in erythroblasts
Iron enters into the mitochondria
Cannot be utilized to synthesize heme
Iron accumulates in mitochrondria of erythroblasts
Ringed sideroblast
Types of Sideroblast
• Sideroblasts are abnormal nucleated erythroblasts with granules of iron
(siderotic granules) in cytoplasm.
• 3 types 
: ≥ 5 siderotic granules, but

i. Type 1 sideroblasts : < 5 siderotic granules in cytoplasm.
ii. Type 2 sideroblasts
sideroblasts : ≥ 5 siderotic
not in perinuclear distribution.
iii. Type 3 or ringed
granules in perinuclear distribution.
Megaloblastic anaemias
• The megaloblastic anaemias are disorders caused by impaired DNA
synthesis
• Vit B12 and folic acid are required for DNA synthesis.
• So megaloblastic anaemia is due to deficiency of vit. B12 and folic

acid
THYMIDYLATE SYNTHETASE REACTION
dUMP dTMP DNA
Methylene THF DHF PGA

DHF reductase
THF
Methionine
Methyl HOMOCYSTEINEMETHIONINE
vitamin B12 REACTION
Homocysteine
Methyl THF = Block due to folate deficiency
(Plasma folate) = Block due to drug with norDmr.aPlrtiyisasnukea
Inadequate DNA synthesis
Defective nuclear maturation
Maturation of the nucleus lag behind to that of the cytoplasm
Nuclear/Cytoplasmic asynchrony
Formation of megaloblasts and macrocytes

ERYTHROID SERIES
CLINICAL FEATURES
• 1. Anaemia (In both vit.B12 and folate def.)
• 2. Neurologic manifestations (only in vit.B12 def. Not in folate def.)


Subacute combined degeneration of the spinal cord
Peripheral neuropathy
 Numbness, paraesthesia, weakness, ataxia, poor
finger coordination and diminished reflexes.
Lab diagnosis
Blood Bone Marrow Biochemistry Special Tests
a) Hb a) Cellularity a) Serum iron a) Schilling

b) RBC b) Erythropoiesis b) Serum Ferritin test
c) Retic c) Marrow Iron b) FIGLU
d) Indices
e) WBC
f) Platelets
Schilling Test
W/intrinsic After 5 Days W/Pancreatic
58 Co-Cbl Factor of Antibiotics Enzymes
Pernicious
Anemia Reduced Normal Reduced Reduced
Bacterial
overgrowth Reduced Reduced Normal Reduced
Chronic
pancreatitis Reduced Reduced Reduced Normal
Aplastic anaemia
• Aplastic anaemia result from aplasia of the bone marrow
• In aplastic anaemia, there is pancytopenia i.e. simultaneous

presence of
1. Anaemia
2. Leucopenia
3. Thrombocytopenia
Blood picture
a) Haemoglobin  Fall
b) Red cells  Normocytic normochromic anaemia
c) Reticulocyte  reduced or zero
d)WBC  Leucopenia The absolute granulocyte count is

particularly low (below 1500/μl) with relative lymphocytosis.
e) Platelet  Thrombocytopenia
Bone marrow picture
Cellularity 
• A bone marrow aspirate  ‘dry tap’.

• A trephine biopsy  Hypocellular or aplastic marrow due to
replacement by fat.
• Haematopoietic stem cells bearing CD34 marker are markedly
reduced or absent.
WBC
Granulocytes Agranulocytes
Neutrophils Eosinophils Basophils Lymphocytes Monocyte

HSC
Lymphoid stem cells Myeloid (trilineage) stem cells
Prolymphocyte
Granulocyte-monocyte p. Erythroid p Megakaryocytes
Lymphocytes Neutrophils RBC Platelet

Eosinophils
Basophils
Monocytes
• Leukemia is used for lymphoid neoplasms presenting with
widespread involvement of the bone marrow usually
accompanied by the presence of large number of tumour
cells in the peripheral blood.
• Lymphoma is used to describe proliferations arising as

discrete tissue masses (lymph nodes, spleen, or extranodal
tissues).
• Lymphoma may have leukemia and vice versa.

Classification of Leukemias
1) Lymphoid:
• (i) Acute Lymphoid leukemia (ALL)
• (ii) Chronic Lymphoid leukemia (CLL)
2) Myeloid:
• (i) Acute Myeloid leukemia (AML)
• (ii) Chronic myeloid leukemia (CML)
Leukemias
Lymphoid Myeloid
Acute Chronic Acute Chronic
ALL CLL AML CML

Myeloblast Lymphoblast
Size Larger Smaller

Cytoplasm Moderate Scanty
Auer rod May be present Absent
Nuclear Fine Coarse
chromatin Prominent, 1-4 rI.nPdrii
Nucleoli ysatnink ev
actSach
• Acute leukemias have a high rate of proliferation
without differentiation and their clinical course is
rapid.
• Chronic leukemias have a low rate of proliferation of

tumor cells with good differentiation and their clinical
course is slow.
Lymphomas
Hodgkin's Non-Hodgkin's
Lymphom Lymphoma
a

FEATURE HODGKIN'S NON-HODGKIN'S
1. Cell derivation B-cell 90% B
10% T
2. Nodal involvement Localised, may Disseminated nodal
spread to Spread
contiguous nodes
3. Extranodal spread Uncommon Common
4. Bone marrow Uncommon Common
involvement
5. Constitutional symptoms Common Uncommon
6. Chromosomal defects Aneuploidy Translocations, deletions
7. Spill-over Never May spread to blood
8. Prognosis Better Bad
(75-85% cure) (30-40% cure)
Types of RS cells
WHO Classification of Hodgkins lymphoma
The classification is based on Immunophenotyping of RS cells
1. Classical HD  RS cells positive for CD 15 and CD 30
2. Non-classical /Nodular lymphocytic predominance type  RS

cells positive for CD 20 and BCL-6 but are negative for CD 15
and CD 30.
Classic subtypes Non classical
• Nodular sclerosis • Lymphocyte predominant

• Mixed cellularity
• Lymphocyte-rich
• Lymphocyte depletion

Lymphocyte
Lymphocyte predominant
Nodular sclerosis Mixed cellularity Lymphocyte rich depleted (non classical HL)
‒ MC type ‒ MC type in India ‒ Associated with
HIV
‒ M=F ‒ M>F ‒ M>F ‒ M>F ‒ M>F
‒ Lacunar cell RS ‒ Classical RS cells ‒ Classical RS cells ‒ Pleomorphic RS ‒ LH (popcorn cells)

cell cell RS cell
‒ CD15 + CD30+ ‒ CD15 + CD30+ ‒ CD15 + CD30 + ‒ CD15 + CD30+ ‒ CD20 + BCL6 +,
and CD20- EMA + CD15
‒ —, CD30-
‒ No association ‒ Associated with ‒ Associated with ‒ Associated with ‒ Not associated

with EBV EBV EBV EBV with EBV
‒ Excellent ‒ Prognosis very ‒ Good to excellent ‒ Poor prognosis ‒ Excellent
prognosis good prognosis prognosis
‒ Adolescent ‒ Biphasic incidence ‒ Old age group ‒ Old age group ‒ Young males
(young and > 55
years) Dr. Priyanka Sachdev
Nodular sclerosis
Fibrous bands are present which divide cellular areas into nodules:
nodular sclerosis.
• Lacunar RS cells are seen on histology
Mixed cellularity
Replacement of entire affected lymph nodes by heterogeneous mixture of
various types of apparently normal cells (lymphocytes, histiocytes,
eosinophils, neutrophils and plasma cells)
• Clasical Reed-Sternberg cells are seen
Lymphocytic Rich
Proliferation of small lymphocytes admixed with a varying number of
histiocytes forming diffuse pattern
• Classical variant of RS cells seen
Lymphocyte depletion
There is paucity of lymphocytes.
• It has maximum area of necrosis
• Pleomorphic variants RS cells are seen
Nodular Lymphocyte-predominant
Non classical type
These cases of HD have a nodular
growth pattern
• Like lymphocyte-rich pattern of classic type, there is predominance
of small lymphocytes
• Popcorn cells (Lympho histocytic cells: L&H cells ) are seen
Ann Arbor Staging
• Stage I  Involvement of single lymph node or single

extralymphoid site
• Stage II  Involvement of 2 or more lymph node on the same side

of diaphragm
• Stage III  Involvement of both sides of diaphragm
• Stage IV  Diffuse or disseminated involvement of one or more

extra lymphoid organs or tissue with or without associated lymph
node involvement
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C e l l A d a p t a ti o n s

Reversible Cell injury

Irreversible Cell injury

In order to survive and continue to function

Cells adjust their structure and functions

Dr. Priyanka Sachdev

1. Hypertrophy Increase in the size of cells

2. Hyperplasia  Increase in number of cells

3. Atrophy  Decrease in the size of cells / shrinkage of cells

4. Metaplasia Transformation of one adult cell type with another

5. Dysplasia  ‘Disordered cellular development’

Dr. Priyanka Sachdev

• Increase in the number of cells , not size of cell, resulting in enlargement

• May or may not be seen together with hypertrophy

Dr. Priyanka Sachdev

Dr. Priyanka Sachdev

1. Hyperplasia of female breast at puberty, pregnancy and lactation

1. Endometrial hyperplasia following oestrogen excess

Dr. Priyanka Sachdev

Dr. Priyanka Sachdev

Dr. Priyanka Sachdev

Dr. Priyanka Sachdev

Dr. Priyanka Sachdev

Dr. Priyanka Sachdev

1. Atrophy of thymus in adult life.

Normal Pregnancy Parturition

2. Ischaemic atrophy  atrophic kidney in atherosclerosis of

3. Neuropathic atrophy  e.g. Poliomyelitis,Motor neuron

4. Disuse atrophy  e.g. Wasting of muscles of limb

6.Pressure atrophy  eg. Erosion of the skull by meningioma ,

7. Idiopathic atrophy  where no obvious cause is present

Dr. Priyanka Sachdev

Dr. Priyanka Sachdev

Dr. Priyanka Sachdev

• A reversible change in which one mature/adult cell type is

• If injury or stress abates, the metaplastic tissue may revert to its

Dr. Priyanka Sachdev

Normal columnar epithelium  squamous epithelium

2. In gallbladder (normally lined by simple columnar epithelium) in

3. In prostate (normally lined by simple columnar epithelium) in

4. In uterine endocervix (normally lined by simple columnar

Dr. Priyanka Sachdev

• Normal squamous epithelium  columnar epithelium

1. Barrett’s oesophagus  change of normal squamous

2. Cervical erosion  Ectocervix - change of normal squamous

Normal Barrett’s Oesophagus

Dr. Priyanka Sachdev

Dr. Priyanka Sachdev

• Disordered cellular development

• Characterised by cellular cytologic changes

• On removal of stimulus, the changes may disappear.

1. Increased number of layers

Dr. Priyanka Sachdev

Dr. Priyanka Sachdev

Dr. Priyanka Sachdev , MD

Dr. Priyanka Sachdev

Reversible Cell injury

Irreversible Cell injury

Lysosomes – Autophagy – Rupture