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1. Introduction To Pathology

Dr .Abdo Kedir(MD,Pathologist)

2. Pathology
•Greek (pathos -
suffering, logos -study).
•A scientific study of
disease
•Bridging discipline which
encompasses both basic
science and clinical
practice.
2

3. CONT…
•It is divided into
•General pathology
responses to pathologic stimuli
•Systemic pathology - responses of specialized
organs pathologic stimuli

4. •Pathology gives explanations of a disease by
studying the following four aspects of the
disease.
•1. Etiology,
•2. Pathogenesis,
•3. Morphologic changes and
•4. Functional derangements and clinical
significance.

5. 1. Etiology - means the cause of the disease.
•Can be known (1ry) or unknown (idiopathic)
•primary cause is a back bone for the diagnosis
and treatment development
•Etiologic factors
–genetic/intrinsic
–Acquired
–multifactorial (Env’t & genetics)

6. 2. Pathogenesis – means mechanism for
development of the disease
•Sequence of events that leads to morphologic
changes.

7. 3. Morphologic changes –
•refer to the structural alterations in cells or
tissues that occur following the pathogenetic
mechanisms
•Can be grossmicroscopic
•The changes may be specific to a disease,
that help pathologist diagnose the disease

8. 4. Functional derangements and clinical features
•are consequences of morphologic changes
Out come and prognosis
–Cure/resolution
–Disability/permanent damage
–Death

9. •In summary, pathology studies:-
•Etiology  
changes  
Prognosis of all disease
•Understanding of the above core aspects of
disease (i.e. understanding pathology) will help
one to understand how the clinical features of
different diseases occur & how their treatments
work

10. Diagnostic techniques used in pathology
•The pathologist uses the following techniques to
the diagnose diseases:
–
–Cytopathology
–Hematopathology
–Immunohistochemistry
–Microbiological examination
–Biochemical examination
–Cytogenetics
–Molecular techniques
–Autopsy

11. A.Histopathological techniques
•studies tissues abnormalities under
microscope.
•The gold standard for pathologic diagnosis.
•Tissues obtained by biopsy.
•Biopsy
–a tissue sample from a living person to identify
the disease.
–can be either incisionalexcisional.

12. •B. Cytopathologic methods
•study of cells from various body sites to
determine the cause or nature of disease.
•Advantages :
–it is cheap, takes less time and needs no
anesthesia to take specimens.
–it is complementary to histopathological
examination.

13. •Cytopathologic methods includes:
•1. Fine-needle aspiration cytology (FNAC)
–cells are obtained by aspirating the diseased organ
uses a very thin needle
–the aspirated cells are then stained and studied under
the microscope.
–Superficial organs (e.g. thyroid,breast, LNs, skin and
soft tissues)
•can be easily aspirated.
–Deep organs; such as the lung, liver, pancreas, kidney
•aspirated with guidance
scan.

15. •2. Exfoliative cytology
–examination of cells that are shed
spontaneously into body fluids or
secretions.
–Includes sputum, CSF, effusions in body
cavities (pleura, pericardium, peritoneum)

16. •3. Abrasive cytology
–Refers to methods by which cells are dislodged
various tools
membranes, and serous membranes).
–E.g. Pap smears: preparation of cervical smears
with a spatula or a small brush to detect cancer of
the uterine cervix at early stages.

18. •Applications of cytopathology:
–1. Screening or early detection of asymptomatic
cancer.
–2. Diagnosis of symptomatic cancer
–3. To diagnose cysts, inflammatory conditions and
infections of organs
–4. Surveillance of patients treated for cancer
•periodic urine cytology to monitor the
recurrence of cancer of the UT

19. •C. Hematological examination
–abnormalities of the cells of the blood and their
precursors in BM are investigated
–Used to diagnose different kinds of anemias & leukemias.
•D. Immunohistochemistry
–used to detect a specific antigen in the tissue in order to
identify the type of disease.
•E. Microbiological examination
–Identifying micro-organisms from body fluids,cells and
excised tissues
–Uses microscopy,cultural and serological techniques

20. •F. Biochemical examination
–Assessment of metabolic disturbances of disease
–Using assay of various normal and abnormal
compounds in the blood, urine, etc.

21. •G. Molecular techniques
–used to detect genetic diseases.
–The techniques such as fluorescent in situ
hybridization, Southern blot, PCR etc...
•H. Cytogenetics,
–Asses chromosomal abnormalities in the cells using
of molecular techniques

22. •I. Autopsy
–Examination of the dead body to identify the
cause of death.
–can be done for forensicclinical

23. Cellular Responses to Stress and Noxious Stimuli
•Homeostasis
–
normally
–an equilibrium of cells with their
environment for adequate function
–disturbance of it leads to disease onset

25. •Example: heart muscle
•Increased hemodynamic loads
muscle becomes enlarged (adaptation)
blood supply to the myocardium is
inadequate 
irreversible injury and die

26. •Stresses may also induce the following
changes in cells and tissues
–intracellular accumulations,
–pathologic calcification, and
–Cell aging

27. CELLULAR ADAPTATIONS TO STRESS
•Adaptations
–reversible functional and structural responses
–a new but altered steady states is achieved
–allow the cell to survive and continue to function
during changes in physiologic states (e.g.,
pregnancy) and some pathologic stimuli
–It is a response by cells for physiologic stresses or
pathologic stimuli

28. •Physiologic adaptations
–responses of cells to normal stimulation by
hormonesendogenous chemical mediators
e.g., the hormone-induced enlargement of the
breast and uterus during pregnancy
•Pathologic adaptations
–responses to stress that allow cells to modulate
their structure and function and thus escape
injury

29. •Adaptation can be by:-
–Hypertrophy
–Atrophy
–Hyperplasia
–Metaplasia

30. Hypertrophy
• resulting in
increase in the size of the organ
•Cellular enlargment is due to increased
synthesis of cell structural components and
organelles leads to an increase in organ size
and function.
•Causes

•b. specific hormonal stimulation

31. Physiologic hypertrophy

32. Pathological Hypertrophy
Pathologic hypertrophy

33. Hyperplasia
•it is an increase in the number of normal cells
that leads to an increase in the size of the
organ

34. •Hyperplasia can be physiologic or pathologic.
•physiologic hyperplasia
•(1) hormonal hyperplasia
–eg. Enlargment of female breast at puberty and during
pregnancy
•(2) compensatory hyperplasia
hyperplasia that occurs when a portion
of the tissue is removed or diseased
eg. Hepatocyte hyperplasia when a liver is resected

35. •pathologic hyperplasia
hormonal or GF stimulation,
•Examples
1. in balance between estrogen and progesterone
 abnormal
menstrual bleeding
2.the growth factors may be produced by papilloma
viruses or by infected cell
epithelium 
•Pathologic hyperplasia , if untreated may
developed to cancer

36. Regenerative capacity of cells
a.Labile cells (stem cells)
–divide continuously
–mainly undergo hyperplasia as an adaptation to injury
–e.g., stimulation of RBC stem cells by EPO in blood loss.
b. Stable cells (resting cells)
–divide infrequently
–undergo hyperplasia and/or hypertrophy
–Eg. hyperplasia of hepatocytes in liver injury;
•hyperplasia and hypertrophy of smooth muscle cells in the uterus
during pregnancy)
c. Permanent cells (non replicating cells)
–highly specialized cells
–undergo hypertrophy only
–e.g., cardiac and striated muscle

37. Atrophy
•Shrinkage in the size of the cell by the loss of
cell substance is known as atrophy.
•
the entire tissue or organ diminishes in size,
becoming atrophic
•atrophic cells may have diminished function,
they are not dead.

38. •Causes :
•1. disuse
•
•3. diminished blood supply
•4. loss of endocrine stimulation
–e.g., hypopituitarism causing atrophy of target
organs such as the thyroid
•5. aging (senile atrophy).

40. •Cellular mechanisms of Atrophy
•1. decreased protein synthesis because of
reduced metabolic activity
•
ubiquitin-proteasome pathway
•Nutrient deficiency and disuse 
ubiquitin ligases, 
cellular proteins
proteins and degrade them

41. Metaplasia
•replacement of one fully differentiated cell type
by another
•cells sensitive to a particular stress are replaced
by other cell types better able to withstand the
adverse environment
•
"reprogramming" of stem cells rather than
transdifferentiation of already differentiated
cells.

42. •Types of metaplasia
•a. Squamous: columnar
epithelium by squamous epithelium e.g.,
squamous metaplasia of mainstem bronchus
•b. Glandular: replacement of squamous
epithelium with intestinal cells (goblet cells,
mucus secreting cells)
Eg . Barrett's esophagus

44. •Advantage:
–Protective against inciting stimuli
•Disadvantage:
–Loss of functional capability of original cell type
–Risk of cancerous transformation

45. Cell injury
•Results when cells failed or unable to adapt to
stresses, injurious agents or intrinsic
abnormalities
•Injury may progress through a reversible stage
 
death

46. CAUSES OF CELL INJURY
A. Hypoxia: is decreased oxygen supply to tissues
•
1.Ischemia which- is a decreased blood flow

2. Anemia- a reduction in the number of oxygen
carrying RBCs
3. Carbon monoxide poisoning - decreases the oxygen-
capacity of RBCs by chemical alteration of
hemoglobin
4. pulmonary disease - Poor oxygenation of blood

47. B. Chemical Agents




•Mechanisms -- by altering membrane
permeability, osmotic homeostasis, or the
integrity of an enzyme or cofactor

48. C. Infectious Agents

long tapeworms
D.Immunologic Reactions
- Examples include autoimmune reactions and
allergic reactions against environmental
substances in genetically susceptible
individuals

49. E. Genetic Defects
- leads to cell injury by resulting deficiency of
functional protein

(eg.Down syndrome ) or microscopic( eg.sickle
cell anemia)

50. F. Nutritional Imbalances
- deficiencies or excesses
G . Physical Agents
- Trauma, extremes of temperatures,
radiation, electric shock …
H. Aging
- Cellular senescence decreased replicative
and repair abilities of individual cells and
tissues
damage the death of cells and of the
organism

51. MECHANISMS OF CELL INJURY
•GENERAL PRINCIPLES
1.The cellular response to injurious stimuli
depends on the type of injury, its duration,
and its severity.
–low doses of toxins or a brief duration of
ischemia -> reversible cell injury.
–larger toxin doses or longer ischemic
intervals -> irreversible injury and cell
death.
51

52. 2 .The consequences of
stimulus

– show no irreversible
injury after complete ischemia for 2 to
3 hrs but
–cardiac muscle dies after only 20 to 30
minutes.
52

53. 3. Cellular function is lost far before cell death
occurs, and the morphologic changes of cell
injury (or death) lag far behind both.
•Onset of Injury
cells  irreversible
biochemical alterations leading to cell death
ultrastructural, light microscopic, and grossly
visible morphologic changes.
53

54. •Example
•myocardial cells –
–non contractile after 1 to 2 minutes of
ischemia
–die after 30 minutes of ischemia
–do not appear dead by ultrastructural
evaluation
hours, and by light microscopy
hours.
54

55. Sequential development of biochemical and morphologic changes

56. 4.Five intracellular systems are particularly vulnerable:
1. cell membrane integrity,
•critical to cellular ionic and osmotic homeostasis;
2. adenosine triphosphate (ATP) generation,
•largely via mitochondrial aerobic respiration;
3. protein synthesis; and
4. the integrity of the genetic apparatus.
5. the cytoskeleton
56

57. Biochemical basis of cell injury
1. Depletion of ATP
•Depletion of ATP to < 5% to 10% of normal levels has
widespread effects on many critical cellular systems.
•
–reduced supply of oxygen and nutrients
–
–the actions of some toxins (e.g., cyanide).
•Effect depends on glycolytic capacity of the tissue
(e.g. liver better survive than the brain)

58. Effects of ATP depletion
1. Anaerobic glycolysis is used for ATP synthesis and
is accompanied by:
phosphofructokinase caused by
low citrate levels and increased AMP
intracellular pH caused by an
excess of lactate leading to decreased activity of
many cellular enzymes
2. Impaired Na, K+ -ATPase pump, resulting in
diffusion of Na+ and H20 into cells and causing
cellular swelling

59. 3. Impaired calcium (Ca 2+)-ATPase pump,
resulting in increased cytosolic Ca2+
4. Decreased protein synthesis, resulting from
the detachment of ribosomes from the rough
EPR

61. 2.Influx of Calcium
•Increased cytosolic Ca2+ leads to:
1. Enzyme activation
phospholipase: increases membrane permeability
-- Proteases: damages membrane & structural
proteins
-- Endonucleases: damages nuclear chromatin, causing
nuclear fading (karyolysis)
-- : hastens ATP depletion
2. Reentry of Ca2+ into mitochondria: increases
mitochondrial membrane permeability, with release
of cytochrome C (activates apoptosis)

63. 3. Damage to Mitochondria
•There are two major consequences of
mitochondrial damage :
1.Formation of mitochondrial permeability
transition pore
–which leads to the loss of mitochondrial membrane
potential and pH changes failure of oxidative
phosphorylation 
culminating in necrosis
2. leakage of cytochrome into the cytosol death
by apoptosis

65. •4. Free radicals accumulation
•Free radicals are chemical species with a single
unpaired electron in an outer orbital
•Such chemical states are extremely unstable
and readily react with inorganic and organic
chemicals
•
nucleic acids as well as a variety of cellular
proteins and lipids

66. •Reactive oxygen species (ROS)
–oxygen-derived free radical
–has a well established role in cell injury
–produced normally in cells during mitochondrial
respiration and energy generation, but they are
degraded and removed by cellular defense systems.
•
scavenging systems are ineffective, the result is an
excess of these free radicals, leading to a
condition called oxidative stress

67. Ischemia-Reperfusion Injury
•If cells are reversibly injured by ischemia, the
restoration of blood flow has two possible
effects
•1. cell recovery-- in most cases
•2. a paradoxical exacerbated injury--
occasionally
–This is so-called ischemia-reperfusion injury
–It contribute significantly to tissue damage in
myocardial and cerebral infarctions.

68. Mechanisms of reperfusion injuries
1.increased generation of ROS :

the damaged parenchyma cells
and endothelial cells and from infiltrating
leukocytes.
2.Ischemic injury is associated with inflammation,
which may increase with reperfusion because of
increased influx of leukocytes and plasma proteins
–The products of activated leukocytes may cause
additional tissue injury

69. THE MORPHOLOGY OF CELL AND TISSUE INJURY
•Noxious stimuli 
alterations  
morphologic changes of cell injury or death
•For example, :
- ischemic myocardial cells become non
contractile  
then LM

70. Morphologic correlates of reversible
cell injury
A. Cellular swelling
•Also called hydropic changevacuolar
degeneration
•The first manifestation of almost all forms of
injury to cells
•
ion pumps in the plasma membrane, leading to
an inability to maintain ionic and fluid
homeostasis.
•
microscope

71. •Grossly
–pallor, increased turgor, and increase in weight of
the organ.
•Microscopic examination may reveal
–small, clear vacuoles within the cytoplasm;
•Which are distended and pinched-off segments of ER

72. B. Fatty change
•manifested by the appearance of lipid
vacuoles in the cytoplasm.
•
dependent on fat metabolism, such as
hepatocytes and myocardial cells.

73. •Ultrastructural
(1) Plasma membrane alterations such as
blebbing, blunting or distortion of microvilli, and
loosening of intercellular attachments;
(2) Mitochondrial changes such as swelling
(3) Dilation of the ER with detachment of
ribosomes and dissociation of polysomes; and
(4) Nuclear alterations, with clumping of
chromatin.

74. Morphologic correlates of
irreversibility
•Two phenomenaconsistently characterize
irreversibility:
•1.The inability to reverse mitochondrial
dysfunction
and ATP generation) even after resolution of
the original injury, and
•2. profound disturbances in membrane
function

75. Cell death

76. Necrosis
• groups
accompanied by an inflammatory infiltrate
•largely resulting from the degradative action
of enzymes
from
–the lysosomes of the dying cells themselves or
–from the lysosomes of leukocytes that are
recruited as part of the inflammatory reaction to
the dead cells
•
membrane integrity, and their contents often
leak out

77. Morphology of necrotic cells
•They show increased eosinophilia
•have a more glassy homogeneous appearance
•Cytoplasm becomes vacuolated
•myelin figures accumulated
•Calcifications

78. •Ultrastructure morphologic changes of
necrotic cells
–Profound nuclear changes includes karyolysis,
pyknosis, karyorrhexis

79. Nuclear changes: - due to
nonspecific DNA breakdown
•Pyknosis = nuclear
condensation(shrinkage) and
↑ basophilia
•Karyorrhexis [rhexis,
rupture]= nuclear
fragmentation
•Karyolysis= loss of DNA → ↓
basophilia

80. Patterns of Tissue Necrosis
Coagulative necrosis
•when component of cells are dead but the
basic tissue architecture is preserved
•Injurydenatures enzymes (in addition to
structural proteins)
of the dead cells
persist for days or weeks
preserved.
•Coagulative necrosis is characteristic of
infarcts
organs except the brain

82. *Gangrenous necrosis
•not a distinctive type of necrosis but
commonly used in clinical practice to a
limb that has lost its blood supply and
undergone coagulative necrosis
•when bacterial superinfection is
superimposed coagulative necrosis is
modified by the liquefactive action of the
bacteria and the attracted leukocytes (so-
called wet gangrene).
82

83. Bowel-gangrenous
Diabetic
gangrene
83

84. Liquefactive necrosis
•It Is necrotic degradation of tissue that softens and
becomes liquified
•Mechanism
•microbes 
cells  
formation of liquid viscous mass
Examples
•1. CNS infarction: autocatalytic effect of hydrolytic
enzymes generated by neuroglial cells produces a cystic
space
2. Abscess in a bacterial infection: hydrolytic enzymes
generated by neutrophils liquefy dead tissue

86. Caseous necrosis
•The necrotic area appears friable yellow-white or
cheese-like thus called "caseous"
–formed by the release of lipid from the cell
walls of Mycobacterium tuberculosis and
systemic fungi (e.g., Histoplasma) after
destruction by macrophages.
•tissue architecture is completely obliterated and
cellular outlines cannot be discerned

88. •Fat necrosis
•Refers to focal areas of fat destruction, typically
resulting from release of activated pancreatic
lipases into the substance of the pancreas and the
peritoneal cavity
•It is associated with acute pancreatitis
•Mechanisms
(1) Activation of pancreatic lipase (e.g., alcohol
excess): hydrolysis of triacylglycerol in fat cells
(2) Conversion of fatty acids into soap
(saponification): combination of fatty acids and
calcium

89. •Gross appearance:
–chalky yellow-white
deposits (fat
saponification)
–
peripancreatic and
omental adipose
tissue.

90. •Non enzymatic fat necrosis
–results from hypoxic necrosis or mechanical injury
to fat cells.
–The fat liquefies at body temperature and is
released as an oily mass, resulting in formation of
oil cysts.
–Eg. In the breast following trauma
–In subcutaneous tissue
90

91. APOPTOSIS
•a pathway of cell death that is induced by a
tightly regulated suicide program
•cells destined to die activate enzymes capable
of degrading the cells' own nuclear DNA and
cellular proteins.
•apoptosis,
–fragments of the apoptotic cells then break off,

92. •The plasma membrane of the apoptotic cell
–remains intact but altered in such a way that the
cell and its fragments become avid targets for
phagocytes. Therefore
•dead cell is rapidly cleared before its contents have
leaked out
•cell death by appoptosis does not elicit an
inflammatory reaction in the host.

93. •apoptosis differs from necrosis, which is
characterized by loss of membrane integrity,
enzymatic digestion of cells, leakage of cellular
contents, and frequently a host reaction
•However, apoptosis and necrosis sometimes
coexist, and apoptosis induced by some
pathologic stimuli may progress to necrosis.

94. Physiologic
•1. The programmed destruction of cells
during embryogenesis,
•2. Involution of hormone-dependent tissues
upon hormone deprivation,
•3.Cell loss in proliferating cell populations to
maintain a constant number,

95. •4.Death of cells that have served their useful
purpose,
–such as neutrophils and lymphocytes at the end of
an immune response
•5.Elimination of potentially harmful self-reactive
lymphocytes,
•6.Cell death induced by cytotoxic T lymphocytes,
–to kill and eliminate virus-infected and neoplastic
cells

96. Apoptosis in Pathologic Conditions :
•1. DNA damage
–Radiation, cytotoxic anticancer drugs and hypoxia
can damage DNA,
–either directly or via production of free radicals
–If repair mechanisms cannot
the cell triggers intrinsic mechanisms that induce
apoptosis
–larger doses of the same stimuli result in necrosis

97. •2. Accumulation of misfolded proteins
–resulted due to
•mutations in the genes encoding proteins or
free radicals damage
•Excessive accumulation of these proteins in the
ER ER stressapoptotic death of cells

98. •3. Cell injury in certain infections,
infections,
–Apoptosis induced by
•the virus (as in adenHIV infections) or
•the host immune response (as in viral hepatitis)
•4. Pathologic atrophy in parenchymal organs after
duct obstruction,
–such as occurs in the pancreas, parotid gland, and
kidney

99. Mechanism of Apoptosis
•Two distinct pathways for caspase activation
–the mitochondrial pathway
–the death receptor pathway
•Both differ in their induction and regulation,
but culminate in the activation of
"executioner" caspases

100. Mitochondrial (Intrinsic) Pathway of
Apoptosis
Injurious agent 
accumulation of misfolded ptn 
pro apoptotic members of BCL2 family
(Bax,Bak)
membrane to form channel
and other ptns escape to cytosol 
caspases 

101. Death Receptor (Extrinsic) Pathway of
Apoptosis
•Many cells express surface molecules, called
death receptors, that trigger apoptosis.

103. PATHOLOGIC CALCIFICATION
•An abnormal deposition of calcium salts, together with smaller
amounts of iron, magnesium, and other minerals
•
•Of two type
1. Dystrophic calcification

- it occurs in the absence of calcium metabolic
(i.e., with normal serum levels of calcium).
2. metastatic calcification

- almost always reflects hypercalcemia
NB. hypercalcemia is not a prerequisite for dystrophic
calcification but it can exacerbate it.

104. Dystrophic Calcification
•Dystrophic calcification:
sites of cell injury and necrosis
•It is virtually inevitable in the atheromas
advanced atherosclerosis, associated with intimal
injury in the aorta and large arteries and
characterized by accumulation of lipids
•
incidental finding indicating insignificant past cell
injury, it may also be a cause of organ
dysfunction.
•
damaged heart valves, resulting in severely
compromised valve motion.

106. Metastatic Calcification
•Metastatic calcification can occur in normal
tissues whenever there is hypercalcemia.
•The four major causes of hypercalcemia are :
•(1) increased secretion of parathyroid hormone,
due to either primary parathyroid tumors or
production of parathyroid hormone-related
protein by other malignant tumors;
•(2) destruction of bone
accelerated turnover (e.g., Paget disease),
immobilization, or tumors (increased bone
catabolism associated with multiple myeloma)

107. •(3) vitamin D-related disorders
vitamin D intoxication and sarcoidosis
which macrophages activate a vitamin D
precursor); and
•(4) renal failure,
leads to secondary hyperparathyroidism.

108. Cellular aging
•represents a progressive
accumulation of sublethal injury.
•Lead to
–
–cell death, or
–diminished capacity to respond to
injury.

109. •Cellular functions decline:
–Mitochondrial oxidative phosphorylation
–synthesis of structural,
–enzymatic, and
–receptor proteins.
–diminished capacity for nutrient uptake
–repair of chromosomal damage.

111. •The morphologic alterations in senescent cells:
–irregular nuclei,
–pleomorphic vacuolated mitochondria,
–diminished endoplasmic reticulum, and
–distorted Golgi apparatuses.
–a steady accumulation of lipofuscin pigment
–abnormally folded proteins, and
–advanced glycosylation end products