General and Systemic Pathology Concepts-A Global Overview

General & Systemic Pathology Concepts
Prepared and presented by
Marc Imhotep Cray, M.D.
“A broad-brush introduction to select core concepts and disorders.”

Topical Outline
2
 Introduction to Pathology
 Cell & Tissue Injury and Inflammation
 Neoplasia
 Cardiovascular System
 Respiratory System
 Gastrointestinal System
 Renal System
 Nervous System
 Musculoskeletal System
 Endocrine System

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 General pathology is the study of mechanisms of disease, with
emphasis on etiology and pathogenesis.
 Systematic pathology is the study of diseases as they occur
within particular organ systems-it involves:
 Etiology
 Pathogenesis
 Epidemiology, macro- and microscopic appearance
 Specific diagnostic features
 Natural history and
 Sequelae
 Clinical pathology is often referred to as laboratory medicine
and includes a number of diagnostic disciplines.

Marc Imhotep Cray, M.D. 5
Pathology provides the basis for understanding:
 The mechanisms of disease
 The classification of diseases
 The diagnosis of diseases
 The basis of treatment
 Monitoring the progress of disease
 Determining prognosis
 Understanding complications

Systematized Nomenclature of Medicine
6
 SNOMED-standard classification of disease-considers
following aspects:
 Topography
 Morphology
 Etiology
 Function
 Disease
 Procedure
 Occupation

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Techniques of Pathology
Gross pathology – macroscopic investigation and observation of disease
Light microscopy – thin section of wax or plastic permeated tissues, snap-
frozen tissues
Histochemistry – microscopy of treated tissue sections (to distinguish cell
components)
Immunohistochemistry and immunofluorescence – tagged antibodies
(monoclonal better)
Electron microscopy
Biochemical techniques – e.g. fluid and electrolyte balance, serum enzymes
Cell cultures – also allowing cytogenetic analysis
Medical microbiology – direct microscopy, culturing and identification
Molecular pathology – in situ hybridization (specific genes/mRNA),
polymerase chain reaction (PCR)

Cell & Tissue Injury and
Inflammation
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Basic Concepts
 Cellular and tissue growth is a normal component of normal
physiology
 Complex intra- and intercellular signaling mechanisms control
rate and extent of growth
 Many disease processes are characterized by alterations in rate
and control of cellular and tissue turnover
 Defects in these normal control mechanisms may lead to disease
states such as neoplasia
9

Basic Concepts (2)
10
 There are several ways in which constituents of body can alter
in size in association with a normal physiological mechanism or
as part of a disease process
 Cells and tissues may increase in size via
o Hyperplasia= usually results from increased physiologic
demands or hormonal stimulation or
o Hypertrophy=in response to increased physiologic or
pathophysiologic demands
 A decrease in size occurs via atrophy= causes (1) disuse (2)
denervation(3) ischemia (4) nutrient starvation (5)
interruption of endocrine signals (6) & persistent cell injury

Basic Concepts (3)
11
 Metaplasia= is process whereby differentiated (i.e. mature)
cells change from
o Examples: Chronic irritation of bronchial mucosa by cigarette smoke
leads to conversion of ciliated columnar epithelium to stratified
squamous epithelium
• Vitamin A is necessary to maintain epithelia
 Related: Ethiopian National Vitamin A Deficiency Survey
Report, 2008.
o Barrett’s esophagus Specialized intestinal metaplasia=replacement
of nonkeratinized stratified squamous epithelium w intestinal
epithelium (nonciliated columnar w goblet cells in distal esophagus
• Due to chronic reflux esophagitis (GERD)
• Associated w risk of esophageal adenocarcinoma

Basic Concepts (4) Cells and Tissues Insults
12
 Cells and tissues may be damaged by a range of insults:
 physical (trauma and extremes of heat)
 chemical (e.g. acid)
 neoplastic (e.g. cancers infiltrating adjacent tissue)
 infective (e.g. bacterial pneumonia)
 immune (e.g. autoimmune diseases rheumatoid arthritis)
 iatrogenic (e.g. drugs causing gastric ulceration)

Inflammation (1)
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 Evolution of Inflammation
 Engulfment/entrapment
 Neutralization of irritant
 Elimination of injurious agent
Definition= A local response to infection or injury
 Inflammation is a complex reaction of a tissue and its
microcirculation to a pathogenic insult characterized by
generation of inflammatory mediators and movement of
fluid & leukocytes from blood into extravascular tissues
 It is a major component of response to cellular and tissue
injury

Inflammation (2)
14
 Inflammation Characterized by
o increased blood flow (redness and warmth: rubor
and calor)
o swelling (tumor) and
o pain (dolor)
within affected area
o systemic effects including malaise and pyrexia

The inflammatory response (3)
15
Is fundamentally a protective/defensive response
Persists until inciting stimulus is removed & mediators are
dissipated or inhibited
Can be potentially harmful:
 Anaphylactic shock (peanut allergy)
 Systemic inflammatory response syndrome (SIRS)
Is closely intertwined with repair
Therapeutic strategies target critical control points in
inflammatory pathways

Inflammation: “the players” (5)
16

Acute Inflammation: major components (4)
17
Vascular changes:
Vasodilation and increased blood flow
Increased vascular permeability
Cellular events:
Leucocyte transmigration
Phagocytosis
Chemical mediators (acute & chronic)

Acute inflammation
18
 Acute inflammation occurs during early phase of a
reaction to cellular/tissue damage
 It is characterized histologically by presence of acute
inflammatory cells (neutrophils) within affected tissue
 Acute inflammation may resolve if underlying
stimulus is removed, or  it may progress to chronic
inflammation

Acute inflammation (2)
19
 Acute inflammation occurs through release of
inflammatory mediators from damaged tissues and
other cells
 This leads to a combination of increased vascular
permeability and chemotaxis: attraction of inflammatory
cells to area secondary to release of chemicals from site
of inflammation

Cardinal Signs of Inflammation (6)
20
 Redness (rubor)
 Swelling (tumor)
 Heat (calor)
 Pain (dolor)
 Loss of function (functio laesa)
(fifth cardinal sign added by Virchow)

Cardinal Signs
21
 Patient with a Methicillin-resistant Staphylococcus aureus
wound infection, and classic signs of inflammation
Rubin R and Strayer DS Eds. Rubin’s Pathology: Clinicopathologic Foundations
of Medicine, 6th Ed. Baltimore: Lippincott Williams & Wilkins, 2012.

Cardinal Signs
22
 X-ray of previous patient showing non-union of fracture
 Holes are from orthopedic screws

Cardinal Signs
23
 Bone scan of same patient, showing uptake in
area of active inflammation

Blood Cells and Platelets
24

Production of blood cells by bone marrow
25Widmaier, EP. Vander’s Human Physiology : The Mechanisms of Body Function. 13th Ed. McGraw-Hill, 2014.

Light micrograph of a human blood smear
26Widmaier, EP. Vander’s Human Physiology : The Mechanisms of Body Function. 13th Ed. McGraw-Hill, 2014.

Cells of Inflammation
27
Leukocytes (WBCs) are major cellular participants in
inflammation and include
 Neutrophils
 T and B lymphocytes
 Monocytes-macrophages
 Eosinophils
 Mast cells and basophils
 Each cell type has specific functions but they overlap and
change as inflammation progresses
 Inflammatory cells and resident tissue cells interact with
each other in a continuous response during inflammation

Cells of inflammation: morphology & function (1)
28
Neutrophil
Rubin R and Strayer DS Eds. Rubin’s Pathology: Clinicopathologic Foundations of Medicine, 6th Ed. Baltimore: LLW, 2012.

Effector functions of neutrophils
29Rubin R and Strayer DS Eds. Rubin’s Pathology: Clinicopathologic Foundations of Medicine, 6th Ed.
Baltimore: LLW, 2012.

30
Endothelial cell

31
Monocyte/macrophage

More cells of inflammation: morphology
and function (4)
32

More cells of inflammation (5)
33Rubin R and Strayer DS Eds. Rubin’s Pathology: Clinicopathologic Foundations of Medicine, 6th Ed.

More cells of inflammation: morphology
and function (6)
34
Rubin R and Strayer DS Eds. Rubin’s Pathology: Clinicopathologic Foundations of Medicine, 6th Ed.

Acute inflammation (7)
35
 Densely packed (PMNs) with
multilobed nuclei (arrows)
Rubin R and Strayer DS Eds. Rubin’s Pathology: Clinicopathologic
Foundations of Medicine, 6th Ed. Baltimore: LLW, 2012.

Acute Inflammation (8)
36
1. Vasodilation/ increased blood
flow
2. Deposition of fibrin and other
plasma proteins (exudate)
3. Transmigration and
accumulation of neutrophils

Acute Inflammation (9)
37
 Vasodilation
 Slowing of circulation
 Stasis and margination

Stasis and Margination
38
 PMNs at margin of a vessel in acutely inflamed tissue
Rubin R and Strayer DS Eds. Rubin’s Pathology: Clinicopathologic
Foundations of Medicine, 6th Ed. Baltimore: LLW, 2012.

Chronic inflammation
39
 Chronic inflammation may occur de novo or develop
as a sequel to acute inflammation especially if
source of cellular/tissue damage persists
 It is characterized histologically by presence of
chronic inflammatory cells: lymphocytes, plasma cells
and macrophages

Chronic inflammation (2)
40
 Granulomatous inflammation is a special form of chronic
inflammation characterized histologically by presence of
granulomas localized collections of macrophages
 Multinucleate giant cells may also be present
 Causes of granulomatous inflammation include
 tuberculosis
 fungal infections
 tissue reactions to foreign material and
 specific diseases such as sarcoidosis and Crohn’s disease

Chronic inflammation (3)
41
 Lymphocytes (double-
headed arrow), plasma cells
(arrows) and a few
macrophages (arrowheads)
are present

Consequences of inflammation: definitions
42
Several definitions help in understanding of consequences of
inflammation:
■ Edema is accumulation of fluid in extravascular space and
interstitial tissues
■ An effusion is excess fluid in body cavities (e.g., peritoneum or
pleura)
■ A transudate is edema fluid with a low protein content (specific
gravity <1.015)
■ An exudate is edema fluid with a high protein conc. (specific
gravity >1.015),  frequently contains inflammatory cells
 Exudates are seen early in acute inflammation and are produced by
mild injuries, such as sunburn or traumatic blisters

Consequences of inflammation: definitions (2)
43
■ A serous exudate, or effusion, is characterized by
absence of a prominent cellular response and has a
yellow, straw-like color
■ Serosanguineous refers to a serous exudate, or
effusion, that contains red blood cells and has a
reddish tinge

Consequences of inflam: definitions (3)
44
■ A fibrinous exudate has large amounts of fibrin due to
activation of coagulation system
o When a fibrinous exudate occurs on a serosal surface, such as pleura
or pericardium, it is termed “fibrinous pleuritis” or “fibrinous
pericarditis”
■ A purulent exudate or effusion contains prominent cellular
components
o Purulent exudates and effusions are often associated with pathologic
conditions, such as pyogenic bacterial infections, in which
polymorphonuclear neutrophils (PMNs) predominate
■ In suppurative inflammation, a purulent exudate is with
significant liquefactive necrosis it is equivalent of pus

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Vascular Leakage

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Margination, rolling,
activation and adhesion
Transmigration (diapedesis)
Migration toward site of
injury along a chemokine
gradient
Leukocyte Extravasation and Phagocytosis

Leukocyte Extravasation & Phagocytosis:
Animation
47

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Local inflammatory events occurring in response to a wound
Widmaier, EP. Vander’s Human Physiology : The Mechanisms of Body Function. 13th Ed. McGraw-Hill, 2014.

49
Chemical Mediators of Inflammation
Tissue injury stimulates production
of inflammatory mediators in
plasma & release into circulation
Additional factors are generated by
tissue cells & inflammatory cells
Vasoactive and chemotactic
mediators promote edema and
recruit inflammatory cells to site of
injury
Rubin R and Strayer DS Eds. Rubin’s Pathology: Clinicopathologic Foundations of
Medicine, 6th Ed. Baltimore: Lippincott Williams & Wilkins, 2012

Chemical Mediators of Inflammation (2)
50
Chemicals that are released from damaged tissues
and inflammatory cells orchestrates inflammatory
process
 e.g. histamine, prostaglandins, leukotrienes & TNF-α
Protein cascades originating within plasma are
also important in regulating response to tissue
injury
 e.g. coagulation, fibrinolytic, complement and kinin
cascades

Inflammation Resolution
51
 Resolution of inflammation is associated with
organization of inflammatory reaction:
 granulation tissue formation and
 myofibroblast proliferation
followed by
 A variable degree of collagen deposition (fibrous
scarring)
o Collagen deposition more pronounced if inflammatory
process has been prolonged

Tissue Injury and Healing
52
 Tissue injury is usually followed by hemostasis= inflammatory
response  tissue restructuring w a variable degree of scarring
 Factors impairing healing include:
 old age
 poor nutritional state
 excessive tissue damage
 poor apposition of wound edges (or bony fragments after a
fracture)
 presence of foreign material
 poor blood supply
 infection

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1.Tissue injury results in immediate and prolonged vascular
changes. Chemical mediators and damaged tissue cells
stimulate vasodilation and vascular injury leading to
2. leakage of fluid into tissues (edema)
3. Platelets are activated to initiate clot formation and
hemostasis and increase vascular permeability via histamine
release
4. Vascular endothelial cells contribute to clot formation,
anchor circulating neutrophils via upregulated adhesion
molecules and retract to allow increased vascular permeability
to plasma and inflammatory cells at same time
5. microbes (red rods) initiate activation of the complement
cascade, which, along with soluble mediators from
macrophages,
6. recruits neutrophils to site of tissue injury.
7. Phagocytosis (See next sequence of slides.):
Neutrophils and macrophages eliminate microbes and remove
damaged tissue so that repair can begin Rubin R and Strayer DS Eds. Rubin’s Pathology: Clinicopathologic Foundations
Summary of inflam. response to injury

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Chemistry of Phagocytosis
 Activated neutrophils and macrophages kill phagocytosed
microbes (and damaged tissue) by action of microbicidal
molecules in phagolysosomes
 Three classes of microbicidal molecules are most important
1. Reactive oxygen species (ROS)=highly reactive oxidizing
agents that destroy microbes (& other cells)
 Called respiratory burst b/c it occurs during oxygen consumption
(cellular respiration)
2. Nitric oxide
3. Proteolytic enzymes

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Chemistry of Phagocytosis (2) Reactive oxygen
species (ROS)
 Oxygen (O2) has a major role as the terminal electron acceptor in
mitochondria
 It is reduced from O2 to H2O and resultant energy is harnessed as an
electrochemical potential across mitochondrial inner membrane
 Conversion of O2 to H2O entails transfer of four electrons three
partially reduced species, representing transfers of varying
numbers of electrons, are intermediate between O2 and H2O
 These are O2 − = superoxide (one electron); H2O2= hydrogen peroxide
(two electrons); OH•= hydroxyl radical (three electrons)

56
Phagocytosis and intracellular destruction of a microbe
Widmaier, EP. Vander’s Human Physiology : The Mechanisms of Body Function. 13th Ed. McGraw-Hill, 2014.

Marc Imhotep Cray, M.D. 57
Phagocytosis & intracellular destruction of a microbe (2)
Abbas AK, Lichtman AH, Pillai S. Cellular And Molecular Immunology. Saunders-Elsevier, 2015.

58
A scanning electron microscope image of a single
neutrophil (yellow), engulfing anthrax bacteria
(orange)
http://upload.wikimedia.org/wikipedia/com
mons/f/f2/Neutrophil_with_anthrax_copy.jpg
Widmaier, EP. Vander’s Human Physiology : The
Mechanisms of Body Function. 13th Ed. McGraw-
Hill, 2014.
Scanning electron microscope (SEM) images of a single neutrophil
and macrophage (LR) engulfing bacterium.
Phagocytosis illustrated

Phagocyte respiratory burst
(oxidative burst)
59
 Primary free radical–generating system is phagocyte oxidase
system
 Involves activation of phagocyte NADPH oxidase complex (e.g.,
in neutrophils, monocytes) which utilizes O2 as a substrate
 Plays an important role in immune response rapid release
of reactive oxygen species (ROS)
 NADPH plays a role in both creation and neutralization of ROS
 Myeloperoxidase (produces hypochlorite) is a blue-green
heme-containing pigment that gives sputum its color

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Phagocyte oxidase system (Redox RXN)
Phagocyte oxidase is a multisubunit enzyme that is assembled in activated
phagocytes mainly in phagolysosomal membrane
 activated by many stimuli, including IFN-γ and signals from TLRs
Function of phagocyte oxidase is to reduce molecular oxygen into ROS*
such as superoxide radicals (O2−) with reduced form of nicotinamide
adenine dinucleotide phosphate (NADPH) acting as a cofactor
Superoxide is enzymatically dismutated into hydrogen peroxide which is
used by enzyme myeloperoxidase to convert normally unreactive halide ions
into reactive hypohalous acids (hypochlorite) that are toxic for bacteria
*Other ROS include H2O2= hydrogen
peroxide & OH•= hydroxyl radical

Phagocyte respiratory burst (2)
61
Le T and Bhushan V. Microbiology. In: First Aid for the USMLE Step 1 2016. McGraw-Hill, 2016.

62
Oxidative stress “a key trigger for cell & tissue injury and
adaptive responses”
For human life, oxygen is both a blessing and
a curse
 Without it, life is impossible, but some of its
derivatives are partially reduced oxygen species
that can react with, and damage, virtually any
molecule they reach i.e., ROS (free radicals)
Reactive Oxygen Species
 N.B. ROSs causes of cell and tissue injury in many
settings (Illust.)
Copstead LC, Banksia JL. Pathophysiology, 5th Ed. St. Louis,
Missouri: Saunders-Elsevier, 2013.
Of note: Increased free radicals in heart can occur
post MI reperfusion. Such toxic oxygen radicals are
released from neutrophils when blood flow is
restored following ischemia= Reperfusion injury

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Phagocyte respiratory burst (3) Phagocytic cell disorder
 Deficiency of one of components of phagocyte oxidase results in CGD
(chronic granulomatous disease) = an X-linked inherited deficiency
 Phagocytes can utilize H2O2 generated by invading organisms & convert it to
ROS
 Catalase-negative bacteria are effectively killed b/c microbes produce
small amounts of peroxide leading to microbial death
however
 CGD patients are at risk for infection by catalase ⊕ species (e.g., S
aureus, Aspergillus [fungus]) capable of neutralizing their own H2O2
leaving phagocytes without ROS for fighting infections
Related notes:
Pyocyanin of P. aeruginosa functions to generate ROS to kill competing microbes
Lactoferrin is a protein found in secretory fluids and neutrophils that inhibits
microbial growth via iron chelation

Immune System:
Protection from harmful microorganisms
64
 Complex systems exist to protect body from
microorganisms
 Some of these systems are innate and have a broad-based
action (non-specific) while others are acquired as result of
an adaptive immune response act more specifically
 Functions of immune system are carried out by
immunoreactive cells circulating within blood and
present within tissues (See inflammation section above) as
well as by circulating antibodies

Innate and Adaptive Immunity
65
 Defense against microbes is mediated by early reactions
of innate immunity and later responses of adaptive
immunity
 Innate immunity (also called natural or native
immunity) provides early line of defense against
microbes consists of cellular and biochemical defense
mechanisms in place even before infection and
respond rapidly to infections
 React to products of microbes and injured cells they
respond in same way to repeated exposures

Mechanisms of innate immunity
66
 Target structures common to groups of related microbes & do
not distinguish fine differences betw microbes (non-specific)
 Principal components of innate immunity are
1) physical and chemical barriers such as epithelia and
antimicrobial chemicals produced at epithelial surfaces
2) phagocytic cells (neutrophils, macrophages), dendritic
cells, and natural killer (NK) cells and other innate lymphoid
cells
3) blood proteins, including complement system and other
mediators of inflammation

Innate and Adaptive Immunity cont.
67
 Adaptive immunity (also called specific or acquired immunity) stimulated
by exposure to infectious agents and increase in magnitude and defensive
capabilities with each successive exposure to a particular microbe
 b/c this form of immunity develops as a response to infection and
adapts to infection called adaptive immunity
defining characteristics of adaptive immunity are
 ability to distinguish different substances, called specificity, and
 ability to respond more vigorously to repeated exposures to same
microbe, known as memory (anamnestic response)
unique components of adaptive immunity are cells called lymphocytes and
their secreted products such as antibodies

Innate and adaptive immunity illustrated.
68Abbas AK, Lichtman AH, Pillai S. Cellular And Molecular Immunology. Saunders-Elsevier, 2015.

69
Types of Adaptive Immune Responses
There are two types of adaptive immune responses, called humoral
immunity and cell-mediated immunity mediated by different
components of the immune system and function to eliminate different types
of microbes
 Humoral immunity is mediated by molecules in blood and mucosal secretions, called
antibodies produced by cells called B lymphocytes (also called B cells)
o Antibodies recognize microbial antigens, neutralize infectivity of microbes, and
target microbes for elimination by various effector mechanisms
 Humoral immunity is the principal defense mechanism against extracellular
microbes and their toxins b/c secreted antibodies can bind to these microbes and
toxins and assist in their elimination (e.g. bacterial infections)
o Antibodies themselves are specialized and may activate different mechanisms to combat
microbes (effector mechanisms)

70
Types of Adaptive Immune Responses cont.
 Cell-mediated immunity (also called cellular immunity) is mediated by T
lymphocytes (also called T cells)
 Intracellular microbes, such as viruses and some bacteria, survive and
proliferate inside phagocytes and other host cells, where they are inaccessible
to circulating antibodies
 Defense against such infections is a function of cell-mediated immunity which
promotes destruction of microbes residing in phagocytes or killing of infected cells to
eliminate reservoirs of infection
 Some T lymphocytes also contribute to eradication of extracellular microbes
by recruiting leukocytes that destroy these pathogens and by helping B cells
make effective antibodies

Types of adaptive
immunity illust.

Active immunity and Passive immunity
72
 Active immunity= Protective immunity against a microbe is
usually induced by host’s response to microbe
 The form of immunity that is induced by exposure to a foreign antigen
is called active immunity b/c immunized individual plays an active role
in responding to antigen
 Individuals and lymphocytes that have not encountered a
particular antigen are said to be naïve implying they are
immunologically inexperienced; contrastly
 Individuals who have responded to a microbial antigen and are
protected from subsequent exposures to that microbe are said
to be immune
N.B. Only active immune responses
generate immunologic memory.

Active immunity and Passive immunity cont.
73
 Passive immunity= Immunity conferred on an individual by
transferring serum or lymphocytes from a specifically
immunized individual, a process known as adoptive transfer
 Recipient of such a transfer becomes immune to particular
antigen without ever having been exposed to or having
responded to that antigen thus, called passive immunity
o Passive immunization = useful method for conferring resistance
rapidly, without having to wait for an active immune response to
develop
 A physiologically important example of passive immunity
transfer of maternal antibodies through placenta to fetus
enables newborns to combat infections before they develop
ability to produce antibodies themselves

Active and passive immunity illustrated

Autoimmune diseases
75
 Autoimmune diseases occur when immune system
attacks ‘self’ cells and tissues
 this is referred to as a breakdown of “immune
tolerance”
 This leads to inflammation and tissue damage,
which may be
o highly localized (e.g. type 1 diabetes mellitus) or
o generalized (e.g. systemic lupus erythematosus)

Immune System Defects
76
 Defects may occur within immune system
May be:
 congenital (e.g. severe combined immunodeficiency) or
 acquired (e.g. reaction to chemotherapy, infection with
human immunodeficiency virus (HIV))
May affect:
 a specific component of immune system or
 have more widespread effects within several components
 Defects usually lead to increased susceptibility to a range of
infections

Mechanisms of Cell Death:
Apoptosis vs Necrosis
77
 There are two major mechanisms by which cells can die
 Apoptosis (programmed cell death) is an energy-requiring
process leading to death of individual cells, which does not
incite an inflammatory reaction
o Apoptosis may be physiological or pathological in nature
 Necrosis does not require energy, usually affects groups of
cells and typically incites an inflammatory reaction
usually acute in nature

Cells and Tissue Degenerative Processes
78
 Various degenerative processes can occur within cells and tissues as a result
of disease states, for example:
 Calcification may occur if serum calcium conc. is chronically elevated
(‘metastatic’ calcification) or within an abnormal tissue (e.g. a tumor or
focus of chronic inflammation ‘dystrophic’ calcification
 Amyloid is an insoluble protein with a β-pleated sheet structure that is
deposited either locally or in a widespread manner in various chronic
disease states such as chronic inflammatory conditions (e.g.
tuberculosis) or low-grade neoplasms of B-lymphocyte lineage (e.g.
lymphoplasmacytic lymphoma)
 Other forms of degenerative change include glycogen accumulation,
hyaline change and myxomatous change

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Cells and Tissue Pigment Accumulation
 Hemosiderin is an iron-containing pigment that may be deposited in tissues
following red cell destruction and hemoglobin breakdown (e.g. after a
hemorrhage) or w/in organs such as liver in genetic hemochromatosis
 hemosiderin granules impart yellow to brown color of healing bruise
 Lipofuscin (or lipochrome) is a wear-and-tear pigment that is deposited in
organs such as heart and liver
 Melanin is produced by melanocytes in skin and is commonly found in
tumors showing melanocytic differentiation (e.g. malignant melanoma)
 Bilirubin is a bile pigment that accumulates in jaundice, either in
conjugated or unconjugated form (yellow sclera & skin= icterus)
 Anthracosis is a black color comes from carbon pigments in dust inhaled
over years, engulfed by macrophages, and sent via lymphatics to nodes
 It looks bad but does not compromise lung function
 Smokers will have more anthracosis an accumulation exogenous

Shock
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 Shock is a clinical condition characterized by a fast pulse rate
(usually > 100 beats/min) and a low blood pressure (systolic
blood pressure usually < 100 mmHg)
 Common types of shock are
 hypovolemic (low blood volume, e.g. in hemorrhage),
 cardiogenic (heart pump failure, e.g. in myocardial infarction)
 septic (severe infection)
 Less common types are
 anaphylactic (type I hypersensitivity reaction, e.g. penicillin
allergy)
 neurogenic (loss of sympathetic vasomotor tone, e.g. in a
spinal cord injury)

Body protective mechanisms
81
 Body possesses many mechanisms that aim to
protect against potentially injurious agents
 These mechanisms may be
o Behavioral
o Anatomical or
o Immunological

Congenital diseases vs Inherited diseases
82
 Congenital diseases are those that are present at birth
 Inherited diseases are those passed on from parents via
transfer of a genetic defect (e.g. familial adenomatous
polyposis)
 Congenital diseases may be inherited from parents but
may also occur though chromosomal abnormalities that
originate during gametogenesis or fertilization (e.g. Down’s
syndrome) or ‘insults’ sustained by fetus before birth (e.g.
congenital infections)

Neoplasia
84
 Neoplasia means “new growth” and indicates presence of
cells or tissues showing evidence of abnormally controlled
or disordered growth
 Neoplasms comprise cells that show differentiation along one
or more pathways of development
Benign vs Malignant
 Benign neoplasms expand locally but do not invade
adjacent tissues or spread to distant sites, while
 Malignant neoplasms (cancers) invade adjacent tissues
and spread to distant sites

85
Neoplasia (2)
Preneoplastic and neoplastic cellular changes
 Neoplasia Uncontrolled, clonal proliferation of cells
 Can be benign or malignant
 Dysplasia Disordered, non-neoplastic cell growth
 Used only with epithelial cells
 Mild dysplasia is usually reversible
 Severe dysplasia usually progresses to carcinoma in situ
 Differentiation degree to which a malignant tumor resembles its tissue of
origin
 Well-differentiated tumors closely resemble their tissue of origin
 poorly differentiated look almost nothing like their tissue of origin
 Anaplasia Complete lack of differentiation of cells in a malignant neoplasm

Neoplasia (3)
86
 Genetic and environmental factors influence development of
neoplasia
 Most germline (i.e. inherited and present in all cells)
genetic influences on neoplasm development are
polygenic in nature, while
 A minority of neoplasms occur in association with a clearly
defined inherited defect in a single gene (monogenic)
 Neoplasms vary in their relative incidence between
populations and different geographical areas as a result of
differences in gene pools and environmental contributors to
disease development

Neoplasia (4)
87
 Neoplasm development is characterized by
accumulation of genetic defects within neoplastic cells
 In some neoplasms, this sequence is well characterized
 In others specific genetic mutations are found sufficiently
commonly that their detection may be used to confirm the
diagnosis of tissue type or to help to determine likely
biological behavior of neoplasm (i.e. how aggressively the
neoplasm is likely to grow)

Neoplasia (5)
88
 Benign tumors may compress adjacent tissue but do
not invade it
 Malignant tumors grow locally, infiltrate adjacent
tissue and metastasize via lymphatic channels and
blood vessels to distant sites
 Benign tumors can cause death by compressing vital
structures (e.g. within brainstem) but otherwise
generally possess a much better prognosis than
malignant tumors

Neoplasia (6)
89
 Malignant tumors commonly cause extensive local
tissue damage but tumor metastasis to distant sites
is often key process that causes death in advanced
malignancy
 Benign and malignant tumors may also produce
chemicals such as hormones and, therefore, be
associated with clinical symptoms of hormone excess
 Called a “paraneoplastic syndrome”

90
Neoplasia (7)
Clinical and pathological features of neoplasms can indicate whether
they are benign or malignant in nature
Histopathological examination of malignant neoplasms is important to
determine how aggressively neoplasm is likely to grow and metastasize
Features such as
 tumor type
 grade (histological assessment of aggressiveness)
 size and
 presence of lymph node metastases
are most commonly assessed features used to predict biological behavior
of malignant neoplasms (See Grading & Staging, slides # 74 & 75.)

Neoplasia (8)
91
 Most cancers (>90%) arise from "epithelial" tissues,
such as inside lining of colon, breast, lung or prostate
 These are referred to as carcinomas and usually
affect older people
 Contrastly, sarcomas are tumors that arise from
"mesenchymal" tissues such as bone, muscle,
connective tissue, cartilage and fat

Neoplasia (9) Lung cancer
92
 Lung cancer is an aggressive neoplasm for which cigarette
smoking is major risk factor
 Almost all lung cancers are carcinomas
 Neoplasm can invade local structures including mediastinum
and chest wall and commonly metastasizes to distant sites
 Many patients present when disease is at an advanced local
stage or with widespread metastases and when surgical
removal is not possible

93
Klatt EC. Robbins and Cotran Atlas of Pathology, 3rd Ed. Philadelphia: Saunders, 2015.

94

95

96

97

Bronchogenic carcinoma, gross
The large carcinoma ( ) in the upper lobe is
arising in a lung with centriacinar
emphysema, suggesting cigarette smoking as
the risk factor
There are patchy infiltrates in lower lobe
representing pneumonia, likely from central
airway obstruction by this large mass
There is inferior congestion, likely
exacerbated by heart failure

100Klatt EC. Robbins and Cotran Atlas of Pathology, 3rd Ed. Philadelphia: Saunders, 2015.

101

Neoplasia (10) Breast cancer
102
 Breast cancer is second most common malignancy in women
(only exceeded by lung cancer in populations where cigarette
smoking is common)
 Almost all breast cancers are carcinomas
 Most often present as breast masses and invade local structures
including skin and breast wall as well as metastasizing to local
lymph nodes and distant sites
 While breast cancer is an important cause of mortality among
middle aged and older women modern advances in therapy
have significantly improved outcome

103

105

108

109

Neoplasia (11) Colorectal cancer
110
 Colorectal cancer is one of three most common cancers in
Western populations
 it is likely that environmental factors, including Western diet with low
roughage, contribute to this
 Almost all colorectal cancers are carcinomas
 These neoplasms grow locally and pts. may present w rectal
bleeding, a change in bowel habit or w acute abdominal
symptoms caused by bowel obstruction or perforation
 Metastasis to local lymph nodes and distant sites (most
commonly liver) may occur
 Surgical removal when disease is localized to bowel wall is
often associated with a favorable outcome

111

112

113

Neoplasia (12) Prostatic cancer
115
 Prostatic cancer is increasing in incidence among middle-aged
and elderly men although this may partly reflect increased
detection of disease in its early stages in screening programs
 Almost all prostatic cancers are carcinomas
 May invade local pelvic structures and metastasize to distant
sites, especially bone
 While advanced prostatic cancer is commonly fatal, localized
disease (most commonly identified by screening) may be curable
with prostatectomy
 Progression of advanced disease may be slowed with
hormonal therapy

116

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118

119

120

121

122

124

125

126

127

128

Neoplasia (13)
129
 Certain neoplasms occur primarily in childhood 
e.g. neuroblastoma and nephroblastoma
 Elderly individuals develop wear-and-tear diseases 
 osteoarthritis
 atherosclerosis-associated conditions e.g.
ischemic heart disease [IHD]) and
 Elderly individuals are at increased risk of many
neoplasms

130
Neoplasia (14)
 Neoplasm development is commonly associated with genetic
abnormalities within neoplastic tissue however, proportion of
neoplasms that occur as a result of a single inherited germline genetic
abnormality (i.e. a mutation present within all of cells making up an
individual) is relatively low
 Examples include inherited predispositions to breast cancer and
colorectal cancer
o Although relatively uncommon, these inherited syndromes are
important since affected individuals may develop cancer at a young
age and sometimes develop multiple cancers
o Identification of affected families may allow cancer prevention
programs and/or detection of cancers at an early stage

Neoplasia (15) Tumor grade vs stage
131
Grade
Degree of cellular differentiation and mitotic activity on
histology
 Range from low grade (well differentiated) to high grade
(poorly differentiated, undifferentiated or anaplastic)
Stage
 Degree of localization/spread based on site and size of 1°
lesion, spread to regional lymph nodes, presence of
metastases
 Based on clinical (c) or pathology (p) findings
Example: cT3N1M0
 Stage almost always has more prognostic value than grade

TNM staging system
132
 TNM staging system (Stage = Spread):
T = Tumor size
N = Node involvement
M = Metastases
 Each TNM factor has independent prognostic
value M factor often most important

Disease screening
133
 Disease screening means attempting to detect disease
processes at an early (asymptomatic) stage when prompt
treatment should result in an improved prognosis
 Diseases are required to fit various criteria in order to be
suitable for screening
 US screening programs are currently in place for
 neoplastic diseases such as breast & cervical cancer & for
 non-neoplastic diseases such as neonatal hypothyroidism
and phenylketonuria (PKU)

Disease and Extremes of Age
134
 Body is particularly susceptible to certain conditions
at extremes of age
For example
 Premature babies possess immature body systems and
are prone to infections and specific difficulties associated
with organs that are not fully developed (e.g. respiratory
failure, gut failure)
 Elderly individuals are at increased risk of many
neoplasms, atherosclerosis-associated conditions,
osteoarthritis etc.

Atherosclerosis
136
 Atherosclerosis is a very common disease process occurring
within arteries, especially large elastic arteries and their
major branches
 Earliest lesions comprise ‘fatty streaks’ within arterial
intima
 Established atherosclerotic plaques comprise a “cap” of
fibrous tissue beneath which are pools of fat, foamy
macrophages and smooth muscle cells
 Dystrophic calcification is common in older lesions
 Plaque surface may ulcerate (plaque rupture) leading to
a thrombus that coats plaque acute vascular occlusion
See: Atherosclerosis and Thrombosis Illustrated Notes
Online version
- Offline

137
Arteriosclerosis
Arteriosclerosis is a general term for several
disorders that cause thickening and loss of
elasticity in the arterial wall
 Atherosclerosis, the most common form, is
also most serious b/c it causes coronary
artery disease and cerebrovascular disease
Atherosclerosis is patchy intimal plaques
(atheromas) in medium-sized and large arteries
 plaques contain lipids, inflammatory cells, smooth
muscle cells, and connective tissue
Coronary artery with atherosclerotic
narrowing, microscopic
Normal coronary artery, microscopic
From:WebpathCardiovascularPathologyimageplates

Ischemic heart disease (IHD)
138
 IHD is leading cause of death among adults within
Western populations
 It occurs secondary to narrowing of one or more of coronary
arteries most commonly as a result of atherosclerotic
changes
 Ischemic heart disease commonly results in angina and
may lead to myocardial infarction and/or cardiac failure
 Sudden death may occur with or without evidence of MI

Diagnostic Classifications & Terminology
139
 Anatomic Diagnosis= Atherosclerosis (ASHD)
 Etiologic Diagnosis= Coronary Heart Disease (CHD, IHD,
CAD)
 Physiologic Diagnosis= e.g., Angina Pectoris
 Functional Diagnosis= Stable vs Unstable Angina vs
MI [STEMI vs NSTEMI]=ACS

Coronary heart disease (CHD or IHD)
Defined (Etiologic Dx)
140
 Coronary heart disease  proper circulation of blood
and oxygen are not provided to heart and surrounding
tissue
 due to a narrowing of small blood vessels, which normally
supply heart with blood and oxygen

141
Causes (Anatomic Dx)
Typical cause of coronary heart
disease is atherosclerosis
takes place with plaque and fatty
build up on artery walls
narrowing vessels

142
Atherosclerosis:
pathogenic progression

143
Pathobiology of Atherosclerosis
(pathogenesis)
When excess cholesterol deposits on cells and on
the inside walls of blood vessels it forms an
atherosclerotic plaque
First step of atherosclerosis is injury to
endothelium  results in atherosclerotic lesion
formation
When plaque ruptures blood clots form lead
to decreased blood flow resulting in
cardiovascular events (ACS/MI) Coronary artery, severe atherosclerosis, gross
Coronary artery, mild atherosclerosis, gross
From:WebpathCardiovascularPathologyimageplates

144
Pathobiology of Atherosclerosis (2)
Symptoms develop when growth or
rupture of plaque reduces or
obstructs blood flow
Diagnosis is clinical and confirmed
by angiography, or other imaging
tests
Treatment includes risk factor
management and dietary
modification, physical activity,
antiplatelet drugs, and
antiatherogenic drugs
Heart and LAD coronary artery with
recent thrombus, gross
 Anterior surface of heart
demonstrates an opened left
anterior descending coronary
artery
 Within lumen of coronary can be
seen a dark red recent coronary
thrombosis
 The dull red color to myocardium
as seen below glistening
epicardium to lower right of
thrombus is consistent with
underlying myocardial infarction
From: Webpath Cardiovascular Pathology
image plates

Risk Factors for Atherosclerosis
145
 Risk factors atherosclerosis include:
 Dyslipidemia (hypercholesterolemia/LDL-C)
 diabetes mellitus
 cigarette smoking
 family history
 sedentary lifestyle
 obesity
 Hypertension
 Positive Family Hx CVD & premature death
 Lipoprotein(a) [abbreviated Lp(a)]
o Apparently, only men, but not women, are affected by this risk

Treatment
146
Coronary heart disease Tx methods may include: (depends
on presenting Physiologic Dx)
1. Angioplasty with stenting
2. Coronary artery bypass surgery (CABG)
3. Medication
4. Minimally invasive heart surgery
5. Proper diet and exercise
6. Quitting smoking
7. Treatment of other comorbidities, HTN, DM, Obesity

147

Cerebrovascular disease
148
 Apart from ischemic heart disease, atherosclerosis
also commonly affects carotid and intracranial
arteries leading to cerebrovascular disease (e.g.
strokes [CVA], vascular dementia) while
 aortic and iliac artery atherosclerosis leads to
aortic aneurysm formation and peripheral vascular
disease (e.g. intermittent claudication and foot
gangrene)

149

Thrombosis
150
 Thrombosis occurs after activation of clotting cascade
and is a vital physiological mechanism for limiting
blood loss when hemorrhage occurs
 Thrombosis occurring as part of a disease process
lead to local vascular occlusion (e.g. coronary artery
thrombosis) or to distant vascular occlusion
(thromboembolism, e.g. pulmonary thromboembolism
secondary to deep vein thrombosis)

151

Embolism
152
 An embolism occurs when an embolus migrates from
one part of body and causes a blockage of a distant
blood vessel
 embolus can be made up of materials other than a
thrombus, for example
o Air
o Amniotic fluid
o Fat or
o Tumor tissue

153

Valvular Heart Disease
154
 The mitral and aortic valves are valves most commonly
affected by degenerative disease in adults
 Stenosis or incompetence of these valves may lead to
cardiac failure and (apart from mitral stenosis) left
ventricular cardiac hypertrophy
 aortic stenosis is a not uncommon cause of sudden death
 Rheumatic fever is an important cause of mitral valve stenosis
in older patients
 Damaged cardiac valves are prone to secondary bacterial
infection (endocarditis) which itself can lead to further
valvular damage

155

156

157
Viral Myocarditis and Cardiomyopathy
 Unusual conditions of myocardium such as viral myocarditis
and cardiomyopathy (e.g. hypertrophic cardiomyopathy) are
important causes of sudden death in young adults
 Obstructive hypertrophic cardiomyopathy (subset) asymmetric
septal hypertrophy and systolic anterior motion of mitral valve,
outflow obstruction, dyspnea, possible syncope
 In hypertrophic cardiomyopathy diastolic dysfunction ensues
 Cardiomyopathies may result from a genetic defect or
secondary to cardiac muscle damage, following, for example
 viral myocarditis or
 chronic excess alcohol consumption (dilated cardiomyopathy)
o In dilated cardiomyopathy systolic dysfunction ensues

Congenital heart disease
164
 There are many forms of congenital heart disease resulting in
 anatomical abnormalities of heart (e.g. ventricular septal
defect, valvular atresia) and
 associated structures (e.g. patent ductus arteriosus)
 Congenital heart defects leading to introduction of systemic
venous blood directly into systemic arterial circulation
commonly cause cyanosis

165

166

Cardiac failure
167
 Cardiac failure occurs when heart is unable to eject blood
sufficiently effectively during systole
 Common causes of heart failure include
 ischemic heart disease
 cardiac valvular disease
 hypertensive heart disease
 chronic lung disease
 Less common causes include pericardial constriction and
dilated cardiomyopathy
 LV cardiac failure results in pulmonary vascular congestion
and edema (PE)
 RV cardiac failure produces a raised jugular venous pressure,
hepatic venous congestion & peripheral edema
N.B. Under conditions of poor tissue
perfusion, there will be more anaerobic
glycolysis and more acidosis in cells
throughout the body. The blood lactate
rises in this condition.

169

Hypertension
170
 Hypertension is common, often asymptomatic and has many
causes including
 Stress
 Obesity
 Renal artery stenosis and
 Hormonal defects such as Cushing’s syndrome and Conn’s
syndrome
 Chronic hypertension is characterized by an imbalance in
sodium and water homeostasis
 Untreated hypertension can lead to accelerated
atherosclerosis and to end-organ damage, including
hypertensive nephropathy, hypertensive heart disease and
intracerebral hemorrhage

171

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173

174

Pneumonia
176
Pneumonia means inflammation within lung
and most commonly occurs as a result of an
infection
 Many microorganisms may infect lung tissue,
but among most common are viruses and
bacteria:
 bacteria resulting in most common and
severe forms of pneumonia

Pneumonia (2)
177
 Pneumonia may be acquired within community or
while in hospital and these circumstances are
associated with different infective organisms
 Pneumonia may primarily involve
 one pulmonary lobe (lobar pneumonia) or be
 more widespread and centered on respiratory
bronchioles (bronchopneumonia)
o Bronchopneumonia is a common terminal event
in pts. w other serious diseases

179

181

Tuberculosis
183
 Tuberculosis affects millions of individuals worldwide and most
commonly occurs in developing countries
 There is a strong association between tuberculosis and HIV
infection particularly in Africa
 Tuberculosis is caused by Mycobacterium tuberculosis
bacterium and is classically associated w extensive tissue
necrosis and granulomatous inflammation
 TB Infection may be localized (e.g. to lung) or widespread
 latter is commonly fatal
 Treatment usually requires prolonged therapy with multiple
special antibiotics

Pulmonary tuberculosis: primary vs secondary
184
Ghon complex is typical of
primary tuberculosis and consists
of a subpleural granuloma,
usually involving lower part of
upper lobe or upper part of lower
lobe, and ipsilaterally enlarged
hilar lymph nodes, which also
contain tuberculous granulomas
Secondary tuberculosis (Sec)
typically presents in form of
apical lesions
Damjanov I, Pathology Secrets 3rd ed.
Mosby-Elsevier, 2009.

185

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189

190

191

Chronic obstructive pulmonary disease (COPD)
192
 COPD is characterized by presence of
 emphysema (lung tissue destruction) and
 chronic bronchitis (excess bronchial mucus and airway wall
thickening)
in variable proportions
 There is a strong association with cigarette smoking
 Disease is chronic, results in an ‘obstructive’ pulmonary
function defect & is often complicated by pulmonary infection
 Death eventually occurs through respiratory failure, sepsis or
right ventricular cardiac failure

193

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195

Asthma
196
 Asthma is a reversible obstructive pulmonary airway defect
associated with bronchial smooth muscle hypersensitivity
and excess bronchial mucus production
 An acute asthma attack is characterized by
bronchoconstriction and airway blockage by mucus plugs
leads to wheezing and in very severe cases  respiratory
failure (status asthmaticus)
 Treatment with inhaled bronchodilators (e.g. β2-
adrenoceptor agonists) and anti-inflammatory agents (e.g.
inhaled steroids) is effective in majority of pts.

197

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200

Restrictive Lung Disease (RLD)
201
 Diseases that make lung tissue stiffer result in
restrictive lung disease:
 lungs are unable to expand fully and total lung
capacity (TLC) is reduced
 Conditions most commonly associated with a
restrictive lung function defect include fibrosis (e.g.
cryptogenic fibrosing alveolitis, asbestosis)

202

203

204

Barrett esophagus
206
 Chronic GERD (gastroesophageal reflux disease) with
esophageal mucosal injury can lead to metaplasia
of normal esophageal squamous mucosa into gastric-
type columnar mucosa, but with intestinal-type
goblet cells= known as Barrett esophagus
 Ten percent of patients with chronic gastric reflux may
develop Barrett esophagus
 Ulceration leads to bleeding and pain inflammation
with stricture may ensue

207

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209

210

211

Peptic ulcer disease (PUD)
212
 PUD is common in Western populations and involves
mucosal ulceration within stomach and duodenum
 Helicobacter pylori infection is by far the most common
underlying cause
 Peptic ulcers cause abdominal pain while complications
include GI hemorrhage and perforation of gastric or
duodenal wall
 Perforation usually causes peritonitis but
 Perforation into pancreas may cause acute pancreatitis

Internal and external features of stomach
213
Drake RL, et al. Gray’s Atlas Of Anatomy, 2nd Ed. Churchill Livingstone, 2015.

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218

219

220

221

222

Marc Imhotep Cray, M.D. 223Moore KL, Dalley AF, Agur A. MOORE Clinically Oriented Anatomy, 7th ed. LLW,
2014.
Abdominal contents in situ and in relation
to alimentary system

Malabsorption
224
 Malabsorption of nutrients from food may be
caused by
 pancreatic exocrine insufficiency (e.g. chronic
pancreatitis) or
 a specific or generalized defect w/i luminal GIT
o Specific defects include pernicious anemia [damage to
intrinsic factor (IF)] producing parietal cells w/i
specialized gastric mucosa)
o generalized defects include post-infectious diarrhea
(damage to small intestinal microvillous brush border)

Gallstones
225
 Gallstones are very common
 They occur when cholesterol or bile pigments
crystallize within concentrated bile and usually form
within gallbladder
 Complications include
 acute and chronic cholecystitis
 obstructive jaundice and
 acute pancreatitis

226

227

Acute & Chronic Pancreatitis
228
 Acute pancreatitis is a potentially life-threatening
condition that most commonly occurs secondary to
alcohol abuse and/or gallstones
 Chronic pancreatitis is an insidious condition that
most commonly develops secondary to chronic
alcohol abuse
 Both conditions can  lead to pancreatic exocrine
(and sometimes endocrine) insufficiency

229

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232

233

234

Diabetes Mellitus: Type 1 vs Type 2
235
T1DM occurs secondary to autoimmune
destruction of pancreatic insulin producing beta
cells in islet
 T1DM develops most commonly in children and
young adults as a result of a combination of an
inherited genetic predisposition to autoimmune
disease plus a triggering factor that may be a viral
infection

Diabetes Mellitus: Type 1 vs Type 2 cont.
236
 T2DM occurs primarily though increasing resistance
of peripheral tissues to insulin and it typically
develops in middle-aged and elderly people where
it is closely associated with obesity
 DM may also occur as a secondary phenomenon in
conditions such as Cushing’s disease or as a side effect
of treatments such as steroid therapy

Acute & Chronic Complications of DM
237
 Acute complications of DM include hyperglycemia with
ketoacidosis (type 1 diabetes) or hyperosmolar coma
(type 2 diabetes) and hypoglycemia
 hypoglycemia occurs secondary to therapy (i.e. insulin
replacement in type 1 or oral hypoglycemic agents in type 2)
 Chronic complications of DM include an increased
susceptibility to infections, accelerated atherosclerosis
and microvascular angiopathy  leading to
retinopathy and forming a component of diabetic
nephropathy

Liver Fatty Change, Hepatitis & Cirrhosis
238
 Fatty change is a common liver condition with many
causes, including excess alcohol consumption, DM,
obesity, drug reactions and various other forms of
metabolic disturbance
 Cirrhosis is nodular transformation of liver
characterized by hepatocyte regeneration together
with bands of fibrous scar tissue
 causes for cirrhosis include chronic alcohol abuse, viral
hepatitis and autoimmune conditions (e.g. autoimmune
hepatitis, primary biliary cirrhosis)

239
Klatt EC. Robbins and Cotran Atlas of Pathology, 3rd Ed.
Philadelphia: Saunders, 2015.

240

241

242

243

244

Cirrhosis and portal hypertension
 Cirrhosis diffuse bridging fibrosis and
regenerative nodules disrupt normal architecture of
liver
 increase risk for hepatocellular carcinoma (HCC)
 Etiologies include alcohol (60–70% of cases in
US), nonalcoholic steatohepatitis, chronic viral
hepatitis, autoimmune hepatitis, biliary disease,
genetic / metabolic disorders
 Portal hypertension increase pressure in portal
venous system
 Etiologies include cirrhosis (most common cause
in Western countries), vascular obstruction (e.g.,
portal vein thrombosis, Budd- Chiari syndrome),
schistosomiasis Le T and Bhushan V. Microbiology. In: First Aid for the
USMLE Step 1 2016. McGraw-Hill, 2016.

246

247

Urinary tract infections
250
 UTIs are much more common in females than males
and usually occur secondary to infection with fecal
bacteria such as Escherichia coli
 Infections commonly involve bladder (causing cystitis)
but may also involve kidneys (causing pyelonephritis)
 Predisposing factors include female gender, urinary
calculi and urinary stasis
 UTIs are a common cause of septicemia, especially
within the elderly

251

252

Glomerulonephritis
253
 Glomerulonephritis means inflammation centered on
glomeruli remainder of nephron may show secondary
changes
 Glomerulonephritis may occur as an acute or chronic
condition and  causes
 nephritic syndrome (especially in children)
 nephrotic syndrome and
 renal failure (acute and chronic)
 There are multiple causes and several distinct histological
subtypes, each with a different clinical outcome

254

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257

258

259

260

Increased intracranial pressure (ICP)
262
 Raised ICP may occur secondary to intracranial
hemorrhage (usually acute onset) or as a result of a
space-occupying lesion such as a neoplasm (usually
gradual onset)
 Early effects include cranial nerve compression (e.g. third
nerve compression leading to pupillary dilatation)
 Later effects include herniation of brain tissue through an
anatomical aperture (e.g. the foramen magnum), which
when severe may lead to brainstem compression and
death

263

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269

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Le T and Bhushan V. Microbiology. In: First Aid for the USMLE Step 1 2016. McGraw-Hill, 2016.

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272

Strokes (CVA)
273
 CVA present clinically as sudden neurological defects
and may be caused by
 intracranial hemorrhage (e.g. subarachnoid or
intracranial hemorrhage) or
 cerebral infarction (usually secondary to thrombotic or
embolic occlusion of a carotid or intracranial artery)
 Strokes may lead to death or permanent severe
neurological defects but modern therapies can
result in remarkable clinical recovery

Dementia
274
 Dementia is a progressive global decline in
intellectual capacity that occurs with increasing
frequency with advancing age
 Two most commonly encountered forms are
 Alzheimer’s disease (AD) (sometimes familial) and
 Vascular (multi-infarct) dementia (VaD)
 Less common dementias are Huntington’s disease
(an inherited condition) and Pick’s disease

275

276

277

Vascular (multi-infarct) dementia, gross
 Multiple vascular events, including embolic
arterial occlusion, atherosclerosis with
vascular narrowing and thrombosis, and
hypertensive arteriolar sclerosis may lead
to focal but additive loss of cerebral tissue
 Cumulative effect of multiple small areas of
infarction ( ) may result in clinical findings
equivalent to AD along with focal neurologic
deficits or gait disturbances
 Vascular dementia marked by loss of
higher mental function in a stepwise, not
continuous, fashion

Osteoporosis & Osteomalacia
280
 Osteoporosis is loss of bone matrix (density) and most
commonly occurs in postmenopausal women
 hormone replacement therapy is an important
prophylaxis against its development
 Osteomalacia is loss of bone mineralization and occurs b/c of
poor dietary vitamin D intake or defects in vitamin D and
calcium metabolism (e.g. chronic renal failure)
 Osteoporosis and osteomalacia predispose to fractures
especially of hip, wrist and thoracolumbar spine

281
DEXA (dual-energy x-ray absorptiometry) chart
 Bone mineral density (BMD) is best assessed
with radiologic imaging, and
dual-energy x-ray absorptiometry (DEXA) scans
 provide a standardized way of assessing risk
for fracture from osteoporosis
 A graphical display of a DEXA scan for hip
(femur) comparing BMD age and T-score (in
standard deviations above or below comparable
healthy young adult woman’s mean BMD)
 The asterisk representing a woman at age 48 is
within expected range for age
 The circle marks BMD for a woman age 60 and is
concerning for greater bone loss from osteopenia
(−1 to −2.5) but not yet osteoporosis
 The X marks the BMD for a woman age 76 and is
in range of osteoporosis (exceeding −2.5) with
increased risk for fracture

282

283

Osteoarthritis
284
 Osteoarthritis is a wear-and-tear condition most
commonly affecting major weight-bearing joints and
characterized by erosion of articular cartilage and
osteophyte formation
 Predisposing factors include ‘excess’ physical activity
(e.g. sports people) and prior damage to joint or
associated bones both result in abnormal joint
stresses

285

Rheumatoid arthritis (RA)
287
 Rheumatoid arthritis is a multisystem disorder
comprising a symmetrical inflammatory polyarthritis
together w extra-articular manifestations including
pulmonary fibrosis and subcutaneous nodules

289

290

Endocrine hormones pathologies
292
 Endocrine hormones are key factors in regulation of
metabolism, and correct regulation of their production is
essential
 Excess endocrine hormone production results in conditions
such as
 Cushing’s syndrome (excess glucocorticosteroids)
 Conn’s syndrome (excess mineralocorticoids)
 Graves’ disease (excess thyroid hormone) and
 Acromegaly (excess growth hormone)
 Insufficient endocrine hormone production results in
conditions such as
 Addison’s disease (insufficient corticosteroids) and
 Hypothyroidism

Question 1
294
A 45-year-old man has had a fever and dry cough for 3 days, and
now has difficulty breathing and a cough productive of sputum. On
physical examination his temperature is 38.5 C. Diffuse rales are
auscultated over lower lung fields. A chest radiograph shows a
right pleural effusion. A right thoracentesis is performed. The fluid
obtained has a cloudy appearance with a cell count showing
15.500 leukocytes per microliter, 98% of which are neutrophils.
Which of the following terms best describes his pleural process?
A Serous inflammation
B Purulent inflammation
C Fibrinous inflammation
D Chronic inflammation
E Granulomatous inflammation

Answer 1
295
(A) Incorrect. A transudate in a serous effusion has few cells.
(B) CORRECT. The neutrophils suggest an acute process; the fluid is
characteristic for an exudate. Such a large amount of purulent
exudate in the pleural space can be termed an empyema.
(C) Incorrect. Fibrin can often accompany acute inflammatory
processes, but a process with so many neutrophils is best
characterized as a purulent exudate.
(D) Incorrect. Chronic inflammation has a preponderance of
mononuclear cells, not neutrophils.
(E) Incorrect. A granulomatous response is characterized by
mononuclear cells.

Question 2
296
A 56-year-old man has had increasing difficulty breathing for the
past week. On physical examination he is afebrile. Auscultation of
his chest reveals diminished breath sounds and dullness to
percussion bilaterally. There is 2+ pitting edema present to the
level of his thighs. A chest radiograph reveals bilateral pleural
effusions. Which of the following laboratory test findings is he
most likely to have?
A Hypoalbuminemia
B Glucosuria
C Neutrophilia
D Anemia
E Hypernatremia

Answer 2
297
(A) CORRECT. The decrease in oncotic pressure from decreased serum
albumin, the blood protein that accounts for most of the oncotic pressure,
can be significant. This can be a cause for edema and fluid transudates. Too
little circulating protein doesn't keep in or draw water into the vasculature
(B) Incorrect. Glucosuria with diabetes mellitus can explain loss of free
water with dehydration, not edema.
(C) Incorrect. Neutrophilia suggests an acute inflammatory response, which
can produce localized edema in the area of inflammation.
(D) Incorrect. Anemia reduces oxygen carrying capacity; if severe, it could
eventually lead to a high output congestive heart failure that would initially
involve mainly the left heart, with consequent pulmonary congestion and
edema.
(E) Incorrect. An increased serum sodium suggests loss of free water and
dehydration, not edema.

Question 3
298
43. A 48-year-old woman goes to her physician for a routine
physical examination. A 4 cm diameter non-tender mass is palpated
in her right breast. The mass appears fixed to the chest wall.
Another 2 cm non-tender mass is palpable in the left axilla. A chest
radiograph reveals multiple 0.5 to 2 cm nodules in both lungs.
Which of the following classifications best indicates the stage of her
disease?
A T1 N1 M0
B T1 N0 M1
C T2 N1 M0
D T3 N0 M0
E T4 N1 M1

Answer 3
299
(A) Incorrect. This classification is for a small primary cancer with
nodal metastases but no distant metastases.
(B) Incorrect. This classification is for a small primary cancer with no
lymph node metastases but with distant metastases.
(C) Incorrect. This classification is for a larger primary cancer with
nodal metastases but no distant metastases.
(D) Incorrect. This classification is for a larger primary cancer with
no metastases to either lymph nodes or to distant sites.
(E) CORRECT. She has a large invasive (high T) primary tumor mass
with axillary node (N > 0) and lung metastases (M1).

Question 4
300
Review of a series of surgical pathology reports indicates that a
certain type of neoplasm is diagnosed as grade I on a scale of I to IV.
Clinically, some of the patients with this neoplasm are found to
have stage I disease. Which of the following is the best
interpretation of a neoplasm with these designations?
A Unlikely to be malignant
B Arising from epithelium
C May spread via lymphatics and bloodstream
D Has an in situ component
E Well-differentiated and localized

Answer 4
301
(A) Incorrect. Criteria for malignancy must be satisfied first, then
grading and staging follow.
(B) Incorrect. Grading and staging are most useful for epithelial
malignancies, but are not reserved specifically for them.
(C) Incorrect. It may indeed spread to lymph nodes, particularly if it
is a carcinoma, or distant sites, but is less likely to do so if it has a
low grade and it remains small and localized.
(D) Incorrect. It may have an in situ component, but the behavior of
most neoplasms is judged by the worst part of it, and stage I puts it
beyond in situ.
(E) CORRECT. A well-differentiated and localized neoplasm usually
has both a low grade and low stage. In such cases surgery is more
likely to be curative.

Question 5
302
A 55-year-old man has a 30-year history of poorly controlled
diabetes mellitus. He has had extensive black discoloration of skin
and soft tissue of his right foot, with areas of yellowish exudate, for
the past 2 months. Staphylococcus aureus is cultured from this
exudate. A below-the-knee amputation is performed. The
amputation specimen received in the surgical pathology laboratory
is most likely to demonstrate which of the following pathologic
abnormalities?
A Neoplasia
B Gangrene
C Coagulopathy
D Hemosiderosis
E Caseation

Answer 5
303
(A) Incorrect. A neoplasm is a mass lesion.
(B) CORRECT. Gangrenous necrosis is a typical complication of
diabetes mellitus with marked peripheral vascular disease.
Gangrene is a form of coagulative necrosis that involves a body part,
including several tissues. The infection adds an element of
liquefactive necrosis, best described as 'wet gangrene.
(C) Incorrect. Such a disorder, with either thrombosis or
hemorrhage, would be more likely manifested throughout the body.
Coagulopathy is not a feature of diabetes mellitus
(D) Incorrect. Hemosiderin may form locally from remote
hemorrhage. With iron overload, it collects in tissues of the
mononuclear phagocyte system.
(E) Incorrect. Caseation is a part of granulomatous inflammation.
Caseating granulomas are soft, cheesy, and white.

Question 6
304
The lifestyle patterns of healthy persons from 20 to 30 years of age
are studied. A subset of these persons have a lifestyle characterized
by consumption of a lot of pizza and very little physical exercise.
Which of the following tissue changes is most likely to develop in
this subset of persons as a consequence of this lifestyle?
A Fatty metamorphosis of liver
B Pancreatic fat necrosis
C Fatty degeneration of myocardium
D Hypertrophy of adipocyte
E Metaplasia of muscle to adipose tissue

Answer 6
305
(A) Incorrect. Fatty change in the liver is due to toxic and metabolic
derangements, such as those that occur with malnutrition or
alcoholism.
(B) Incorrect. Pancreatic fat necrosis may occur from injury from
inflammation or trauma.
(C) Incorrect. Fatty change in the heart is a consequence of toxic or
hypoxic events.
(D) CORRECT. The fat cells (adipocytes) increase in size
(hypertrophy) with obesity in adults, and this is the predominant
effect of weight gain.
(E) Incorrect. Muscle does not typically undergo metaplasia in
response to weight gain. Adipocytes in fascial planes and around the
muscle can increase in size. The muscle may atrophy in response to
the sedentary lifestyle.

Question 7
306
A 44-year-old woman has had episodes of right upper quadrant
pain during the past 2 weeks. Her stools have become pale in color
over the past 3 days. Laboratory studies show a serum total
bilirubin of 9.7 mg/dL. A cholangiogram shows that a gallstone has
passed into the common bile duct, resulting in obstruction of the
biliary tract. Which of the following cellular alterations is most
likely to be visualized on her skin surfaces?
A Hemosiderosis
B Calcification
C Lipofuscin deposition
D Icterus
E Steatosis

Answer 7
307
(A) Incorrect. Excessive iron can be accumulated through increased
absorption, increased intake, or prolonged transfusion therapy.
(B) Incorrect. Dystrophic calcification can occur in areas of tissue
damage, as in granulomatous diseases. The liver is not a typical
spot for metastatic calcification.
(C) Incorrect. Steatosis occurs with direct injury to hepatocytes, not
biliary tract obstruction
(D) CORRECT. She probably has a 'jaundiced' appearance to her
sclerae and skin due to the increased amount of bilirubin. The bile
pigments impart a yellow color to the tissues. She has biliary tract
obstruction from cholelithiasis and choledocholithiasis.
(E) Incorrect. Fatty change is a process that occurs in the liver, and
biliary tract obstruction does not typically cause it.

Question 8
308
A 45-year-old man has a traumatic injury to his forearm and
incurs extensive blood loss. On physical examination in the
emergency department his blood pressure is 70/30 mm Hg.
Which of the following cellular changes is most likely to represent
irreversible cellular injury as a result of this injury?
A Epithelial dysplasia
B Cytoplasmic fatty metamorphosis
C Nuclear pyknosis
D Atrophy
E Anaerobic glycolysis
F Autophagocytosis

Answer 8
309
(A) Incorrect. Although dysplasia can be a premalignant condition,
it is still reversible.
(B) Incorrect. Fatty change is potentially a reversible condition.
(C) CORRECT. The hypotension leads to diminished tissue perfusion
with ischemic injury. Nuclear chromatin clumping is reversible, but
nuclear pyknosis is not.
(D) Incorrect. 'Downsizing' of the cell in atrophy is reversible.
(E) Incorrect. A lack of sufficient oxygen may lead to anaerobic
metabolism, but this can be temporary until the hypoxia is relieved.
(F) Incorrect. The cell 'downsizes' with autophagocytosis of
cytoplasmic organelles, via its own lysosomes, but the cell does not
die.

Question 9
310
A 73-year-old man suffers a "stroke." On physical examination he
cannot move his right arm. A cerebral angiogram demonstrates
occlusion of the left middle cerebral artery. An echocardiogram
reveals a thrombus within a dilated left atrium. Which of the
following is the most likely pathologic alteration from this event that
has occurred in his brain?
A Cerebral softening from liquefactive necrosis
B Pale infarction with coagulative necrosis
C Predominantly the loss of glial cells
D Recovery of damaged neurons if the vascular supply is
reestablished
E Wet gangrene with secondary bacterial infection

Answer 9
311
(A) CORRECT. Liquefactive necrosis typifies brain infarction. The
brain tissue contains abundant lipid. After the initial softening,
tissue macrophages will increase and clear the debris, leaving a
cystic space. Since neurons cannot regenerate, the size of the infarct
determines the amount of functional loss. The brain has some
capacity for rewiring, but this diminishes with age.
(B) Incorrect. Infarction of most organs is accompanied by
coagulative necrosis, but not the brain.
(C) Incorrect. Neurons are far more sensitive to hypoxia than glial
cells.
(D) Incorrect. It is unlikely that the vascular supply can be
reestablished in a matter of minutes.
(E) Incorrect. Gangrenous necrosis is more typical of a body part,
such as a toe or a foot

Question 10
312
A 30-year-old woman is claiming in a civil lawsuit that her husband
has abused her for the past year. A workup by her physician reveals
a 2 cm left breast mass. There is no lymphadenopathy. No skin
lesions are seen, other than a bruise to her upper arm. An
excisional biopsy of the breast mass is performed. On microscopic
examination, the biopsy shows fat necrosis. This biopsy result is
most consistent with which of the following etiologies?
A Physiologic atrophy
B Breast trauma
C Lactation
D Radiation injury
E Hypoxic injury

Answer 10
313
(A) Incorrect. At age 30 she is premenopausal.
(B) CORRECT. Fat necrosis is seen with trauma to the breast, and
her lawyer will make good use of that documentation. The pattern
of multiple injuries of differing ages at different sites suggests
abuse.
(C) Incorrect. Lactation leads to a physiologic hyperplasia of the
breast with increase in lobules.
(D) Incorrect. A variety of vascular and parenchymal changes can
occur with radiation injury.
(E) Incorrect. The breast is not a site for hypoxic injury.

314
THE END
See next slide for links to tools and resources for further study.

Tools & resources for further study :
315
eNotes:
IVMS General Pathology Lecture Notes.pdf
Images:
IVMS-Gross Pathology, Histopathology, Microbiology and Radiography High
Yield Image Plates.pdf
Atlas:
Klatt EC. Robbins and Cotran Atlas of Pathology 3rd Ed. Elsevier-Saunders,
2015.
WebPath Website:
http://www-medlib.med.utah.edu/WebPath/webpath.html
Textbooks:
Kumar V and Abbas AK. Robbins and Cotran Pathologic Basis of Disease 8th
ed. Philadelphia: Saunders, 2014.
Rubin R and Strayer DS Eds Baltimore: Lippincott Williams & Wilkins, 2012.

General and Systemic Pathology Concepts-A Global Overview

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