MLS 222

Department of Medical Laboratory Science

SCHOOL OF NATURAL SCIENCES

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 MLS 212
COURSE LEARNING OUTCOMES
At the end of the module, you should be
able to:
1. Explain the different terms and processes
associated with pathology.
2. Determine the different changes (cell injury,
cell adaptation, inflammation, tissue repair
and cell death) that occur related to
pathologic conditions as well as
pathophysiologic mechanisms.
3. List optimum working conditions, standard
operating procedures for an anatomic
laboratory and ethical behaviour in relation
to clinical specimen handling.
4. Determine the different collection methods
for histopathologic and cytological samples
for tissue processing and their proper
disposal of clinical samples for
environmental safety.
5. Make use of the different principles of
routine and automated process, and
related equipment/materials/reagents
involved in proper histopathologic
processing (fixation, decalcification,
dehydration, clearing, impregnation,
embedding, trimming and sectioning,
staining, mounting and labelling.)

HISTOPATHOLOGIC AND
6. Determine the different problems
encountered in histopathologic processing,

CYTOLOGIC TECHNIQUES
their probable causes and apply
recommended solutions.

LECTURE 7. Utilize
processes,
different principles
and
of routine
related
equipment/materials/reagents involved in
standard cytological processing for cell
blocking (fixation, dehydration, clearing,
impregnation, embedding, trimming and
sectioning, staining, mounting and labeling)
and cytological smears for Papaniculao
staining.
8. Explain recent advances in histopathologic
and cytopathologic techniques with
incorporation of rapid tissue processing and
immunohistochemical techniques tor tissue
processing. 2
9. Discuss terms and general procedures
associated
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 The body is a cell state in which every cell is
a citizen. Disease is merely the conflict of the
citizens of the state brought about by the
action of external forces. Rudolf Virchow

COURSE INTRODUCTION
Dear Future Registered Medical Technologists,

Congratulations for moving up in pursuing your career. As professionals willing to engage in

rendering services for the purpose of aiding the physician in the diagnosis, study and treatment of
diseases, welcome to MLS 222!

This subject is part of the board examination. By doing this course, it will enable you to be
familiar with the basic concepts of disease processes correlating the etiology of diseases with the
course developement of anatomic and clinical changes brough about by the disease.

You are expected to learn the theories of histopathologic techniques and by doing so, be
able to perform techniques essential I the production of histopathologic slides for the diagnosis of
diseases including special staining procedures and other related techniques. It will also introduce
you to the study and identification of cells in the diagnosis of diseases using cytological techniques. In
like manner, you are expected to perform these techniques in the future to identify abnormal cells in
the diagnosis of diseases using cytological techniques while complying with quality control.

During this pandemic, we are in a special educational setting. Your utmost discipline,
commitment and perseverance will be the determining factor in your success. Actual life lessons in
the process of learning this course are immeasurable by numbers. Always do your best for a better
future.

Pray. Hope. Do not worry!

Histopath Facilitators

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MODULE 1 – Review of Pathology
This module will equip you with the necessary information to grasp the role of the
histopathology laboratory in diagnostics. Necessarily you will be reminded of the pathologic
concepts you learned in Anatomy and Physiology with Pathophysiology to understand the purpose
of the processes and procedures being done in the pathology laboratory. Additionally, these
concepts will be discussed in greater detail in terms of pathophysiology to provide a practical
understanding on how a pathologist would interpret slides for diagnostic purposes.

MODULE SELF MONITORING FORM

To help you keep track of your module tasks, you are provided below with a self-monitoring
form. Take the time to tick on the “Yes” box for each activity that you finish and be reminded about
pending activities that you are yet to do. Remember that your success in achieving the module
objectives depends entirely on how conscientious you are of your own progress.

Done?
ACTIVITIES
YES NO

Read the Module Introduction, Module Contents, and Module Objectives

Do Lecture Activity 1.1.1. David’s Distended Jugular Vein

Read Lecture Activity 1.1.2 Read

Do Lecture Activity 1.1.3. The Clinical Laboratory

Do Lecture Activity 1.2.1. Flat line

Do Lecture Activity 1.2.2 Read

Do Lecture Activity 1.2.3. Atherosclerosis

Do Lecture Activity 1.3.1 Key Facts about Cancer

Do Lecture Activity 1.3.2. Read

Do Lecture Activity 1.3.3. Carcinogenesis

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MODULE CONTENTS
Module Introduction ........................................................................................................................ 3
Module Self-Monitoring Form .......................................................................................................... 4
Module Contents .............................................................................................................................. 5
Module Objectives ........................................................................................................................... 5
Unit 1- Definition of terms
Explore: ‘David’s Distended Jugular Vein
Lecture Activity 1.1.1 ……………………………………………………………………………………… 6
Explain: Read
Lecture Activity 1.1.2 ……………………………………………………………………………………… 7
Elaborate: The Clinical Laboratory
Lecture Activity 1.1.3 ……………………………………………………………………………………… 9
Unit 2 – Cellular Response to Stress and Toxic Insults: Adaptation, Injury and Death
Engage: Flat line
Lecture Activity 1.2.1 ……………………………………………………………………………………… 11
Explain: Read
Lecture Activity 1.2.2………………………………………………………………………………………. 12
Elaborate: Atherosclerosis
Lecture Activity 1.2.3………………………………………………………………………………………. 30
Unit 3- Neoplasia
Enggage: Key Facts about Cancer
Lecture Activity 1.3.1………………………………………………………………………………………. 31
Explain: Read
Lecture Activity 1.3.2………………………………………………………………………………………. 32
Elaborate: Carcinogenesis
Lecture Activity 1.3.3……………………………………………………………………………………..... 38
References ………………………………………………………………………………………………….. 39

MODULE OBJECTIVES:
After you are done reading and doing the tasks in this module, you are expected to be able
to:
1. Describe different terms related to pathology.
2. Describe the divisions and scope of pathology.
3. Discuss the pathophysiology of disease.
4. Discuss cell adaptation injury and death.
5. Describe neoplasia in terms of general pathogenesis, nomenclature, and prognostic
classifications.

Lecture Unit 1.1 – Definition of terms

Unit Objectives:
1. Define terms in pathology including its branches.

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 2. Discuss the pathophysiology of disease.

Lecture Unit 1.2- Cellular responses to Stress and Toxic Insults: Adaptation, Injury and Death
Objectives:
1. Differentiate the types of cell adaptation due to sudden changes in the internal mileu
2. Identify which are reversible, irreversible and pre-cancerous lesions.
3. Explain the pathophysiology of different adaptations.
4. Explain the mechanisms involved in degeneration and pigmentation.
5. Enumerate the different somatic changes in cell injury.
6. Discuss the alterations in cells and tissues after an injury.
7. Differentiate the types of cell death.
8. Describe the different pathways leading to intracellular accumulation and give examples
for each.
9. Describe the gross and morphologic changes associated with the different patterns of
necrosis

Lecture Unit 1.3– Neoplasia

1. Describe general cancer pathogenesis and its causes.
2. Differentiate Benign from malignant tumors.
3. List the types of cancers arising from parent cells and identifying their benign and
malignant forms.
4. Enumerate the hallmarks of cancer.
5. Describe staging and grading of cancer and their significance.

DEFINITION OF TERMS
UNIT 1

Lecture activity 1.1.1. “David’s” distended jugular vein

(20 points)

500 years after Michelangelo sculpted “David”, Dr.

Danie Gelfman in 2018, had the chance to see this
iconic marble masterpiece first-hand. With a “clinical
eye” one of the first things he noticed was the bulging
jugular vein which is considered abnormal and a sign of
right sided heart failure. When the then 29-year-old
Michelangelo sculpted David, it was supposed to be a
symbol of youthful energy and health. Something was
amiss. He looked further and did not notice any
enlargement in the abdomen nor swelling of the feet,
typical of heart failure. He therefore assumed that with

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the look of anxiety on David’s’ face, slingshot on his shoulder and a stone on his right hand- that it
was a temporary physiological distention that appears just before a physical exertion. David in this
sculpture was just getting ready to slay Goliath (Rudavsky & Bongiovanni, 2020). Talk about amazing
detail. Now, it is no longer uncommon to bring students to museums for visual thinking exercises, like
looking for “signs” that may reflect physiological or even pathological mechanisms.
1. Search the net and share a similar story of an artwork in whatever media that somehow reflect
physiology or even pathology.
2. Briefly discuss the mechanism involved in the sign that your sharing demonstrated.

Lecture Activity 1.1.2

UNIT 1.2 – Read

Introduction

There is a multitude of terms referring to distinct conditions in Pathology. These terms are
essential in transmitting information in a complex discipline such as this. The roots of these terms
derived from Latin are in common usage in medical terminology and the science of pathology is no
exemption. You have encountered a lot of this terms in your previous courses, the terms described
here will in no way be exclusive to pathology but rather a part of the language that makes the
practice of medicine more exact and less prone to ambiguity.

Pathology is the study (logos) of disease (pathos).

 it is devoted to the study of the structural, biochemical, and functional changes in cells, tissues,
and organs that underlie disease.
 Purpose:
o It attempts to explain the why’s and wherefores of the sign and symptoms manifested
by patients.
o Provides a rational basis for clinical care and therapy.
 Bridge between the basic sciences and clinical medicine
 Scientific foundation for all of medicine

2 Traditional Divisions of Pathology

 General Pathology- concerned with common reactions of cells and tissue to injurious stimuli.
o They are not tissue specific.

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 o Ex. Inflammation caused by bacterial infection appears similar in most tissues.
 Systemic Pathology- examines the alterations and underlying mechanisms in organ specific
diseases.
o Ex. Ischemic heart disease

4 Aspects of disease process that form the core of pathology:

1. Etiology- cause
 2 General kinds of etiology
o Genetic – inherited mutations, and disease associated gene variants, or polymorphisms)
o Acquired – due to:
 Infectious agents
 Nutritional deficiency
 Chemical poisons
 Physical agents
 Abnormality in immunological reactions
 Psychological factors

* classifying disease as being caused by one or the other has less of a majority application.
The most common afflictions like cancer or atherosclerosis are multifactorial and arise from
the effects of various external triggers on a genetically susceptible individual. The relative
contribution of inherited susceptibility and external influences varies in different diseases.
2. Pathogenesis- sequence of biochemical and molecular events that follow the exposure of cells or
tissues to injurious agent.
 One of the main domains of pathology.
3. Morphologic changes- Structural alterations induced in the cells and organs of the body that are
either characteristic or diagnostic of an etiologic process.
 Used traditionally by diagnostic pathology to determine the nature of a disease and to
follow its progression.
 Limited by morphologically identical lesions arising from distinct molecular mechanisms
such as in the study of tumors, breast cancers that are morphologically indistinguishable
from each other but may have widely different courses, therapeutic response and
prognosis.
*molecular analysis like next generation sequencing has begun to reveal genetic differences
that predict tumor behavior as well as their therapeutic response. New technological
advances, the use of “omics” technologies (genomics, proteomics, metabolomics) to study
pathogenic mechanisms are now available.

4. Clinical Manifestations- functional consequences of the disease

 The end results of genetic, biochemical, and structural changes in cells and tissues are
functional abnormalities which lead to clinical manifestations (symptoms and signs) as well
as its progression (clinical course and outcome)

As outlined above, the core aspects of pathology are made up of the components that characterize
the DISEASE PROCESS. For every disease there is a cause (Etiology) which interacts with the living
system. How this interaction takes place is the Pathogenesis and the actual changes because of that
interaction are the Morphologic changes. The structural changes effected on the cells alter their

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function are manifested as functional derangements and clinical manifestations. They may either be
signs (objective manifestation) or symptoms (subjective manifestations). From the start of the disease
to its eventual resolution, disability or death is the progression of the disease which is referred to as the
clinical course and outcome.

Lecture Activity 1.1.3. The Clinical Laboratory (15 points)

It is no coincidence that the Medical Technology Laboratory is also called the clinical
pathology laboratory. At work in the different sections are the concepts and principles of specific
subdivisions of pathology. Tabulate 5 sections in a clinical laboratory on the first column. On the
second column, identify and describe the subdivision of pathology that is at work in each section. On
the third column, give at least 3 tests/activities that are done in each section.

BASIC TERMS IN PATHOLOGY

1. Disease, Disorder, Syndrome

 Disease- a pathophysiological response to internal and external factors
o Abnormalities in systemic functions become the basis for diagnosis and treatment.
o Abnormalities cause both physical and emotional signs and symptoms as well as
pain, dysfunction, distress, social problems or death
o Ex. Cardiovascular disease
 Disorder- A disruption of the disease to the normal or regular functions in the body or a part
of the body
o Ex. Arrhythmia is a disorder arising from the disease Cardiovascular disease.
- Arrhythmia is not a disease; it is a disorder characterized with irregular
heartbeat that occurs because of having cardiovascular disease.
o Disorders can be classified as:
- Mental
- Physical
- Genetic
- Emotional
- Behavioral
- Structural

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 Syndrome- Refers to a disease or a disorder that has more than one identifying feature or
symptom.
o Ex Downs syndrome- distinctive physical features at birth due to an extra copy of
chromosome 21
2. Diagnosis, Prognosis
 Diagnosis- determination of the nature of a disease expressed in a concise manner
 Prognosis- probable outcome of a disease in a living individual.
o It is the clinicians estimate of the severity and possible result of a disease
o A forecast of the probable course and outcome of a disease, especially of the
chances of recovery
3. Acute, Chronic
 Acute- Sudden onset or rapid course
o Short (often less than a month) clinical course
o Usually respond to therapy and return to a state of complete, normal or premorbid
state
o Ex. Bronchitis, appendicitis, Upper respitratory tract infections
 Chronic- Slow onset or long duration
o Ex. Asthma, COPD, Diabetes Mellitus, Chronic Kidney disease
4. Idiopathic, Iatrogenic, Nosocomial, Community acquired
 Idiopathic- a disease with no identifiable cause
o A diagnosis of exclusion.
o There is limited literature describing the methodology to define a disease with no
clear diagnostic criteria.
 Iatrogenic- pathology caused by a physician and their treatment.
o Ex. Retained forceps after abdominal surgery causing intestinal obstruction.
 Community acquired infection- infection acquired outside a health care facility.
 Nosocomial- hospital acquired infection.
o Occurs within 48 hours of hospital admission , 3 days of discharge or 30 days of
operation.
5. Non-communicable, communicable, infectious, contagious
 Non communicable diseases (NCD)- Diseases that are not transmitted through contact
with an infected or afflicted person.
o They are caused by various genetic, physiological, environmental, and behavioral
factors.
o 4 main types of NCD’s (WHO)
- Cancer
- Cardiovascular diseases
- Chronic Respiratory diseases (Asthma and COPD)
- Diabetes
 Communicable diseases- diseases that can be spread from one organism to another. This
includes spread from one person to person or animal to humans (zoonotic).

The manner of spread can be described by 2 terms

o Infectious- to affect of contaminated someone with pathogenic microorganisms.

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 Major ways of spread:
- Direct contact with an infected person, animal or their discharges (saliva;
body fluids such as blood, urine, semen; respiratory droplets/ aerosols )
- Direct contact with contaminated object
- Contaminated food or water
- Disease carrying insects (Vectors)
o Contagious- spread through direct bodily contact with an infected person, their
discharges or an object or surface they have contaminated.
- From Latin ‘contagio’- touching, contact.

*All communicable diseases are infectious but not all are contagious. An infectious
disease is contagious when it spreads through direct, bodily contact with an infected
person, their discharges, or an object or surface they have contaminated.

Malaria is infectious because it caused by a parasite, but it is not contagious because a

vector is needed to transmit the infection.

Tetanus is infectious but not contagious because you do not get it by shaking hands
with someone who has tetanus.

COVID 19 is both infectious and contagious because you can get directly from a
person by aerosol spray and from inanimate objects contaminated with a discharge
from an infected person.

CELLULAR RESPONSE TO STRESS AND TOXIC INSULTS: ADAPTATION, INJURY AND

DEATH
UNIT 2

Lecture Activity 1.2.1.: Flat line (10points)

One of the more difficult things to do in

the hospital is to declare a patient dead.
Cardiac arrest requires an immediate lifesaving
response. Cardiorespiratory resuscitation (CPR) is
immediately initiated by the receiving member
of the health care team and a code is announced thru the public address system. Commonly ‘code
blue’ is used but it is institution dependent. Some would use ‘Corazon team’ nevertheless, the code
puts a group of highly trained staff into to action to provide advance life support. How long

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resuscitation is given is also institution dependent. Some would resuscitate for 30 minutes and ask the
next of kin if they would like the team to continue with the CPR just before the 30-minute mark lapses.
Ultimately, it is the decision of the next of kin to request a halt to the resuscitation attempt and a cue
for the physician to note the time and announce the time of death.

1. The situation described above is a necessary protocol to be strictly followed. Share actual
experiences or movies you have seen related to this. Explain why the physician does not
make an active unilateral decision of declaring a patient dead?

Lecture activity 1.2.2

UNIT 2.2: Read

Introduction

Your normal cells are confined to a narrow range of function and structure dictated by the
state of metabolism, differentiation, and specialization; and by constraints imposed by
neighboring cells; and by the availability of metabolic substrates. It can handle physiologic demands
by maintaining a healthy steady state called homeostasis.

Adaptations are reversible functional and structural responses to changes in physiologic states and
some pathologic stimuli, during which new but altered steady states are achieved,
allowing the cell to survive and to continue its function (Fig 2-1 and table 2-1).

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 Figure 2-1 Stages of the cellular response to stress and injurious stimuli (Kumar, V., Abbas,
A. K., & Aster, J. C. 2015).

The adaptive response may consist of an increase in the size of the cells (Hypertrophy) and functional
activity, an increase in their number (hyperplasia), a decrease in the size and metabolic activity of
cells (atrophy), or a change in the phenotype of cells (metaplasia). When the stress is eliminated the
cell can recover to its original state without having suffered any harmful consequences (Fig 2-1).

FORMS OF ADAPTATIONS IN RESPONSE TO ENVIRONMENTAL CHANGES

1. Hypertrophy refers to an increase in the size of the cells resulting into an overall increase of the
organ as well.
 No new cells just larger cells due to increase in synthesis and assembly of additional
intracellular structural components.
 Cells capable of division may at the same time respond with hyperplasia.
 Cells incapable of division (ex. Myocardial fibers) increase in tissue mass is only by
hypertrophy.

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  Physiologic hypertrophy- due to increase in functional demand or by stimulation by
hormones or growth factors (ex. Increase workload among body builders; estrogenic
hormone induced increase in the uterine size during pregnancy. (Fig 2-2)

Figure 2-2. Physiologic hypertrophy of the uterus during pregnancy (Kumar, V., Abbas, A. K., &
Aster, J. C. 2015).

 Pathologic hypertrophy- Chronic hemodynamic overload due to hypertension of faulty

valves cause the myocardial fibers to hypertrophy.
o Beyond a certain point hypertrophy of myocardial cells become mal adaptive and
can lead to heart failure, arrhythmias and sudden death
- At a certain point the myocardial cells could no longer cope with the
increased burden. Regressive changes occur leading to lysis and loss of
myofibrillar contractile elements. The net result is cardiac failure.

2. Hyperplasia is an increase in the size of an organ or tissue caused by an increase in number of

cells in response to a stimulus.
 Frequently occur together with hypertrophy.
 Occurs only in cells that are capable of division.
 Physiologic hyperplasia- due to the action of hormones or growth factors. Occurs in
several circumstances:
o Need to increase functional capacity of the hormone sensitive organs.
- Hormonal hyperplasia is exemplified by glandular proliferation in the female
breast during puberty and pregnancy.
o Need for compensatory increase after damage or resection.
- Liver transplantation; Bone marrow hemopoiesis may increase as much as 8
folds when stimulated by the growth factor erythropoietin
 some cases, hyperplasia occurs together with hypertrophy. During pregnancy, uterine
enlargement is caused by both hypertrophy and hyperplasia of the smooth muscle cells in
the uterus.
 Pathologic hyperplasia- caused by excessive or inappropriate actions of hormones or
growth factors on target cells.
o Ex. Endometrial hyperplasia due to an excess in estrogen; Prostatic enlargement
due to an excess in androgens

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 o Distinct from cancer but may be fertile soil in which cancerous proliferations may
eventually arise (endometrial hyperplasia is at risk for endometrial cancer)
o Papillomaviruses cause epithelial hyperplasia causing mucosal lesions which are
considered precursors for cancer (ex. Cervical cancer)
3. Atrophy is a decrease in the size of an organ or tissue and results from a decrease in the mass of
pre-existing cells.
 Most often, causal factors are disuse, nutritional or oxygen deprivation, diminished
endocrine stimulation, aging, and denervation (lack of nerve stimulation in peripheral
muscles caused by injury to motor nerves).
 Characteristic features often include the presence of autophagic granules, which are
intracytoplasmic vacuoles containing debris from degraded organelles.
 Physiologic atrophy- common during normal development. The decrease in the uterus
shortly after parturition
 Pathologic atrophy- can be local or generalized.
o Decrease workload or atrophy of disuse- skeletal muscle atrophy due to fractured
bone immobilized in a plaster cast or in a patient restricted to bed rest (sekeletal
muscle decrease in number due to apoptosis).
- May be accompanied by osteoporosis.
o Loss of innervation-loss of nutritional supply to skeletal muscles resulting in loss in
metabolism and function.
o Diminished blood supply- ischemia due to atherosclerosis ( slowly developing arterial
occlusive disease) Late in adult life senile atrophy may result from progressive
atrophy of the brain; Alzhiemer’s (Fig 2-3)
o Inadequate nutrition- Profound protein-
calorie malnutrition (marasmus); Cachexia
in patients with chronic inflammatory
diseases and cancer
o Loss of endocrine stimulation- loss of
estrogen stimulation after menopause
causes atrophy of the endometrium,
vaginal epithelium, breast
o Pressure- tissue compression. Enlarging
benign tumor causes atrophy of surrounding
uninvolved tissue.
- Atrophy is due to ischemic changes
caused by a compromised blood
supply by the pressure of the
expanding mass
4. Metaplasia is the replacement of one differentiated tissue
by another.
 Squamous metaplasia is exemplified by the
replacement of columnar epithelium at the
squamocolumnar junction of the cervix by
squamous epithelium(Fig2-5).
o It can also occur in the respiratory Figure 2-3 Brain atrophy in
epithelium of the bronchus, in the
Alzhiemer’s disease (Cadar, D,
endometrium and in the pancreatic duct.
2009)
o Associated conditions include chronic

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 irritation as in squamous metaplasia of the bronchi with long-term use of tobacco
and vitamin A deficiency. This process is often reversible (Fig 2-5)
 Osseous metaplasia is the formation of new bone at sites of tissue injury. Cartilaginous
metaplasia may also occur.
 Myeloid metaplasia (extramedullary hematopoiesis) is proliferation of hematopoietic tissue
at sites other than the bone marrow, such as the liver and spleen.
 Metaplasia does not result from a change in the phenotype of an already differentiated
cell type; instead, it is the result of a reprogramming of stem cells that are known to exist in
normal tissues, or of undifferentiated mesenchymal cells present in connective tissue.

Figure 2-5 Metaplasia of columnar to squamous epithelium. A, Schematic diagram.

B, Metaplasia of columnar epithelium (left) to squamous epithelium (right) in a
bronchus. (Kumar, V., Abbas, A. K., & Aster, J. C. 2015).
C E L L IN JU R Y
 Cell injury occurs when:
o The limits of adaptive responses are exceeded if cells are exposed to injurious
agents or stress, deprived of essential nutrients.
o Become compromised by mutations that affect essential cellular constituents, a
sequence of events follow that is termed as.
o Cell injury is reversible up to a point, but if the injurious stimulus is persistent or
severe, the cell suffers irreversible injury and cell death may ensue.

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 o The removal of damaged, unneeded, and aged cells through cell death is a
normal and essential process in embryogenesis, the development of organs, and
the maintenance of homeostasis into adulthood.
o There are two pathways of cell death, necrosis, and apoptosis. Nutrient
deprivation triggers an adaptive cellular response called autophagy that may also
culminate in cell death (Fig 2-6).

Figure 2-6 Cellular responses to cell injury (Kumar, V., Abbas, A. K., & Aster, J. C. 2015).

Table 2-1 Cellular Responses to Injury (Kumar, V., Abbas, A. K., & Aster, J. C. 2015).

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CAUSES OF CELL INJURY (Table 2-1)

1. Hypoxic cell injury

 Oxygen deprivation or hypoxia causes cell injury by reducing aerobic oxidative respiration.
 Causes of hypoxia include:
o reduced blood flow (ischemia);
o inadequate oxygenation of the blood due to cardiorespiratory failure;
o decreased oxygen-carrying capacity of the blood, as in anemia or carbon
monoxide poisoning.
 Depending on the severity of the hypoxic state, cells may:
o adapt,
o undergo injury.
o Die
 At the early stage of hypoxic cell injury:
o the mitochondria are first affected with resultant decreased oxidative
phosphorylation and adenosine triphosphate (ATP) synthesis.

Consequences of decreased ATP availability include

o Failure of the cell membrane pump resulting in increased intracellular sodium and
water and decreased intracellular potassium. This process causes cellular swelling
and swelling of organelles.
- Cellular swelling or hydropic change is characterized by the presence of
large vacuoles in the cytoplasm.
- Swelling of the endoplasmic reticulum is one of the first ultrastructural
changes evident in reversible injury.
- Swelling of the mitochondria progresses from reversible low-amplitude
swelling to irreversible high amplitude swelling which is marked dilatation of
the inner mitochondrial space.
o Disaggregation of ribosomes leads to failure of protein synthesis. Ribosomal
disaggregation is also promoted by membrane damage.
o Stimulation of phosphofructokinase activity results in increased glycolysis,
accumulation of lactate, and decreased intracellular pH. Acidification causes
reversible clumping of nuclear chromatin.
 At the late stage, hypoxic cell injury eventually results in membrane damage to plasma and to
lysosomal and other organelle membranes, with loss of membrane phospholipids.

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 Reversible morphologic signs of damage include:
o
- the formation of myelin figures (whorl-like structures, probably originating from
damaged membranes)
- cell blebs (a cell surface deformity, most likely caused by disorderly function
of the cellular cytoskeleton)
 Finally, cell death is caused by severe or prolonged injury.
o The point of no return is marked by:
- irreversible damage to cell membranes, leading to massive calcium influx,
extensive
- calcification of the mitochondria, and cell death. Intracellular enzymes and
various other proteins are released from necrotic cells into the circulation as a
consequence of the loss of integrity of cell membranes.
- This phenomenon is the basis of a number of useful laboratory determinations
as indicators of necrosis.
 The vulnerability of cells to hypoxic injury varies with the tissue or cell type.
 Hypoxic injury becomes irreversible after:
o three to five minutes for neurons. Purkinje cells of the cerebellum and neurons of
the hippocampus are more susceptible to hypoxic injury than are other neurons.
o One to two hours for myocardial cells and hepatocyes
o many hours for skeletal muscle cells.
2. Free radical injury
 Free radicals are molecules that have a single unpaired electron in the outer orbital.
 Examples include activated products of oxygen reduction, such as the superoxide and the
hydroxyl radicals.
 Mechanisms that generate free radicals include:
o Normal metabolism
o Oxygen toxicity such as alveolar damage that can cause adult respiratory distress
syndrome or as in retrolental fibroplasias (retinopathy of prematurity), is an ocular
disorder of premature infants that leads to blindness.
o Ionizing radiation
o Ultraviolet light
o Drugs and chemicals, many of which promote both proliferation of the smooth
endoplasmic reticulum (SER) and induction of the p-450 system of mixed function
oxidases of the SER. Proliferation and hypertrophy of the SER of the hepatocyte are
classic ultrastructural markers of barbiturate intoxication.
o Reperfusion after ischemic injury
 Mechanisms that degrade free radicals:
o Intracellular enzymes such as glutathione peroxidase, catalase, and superoxide
dismutase
o Exogenous and endogenous antioxidants such as Vitamin A, Vitamin C, Vitamin E,
Cysteine, Glutathione, Selenium, Ceruloplasmin, and Transferrin.
o Spontaneous decay
3. Chemical cell injury
 Chemical agents and drugs may produce cell injury.
 A variety of simple chemicals like:
o salt in hypertonic concentrations may cause cell injury directly.
o Trace amounts of oxygen in high concentrations is toxic.
o Common household items can cause potential injury to your cells.

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 - Ex.liver cell membrane damage induced by carbon tetrachloride (CCl4).
- CCl4 is processed by the p-450 system of mixed function oxidases within the
SER, producing the highly reactive free radical Trichloromethane (CCl3-).
- CCl3- diffuses throughout the cell, initiating lipid peroxidation of intracellular
membranes.
- Widespread injury results to disaggregation of ribosomes, resulting in
decreased protein synthesis.
- Failure of the cell to synthesize the apoprotein moiety of lipoproteins causes
an accumulation of intracellular lipids (fatty change).
- It may also cause plasma membrane damage due to by-products of lipid
peroxidation in the SER, resulting in cellular swelling and massive influx of
calcium, with resultant mitochondrial damage, denaturation of cell proteins,
and cell death.
4. Infectious agents
 Infectious agents range from viruses, bacteria, fungi, and higher forms of parasites. The ways
by which these biologic agents cause injury have diverse mechanisms.
5. Immune system
 Injurious reactions to endogenous self-antigens are responsible for autoimmune diseases.
 Immune reactions to many external agents such as viruses and environmental substances are
also important causes of cell and tissue injury.
6. Genetic abnormalities
 Genetic abnormalities may cause cell injury because of genetic aberration or substitution can
lead to clinical phenotypes ranging from congenital malformations and deficient protein
function, such as enzyme defects or accumulation of damaged DNA or misfolded proteins,
both trigger cell death when beyond repair.
 DNA sequence variants can influence susceptibility of cells to injury by chemicals and other
environmental insults.

Up to this point, the core aspects of pathology you have been reading about are etiology,
pathophysiology, and morphological changes. The stresses and noxious influences interacting with
the living system creates structural and functional changes effected by a series of events initiated by

20
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the cause. The morphological alterations described above are at the ultrastructural level. That means
only visible on electron microscopy, not on light microscopy. These changes may also be seen
through histochemistry which determines the chemical changes in the cell with the use of stains,
indicators, and microscopy. By the time these changes are observed using ultrastructural and
histochemical techniques, it very possible that irreversible cell injury has already occurred (Figure 2-7).
Figure 2-7 Sequential development of biochemical and morphologic
changes in cell injury (Kumar, V., Abbas, A. K., & Aster, J. C. 2015).
M O R P H O L O G IC A L T E R A T IO N S IN C E L L IN JU R Y
1. R E V E R S IB L E C E L L IN JU R Y
B asic A lteratio n s:
 All stresses and noxious influences exert their effects first at the molecular and biochemical level
 Time lag between stress and the morphologic changes of cell injury
o Histochemical and Ultrastructural techniques- Minutes to hours after injury
o Light Microscopy and gross examination- hours to days
o Ischemia of myocardial cell
- Cell swelling in a matter of minutes
- Irreversible in an hour or two
- Unmistakable light microscopic changes- 4-12 hours after onset of Ischemia
 R eversib le cell in ju ry is d u e to :
o Decreased ATP generation
o Loss of cell membrane integrity
o Defects in protein synthesis
o Cytoskeletal damage
o DNA damage
 M o rp h o lo g y o f reversib le cell in ju ry (U ltrastru ctu ral):
o Plasma membrane- Generalized swelling of the cell and its organelles.
- Blebbing, blunting and loss of microvilli.
o ER- dilation with detachment of polyribosomes, intracytoplasmic myelin figures
o Mitochondrial changes- swelling and appearance of amorphous densities
o Clumping of nuclear chromatin
 M o rp h o lo g y o f reversib le in ju ry u n d er th e lig h t m icro sco p e
o C ellu lar sw ellin g - occurs as result of the cells failure to maintain ionic and fluid
homeostasis due to the failure of energy-dependent ion pumps in the plasma membrane.
- More apparent on the whole organ. It manifests with pallor, increased turgor and
weight.
- Small clear vacuoles are seen in the cytoplasm- represent pinched off segments of
ER. (H yd ro p ic ch an g e o r vacu o lar d eg en eratio n )
- Increased eosinophilic staining which becomes more pronounced with progression to
necrosis
o F atty ch an g e- occurs in hypoxic injury and various forms of toxic or metabolic injury
- Manifested by appearance of lipid vacuoles in the cytoplasm
- Seen in cells involved in and dependent on fat metabolism
- Ex. Hepatocytes, myocardial cells

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 *T he reversible nature of this stage is due to the cells capacity w ithin lim its to repair itself and return
itself to norm alcy. H ow ever, persistent, or excessive injury causes the cells to reach a “point of no
return” into irreversible injury and cell death.

2. CELL DEATH
 Tissue death has two contrasting morphologic patterns:
o Necrosis
o Apoptosis.
 NECROSIS is the sum of the degradative and inflammatory reactions occurring after tissue
death caused by injury (e.g. hypoxia and exposure to toxic chemicals)
o The morphology of necrosis is the result of denaturation of intracellular proteins
and enzymatic digestion of the lethally injured cell.
o The enzymes that digest the necrotic cell happens by 2 processes:
- Autolysis refers to degradative reactions in cells caused by intracellular
enzymes indigenous to cell.
- From the lysosomes of the dying cells themselves
- Postmortem autolysis occurs after the death of the entire organism and is not
necrosis.
- Heterolysis refers to cellular degradation by enzymes derived from sources
extrinsic to the cell.
- Ex. From leucocytes like macrophages
o As the enzymes digest the cell, they are unable to maintain membrane integrity
and their contents often leak out causing inflammation of the surrounding tissue
o Digestion of cellular contents and host response may take hours to develop and so
there will be no detectable changes in cells if, for example, a myocardial infarct
caused sudden death.
- The earliest histologic evidence of myocardial necrosis does not become
apparent until 4-12 hours later
- Due to the loss of plasma membrane integrity, cardiac specific enzymes and
proteins are rapidly released from the necrotic muscle and can be detected
in the blood as early as 2 hours after myocardial necrosis

PATTERNS OF NECROSIS

Cell death morphology at this point is focused on individual cells. When large numbers of cells die
the tissue or organ is said to be necrotic; thus, a myocardial infarct is necrosis of a portion of the heart
cause by the death of many myocardial cells. Necrosis of tissues has several morphologically distinct
patterns which a pathologist may take note of because they may provide clues about the
underlying cause.

1. Coagulative necrosis results most often from a sudden cutoff of blood supply to an organ
(ischemia), particularly the heart and kidney (solid organs).
 General preservation of tissue architecture is characteristic in the early stages.
o The intense intracellular acidosis not only denatures the structural proteins but also
the proteolytic enzymes released from the lysosome: as a result eosinophilic
anucleate cells may persist for days to weeks which are referred to as the
“Tombstone appearance”of the cells.

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  As it progresses, increased cytoplasmic eosinophilia occurs because of protein denaturation
and loss of cytoplasmic RNA.
 Nuclear changes, the morphologic hallmark of irreversible cell injury and necrosis are
characteristic.
 These include:
o Pyknosis, chromatin clumping and shrinking with increased basophilia.
o Karyorrhexis, fragmentation of chromatin
o Karyolysis, fading of chromatin material.
- Disappearance of stainable nuclei
 Ultimately the necrotic cells are removed by heterolysis by infiltrating leucocytes.
 A localized area of coagulative necrosis is called an infarct.
2. Liquefactive necrosis results to characteristic digestion, softening, and liquefaction of tissue.
 Examples include ischemic injury to the central nervous system (CNS) characteristically results
in liquefactive necrosis.
 After the death of CNS cells, liquefaction is caused by autolysis.
 It is seen in focal bacterial or occasionally fungal infections that stimulate inflammation.
 Suppurative infections characterized by the formation of pus (liquefied tissue debris and
neutrophils) by heterolytic mechanisms.
 The necrotic material is frequently creamy yellow because of the presence of pus.
3. Caseous necrosis occurs as part of granulomatous inflammation and is a manifestation of partial
immunity caused by the interaction of T lymphocytes (CD4+, CD8+, and CD4-CD8-),
macrophages, and probably cytokines, such as interferon-γ, derived from these cells.
 Caseous necrosis combines features of both coagulative necrosis and liquefactive necrosis.
 On gross examination, caseous necrosis has a cheese-like (caseous) consistency, a friable
white appearance.
 On histologic examination, caseous necrosis has an amorphous eosinophilic appearance.
 Tuberculosis is the leading cause of caseous necrosis.
4. Gangrenous necrosis most often affects the lower extremities or bowel and is secondary to
vascular occlusion.
 Not a specific pattern of cell death but is a commonly used term in clinical practice.
 Usually applied to a limb, generally the lower leg that has lost is blood supply.
 When complicated by infective heterolysis and consequent liquefactive necrosis, gangrenous
necrosis is called wet gangrene.
 When characterized primarily by coagulative necrosis without liquefaction, gangrenous
necrosis is called dry gangrene.
 When infection is caused by Clostridium perfringens which produces gas and a feeling of
crepitus it is called gas gangrene
5. Fibrinoid necrosis is often associated with immune-mediated vascular damage.
 Occurs when complexes of antigens and antibodies are deposited in the walls of arteries
 There is deposition of fibrin-like proteinaceous material in the arterial walls that appears to be
smudgy and acidophilic.
6. Fat necrosis occurs in two forms:
 Traumatic fat necrosis occurs after a severe injury to tissue with high fat content, such as the
breast.
 Enzymatic fat necrosis, which is a complication of acute hemorrhagic pancreatitis (a severe
inflammatory disorder of the pancreas),
o involves proteolytic and lipolytic pancreatic enzymes diffuse into inflamed tissue
and literally digest the parenchyma.

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 o Fatty acids are then liberated by the digestion of fat and form calcium soaps
(saponification, or soap formation). Vessels are eroded, with resultant hemorrhage.
- Appear as grossly visible chalky- white areas which enable the surgeon or the
pathologist to identify the lesion.
o Histologic morphology: necrosis takes the form of shadowy outlines of necrotic fat
cells with basophilic calcium deposits surrounded by inflammatory reaction.

The 100 trillion cells of the body are members of a highly organized community where total number of
cells are regulated by controlling the both the rate of cell division and cell death. When cells are no
longer needed or become a threat to the organism, they undergo a programmed cell death called
apoptosis. Cells that die by necrosis swell and burst due to loss of cell membrane integrity and in the
process spill their contents, causing inflammation and injury to neighboring cells. Apoptosis on the
other hand is an orderly cell death that causes the cell to shrink and condense, to disassemble its
cytoskeleton and alter its cell surface so that phagocytic cells can attach to it and digest it rapidly
before any leakage of its contents occurs, and neighboring cells usually remain healthy (Table 2-2).

 APOPTOSIS Often referred to as programmed cell death, apoptosis is a second morphologic

pattern of tissue death.
o Apoptosis is a Greek term for “falling away from.” This is an important mechanism
for the removal of cells.
o Purpose:
- Eliminate cells that are no longer needed.
- Maintain a steady number of various cell populations in tissues.
o Morphologic features include a tendency to involve single isolated cells or small
clusters of cells within a tissue.
o Progression through a series of changes marked by a lack of inflammatory
response include blebbing of plasma membrane, cytoplasmic shrinkage, and
chromatin condensation; budding of cell and separation of apoptotic bodies
(membrane-bound segments); and phagocytosis of apoptotic bodies. There is
also involution and shrinkage of affected cells and cell fragments, resulting in small
round eosinophilic masses often containing chromatic remnants as exemplified by
Councilman bodies in viral hepatitis.

o Physiologic Apoptosis:
- Destruction of cells during embryogenesis, implantation, organogenesis,
developmental involution, and metamorphosis
- Involution of hormone dependent tissues upon hormone withdrawal, such as
endometrial cell breakdown during menstrual cycle, ovarian follicular atresia
in menopause, regression of lactating breast after weaning, prostatic atrophy
after castration.
- Cell loss in proliferating cell populations, such as immature lymphocytes in the
bone marrow and thymus and B lymphocytes in germinal centers that fail to
express useful antigen receptors, and epithelial cells in intestinal crypts, so as
to maintain a constant number (homeostasis)
- Elimination of potentially harmful self-reactive lymphocytes, either before or
after they have completed their maturation, to prevent autoimmune
reactions.

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 - Death of host cells that have served their useful purpose, such as neutrophils
in an acute inflammatory response and lymphocytes at the end of an
immune response. In this case they are deprived of necessary survival signals,
such as growth factors.
o Pathologic Apoptosis- Apoptosis eliminates cells that are injured beyond repair
without eliciting a host reaction, thus limiting collateral tissue damage.
- DNA damage, Radiation, cytotoxic anticancer drugs and hypoxia can
damage DNA, either directly or by production of free radicals. If repair
mechanism cannot cope with the injury, the cell triggers intrinsic mechanisms
that induce apoptosis. Elimination of the cell is a better alternative that risking
malignant transformation.
- Accumulation of misfolded proteins, improperly folded proteins arise from
mutations in the genes encoding these proteins or because extrinsic factors
such as damage caused by free radicals. Excessive accumulation of these
misfolded proteins in the ER is called ER stress, culminates in apoptotic cell
death. Apoptosis caused by accumulation of misfolded proteins has been
invoked as the basis of several degenerative diseases of the CNS and other
organs.
- Cell death in certain infections, particularly viral infections, in which loss of
infected cells is largely due to apoptosis that may be induced by the virus
(adenovirus and HIV infections) or by the host immune response (as in viral
hepatitis). This is a T cell mediated response to viral proteins in an attempt to
eliminate reservoirs of infection.
- Pathologic atrophy in parenchymal organs after duct obstruction, such as in
the pancreas, parotid gland and the kidney.

MORPHOLOGY OF APOPTOSIS
o Cell Shrinkage- cells smaller, cytoplasm is denser and the organelles, although
relatively normal, are more tightly packed
o Chromatin condensation- most characteristic feature of apoptosis
- Chromatin aggregates peripherally under the nuclear membrane, into dense
masses of various shapes and sizes.
- The nucleus itself may break up producing 2 or more fragments.
o Formation of cytoplasmic blebs and apoptotic bodies- the cell shows extensive
surface blebbing, then undergoes fragmentation into membrane bound
apoptotic bodies composed of cytoplasm and tightly packed organelles with or
without nuclear fragments.
o Phagocytosis of apoptotic cells or cells bodies usually by macrophages
- Apoptotic bodies are rapidly ingested by phagocytes and degraded by the
phagocyte’s lysosomal enzymes.
- Plasma membranes are thought to remain intact during apoptosis until the
last stages hence, do not spill their contents into extracellular environment
and usually do not trigger inflammation and keeps neighboring cells healthy.

*On H&E apoptotic cells appear round or oval mass of intensely eosinophilic cytoplasm with
fragments of dense nuclear chromatin. The cell shrinkage and formation of apoptotic bodies

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 are rapid and quickly phagocytosed and does not illicit inflammation such that considerable
apoptosis may occur in tissue before it becomes apparent in histologic sections.

Table 2-2: Difference between Necrosis and Apoptosis. (Kumar, V., Abbas, A. K., & Aster,
J. C. 2015).

INTRACELLULAR ACCUMULATIONS

As an effect of cell injury, there may be metabolic alterations within the cell. Possible clues to this
deranged function are intracellular accumulations of various substances in abnormal amounts. These
substances may be harmless or associated with varying degrees of injury. They may be located in the
cytoplasm, within organelles (typically lysosomes) or in the nucleus, and it may be synthesized in the
affected cells or may be produced elsewhere.

4 Main Pathways of Abnormal Intracellular Accumulations

1. Inadequate removal of a normal substance secondary to defects in mechanisms of packaging
and transport
 Ex. Fatty change in the liver
2. Accumulation of an abnormal endogenous substance as a result of genetic or acquired defects
in its folding, packaging, transport, or secretion
 Ex Mutated forms of α1-antitrypsin
3. Faillure to degrade a metabolite due to inherited enzyme deficiencies.
 Ex. Storage diseases

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4. Deposition and accumulation of an abnormal exogenous substance when the cell has neither
the enzymatic machinery to degrade the substance nor the ability to transport it to other sites
 Ex. Accumulation of carbon or silica particles

LIPIDS

1. FATTY CHANGE (FATTY METAMORPHOSIS AND STEATOSIS)

 Fatty change is characterized by the accumulation of intracellular parenchymal triglycerides
and is observed most frequently in the liver, heart, and kidney.
 For example, in the liver, fatty change may be secondary to alcoholism, diabetes mellitus,
malnutrition, obesity, or poisonings.
 Imbalance in the uptake, utilization, and secretion of fat is the cause of fatty change, and this
can result from any of the following mechanisms:
o Increased transport of triglycerides or fatty acids to affected cells.
o Decreased mobilization of fat from cells, most often mediated by decreased
production of apoproteins required for fat transport. Fatty change is thus linked to
the disaggregation of ribosomes and consequent decreased protein synthesis
caused by failure of ATP production in CCl4- injured cells.
o Decreased use of fat by cells.
o Overproduction of fat in cells
2. Cholesterol and Cholesterol Esters
 Cellular metabolism of cholesterol is tightly regulated such that most cells use cholesterol for
the synthesis of cell membranes.
 Atherosclerosis. In atherosclerotic plaques, smooth muscle cells and macrophages within the
intimal layer of the aorta and large arteries are filled with lipid vacuoles, most of which are
made up of cholesterol and cholesterol esters.
o Such cells have a foamy appearance (foam cells), and aggregates of them in
the intima produce the yellow cholesterol-laden atheroma’s characteristic of this
serious disorder.
o Some of these fat-laden cells may rupture, releasing lipids into the extracellular
space.
o The extracellular cholesterol esters may crystallize in the shape of long needles,
producing quite distinctive clefts in tissue sections.
 Xanthomas Intracellular accumulation of cholesterol within macrophages is also characteristic
of acquired and hereditary hyperlipidemic states.
o Clusters of foamy cells are found in the subepithelial connective tissue of the skin
and in tendons, producing tumorous masses known as xanthomas.
 Cholesterolosis. This refers to the focal accumulations of cholesterol-laden macrophages in
the lamina propria of the gallbladder.
 Niemann-Pick disease, type C. This lysosomal storage disease is caused by mutations affecting
an enzyme involved in cholesterol trafficking, resulting in cholesterol accumulation in multiple
organs.

PROTEINS
Excesses of proteins within the cells sufficient to cause morphologically visible accumulation
have diverse causes.

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1. Reabsorption droplets in proximal renal tubules are seen in renal diseases associated with protein
loss in the urine (proteinuria).
 In the kidney small amounts of protein filtered through the glomerulus are normally reabsorbed
by pinocytosis in the proximal tubule.
 In disorders with heavy protein leakage across the glomerular filter there is increased
reabsorption of the protein into vesicles, and the protein appears as pink hyaline droplets
within the cytoplasm of the tubular cell
 The process is reversible; if the proteinuria diminishes, the protein droplets are metabolized and
disappear.
2. The proteins that accumulate may be normal secreted proteins that are produced in excessive
amounts, as occurs in certain plasma cells engaged in active synthesis of immunoglobulins.
 The ER becomes hugely distended, producing large, homogeneous eosinophilic inclusions
called Russell bodies.
3. Defective intracellular transport and secretion of critical proteins .
 In α1-antitrypsin deficiency, mutations in the protein significantly slow folding, resulting in the
buildup of partially folded intermediates, which aggregate in the ER of the liver and are not
secreted.
 The resultant deficiency of the circulating enzyme causes emphysema
 In many of these diseases the pathology results not only from loss of protein function but also
ER stress caused by the misfolded proteins, culminating in apoptotic death of cells.
4. Accumulation of cytoskeletal proteins.
 There are several types of cytoskeletal proteins:
o microtubules (20–25 nm in diameter)
o thin actin filaments (6–8 nm)
o thick myosin filaments (15 nm)
o intermediate filaments (10 nm)
 Intermediate filaments, which provide a flexible intracellular scaffold that organizes the
cytoplasm and resists forces applied to the cell, are divided into five classes.
o keratin filaments (characteristic of epithelial cells)
o neurofilaments (neurons)
o desmin filaments (muscle cells)
o vimentin filaments (connective tissue cells)
o glial filaments (astrocytes)
 Accumulations of keratin filaments and neurofilaments are associated with certain types of
cell injury.
o Alcoholic hyaline is an eosinophilic cytoplasmic inclusion in liver cells that is
characteristic of alcoholic liver disease and is composed predominantly of keratin
intermediate filaments.
 The neurofibrillary tangle found in the brain in Alzheimer disease contains neurofilaments and
other proteins.
5. Aggregation of abnormal proteins. Abnormal or misfolded proteins may deposit in tissues and
interfere with normal functions. The deposits can be intracellular, extracellular, or both, and the
aggregates may either directly or indirectly cause the pathologic changes.
o Certain forms of amyloidosis fall in this category of diseases. These disorders are
sometimes called proteinopathies or protein-aggregation diseases.

HYALINE CHANGE

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1. Intracellular hyaline change is caused most often by nonspecific accumulations of proteinaceous
material with a characteristic homogenous, glassy, and eosinophilic appearance in hematoxylin
and eosin sections.
 It is widely used as a descriptive histologic term rather than a specific marker for cell injury.
 This morphologic change is produced by a variety of alterations and does not represent a
specific pattern of accumulation.
 Intracellular accumulations of protein, described earlier (reabsorption droplets, Russell bodies,
alcoholic hyaline), are examples of intracellular hyaline deposits.
2. Extracellular hyaline has been more difficult to analyze.
 Collagenous fibrous tissue in old scars may appear hyalinized, but the biochemical basis of this
change is not clear.
 In long-standing hypertension and diabetes mellitus, the walls of arterioles, especially in the
kidney, become hyalinized, resulting from extravasated plasma protein and deposition of
basement membrane material.

GLYCOGEN
 Glycogen is a readily available energy source stored in the cytoplasm of healthy cells.
 Excessive intracellular deposits of glycogen are seen in patients with an abnormality in either
glucose or glycogen metabolism. Whatever the clinical setting, the glycogen masses appear
as clear vacuoles within the cytoplasm.
 Diabetes mellitus is the prime example of a disorder of glucose metabolism.
o Glycogen is found in renal tubular epithelial cells, as well as within liver cells, β cells
of the islets of Langerhans, and heart muscle cells.
 Glycogen accumulates within the cells in a group of related genetic disorders that are
collectively referred to as the glycogen storage diseases, or glycogenoses.
o In these diseases enzymatic defects in the synthesis or breakdown of glycogen
result in massive accumulation, causing cell injury and cell death.

EXOGENOUS PIGMENTS
 The most common exogenous pigment is carbon (coal dust),
o a ubiquitous air pollutant of urban life.
o When inhaled it is picked up by macrophages within the alveoli and is then
transported through lymphatic channels to the regional lymph nodes in the
tracheobronchial region.
o Accumulations of this pigment blacken the tissues of the lungs (anthracosis) and
the involved. lymph nodes.
o In coal miners the aggregates of carbon dust may induce a fibroblastic reaction
or even emphysema and thus cause a serious lung disease known as coal worker's
pneumoconiosis
o Tattooing is a form of localized, exogenous pigmentation of the skin.
- The pigments inoculated are phagocytosed by dermal macrophages, in
which they reside for the remainder of the life of the embellished (sometimes
with embarrassing consequences for the bearer of the tattoo!).
- The pigments do not usually evoke any inflammatory response.

ACCUMULATIONS OF ENDOGENOUS PIGMENTS

1. Lipofuscin is an insoluble pigment, also known as lipochrome or wear-and-tear pigment.
 Lipofuscin is composed of polymers of lipids and phospholipids in complex with protein,

29
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  Intracellular Accumulations suggesting that it is derived through lipid peroxidation of
polyunsaturated lipids of subcellular membranes.
 Lipofuscin is not injurious to the cell or its functions.
 Its importance lies in its being a telltale sign of free radical injury and lipid peroxidation.
 The term is derived from the Latin (fuscus, brown), referring to brown lipid. In tissue sections it
appears as a yellow brown, finely granular cytoplasmic, often perinuclear, pigment.
 It is seen in cells undergoing slow, regressive changes and is particularly prominent in the liver
and heart of aging patients or patients with severe malnutrition and cancer cachexia.
2. Melanin This pigment is formed from tyrosine by the action of tyrosinase, synthesized in
melanosomes of melanocytes within the epidermis, and transferred by melanocytes to adjacent
clusters of keratinocytes and also to macrophages (melanophores) in the subjacent dermis.
 Increased melanin pigmentation is associated with sun tanning and with a wide variety of
disease conditions. Decreased melanin pigmentation is observed in albinism. and vitiligo.
3. Bilirubin This pigment is a catabolic product of the heme moiety of hemoglobin and, to a minor
extent, myoglobin.
 In various pathologic conditions, bilirubin accumulates and stains the blood, sclera, mucosae,
and internal organs, producing a yellowish discoloration called jaundice.
 Hemolytic jaundice is associated with the destruction of red cells.
 Hepatocellular jaundice is associated with parenchymal liver damage, and
 Obstructive jaundice, which is associated with intra- or extrahepatic obstruction of the biliary
tract.
4. Hemosiderin is a hemoglobin-derived, golden yellow-to-brown, granular or crystalline pigment
that serves as one of the major storage forms of iron.
 Iron is normally carried by specific transport proteins, transferrins. In cells, it is stored in
association with a protein, apoferritin, to form ferritin micelles.
 Ferritin is a constituent of most cell types. When there is a local or systemic excess of iron, ferritin
forms hemosiderin granules, which are easily seen with the light microscope.
 Hemosiderin pigment represents aggregates of ferritin micelles. Under normal conditions small
amounts of hemosiderin can be seen in the mononuclear phagocytes of the bone marrow,
spleen, and liver, which are actively engaged in red cell breakdown.
 Local or systemic excesses of iron cause hemosiderin to accumulate within cells.
 Local excesses result from hemorrhages in tissues.
o The best example of localized hemosiderosis is the common bruise.
o Extravasated red blood cells at the site of injury are phagocytosed over several
days by macrophages, which break down the hemoglobin and recover the iron.
After removal of iron, the heme moiety is converted first to biliverdin (“green bile”)
and then to bilirubin (“red bile”).
o In parallel, the iron released from heme is incorporated into ferritin and eventually
hemosiderin. These conversions account for the often-dramatic play of colors seen
in a healing bruise, which typically changes from red-blue to green-blue to
golden-yellow before it is resolved.
 When there is systemic overload of iron hemosiderin may be deposited in many organs and
tissues, a condition called hemosiderosis. The main causes of hemosiderosis are:
o increased absorption of dietary iron,
o hemolytic anemias, in which abnormal quantities of iron are released from
erythrocytes,
o repeated blood transfusions because the transfused red cells constitute an
exogenous load of iron.

30
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Lecture Activity 1.2.3. Atherosclerosis (30points)

Atherosclerosis literally means “hardening of the arteries”. It is a

generic term for arterial wall thickening and loss of elasticity. Its
major consequences are myocardial infarction, cerebral
infarction, aortic aneurysms, and peripheral vascular disease. Make concept map of its
pathophysiology. Take note of the scoring rubric below.

9-10 6-8 3-5 0-2

All relevant cause More than half of Less than half of the Few relevant
and effect the relevant cause cause-and-effect cause and
interactions are and effect interactions are effect
CONTENT
included and interactions are included and interactions are
correct included and correct included and
correct correct
Understanding of Understanding of Understanding of Poor
cause-and-effect cause-and-effect cause and effect understanding
interactions are interactions are interactions are of cause-and-
clearly clearly clearly effect
LOGIC AND
demonstrated by demonstrated by demonstrated but interactions with
UNDERSTANDING
correct links and correct links but with some errors significant errors
descriptive words some descriptive ( eg. Incorrect links
words are and descriptive
inappropriate words)
Concept map is Concept map is Concept map is Concept map is
neat, clear and neat, clear and neat, clear and untidy with links
legible and has legible and has legible but with difficult to follow
PRESENTATION easy to follow easy to follow links, some links that are
links, no spelling has some spelling difficult to folow,
errors errors has some spelling
errors

NEOPLASIA
UNIT 3

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Lecture activity 1.3.1

Key Facts About Cancer

1. About 16% of people die of cancer

2. 70% of all deaths occur in low- and middle-income countries.
3. In 2017, less than 30% of low-income countries reported treatment services were generally
available compared to more than 90% of high-income countries.
4. Worldwide, only about 14% of people who need palliative care currently receive it
5. Between 30-50% of cancers are preventable. Tobacco use is the single largest preventable
cause and is responsible for approximately 22% of all cancer related deaths.

Lecture Activity 1.3.2 Read

UNIT 3.2 READ.

Introduction

Cancer is the second leading cause of death behind heart disease. Deaths from heart disease
have declined 45% in the United States since 1950 and continue to decline. Cancer has overtaken
heart disease as the number one cause of death in persons younger than age 85. Lung cancer is the
most common cancer and the most common cause of death in the world. It has been estimated
that nine modifiable risk factors are responsible for more than one third of cancers worldwide. These
include smoking, alcohol consumption, obesity, physical inactivity, low fruit and vegetable
consumption, unsafe sex, air pollution, indoor smoke form household fuels and contaminated
injections.

The diagnosis of cancer relies most heavily on invasive tissue biopsy and should never be
made without obtaining tissue. No noninvasive diagnostic test is sufficient to define a disease process
as cancer. Histopathologic techniques are required for this purpose.

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NOMENCLATURE

Neoplasm/ Neoplasia- new growth

Tumor- originally applied to swelling caused by inflammation, but the non-neoplastic usage has
almost vanished; thus the term now is equated with neoplasm.
Oncology (Greek oncos= tumor)- is the study of tumors/neoplasms

Modern definition of neoplasm

 a disorder of cell growth that is triggered by a series of acquired mutations affecting a
single cell and it clonal progeny.
 Causative mutations give the neoplastic cells a survival and growth advantage, resulting in
excessive proliferation that is independent of physiologic growth signals (autonomous)

2 Basic components of tumors

1. Neoplastic cells- constitute the tumor parenchyma.
 Basis for classification and their biologic behavior
2. Reactive stroma- made up of connective tissue, blood vessels and variable numbers of cells of
the adaptive and innate immune system
 Basis for tumor growth and spread

Benign tumors (Table 3-1):

 When its gross and microscopic appearances are considered relatively innocent, implying
that it will remain localized, will not spread to other sites, and is amenable to local surgical
removal.
 Patient generally survives but may cause significant morbidity and are sometimes fatal.
 Suffix -oma is attached to the name of the from which the tumor originates.
o Tumors of mesenchymal cells follow this rule.
- Fibroma- from fibrous tissue
- Chondroma- from cartilaginous tissue
o For epithelial tumors
- Based on their cells of origin
 Adenoma- derived from glands but not necessarily producing glandular
patterns.
- Based on their microscopic pattern
 Papillomas- microscopic and macroscopic fingerlike warty projections
- Based on macroscopic architecture
 Cystadenomas- large cystic masses in the ovary
 Polyp- macroscopically visible projection above a mucosal surface
 Adenomatous polyp- if the poly has glandular tissue.
Malignant tumors(Table 3-1):
 Collectively called cancers.
 Derived from the latin word for crab because they tend to adhere to any part that they
seize on
 Malignant tumors can invade and destroy adjacent structures and spread to distant sites
(metastasize) to cause death.
 Sarcomas- malignant tumors arising from solid mesenchymal tissues.
o Fibrosarcoma, chondrosarcoma, leiomyosarcoma and rhabdomyosarcoma
 Leukemias- arise from blood forming cells.

33
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  Lymphomas- arise from lymphocytes or their precursors.
 Carcinoma- arise from epithelial cell origin and from any of the 3 germ layers.
o Ectoderm- from epidermis
o Mesoderm- renal tubules
o Endoderm- lining of the gastrointestinal tract
o May be further qualified.
- Squamous cell carcinoma- tumor resemble stratified squamous epithelium.
- Adenocarcinoma- neoplastic epithelial cells grow in a glandular pattern.
o Based on tissue or organ of origin
- Renal cell adenocarcinoma
- Bronchogenic squamous cell carcinoma
 Undifferentiated malignant tumor- cells of unknown tissue origin

Mixed tumors (Table 3-2):

 Divergent differentiation of a single neoplastic clone
 Contain epithelial components scattered within a myxoid stroma that may contain islands
of cartilage or bone- pleomorphic adenoma.
 Most neoplasm arise from a single germ layer.
 Teratoma- contains recognizable mature and immature cells or tissues belonging to more
than one germ layer (sometimes all three)
o Arises from totipotential germ cells that are normally present in the ovary and testis
or in abnormal midline embryonic rests
- Can differentiate into any of the cell types found in the human body
- Ex. Ovarian cystic teratoma (dermoid cyst)- cystic tumor lined by skin with
hair , sebaceous glands, and tooth structures

Table 3.1. Comparisons between Benign and Malignant Tumors (Kumar, V., Abbas, A. K., &
Aster, J. C. 2015).

Table 3-2 Nomenclature of tumors (Kumar, V., Abbas, A. K., & Aster, J. C. 2015).

34
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 35
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Being told that a tumor is benign and not malignant means the whole world to a patient being
assessed for a mass or new growth. It is one of the most important distinctions a pathologist makes
and does so with absolute proficiency due to the extremes in significance the two terms may mean.
In most instances differentiating benign from malignant can be made with considerable confidence
based on morphology. Occasionally it is not as easy, and therefore will require molecular profiling or
other molecular ancillary tests.

CHARACERISTICS OF BENIGN AND MALIGNANT TUMORS

1. Differentiation refers to the extent to which neoplastic parenchymal cells resemble the
corresponding normal parenchymal cells, both morphologically and functionally.
 Lack of differentiation is called anaplasia.
 In general, benign tumors are well differentiated.
 Malignant neoplasms are characterized by a wide range of parenchymal cell
differentiation, from surprisingly well differentiated to completely undifferentiated.
 Malignant neoplasms that are composed of poorly differentiated cells are said to be
anaplastic. Lack of differentiation, or anaplasia, is considered a hallmark of malignancy.

Distinction between dysplasia and anaplasia is important because crossing over from dysplasia to
anaplasia is considered the point of malignant transformation. Morphology of these will be discussed
in greater detail in laboratory.

2. Rates of growth
 By the time a solid tumor is clinically detected, it has already completed a major portion of
its life span. This is a major impediment in the treatment of cancer and underscores the
need to develop diagnostic markers to detect early cancers.
 The rate of growth of a tumor is determined by three main factors:
- the doubling time of tumor cells,
- the fraction of tumor cells that are in the replicative pool (growth fraction),
- the rate at which cells are shed or die.
 Clinical and experimental studies suggest that during the early, submicroscopic phase of
tumor growth, the vast majority of transformed cells are in the proliferative pool.
 As tumors continue to grow, cells leave the proliferative pool in ever-increasing numbers as
a result of shedding, lack of nutrients, necrosis, apoptosis, differentiation, and reversion to
the non-proliferative phase of the cell cycle (G0).
 Thus, by the time a tumor is clinically detectable, most cells are not in the replicative pool.
Even in some rapidly growing tumors, the growth fraction is only about 20% or less

36
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 The growth fraction of tumor cells has a profound effect on their susceptibility to cancer

chemotherapy. Because most anticancer agents act on cells that are in cycle, it is not
difficult to imagine that a tumor that contains 5% of all cells in the replicative pool will be
slow growing but relatively refractory to treatment with drugs that kill dividing cells.
- One strategy used in the treatment of tumors with low growth fraction (e.g.,
cancer of colon and breast) is first to shift tumor cells from G0 into the cell
cycle. This can be accomplished by debulking the tumor with surgery or
radiation. The surviving tumor cells tend to enter the cell cycle and thus
become susceptible to drug therapy. Such considerations form the basis of
combined-modality treatment.
- Some aggressive tumors (such as certain lymphomas and leukemias) that
contain a large pool of dividing cells literally melt away with chemotherapy
and may even be cured.
3. Cancer stem cells and cancer lineages
 The continued growth and maintenance of many tissues that contain short-lived cells, such
as the formed elements of the blood and the epithelial cells of the gastrointestinal tract
and skin, require a resident population of tissue stem cells that are long-lived and capable
of self-renewal.
 Tissue stem cells are rare and exist in a niche created by support cells, which produce
paracrine factors that sustain the stem cell.
 Tissue stem cells divide asymmetrically to produce two types of daughter cells—those with
limited proliferative potential, which undergo terminal differentiation and die, and those
that retain stem cell potential.
 Cancers are immortal and have limitless proliferative capacity, indicating that like normal
tissues, they also must contain cells with “stemlike” properties. The concept of cancer stem
cells have several important implications. Most notably:
- if cancer stem cells are essential for tumor persistence, it follows that these
cells must be eliminated to cure the affected patient.
- It is hypothesized that like normal stem cells, cancer stem cells have a high
intrinsic resistance to conventional therapies, because of their low rate of cell
division and the expression of factors, such as multiple drug resistance-1
(MDR1), that counteract the effects of chemotherapeutic drugs.
- Thus, the limited success of current therapies may in part be explained by
their failure to kill the malignant stem cells that lie at the root of cancer.
Cancer stem cells could arise from normal tissue stem cells or from more
differentiated cells that, as part of the transformation process, acquire the
property of self-renewal.
4. Local invasion
 Nearly all benign tumors grow as cohesive expansile masses that remain localized to their
site of origin and do not have the capacity to infiltrate, invade, or metastasize to distant
sites, as do malignant tumors.
- Because they grow and expand slowly, they usually develop a rim of
compressed connective tissue, sometimes called a fibrous capsule, which
separates them from the host tissue.

37
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 -
Such encapsulation does not prevent tumor growth, but it keeps the benign
neoplasm as a discrete, readily palpable, and easily movable mass that can
be surgically enucleated.
 In general, the more aggressive, the more rapidly growing, and the larger the primary
neoplasm, the greater the likelihood that it will metastasize or already has metastasized.
 There are exceptions, however.
- Small, well-differentiated, slowly growing lesions sometimes metastasize widely;
- Some rapidly growing, large lesions remain localized for years.
 Approximately 30% of newly diagnosed individuals with solid tumors (excluding skin cancers
other than melanomas) present with metastases.
 Metastatic spread strongly reduces the possibility of cure.
 Pathways of spread:
- Direct seeding of body cavities or surfaces
 Most common to peritoneal cavity but other cavities may be affected
 Most common with ovaria carcinoma
- Lymphatic spread
 Most common pathway for initial dissemination of carcinomas
- Hematogenous spread.
 Typical of sarcomas but is also seen in carcinomas

Lecture Activity 1.3.3. Carcinogenesis

Make a concept map of an overview of carcinogenesis. Make use of the terms supplied below in
making the map. Take note of scoring rubric below.

 Activation of growth promoting oncogenes.

 Altered gene products(proteins); abnormal structural and regulatory proteins.
 DNA damage
 Environmental agents that damage DNA
o Chemicals
o Radiation
o Viruses
 Failed repair
 Impaired apoptosis
 Inactivation of tumor suppressor genes
 Inherited mutations in genes affecting.
o DNA repair
o Cell growth

38
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 o Apoptosis
 Malignant tumor
 Mutations is somatic cells.
 Normal cell
 Successful repair

Consider the scoring rubric below:

9-10 6-8 3-5 0-2

All relevant cause More than half of Less than half of the Few relevant
and effect the relevant cause cause and effect cause and
interactions are and effect interactions are effect
CONTENT
included and interactions are included and interactions are
correct included and correct included and
correct correct
Understanding of Understanding of Understanding of Poor
cause and effect cause and effect cause and effect understanding
interactions are interactions are interactions are of cause and
clearly clearly clearly effect
LOGIC AND
demonstrated by demonstrated by demonstrated but interactions with
UNDERSTANDING
correct links and correct links but with some errors significant errors
descriptive words some descriptive ( eg. Incorrect links
words are and descriptive
inappropriate words)

39
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 Concept map is Concept map is Concept map is Concept map is
neat, clear and neat, clear and neat, clear and untidy with links
legible and has legible and has legible but with difficult to follow
PRESENTATION easy to follow easy to follow links, some links that are
links, no spelling has some spelling difficult to folow,
errors errors has some spelling
errors

References

Cadar, Dorina. (2009). Volumetric Evaluations of Brain Imaging (MRI) and Cognitive Correlates in
Alzheimer’s disease, Mild Cognitive Impairment and Elderly controls. 10.13140/RG.2.1.4981.9286.

Hall, John E.. (2016). Guyton and Hall: Textbook of Medical Physiology (13th
ed.). Philadelpia,PA: Elsevier.

Jameson, J. L., & Loscalzo, J. (2015). Harrison's principles of internal medicine (19th edition.). New York:
McGraw Hill Education.

Menon, D. (2020, Dec 27). Disease, disorder, condition, syndrome- what’s the difference? Health
Writer Hub. https://www.healthwriterhub.com/disease-disorder-condition-syndrome-whats-the-
difference/#:~:text=A%20disease%20is%20a%20pathophysiological,a%20specific%20health%2
Drelated%20cause.

Mohan, H. (2010). Textbook of Pathology (6th edition). New Delhi: Jaypee Brothers

Kumar, V., Abbas, A. K., & Aster, J. C. (2015). Robbins and Cotran pathologic basis of disease (Ninth
edition.). Philadelphia, PA: Elsevier/Saunders.

Rudavski, S., Bongiovanni, D. (2020, Jan 16). How an Indiana doctor found a medical mystery in
Maichelangelo’s “David”. Indianopolis Star.
https://www.usatoday.com/story/news/health/2020/01/16/michelangelos-david-reveals-
medical-mystery-500-years-later/4486227002/

40
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