BCM-129-OvEL5-8.pptx

LECTURE OVERVIEWS
Course: General Pathology
Training Level: Undergraduate
Department: Clinical Medicine
University of Kabianga (UoK)
© 2020. Dr. Joseph K. Choge, PhD

General Pathology
Purpose of the Course - 1
Purpose of the Course:
The course will enable the learner to
comprehend:
How disease processes alter structure and
function of the human body
How the body responds to the alterations

General Pathology
Course Outline - 2
Learning Outcomes:
At the end of this course, the student is expected to: -
1. Describe the pathological processes of inflammation
and healing/repair.
2. Outline aetiological classification, pathology and
mechanisms of common infections, tumours,
communicable and non-communicable diseases and
other disorders.
3. Describe the pathophysiology and immunopathology
of the common disorders involving the various body
systems.

LECTURE FIVE OVERVIEW
General Pathology
Haemodynamic
Dysfunction
© 2020 Dr. Joseph K. Choge, PhD

Haemodynamic Disorders
Introduction - 1
• Intact blood circulation
relied upon for continuous
delivery of essential
substances*
• Excretion of wastes also
removed by cardiovascular
system (CVS)
• Delivery and elimination are
controlled by cellular
exchanges*
 Assignment 5.1
1. Name the essential
substances transported by
circulatory system.
2. List the waste products
removed by CVS
3. Name the cellular spaces
among which essential
substances and waste
products are exchanged.

Haemodynamic Disorders
Introduction - 2
 Haemodynamic
Disorders (due to
altered blood volume)
include:
1. Hyperaemia *
2. Congestion*
3. Oedema*
4. Haemorrhage*
5. Shock*
• Haemodynamic
Disorders (due to
impaired blood
circulation) include:
6. Thrombosis*
7. Embolism*
8. Infarction*
-------------------------------
Assignment 5.2:
Clearly describe each of the
haemodynamic disorders.

Congestion and Hyperaemia
Causes of Congestion & Hyperaemia - 3
 Passive Hyperaemia may be
due to:
1. Deoxygenated blood
2. Impaired venous return
causing damming back of
blood ; Rt. Ventr.Failure
3. Localized venous
obstruction: e.g.
 Left ventricular F (CCF)
 DVT
 Budd-Chiari Syndrome
 Judicial hanging/Trauma
• Active Hyperaemia may be
due to: *
1. Oxygenated blood (area
looks very red)
2. Arteriolar dilation with
increased flow of blood
into capillary beds
3. Inflammation: at sites of
inflammation

Effects of Lung Congestion - 4
Effects of Lung Congestion*:
1. Haemorrhage (ruptures of small capillaries)*
2. Pulmonary Oedema*
3. Pulmonary Hypertension *
4. Lung Fibrosis*
5. Haemosiderosis: iron deposit due to RBC
breakdown (also possible) *

• The increased pressure in the alveolar capillaries has four
major consequences:
1. Haemorrhage: Microhemorrhages release erythrocytes
into the alveolar spaces, where they are phagocytosed
and degraded by alveolar macrophages; The released
iron, in the form of hemosiderin, remains in the
macrophages, which are then called “heart failure cells”.
2. Pulmonary Hypertension: The increased capillary
pressure is transmitted to the pulmonary arterial system,
a condition labelled pulmonary hypertension. This
disorder leads to right-sided heart failure and consequent
generalized venous congestion.

Effects of Lung Congestion:
3. The increased hydrostatic pressure forces fluid
from the blood into the alveolar spaces, resulting
in pulmonary edema, a dangerous condition that
interferes with gas exchange in the lung.
4. Fibrosis: The increased pressure, together with
other poorly understood factors, stimulates
fibrosis in the interstitial spaces of the lung. The
presence of fibrosis and iron is viewed grossly as
a firm, brown lung (“brown induration”).

Effects of Lung Congestion:
• Acute left ventricular failure – Acute pulmonary
congestion
• Accumulation of transudate
• Pulmonary oedema
• Chronic pulmonary congestion
• Microhemorrhages
• Pulmonary fibrosis
• Pulmonary hypertension

Effects of Liver Congestion - 8
1. Chronic passive congestion of liver*
2. Portal hypertension*
3. Pressure atrophy of the centr-ilobular
hepatocytes*
4. Cirrhosis

Effects of Splenic Congestion - 9
1. Fibro-congestive Splenomegaly*
2. Diffuse fibrosis*

Haemorrhage
Definitions & Classification - 10
 Haemorrhage: is the loss of blood from the cardiovascular phase
(circulation)*; Haemorrhage is grouped according to size:
1. Petechiae: Minute 1- to 2-mm hemorrhages in skin, mucous
membranes, or serosal surfaces*
2. Purpura: Larger (>3 mm) hemorrhages*
3. Ecchymoses: Larger (> 1 to 2 cm) subcutaneous hematomas
(bruises)*
• Large accumulations of blood in body cavities are called
hemothorax, hemopericardium, hemoperitoneum, or
hemarthrosis, depending on the location

Haemorrhage
Causes of Haemorrhage - 11
1. Trauma: RTA; Burns; Insect bites; Others*
2. Infections:
 Parasitic: Hookworm; D. latum; Kalaazar; Others
 Bacterial: Septicaemia; Others
 Viral: Haemorrhagic fevers
3. Bleeding disorders: Haemophilia; others
4. Tumours:
 Malignant: Ca cervix; Ca endometrium; others
 Benign: Fibroids; Others
5. Other causes
(Refer to causes of anaemia)

Shock
Definition; Types of Shock - 12
 Shock : Circulatory failure of acute onset; Systemic hypoperfusion
resulting from a reduction in either cardiac output or the effective
circulating blood volume*
• Types of Shock: *
1. Cardiogenic: decreased cardiac output from any cause
2. Hypovolemic: massive loss of blood/fluid
3. Septic: infection causing vasodilation
4. Anaphylactic: systemic circulation collapse due to Type I
response
5. Neurogenic: peripheral vasodilation with pooling of
blood
6. Any condition causing DIC

Shock
Mechanisms of Shock - 13
 Cardiogenic Shock : Heart not pumping efficiently/stopped *
 Hypovolemic Shock :
 Inadequate/decreased blood or plasma volume *
 Blood Vessel Dilation : Volume of vascular system too
large for blood available for adequate circulation*
 Anaphylactic Shock : Release of excess histamine from mast
cells (IgE mediated hypersensitivity) leading to systemic
vasodilation and increased vascular permeability

Shock
Mechanisms of Shock - 14
Septic Shock: Mechanism: *
• Peripheral vasodilation and pooling of blood;
• Endothelial activation and injury;
• Leukocyte-induced damage;
• Disseminated intravascular coagulation (DIC);
– Activation of cytokine cascades in response to
inflammation
Neurogenic Shock: Anesthetic accident or spinal cord
injury leading to loss of vascular tone and peripheral
pooling

Shock
Stages of shock - 15
• Stage 1: Non-progressive shock compensation*
Pathogenesis
Clinical manifestation:
Stage 2: Progressive Shock*
Tissue hypoperfusion
Pathogenesis
Clinical Manifestation
Stage 3: Irreversible Shock*
 Widespread cell injury = irreversible shock = death

Shock
Effects of shock - 16
Organs Affected in Shock
• Brain: Hypoxia; infarction*
• Heart: Infarction; necrosis*
• Lungs: Diffuse alveolar damage*
• Kidney: Acute tubular necrosis (from
ischaemic injury)*
• Gastrointestinal Tract (GIT): H’rrhagic G/E*
• Adrenals: Lipid depletion; stress (steroids)*

Oedema
Definition - 17
• ‘Oedema’ is the medical term for fluid
retention in the body
• Abnormal accumulation of fluid in the
interstitium (interstitial tissues)*
• Oedema most commonly occurs in the feet
and legs, (peripheral oedema)

Oedema
Causes - 18
•Oedema is a build-up of
fluid in the body's tissues
that often causes swelling
in the feet and ankles
(Top: Pitting pedal
oedema)
• Bottom: Facial oedema
from venous obstruction
due to prolonged lying
down; same patient after
oedema subsided later in
the day

Oedema
Types - 19
Top: Left and right ring
fingers of the same
individual. The distal
phalanx of the finger on
the right exhibits edema
due to acute paronychia
Bottom: Foot, about 2
weeks post surgery
because of compartment
syndrome

Oedema
Types - 20
Types of oedema
1. Peripheral oedema
2. Cerebral oedema – affecting the brain
3. Pulmonary oedema – affecting the lungs
4. Macular oedema – affecting the eyes
5. Idiopathic oedema is a term used to describe
cases of oedema where a cause can't be found.
6. Lymphoedema*

Oedema
Causes – 21
 GENERAL (SYSTEMIC) CAUSES OF OEDEMA:
• Prolonged sitting/tight clothing
• Causes due to Decreased Plasma Osmotic Pressure
• Excessive protein loss from kidney disease
• Liver failure (from cirrhosis, hepatitis, portal hypertension,
portal hepatic anastomoses)
• Protein deficiency (e.g. kwashiorkor)
• Beriberi
• Impaired Lymphatics:
• Malignancy blocking lymphatics
• Surgical removal/destruction of lymph nodes by
inflammation

Oedema
Causes – 22
• Increased small vessel permeability:
• Chemical mediators: increase small vessel permeability
in affected areas; Plasma proteins then leave the
circulation and the osmotic pressure draws fluid into
the affected area, causing oedema
• This type of oedema occurs in:
 Anaphylaxis
 Asthma
 Hay fever

Oedema
Causes – 23
• Primary Sodium Retention (with its obligatory
associated water)
• This causes both increased hydrostatic pressure
and reduced osmotic pressure
• This occurs in case of:
 Excessive salt intake
 Renal dysfunction (e.g. renal failure or
post-streptococcal glomerulonephritis)

Oedema
Causes – 24
 LOCAL CAUSES OF OEDEMA:
• Pulmonary oedema (CCF, inflammatory irritation of lungs,
e.g. by phosgen gases)
• Obstruction of lymphatics: (e.g. by filariasis, congenital
absence of lymphatics, breast cancer affecting skin and
lymphatics)
• Cerebral oedema following head injury
• Post-operative oedema (following breast cancer removal
and its affected lymph nodes)

Oedema
Causes – 25
 LOCAL CAUSES OF OEDEMA:
• Impaired venous drainage (e.g. by
thrombosis)
• Increased vascular permeability (e.g. by
inflammation)
• Hypersensitivity:
(e.g. laryngeal oedema due to anaphylactic
shock, inhalation of noxious substances that
may cause suffocation; insect stings)

Thrombosis
Definitions – 26
•Thrombosis is the
formation of a blood clot
inside a blood vessel, *
•A clot that breaks free and
begins to travel around the
body is known as an
embolus*

Thrombosis
Definitions – 27
When a blood vessel is injured, the
body uses platelets (also called as
thrombocytes) and fibrin to form a
blood clot to prevent blood loss. Even
when a blood vessel is not injured,
blood clots may form in the body
under certain conditions.
If the thrombus is large leading to
partial blockade of blood flow to a
tissue, hypoxia (lack of adequate
Oxygen) can occur and metabolic
products such as lactic acid can
accumulate. A larger thrombus causing
a much greater obstruction to the
blood flow may result in anoxia
(complete lack of Oxygen and
infarction) and tissue death.

Embolism
Definitions – 28
1. Embolism/Embolus: refers to a clot that breaks
free and begins to travel around the body
2. Thrombo-embolism: is the term used to
describe what happens if the clot breaks loose
and travels through the bloodstream*
• ‘Thromboembolism’ is the combination of
thrombosis and its main complication, embolism

Infarction
Definition – 29
• Infarction refers to tissue death/tissue necrosis
• Infarction is caused by a local lack of oxygen, due to an
obstruction of the tissue's blood supply
• The resulting lesion from infarction is referred to as an
‘infarct’ (from the Latin infarctus, "stuffed into“)
• Myocardial infarction is the partial death of heart
tissue commonly known as heart attack

Thrombosis
Causes of thrombosis - 30
The main causes of thrombosis are given as
Virchow's triad*:
1. Hyper-coagulability (thrombophilia)*
2. Endothelial cell injury*
3. Disturbed blood flow*

Thrombosis
Causes of Hyper-coagulability:
1. Genetic deficiencies
2. Autoimmune disorders
3. Treatments for cancer (radiation,
chemotherapy)*

Thrombosis
Causes of Endothelial cell injury:
1. Trauma,
2. Surgery,
3. Infection
4. Turbulent flow at bifurcations
• The main mechanism is exposure of tissue
factor to the blood coagulation system

Thrombosis
Causes of Disturbed Blood Flow*:
1. Stagnation of blood flow past the point of
injury, or venous stasis
(e.g. in heart failure, after long periods of
sedentary behavior)*
2. Atrial fibrillation, causes stagnant blood in
the left atrium (LA) or left atrial appendage
(LAA)*
3. Cancers or malignancies (e.g. leukemia)*

Thrombosis
Classification of thrombosis - 34
Distinct Forms of Thrombosis*:
1. Venous thrombosis
2. Arterial thrombosis
• Each of these can be presented by several
subtypes

Thrombosis
 Diseases associated with Venous Thrombosis*:
1. Deep vein thrombosis (DVT)*
2. Portal vein thrombosis*
3. Renal vein thrombosis*
4. Jugular vein thrombosis*
5. Budd-Chiari syndrome*
6. Paget-Schroetter disease*
7. Cerebral venous sinus thrombosis
8. Cavernous sinus thrombosis*

Thrombosis
 Diseases associated with Arterial Thrombosis*:
1. Atheroma (Atherothrombosis/Atherosclerosis)*
2. Atrial fibrillation*
3. Direct current cardioversion of atrial fibrillation
4. Stroke*
5. Myocardial infarction*
6. Hepatic artery thrombosis (following liver
transplantation)*

Thrombosis
Consequences of thrombosis –37
 Consequences/Natural history/Pathogenesis
of thrombosis:
1. Embolization*
2. Lysis*
3. Ischaemia/infarction*
4. Fibrous tissue formation (fibrosis)
5. Histological re-organisation*
 Occlusive thrombus: complete thrombosis occlusion; wound
healing with scar formation*
 Mural thrombus: partial thrombotic occlusion; wound
healing with platelet-derived growth factor degranulation*

Thrombosis
Risk Factors of thrombosis - 38
Risk factors of Thrombosis:
1. Cigarette smoking*
2. Overweight*
3. Pregnancy
4. Sedentary lifestyle and behavior/Prolonged
immobility*
5. Certain heart conditions (e.g. RHD; Infective
endocarditis)
6. Certain medications,
7. Surgery (especially, of hip/lower limb regions)
8. Inherited blood clotting disorders

Embolism
Consequences of Embolization - 39
1. Septic embolization: leads to
2. Metastatic abscesses/septicaemia (if
embolus is infected with bacteria)*
3. Infarction (tissue necrosis/death)*
 Myocardial ischaemia*: leads to
 Myocardial infarction*

Thrombosis; Embolism
Treatment/Prevention - 40
Anticoagulants:
1. Heparin
2. Warfarin
These anticoagulants (Vitamin K antagonists)
may prevent thrombo-embolism
 however, they have their disadvantages:
prolonged bleeding tendency, among others*
More cost-benefit analysis studies in this area
required

Thrombosis
Prevention of thrombosis - 41
 Risk factors and Prevention:
1. Refrain from smoking
2. Weight reducing exercises and diet.
3. Avoid sedentary lifestyle and behavior: make regular
voluntary movements, use of compression stockings, which
mechanically support the vein to inhibit the formation of
blood clots
• Anticoagulants may increase the risk of major bleeding
slightly, but has been found to offer a benefit in both the
prevention and treatment of thrombosis.

Infarction
Causes/Risk Factors of Infarction - 42
• (1) Artery blockage by:
Thrombus; Embolus ; Atheroma; others
• (2) Mechanical compression of blood vessel by:
Tumours, Hernia, Volvulus; others
• (3) Blood vessel Rupture/Trauma by:
Atheroma; vasculitis/vasculitides
• (4) Vasoconstriction due to:
Cocaine, may cause myocardial infarction
• (5) Hypertension & Atherosclerosis*

Infarction
Classification of Infarction - 43
 Classification by histopathology*
• White infarctions (anemic infarcts)*
• Red infarctions (hemorrhagic infarcts)*
 Classification by localization:*
• Myocardial infarction(heart attack)
• Cerebral infarction (ischaemic stroke)
• Pulmonary infarctionS
• Splenic infarction
• Limb infarction
• Bone infarction
• Testiicular infarction (torsion testis)
• Eye infarction

Infarction
Diseases associated with Infarction - 44
• Diseases commonly associated with infarctions
include*:
• Peripheral artery occlusive disease (the most
severe form of which is gangrene)
• Antiphospholipid syndrome
• Sepsis
• Giant-cell arteritis (GCA)
• Hernia
• Volvulus
• Sickle-cell disease

Infarction
Diseases associated
with Infarction - 45
•An acute myocardial
infarction, also known as a
heart attack, is when a
blood vessel in the heart
suddenly becomes blocked,
and the blood stops moving
to part of the heart
•This part of the heart does
not get oxygen so the
muscle there begins to die.
•Blood clots are the most
common cause of heart
attacks.

Infarction
Symptoms - 46
Heart attack (myocardial infarction)
Warning signs in women
•Many women have different
symptoms than men. The most
common symptoms include
shortness of breath, weakness,
and feeling tired.
•Signs that a person is having a
heart attack show over several
minutes, and rarely come
immediately. Most people having
a heart attack have chest pain.
• Chest pain can be caused by
ischaemia (a lack of blood and
oxygen) of the heart muscle; this
is called angina pectoris. Pain can
often also be felt in the left arm,
and sometimes in the lower jaw,
the neck, the right arm, the back,
and in parts of the abdomen.

Myocardial Infarction
Treatment - 47
• The most important thing is to save as much
myocardium as possible and prevent more
complications*
1. Reperfusion: but this may result is reperfusion
injury
2. Antithrombotics: but this increases risk of
bleeding
3. First aid
Oxygen prn
Anticoagulants prn: (e.g. Aspirin)

General Pathology
Lecture 6
Neoplasia
By
Dr. J.K Choge; PhD
Course: Pathology
Course Code: BCM 129
Semester Two
Academic Year: 2019/2020
University of Kabianga

LECTURE SIX OVERVIEW
General Pathology
Neoplasia

Neoplasia
Introductory Terminology - 1
Important descriptive
Terms related to
Tumours:
• Neoplasm*
• Neoplasia*
• Benign*
• Malignant*
• Clonality/Monoclonal*
• Differentiation*
Assignment 6.1:
1. Explain how each of the
terms listed opposite are
used to describe tumours.
2. List other terms that
describe tumour
behaviour (most of these
will be met later in the
course).

Neoplasia
Introductory Terminology – 2
Terminologies to describe the types of
Neoplasms*
• Anaplasia: (structural differentiation loss within
cell or group of cells)
• Aplasia: (organ or part of organ missing)
• Hypoplasia: (congenital below-average number
of cells, especially when inadequate)
• Hyperplasia: (proliferation of cells)
• Neoplasia: (abnormal proliferation)
• Dysplasia: (change in cell or tissue phenotype)

Neoplasia
Introductory Terminology – 3
Terminologies to describe the types of
Neoplasms*
• Metaplasia: (conversion in cell type)
• Prosoplasia: (development of new cell function)
• Desmoplasia : (connective tissue growth)
• Atrophy: (reduced functionality of an organ, with
decrease in the number or volume of cells)
• Hypertrophy: (increase in the volume of cells)

Neoplasia
Types of Tumour Growth Disorders – 4
Tumour Growth Disorders:
• Reduction in mass: Agenesis;
Hypoplasia; Atrophy
• Increased mass: Hyperplasia;
Hypertrophy (cells/parts)
• Other Tissue Mass Changes:
(Dedifferentiation):
Metaplasia; Dysplasia; Benign;
Malignancy; Regeneative
atypia*
Assignment 6.2:
1. Outline the disorders of
growth of tumours and
give relevant examples
of each.
2. Which of these changes
of growth involve
malignancies and which
are not?

Neoplasia
Malignancy Characteristics - 5a
General Characteristics of Malignant
Neoplasms*:
1. Progressive*
2. Purposeless*
3. Regardless of surrounding tissues*
4. Not related to the needs of the body*
5. Parasitic*

Neoplasms
Malignancy Characteristics - 5b
Characteristics of malignant
neoplasms:
• More rapid increase in
size
• Less differentiation (or
lack of differentiation,
called anaplasia)
• Tendency to invade
surrounding tissues
• Ability to metastasize to
distant tissues
Assignment 6.3:
1. Describe other
characteristics (other than
those already noted) of
malignancy.*
2. Explain the relationship
between malignancy
characteristics and arising
clinical features.

Neoplasms
Malignancy Characteristics - 5c
Cytologic features of malignant neoplasms:
• Abnormal nuclei (prominent; irregular;
Increased nuclear size)*
• Pleomorphism: nuclear /cell size variation*
• Anaplasia: lack of differentiation*
• Hyperchromatism: increased nuclear DNA
content with subsequent dark staining*
• Mitosis ability: irregular/bizarre mitosis*

Neoplasms
Spread of Malignant Tumours – 6a
Spread of Malignant Neoplasms
1. Local Invasion*
2. Lymphatic spread*
3. Haematogenous spread*
4. Seeding*
5. Others:
 CNS (CSF) spread
 Intra-epithelial spread*

Neoplasms
Spread of Malignant Tumours – 6b
Mechanisms of Spread of Malignant Neoplasms
• Step 1: Direct Spread and Invasiveness*
• Step 2: Angiogenesis*
• Step 3: Vascular Invasion*
• Step 4: Establishment of New Colony*

Neoplasia
Aetiology/Carcinogenesis - 7
• Aetiological/Predisposing
factors of malignant
tumours:
• Clonality: Cancer from
single cell
• Incidence: Age, Gender,
Race, Geographical; e.t.c
• Carcinogens: Oncogenes;
Oncogenic viruses*
------------------------------
• Refer Carcinogenesis additional
notes*
Assignment 6.4
1. Outline the known and
suspected causes and
predisposing factors of
various malignancies.
2. What are the
investigations and
management approaches
currently in place?

Neoplasia
Classifications - 8a
• The World Health
Organization (WHO)
classifies neoplasms into four
main groups*:
1. Benign neoplasms
2. In situ neoplasms
3. Malignant neoplasms
4. Neoplasms of
uncertain/unknown
behavior
• Malignant neoplasms are also
simply known as cancers
 Assignment 6.5:
1. Name the various other
classifications of
neoplasms (e.g. Ann
Abbor, Dukes, e.t.c) and
specify their usefulness.
2. Explain the difference
between ‘Grading’ and
‘Staging’ of tumours; give
examples of each. *

Neoplasia
Classifications - 8b
Property Benign Neoplasm Malignant Neoplasm*
Growth rate Usually slow Rapid growth
Edges Circumscribed; often capsulated Irregular, ill-defined; non-
encapsulated
Localization Remains localized Cells transferable to other areas (via
blood, lymphatics, tissue planes,
serous cavity, e.t.c) to set up
satellite tumours
Local Effects Merely compress normal tissues Invades and destroys normal tissues
Other
Effects
•Pressure effects of blood
vessels, tubes, nerves, organs,
and other body structures
•Tumour removal relieves the
pressure
•Pressure effects but also destroys
local structures
•Removal of tumour does not
relieve function (new tumour
growth replaces/aggravates
previous effect)

Neoplasia
TNM Classification/Staging of Malignant Tumours*- 8c
• The TNM Classification of Malignant Tumours (TNM) is a
cancer staging notation system that gives codes to describe
the stage of a person's cancer, when this originates with a
solid tumor
• T - describes the size of the original (primary) Tumor and
whether it has invaded nearby tissue
• N - describes nearby (regional) lymph Nodes that are involved
• M - describes distant Metastasis (spread of cancer from one
part of the body to another)

Neoplasia
TNM Classification/Staging
of Malignant Tumours*- 8d
Diagram showing the T stages of bladder
cancer (Illustration opposite)
Mandatory parameters
•T: size or direct extent of the primary tumor
Tx: tumor cannot be evaluated
Tis: carcinoma in situ
T0: no signs of tumor
T1, T2, T3, T4: size and/or extension of the
primary tumor
•N: degree of spread to regional lymph nodes
Nx: lymph nodes cannot be evaluated
N0: tumor cells absent from regional lymph
nodes
N1: regional lymph node metastasis present;
(at some sites: tumor spread to closest or
small number of regional lymph nodes)
N2: tumor spread to an extent between N1
and N3 (N2 is not used at all sites)
N3: tumor spread to more distant or
numerous regional lymph nodes (N3 is not
used at all sites)
•M: presence of distant metastasis
M0: no distant metastasis
M1: metastasis to distant organs (beyond
regional lymph nodes)
•The Mx designation was removed from the
7th edition of the AJCC/UICC system

Neoplasia
TNM Classification/Staging of Malignant Tumours*- 8e
Other parameters
• G (1–4): the grade of the cancer cells (i.e. they are "low
grade" if they appear similar to normal cells, and "high
grade" if they appear poorly differentiated)
• S (0-3): elevation of serum tumor markers
• R (0-2): the completeness of the operation (resection-
boundaries free of cancer cells or not)
• L (0-1): invasion into lymphatic vessels
• V (0-2): invasion into vein (no, microscopic, macroscopic)
• C (1–5): a modifier of the certainty (quality) of the last
mentioned parameter

Neoplasia
TNM Classification/Staging of Malignant Tumours*- 8f
Prefix modifiers
• c: stage given by clinical examination of a patient. The c-prefix is
implicit in absence of the p-prefix
• p: stage given by pathologic examination of a surgical specimen
• y: stage assessed after chemotherapy and/or radiation therapy; in
other words, the individual had neoadjuvant therapy
• r: stage for a recurrent tumor in an individual that had some period
of time free from the disease
• a: stage determined at autopsy
• u: stage determined by ultrasonography or endosonography
• Clinicians often use this modifier although it is not an officially
defined one
• For the T, N and M parameters exist subclassifications for some
cancer-types (e.g. T1a, Tis, N1i)

Neoplasia
TNM Classification/Staging of Malignant Tumours* - 8g
Ann Arbor staging
• Ann Arbor staging is the staging system for lymphomas, both in
Hodgkin's lymphoma (previously called Hodgkin's disease) and
Non-Hodgkin lymphoma (abbreviated NHL)
• It was initially developed for Hodgkin's, but has some use in
NHL. It has roughly the same function as TNM staging in solid
tumors
• The stage depends on both the place where the malignant tissue
is located (as located with biopsy, CT scanning and increasingly
positron emission tomography) and on systemic symptoms due
to the lymphoma ("B symptoms": night sweats, weight loss of
>10% or fevers)

Neoplasia
TNM Classification/Staging of Malignant Tumours* - 8h
Principal stages of Ann Arbor staging
• The principal stage is determined by location of the tumor:
• Stage I indicates that the cancer is located in a single region, usually one
lymph node and the surrounding area. Stage I often will not have outward
symptoms.
• Stage II indicates that the cancer is located in two separate regions, an
affected lymph node or organ and a second affected area, and that both
affected areas are confined to one side of the diaphragm - that is, both are
above the diaphragm, or both are below the diaphragm.
• Stage III indicates that the cancer has spread to both sides of the
diaphragm, including one organ or area near the lymph nodes or the
spleen.
• Stage IV indicates diffuse or disseminated involvement of one or more
extralymphatic organs, including any involvement of the liver, bone
marrow, or nodular involvement of the lungs.

Neoplasms
TNM Classification/Staging
of Malignant Tumours*- 8i
•Stage 0: carcinoma in situ.
•Stage I: cancers are localized to one part
of the body. Stage I cancer can be
surgically removed if small enough.
•Stage II: cancers are locally advanced.
Stage II cancer can be treated by chemo,
radiation, or surgery.
•Stage III: cancers are also locally
advanced. Whether a cancer is
designated as Stage II or Stage III can
depend on the specific type of cancer; for
example, in Hodgkin's Disease, Stage II
indicates affected lymph nodes on only
one side of the diaphragm, whereas Stage
III indicates affected lymph nodes above
and below the diaphragm. The specific
criteria for Stages II and III therefore differ
according to diagnosis. Stage III can be
treated by chemo, radiation, or surgery.
•Stage IV: cancers have often
metastasized, or spread to other organs
or throughout the body. Stage IV cancer
can be treated by chemo, radiation, or
surgery.

Lymphomas
Introduction - 9a
• Lymphomas are types of cancer derived from
lymphocytes, (a type of white blood cell)
• Lymphomas are treated by combinations of
chemotherapy, monoclonal antibodies (CD20),
immunotherapy, radiation, and hematopoietic
stem cell transplantation.

Lymphomas
Classification – 9b
• Classified into two, based on histological characteristics:
(1) Hodgkin’s lymphomas
(2) Non-Hodgkin’s lymphomas
 Large cell (diffuse large cell)
 Immunoblastic (T or B cell)
 Histiocytic (Monocyte)
 Burkitt’s (B cell)
 Small cell
• Hodgkin's lymphoma is one of two common types of
cancers of the lymphatic system
• Non-Hodgkin's lymphoma, is far more common

Hodgkin’s Lymphoma
Nomenclature – 9c
• Hodgkin's lymphoma (formerly known as
Hodgkin's disease ) is a cancer of the lymphatic
system, which is part of your immune system
• Hodgkin's disease,is a type of lymphoma, which
is a cancer originating from white blood cells
called lymphocytes
• Named after Thomas Hodgkin, a graduate of the
University of Edinburgh Medical School, who first
described abnormalities in the lymph system in 1832

Classification - 9d
• Classical Hodgkin's lymphoma (excluding
nodular lymphocyte predominant Hodgkin's
lymphoma) can be sub-classified into 4
pathologic subtypes
• Sub-types based upon Reed–Sternberg cell
morphology and the composition of the
reactive cell infiltrate seen in the lymph
node biopsy specimen (the cell composition
around the Reed–Sternberg cell(s)

Classification – 9e
NAME DESCRIPTION
Nodular sclerosing HL
Is the most common subtype and is composed of large tumor nodules
showing scattered lacunar classical RS cells set in a background of
reactive lymphocytes, eosinophils and plasma cells with varying
degrees of collagen fibrosis/sclerosis.
Mixed-cellularity subtype
Is a common subtype and is composed of numerous classic RS cells
admixed with numerous inflammatory cells including lymphocytes,
histiocytes, eosinophils, and plasma cells without sclerosis. This type
is most often associated with EBV infection and may be confused with
the early, so-called 'cellular' phase of nodular sclerosing CHL.
Lymphocyte-rich or Lymphocytic
predominance
Is a rare subtype, show many features which may cause diagnostic
confusion with nodular lymphocyte predominant B-cell Non-
Hodgkin's Lymphoma (B-NHL). This form also has the most favorable
prognosis.
Lymphocyte depleted
Is a rare subtype, composed of large numbers of often pleomorphic RS
cells with only few reactive lymphocytes which may easily be
confused with diffuse large cell lymphoma. Many cases previously
classified within this category would now be reclassified under
anaplastic large cell lymphoma

Classification (Cont’d) - 9f
New WHO/Revised European-American Classification
of Lymphoid Neoplasms (Classification of Hodgkin
Lymphoma): *
• Nodular Lymphocyte Predominance
• Classical Hodgkin Lymphoma
• Lymphocyte rich
• Mixed cellularity
• Nodular sclerosis
• Lymphocyte Depletion

Classical Hodgkin’s Lymphoma
Classification (cont’d) – 9g
• Subtypes of classical Hodgkin's lymphoma include:
 Nodular sclerosis Hodgkin's lymphoma
 Mixed cellularity Hodgkin's lymphoma
 Lymphocyte-depleted Hodgkin's lymphoma
 Lymphocyte-rich classical Hodgkin's lymphoma
• Classical Hodgkin's lymphoma is the more common
type of this disease
• People diagnosed with classical Hodgkin's lymphoma
have large, abnormal cells called Reed-Sternberg cells in
their lymph nodes

Risk factors - 9h
• Aetiology: Unknown; most occurs when an infection-fighting cell called a B cell
develops a mutation in its DNA
• Risk factors
(1) Age: Hodgkin's lymphoma is most often diagnosed in people between the ages of 15
and 35, as well as those older than 55; Peak incidence in young adults
(2) Family history of lymphoma: Anyone with a brother or a sister who has Hodgkin's
lymphoma or non-Hodgkin's lymphoma has an increased risk of developing Hodgkin's
lymphoma
(3) Gender: Males are slightly more likely to develop Hodgkin's lymphoma
(4) Past Epstein-Barr infection: People who have had illnesses caused by the Epstein-Barr
virus, such as infectious mononucleosis, are more likely to develop Hodgkin's lymphoma
than are people who haven't had Epstein-Barr infections
(5) A weakened immune system: HIV/AIDS or an organ transplant requiring medications
to suppress the immune response, increases the risk of Hodgkin's lymphoma
(6) Prolonged use of human growth hormone
(7) Exposure to exotoxins, such as Agent Orange

Pathogenesis – 9i
• In Hodgkin's lymphoma, cells in the lymphatic system
grow abnormally and may spread beyond the lymphatic
system
• As Hodgkin's lymphoma progresses, it compromises
your body's ability to fight infection
• Hodgkin's lymphoma is characterised by the orderly
spread of disease from one lymph node group to another
and by the development of systemic symptoms with
advanced disease
• When Hodgkins cells are examined microscopically,
multinucleated Reed–Sternberg cells (RS cells) are the
characteristic histopathologic finding

Clinical Features – 9j
(1) Lymphadenopathy :
• Initially painless but painful shortly after alcohol
consumption;
• frequently cervical & supraclavicular
Systemic features (about 1/3 of cases = stage B symptoms):
(2) Itchy skin: due to eosinophilia
(3) Night sweats
(4) Unexplained weight loss
(5) Lassitude
(6) Splenomegaly (about 30%); Hepatomegaly (5%);
Hepatosplenomegaly

Clinical Features – 9k

Clinical Features (Cont’d) – 9l
(7) Lower Back ache
(8) Petechiae: (due to low platelet count, as a
result of bone marrow infiltration, decreased
production, increased removal)
(9) Cyclical fever (Pel-Ebstein fever = P-E):
• Cyclical high-grade fever

Diagnosis - 9m
• Hodgkin's lymphoma must be distinguished from non-
cancerous causes of lymph node swelling
(1) Lymph Node Biopsy: Definitive diagnosis; usually
excisional biopsy with microscopic examination)
(2) Blood Tests: performed to assess function of major
organs and to assess safety for chemotherapy
(3) Position emission tomography (PET) used to detect
small deposits that do not show on CT scanning. PET
scans are also useful in functional imaging (by using a
radiolabeled glucose to image tissues of high
metabolism).
(4) Gallium Scan: may be used instead of a PET scan

Management - 9n
(1) Chemotherapy/Radiotherapy:
• For early stage disease (IA or IIA)
• Choice of treatment depends on the age, sex, bulk and the
histological subtype of the disease
(2) Combined chemotherapy:
• For patients with later disease (III, IVA, or IVB)
(3) Combined Chemotherapy + Radiotherapy:
• For patients of any stage with a large mass in the chest
(4) Haemopoietic Stem Cell Transplantation

Prognosis – 9o
• Advances in diagnosis and treatment of Hodgkin's lymphoma
have continued to improve prognosis towards full recovery
• One recent European trial (2007) showed a 5-year survival rate
for those patients with a favorable prognosis was 98%, while that
for patients with worse outlooks was at least 85%
• Adverse prognostic factors:
 Age ≥ 45 years
 Stage IV disease
 Hb < 10.5 g/dl
 Lymphocyte count < 600/µl or < 8%
 Males
 Albumin < 4.0 g/dl
 WBC count ≥ 15,000/µl

Epidemiology – 9p

Non-Hodgkin’s Lymphomas
Classification - 10a
• The non-Hodgkin lymphomas (NHLs) are diverse group of blood
cancers that include any kind of lymphoma except Hodgkin's
lymphomas
• Types of NHL vary significantly in their severity, from indolent to very
aggressive
• Non-Hodgkin lymphomas were classified according to the 1982
Working Formulation (now obsolete) recognized 16 types
• The latest lymphoma classification, the 2008 WHO classification,
largely abandoned the "Hodgkin" vs. "Non-Hodgkin" grouping.
Instead, it lists over 80 different forms of lymphomas in four broad
groups
• Non-Hodgkin lymphoma resulted in 210,000 deaths globally in 2010
up from 143,000 in 1990

Non-Hodgkin’s Lymphomas
Aetiological Agents - 10b
• Infectious agents:
– Epstein-Barr virus – associated with Burkitt's lymphoma, Hodgkin's lymphoma, follicular
dendritic cell sarcoma, extranodal NK-T-cell lymphoma
– Human T-cell leukemia virus – associated with adult T-cell lymphoma
– Helicobacter pylori – associated with gastric lymphoma
– HHV-8 – associated with primary effusion lymphoma, multicentric Castleman disease
– Hepatitis C virus – associated with splenic marginal zone lymphoma, lymphoplasmacytic
lymphoma and diffuse large B-cell lymphoma
– HIV infection
• Some chemicals, like polychlorinated biphenyls (PCBs), diphenylhydantoin,
dioxin, and phenoxy herbicides
• Medical treatments, like radiation therapy and chemotherapy
• Genetic diseases, like Klinefelter's syndrome, Chédiak-Higashi syndrome,
ataxia telangiectasia syndrome
• Autoimmune diseases, like Sjögren’s syndrome, celiac sprue, rheumatoid
arthritis, and systemic lupus erythematosus

Neoplasia
Other Classifications of Malignancies – 10c
Malignant tumours are classified into two,
based on where they are from:
1. Sarcomas: are malignant tumours arising
from mesenchymal (connective) tissues*
2. Carcinomas: are malignant tumours that
arise from epithelial cells*

Neoplasia
Other Classifications of Malignancies – 11a
 Sarcomas:
• Arise from connective tissues;
composed of parenchymal cell
 Examples of Sarcoma/Origin:
• Fibrosarcoma: fibrous tissue
• Liposarcoma: Adipose tisse
• Chondrosarcoma: Cartilage
• Osteosarcoma: Bone
• Angiosarcoma: Blood vessels
• Lymphosarcoma: Lymph
vessels
 Examples of Sarcoma/Origin:
• Rhabdomyosarcoma: Striated
muscles
• Leiomyosarcoma: Smooth
muscles
• Synovial sarcoma: Synovium
• Mesothelioma
(Mesotheliosarcoma):
Mesothelium
• Invasive meningioma
(Meningiosarcoma): Brain
coverings
• Leukaemia: Blood cells

Neoplasia
Other Classifications of Malignancies – 11b
 Carcinomas:
• Arise from epithelial cells; have
parenchymal cells
 Examples of Carcinomas/Origin:
• Squamous cell carcinoma:
Stratified squamous
• Basal cell carcinoma: Renal
epithelium
• Adenocarcinoma; Papillar
carcinoma and Cystadenoma:
Epithelial lining of glands and
ducts
• Bronchogenic carcinoma:
Respiratory passages
• Renal cell carcinoma: Renal
epithelium
Examples of Carcinomas/Origin:
• Hepatocellular carcinoma
(Hepatoma): Liver cells
• Urothelial carcinoma: Urinary
tract epithelium
• Choriocarcinoma: Placental
epithelium
• Seminoma: Testicular epithelium
(germ cells)
• Malignant melanoma: tumour of
melanocytes

Neoplasia
Other Classifications of Malignancies – 11c
 Special Tumours:
•There are special tumours that have more than one
neoplastic cell but are derived from one germ cell layer
Examples of Special Tumours:
1. Wilm’s tumour (nephroblastoma): arises from renal
tissues;
2. Malignant mixed tumour of salivary glands: arises from
salivary glands
3. Other special tumours,
 Teratoma (immature teratoma; teratoma carcinoma)*
• N.B: Write short notes on Wilm’s tumour (important in
paediatrics)

Neoplasia
Common Malignancies – 11d
• Acute Lymphoblastic Leukemia (ALL)
• Acute Myeloid Leukemia (AML)
• Adolescents, Cancer in
• Adrenocortical Carcinoma
– Childhood
• AIDS-Related Cancers
– Kaposi Sarcoma
– AIDS-Related Lymphoma
– Primary CNS Lymphoma
• Anal Cancer
• Appendix Cancer
• Astrocytomas, Childhood
• Atypical Teratoid/Rhabdoid Tumor, Childhood, Central Nervous System

Neoplasia
Common Malignancies – 11e
• Basal Cell Carcinoma – (Skin)
(Nonmelanoma)
– Childhood
• Bile Duct Cancer, Extrahepatic
• Bladder Cancer
– Childhood
• Bone Cancer
– Ewing Sarcoma Family of Tumors
– Osteosarcoma and Malignant Fibrous
Histiocytoma
• Brain Stem Glioma, Childhood
• Breast Cancer
– Childhood
– Male
– Pregnancy, Breast Cancer and
• Bronchial Tumors, Childhood
• Burkitt Lymphoma - see Non-
Hodgkin Lymphoma
• Brain Tumour
– Astrocytomas, Childhood
– Brain and Spinal Cord Tumors Treatment
Overview, Childhood
– Brain Stem Glioma, Childhood
– Central Nervous System Atypical
Teratoid/Rhabdoid Tumor, Childhood
– Central Nervous System Embryonal
Tumors, Childhood
– Central Nervous System Germ Cell
Tumors, Childhood
– Craniopharyngioma, Childhood
– Ependymoma, Childhood

Neoplasia
Common Malignancies – 11f
• Carcinoid Tumor
– Childhood
– Gastrointestinal
– Carcinoma of Unknown Primary
– Childhood
• Cardiac (Heart) Tumors, Childhood
• Central Nervous System
– Atypical Teratoid/Rhabdoid Tumor,
Childhood
– Embryonal Tumors, Childhood
– Germ Cell Tumor, Childhood
– Lymphoma, Primary
• Cervical Cancer
– Childhood
• Childhood Cancers
• Chordoma, Childhood
• Chronic Lymphocytic Leukemia (CLL)
• Chronic Myelogenous Leukemia
(CML)
• Chronic Myeloproliferative
Neoplasms
• Colon Cancer
• Colorectal Cancer
– Childhood
• Craniopharyngioma, Childhood
• Cutaneous T-Cell Lymphoma - see
Mycosis Fungoides and Sézary
Syndrome
• Duct, Bile, Extrahepatic
• Ductal Carcinoma In Situ (DCIS)

Neoplasia
Common Malignancies – 11g
• Embryonal Tumors, Central
Nervous System, Childhood
• Endometrial Cancer
• Ependymoma, Childhood
• Esophageal Cancer
– Childhood
• Esthesioneuroblastoma,
Childhood
• Ewing Sarcoma
• Extracranial Germ Cell Tumor,
Childhood
• Extragonadal Germ Cell Tumor
• Extrahepatic Bile Duct Cancer
• Eye Cancer
– Intraocular Melanoma
• Retinoblastoma
• Fallopian Tube Cancer
• Fibrous Histiocytoma of Bone,
Malignant, and Osteosarcoma

Neoplasia
Common Malignancies – 11h
• Gallbladder Cancer
• Gastric (Stomach) Cancer
– Childhood
• Gastrointestinal Carcinoid Tumor
• Gastrointestinal Stromal Tumors (GIST)
– Childhood
• Germ Cell Tumor
– Central Nervous System, Childhood
– Extracranial, Childhood
– Extragonadal
– Ovarian
– Testicular
• Gestational Trophoblastic Disease
• Glioma - see Brain Tumor
– Childhood Brain Stem

Neoplasia
Common Malignancies – 11i
• Hairy Cell Leukemia
• Head and Neck Cancer
– Childhood
• Heart Cancer, Childhood
• Hepatocellular (Liver)
Cancer
• Histiocytosis,
Langerhans Cell
• Hodgkin Lymphoma
• Hypopharyngeal Cancer
• Intraocular Melanoma
• Islet Cell Tumors,
Pancreatic
Neuroendocrine
Tumors
• Kaposi Sarcoma
• Kidney
– Renal Cell
– Wilms Tumor and Other
Childhood Kidney
Tumors

Neoplasms
Common Malignancies – 11j
• Langerhans Cell Histiocytosis
• Laryngeal Cancer
– Childhood
• Leukemia
– Acute Lymphoblastic (ALL)
– Acute Myeloid (AML)
– Chronic Lymphocytic (CLL)
– Chronic Myelogenous (CML)
– Hairy Cell
• Lip and Oral Cavity Cancer
• Liver Cancer (Primary)
– Childhood
• Lung Cancer
– Childhood
– Non-Small Cell
– Small Cell
• Lymphoma
– AIDS-Related
– Burkitt - see Non-Hodgkin
Lymphoma
– Cutaneous T-Cell - see Mycosis
Fungoides and SÈzary
Syndrome
– Hodgkin
– Non-Hodgkin
• Primary Central Nervous
System (CNS)

Neoplasms
Common Malignancies -39h
• Macroglobulinemia, Waldenström –
see Non-Hodgkin Lymphoma
• Male Breast Cancer
• Malignant Fibrous Histiocytoma of
Bone and Osteosarcoma
• Melanoma
– Childhood
– Intraocular (Eye)
• Merkel Cell Carcinoma
• Mesothelioma, Malignant
– Childhood
• Metastatic Squamous Neck Cancer
with Occult Primary
• Midline Tract Carcinoma Involving
NUT Gene
• Mouth Cancer
• Multiple Endocrine Neoplasia
Syndromes, Childhood
• Multiple Myeloma/Plasma Cell
Neoplasm
• Mycosis Fungoides
• Myelodysplastic Syndromes
• Myelodysplastic/Myeloproliferative
Neoplasms
• Myelogenous Leukemia, Chronic
(CML)
• Myeloid Leukemia, Acute (AML)
• Myeloma, Multiple
• Myeloproliferative Neoplasms,
Chronic

Neoplasms
Common Malignancies -39i
• Nasal Cavity and Paranasal Sinus Cancer
• Nasopharyngeal Cancer
– Childhood
• Neuroblastoma
• Non-Hodgkin Lymphoma
• Non-Small Cell Lung Cancer

Neoplasms
Common Malignancies -39j
• Oral Cancer
– Childhood
• Oral Cavity Cancer, Lip and
• Oropharyngeal Cancer
• Osteosarcoma and Malignant Fibrous Histiocytoma of
Bone
• Ovarian Cancer
– Childhood
– Epithelial
– Germ Cell Tumor
– Low Malignant Potential Tumor

Neoplasms
Common Malignancies -39k
• Pancreatic Cancer
– Childhood
– Pancreatic Neuroendocrine Tumors (Islet Cell
Tumors)
• Papillomatosis, Childhood
• Paraganglioma
– Childhood
• Paranasal Sinus and Nasal Cavity Cancer
• Parathyroid Cancer
• Penile Cancer
• Pharyngeal Cancer
• Pheochromocytoma
– Childhood
– Pituitary Tumor
• Plasma Cell Neoplasm/Multiple Myeloma
• Pleuropulmonary Blastoma, Childhood
• Pregnancy and Breast Cancer
• Primary Central Nervous System (CNS)
Lymphoma
• Primary Peritoneal Cancer
• Prostate Cancer
• Rectal Cancer
• Renal Cell (Kidney) Cancer
• Renal Pelvis and Ureter, Transitional Cell
Cancer
• Retinoblastoma
• Rhabdomyosarcoma, Childhood

Neoplasms
Common Malignancies -39l
• Salivary Gland Cancer
– Childhood
• Sarcoma
– Ewing
– Kaposi
– Osteosarcoma (Bone Cancer)
– Rhabdomyosarcoma
– Soft Tissue
– Uterine
• Sézary Syndrome
• Skin Cancer
– Childhood
– Melanoma
– Merkel Cell Carcinoma
– Nonmelanoma
• Small Cell Lung Cancer
• Small Intestine Cancer
• Soft Tissue Sarcoma
• Squamous Cell Carcinoma - see Skin Cancer
(Nonmelanoma)
– Childhood
• Squamous Neck Cancer with Occult Primary,
Metastatic
• Stomach (Gastric) Cancer
– Childhood
• T-Cell Lymphoma, Cutaneous - see Mycosis
Fungoides and SÈzary Syndrome
• Testicular Cancer
– Childhood
• Throat Cancer
• Thymoma and Thymic Carcinoma
– Childhood
• Thyroid Cancer
– Childhood
• Transitional Cell Cancer of the Renal Pelvis
and Ureter

Neoplasms
Common Malignancies -39m
• Unknown Primary, Carcinoma
of:
– Childhood
• Unusual Cancers of Childhood
• Ureter and Renal Pelvis,
Transitional Cell Cancer
• Urethral Cancer
• Uterine Cancer, Endometrial
• Uterine Sarcoma
• Vaginal Cancer
– Childhood
• Vulvar Cancer
• Waldenström
Macroglobulinemia – see Non-
Hodgkin Lymphoma
• Wilms Tumor

Neoplasms
General Management of Tumours – 40a
Preventing
Management:
• Investigations: Role of
Screening*
• Specific Treatment
• Supportive
Management
Assignment 6.5:
1. Prevention is key to
management of
cancer. Outline the
role of cancer
screening in this
regard. *
2. Describe the screening
methods currently
used.

Neoplasms
General Management of Tumours – 40b
Management of Benign Tumours
• Generally require no treatment:
 Most require no chemotherapy; no radiotherapy (except
intercranial tumours and haemangiomas, which may
require the latter)
• Watchful waiting: ensure no problems
• Symptomatic treatment prn
 Skin tumours may require cryotherapy, curretage,
electrodesication, laser therapy, dermabrasion, topical
medication, e.t.c
• Surgical treatment prn: e.g.
 Surgical excision of lipoma; skin tumours

Neoplasms
General Management of Tumours – 40c
 Management of Malignant Tumours
• Surgical excision*:
• Radiation Therapy (Radiotherapy/Irradiation)*
• Chemotherapy/Combined Chemotherapy*
• Photodynamic (Post dynamic)Therapy (PDT)*
• Immunotherapy*
• Hormonal Therapy*
• Targeted Therapies(e.g. Monoclonal Antibody Therapy;
Small molecule targeted therapy; others)*
• Angiogenesis Inhibitors*
• Palliative (terminal) care

Neoplasms
General Management of Tumours – 40d
• How to break bad
news to patients*
• How to handle
reactions to the
bad news *
Assignment 6.6:
1. Give examples of areas
which consist of ‘bad
news’ to patients/clients. *
2. Outline suggested steps on
how a clinician should
handle such a situation. *

Organ/Tissue Transplantation – 41a
• Moving of an organ/tissue from one body
part from a donor, to another location*
• Transplantable organs*:
Heart, Lungs, Liver, Kidneys, Pancreas,
Intestines, Stomach, Thymus
• Transplantable Tissues*:
Bones, Tendons, Cornea, Skin, Heart valves,
Nerves, Blood vessels (Veins), Tissues, cells
and fluids; Bone marrow; Blood transfusion

Organ/Tissue Transplantation – 41b
Types of Transplants:
1. Autografts*
2. Allografts and Allotransplantation*
3. Isografts*
4. Xenografts and Xenotransplantation*
5. Split transplants*
6. Domino transplants*
7. ABO incompatibility Transplants*

Transplant Rejection – 42
• Transplant Rejection*
• Immunological
mechanism of
rejection*
• Medical Categories of
Rejection*
• Rejection Diagnosis and
Treatment*
Assignment 6.7:
1. Describe transplant
rejection.
2. Outline the medical
categories of transplant
rejection.
3. How is transplant rejection
diagnosed and treated?
4. What are the adverse
effects encountered
during its treatment?

LECTURE SEVEN OVERVIEW
General Pathology
Calcification Disorders

Introduction - 1
• Abnormality in body
calcium levels occurs under
different circumstances
• Excessive calcium
accumulation is known as
calcification.
• Calcium deficiency may also
occur in certain conditions.
Assignment 7.1:
1. Find out the normal range
of calcium levels in
humans.
2. What specimen(s) is/are
used for calcium
measurements?
3. What terminology is used
to describe abnormal
calcium levels ?

Introduction - 2
• Calcification is a gradual accumulation of
calcium in an area of body tissue, causing
hardening of the tissue*
• Calcification can be:
the body’s protective response to injury
 part of a natural inflammatory reaction to
infection, trauma, autoimmune disorders or
tumors

Introduction - 3
• Calcification becomes a problem when its
location, shape or size interferes with the organ
function*
• Examples of problematic organ calcifications:
Hardening and blockage of cardiac blood vessels
(causing thickening and calcification of mitral
valves)*
Brain calcification*
Kidney calcification*
Others: (e.g. breasts in case of breast cancer)

Common Causes - 4
1. Hypercalcaemia*
2. Musculoskeletal injuries (their healing response)
3. Arteriosclerosis (hardening/calcification of the arteries)
4. Breast Tumours (benign/malignant)
5. Bone or cartilage injury/cancer*
6. Dystrophic calcification (mineralization of tissues*
7. Tissue necrosis*
8. Pericarditis*
9. Chronic pancreatitis*
10. Hyperparathyroidism*
11. Excessive intake of Vitamin D

Risk Factors of Abnormal Calcification - 5
1. Alcoholism
2. Autoimmune disorders
3. Genetic history of a calcium metabolism
disorder
4. Internal tissue injuries that cause
inflammatory reactions
N.B: Not all people with risk factors will get
calcification

Pathological Calcification - 6
Pathological
Calcification: *
• Metastatic
calcification*
• Dystrophic
calcification*
• Lithiasis*
Assignment 7.2:
1. Describe pathological
calcification and give
relevant clinical
situations/examples.
2. Describe:
 Metastatic calcification
 Dystrophic calcification
 Lithiasis

Symptoms of Calcification* - 7
• Bone pain
• Bone spurs (occasionally visible as lumps under skin)
• Breast mass/lump
• Eye irritation or decreased vision
• Impaired growth
• Increased bone fractures
• Muscle weakness/cramping
• New bone deformities (e.g. leg bowing or spine
curvature)
• Progressive weakness
• Tar on teeth

Symptoms of Calcification* - 8
 Symptoms that might indicate a serious calcification
condition:
• Hearing loss (accompanying any other severe symptom)
• Muscle twitching, spasms or seizures (tetany)
• Nausea with or without vomiting
• Severe bone pain
• Severe headache
• Sudden abdominal, pelvic, or lower back pain that may be
severe
• Confusion/Drowsiness
• Chestpain

Complications of Calcification* - 9
Complications of
calcification:
• Kidney stones
• Paget’s disease
(abnormal bone tissue
loss and reformation)
• Pineal gland tumors
• Severe hypercalcemia
Potential Complications:
• Deformity
• Eye pain and vision loss
• Myocardial infarction
(heart attack)
• Peripheral artery
disease
• Spread of cancer
• Stroke

Location/Types of Calcification* - 10
Location/Types of Calcification:
• Skeletal calcification
• Extraskeletal calcification
– (e.g. calciphylaxis)
• Brain Calcification (e.g. Fahr's syndrome)*
• Pleural Calcification & Fibrosis (next slide)*
• Tumour calcification
– (e.g. calcification in ovarian tumours)

Pleural Calcification and Fibrosis* - 11
• Pleural fibrosis and calcification are usually
benign sequelae of pleural inflammation or
asbestos exposure*
• Either post-inflammatory or asbestos related
• These disorders are suspected and diagnosed
based on imaging studies

Post-inflammatory Fibrosis & Calcification: *
• Pleural inflammation commonly causes acute
pleural thickening due to fibrosis
• In most cases, the thickening resolves almost
completely
• Some patients are left with minor degrees of
pleural thickening, which are symptomless/no
impairment of lung function.
• Occasionally, lung fibrosis occurs

Post-inflammatory Fibrosis & Calcification:
• Chest x-ray/CT Scanning shows asymmetry of
the lungs with thickened pleura (trapped lung).*
• Pleural fibrosis after inflammation can
occasionally calcify*
• Post-inflammatory calcifications are invariably
unilateral

Pleural Calcification and
Fibrosis* - 14
Asbestos-Related
Calcification & Fibrosis:
Exposure to asbestos can lead to focal,
plaque-like pleural
fibrosis, at times with
calcification,
May occur up to ≥ 20 years
after the initial exposure
Diagnosis is usually by
chest x-ray*
(Opposite picture showinng
chest X-ray of asbestos-
related plaques)
Picture Courtesy:
http://www.msdmanuals.
com

 Asbestos-Related Calcification & Fibrosis:
• Pleural plagues usually in the lower 2/3 of the thorax and
are bilateral, although may affect any other part
• Calcification most often affects the parietal and
diaphragmatic pleura and spares the costo-phrenic sulci
and apices
• Calcification may be the only evidence of exposure
• Dense pleural fibrosis surrounding the entire lung and >1
cm in thickness can also follow asbestos exposur.

Asbestos-Related Calcification & Fibrosis:
• Asbestos is composed of fibrous mineral
silicates of different chemical
compositions
• When inhaled, asbestos fibers settle
deep in the lungs, causing scars

• Asbestos inhalation also can cause the
pleura (two layers of membranes
covering the lungs) to thicken
• These thickenings are called pleural
plaques (non-carcinogenic)

• Inhaling asbestos fibers can occasionally
cause pleural effusion*
• This fluid accumulation is called benign
asbestos effusion (non-carcinogenic)

• People with asbestos effusion may dyspnoeic
because of fluid accumulation
• Pleural plaques tend to cause only mild
dyspnoea resulting from stiffness of the chest
wall
• Sometimes plaques cause no symptoms but
decrease lung function

Differential Diagnoses:
• Mediastinal and Pleural Disorders
• Mediastinal Masses
• Mediastinitis
• Pleural Effusion
• Pleural Fibrosis and Calcification
• Pneumomediastinum
• Pneumothorax
• Viral Pleuritis

Diagnosis of Calcification - 21
1. X-ray/CT Scan/MRI: detect calcification in
internal organs
2. Mammography: detect calcification due to
breast cancer
3. Blood calcium levels: to detect
hypercalcaemia
4. Blood: Complete Blood Count: detect
infections
5. Tissue Biopsy: to detect malignancy

Treatment of Calcification - 22
Treatment for calcification will depend on:
Where calcium deposits occur
Their underlying cause
What, if any, complications arise
Arising symptoms (Symptomatic treatment0

Treatment of Calcification - 23
• Surgery: Surgical removal of calcium deposits
(renal stones)
• Treatment is mainly symptomatic:
Diuretics: to prevent future kidney stones
Anti-inflammatory Analgesics/Ice packs: for
renal colicky pain

Calcium Deficiency Disorders - 24
Calcium Mineral
Deficiency Disorders: *
• Rickets*
• Osteomalacia*
• Osteoporosis*
• Dental caries*
• Assignment 7.:
1. Explain how calcium
deficiency contributes
to each of the calcium
deficiency disorders.
2. Differentiate between
rickets and
osteomalacia.

LECTURE EIGHT OVERVIEW
General Pathology
Haemoglobinopathies
and Anaemia

Haemoglobinopathies
Introduction - 1
• Haemoglobin is produced
by genes that control
expression of haemoglobin
protein
• Structural disorders
affecting haemoglobin are
known as
haemoglobinopathies*
• For our purposes, we will
confine to two main
structural abnormalities
(SiCkle Cell Disease; SCD
and thalassaemia)
• Anaemia is the main
clinical feature of these
disorders
• However, let’s first glance at
classification of
haemoglobinopathies

• (1) Membrane (RBC) Defects:
 Hereditary spherocytosis,
 Hereditary elliptocytosis
 Hereditary persistence of fetal hemoglobin (HPFH)*
• (2) Structural Haemoglobin Defects:
 Sickle Cell Disease (SCD),
 Thalassaemias (α and β)
• (3) Enzyme Defects:
 Glucose-6-Phosphate Dehydrogenase (G6PD)
deficiency;
 Pyruvate kinase (PK) deficiency
Haemoglobinopathies
Classification - 2

Haemoglobinopathies
Sickle Cell Disease: Overview - 3
 Drepanocytosis (SCD):
• Autosomal recessive RBC
disorder
• RBC assumes sickle shape
under certain conditions*
• Haemolysis*
• Sickle cell crisis*
Assignment 8.1:
1. List the environmental
conditions that predispose
to sickling.
2. Discuss the pathological
consequences of sickling .
3. Discuss clinical features
and complications of sickle
cell crisis.

Haemoglobinopathies
Sickle Cell Disease Blood vessel picture - 4

Haemoglobinopathies
SCD: Crises & Clinical Picture - 5
• Pathophysiology of
SCD*
• Sickle Cell Crises and
their predisposing
factors*
• Clinical manifestations*
• Complications*
Assignment 8.2:
1. Discuss the
pathophysiology of
SCD in relationship to
the predisposing
factors, resulting
clinical features and
complications.
2. How is SCD crisis
managed ?

Sickle Cell Disease - 6
Other Organ Dysfunction features
• Kidneys: Nephrotic syndrome, Chronic renal failure, Proteinuria, Increased
renal blood flow, Renal tubular acidification defect; Increased glomerular
filtration rate; Renal papillary necrosis *, Painless haematuria;
• Liver and Biliary system: Abnormal L.F.Ts; Sudden painful/chronic
hepatomegaly; cholelithiasis; Intra-hepatic vaso-occlusion crisis
• Eyes: Retinopathy
• Ears: Sensori-neural hearing loss
• Adenoids/Tonsils: Adenotonsillar adenopathy
• Chronic leg ulcers: due to poor blood supply
• Skin: Cutaneous ulcers due to thrombotic blockage of blood vessels
• Growth and Development: Delayed growth and sexual maturation,
functional hyposplenia, autosplenectomy can occur
• Priapism:. Painful and sustained penile erection, due to vaso-occlusion in
the corpora cavenosus; Repeated episodes may result in impotence *

Sickle Cell Disease - 7
Diagnosis of SCD/Anaemia
(i) In utero diagnosis: By restriction endonuclease analysis of
DNA from foetal fibroblasts obtained by amniocentesis
(i) Newborn period: SCD identified by:
(a) electrophoresis,
(b) PCR amplification of DNA
(i) Older Children:
(a) Sickling Test-induced by adding sodium
metabusulfite to the smear
(b) Electrophoresis

Sickle Cell Disease – 8
Management of SCD
(1) EXCHANGE TRANSFUSION: Limits acute sickling in poorly perfused areas of the brain;
Maintenance exchange transfusion may be needed for about 4 years, to keep Hb S <20% so as to lower
recurrence of stroke to <10% *
(2) ANTI-SICKLING TREATMENT:
(a) Foetal haemoglobin - stimulating agents (to increase foetal haemoglobin) : e.g. Hydroxyl urea that may
prevent further stroke; More recent agents include: 5-Azaxytidine, Recombinant human erythropoietin,
Butyric acid analogues
(b) Red cell HbS-reducing agents: Decreased salt intake, DDAVP, Antibiotics (Monencin, Gramicin, others),
Calcium channel blockers: (Nitrendipine, Nifedipine, Verapamil); Membrane active agents: (Cetiedil,
Tellurite, Zinc)
(c) Hb solubility - increasing agents: Covalent Agents: (Cyanate, Carbamyl phosphate, Cytamine, Pyridoxal,
Methyl acetimidate, Dimethyl acetimidate, Glyceraldehyde, Dibromoacetyl salicylic acid, Bis-(3,5-
dibromosalicyl) fumerate, Bis-(3,5-’Dibromosalicyl) succinate, Nirtogen mustard; Non-covalent agents:
Urea, Butylurea, I-phenylalanine
(3) BONE MARROW TRANSPLANTATION: Contemplated in severe cases; i.e. in case of repeated chest
syndrome and CNS complications
(4) GENERAL CARE: Good nutrition; Folate supplements; Regular immunization; Daily penicillin
prophylaxis until at least five years of age (prevent infections); For crises: Hydration prn; Narcotic analgesics
prn. Ideally, the child should be managed in a multi-disciplinary specialization services for parents and affected
children
(5) PREVENTION: Genetic Counseling, to those affected (children and parents); Family Planning (to
already married couples, who have had normal children, to stop having more children- risk of SCD child

Sickle Cell Trait (Heterozygous form)
Clinical Manifestations - 9
Clinical picture:
• Clinical features are similar to SCD but are less severe;
• However, severe infarctions can occur and may be fatal;
• Hb S concentration in red cells is low in sickle cell trait; hence sickling doesn’t
occur under normal circumstances;
• Usually asymptomatic;
• Haematuria may occur
Haematology picture:
• Anaemia is mild;
• Blood smear may show target cells ± sickle cells;
• Sickle cell preparations are positive;
• Hb electrophoresis shows SC pattern
Significance of Sickle Cell Trait:
• Genetic implications may mandate counseling those with haemoglobin SC trait;
• Consists of Hb-S and Hb-C.

Thalassaemia – 10
Epidemiology:
• Common in Mediterranean countries, India, Far East and parts of North Africa;
• Haemoglobin S and B thalassaemia traits are combined.
Pathophysiology:
• Typical facial features occur due to bone marrow hperplasia
Clinical/Haematological features: *
• May vary depending upon the amount of synthesis of adult haemoglobin;
• B thalassaemia presents with: progressive, severe haemolytic anaemia; clinically
apparent after 6 months of age; failure to thrive; growth retardation; delayed
puberty; hepato-splenomegaly; hyposplenism
• Frontal bossing, osteoporosis and pathological fractures; jaundice and gallstones
also found
• If the adult haemoglobin is 0%, the patient will have severe features of the diseases.
• Iron toxicity following exchange transfusion: Diabetes mellitus, cirrhosis, CCF,
adrenal insufficiency, failure to undergo puberty; possible death
Management:
• Transfusion therapy with packed cells every 4 weeks;
• Chelation therapy: to treat likely iron overload following transfusion
• Splenectomy: This reduces transfusion requirements and should be considered for
patients with hypersplenism
• Bone marrow Transplantation: Weighed against risk of life-long transfusion;
commonly used in the developed world

Thalassaemia – 11
Genetics of Thalassaemia

Thalassaemia -12
Biochemistry & Pathophysiology of Thalassaemia

Enzyme Defects – 12
Glucose-6-Phosphate Dehydrogenase Deficiency
Epidemiology: Most severe forms of G6PD deficiency affect those of Mediterranean and
Chinese ancestry; Others are Middle East and Oriental populations; Commonest enzyme
defect; affects > 400 million world wide
Pathogenesis/Pathophysiology: G6PD is the first enzyme of the pentose phosphate path
way of glucose metabolism; G6PD deficiency, an X-linked recessive disorder, reduces the
cell’s ability to inactivate or reduce oxidizing compounds;
Clinical features: Neonatal jaundice; acute haemolytic anaemia; splenomegaly; haemolytic
episodes occur 2-3 days after oxidant ingestion
Precipitating drugs: Antimalarials: (Primaquine, Pamaquin, chloroquine); Antibiotics:
(Sulphonamides, Nitrofurantoin, Nalidixic acid, Ciproxin); Analgesics: (Aspirin, Phenacetin);
Others: (Dapsone, Naphthalene (mothballs); Anti-helminthics: (Napthol; Stibophen,
Niridazole); Infections: (Hepatitis A and B; Cytomegalovirus, Pneumonia, Typhoid fever);
Miscellaneous: (Vit.K; Probenecid)
Management: Exchange transfusion (neonates); Blood transfusion during haemolysis;
Avoid drugs/foods precipitating attacks/symptoms

Enzyme Defects – 13
Pyruvate Kinase (PK) Deficiency
Epidemiology:
• Autosomal recessive disorder; affects Northern Europe descendants; Less common
than G6PD deficiency
Pathophysiology:
• PK deficiency affects the ability of the cells to generate energy
• Consequently, potassium leakage from the cells results in haemolysis
Haematology picture:
• Usually presents with moderate anaemia; high reticulocyte count produces
macrocytosis and hyperchromasia; spiculated pyknocytes; Red cell PK level
decreased to 5% of normal; PK level in reticulocytes is high; measured level may
need to be adjusted for the reticulocyte count
Intermittent Treatment:
• Transfusion: for severely affected patients
• Exchange Transfusion: for severely affected neonates
• Splenectomy: decreases transfusion requirements; should be avoided till > 5yrs of
age, if possible

Membrane (RBC) Defects – 14
Hereditary Spherocytosis (HS)
Genetics: Autosomal dominant in 80% of affected; affects all races
Pathophysiology:
• HS is due to abnormality of an RBC membrane protein (usually spectrin), resulting in membrane instability
• Characteristic spherical shape due to a combination of membrane weakness and high permeability to
sodium and water
• Weakened cells are sequestrated and destroyed in the spleen
Clinical Picture:
• Variable degrees of anaemia, jaundice and splenomegaly, mostly in early childhood
• Important: HS is common in infants with Haemolytic Disease of the Newborn (HDN)
• After diagnosis is made, ultrasound to exclude gallstones should be made
Haematological picture:
• Anaemia is: mild, normocytic but frequently hyperchromic
• Peripheral smear: shows microspherocytosis and polychromasia; reticulocyte count and bilirubin are high
• Osmotic fragility test: Increased (if available)
Treatment:
• Folic acid supplementation; 1 mg/day
• Leucocyte-depleted packed cell transfusion: for severe erthroblastopenic crisis
• Splenectomy: Treatment of choice for cure; most require it if spectrin content is <30%; best for >5ys
• Prophylaxis: Splenectomized children should be given either Haemophilus influenzae type B and
pneumococcal vaccines or prophylactic penicillin 250mg BID for life

Membrane (RBC) Defects – 15
Hereditary Elliptocytosis
Genetics/Epidemiology:
• Most elliptocyte-related disorders (seen in peripheral smears) are autosomal
dominant.
• More common among West Africans than Western populations
Pathophysiology:
• Abnormality in the protein of the RBC membrane
Clinical/Haematological picture:
• Mild cases have no symptoms
• More severe varieties have neonatal poikilocytosis and haemolysis, mild,
chronic haemolytic anaemia or hereditary pyropoikilocytosis (a severe
disorder with microspherocytosis and poikilocytosis)
Treatment:
• Supportive care: for children with severe haemolytic anaemia, until age of
5 yrs, when they can have
• Splenectomy

Anaemia
Introduction - 2
General Concepts
• Various Definitions
• Causes of anaemia
Assignment 8.3:
1. Review various
definitions of anaemia.
2. Outline the causes of
anaemia.

Anaemia
Classification/Categories - 3
• (1) Mild Anaemia: Hb of 8-10.9g/dl
• (2) Moderate Anaemia: Hb of 5.1-7.9g/dl
• (3) Severe Anaemia: Hb <5 g/dl
• Blood transfusion is recommended for severe
anaemia (Hb <5g/dl). (Lackritz et al., 1992)

Anaemia
Physiology of Haemopoiesis - 4
• Haemoglobin formed by pairing of globin
chains; each molecule contains two globin
chain pairs.
• During fetal life, different globin chains are
produced.
• The resulting haemoglobin in children differs
from that in adults.

Anaemia
Physiology of Haemopiesis - 5
•Normal haemopoiesis starts in yolk sac, at about 4
weeks of gestation (0-3 months of pregnancy).
•The liver and spleen take over haemopoiesis at
about 6 weeks gestation (1-9 months of gestation).
• Bone marrow takes over nearer term (birth)
onwards.

Anaemia
Types of Haemoglobin - 6
(1) Embryonal haemoglobins
- Consist of β4 and α2β2 chains
- Later replaced by fetal haemoglobin
(2) Foetal haemoglobin (Hb F)
-Contain α2γ2 chains (main chains in foetus)
- Hb F production stops at birth;
- Hb F larger than Hb A; hence higher O2 affinity
-Hb F production stops at birth
(3) Haemoglobin A (Adults)
- Its production begins at birth (c 3-6 months after birth)
- Smaller in size than Hb F

Anaemia
Reasons for Hb fall after Birth - 7
• (1) Decreased erythropoietic activity
(due to decreased production)
• (2) Increased Hb F removal from circulation
• (3) Rapid body growth
- causing decreased HbF concentration
- Exaggerated in preterms
• (4) Haemodilution

Anaemia
Causes (Newborn Period) - 8
(1) Haemolytic causes:
-Incompatibilities (ABO, Rhesus, Kelly, others)
- Infections (Neonatal sepsis, ‘TORCHES’)
-Haemoglobinopathies (Thalassaemia)
-Autoimmune /Antibodies (SLE, Lymphomas,
Penicillins)
- Enzymopathies (G6PD & Pyruvate kinase
deficiencies)
- Membrane (RBC) defects (Hereditary spherocytosis )

Anaemia
Causes (Newborn Period) - 9
(2) Haemorrhagic causes (Obstetrics-related):
-Prenatal period: - Feto-maternal transfusion (trauma)
- Chronic maternal anaemia (pregnancy)
-Perinatal period:
–Twin-to-Twin Transfusion (TTS)
- Traumatic –Ruptured U/Cord, Placenta,
Liver, Spleen, Amniocentesis,
Delivery (APH, Abruptio,
delayed cord clumping,
Holding placenta below baby before
clumping,accidental placental
incision)
-Post-natal period–Iatrogenic (XS blood sampling; Vit. K-dependent HDN)
-Others (rare) – Congenital hypoplastic anaemia

Anaemia
Causes at Birth - 10
Causes of Anaemia at Birth:
• (1) Haemolytic disease (HDN)- Commonest
• (2) Tearing/bad cutting of umbilical cord (delivery)
• (3) Faulty/Abnormal umbilical cord insertions/clamping
• (4) Communicating placental vessels
• (5) Placenta praevia or
• (6) Abruptio placenta
• (7) Haemorrhage from foetal side of placenta, (due to accidental incision
of placenta during Caeserian section or by transplacental haemorrhage)
• (8) Twin-Transfusion Syndrome (TTS): Blood moves from one to the other
• (9) Excess scalp blood sampling: especially in manageming foetal distress

Anaemia
Delayed Anaemia Causes (Neonatal period)- 11
Causes of Anaemia later in Neonatal Period (Delayed Anaemia)
• (1) Haemolytic disease of the Newborn, (with or without exchange transfusion or
phototherapy)
• (2) Vitamin K overdosage: (Synkavite) given in large doses may cause anaemia in
prematures: characterized by Heinz bodies in the erythrocytes
• (3) Congenital haemolytic anaemia (hereditary spherocytosis)
• (4) Hereditary non-spherocytic haemolytic anaemia: due to enzymopathies
• (5) Bleeding from: Haemangiomas of upper G.I.T, Gastric Ulcers (from Meckel’s
diverticulum)
• (6) Repeated blood sampling: for various investigations
• (7) Mineral deficiencies: e.g. copper, may cause anaemia in infants on total parenteral
nutrition
• (8) ‘Physiological Anaemia’: fall in Hb content noticed at 8-12 weeks in term infants to
about 11gm/dl; at 6 weeks it falls to about 7-10 g/dl
Treatment:
• Transfusion with packed red cells: for anaemia of < 8g/dl
• (N.B: 2 mls/Kg of packed cells raises Hb by about 1g/dl)

Anaemia
Causes during 1st few days of life - 12
Causes of Anaemia during first few days of life:
• (1) Haemolytic Disease of the Newborn – Commonest
• (2) Haemorrhagic Disease of the Newborn
• (3) Improperly clumped cord
• (4) Large cephalohaematoma
• (5) Subscapular bleeding: from ruptured liver, spleen,
adrenals, kidneys
• (6) Intracranial haemorrhage

Anaemia
Causes (Older children/Adults) - 13
(1) Haemolytic causes:
-Infections – (Malaria, Clostridium & Gram
negative septicaemias)
-Drugs-(Thiacetazone, Sulphurs, Chloramphenicol,
Cytotoxics, Vit. K analogues, Primaquine)
- Hypersplenism
-Haemoglobinopathies- SCD, Thalassaemias
-Enzymopathies -G6PD deficiency
- Pyruvate kinase deficiency
- Abnormal Autoimmune Antibodies
-ABO incompatibility

Anaemia
Causes (Older children/Adults) - 14
(2) Haemorrhagic causes:
-Acute blood loss –Trauma-(RTAs, Epistaxis,
Burns, Surgery, G.I.T bleeding)
-Chronic blood loss
- Parasites-(Hook worm, Trichuriasis, D. latum,
Kala-azar, Amoebiasis)
- Others – Bleeding disorders (Haemophilias,
Scurvy, Purpuras)

Anaemia
Causes (Older children/Adults)- 15
(3) Diminished/Defective RBC Production:
(a) Lack of haemopoietic factors:
-Nutritional deficiency – (Iron, Folic acid, Protein
(PEM), Copper, Vitamins)
(b) Lack of haemopoietic tissue (Bone marrow failure)
- B/marrow replacement: (Leukaemias,
Neuroblastoma, Lymphomas)
- Reduced erythropoietin production: (Renal d’se,
Hypothyroidism, Hypopituitarism)
(c) Aplastic Anaemias: (Drugs-Chloramphenicol,Cytotoxics,
Benzenes, Insecticides; Hepatitis, Epstein-Barr Virus,
Autoimmunity, Radiation- induced, Poisons)

Anaemia
Clinical Features - 16
• (a) Symptoms resulting from tissue hypoxia:
- (Fatigue, Dyspnoea on exertion)
• (b) Manifestations also due to compensatory
attempts to ameliorate hypoxia:
- (Hyperventilation, Tachycardia, Increased
cardiac output, Oedema)- are signs of massive
haemorrhage
• (c) Suggestive clinical picture: History, Physical and
Laboratory examination: (Oedema; vital signs-BP,
Pulse, Respiration); Low Hb)

Anaemia
Clinical Features of Iron Deficiency Anaemia - 17
Essentials of Diagnosis:
• Suggestive history : (e.g. Poverty); *Worm infestation; Failure to thrive ,
Irritability, Fatigue, Good weight gain but flaby, Poor intellectual performance and
muscle tone, Anorexia; *Poor dietary intake of iron; Age usually 6months-2yrs;
rare after 3 yrs; ; Pica common in all age groups
• Physical examination: Pallor, Delayed motor development, Koilonychia, Tongue
atrophy, Stomatitis, Gastric achlorhydria and altered small bowel mucosa causing
protein and occult blood losses
• Laboratory picture:
Microcytic hypochromic anaemia picture
• Low -(MCV, MCH for age, serum iron, serum feriritin, haematocrit)/PCV;
• Elevated -(Total iron-binding capacity, Free Erythrocyte Protoporphyrin-FEP;
Normal reticulocyte count but elevated in severe cases)
• If iron trial therapy results in rise in Hb, then iron deficiency is confirmed.

Anaemia
Complications of Iron Deficiency Anaemia - 18
• (1) Increased susceptibility to infections
• (2) Heart Failure – In severe cases
• (3) Delayed motor development
• (4) Protein-Energy Malnutrition –May be
precipitated due to anorexia and irritability

Anaemia
Clinical Features of Megabloblastic & Folic Acid
Deficiency Anaemia - 19
• Essentials of Diagnosis:
(Pallor, Fatigue, Macrocytic anaemia; Megaloblastic bone marrow)
• Common Causes:
(1) Folic acid deficiency
(2) Vitamin B12 deficiency
(3) Ascorbic acid deficiency
(4) D. latum (fish tape worm)
(5) Drugs (anticonvulsants-Phenytoin, Primidone,
Phenobarbital, Phenylbutazone); INH & cycloserine,
Nitrofurantoin; Methotrexate);
(6) Sickle cell disease

Anaemia
Clinical Features of Folic Acid Deficiency - 20
• Dietary deficiency occurs most frequently in infancy.
• Suggestive history: (Anorexia, Weakness in infancy; occurs acutely within first few months of life; rarely
associated with neurological features).
• Physical examination: Pallor; Occasional glossitis and beefy red tongue.
• Laboratory picture:
-Low (Hb, RBC count, Reticulocyte count, leucocytes,
neutrophils, platelets-moderately low)
-Peripheral Bld smear: Macrocytic; significant
anisocytosis and poikilocytosis
- RBCs: Normochromic but may be hypochromic if iron deficiency is
coexistent.
-Bone Marrow: Megaloblastic, nucleated RBCs ; with delayed maturation
- Urine: Formiminoglutamic acid (FIGLU) –Present in urine after histidine
loading.
- Schilling Test: Shows failure of vitamin B12 absorption due to lack of gastric intrinsic factor.
-Will differentiate folic acid from B12 deficiency

Anaemia
Investigations - 21
Investigations depend on suspected cause(s):
• (a) Hb Level/PCV level – Low in case of anaemia
• (b) Investigate for various infections:
-(Stool o/c, BS, Cultures, e.t.c)
• (c) Investigate for haemoglobinopathies/Enzymopathies:
- (Peripheral blood films-SCD, Spherocytosis, BS for MPs)
- Indirect Coomb’s test-(+ve in incompatibilities; -ve in membrane
defects)
- Kleihauer Test- (Checking mother’s bld for feto-maternal
haemorrhage)
• (d) Others: Bleeding /clotting time, Blood pH, APT test, e.t.c
• Treat anaemia as per cause (s)

Anaemia
Iron Deficiency Anaemia Therapy - 22
• (1) Haematinics (oral iron): FeSO4 1.5-2mg/kg TDS X 2-
3months (Mild cases) or
• (2) Parenteral Iron (Imferon): Intramuscular.
 Total Dose Iron = (Desired Hb – Initial Hb) X 80X 3.4X Kg
100
 Additional 30% given to replace deficient iron stores
• (3) Ascorbic Acid (Vitamin C): Large doses given to increase iron
absorption from food; but probably doesn’t affect the efficacy of
iron medication.
• (4) Blood Transfusion PRN:
(a) Whole blood (mls) = 6X Hb deficit X weight (kg);
(b) Packed RB cells (mls) = ≤ 10 mls/kg
• (5) Encourage iron-rich diet

Anaemia
Folic Acid Deficiency Anaemia Therapy - 23
(1) Oral folic acid: Given as tablets (5mg OD X 2-3
weeks) usually sufficient; a significant rise in
reticulocyte count will occur within a few days
after start of recovery.
(2) Ascorbic Acid (Vitamin C): A dose of 200mg/Day is
given orally concurrently with folic acid.
(3) Vitamin B12: This may be given in case of coexistent
generalized malnutrition.
N.B: For preterm infants, folic acid should be given at a dose
of 25-50micrograms/Day X 3 months of life, because their
absorption of folate is poor.

Sideroblastic Anaemias
Overview
• Background*
Ring sideroblasts are named so because iron-
laden mitochondria form a ring around the
nucleus
They are nucleated erythroblasts(precursors
to mature red blood cells) with granules of
iron accumulated in the mitochondria
surrounding the nucleus

Classification
OMIM Name Gene
300751
X-linked
sideroblastic
anemia (XLSA)
ALAS2
301310
sideroblastic
anemia with
spinocerebellar
ataxia (ASAT)
ABCB7
205950
pyridoxine-
refractory
autosomal
recessive
sideroblastic
anemia
SLC25A38
206000
pyridoxine-
responsive
sideroblastic
anemia
(vitamin B6
deficiency;
pyridoxal
phosphate
required for
 Classification*
• The WHO International Working
Group on Morphology of MDS
(IWGM-MDS) defined three types of
sideroblasts:
• Type 1 sideroblasts: fewer than 5
siderotic granules in the cytoplasm
• Type 2 sideroblasts: 5 or more
siderotic granules, but not in a
perinuclear distribution
• Type 3 or ring sideroblasts: 5 or more
granules in a perinuclear position,
surrounding the nucleus or
encompassing at least one third of
the nuclear circumference.
• Type 1 and type 2 are found in Non-
sideroblastic anemias. Type 3 is found
only in Sideroblastic anemia.

Aetiologic Classification
• Congenital Causes*
 X-linked:
 Pyridoxine-responsive*
 Pyridoxine-resistant*
• Acquired Causes*
• Clonal (Myelodysplastic
syndrome) type*
• Non-clonal (metabolic) type*
 Copper deficiency*
 Nephrotic syndrome*
 Gastric Surgery*
 Excess zinc intake*
 Anti-TB drugs*
 Alcohol*
• Refer to key to abbreviations*

• Causes of sideroblastic anemia can
be categorized into three groups:
1. Congenital sideroblastic anemia
2. Acquired clonal sideroblastic
anemia* and
3. Acquired reversible sideroblastic
anemia*
• All cases involve dysfunctional heme
synthesis or processing. This leads to
granular deposition of iron in the
mitochondria that form a ring around
the nucleus of the developing red
blood cell. Congenital forms often
present with normocytic or
microcytic anemia while acquired
forms of sideroblastic anemia are
often normocytic or macrocytic.
• Congenital sideroblastic anemia
– X-linked sideroblastic anemia: This is
the most common congenital cause of
sideroblastic anemia and involves a
defect in ALAS2,[8] which is involved in
the first step of heme synthesis.
Although X-linked, approximately one
third of patients are women due to
skewed X-inactivation (lyonizations).
– Autosomal recessive sideroblastic
anemia involves mutations in the
SLC25A38 gene. The function of this
protein is not fully understood, but it is
involved in mitochondrial transport of
glycine. Glycine is a substrate for ALAS2
and necessary for heme synthesis. The
autosomal recessive form is typically
severe in presentation.
– Genetic syndromes: Rarely,
sideroblastic anemia may be part of a
congenital syndrome and present with
associated findings, such as ataxia,
myopathy, and pancreatic insufficiency.

• Acquired clonal sideroblastic anemia
– Clonal sideroblastic anemias fall under
the broader category of myelodysplastic
syndromes (MDS). Three forms exist
and include refractory anemia with
ringed sideroblasts (RARS), refractory
anemia with ringed sideroblasts and
thrombocytosis (RARS-T), and refractory
cytopenia with multilineage dysplasia
and ringed sideroblasts (RCMD-RS).
These anemias are associated with
increased risk for leukemic evolution.
• Acquired reversible sideroblastic
anemia
– Causes include excessive alcohol use
(the most common cause of
sideroblastic anemia), pyridoxine
deficiency (vitamin B6 is the cofactor in
the first step of heme synthesis[9]), lead
poisoning[10] and copper deficiency
Excess zinc[12] can indirectly cause
sideroblastic anemia by decreasing
absorption and increasing excretion of
copper. Antimicrobials that may lead to
sideroblastic anemia include isoniazid
(which interferes with pyridoxine
metabolism), chloramphenicol (which,
by inhibiting the synthesis of
mitochondrial membrane protein,
impairs mitochondrial respiration[),
cycloserine, and linezolid.[14]

Copper Deficiency
Overview/Aetiology
Aetiology:
• Bariatric surgery*(e.g.
gastric bypass surgery),
• Deficiency of Iron and
vitamin B12*
• Zinc toxicity*
Aetiology (others):
• Hereditary Disorders:
Menkes Disease*
• Excess iron
supplements
• Coeliac disease
(malabsorption)
• Lead poisoning*

Pathophysiology
Heme synthesis

Pathophysiology
Cytochrome c Oxidase mechanism in
mitochondrial membrane

Pathophysiology

Copper Deficiency
Copper Dependent Enzymes and Their Function
Group Enzyme Function
Oxidases
Flavin-containing amine
oxidase
Metabolism of
neurotransmitters:
noradrenaline, dopamine,
serotonin and some dietary
amines
Protein-lysine-6-oxidase (lysyl
oxidase)
Connective tissue synthesis-
cross-linking of collagen and
elastin
Copper-containing amine
oxidase
Metabolism of amines-
histamines, putrescine,
cadaverine
Cytochrome c oxidase
Oxidative phosphorylation,
electron transport in the
mitochondrial membrane
Superoxide dismutase (Cu/Zn
dismutase)
Antioxidant and free radical
scavenger, oxidizes
dangerous superoxides to

Copper Deficiency
Copper Dependent Enzymes and Their Function
Group Enzyme Function
Hephaestin (ferroxidase)
Iron transport and oxidation of
Fe2+ to Fe3+ in intestinal cells
to enable iron uptake
Monooxygenases
Dopamine beta-
monooxygenase
Conversion of dopamine to
norepinephrine
Peptidylglycine
monooxygenase
Peptide hormone maturation-
amidation of alpha-terminal
carboxylic acid group of
glycine
Monophenol monooxygenase
(Tyrosinase)
Melanin synthesis
Methylation Cycle Methionine synthase
Transfer of methyl group from
methyltetrahydrofolate to
homocysteine to generate
methionine for the methylation
cycle and tetrahydrofolate for
purine synthesis

Clinical Presentation
 History: Symptoms:
• Incoordination (cerebellar symptoms)
• Failure of growth
• Diarrhea (malabsorption)
• Polyuria, blindness, deafness
(associated with DIDMOAD
syndrome)
• History of exposure to cold for
prolonged periods
• Family history of mitochondrial
disease and anemia
• Medication history of antibiotics,
antituberculous agents, chelators, or
chemotherapy
• Ingestion of supplements, especially
zinc
 History: Symptoms:
• Prolonged dependence on parenteral
nutrition, with insufficient
replacement of copper
• Chronic dialysis with higher than
normal zinc levels in dialysis fluid
• Psychiatric disease with possible coin
ingestion
• Alcoholism
• Exposure to lead, such as via pipes in
older houses
• History of myelodysplastic syndrome
• General symptoms of anemia,
including malaise, fatigue, and
dyspnea on exertion

Pyridoxine Deficiency
Background/Pathophysiology
• Background*
• Epidemiology*
• Pathophysiology*

 Physical Examination: Signs
• General - Growth retardation
in children
• Vital signs - Hypothermia
• Oral - Lead line on teeth
margins
• Skin - Photosensitivity
(porphyria), petechiae
(myelodysplastic syndrome)
• Eyes - Optic atrophy
(associated with DIDMOAD
syndrome)
• Neurologic - Ataxia,
diminished deep-tendon
reflexes, incoordination
 Physical Examination: Signs
• Cardiovascular - Fatigue
• Respiratory - Dyspnea
• Abdominal - Splenomegaly
• Musculoskeletal - Muscular
weakness
• Genitourinary - Pink staining of
diapers from porphyrins in
urine

Hereditary Disorders: Menkes
Disease
A baby with Vitamin B-6
(Pyridoxine) and copper
deficiency. Symptoms of the
sparse, steel colored "kinky hair"
and paleness
(Image courtesy: Datta AK, Ghosh
T, Nayak K, Ghosh M, Cases J.
2008. 1(1): 158. [Open
Access].PMID. 18801184, PMCID:
PMC 2559824).

Pyridoxine Deficiency
Clinical Presentation*
• History: Symptoms*
 Contributing Factors*
 Other patient history*
 Symptoms /conditions
associated with low
pyridoxine levels*
 Symptoms and conditions
associated with
secondary niacin
deficiency (ie, pellagra)*
• Physical Examination:
Signs*
Picture of a 55-year old patient, taking
isoniazid to treat TB of the G.I.T.
Dermatological changes are due to
peripheral neuritis, a side effect of
isoniazid. Image courtesy: OpenStax
CNX, Rice University/Herbet L. Fred
MD; Herdrick A Van Dijk.

Pyridoxine Deficiency
Clinical Presentation*
• History: Symptoms*
 Contributing Factors*
 Other patient history*
 Symptoms /conditions
associated with low
pyridoxine levels*
 Symptoms and conditions
associated with
secondary niacin
deficiency (ie, pellagra)*
• Physical Examination:
Signs*
A patient with pellagra, due to chronic lack of vitamin B3 (niacin) in
the diet (Picture courtesy: Centers for Disease Control and
Prevention: CDC). This may also follow isoniazid therapy. It is also
common among people whose staple food is mainly maize. It may
persist despite pyridoxine supplementation. Cardinal features of
pellagra are ‘’4 Ds’’: Photosensitive Dermatitis, Diarrhoea,
Dementia and Death (if not treated).

Differential Diagnoses
Differential Diagnoses
• Iron Deficiency Anemia
• Acute Myeloid Leukemia (AML)
• ALA Dehydratase Deficiency Porphyria
• Congenital Erythropoietic Porphyria
• Hereditary Coproporphyria
• Myelodysplastic Syndrome
• Secondary Thrombocytosis

Investigations
Management Outline:
• Investigations/Diagnosis
• Specific Treatment
• Supportive/Symptomatic
management
• Preventive Management
Laboratory Studies:
• Complete Blood Count*
• Peripheral smear
• Iron Studies
• Bone marrow aspiration
• Bone marrow biopsy
• PCR
• Urine porphyrin profile*
Others
• Imaging Studies: MRI

Laboratory Picture
Sideroblastic anaemia, due to vitamin B-6
and/or copper deficiency. It may also occur
following lead poisoning (but not lead
deficiency). Image courtesy: Wikimedia
Commons/Paulo Henrique Orlandi Mourao.
Upper middle right: ron and total iron-
binding capacity in physiology and
pathology
Extreme right: Sideroblast cell

Treatment & Management
Management Outline:
• Investigations
• Specific Treatment:
 Antidotes*
 Transplants*
• Supportive/Symptomatic
management:
• Preventive Management*
• Remove toxic agents:
 Antidotes*: Iron
overload(Desferrioxamine)
 Bone marrow Transplant*
 Liver Transplant*
• Vitamin B Therapy:
 Pyridoxin*
 Thiamin*
• Boost Hb: Haematinics*:
 Folic acid
 Ferrous sulphate
 Blood Transfusion*

Epidemiology/Prognosis
Epidemiology*
Prognosis*
Patient Education*
 Genetic Counseling*
 Documentation of
clinical outcome
invaluable

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