DISORDERS OF GROWTH

Dr. Kagira JM
DISORDERS OF GROWTH
At the end of this series of lectures, students should:-
• Have a sound understanding of the concepts of controlled & uncontrolled
disorders of growth
• Be familiar with the commonly used terms in Disorders of Growth
• Have a sound understanding of the role of viral agents & physical agents in the
aetiopathogenesis in neoplasia and be able to give relevant examples
DISORDERS OF GROWTH: AQUIRED
• Disorders of Growth:
– Alterations in the rate of cell division & differentiation of cells within organs or
tissues in response to a change in cellular homeostasis caused by an agent of
disease
Disorders of Growth
1) Controlled (Non-neoplastic)
• Rate of cell division & differentiation altered but still within the control of
normal mechanism
• Alterations represent either physiological adaptations or pathological change
• Changes are reversible if the inciting stimulus is removed

2) Uncontrolled (Neoplastic)
• Cells proliferate without the constraints of normal cellular controls
• Fail to reach full differentiation
• Result in the growth of tumours or neoplasms & irreversible
NON-NEOPLASTIC DISORDERS OF GROWTH (controlled alterations in
cell growth)

1. HYPERTROPHY
• Increase in cell size & result in increase in the size of the organ
• Due to the increased synthesis of structural proteins & organelles
• Causes: physiological or pathological
• Pure hypertrophy occurs only in those organs in which cells have
lost the ability to divide; eg., skeletal & cardiac muscle
(A) Physiological hypertrophy:
• Massive physiological growth of the uterus during pregnancy
involves both hypertrophy & hyperplasia - from oestrogen
stimulation
• Development of muscles in a race horse, or a weight lifter- only
from hypertrophy of individual muscle cells induced by increased
workload
(B) Adaptive response:
• As an adaptive response occurs as muscular enlargement in two
settings
• Striated muscle cells in both heart & skeletal muscles can undergo
only hypertrophy in response to increased demand

(C) Compensatory hypertrophy:

• May be a physiological or pathological response
• Result of impaired function of an organ system
• Eg., When one kidney is damaged, the other gradually enlarges and
compensates for the loss
Hypertrophy:
• Macroscopically: the organ or tissue is larger & heavier than normal
• Microscopically: increase in the size of cells & fewer cells in each
microscopic field
• Significance and results: results in an increased function of an
organ or tissue
2. ATROPHY
• Refers to wasting of tissues and is the opposite of hypertrophy involving
decrease in cell size & cell number
• Is shrinkage in size of the cell from loss of cell substance
• Entire tissue or organ diminishes in size

Causes :
(A) Physiological (physiological atrophy). Examples:
• Disappearance of the thymus as an organism reaches sexual maturity
• Involution (reduction in size) of the uterus after pregnancy
• Involution of mammary gland after lactation
• Atrophy of the endometrium during anoestrus

(B) Aging (senile atrophy): associated with cell loss

(C) Inadequate nutrition (starvation atrophy): During starvation, glycogen
and fat are the first to disappear, then the protein of the body musculature,
and finally the protein of the vital organs
• Results in marked muscle wasting
(D) Decreased workload (disuse atrophy)
• Reduction in the size of cells result of decreased workload or
inactivity
• Eg: broken limb is immobilized in a plaster cast, atrophy of skeletal
muscle occurs

(E) Loss of innervation (denervation or neurotropic atrophy)

• Normal function of skeletal muscle depends on its nerve supply.
• Damage to the nerves leads to rapid atrophy of the muscle fibres
supplied by them
• Example: When the nerve supply to a limb is cut muscles of that
limb atrophy

(F) Diminished blood supply (angiotrophic atrophy)

• May result from anaemia, ischaemia, or chronic passive congestion
• Atrophy in the hind limbs occurs when a parasite (strongylus larvae)
occludes the femoral artery
(G) Pressure (pressure atrophy)
• Occurs when a mild mechanical force is applied continuously to cells over
a long period of time
• Due to malnutrition associated with ischaemia
• Commonly observed in tissues adjacent to tumours, abscesses, and
haematocysts

(H) Loss of endocrine stimulation (endocrine atrophy)

• Occurs either from loss of endocrine stimulation, or from excessive
endocrine secretion. Examples:
• Hypersecretion of the thyroid results in extreme emaciation and atrophy
as a result of greatly increased rate of metabolism.
• Oestrogen produced by testicular tumours causes atrophy of the
seminiferous cells of testicle and epithelium of the accessory sex glands.
• Atrophy of the prostate gland following castration
• Atrophy of the uterus after ovariectomy (removal of ovaries).
3. HYPERPLASIA
• Refers to an increase in cell number (rather than cell size)
• Cells capable of mitotic division may divide when stressed or stimulated
by increased activity, and thus constitute hyperplasia
• Closely related to hypertrophy - often develop together -- increase in
organ size
– Eg., Prostrate, Pregnant uterus
Physiological hyperplasia eg.,:
• Hormonal hyperplasia - proliferation of the glandular epithelium of the mammary
gland at puberty and during pregnancy
• Compensatory hyperplasia: occurs when a portion of the tissue is removed (e.g. in
partial hepatectomy)
Pathological hyperplasia causes:
[A] Repeated and prolonged irritation by mechanical, chemical, and thermal agents.
• Examples: Calluses on the elbows and stifles & hands of workmen
(B) Endocrine disturbances: Hyperplasia of the prostate occurs in old
dogs
• Can be prevented if the animal is castrated, or if oestrogen is
administered
(C) Nutritional disturbances:
• Iodine deficiency results in hyperplasia of the thyroid (goitre)
• Vitamin A deficiency results in hyperplasia and hyperkeratinization
of epithelium in oesophagus of the chicken.
(D) Infectious causes:
• Pox viruses (cowpox, fowl pox) cause hyperplasia of epithelium
• Hyperplasia of the epithelium of the lips occurs in sheep infected
with contagious ecthyma virus
(E) Wound healing:
• Growth factor-stimulated fibroblasts and blood vessels proliferate
to facilitate repair
4. METAPLASIA
• Replacement of one cell type with another (metaplasia = metamorphosis)
• Epithelial tissue: involves conversion to stratified squamous epithelium
• Causes include:
[A] Repeated & prolonged irritation: eg., squamous metaplasia in the
respiratory tract in response to chronic irritation
• Pseudostratified columnar ciliated epithelium to stratified squamous
epithelium as the result of injury from lungworms & in habitual cigarette
smokers

[B] Nutritional disturbances:

• Deficiency of vitamin A causes cuboidal or columnar epithelium to change
to stratified squamous epithelium in a variety of locations eg., lachrymal
ducts
• Seen in mucous glands of the oesophagus of the chicken.
[C] Endocrine disturbances: mammary gland tumour in dogs is caused by
endocrine disturbances
5. DYSPLASIA
• Disorderly arrangement of cells
• Recognised in epithelial tissues & refers to a proliferation of cells
• A consequence of prolonged hyperplastic change
• Regarded as a pre-neoplastic change & has a propensity to progress to
full-blown neoplasia
• Is a loss in the uniformity of individual cells & a loss in their architectural
orientation
Dysplastic cells characteristics:
i. Variation in size & shape
ii. Deeply stained (hyperchromatic) nuclei that are abnormally large for
the size of the cell
iii. Mitotic figures are more abundant than usual, and appear in abnormal
locations
• When marked & involve the entire thickness of the epithelium, the lesion
is referred to as carcinoma in situ - a preinvasive stage of cancer
• Cervix & respiratory tract - dysplasia is strongly implicated as a precursor
of cancer
NEOPLASTIC DISORDERS OF GROWTH (uncontrolled alterations in cell growth)
• Neoplasia: growth of tumours (neoplasm)
• Neoplasm: mass formed from an uncontrolled proliferation of cells
• Study of tumours = Oncology
• Proliferation is irreversible & continue to enlarge unless:
1. Effective therapeutic intervention
2. Effective anti-neoplastic response by the host (rare)
3. Host dies either from the effects of the neoplasm
• Uncontrolled proliferation- irreversible change in the cells' behaviour’
• Neoplasm:
– Clonal proliferation of a single cell - after transformation
– Retain features of tissue of origin
– Classification: tissue or cell type of origin
– Stimulate the growth of supporting connective tissue & blood vessels
essential for their survival.: stroma
PATHOGENESIS OF NEOPLASM
AETIOLOGY OF CANCER
• Factors associated with the aetiology (causation) of neoplasms can be
divided into Intrinsic & Extrinsic factors

Intrinsic (Predisposing) Factors

1. Heredity: strains of birds with resistance to the lymphoid leukosis virus
• Human - Hereditary predisposition to breast colon, ovary, prostate, uterus
cancer
2. Age: Frequency of cancer increases with age:
• Due to the accumulation of somatic mutations over a period of time
• Decline in immune competence that accompanies aging
3. Pigmentation:
• In white and grey horses, melanosarcomas are more common
• Hereford/Friesians cattle squamous-cell carcinoma of the eye is more
common.
4. Sex: there is a difference between the male & female in the incidence of
tumours in genital organs

5. Tumour immunity: Both cell-mediated and humoral immunity have anti-

tumour activity
Extrinsic Factors
• Genetic damage lies at the centre of carcinogenesis, that is,
production of cancer.
• Large number of external agents shown to be neoplastic
Categories:
• (1) chemicals, (2) radiant energy, (3) chronic irritation, (4)
hormones, (5) parasites, and (6) oncogenic viruses.
CHEMICAL CARCINOGENS
• Fall into two categories:
(1) Direct-acting agents. do not require chemical transformation for
producing cancer
(2) Indirect-acting agents: Become active only after metabolic
conversion
• Referred to as 'procarcinogens‘
• Their active end products are called 'ultimate carcinogens‘
• Majority of the chemical carcinogens are indirect-acting
1. Direct-Acting Agents
• Require no metabolic conversion to become carcinogenic
• Eg: cyclophosphamide, chlorambucil, nitrosoureas- cause
leukaemia
2. Indirect-Acting Agents
A. Polycyclic aromatic hydrocarbons:
• Require metabolic conversion before they are active
• Potent carcinogens, eg., benzanthacene, benzapyrene,
methylcholanthrene
• Polycyclic hydrocarbons:
– eg., benzapyrene are produced in the combustion of tobacco in
cigarette smoking - lung cancer in cigarette smokers
– Produced from animal fats in the process of roasting meats
– Present in smoked meats and fish
B. Aromatic amines and azo dyes:
– Beta-naphthylamine - 50-fold increased incidence of bladder cancers
in workers heavily exposed to the aniline dye & rubber industries
– Some of the azo dyes were developed to colour food eg., butter-
yellow to colour margarine
2. Indirect-Acting Agents
• Natural plant and microbial products (naturally occurring carcinogens):
• EG: Aflatoxin Bt
– Hepatic carcinogen produced by Aspergillus flavus
– Grows on improperly stored grains & groundnut
3. Miscellaneous agents:
• Large number of other chemicals
Egs:
• Asbestos (lung & gastrointestinal cancers),
• Arsenic (skin cancer)
• Chromium, nickel (cancer of the lung)
• Insecticides - aldrin, dieldrin
• Nitrosamines and nitrosamides [from tobacco] (gastric carcinoma)
– Biological agents - Oncogenic (carcinogenic) viruses:
• Oncogenic RNA viruses: eg., retroviruses eg., feline leukaemia virus
• Oncogenic DNA viruses: eg., papilloma viruses which cause warts
RADIATION CARCINOGEN – read on your own
• Ultraviolet (UV) rays of sunlight, x-rays, nuclear fission - established
carcinogen.
• UV: ocular & periocular squamous-cell carcinoma in white-faced
Hereford cattle, due to lack of protective pigmentation in the eyelid
• Humans –
– x-ray workers may develop skin cancers
– Exposure to sunlight (UV rays) in persons with fair skin can lead to skin
cancer
• Ionizing radiation - activate ras genes & inactivate tumour suppressor
genes
HORMONES
• Dog - high incidence of mammary tumours associated with disturbances
of hormone balance
• Stilbestrol (synthetic oestrogen) - established carcinogenic agents in
animals
• Humans - endogenous oestrogen excess/ hormonal imbalance- role in the
production of breast cancer (carcinoma)
• Ovarian tumours that secrete oestrogen are associated with breast cancer
in post-menopausal women
• Prolonged post-menopausal oestrogen therapy in women moderately
increases the risk of breast cancer
• Human - uterine fibroids thought to be caused by excessive oestrogenic
stimulation.
PARASITES- – read on your own
• By causing chronic irritation, may lead to neoplasia
• Examples:
– Dog: Spirocerca lupi invades the wall of the lower oesophagus &
produce fibrosarcomas or osteosarcomas
– Eimeria stiedae invasion of the liver of the rabbit results in multiple
adenomas of the bile ducts
– Human: Schistosoma haematobium cause of carcinoma of the human
bladder
MOLECULAR MECHANISM OF CANCER DEVELOPMENT
• Neoplasia: genetic disease of cells - neoplastic transformation of cells
• Mutation must occur in a gene involved in cell proliferation
• Genes can be divided into two groups:
(i) Proto-oncogenes (the accelerators)
• Essential for controlling normal cell division
• Products: proteins which when activated will stimulate one of the steps
leading to mitosis
• Mutant proto-oncogene: oncogene whose products remain in the
activated state - cell receives a constant stimulus to divide

(ii) Tumour suppressor genes (the brakes)

• Essential for normal control of cell division
• Products oppose the effects of proto-oncogene expression
• Lead to a suppression of cell division
• Mutant tumor suppressor genes - recessive; both alleles must be
affected for the mutation to be manifested
phenotypically
• Its like releasing the brake on cell proliferation
• Proto-oncogenes & tumour suppressor genes influence cell division.
• They influence:
1. Production of growth factors
2. Expression of receptors for growth factors and other stimulators of cell
growth such as hormones & adhesion molecules
3. DNA replication
4. Apoptosis
VIRAL ONCOGENESIS (Oncogenic Viruses) – read on your own
• Certain viruses (e.g., human T –cell leukaemia virus type 1, Epstein-Barr
virus, hepatitis B virus) are responsible for some forms of human cancer
• Oncogenic viruses fall into two classes:
– RNA viruses
– DNA viruses
• RNA oncogenic viruses [Oncornaviruses/Oncoviruses/Retroviruses]
• DNA oncogenic viruses include Papovavirus, Herpesvirus, Hepadnavirus,
Adenovirus
Mechanism of Action of RNA Oncogenic Viruses
• Animal retroviruses transform cells by two mechanisms
• Rapidly or acutely transforming viruses contain a transforming viral
oncogene (v-onc)
• Slowly transforming viruses- the proviral DNA is always inserted near a
cellular oncogene
– Under the influence of a strong retroviral promoter, the adjacent
normal or mutated cellular oncogene is overexpressed
– Mechanism of transformation = 'insertional mutagenesis'
TUMOUR GROWTH
• Growth: Number of cells undergoing replication must exceed those being lost
• Orchestrate the growth of an adequate blood supply ('tumour angiogenesis)
• Neoplastic cell secrete proteolytic enzymes & capable of motility: invade the
extracellular matrix or enter a vessel
• Metastasis: Cell must survive blood passage & bind to vascular endothelium
in another tissue
Macroscopic Appearance of tumours
• No definite size, shape, colour, or consistency
• Appearance influenced by:
1. Location
2. Type of tumour
3. Blood supply
4. Rate of growth
5. Length of time
• Size: measure from 1-2CM to several centimetres in diameter
• Weight: few mg - 60 kg
• Shape:
– Is quite variable
– Round, elliptical, or multi-lobulated
– Slowly growing tumour tends to be spherical or pedunculated
– Rapidly growing neoplasm is usually irregular in shape, or is
multi-lobulated
• Colour:
– Greyish white, but may be yellow, red, brown, or black
– Areas of necrosis often appear as white or yellow
• Consistency varies with the type of tissue
– Tumours of bone are very hard
– Collagen - dense and firm
– Soft and friable - encephaloid in consistency, because they
resemble brain tissue
– Soft and liquefied- degeneration, suppuration, and necrosis are
present
– Tumours contain mucin - slimy
CLASSIFICATION OF NEOPLASMS –
• Important when deciding upon the appropriate therapy
– Either benign or malignant
– Cell type from which they arose (cell of origin)
BENIGN
• Solitary, slow growing, well-circumscribed, rounded mass compressing, but
not growing into, surrounding tissue
• Can have thin fibrous capsule & easily 'shelled out' of the surrounding tissue
during surgery
• Epithelial neoplasm - can grow upwards & outwards giving rise to a cauliflower
(or broccoli) shaped mass on a stalk or peduncle
– polyps or papillomas
• Beneath epithelial surfaces- ulceration due to trauma
• Microscopic:
– Well-differentiated
– Cells uniform & orderly
MALIGNANT
• Have indistinct borders, less clearly circumscribed
• From beneath a surface (eg., mucosa) - ulceration of the overlying epithelium
• Foci of necrosis & haemorrhage arise where blood vessel walls are invaded
leading to rupture of the vessel & ischaemia
• Microscopic features:
– Behaviour - lack normal structures & doesn't respect normal boundaries
(poorly differentiated – anaplasia)
– Indistinct borders - small clumps of neoplastic cells seen within blood or
lymphatic vessels - invasive, metastasis
– Variable morphology - pleomorphism:
• Cytoplasm: variation in the staining or in the amount of cytoplasm
• Nucleus: variation in staining intensity or the number or size of nuclei
• Mitosis: rapid growth rate
• When a tumour cell becomes malignant, it reverts to the more embryonal
type
• Reversion is called ANAPLASIA.
• Anaplasia is characterized by:
1. Hyperchromasia & enlargement of the nucleus:
• Nuclei are extremely hyperchromatic and large
• Nuclear-cytoplasmic ratio may be 1:1, instead of the normal 1:4 or 1:6
• Nuclei - vary in their size and shape
2. Enlargement of the nucleolus:
• Nucleoli are also extremely large
• May become two or three times their normal size
3. Increased number of mitotic figures:
• The more rapidly the cells are multiplying, the greater the number of mitotic
figures
• Mitotic figures are distinctly atypical
4. Giant cells:
• Much larger than the neighbouring cells & possess either one very big
nucleus, or several nuclei
• Nucleus is dividing more rapidly than cytoplasm - multiple nuclei are
found within the cell - tumour giant cells
5. Hyperchromasia of the cell:
• Intensely the cell stains with haematoxylin especially the nucleus
6. Embryonal type cells:
• Cell loses its resemblance to the cells from which it originated
• Approaches the undifferentiated embryonal cell type
• Cell growth is no longer under the control of growth regulating mechanism
of the body.
Nucleoli

Multinucleated

binucleus
Mitosis
METASTASIS
• Groups of tumour cells that are discontinuous with the primary tumour –
secondaries
• Common routes by which a malignant neoplasm can metastasise:
1. Exfoliation & Implantation: important in the body cavities eg., spread of
haemangiosarcoma from spleen to peritoneal cavity
2. Haematogenous spread: requires the invasion of blood vessels (esp. capillaries
& venous system)
– Tumour emboli lodge in the first capillary bed that they reach
3. Lymphatic spread:
• Common route
• Depends upon the site of the primary tumour & lymphatic drainage from that
site
• Eg., mammary adenocarcinomas spread via the lymphatics to draining lymph
nodes (axillary)
NOMENCLATURE
• Benign tumour: cell type in Latin or Greek & suffix '-oma'
• Malignant neoplasm: cell type in Latin or Greek & suffix 'carcinoma' or
'sarcoma'.
• Carcinoma: malignant neoplasms arising from epithelial tissues
• Sarcoma: malignant neoplasms arising from mesenchymal tissues (connective
tissues, skeletal tissues, muscle etc).
• Adenoma (benign) or an adenocarcinoma (malignant): glandular origin
• Leukaemia - presence of neoplastic lymphoid or haematopoietic cells in the
blood stream
Effects on the host
Local effects:
1. Atrophy of adjacent tissue: due to direct compression & ischaemia
2. Invasion: Result in a gradual loss of organ function as normal tissue is
replaced by neoplastic tissue. e.g. loss of lung tissue with carcinoma;
pathological fracture of bone due to invasion of cortex
3. Ulceration & infection: Invasion through epithelium or loss of epithelium due
to surface trauma can allow entry of infection at the site
4. Anatomical distortion: Eg., impaired vision as tumour distorts optics of eye
5. Blockage: Neoplasms expand & compress structures such as gut, ducts or
vessels from the outside or create an obstruction if growing within the lumen
6. Scarring: Neoplasms stimulate the formation of large amounts of fibrous
tissue - can undergo contraction leading to blockages
7. Pain: may be a major cause of debilitation
B. Systemic effects:
1. Metastasis: Depend on organs involved eg., renal failure, CNS seizures
2. Cachexia (wasting): causes loss of appetite (anorexia), blood loss & chronic pain. Wasting
due to diversion of nutrients to the neoplasm
3. Blood loss: from ulcerated neoplasms either on the skin or in the GIT - lead to anaemia
4. Infarction: Emboli composed of necrotic neoplastic tissue can be released into the
circulation - lead to infarction in distant organs
5. Paraneoplastic syndromes: systemic disorders which develop because of functional
activity expressed by the cells of the neoplasm. Eg:
• Feminisation in male dogs (oestrogen secreting tumour of testis)
• Acute hypoglycaemia (insulin secreting tumour of pancreatic islet)
Diagnosis of neoplasia
Clinical signs
• Mass on the skin or in an internal organ by palpation, radiography
• Local & systemic effects exerted by the neoplasm on the host
• Age, sex, breed and species of an animal may further assist in diagnosis
• Presence of a mass (space occupying lesion) does not necessarily mean
neoplasia (eg., granuloma)
Cytology
– Microscopic examination of stained smear of cells taken from the mass
– Insert needle into mass, aspirate & spray material onto a slide
– Press cut surface of the mass directly onto a slide
– Slide is examined for the presence of neoplastic cells & features of
malignancy (pleomorphism, nuclear abnormalities etc)
– Cytology: cheap & quick
• Histopathologic examination (biopsy):
– Allows margins of neoplasm to be examined - informs surgeon whether or
not the entire neoplasm has been removed
– Tissue structure: definitive diagnosis made
– Techniques include: routine H&E stained sections, immunohistochemistry,
electron microscopy
• Both cytologic & histopathologic examination: can also be performed on local
lymph nodes to determine if metastasis has occurred
• Pulmonary metastasis - done by radiographing the thorax
Recent aids immunological diagnosis of cancer
include: read on your own
– Immunocytochemistry (monoclonal antibodies)
– Southern blot analysis
– Flow cytometry
• Can be applied to:
– Exfoliated cancer cells
– Tissue aspirations
– Biopsy specimens
Biochemical assays - read on your own
• Done for tumour-associated enzymes, hormones, and other tumour
markers in the blood
• Circulating tumour markers:
(A) Carcino-embryonic antigen (CEA)
(B) Alpha-foetoprotein
• Also increased in several other disorders that are not neoplastic
• Lack in specificity and sensitivity required for the detection of cancers

Molecular Diagnosis
(1) PCR - differentiate between monoclonal (neoplastic) & polyclonal
(reactive) proliferations
(2) Fluorescent in situ hybridization (FISH) technique - useful in detecting
translocation characteristic of many tumours