it is lect for awareness about cancer

1.  Growth refers to increase in size.
 This term is applicable to individual cells or their sub cellular components (eg.
mitochondria)to groups of cells and tissuesto whole organsto parts of organisms
(eg. limbs)to whole organismsGrowth can occur byby multiplication (increase in
cell number)by increase in size of components (so called auxetic growth)by
increase in intercellular material (so called accretionary growth)by a
combination of the above In order to understand growth there is a need to
consider the following issues
 Organismal growth

 Morphogenesis

 Differentiation

 Cell number control
 Important disorders of growth should be considered including neoplasia. An
introduction to this area can be found at:-
 Disorders of cellular growth


2.  Growth of whole organisms is a complex issue
with vast changes during embryonic and fetal
development equivalent to some 42 cell doublings
over the 40 weeks gestation of a human
being.Differential growth and migration
contribute the events in embryological life with
maximal growth occurring at 20 weeks
gestation.Genetic contributions to growth exist as
well as environmental factors.Growth is controlled
by and is susceptible to variations in:genetic
factorshormonal factorsnutritionenvironmental
factorsother disease

3.  Morphogenesis is the complex process by which the specific shapes of cells, tissues,
organs and ultimately whole organisms occurs. It involves both cell growth and
differentiation as well as migration of cell populations. It can also involve programmed
cell death or apoptosis.In developing an organism from a fertilised egg there are three
requirements: Carefully regulated increase in cell number Differentiation of appropriate
cell types Careful spatial arrangement of the correct number of the correct cell types
 The process of forming particular organs during development is termed organogenesis.
 In the adult there is a continuing need to carefully define cell numbers and cell
phenotypes, and to form these cells into highly ordered tissues with characteristic
organisations. These organisations that we recognise as normal histological patterns, for
example of epithelia, are dynamic structures with ongoing proliferation, differentiation
and cell loss. These dynamic structures contain cells with different proliferative
capacities in hierarchical arrangements.
 Hence morphogenesis involves the initial patterning of specific tissues and organs in
embryonic and fetal development but similar processes are associated with the
maintenance of these structures in the adult (post natal) state. Furthermore these
processes can be deranged both in development and also in post-natal disease.

4.  Anomalies of organogenesis
includeAtresiaHypoplasia and
AplasiaAgenesis/Aplasia Maldifferentiation
Ectopia and heterotopia

5. Anomalies of organogenesis include
Atresia
Hypoplasia and Aplasia
Agenesis/Aplasia
Maldifferentiation
Ectopia and heterotopia

6.  The word differentiation is used in two ways in pathology and biology: to
describe both a process and a state (see below). Here we need to begin by
considering the process of differentiation.All cells in the body (with the
exceptions of gametes that have undergone meiosis, and lymphocytes that have
undergone antigen receptor gene rearrangements) have exactly the same
genetic constitution. Thus every cell type whether it be skin cell or neurone,
hepatocyte or renal tubular cell has the same GENOTYPE and
thus POTENTIAL for gene expression, despite having very different
PHENOTYPES, or specific profile of gene expression. There are about 3 x 109
nucleotides in the human genome encoding about 30,000 to 40,000
genes. Hepatocytes differ from neurones in the pattern of gene expression -
some genes are expressed in both and some are restricted to specific cell
types.Differentiation is a process usually resulting in a cell becoming different
(differentiating) from its parent cells. Hence the second way in which the word
is used is to specify one differentiated state (say a neurone) in contrast to
another differentiated sate (say an hepatocyte).Differentiation is thus the
molecular and biochemical process of regulated gene expression that results in
different phenotypes resulting from the same genotype. An overview [for the
more advanced student] of the mechanisms involved in differentiation is
presented in this link.

7. d differential gene expression or phenotype. Nuclear transplantation experiments have demonstrated
umber of 8 to 20 base pair sequences, to which can bind sequence specific gene regulatory proteins,
by alignment of the helices with DNA coils. Some homeodomain containing transcriptional regulato

8.  Progression from simple to complex involves the spatially and temporally highly regulated process of selective gene expression in the cells that
comprise an organism. Differentiation can thus be defined as the process of regulated gene expression that gives rise to different phenotypes from a
common genotype. Differentiation can also refer to a state of regulated differential gene expression or phenotype. Nuclear transplantation
experiments have demonstrated that somatic cells differentiate by alterations in patterns of gene expression while retaining a complete genome:
differentiation occurs by regulation of gene expression by a composite of intrinsic and extrinsic factors. There are many layers of control, and
regulation is possible at every step in the pathway from DNA to protein via RNA intermediates (see Figure).
 For most genes, control at the level of transcription of DNA into mRNA appears to be of primary significance. A general strategy in eukaryotes
involves a promoter element. This is required for accurate and efficient transcription, located close upstream (5’) to the protein coding DNA
sequence. The promoter acts together with more distantly located enhancer sequences. These are required to enhance the rate of transcription from
the promoter, which may be either upstream (5’) or downstream (3’) and in either orientation. Most promoters and enhancers are modular in
construction, being composed of a number of 8 to 20 base pair sequences, to which can bind sequence specific gene regulatory proteins, or
transcription factors, which may act in a positive or negative manner. It is believed that a relatively small number of regulatory proteins can control
transcription in a combinatorial manner, with input from several regulatory proteins determining gene activity. Regulation may be by inhibition of
positive regulatory factors or by activation of negative factors. Interactions between different DNA binding proteins, between DNA binding proteins
and other ligands or their alteration by modification such as phosphorylation may alter the binding to DNA and the level of transcriptional activation
or repression.
 A series of DNA binding proteins have been defined and their structures determined. Several generalizations can be made. They tend to have a
modular design with separate DNA binding and modulating domains. However, there is remarkable evolutionary conservation of at least some parts
of these molecules. It appears that the modulating domains can interact with other proteins and these interactions are essential for functioning of the
transcriptional regulators. A nomenclature has arisen on transcriptional regulators including terms such as homeobox, zinc finger and leucine zipper.
The ‘homeobox’ or homeodomain is a highly conserved 60 amino acid sequence which appears to be part of the DNA binding domain and contains a
‘helix-turn-helix’ motif allowing binding to DNA by alignment of the helices with DNA coils. Some homeodomain containing transcriptional
regulators also contain a second conserved region termed POU which also appears important in controlling gene expression, particularly in
development. The ‘zinc finger’ is a second form of DNA binding domain seen in transcriptional regulators where a single Zn2+ ion is co-ordinately
bound to protein loops containing a pair of cysteins and a pair of histidines or two pair of cysteins. The ability of a transcriptional factor to bind to a
second protein (and thus to alter its properties) is sometimes a consequence of the presence of ‘leucine zippers’, i.e. regularly spaced leucine residues
on both proteins. These leucines allow dimerization because of their hydrophobicity. The mechanisms of sequence specific transcriptional regulation
based upon protein-DNA interactions are reviewed elsewhere.

9.  It is now recognised that gene regulatory proteins may control (positively or negatively) their own transcription and that of other regulatory proteins
forming cybernetic networks that determine the complex patterns of gene expression required in metazoan organisms. Such networks may then
generate stable states of gene expression as a consequence of the relative abundance of different transcription factors binding to enhancer and
promoter elements. For example, in muscle it has been shown that a small number of DNA binding proteins (myoD1, myd, myogenin etc) can regulate
the myogenic phenotype. The introduction into a fibroblast of myoD1 in a suitable expression vector can induce a programme of muscle specific gene
expression although other factors are also involved in the full expression of muscle differentiation. It seems probable that cascades of regulatory gene
expression with mixtures of diffusible trans acting DNA binding proteins binding to cis regulatory sequences are central to the control of
differentiation but other mechanisms also have a role. For example, the physical state of chromatin influences gene expression with heterochromatin
being transcriptionally inactive, and methylation of cytosine residues may be an important means of inactivating certain genes. Post-transcriptional
modifications of RNA are a further important layer of control. The processing of mRNA and its export from the nucleus have been described and
important structural alterations of mRNA can occur. For example, splicing events can give rise to a number of different mRNAs from the same gene
by removal of exons, introns or use of internal splice sites. Such alternate splicing events can be important means of generating quite different
proteins from the same gene in a manner related to development or differentiation. The use of alternate promoter sequences may have a similar effect.
Another structural alteration involves the use of different 3’ poly A addition sites which can give rise to proteins of different length. Control of
translation of mRNA into protein may be effected by binding of regulatory proteins to the 5’ mRNA leader sequence or by alterations in mRNA
stability. For example, it has been found that regulatory proteins typically have mRNAs with very short half lives. Stability of mRNA is usually
determined by intrinsic mRNA sequences, typically at the 3’ end, and the half life may be extensively altered by extracellular signals including growth
factors. Finally, the use of alternate translational start sites can give rise to quite different protein species from the same original mRNA. The process
of differentiation is associated with a progressive restriction in the potentiality of cells, so that in the adult, the cells of any given normal tissue have a
very restricted capacity to express the whole genome. Furthermore, cells retain the memory of this restricted genotype, and they ‘remember’ their
nature even when placed in a novel environment: patterns of gene expression are stable and heritable. Although some modulation of differentiated
phenotype can occur as a consequence of environmental stimuli such as growth factors, extracellular matrix molecules and contiguous cells, radical
modifications are rarely observed: a keratinocyte does not spontaneously express a neural phenotype. The nature of the cell’s memory of its state of
differentiation is uncertain: it may in part reflect methylation status and structural alterations of chromatin. However, it seems increasingly likely that
transcriptional control by cascades of regulatory DNA binding proteins underpins this phenomenon. Whatever the mechanisms, it is clear that during
development and differentiation external (epigenetic) influences induce heritable changes in gene expression. For further reading see also see
Alberts et al The Molecular Biology of the Cell, 3rd Edition, Garland press, and in particular Chapters 9 [Control of gene expression] and 22
[Differentiated cells and the maintenance of tissues].


11.  The regulation of cell number in an adult tissue is critically controlled in very precise limits yet can
(in many situations) respond to changing circumstances. An example of this is the ability of the bone
marrow to produce more leucocytes in response to infection or more erythrocytes in response to
blood loss.
 Cell number is the balance of cell production (due to proliferation via the cell cycle) and cell loss via a
number of means including cell death by the process of apoptosis.
 Think in terms of a bath with the tap running, a given level of water and the plug hole open. Water is
entering and leaving and the level of water depends upon the relative rate of water entering the bath
and leaving the bath. You can increase the level of the bath water by putting a plug in the hole (or
reducing the size of the hole) or by turning the tap such that more water enters . . . or both.
 We recognise the existence of three broad classes of cell type in terms of proliferative (or
regenerative) capacity.
 Labile cells (sometimes called continuously renewing cells) Stable cells (sometimes called
conditionally renewing cells) Permanent cells
 Labile cells proliferate continuously through post-natal life and have a very high regenerative
capacity. These can be very susceptible to toxic agents such as anti-cancer chemotherapy drugs and
radiation. Examples of labile cells include bone marrow, epithelia of mouth, skin, gut and bladder.
 Stable cells divide [usually] only infrequently but can be stimulated to divide when cells are
lost. Examples of this group include bone, liver, renal tubular cells, fibroblasts in connective tissue,
etc.
 Permanent cells normally only divide in embryonic and fetal life (or maybe in the early post natal
period). Cells in this category cannot be replaced when lost and they have only a very limited (if any)
capacity to divide. This group includes cardiac muscle cells, photoreceptors in the retina and
neurones.
 Inevitably this classification is only an approximation and exceptions are being found, but it remains
very useful.
 Many aspects of pathology and clinical practice derive from alterations in in the regulation of process
that control cell number, not least of which is neoplasia (or cancer).
 Further understanding of cell number requires some knowledge of the following topics.
 Proliferative hierarchies and stem cells
 The cell cycle
 Apoptosis
 Control systems


12. PROLIFERATIVE HEIRARCHY
 If one considers the typical labile cell populations of (for example) the
squamous epithelium of the skin or of the gastro-intestinal tract there is a
spatially organised arrangement of proliferative cells as well as of terminally
differentiated non proliferative (and highly specialised) cells.
 You should revise the histology of skin (and other squamous epithelia) and the
colon and small intestine.
 SkinGutOn the basement membrane sit basal cells which can proliferate and give
rise to cells that migrate upwards, proliferating initially but then stopping and
undergoing terminal differentiation. These cells ultimately lose their nuclei and are
shed.On the basement membrane at the crypt base exist a population of highly
proliferative cells that divide and whose progeny move up the crypt, exit the
proliferative compartment and differentiate to give the various specialised cell types
of the crypt and villus (in small bowel).
 Stem cells (proliferative and multipotential)
 give
 Amplifying cells (proliferative but committed)
 give
 Terminally differentiated cells (non proliferative)

 This organisation is common to all labile cell populations and something
similar might exist in (in fact) all cell populations.
 The key point about this kind of organisation (or hierarchy) is that it can be
controlled with great precision such that the number of cells can be regulated
by a variety of positive and negative factors.
 An important point about stem cells is that as well as having proliferative

13. CELL CYCLE
 The critical steps in cell division include
 ensuring the accurate doubling of a cell's genetic information, that this genetic information is
segregated and separated into the two daughter cells.
 This process must be carefully coordinated and only initiated when the cell is ready. The
consequences of error in this process are potentially devastating, either in terms of failed division
(and inability to grow) or division but with genetic error (and the consequences of mutation).
 The whole point about the cell cycle is the careful coordination and control of this process. The
discoverers of key steps in this process won the 2001 Nobel Prize for Medicine.
 Resting cells are said to be in G0 (G zero)
 After appropriate stimulation (including growth factors), a G0 cell moves into G1 (G one where G
stands for gap), a phase of preparation for cell division.
 S phase (synthesis phase) refers to the period when there is semi-conservative replication of nuclear
DNA.
 At the end of S phase the cell enters a second gap period called G2.
 At the end of this the cell undergoes mitosis in M phase. Here the duplicated DNA undergoes a
choreographed separation and separation of the daughter chromosomes into two new 'nuclei'
 Cytokinesis is the process of separating the new nuclei and half of the parental cell stuff (cytoplasm
etc) into the new daughter cells.
 Notice that the term INTERPHASE refers to all the phases of the cell cycle except M Phase
 After cytokinesis cells may re-enter another cell cycle via G1 or become quiescent and enter
G0. Some G0 cells NEVER divide again and are referred to as being TERMINALLY
DIFFERENTIATED.


14. APOPTOSIS
 Necrosis is a pathological process in which cells and tissues die in a living organism with
failure of membrane integrity. That is the cell membrane (and other membranes inside
cells) become permeable as opposed to their usual state. This process follows cell injury
and the resultant dead (and dieing) cells induce an inflammatory reaction.Necrosis must
be clearly distinguished from apoptosis where cell death results from energy dependent,
metabolically active, endogenous cellular processes where membrane integrity is
maintained and where the dying cells do not elicit an inflammatory reaction.Apoptosis is
a physiological process that results in the deletion of individual cells in physiological
growth control and in a range of disease states. Reduced apoptosis contributes to cell
accumulation eg. neoplasia Increased apoptosis contributes to cell loss eg. atrophy
 Much is now known about the molecular basis of apoptosis, in terms of the mechanisms
by which it is regulated and also the detailed biochemical pathways in side the cell that
are involved. The 2002 Nobel Prize for Medicine was awarded to 3 scientists who made
important discoveries about the mechanisms of apoptosis.

 Exercise
 Construct a table that compares and contrasts the features of apoptosis and necrosis
 Click here for a model answer

15. Apoptosis Necrosis
Physiological or pathological Always pathological
Single cells Sheets of cells
Energy dependent Energy independent
Cell shrinkage Cell swelling
Membrane integrity maintained Membrane integrity lost
Role for mitochondria and
cytochrome C
No role for mitochondria
No leak of lysosomal enzymes Leak of lysosomal enzymes
Characteristic nuclear changes Nuclei lost
Apoptotic bodies form Do not form
DNA cleavage No DNA cleavage
Activation of specific proteases No activation
Regulatable process Not regulated
Evolutionarily conserved Not conserved
Dead cells ingested by neighbouring
cells
Dead cells ingested by neutrophils and
macrophages

16. CONTROL SYSTEM
 An absolutely fundamental point in considering how cells behave in
tissues is that the processes of differentiation and growth (including the
cell cycle and apoptosis) are regulated by many different levels of
control - both by positive factors (that stimulate a given process) as
well as negative factors (that inhibit a given process).
 The regulatory systems are biochemical pathways that act as
'governors' in the same way that the accelerator and brake on a car act
as controlling devices that ensure the correct functioning (eg. speed) of
a car. Those biochemical pathways are themselves controlled by many
positive and negative factors. The components of those pathways are
the protein products of genes: these are also controlled by positive and
negative factors . . . . and so on . . .
 Thus there are many levels of control ensuring the correct functioning
of cells . . . and of tissues . . . and of organs . . . etc!

17. CELL GROWTH DISORDER
 A series of growth disorders can occur at the
cellular level and a knowledge of these underpins
much of the subsequent course in Cancer. A clear
understanding of these terms is essential as is the
ability to be able to define them and use the terms
in your future work.
 These words are easily confused: be careful!
 Some particularly confusing words are also used
and can be found at this link.


18. HYPERTROPHY
 Hypertrophy is the increase in the size of a cell (or tissue) without cell
division (no cell number increase).
 It can occur by itself but usually occurs in combination with an
increase in cell number (hyperplasia).
 The best example of pure hypertrophy is the increase in size of skeletal
muscle that occurs with training in athletes (a physiological response to
increased muscle activity) or in the cardiac muscle of the left ventricle
(as a response to outflow obstruction caused by, for example, systemic
hypertension).
 A combination of hypertrophy (cell size) and hyperplasia (cell number)
can occur in the smooth muscle of the uterus during pregnancy as a
physiological consequence of hormonal action.


19.  Hyperplasia is the increase in the number of a cells in a tissue as a consequence
of cell division (no cell size increase).It can occur by itself but usually occurs in
combination with an increase in cell size (hypertrophy).A good example of
hyperplasia is the adaptive increase in erythrocyte production leading to
increased numbers of red cells in individuals living at high altitude. The low
pO2 leads to increased erythropoietin production that stimulates bone marrow
erythropoiesis.A combination of hyperplasia (cell number) and hypertrophy
(cell size) can occur in the smooth muscle of the uterus during pregnancy as a
physiological consequence of hormonal action.Some pathological states are
associated with hypertrophy and hyperplasia (to varying degrees). Examples
include Prostate (benign prostatic hyperplasia Thyroid (Graves' disease)
Breast in the male (gynaecomastia) Capillary vessels (in the retina in diabetes
mellitus)
 Some conditions exist where there are increased number of cells due to
increased proliferation (or reduced cell death) for unknown reasons, yet the
increases are not neoplastic. These might be considered as 'apparently
autonomous hyperplasias'. Examples include: psoriasis (skin condition)
Paget's disease of bone Fibromatosis (proliferation of fibroblasts)

20.  Hyperplasia is the increase in the number of a cells in a tissue as a consequence
of cell division (no cell size increase).It can occur by itself but usually occurs in
combination with an increase in cell size (hypertrophy).A good example of
hyperplasia is the adaptive increase in erythrocyte production leading to
increased numbers of red cells in individuals living at high altitude. The low
pO2 leads to increased erythropoietin production that stimulates bone marrow
erythropoiesis.A combination of hyperplasia (cell number) and hypertrophy
(cell size) can occur in the smooth muscle of the uterus during pregnancy as a
physiological consequence of hormonal action.Some pathological states are
associated with hypertrophy and hyperplasia (to varying degrees). Examples
include Prostate (benign prostatic hyperplasia Thyroid (Graves' disease)
Breast in the male (gynaecomastia) Capillary vessels (in the retina in diabetes
mellitus)
 Some conditions exist where there are increased number of cells due to
increased proliferation (or reduced cell death) for unknown reasons, yet the
increases are not neoplastic. These might be considered as 'apparently
autonomous hyperplasias'. Examples include: psoriasis (skin condition)
Paget's disease of bone Fibromatosis (proliferation of fibroblasts)

21. Hyperplasia
 Hyperplasia is the increase in the number of a cells in a tissue as a consequence
of cell division (no cell size increase).It can occur by itself but usually occurs in
combination with an increase in cell size (hypertrophy).A good example of
hyperplasia is the adaptive increase in erythrocyte production leading to
increased numbers of red cells in individuals living at high altitude. The low
pO2 leads to increased erythropoietin production that stimulates bone marrow
erythropoiesis.A combination of hyperplasia (cell number) and hypertrophy
(cell size) can occur in the smooth muscle of the uterus during pregnancy as a
physiological consequence of hormonal action.Some pathological states are
associated with hypertrophy and hyperplasia (to varying degrees). Examples
includeProstate (benign prostatic hyperplasiaThyroid (Graves' disease)Breast
in the male (gynaecomastia)Capillary vessels (in the retina in diabetes
mellitus)Some conditions exist where there are increased number of cells due
to increased proliferation (or reduced cell death) for unknown reasons, yet the
increases are not neoplastic. These might be considered as 'apparently
autonomous hyperplasias'. Examples include:psoriasis (skin condition)Paget's
disease of boneFibromatosis (proliferation of fibroblasts)

22. Atrophy
 Atrophy denotes the decrease in the size of an organ (or
cell) and can be a consequence of reduction in cell size or
number.
 It may be mediated by reduced cell proliferation OR by
increased cell loss due increased apoptosis.
 Atrophy can occur as a physiological response as in the
post-menopausal decrease in size of the uterus. Atrophy
can also be a pathological process. A good example is the
reduced size of a limb's muscle mass with decreased
use. Similarly loss of innervation, reduced oxygen supply
or blood supply might have the same effect.

23. hypoplasia
 A failure in the development of the normal
size of an organ is called hypoplasia. It an
affect a whole organ or simply a part of an
organ.
 Aplasia is the total absence of development
of an organ and is is synonymous with
agenesis
 This should be viewed in the light of
organogenesis

24. Metaplasia is defined as the transformation of one type of one mature differentiated
cell type into another mature differentiated cell type, as an adaptive response to some
insult or injury. By such a change in differentiation (and hence patterns of gene
expression) the cells are more resistant to the effects of the insult. It is usually a
reversible phenomenon.
Examples include:
Squamous metaplasia of the columnar epithelial cells of salivary gland ducts when
stones are present.
Squamous metaplasia of the transitional epithelium of the bladder when stones are
present or associated with infection with the parasite Schistosoma haematobium.
Development of glandular epithelium (glandular metaplasia) in the oesophagus in
patients with gastric acid reflux. This is called Barrett's esophagus.
Osseous metaplasia in connective tissue.
The significance of these events is that they indicate insults occurring and in some
situations they may be associated with pre-malignant states, as is the case in Barrett's
esophagus. Note that metaplasia does not itself progress to neoplasia but the insults)
that induce metaplasia may induce tumour development.
The term transdifferentiation can be a synonym for metaplasia. In established
tumours transdifferentiation [or metaplasia] can occur but it is usual to restrict the
Metaplasia

25. mechanisms of METAPLASIA
 This is an advanced topic
 This is an area of active research since it illustrates the importance of an understanding of the mechanisms of
differentiation.
 Two models of metaplasia or transdifferentiation exist.
 At one extreme it might be that a given differentiated cell type can convert directly into another differentiated cell
type.
 An alternative view is that the apparent conversion of one differentiated cell type by another is a consequence of re-
specification of a stem cell such that now its progeny have a different pattern of gene expression (and hence
differentiated state or phenotype) compared with the normal.
 It is a fact that, in general, the differentiated state of a cell is a rather fixed and unchanging attribute. For example a
skin cell does not spontaneously convert into a neurone. However the fertilised oocyte has total plasticity since its
progeny can become all the different cells of the adult body.
 An increasing body of information shows that stem cells have a wide potential array of progeny cells with different
phenotypes. This is usually quite restricted under normal physiological situations. For example in the gastrointestinal
tract there is evidence that all four differentiated cell types of the colonic crypt epithelium (mucous cells, absorptive
cells, goblet cells and endocrine cells) can all derive from a common precursor stem cells located at the base of the
crypt.
 What is clear is that we have a remarkably poor understanding of the detailed mechanisms that determine regulated
gene expression in the context of differentiation.
 Slack has proposed that metaplasia represent the mammalian equivalent of homeotic mutations that occur in
invertebrates and allow (in development) the respecification of a developing body part due to a mutation in master
regulator genes. See for example his paper in the Lancet in 1985 or a more recent review.
 Importantly this kind of complex area indicates the inter-dependence of much of modern biology and medicine, such
that to understand pathological and clinical phenomena will require understanding of basic biological issues such as
stem cells, mechanisms of differentiation and the like.


26. Dyplasia
 Dyplasia is a very important disorder of growth since it is a pre-malignant condition of real clinical
significance. It can be thought of as a set of disorders that are a 'half way house' between hyperplasia
and neoplasia. A number of features characterise dysplasia.
 Dysplasia is associated with increased cell number as a consequence of increased cell proliferation
(more mitoses will be seen) and (possibly) reduced cell death by apoptosis.
 Dysplasia is associated with nuclear abnormalities such as hyperchromasia (increased cell staining
with haematoxylin) and pleomorphism (altered nuclear size and nuclear shape).
 Dysplasia may be associated with abnormalities of cellular differentiation.
 Dysplasia may be caused by diverse cellular insults including physical, chemical and viral insults.
 Dysplasia may be reversible (at least in its early stages)
 Dysplastic lesions are often Pre-neoplasic. For example:
 Dysplasia in the cervix associated with human papilloma virus (HPV) infection Dysplasia in the
metaplastic squamous epithelium of the bronchus in smokers
 Many of the morphological features of dysplastic resemble those of overtly neoplastic cells and
correlate well with the properties of tumour cells in experimental systems
 See the following links:
 Neoplasia
 Properties of tumour cells
 Benign & malignant
 Pre-neoplasia
 Screening


27. Neoplasia
 Neoplasia means literally new growth, but the characteristics of neoplasms are complex and this definition is not
sufficient.
 A definition proposed by Rupert Willis in the 1930s remains useful, although there are some exceptions to all the
separate components of the definition.
 "A neoplasm is an abnormal mass of tissue, the growth of which is uncoordinated with that of normal tissues, and that
persists in the same excessive manner after the cessation of the stimulus which evoked the change"
 An important additional component over and above this is
 "the presence of genetic alterations that alter cell growth"
 An alternative OPERATIONAL definition of neoplasia is
 "a growth disorder characterised by genetic alterations that lead to loss of the normal control mechanisms that
regulate cell growth, morphogenesis and differentiation"

 Confusing words . . . . . .
 The word TUMOUR simply means swelling and not all swellings are neoplasms and some neoplasms do not form
swellings per se (eg. leukaemia - a tumour of blood cells derived from the bone marrow). Nevertheless the word
tumour is often used interchangeably with neoplasm. Note also that not all neoplasms are malignant. This is
discussed further in the section on classification.
 Another potentially confusing word is CANCER. This is usually used to denote a malignant neoplasm as opposed to a
benign neoplasm. It is very easily confused with the word CARCINOMA which denotes a malignant tumour of
epithelial tissues.
 Terminology is a pretty dull subject BUT it is vitally important since mistakes in terminology can have disastrous
consequences for patients!
 Other words can be very confusing and are listed on this link


28. Neoplasm AN OVERVEIW
 Neoplasms are common.
 The word 'cancer' is used by patients and it engenders considerable fear.
 Neoplasms, of some kind, affect about one in three people over their lifetimes.
 Neoplasia is perceived as being a single disease when in fact is a very many different diseases linked by similar
features.
 Considerable progress has been made in understanding the aetiology, pathogenesis and behaviour of neoplasia and
this has led to much better management of patients.
 We have defined neoplasia as:
 "a growth disorder characterised by genetic alterations that lead to loss of the normal control mechanisms that
regulate cell growth, morphogenesis and differentiation"
 The following overview of this area is divided into two main sections
 The biology of neoplasia
 the properties of tumour cells;
 the evidence that tumours have a genetic basis;
 an overview of the molecular events associated with neoplasia;
 and an overview of carcinogenesis (or the causation of tumours).
 Neoplasia: The clinical problem
 The epidemiology,
 classification,
 and behaviour of tumours,
 as a basis for considering the
 management of patients with neoplasia


29.  Neoplasms are common.
 The word 'cancer' is used by patients and it engenders considerable fear.
 Neoplasms, of some kind, affect about one in three people over their lifetimes.
 Neoplasia is perceived as being a single disease when in fact is a very many different diseases linked by similar
features.
 Considerable progress has been made in understanding the aetiology, pathogenesis and behaviour of neoplasia and
this has led to much better management of patients.
 We have defined neoplasia as:
 "a growth disorder characterised by genetic alterations that lead to loss of the normal control mechanisms that
regulate cell growth, morphogenesis and differentiation"
 The following overview of this area is divided into two main sections
 The biology of neoplasia
 the properties of tumour cells;
 the evidence that tumours have a genetic basis;
 an overview of the molecular events associated with neoplasia;
 and an overview of carcinogenesis (or the causation of tumours).
 Neoplasia: The clinical problem
 The epidemiology,
 classification,
 and behaviour of tumours,
 as a basis for considering the
 management of patients with neoplasia


30. biology of tumours
 The purpose of this section is to provide an overview of the biological features of tumour cells that will correlate with
and underpin your understanding of the clinical aspects of neoplasia.
 It is widely held that progress in understanding the biology of tumours is key to the development of better ways of
diagnosing and treating patients with tumours as well as hopefully allowing strategies for prevention.
 This is a vast field and one which is growing quickly as a consequence of much research. Nevertheless an excellent
overview of the subject has been provided by Hanahan & Weinberg (The hallmarks of cancer Cell 2000; 100: 57-70).
They have summarised that the following 6 properties can be ascribed to tumours.

 Self-sufficiency in growth signals
 Insensitivity to anti-growth signals
 Evasion of apoptosis
 Unrestricted replicative potential
 Sustained angiogenesis
 Tissue invasion and metastasis
 Here we provide only an overview of this subject in five complementary areas:
 The structure of neoplasms
 Properties of tumour cells
 Evidence that cancer is a genetic disease
 An introduction to the molecular basis of cancer
 Principles of carcinogenesis


31. STRUCTURE OF NEOPLASM
 Within tumours there is a mixture of the neoplastic cells as well as a stroma that is composed of many elements
including fibroblasts, connective tissue matrix, blood vessels and lymphatics and, in some cases, macrophages and
lymphocytes.
 Sometimes the stroma may be very much the predominant feature and is called a DESMOPLASTIC REACTION.
 The pattern of the neoplastic cells and stroma is usually characteristic in any given tumour type. The overall
morphological appearances of any given tumour are used by pathologists to define the classification of that
tumour. As discussed elsewhere (see Classification of tumours) this is essential since different tumours have different
clinical properties in terms of their likely behaviour and response to treatment.

 Tumours can have different shapes and consistencies. For example:
 In solid organs, tumours lead to a palpable lump, and can be HARD, when they are sometimes termed schirrous or
SOFT and termed medullary.
 Clinical hint: it is the stroma that can make a tumour feel hard.
 On surfaces of organs (eg. in the lining of the gut), tumours can be
 sessile (flat)
 pedunculated (polypoid)
 papillary (warty)
 fungating (heaped masses)
 ulcerated
 annular (eg. encircling a lumen as in the gut)

 KEY POINT
 While macroscopic appearances can be very informative, ultimately histological assessment by a pathologist is
required for diagnosis and classification of neoplasia.


32.  neoplastic
y health care professionals can also have devastating consequences. Hence although a rather du
PRECISE CLASSIFICATION OF A NEOPLASM FROM A PATIENT IS
ESSENTIAL
FOR THE CORRECT AND APPROPRIATE PLANNING OF TREATMENT
The purpose of classification
is to provide an aid to diagnosis
to allow the accurate exchange of information
to define clinical sub-groups who
have different biological or clinical features
will benefit from particular types of treatment
have different outcomes (prognosis)
to facilitate epidemiological analysis
It should be recognised that classification changes with time since our knowledge improves.

33.  This is an advanced topic
 This is an area of active research since it illustrates the importance of an understanding of the
mechanisms of differentiation.
 Two models of metaplasia or transdifferentiation exist.
 At one extreme it might be that a given differentiated cell type can convert directly into another
differentiated cell type.
 An alternative view is that the apparent conversion of one differentiated cell type by another is a
consequence of re-specification of a stem cell such that now its progeny have a different pattern of
gene expression (and hence differentiated state or phenotype) compared with the normal.
 It is a fact that, in general, the differentiated state of a cell is a rather fixed and unchanging
attribute. For example a skin cell does not spontaneously convert into a neurone. However the
fertilised oocyte has total plasticity since its progeny can become all the different cells of the adult
body.
 An increasing body of information shows that stem cells have a wide potential array of progeny cells
with different phenotypes. This is usually quite restricted under normal physiological situations. For
example in the gastrointestinal tract there is evidence that all four differentiated cell types of the
colonic crypt epithelium (mucous cells, absorptive cells, goblet cells and endocrine cells) can all derive
from a common precursor stem cells located at the base of the crypt.
 What is clear is that we have a remarkably poor understanding of the detailed mechanisms that
determine regulated gene expression in the context of differentiation.
 Slack has proposed that metaplasia represent the mammalian equivalent of homeotic mutations that
occur in invertebrates and allow (in development) the respecification of a developing body part due to
a mutation in master regulator genes. See for example his paper in the Lancet in 1985 or a more
recent review.
 Importantly this kind of complex area indicates the inter-dependence of much of modern biology and
medicine, such that to understand pathological and clinical phenomena will require understanding of
basic biological issues such as stem cells, mechanisms of differentiation and the like.


34.  Classification of tumours is an important subject: incorrect classification can have huge impact on
patients. In addition, the misuse of terms by health care professionals can also have devastating
consequences. Hence although a rather dull subject it is essential that the principles of classification
are understood and that the student is comfortable and confident in the use of terms.
 PRECISE CLASSIFICATION OF A NEOPLASM FROM A PATIENT IS
 ESSENTIAL
 FOR THE CORRECT AND APPROPRIATE PLANNING OF TREATMENT

 The purpose of classification
 is to provide an aid to diagnosis
 to allow the accurate exchange of information
 to define clinical sub-groups who
 have different biological or clinical features
 will benefit from particular types of treatment
 have different outcomes (prognosis)
 to facilitate epidemiological analysis
 It should be recognised that classification changes with time since our knowledge improves.


35. There are two central and complimentary aspects of classification of
tumours:
Histogenetic classificationBehavioural classificationbased upon the
presumed cell of origin a tumour eg. epithelium
based upon the probable behaviour of a tumour eg. benign or malignant
 Histogenetic
classificationbased
upon the presumed cell
of origin a tumour eg.
epithelium
 Behavioural
classificationbased
upon the probable
behaviour of a
tumour eg. benign or
malignant

36.  Another component of classification of tumours is the use of assessment of differentiation in a tumour (termed
GRADE) and the assessment of the spread of a tumour (termed STAGE).
 Grade & stage Having considered each of these key concepts (histogenesis, behaviour, grade & stage) in isolation, it is
important to see how these words can be used in combinations in practice.
 Some conditions such as dysplasia are considered as pre-neoplasia. This is important since evidence shows that early
diagnosis and treatment at this stage is much better than when neoplasms have become well established.
 Some aspects of classification are rather unsatisfactory and over history a range of terms have been used. This
complicates the subject. In addition some tumours are described by the names of people who first described them or
some aspect of them. An EPONYM is thus a term derived from a person. This and some other problems with
classification are considered further in the next page.
 Eponyms and other problems Finally some simple exercises in the use of nomenclature are presented.
 Simple exercises in nomenclature


 As we have discussed before
 Confusing words . . . . . .
 The word TUMOUR simply means swelling and not all swellings are neoplasms and some neoplasms do not form
swellings per se (eg. leukaemia - a tumour of blood cells derived from the bone marrow). Nevertheless the word
tumour is often used interchangeably with neoplasm. Note also that not all neoplasms are malignant. This is
discussed further in the section on classification.
 Another potentially confusing word is CANCER. This is usually used to denote a malignant neoplasm as opposed to a
benign neoplasm. It is very easily confused with the word CARCINOMA which denotes a malignant tumour of
epithelial tissues.
