Neoplasia

MBChB Pathology Tutorial

 Cell proliferation

Š In what situations does cell

proliferation occur?

Š How is cell proliferation controlled?

 Cell proliferation

Š Cell proliferation is an essential

process occurring in many normal
tissues, for example:

Š Embryogenesis and growth

Š Skin
Š Gastrointestinal tract
Š Blood
 Cell proliferation

Š It is also an essential component of

the response to injury or
inflammation

Š In neoplasia, the normal control of

cell proliferation is lost
 Cell proliferation
Š Cells differ in their capacity to proliferate

Š Some cells are unable to proliferate and

are called permanent cells, for example:
Š Cardiac muscle cells
Š Neurons
 Cells normally proliferate in a controlled
manner following the cell cycle

(Mitosis)
(Mitosis) Permanent cells
e.g.
e.g. Cardiac
Cardiac myocytes,
myocytes,
neurons
neurons
M

(Pre-mitotic)
(Pre-mitotic)
G22
G0
G11
Stable cells
e.g.
e.g. hepatocytes
hepatocytes

S (Pre-synthetic)
(Pre-synthetic)

(DNA
(DNA
Synthesis)
Synthesis)
Labile cells
e.g.
e.g. epidermis
epidermis
 Cell proliferation
Š Entry into the cell cycle is controlled by
growth factors
Š Growth factors bind to cell surface
receptors
Š This sets off a chain of intracellular events
which ultimately results in the transcription
of DNA
 Signal Transduction
Cell
Cell Membrane
Membrane

1.
1. Growth
Growth factors
factors bind
bind
to
to cell
cell surface
surface receptors
receptors

Growth
Growth Factor
Factor

Growth
Growth Factor
Factor
Raf
P Ras Receptor
Receptor
GTP
sos

P MEK
grb2
P

ERK P P
P 2.
2. Enzyme
Enzyme cascades
cascades
within
within the
the cell
cell amplify
amplify
Transcription
Factor the
the signal
signal

3.
3. Activation
Activation of
of gene
gene expression
expression
 Cell proliferation

Š Progression through the cell cycle is

strictly controlled at several
checkpoints

Š This aims to prevent the replication

of cells with damaged DNA
 Cell proliferation

Š If activated, these checkpoint

systems cause arrest of the cell cycle
by promoting inhibitory pathways or
inhibiting activating pathways

Š If the defect cannot be repaired, the

cell will be diverted into apoptosis
What is meant by the terms...

Š Dysplasia?

Š Neoplasia?
 Dysplasia...

Š ...is a disorder of cell growth and

appearance
Š ...is a pre-malignant condition which
may be reversible
 Dysplasia...

Š ...is characterised cytologically by:

Š nuclear pleomorphism;
Š hyperchromatism;
Š loss of cell orientation;
Š cell crowding
This image shows the normal epithelium
which lines the respiratory tract
 Here we see the bronchial lining from a smoker

Increasing grade of DYSPLASIA

Note the loss of

cilia at this point

Basement
Basement membrane
membrane (Type
(Type IV
IV collagen)
collagen)
Normal colonic epithelium Dysplastic colonic epithelium
 Neoplasia...

Š ...the development of an abnormal

tissue mass (neoplasm) in which
growth...
Š is uncoordinated with the surrounding
tissue and...

Š continues after the originating

stimulus is removed
 Neoplasia

Š Neoplasms may be benign or

malignant

Š What features suggest that a

neoplasm is malignant?
A diagnosis of malignancy in a neoplasm is
based on several features:

Š Cell differentiation, i.e. the extent to which

the cells and architecture resemble those
found in the normal tissue

Š Growth rate, often assessed by the mitotic

rate vs. apoptotic rate
A diagnosis of malignancy in a neoplasm is
based on several features:

Š Local invasion – most malignant tumours

invade the surrounding tissues

Š Metastasis – spread to distant organs via

blood or lymphatics
This
This image
image shows
shows aa
poorly
poorly differentiated
differentiated
adenocarcinoma
adenocarcinoma of of
the
the colon
colon

AA small
small glandular
glandular
structure
structure provides
provides aa
clue
clue toto the
the diagnosis
diagnosis
of
of adenocarcinoma,
adenocarcinoma,
however
however thethe
remainder
remainder of of the
the
tumour
tumour bears
bears nono
resemblance
resemblance to to its
its
tissue
tissue of
of origin.
origin.

The
The neoplastic
neoplastic cells
cells
show
show severe
severe nuclear
nuclear
pleomorphism
pleomorphism
The
The number
number of of
cells
cells undergoing
undergoing
mitosis
mitosis in
in this
this
malignant
malignant
neoplasm
neoplasm indicates
indicates
aa very
very rapid
rapid
proliferation
proliferation rate.
rate.

The
The brown
brown pigment
pigment
highlighted
highlighted by by the
the
arrows
arrows is
is aa clue
clue to
to the
the
diagnosis.
diagnosis.
This
This aggressive
aggressive
tumour
tumour is
is aa
melanoma,
melanoma, and and the
the
brown
brown material
material seen
seen
is
is melanin
melanin pigment.
pigment.
 Local Invasion

Basement
Basement membrane
membrane

Some malignant epithelial

neoplasms have a
recognised pre-invasive
(“in-situ”) stage

Invasion through the basement

There is uncontrolled proliferation of
membrane is clear evidence of
the neoplastic epithelial cells. At this
malignant behaviour
stage, however, the underlying
basement membrane is intact
 LYMPHO-
LYMPHO-
VASCULAR
VASCULAR
INVASION
INVASION

This
This colonic
colonic
adenocarcinoma
adenocarcinoma
showed
showed
invasion
invasion ofof
blood
blood and
and
lymphatic
lymphatic
vessels
vessels in
in the
the
mesentery.
mesentery.
PERINEURAL INVASION

NERVE

Some malignant neoplasms, for example

adenocarcinomas of the pancreas and prostate,
frequently show invasion along nerves.
 LYMPH
LYMPH
NODE
NODE
METASTASIS
METASTASIS
 Pathogenesis of
neoplasia

Š DNA damage is fundamental

to the development of
neoplasia

Š What possible causes of DNA

damage can you think of?
 Pathogenesis of neoplasia

Š Chemical carcinogens
Š e.g. benzene
Š Viruses
Š e.g. HPV, EBV
Š Radiation
 Pathogenesis of neoplasia

Š Inherited genetic mutations also affect

a person’s susceptibility to the
development of neoplasia
 Pathogenesis of neoplasia

Š Genetic mutations affecting any of the

proteins involved in the cell cycle and
its control can result in uncontrolled
growth. Such mutations may lead to:
 Pathogenesis of neoplasia
Š Self-sufficiency, i.e. the loss of
reliance on external stimuli (growth
factors)
Š Loss of response to growth inhibiting
mechanisms
Š Resistance to apoptosis
Š Defects in DNA repair mechanisms
 What is meant by the terms:

Š Oncogene?

Š Oncosuppressor gene?
 Self-sufficiency - 1

Š Proto-oncogenes are normal genes which are

involved in the regulation of cell proliferation
and differentiation.

Š Genetic mutations involving one or more

proto-oncogenes may lead to autonomous
cell growth (growth in the absence of external
stimuli).

Š Such a mutated gene is called an oncogene.

 Self-sufficiency - 2

Š The genetic mutations involved in the conversion of a

proto-oncogene to an oncogene are said to be
activating mutations.

Š These mutations result in overexpression of the

gene, or the production of an abnormal gene product
with growth-promoting capabilities.

Š Mutation of only one copy of a proto-oncogene within

a nucleus is sufficient to alter the phenotype of the
cell in favour of autonomous growth.
 The proteins produced by proto-oncogenes include:

1.
1.Growth
Growthfactors
factors

3.
3.Signal
Signaltransduction
transduction 2.
2.Growth
Growthfactor
factor
proteins
proteins receptors
receptors
P Raf
Ras

GTP
sos

P MEK
grb2
P

ERK P P
P

Transcription
Factor
4.
4.Transcription
Transcription 5.
5.Cell
Cellcycle
cycleregulators
regulators
factors
factors
 Oncosuppressor genes

Š Oncosuppressor genes (tumour

suppressor genes) encode proteins which
regulate cell growth
Š Homozygous loss or inactivation of
oncosuppressor genes is fundamental to
the development of neoplasia
 Oncosuppressor genes

Š The protein p53 is involved in the

detection of DNA damage. It causes
arrest of the cell cycle, allowing DNA
repair to occur. If repair is unsuccessful,
p53 triggers apoptosis
Š Mutations of the p53 gene are found in
>50% of human cancers
 Patients with familial
adenomatous polyposis
(FAP) inherit one mutated
copy of the APC tumour
suppressor gene. Loss of the
second normal copy in GI
epithelial cells causes the
development of adenomas.

Familial
Familial Adenomatous
Adenomatous Polyposis
Polyposis (FAP)
(FAP)
 DNA damaging agents
Normal cell
• Chemicals
Chemicals
•• Radiation
Radiation
•• Viruses
Viruses

DNA
DNA DNA
DNA repair
repair
damage
damage mechanisms
mechanisms

Inherited
Inherited mutations
mutations
in
in genes
genes affecting
affecting Failure
Failure of
of DNA
DNA
DNA
DNA repair
repair repair
repair mechanisms
mechanisms

Mutations
Mutations in
in the
the genome
genome
of
of somatic
somatic cells
cells
 A 55 year old man presents to his GP
complaining of rectal bleeding. He is
sent to the GI physicians for
colonoscopy

At colonoscopy, a small polyp is found

in the sigmoid colon. It is snared and
sent to pathology.
 The next slide shows a microscopic
image of the polyp, followed by a
higher power photograph with normal
colonic mucosa for comparison.

What abnormalities can you identify in

the architecture and cytology of the
polyp?
NORMAL POLYP
Is this polyp benign or malignant?
A 60 year old woman presents with the
symptoms of acute bowel obstruction.

A barium enema reveals a stricture in

her transverse colon.
The strictured segment of bowel is
removed and sent to Pathology.

What abnormalities do you see in this

transverse section of the bowel wall at
the site of the stricture?
Microscopic photographs of the
strictured area are shown on the
following slides.
Š Is it benign or malignant? Why?