Neoplasia
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Neoplasia MBChB Pathology Tutorial
Cell proliferation In what situations does cell proliferation occur? How is cell proliferation controlled?
Cell proliferation Cell proliferation is an essential process occurring in many normal tissues, for example:
Embryogenesis and growth Skin Gastrointestinal tract Blood
Cell proliferation It is also an essential component of the response to injury or inflammation In neoplasia, the normal control of cell proliferation is lost
Cell proliferation Cells differ in their capacity to proliferate Some cells are unable to proliferate and are called permanent cells, for example: Cardiac muscle cells Neurons
Cells normally proliferate in a controlled manner following the cell cycle Permanent cells
(Mitosis) (Mitosis)
e.g. e.g. Cardiac Cardiac myocytes, myocytes, neurons neurons
M (Pre-mitotic) (Pre-mitotic)
G22 G11
G0 Stable cells e.g. e.g. hepatocytes hepatocytes
S (DNA (DNA Synthesis) Synthesis)
(Pre-synthetic) (Pre-synthetic)
Labile cells e.g. e.g. epidermis epidermis
Cell proliferation Entry into the cell cycle is controlled by growth factors Growth factors bind to cell surface receptors 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
Raf
P
Ras GTP
P
MEK
Transcription Factor
sos grb2
ERK
P
Growth Growth Factor Factor Receptor Receptor
P
P
2. 2. Enzyme Enzyme cascades cascades within within the the cell cell amplify amplify the the signal signal
3. 3. Activation Activation of of gene gene expression expression
P
Cell proliferation Progression through the cell cycle is strictly controlled at several checkpoints This aims to prevent the replication of cells with damaged DNA
Cell proliferation If activated, these checkpoint systems cause arrest of the cell cycle by promoting inhibitory pathways or inhibiting activating pathways If the defect cannot be repaired, the cell will be diverted into apoptosis
What is meant by the terms... Dysplasia? Neoplasia?
Dysplasia... ...is a disorder of cell growth and appearance ...is a pre-malignant condition which may be reversible
Dysplasia... ...is characterised cytologically by: nuclear pleomorphism; hyperchromatism; loss of cell orientation; 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... ...the development of an abnormal tissue mass (neoplasm) in which growth... is uncoordinated with the surrounding tissue and... continues after the originating stimulus is removed
Neoplasia Neoplasms may be benign or malignant What features suggest that a neoplasm is malignant?
A diagnosis of malignancy in a neoplasm is based on several features:
Cell differentiation, i.e. the extent to which the cells and architecture resemble those found in the normal tissue Growth rate, often assessed by the mitotic rate vs. apoptotic rate
A diagnosis of malignancy in a neoplasm is based on several features:
Local invasion – most malignant tumours invade the surrounding tissues 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 A A small small glandular glandular structure structure provides provides aa clue clue to to the the diagnosis diagnosis of of adenocarcinoma, adenocarcinoma, however however the the remainder remainder of of the the tumour tumour bears bears no no 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 membrane is clear evidence of malignant behaviour
There is uncontrolled proliferation of the neoplastic epithelial cells. At this stage, however, the underlying basement membrane is intact
LYMPHOLYMPHOVASCULAR VASCULAR INVASION INVASION
This This colonic colonic adenocarcinoma adenocarcinoma showed showed invasion invasion of of 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
DNA damage is fundamental to the development of neoplasia What possible causes of DNA damage can you think of?
Pathogenesis of neoplasia Chemical carcinogens e.g. benzene
Viruses e.g. HPV, EBV
Radiation
Pathogenesis of neoplasia Inherited genetic mutations also affect a person’s susceptibility to the development of neoplasia
Pathogenesis of neoplasia 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 Self-sufficiency, i.e. the loss of reliance on external stimuli (growth factors) Loss of response to growth inhibiting mechanisms Resistance to apoptosis Defects in DNA repair mechanisms
What is meant by the terms: Oncogene? Oncosuppressor gene?
Self-sufficiency - 1 Proto-oncogenes are normal genes which are involved in the regulation of cell proliferation and differentiation. Genetic mutations involving one or more proto-oncogenes may lead to autonomous cell growth (growth in the absence of external stimuli). Such a mutated gene is called an oncogene.
Self-sufficiency - 2 The genetic mutations involved in the conversion of a proto-oncogene to an oncogene are said to be activating mutations. These mutations result in overexpression of the gene, or the production of an abnormal gene product with growth-promoting capabilities. 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 proteins proteins Raf
P
Ras GTP
P
MEK
Transcription Factor
sos grb2
ERK
P
2. 2.Growth Growthfactor factor receptors receptors
P
4. 4.Transcription Transcription factors factors
P
P
5. 5.Cell Cellcycle cycleregulators regulators
Oncosuppressor genes Oncosuppressor genes (tumour suppressor genes) encode proteins which regulate cell growth Homozygous loss or inactivation of oncosuppressor genes is fundamental to the development of neoplasia
Oncosuppressor genes 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 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 repair repair mechanisms mechanisms
DNA DNA damage damage
Inherited Inherited mutations mutations in in genes genes affecting affecting DNA DNA repair repair
Failure Failure of of DNA DNA 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.
Is it benign or malignant? Why?
Cell proliferation In what situations does cell proliferation occur? How is cell proliferation controlled?
Cell proliferation Cell proliferation is an essential process occurring in many normal tissues, for example:
Embryogenesis and growth Skin Gastrointestinal tract Blood
Cell proliferation It is also an essential component of the response to injury or inflammation In neoplasia, the normal control of cell proliferation is lost
Cell proliferation Cells differ in their capacity to proliferate Some cells are unable to proliferate and are called permanent cells, for example: Cardiac muscle cells Neurons
Cells normally proliferate in a controlled manner following the cell cycle Permanent cells
(Mitosis) (Mitosis)
e.g. e.g. Cardiac Cardiac myocytes, myocytes, neurons neurons
M (Pre-mitotic) (Pre-mitotic)
G22 G11
G0 Stable cells e.g. e.g. hepatocytes hepatocytes
S (DNA (DNA Synthesis) Synthesis)
(Pre-synthetic) (Pre-synthetic)
Labile cells e.g. e.g. epidermis epidermis
Cell proliferation Entry into the cell cycle is controlled by growth factors Growth factors bind to cell surface receptors 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
Raf
P
Ras GTP
P
MEK
Transcription Factor
sos grb2
ERK
P
Growth Growth Factor Factor Receptor Receptor
P
P
2. 2. Enzyme Enzyme cascades cascades within within the the cell cell amplify amplify the the signal signal
3. 3. Activation Activation of of gene gene expression expression
P
Cell proliferation Progression through the cell cycle is strictly controlled at several checkpoints This aims to prevent the replication of cells with damaged DNA
Cell proliferation If activated, these checkpoint systems cause arrest of the cell cycle by promoting inhibitory pathways or inhibiting activating pathways If the defect cannot be repaired, the cell will be diverted into apoptosis
What is meant by the terms... Dysplasia? Neoplasia?
Dysplasia... ...is a disorder of cell growth and appearance ...is a pre-malignant condition which may be reversible
Dysplasia... ...is characterised cytologically by: nuclear pleomorphism; hyperchromatism; loss of cell orientation; 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... ...the development of an abnormal tissue mass (neoplasm) in which growth... is uncoordinated with the surrounding tissue and... continues after the originating stimulus is removed
Neoplasia Neoplasms may be benign or malignant What features suggest that a neoplasm is malignant?
A diagnosis of malignancy in a neoplasm is based on several features:
Cell differentiation, i.e. the extent to which the cells and architecture resemble those found in the normal tissue Growth rate, often assessed by the mitotic rate vs. apoptotic rate
A diagnosis of malignancy in a neoplasm is based on several features:
Local invasion – most malignant tumours invade the surrounding tissues 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 A A small small glandular glandular structure structure provides provides aa clue clue to to the the diagnosis diagnosis of of adenocarcinoma, adenocarcinoma, however however the the remainder remainder of of the the tumour tumour bears bears no no 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 membrane is clear evidence of malignant behaviour
There is uncontrolled proliferation of the neoplastic epithelial cells. At this stage, however, the underlying basement membrane is intact
LYMPHOLYMPHOVASCULAR VASCULAR INVASION INVASION
This This colonic colonic adenocarcinoma adenocarcinoma showed showed invasion invasion of of 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
DNA damage is fundamental to the development of neoplasia What possible causes of DNA damage can you think of?
Pathogenesis of neoplasia Chemical carcinogens e.g. benzene
Viruses e.g. HPV, EBV
Radiation
Pathogenesis of neoplasia Inherited genetic mutations also affect a person’s susceptibility to the development of neoplasia
Pathogenesis of neoplasia 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 Self-sufficiency, i.e. the loss of reliance on external stimuli (growth factors) Loss of response to growth inhibiting mechanisms Resistance to apoptosis Defects in DNA repair mechanisms
What is meant by the terms: Oncogene? Oncosuppressor gene?
Self-sufficiency - 1 Proto-oncogenes are normal genes which are involved in the regulation of cell proliferation and differentiation. Genetic mutations involving one or more proto-oncogenes may lead to autonomous cell growth (growth in the absence of external stimuli). Such a mutated gene is called an oncogene.
Self-sufficiency - 2 The genetic mutations involved in the conversion of a proto-oncogene to an oncogene are said to be activating mutations. These mutations result in overexpression of the gene, or the production of an abnormal gene product with growth-promoting capabilities. 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 proteins proteins Raf
P
Ras GTP
P
MEK
Transcription Factor
sos grb2
ERK
P
2. 2.Growth Growthfactor factor receptors receptors
P
4. 4.Transcription Transcription factors factors
P
P
5. 5.Cell Cellcycle cycleregulators regulators
Oncosuppressor genes Oncosuppressor genes (tumour suppressor genes) encode proteins which regulate cell growth Homozygous loss or inactivation of oncosuppressor genes is fundamental to the development of neoplasia
Oncosuppressor genes 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 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 repair repair mechanisms mechanisms
DNA DNA damage damage
Inherited Inherited mutations mutations in in genes genes affecting affecting DNA DNA repair repair
Failure Failure of of DNA DNA 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.
Is it benign or malignant? Why?
