Pathology Flashcards
describe the function of tumour suppressor genes and how they work
Tumour Suppressor Genes – the normal function of these genes is inhibition of cell proliferation or repair of damaged DNA – abnormalities (of both alleles) of tumour suppressor genes can drive a normal cell towards a cancerous state eg. BRCA1
they inhibit cell division or stimulate cell death
may also: mutation in the gene such that the resultant protein has reduced or loss of function
Describe the function of oncogenes and how they work
Oncogenes – the normal function of these genes is an increase in cell proliferation – abnormalities of only one allele of an oncogene can drive a normal cell towards a cancerous state eg. HER2
They stimulate cell division or inhibit cell death
they can result in:
- more of the gene product being expressed,
- a mutation in the gene such that the resultant protein has increased function
- expression occurring in the wrong cell type
- at the wrong time
What cancer is associated wit the chemical abstesos
mesothelioma
What cancer is associated with the chemical from aniline dyes
bladder cancer
What cancer is associated with radiation
thyroid cancer
what is a possible cause for cervix cancer
sexual activity - HPV
give an example of a natural gas that can cause cancer
radon gas
What is the cancer associated with HPV
cervical cancer
what is the cancer associated with HepBVirus
liver cancer
what is the cancer associated with Epstein Barr Virus
lymphoma
what is the disease associated with Kaposi’s Sarcoma
Human Herpes Virus 8
what is the cancer associated with hepatitis B and C
hepatocellular carcinoma (HCC)
how does hepatitis B cause HCC
Chronic Hepatits B infection results in a cycle of inflammation necrosis and regeneration of cells. This increased turnover of cells increases the likelihood of genetic mutations developing and hepatocellular carcinoma occuring
what is the cancer associated with Helicobacter pylori
how does it cause cancer
gastric adenocarcinoma and gastric MALT lymphoma
Long-term infection with H. pylori results in chronic inflammation and the subsequent increased cell turnover increases the likelihood of mutations developing
What type of genes are the p53 gene, the APC gene and the Rb gene
tumour suppressor genes
What is the gene associated with Retinoblastoma
Rb
What is the gene associated with FAP
APC
What is the gene associated with HNPCC (Lynch Syndrome)
MSH2/MLH1
What is the gene associated with breast cancer and ovarian cancer
BRCA1/BRCA2
What is the gene associated with Li-Fraumeni syndrome
p53
Compare the sporadic and familial forms of retinoblastoma based off the Knudson Hypothesis
Sporadic form:
- a mutation has to occur in both copies of the retinoblastoma gene, unlikely
- the longer the period of time that elapses the more likely this is, but it is unlikely to occur more than in one cells. Hence tumours occur late and are unilateral.
Familial form:
- the child inherits from one mutant copy of the retinoblastoma gene, so only one additional mutation needed
- the disease occurs earlier and also there is a high probability of it occurring in more than one cell, and thus tumours may be multi-focal and bilateral.
What are the characteristics of Familial adenomatous polyposis (FAP)
- polyposis - the development of multiple benign (noncancerous) adenomatous polyps (>100) in the colon and rectum, which are described as having a “dense carpet-like appearance” on colonoscopy or sigmoidoscopy.
- early age of onset. Polyps begin to develop at an average age of 16 years (range of seven to 36 years).
What are the Clinical features of Li-Fraumeni syndrome
Cancers at a young age:
- Development of adrenocortical carcinoma
- Development of soft-tissue sarcomas
- Acute leukaemias and brain tumours
- Osteosarcomas
- Premenopausal breast cancer is common
What are the genes FGF fibroblast growth factor
PDGF - platelet derived growth factor examples of
growth factors
what are the genes: HER2neu EGFR EGFR C-Kit examples of
Growth factor receptors
what are the genes: V-src K-ras abl examples of
signal transduction pathways
what is the gene c-myc an example of
nuclear protein
what is the gene Bcl2 an example of
resistance to apoptosis
Describe the Philadelphia chromosome (Ph1)
This is a translocation of a portion of the q arm of chromosome 22 to the q arm of chromosome 9, designated t(9:22). The result is that a fusion gene is created by juxtapositioning the Abl1 gene on chromosome 9 to a part of the BCR (“breakpoint cluster region”) gene on chromosome 22
What cancer is characterised by the Philadelphia chromosome (Ph1)
Chronic Myeloid Leukemia
Which drug is prescribed for a patient who is HER2 positive
Trastuzumab
what drugs will a patient not respond to if they have a mutated KRAS gene
cetuximab or panitumumab
An 87 year old woman has invasive breast cancer.
Which laboratory test will be used to inform management?
a) HER2
b) KRAS
c) BCR-ABL
d) FAP
e) APC
a
A 67 year old man has a malignant tumour arising on the surface of the lung and encasing the lung in a solid mass. Which is the most likely cause?
a) Asbestos
b) HHV8
c) Helicobacter pylori
d) Hepatitis C
e) Human papillomavirus
a
A 27 year old man has familial adenomatous polyposis.
Which abnormal gene has he inherited?
a) APC
b) MSH2
c) P53
d) BRCA1
e) RB
a
Givetwo morphological examples ofreversible cell injury
see lecture 2 slide 32 for microscope slides
- Swelling of the cell – Hydropic change:
- (impaired function of energy- dependant ion pumps in plasma membrane ) - Fatty change (Steatosis):
- Deranged lipoprotein transport leads to accumulation of lipid in the cytoplasm of hepatocytes.
- CAUSES:
>Alcohol
>Obesity
define and describe apoptosis
when does it happen
lecture 2 slide 46 for diagram on how it works
- A defined, orderly sequence of intracellular events leading to cell death
- Energy Dependent:activeprocess
- Cells break into fragments-apoptotic bodies & express vitronectin- attracts phagocytes.
- No inflammatory reaction
- single cell at a time pattern to death of cells
Caspases-intracellular proteases which play important role
activated by:
> Extrinsic pathway -signals from outside the cell
> Intrinsic pathway-internal pathways such as DNA damage
Can be physiological:
- Eliminates cells no longer needed maintaining a steady number of various cell populations
- Examples:
>Embryogenesis
- Involution of hormone dependent tissue eg endometrium in menstruation
- Death of host cells after they have served their purpose eg in inflammation
Can be pathological:
- Eliminates cells that are injured beyond repair
- Example:
> DNA damage from toxins or ultraviolet radiation
define necrosis and what causes is
“Catastrophic” cell death following injury
accompanied by the release of potent mediators
of inflammation
Caused by factors such as;
- Decreased oxygen,
- Infection,
- Toxins,
- Trauma
describe coagulative necrosis
Commonest form of necrosis
On microscopy preservation of the basic outline of the cells is seen , until cells removed by phagocytosis
Localised area of necrosis-Infarct - most likely caused by an acute vascular insufficiency eg a blockage of an artery
often see an acute inflammatory reaction
CompareandcontrastApoptosis and Necrosis
see lecture 2 slide 48 for diagram
Apoptosis: - Role = Physiological or Pathological - Cell = > Shrinkage of cell > Single Cells affected - Plasma membrane = Intact - Inflammation = no - Pathways = Specific genes and pathways - Energy dependant = yes
Necrosis: - Role = Pathological - Cell = > Cells enlarge (swelling) > Multiple cells or tissues involved - Plasma membrane = Disrupted - Inflammation = Frequent - Pathways = No specific pathways - Energy dependant = no
describe CASEOUS necrosis
“Caseous”-cheese-like when viewing grossly
Dead tissue shows no structure- cell outlines not evident on microscopy
Characteristic of Tuberculosis
what part of the body is affected with Acute hepatitis
liver
define acute inflammation and list the FIVE clinical features of acute inflammation
The initial protective tissue response to injury or destruction of tissues, which serves to destroy, dilute, or wall off both the injurious agent and the injured tissues.
The three main elements of acute inflammation are changes in small blood vessels, recruitment of neutrophils and increased levels of chemical mediators.
The FIVE “Cardinal” clinical features:
- Redness
- Swelling
- Heat
- Pain
- loss of function
define chronic suppurative inflammation, pus, abscess and empyema.
Chronic Suppurative (pus producing) Inflammation is the PERSISTENT ACCUMULATION of PUS.
PUS = a mixture of living, dead and dying neutrophils (and bacteria), cellular debris and inflammatory exudate
ABSCESS = A collection of pus within a newly formed cavity within TISSUES
EMPYEMA = A collection of pus within a naturally existing ANATOMICAL CAVITY
describe and explain the systemic effects of inflammation
Weight loss:
- Increase in metabolic demands (inflammation uses energy)
Pyrexia:
- Endogenous pyrogens acting on hypothalamus
General, non-specific symptoms:
- The basal ganglia in the brain ganglia are responsible for getting us motivated and moving.
- When inflammation is excessive or persistent, changes in the basal ganglia, probably due to circulating chemicals, can lead to:
>feeling run down
> apathy
> depression
> fatigue
describe some of the benefits and harmful effects of inflammation
Beneficial:
- Dilution of toxins
- Entry of antibodies
- Fibrin formation and isolation of micro-organisms
- Delivery of nutrients and oxygen
- Stimulation of immune system
Harmful:
- Digestion of normal tissue
- Swelling
- Loss of normal function
- Inappropriate or excessive inflammatory response eg. Asthma
what causes acute inflammation
Microbial infections including pyogenic (i.e. pus forming) organisms
Physical agents
e.g. heat, cold, trauma, irradiation
Chemicals
e.g. corrosives, acids, alkalis, toxins
Tissue necrosis of any cause
Foreign bodies
what is the main cell type in acute inflammation
The key cell type is the neutrophil or neutrophil polymorph or polymorphonuclear leucocyte
what are the 7 stages of phagocytosis
- chemotaxis and adherence of microbe to phagocyte
- ingestion of microbe by phagocytes
- formation of a phagosome
- fusion of the phagosome with a lysosome to form a phagolysosome
- digestion of ingested microbe by enzymes
- formation of residual body containing indigestible material
- discharge of waste materials
what is chemotaxis
Chemotaxis is the ability of cells such as neutrophils to move along a concentration gradient towards some chemical substance
what is the role of chemical mediators of inflammation
- Vascular dilatation
- Increased vascular permeability
- Promote leukocyte adhesion
- Promote chemotaxis
A 32 year old man has acute appendicitis and his appendix is removed and examined histologically.
Which inflammatory cells would be present?
a) Eosinophils
b) Lymphocytes
c) Macrophages
d) Neutrophils
e) Plasma cells
d
A 21 year old woman has acute inflammation of her left ovary and left fallopian tube.
Which diagnosis is most likely?
a. Acute salpingo-oophoritis
b. Acute epididymo-orchitis
c. Acute proctitis
d. Acute diverticulitis
e. Acute pancreatitis
a
A 25 year old man with acute pancreatitis feels run down and miserable.
Which region in the brain has been affected by circulating chemicals to cause these symptoms?
a. Basal ganglia
b. Hypothalamus
c. Pituitary gland
d. Cerebellum
e. Fourth ventricle
a
Define what is meant by the term chronic inflammation
- Chronic inflammation refers to a prolonged inflammatory response that involves a progressive change in the type of inflammatory cells present at the site of inflammation.
- It is characterised by the simultaneous destruction and repair of tissues
- It can follow an episode of acute inflammation or develop ab initio as a low grade smouldering form
List the causes of chronic inflammation
Persistent microorganisms that are difficult to eradicate
Immune Mediated Inflammatory Diseases
Prolonged Exposure to potentially toxic agents
list the cell types involved in chronic inflammation
Lymphocytes*
Macrophages*
plasma cells
eosinophils
mast cells
what is the role of macrophages in chronic inflammation
- Phagocytosis
- Production of inflammatory mediators
- Initiation of immune response
what is the role of T-lymphocytes in chronic inflammation
- T-lymphocytes change to effector T-lymphocytes
- these secrete cytokines
these cytokines:
> RECRUITMENT OF OTHER LYMPHOCYTES
> RECRUITMENT OF MACROPHAGES INTO AREA
> PRODUCTION OF INFLAMMATORY MEDIATORS
> DESTRUCTION OF TARGET CELLS
> INTERFERON PRODUCTION
what is granulomatous inflammation
and what is a granuloma
A form of chronic inflammation characterised by the formation of the granuloma (plural granulomata)
A GRANULOMA is a collection of macrophages that have transformed into epithelioid (epithelial –like) macrophages
surrounded by a collar of lymphocytes
with a few plasma cells
what are the causes of granulomatous inflammation
- Micro-organisms:
> Mycobacterium tuberculosis (Tuberculosis)
> Mycobacterium Leprae (Leprosy) - Foreign bodies:
a. Endogenous:
> bone
>uric acid crystals
> adipose tissue
b. Exogenous:
> sutures
> implanted prostheses - Idiopathic:
> Crohn’s Disease
> Sarcoidosis
> Wegener’s granulomatosis
what are the complications associated with chronic inflammation
- Fibrosis, scarring, contracture, stricture
- Loss of function
- Dystrophic calcification (abnormal calcification of tissues)
- Carcinogenesis: DNA damage, NF Kappa Bpathway,effects of immunosuppression
- Amyloid
Explain what is meant by tissue healing and define the terms regeneration and repair
Regeneration = Proliferation of cells and tissues to replace lost structures
Distinguish between tissues that are labile, constantly renewing and quiescent/stable and permanent without the ability to regenerate
Labile Cells:
- Continuously dividing
- Replace dead or sloughed-off cells.
- These tissues contain pools of stem cells, which have enormous proliferative and self-renewing ability
Stable or QuiescentCells: - Conditionally renewing - Divide at a very slow rate normally, but can divide when needed - eg: > Liver > Pancreas > Bone
Permanent Cells: - No effective regeneration - Cells that have left the cell cycle permanently - eg : > Central Nervous System > Cardiac muscle > Skeletal muscle
Explain what is meant by tissue healing and define the terms regeneration and repair
Regeneration =
- The proliferation and migration of specialised cells to restore a tissue (or organ) to normal
- no scarring
Repair:
- Where regeneration cannot occur, healing by ORGANISATION and PROGRESSIVE FIBROSIS of GRANULATION TISSUE occurs.
- scarring
List the stages in the process of tissue healing and define:granulation tissue, organisation and fibrosis
Granulation tissue:
- A specialised type of tissue
- The hallmark of tissue repair
- HISTOLOGY-New small blood vessels (angiogenesis) and proliferation of fibroblasts
Distinguish between tissues that are labile, constantly renewing and quiescent/stable and permanent without the ability to regenerate
Labile Cells: - Continuously dividing - Replace dead or sloughed-off cells. - These tissues contain pools of stem cells, which have enormous proliferative and self-renewing ability - eg: > Skin, > Gut epithelium > Endothelium > Bone marrow
Stable or QuiescentCells: - Conditionally renewing - Divide at a very slow rate normally, but can divide when needed - eg: > Liver > Pancreas > Bone
Permanent Cells: - No effective regeneration - Cells that have left the cell cycle permanently - eg : > Central Nervous System > Cardiac muscle > Skeletal muscle
List the stages in the process of tissue healing and define:granulation tissue, organisation and fibrosis
see lecture 5 slide 16 for diagram of stages
Healing by fibrous repair: 1: - Macrophages clear debris - Fibroblasts proliferate - In-growth of blood vessels - Granulation tissue 2: - Granulation tissue contracts, collagen is laid down 3: - scar
Granulation tissue =
- A specialised type of tissue
- The hallmark of tissue repair
- HISTOLOGY-New small blood vessels (angiogenesis) and proliferation of fibroblasts
Differentiate between healing by primary intention and healing by secondary intention
primary - Degree of disruption minimal
Edges lined up
secondary - Significant disruption of tissue
More likely to heal with scarring
Differentiate between healing by primary intention and healing by secondary intention
primary - Degree of disruption minimal
Edges lined up
secondary - Significant disruption of tissue
More likely to heal with scarring
Healing by primary intention and secondary retention really represent two ends of the spectrum of healing where regeneration is dominant in primary and fibrous repair is dominant in secondary
List and give examples of complications of healing
DEFICIENT SCAR FORMATION:
- WOUND DEHISCENCE, ULCERATION
EXCESSIVE FORMATION OF REPAIR COMPONENTS;
- KELOID, EXUBERANT GRANULATION TISSUE
FORMATION OF CONTRACTURES:
- ESP PALMS, SOLES, ANTERIOR THORAX
Explain how different factors can influence healing-including intrinsic, environmental, dietary and genetic factors
Systemic factors: NUTRITION - Protein Deficiency - Vitamin C deficiency - Zn ,Cu deficiency
METABOLIC STATUS
- Diabetes mellitus
CIRCULATORY STATUS
- Inadequate blood supply-arteriosclerosis, venous abnormalities
HORMONES
Eg:
- glucocorticoids
- Collagen Synthesis Defects eg Ehlers Danlos Syndrome-Rare
Local Factors:
INFECTION
- Delays healing
MECHANICAL FACTORS
- Eg early motion of wounds
FOREIGN BODIES
- Eg sutures, glass, bone
SIZE, LOCATION, TYPE OF WOUND
- Rich vascularity heal faster than poor vascularity
- Small incisional wounds heal faster than large excisional wounds
explain healing in bone
- Haematoma formation
- Initial acute inflammation, organisation
- Granulation tissue –provisional or soft tissue callus-loosely unites bone
- Stem cells in cambium layer of periosteum activate and differentiate into chondrocytes and osteoblasts
- Cartilaginous matrix and osteoid produced–mineralised osteoid-BONY CALLUS
- Initial bone-haphazard-WOVEN BONE
- Remodelled over next few months
explain healing in CNS and PeripheralNerves
- No effective regeneration of neurones in the central nervous system
- Liquefaction (colliquative) necrosis and scarring.
However, in the peripheral nervous system the axons of the cells may regenerate after injury
Define hypertrophy and hyperplasia and give clinical examples
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).
Examples of Physiological hypertrophy:
- skeletal muscle that occurs with training in athletes
- myometrium of uterus during pregnancy (see also hyperplasia!)
Examples of Pathological Hypertrophy:
- cardiac muscle of the left ventricle after outflow obstruction (eg hypertension)
HYPERPLASIA:
Define hypertrophy and hyperplasia and give clinical examples
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).
Examples of Physiological hypertrophy:
- skeletal muscle that occurs with training in athletes
- myometrium of uterus during pregnancy (see also hyperplasia!)
Examples of Pathological Hypertrophy:
- cardiac muscle of the left ventricle after outflow obstruction (eg hypertension)
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).
Types of hyperplasia:
- Hormonal hyperplasia:
> Increases the functional capacity of a tissue when needed
> Myometrium of uterus in pregnancy – see hypertrophy
- Compensatory hyperplasia:
> Increases tissue mass in response (compensation) to some event such as resection
A physiological example:
- 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.
- Increases red cell number and enhances O2 carriage
Pathological hyperplasia: - Psoriasis: > Too many keratinocytes > Thick scaly itchy skin - Benign prostatic hyperplasia: > Enlarged prostate > urinary tract obstruction - Goitre: > hyperplasia of thyroid gland
Define atrophy and metaplasia and give clinical examples
METAPLASIA:
Definition:
- The replacement one type of one mature differentiated cell type with another mature differentiated cell type, as an adaptive response to some insult or injury
- It is usually a reversible phenomenon.
Example:
- Barrett’s oesophagus is a condition in which the tissue lining the oesophagus is replaced by tissue that is similar to the intestinal lining. This process is called intestinal metaplasia.
The exact cause of Barrett’s esophagus is unknown, but gastroesophageal reflux disease (GORD) is a risk factor for the condition. This is a condition in which stomach contents flow back up into the esophagus.
People with Barrett’s esophagus are at increased risk for a rare type of cancer called esophageal adenocarcinoma.
- Toxic effects of tobacco smoke, which leads to airway epithelial injury and the induction of changes such as squamous metaplasia (SM), the reversible replacement of the normal columnar epithelium by squamous epithelium.
- Squamous metaplasia can arise in the bladder secondary to chronic cystitis, indwelling catheters, urinary calculi or schistosomiasis. Squamous metaplasia is a risk factor for subsequent development of carcinoma (mostly squamous cell carcinoma).
Define atrophy and metaplasia and give clinical examples
METAPLASIA:
Definition:
- The replacement one type of one mature differentiated cell type with another mature differentiated cell type, as an adaptive response to some insult or injury
- It is usually a reversible phenomenon.
Example: - Barrett’s oesophagus is a condition in which the tissue lining the oesophagus is replaced by tissue that is similar to the intestinal lining. This process is called intestinal metaplasia. > normal = Squamous epithelium > metaplasia = Columnar epithelium > stimulus = Gastro-oesophageal reflux
- Bronchi:
> normal = Pseudostratified columnar epithelium
> metaplasia = Squamous epithelium
> stimulus = Cigarette smoke - Urinary bladder
> normal = Transitional epithelium
> metaplasia = Squamous epithelium
> stimulus = Bladder stone
ATROPHY:
- 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.
Example:
- Reduced muscle mass after immobilisation
- Alzheimer’s disease
Causes:
- Disuse (decreased workload)
- Loss of innervation
- Diminished blood supply
- Inadequate nutrition
- Loss of endocrine stimulation
- Ageing (senile atrophy)
- Pressure
A 67 year old woman has Alzheimer’s disease.
Which is the most appropriate disease category?
a) Degenerative
b) Infectious
c) Metabolic
d) Neoplastic
e) Vascular
a
An 89 year old man has difficulty starting urination, a frequent need to urinate and difficulty fully emptying the bladder.
Which is the most likely diagnosis?
a. Benign prostatic hyperplasia
b. Benign prostatic hypertrophy
c. Multiple sclerosis
d. Squamous metaplasia of bladder
e. Urethral metaplasia
a
43 year old man is under surveillance for Barrett’s oesophagus. A biopsy is taken from the distal oesophagus and shows glandular mucosa.
Which is the underlying pathophysiology?
a) Atrophy
b) Dysplasia
c) Hyperplasia
d) Metaplasia
e) Neoplasia
d
Define neoplasm (tumour) – benign and malignant
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 is
“the presence of genetic alterations that alter cell growth”
Benign:
- Slow growing
- Never invade local tissues
- Never metastasise (spread to distant sites)
Malignant:
- Variable and may be rapid
- May invade surrounding tissues
- May metastasise
Explain how tumours are classified
Prefixes:
- Adeno- = Glandular epithelium
- Papillo- = Non-glandular epithelium
- Lipo- fat
- oseteo - bone
- Chondro- Cartilage
- Angio- blood vessel
- Rhabdo- skeletal muscle
- Leiomyo- smooth muscle
Suffixes:
- oma = Tumour (USUALLY benign)
- carcinoma = Epithelial malignancy
- sarcoma = Connective tissue malignancy
- aemia = malignancy of bone marrow derived cells (exceptions exist eg. anaemia)
Exceptions:
- ATHEROMA!
- MELANOMA
- MESOTHELIOMA
- LYMPHOMA
Some Tumours are grouped together as “Non-xxx Tumours”
- eg ‘non-small cell carcinoma’
Compare benign and malignant tumours – gross and microscopy
GROSS APPEARANCE:
Benign:
- Usually are well circumscribedor encapsulated
Malignant:
- Often poorly defined or irregular
MICROSCOPIC APPEARANCES:
Benign:
- Few mitoses
- Usually resemble tissue of origin
- Necrosis is rare
- Nuclear morphology is usually normal
Malignant:
- Variable but may be many mitoses
- Variable, but may only poorly resemble tissue of origin
- Necrosis is common
- Nuclear morphology may be variable and can be very abnormal with hyperchromasia, pleomorphism and prominent nucleoli
- Uniform cells = usually benign tumour (or normal tissues)
- Pleomorphic = usually malignant tumour
Explain tumour grade and stage
GRADE:
- the degree of differentiation of a tumour.
- It is the degree to which a tumour cell resembles its presumed normal counterpart as assessed by its morphological appearances by a pathologist.
- In general:
> a low grade [or well differentiated] tumour has a less aggressive course
> than a high grade [or poorly differentiated] tumour.
STAGE:
- Stage refers to the extent of spread
of a tumour.
- Stage is informed by both
clinical and radiological assessment (clinical stage)
- as well as pathological examination of surgical specimens (pathological stage)
Explain the clinical importance of pathological assessment of surgical margins
Classification, grade, stage and status of surgical margins are important as they enable the clinician to make some prediction of the likely prognosis of a patient
AND
are essential information for the logical planning of treatment
Explain the multistep nature of carcinogenesis
many steps from normal cell to invasive cancer
- dysplasia is the bit in between normal to invasive - mild or moderate
- after moderate it can be severe dysplasia (also called carcinoma in situ)
- then invasive cancer
Define dysplasia
- dysplasia is a precancerous abnormality in which cells have acquired some but not all of the genetic abnormalities associated with invasive cancer
- NO EVIDENCE OF INVASION of cells into the surrounding tissues - eg if its the epidermis of the skin then all of the abnormal cells are in the epidermis of the skin whereas invasive the cells will have broken into and invade the cells underneath the epidermis
define carcinoma in situ
severe dysplasia
What does dysplasia look like microscopically?
Many features of cancer present such as haphazard arrangement of cells, crowding of nuclei, increased numbers of mitotic figures etc. BUT NO EVIDENCE OF INVASION of cells into the surrounding tissues
Explain the risks and benefits of screening programs
- false positives - tell a patient that they have pre cancer, have investigations, maybe surgery but they don’t actually have it
- false negatives
- anxiety
- Overtreatment of patients with mild dysplasia
- know in advance - can plan ahead
- early treatment
in the colon what is the name for:
- mild/moderate dysplasia/severe dysplasia (carcinoma in situ)
- invasive cancer
- Tubular, villous and tubulovillous adenoma
- Adenocarcinoma
in the breast what is the name for:
- mild/moderate dysplasia
- severe dysplasia (carcinoma in situ)
- invasive cancer
- Atypical ductal hyperplasia
- Ductal carcinoma in situ (DCIS)
- Infiltrating duct carcinoma
in the cervix what is the name for:
- mild dysplasia
- moderate dysplasia
- severe dysplasia (carcinoma in situ)
- invasive cancer
- CIN 1
- CIN 2
- CIN 3
- Squamous cell carcinoma
in the cervix what is the name for:
- mild dysplasia
- moderate dysplasia
- severe dysplasia (carcinoma in situ)
- invasive cancer
- CIN (Cervical Intraepithelial Neoplasia) 1
- CIN 2
- CIN 3
- Squamous cell carcinoma
A 29 year old woman has had a routine cervical smear which was reported as abnormal. A subsequent biopsy shows CIN3.
Which symptoms would you expect this patient to have?
a. Abdominal pain
b. Weight loss
c. Vaginal discharge
d. No symptoms
e. Vulval itch
D
ROUTINE – shows there were no symptoms
A 87 year old man has a skin biopsy which shows nuclear atypia, hyperchromasia and increased numbers of mitotic figures. However, there is no invasion.
Which is the best diagnosis?
a. Adenocarcinoma
b. Atrophy
c. Dysplasia
d. Hypertrophy
e. Metaplasia
c
A 87 year old man has a skin biopsy which shows nuclear atypia, hyperchromasia and increased numbers of mitotic figures. However, there is no invasion.
Which is the best diagnosis?
a. Actinic keratosis
b. Ductal carcinoma in situ
c. Villous adenoma
d. Tubular adenoma
e. Squamous cell carcinoma
a
define invasion
Infiltration of normal tissues by malignant tumour cells with destruction of tissue.
define metastasis
Metastasis: the process of discontinuous spread
METASTASES: Tumour implants discontinuous with the primary tumour.
List the steps involved in the process of invasion
Abnormal or increased cell motility with loss of contact inhibition
Secretion of proteolytic enzymes
Decreased cellular adhesion
- loosening of intercellular junctions
- degradation
- attachment
- migration
(see lecture 10 slides 8+9)
Outline the role of metalloproteinases in invasion
- Important proteinases in neoplastic invasion
- A family of closely related endopeptidases
- Remodel the extracellular matrix in normal physiology
- Up -regulated in some tumours and important for tissue invasion and metastases
- Metalloproteinases-important for digesting through the basement membrane zone
Define what is meant by angiogenesis and outline its role in the development of malignant tumours
- DEFINITION: Formation of blood vessels
- Solid tumours cannot grow more than 1-2mm in diameter, unless they are vascularised
- Tumours must generate a de -novo blood supply
- Tumours produce various factors that stimulate the formation of new blood vessels.
- Vascular Endothelial Growth Factor (VEGF) is secreted by tumour cells
List the 3 main routes of metastasis in the body giving clinically relevant examples
Direct seeding of body cavities or surfaces (Transcoelomic):
- Peritoneal Cavity-most often
- Pleural cavity
- Pericardial cavity
- Subarachnoid cavity
- Joint space
- Eg Carcinomas arising in the ovaries or the stomach and the peritoneum
Lymphatic spread:
- Most common pathway for initial dissemination of carcinomas, also melanomas
- Pattern of lymph node involvement follows natural pattern of lymph node drainage
- Sarcomas usually do not spread to lymph nodes.
- The first lymph node that the tumour cells reach is called the sentinel node
Haematogenous spread-ie by blood vessels
- Typical of sarcomas but also seen with carcinomas
- LIVER and LUNGS most frequently involved in haematogenous dissemination
Outline the steps and processes involved in metastasis (vascular)
(See lecture 10 slide 16 for diagram)
1 DETACHMENT
2 INVASION of surrounding connective tissue
3 INTRAVASATION into lumen of vessels
4 EVASION of host defence mechanisms
5 EXTRAVASATION of cells from lumen into tissue
Describe how tumours may present clinically . Give a classification
Effects of local disease
Ulcer/bleed/
destroy
An incidental finding
Eg screening,
routine examination
Non-metastatic manifestations of malignancy
Consequence of distant spread
Ulcer/bleed/
destroy
Explain what is meant by the term paraneoplastic syndrome
Syndromes not explained by local effect or metastases or by production of hormones indigenous to the tissue from which the tumour arose.
Arise from tumour secretion of hormones, peptides, or cytokines or from immune cross-reactivity between malignant and normal tissues.
Give examples of para-neoplastic syndromes affecting the CNS, skin, endocrine system and musculoskeletal system
Neurologic Paraneoplastic syndromes:
- Eaton-Lambert syndrome
Cutaneous Paraneoplastic syndromes:
- Acanthosis nigricans
- Hypertrichosis
Endocrine Paraneoplastic syndromes:
- Cushing’s syndrome
Musculoskeletal:
- Hypertrophic osteoarthropathy
Other Paraneoplastic Syndrome:
- Syndrome of Inappropriate Antidiuretic Hormone secretion (SIADH),
describe eaton-lambert syndrome
An immune-mediated, myasthenia-like syndrome - weakness usually affecting the limbs and sparing ocular and bulbar muscles.
The syndrome can precede, occur with, or develop after the diagnosis of cancer.
It occurs most commonly in men with intrathoracic
tumours (70% have small cell lung carcinoma).
Symptoms and signs include
-fatigability, weakness, pain in proximal limb muscles, peripheral paraesthesias, dry mouth, erectile dysfunction and ptosis (droopy eyelid)
describe Acanthosis Nigrans
Characterized by thickened hyper-pigmented skin, predominantly in the axilla and neck regions.
Among paraneoplastic cases, gastric adenocarcinoma is the most commonly associated malignancy.
describe Hypertrichosis
May manifest as sudden appearance of coarse hair on the face and ears
Resolves after resection or treatment of the tumour.
describe SIADH
The Syndrome of Inappropriate Antidiuretic Hormone secretion (SIADH),
Hypo-osmotic, euvolemic hyponatremia (Decreased sodium levels ),
Affects 1%-2% of all patients with cancer.
Small cell lung cancer -approximately 10% to 45% of all patients with small cell lung cancer develop SIADH.
Arises from tumour cell production of antidiuretic hormone (ADH) and atrial natriuretic peptide.
describe Cushing Syndrome
Approximately 5% - 10% of cases of Cushing syndrome are paraneoplastic.
Approximately 50% - 60% of these paraneoplastic cases are lung tumours
(Small cell lung cancer and bronchial carcinoids).
Patients often present with symptoms of paraneoplastic Cushing syndrome before a cancer diagnosis is made.
describe Hypertrophic Osteoarthropathy
- Prominent with certain lung cancers
- Manifests as:
1. painful swelling of the joints (knees, ankles, wrists, elbows, metacarpophalangeal joints)
2. Finger-clubbing.
Define Arteriosclerosis
“Hardening of the arteries”
ATHEROSCLEROSIS-large and medium sized arteries-asymmetrical thickening
Arteriolosclerosis-Thickening of small arteries or arterioles-symmetrical thickening
Discuss the pathogenesis ofatherosclerosis
ATHEROMA-Focal accumulation of lipid in the intima of arteries
Draw a simple line diagram to illustrate the layers of an arterial wall and the cellular and biochemical constituents of a complicated atherosclerotic plaque
lecture 11
slide 7
slide 8 for plaque diagram
List the risk factors for atherosclerosis/ischaemic heart disease
Non modifiable risk factors:
Family history, increasing age, male gender
Modifiable risk factors:
Hyperlipidaemia, hypertension, obesity,
smoking, diabetes mellitus
Uncertain risk factors:
Many
List complications of atheroma
Acute arterial occlusion secondary to plaque rupture and thrombosis
Progressive luminal narrowing producing ischaemia of organ
Erosion of media by plaque leading to aneurysm formation
Dislodgement of plague thrombus or of plaque core constituents to produce emboli
Compare and contrastischaemia and infarction
Ischaemia: - The result of impaired blood flow or perfusion of tissue such that it is deprived of vital nutrients, especially oxygen. - Effects can be REVERSIBLE - Effects depend on DURATION of ischaemia and METABOLIC DEMANDS of the tissue
Infarction: - The death (necrosis) of tissues as a result of ischaemia - Effects are IRREVERSIBLE - Tissues vary in ability to repair and regenerate
Give clinical examples of ischaemia and infarction at various anatomical sites (brain, heart and leg)
lecture 11
slide 32
List the possible complications following amyocardial infarction
DARTH VADER
- Death
- Another MI
- Rupture free wall ventricle / ventricular septum
- Thrombus (mural)
- Heart failure
- Ventricular aneurysm
- Arrhythmia/heart block
- Dressler’s syndrome (and other pericarditis)
- Emboli
- Regurgitation (mitral)
Define hypertension
- Systolic 140 mmHg
- Diastolic 90 mmHg
- These cut off points are approximate and vary
depending on the method of measurement
Explain the causes of hypertension
Primary / Essential hypertension: - 90 % of all cases of hypertension - Cause – No single (organic) physical cause but there are a number of risk factors: > Old age > Family history > African or Caribbean origin > High amount of salt in your food > Lack of exercise > Overweight > Smoking > Excess alcohol > Stress > Urban dwelling
Secondary hypertension:
- A specific cause of hypertension can be identified
- if high bp at unusually young age or severe high bp
- Causes:
> Renal–parenchymal and renovascular diseases
> Endocrine - Pheochromocytoma, Cushing Syndrome, Hyperaldosteronism
> Coarctation of the aorta (narrowing of the aorta)
> Medications – NSAIDs, oral contraception, steroids
> Pregnancy
describe the effects of hypertension in the blood vessels
ATHEROsclerosis: Asymmetrical narrowing of the lumen (L) of LARGER VESSELS by lipid accumulation within the INTIMA
ARTERIOLOsclerosis: SYMMETRICAL narrowing of lumen (L) OF SMALLER VESSELS by depostion of protein within the wall of blood vessels
describe the effects of hypertension in myocardium
Left ventricular hypertrophy :
Symmetrical left ventricular hypertrophy in hypertension
describe the effects of hypertension in the brain
Haemorrhagic stroke often results from rupture of small cerebral microaneurysm that have been weakened, primarily by chronic arterial hypertension.
“Ischaemic Stroke” – atheroma, embolic
describe the effects of hypertension in the kidneys
Hypertensive nephrosclerosis
Benign hypertensive arteriolar nephrosclerosis is progressive renal impairment caused by chronic, poorly controlled hypertension.
Benign hypertensive arteriolar nephrosclerosis results when chronic hypertension damages small blood vessels, glomeruli, renal tubules, and interstitial tissues.
As a result, progressive chronic kidney disease can develop.
describe the effects of hypertension in the eyes
Seen in long history of hypertension or very severe hypertension
Thickened blood vessel walls - reduced blood flow - ischaemia and infarction
Damaged blood vessels - bleeding
Loss of vision
A 78 year old man dies suddenly and unexpectedly. At autopsy there is symmetrical left ventricular hypertrophy.
Which is the most likely cause of death?
a. Hypertrophic cardiomyopathy
b. Hypertension
c. Acute coronary syndrome
d. Myocardial infarction
e. Vasculitis
b
A 15 year old boy dies suddenly and unexpectedly. At autopsy there is asymmetrical left ventricular hypertrophy.
Which is the most likely cause of death?
a. Hypertrophic cardiomyopathy
b. Hypertension
c. Acute coronary syndrome
d. Myocardial infarction
e. Vasculitis
a
A 67 year old man with a 30 year history of hypertension dies suddenly and an autopsy is performed. Histology of the kidney shows that there is symmetrical thickening of the walls of very small blood vessels within the kidney.
Which is the best pathological term for these changes?
a. Atheroma
b. Atherosclerosis
c. Arteriolosclerosis
d. Cystic medial degeneration
e. Vasculitis
c
A 78 year old man dies suddenly and unexpectedly. At autopsy there is symmetrical left ventricular hypertrophy and bilateral narrowing of the renal arteries.
Which is the most likely cause of his renal artery stenosis?
a. Fibromuscular dysplasia
b. Atheroma
c. Aneurysm
d. Vasculitis
e. Cystic medial degeneration
b
A 17 year old boy has raised blood pressure in both arms but very low blood pressure in both legs.
Which is the most likely cause?
a. Coarctation of the aorta
b. Aldosteronoma
c. Phaeochromocytoma
d. Glomerulonephritis
e. Tubulointersitial nephritis
a
list Virchow’s triad and give clinical examples
- Changes in the intimal surface of the vessel:
- Eg atheroma
- Changes in the pattern of blood flow:
- Stagnation eg. Immobility
- Turbulence eg. Atrial Fibrillation
- Changes in the blood constituents;
- Hypercoaguable states - eg. Multiple myeloma – increased plasma proteins, Severe burns – relative loss of plasma in blood
Compare venous and arterial thrombosis
Arterial thrombosis – usually a medical emergency, sudden onset of a severe impairment of organ function such as “stroke” or “heart attack” (INFARCTION)
Venous thrombosis (usually in the leg) - distal tissues become swollen, reddened and tender (congested)
Define embolism
A mass of material [embolus] that can move in the vascular system and become lodged in some vessel and block its lumen
List different categories of embolism including uncommon examples
Thromboembolism
Others:
- Atheromatous emboli
- Amniotic fluid (parturition)
- Gas (nitrogen, carbon dioxide)
- Fat (+/- bone marrow) - (trauma, especially fractured long bones), Brazilian Butt Lift cosmetic surgery
- Tumour (metastasis)
- Foreign material (i.v. drug abusers)
- Infective agents (infected heart valves)
Therapeutic embolism
Pulmonary embolism:
- 95% of venous thrombosis is in the deep leg veins
the rest in deep pelvic veins or
intra cranial venous sinuses
- Most emboli from such sources will therefore travel in the blood stream and arrest in the first vascular bed they meet . . . in the lungs . . . hence pulmonary embolism
Define disseminated intravascular coagulation
Usually a life threatening condition, causes include sepsis, obstetric complication or malignancy. Widespread multiple thrombi within many organs, this consumes clotting factors, and consequently there is simultaneous bleeding.
SIMULTANEOUS CLOTTING AND BLEEDING
definition of a thrombus
A mass that is formed by the constituents of the coagulation system within BLOOD VESSELS or heart. Composed mostly of numerous platelets and red blood cells trapped in a mesh of an insoluble protein called fibrin
A 36 year old woman has a hot, swollen right calf. She has just returned from a 15 hour long haul flight.
Which is the most likely diagnosis?
a) Intermittent claudication
b) Peripheral vascular disease
c) Acute limb ischaemia
d) Femoral artery aneurysm
e) Deep venous thrombosis
e
A 36 year old woman has a hot, swollen right calf. She has just returned from a 15 hour long haul flight.
Which is the most likely cause of her clinical problem?
a) Endothelial cell injury
b) Immobility
c) Arterial occlusion
d) Virchow’s node
e) Aneurysm
b
A 36 year old woman has a hot, swollen right calf. She has just returned from a 15 hour long haul flight. She suddenly becomes acutely unwell and dies.
Which is the most likely cause of death?
a) Acute coronary syndrome
b) Peripheral vascular disease
c) Acute limb ischaemia
d) Pulmonary embolism
e) Femoral artery aneurysm
d
A 76 year old man has severe chest pain at rest and acute coronary syndrome is diagnosed.
Which coronary artery abnormality would most likely cause this clinical picture ?
a) Atheroma
b) Thrombus
c) Atheroma and thrombus
d) Aneurysm and atheroma
e) Aneurysm and thrombus
c
A 36 year old man who is an inpatient in the general medical ward has a cardiac arrest. Resuscitation is unsuccessful. An autopsy is performed.
Which findings would be most likely within the lungs?
a) Carbon dioxide embolism
b) Amniotic fluid embolism
c) Bone marrow embolism
d) Atheromatous embolism
e) Carbon monoxide embolism
c
Define the term aneurysm
Localised, permanent abnormal dilatation of blood vessel
(or left ventricle e.g. Post Myocardial Infarction)
Define oedema
Excess fluid in the interstitial tissues
Define shock
A pathological process that results in inadequate blood flow to sustain normal organ function.
List the causes and effects of shock
causes:
CARDIOGENIC:
- Commonest cause is MYOCARDIAL INFARCTION
HYPOVOLAEMIC: - Haemorrhage-internal or external - Increased vascular permeability and/or dilatation eg: > Neurogenic mechanisms –spinal cord injury > Anaphylactic reactions > Extensive burns > Bacterial toxaemia (Septic Shock)
Compensatory Mechanisms: - Constriction of vessels in ‘non-vital’ tissues to increase peripheral resistance - Increased heart rate - Dilatation of cerebral vessels CLINICAL EXAMINATION SHOWS: Patient is > Cold > Clammy > Has an increased in heart rate
Consequences of Shock:
- Renal failure due to necrosis of renal tubules (ATN – acute tubular necrosis)
- Acute Respiratory Distress Syndrome (ARDS)
- Acute pancreatitis
- Cerebral infarction (especially in watershed areas) / Irreversible neuronal injury
- Infarction of various tissues due to hypoperfusion
Outline the clinicopathological features of:
Dissecting aneurysm
- Blood is forced through a tear in intima
- Haematoma in the media-propagated along blood vessel
- Sharp, tearing pain
Complications:
- Blood ruptures through adventita-massive haemorrhage into pericardium , pleural cavity , other structures
- Blood re-enters aortic lumen-Double-barrelled aorta
- Blood may extend down tributary arteries-compresses lumen-results in end-organ infarction
Pathogenesis:
- Degeneration of the media of the vessel
- Cystic Medial Necrosis
- Mucoid degeneration, elastic fibre fragmentation
Risk factors:
- Hypertension
- Bicuspid aortic valve
- Marfan syndrome
- point mutations in fibrillin gene prevent normal deposition of elastin in extracellular matrix
Outline the clinicopathological features of:
Berry aneurysm
- Occur in the Circle of Willis
- Normal muscular arterial wall replaced by fibrous tissue
- Arise at points of branching
- More common in young, hypertensive patients
Rupture of a Berry Aneurysm-produces a SUBARACHNOID HAEMORRHAGE:
- Symptoms include:
> A ‘Thunderclap headache’
- a sudden and severe headache similar to a sudden hit on the head
> Stiff neck
> Nausea and vomiting
> Loss of consciousness or convulsions
> Stroke-like symptoms such as slurred speech and weakness on one side of the body
Outline the clinicopathological features of:
Charcot-Bouchard aneurysm
- Micro-aneurysms
- Occur in intracerebral capillaries
- Rupture leads to intracerebral haemorrhage
- Associated with both:
> hypertension
> diabetic vascular disease - tiny - only a few mm in diameter
What is the difference between oedema and effusion?
oedema = Excess fluid in the interstitial tissues
Effusion = a collection of fluid in a potential space (eg. pleural cavity)
Describe the clinicopathological features of
cerebral oedema
- Abnormal accumulation of fluid in brain parenchyma
- Results in increased brain volume
- Inside the rigid skull
may result in herniation of brain tissue: so called “coning”
Compare restrictive and obstructive lung disease and explain the role of spirometry in the investigation of these conditions
Obstructive Disease:
Increase in resistance to airflow due to partial or complete obstruction of airways
Restrictive Disease:
- Reduced expansion of lung parenchyma
- Reduced total lung capacity
Spirometry:
- A test that can help diagnose various lung conditions,
- Weight and Height is measured.
- The subject breathes into the spirometer machine
Spirometry measures the amount (volume) and/or speed (flow) of air that can be inhaled and exhaled.
Forced expiratory volume in one second (FEV1).
This is the amount of air you can blow out within one second. With normal lungs and airways you can normally blow out most of the air from your lungs within one second.
Forced vital capacity (FVC). The total amount of air that you blow out in one breath.
FEV1 divided by FVC (FEV1/FVC). Of the total amount of air that you can blow out in one breath, this is the proportion that you can blow out in one second.
Describe the clinicopathological features of asthma
CLINICAL FEATURES
A chronic disease characterized by recurrent attacks of breathlessness and wheezing
PATHOLOGICAL FEATURES
Reversible small airways obstruction characterized by bronchospasm, inflammation and oedema: paroxysmal
Pathogenisis: PROCESSES: - Bronchoconstriction - Airway oedema and inflammation - Airway hyper-reactivity - Airway remodelling
- Type 2 helper T cells, eosinophils, mast cells, and neutrophils—form an extensive inflammatory infiltrate in the airway epithelium and smooth muscle
- Airway remodelling ( by desquamation, subepithelial fibrosis, angiogenesis, smooth muscle hypertrophy).
- Hypertrophy of smooth muscle
Leading to - Narrowing of the airways
- Increased reactivity to allergens, infections, irritants, parasympathetic stimulation
- Triggering of bronchoconstriction
Describe the clinicopathological features of chronic obstructive pulmonary disease (COPD)
Chronic obstructive pulmonary disease (COPD) is a lung disease characterized by chronic obstruction of lung airflow that interferes with normal breathing and is not fully reversible (WHO definition)
Diseases with OBSTRUCTION of the bronchi and bronchioles, usually in a diffuse pattern across the whole lung
Shortness of breath due to difficulty exhaling all the air from the lungs.
At the end of a full exhalation, an abnormally high amount of air may still linger in the lungs.
Describe the clinicopathological features of restrictive lung diseases
- Caused by disease in the interstitium (alveoli) of the lung
- Usually an increase in the amount of fibrous (scar) tissue in the alveolar walls of the lung.
- The lung will be stiff with reduced compliance
- In other cases,
> stiffness of the chest wall
> weak muscles
> or damaged nerves
may cause the restriction in lung expansion.
Some conditions causing restrictive lung disease are:
- Interstitial lung disease, such as Idiopathic pulmonary fibrosis
- Sarcoidosis
- Obesity
- Scoliosis
- Neuromuscular disease
describe the acute and chronic pathological changes in asthma
Acute:
- Bronchial obstruction with distal over-inflation or collapse
- Mucus plugging of bronchi
- Bronchial inflammation-eosinophils lymphocytes, plasma cells
- Curschmann’s spirals –whorls of shredded epithelium within mucus plugs
Chronic:
- Mucous gland hypertrophy
- Development of mucosa-associated lymphoid tissue
- Bronchial wall smooth muscle hypertrophy
- Thickening of bronchial basement membrane
what is emphysema and how might smoking cause it
- Alveolar Wall Destruction and Over-inflation
- Irreversible
- Sometimes divided into centriolular and pan-acinar
Activation of inflammatory pathways
Digestion of lung parenchyma by leukocyte metalloproteinases and elastases (proteases)
Oxidants from cigarette smoke and inflammatory cells
IL-8 secretion recruits neutrophils that are primed by TNFα and cause damage to extracellular matrix
describe CHRONIC BRONCHITIS
A cough productive of sputum on most days for 3 months of the year for at least 2 successive years.
