Pathology Flashcards
3 types of growth receptors
Receptors with intrinsic tyrosine kinase activity
7 transmembrane GPCR
Receptors without intrinsice tyrosine kinase activity
What controls progression through the cell cycle
Cyclin dependant kinases (CDK) activate each other and other enzymes. CDKs are activated by cyclins D, E, A, B
What happens in G1 phase of cell cycle
Growth, cell gets bigger with increased protein synthesis, CDK4 is activated by cyclin D. CDK 4 activates retinoblastoma protein
How does retinoblastoma protein (Rb) regulate cell growth
E2F is responsible for cell division but is stopped from doing so by Rb. When CDK4 phosphorylates Rb, E2F starts cell division
What happens in S phase of cell cycle
Synthesis phase, E2F initiates DNA replication, increases levels of cyclin A. Cyclin A activates CDK2; this promotes DNA replication. Two copies of genome
What happens at G2
Second growth phase, cells get bigger and more protein synthesis. p53 is main checkpoint at end G2
What are TAG repeats
Chromosomes are capped with TTAGGG repeats called Telomeres. This gets smaller with every division
Physiological hyperplasia
Breast tissue formation during puberty
Hyperplasia of endometrial lining of uterus - Pregnancy
Pathological hyperplasia
Excess oestrogen leads to endometrial hyperplasia and abnormal menstrual bleeding, often post menopausal
Lymph nodal swelling is due to hyperplasia or trophy?
Hyperplasia
Physiological atrophy
Uterus after parturition, certain embryological structures
Pathological atrophy
Brain during ischaemia, muscles with reduced workload
Main cell of acute inflammation
Neutrophils
What mediates vasodilation after injury
Histamine and Nitric Oxide
Major cellular changes after injury
Vasodilation - Stasis White cell margination Rolling Adhesion Migration
What is white cell margination
Blood flow slows with vasodilation, hence white cells are able to move along the periphery
What do vessel walls express that bind to white cells
Vascular Cell Adhesion Molecules - VCAM
Intercellular Cell Adhesion Molecule - ICAM
What’s expressed on white cells that bind to vessel walls
Selectins which bind CAMs on endothelial surface
What increase carbohydrate expression on WBCs for selections in endothelial cells
Histamine and Thrombin from inflammatory cells
What increases endothelial expression of ICAM and VCAM
Tumour necrosis factor - TNF and Interleukin 1 - IL1
What increases affinity of VCAM and ICAM for Integrins
Chemokines from site on injury bind to proteoglycans
How do WBCs recognise bacterial/pathogen
Bacteria have terminal mannose residues, WBCs have mannose receptors
What are opsonins
An antibody or other substance which binds to foreign microorganisms or cells making them more susceptible to phagocytosis
How does killing and degradation occur in the phagolysosome
Reactive oxygen species-NADPH oxidase; oxygen gains an electron from NADPH and becomes superoxide
Reactive Nitrogen Species-Nitric Oxide Synthase combines NO with superoxide and produces ONOO
Clinical features of inflammation
Rubor, Calor, Tumor and Dolor
What causes redness and heat in inflammation
Vasodilation leading to increased permeability of vessel
What causes dolor - pain in inflammation
Prostaglandins and Bradykinins
What is resolution of tissue
Complete restoration of tissue to normal after removal of inflammatory components
What is required for resolution
Capacity to regenerate
Good vascular supply
Injurious agent easily removed
What is suppuration
Formation of pus
What is empyema
Collection of pus within an existing anatomical cavity
What is organisation
When the basal membrane is affected, scarring happens. Injuries with basement membrane intact heal rapidly with resolution
Response in most tissues when injury is severe and can’t be rebuilt easily
Granulation tissue formation
What is scarring and fibrosis in the liver known as
Cirrhosis
What are histiocytes
Histiocytes are tissue macrophages or dendritic cells
What are granulomas
Granulomas are a collection of histiocytes or tissue macrophages where the immune system attempts to wall off the substance
What can cause granulomas
Specific infections, parasites, worms, eggs, syphilis, mycobacterium
What is caseous necrosis
Cell death in which the tissue maintain a cheese-like appearance
Consequences of no ATP
Na/K ATPase fails, leads to increase K, swelling
Calcium pump fails, increase intracellular Ca stimulates ATPase, Phospholipase, Protease, Endonuclease Mitochondrial permeability
How long are clot busting drugs viable for
30 mins
Pyknosis
Irreversible condensation of chromatin in the nucleus of the cell undergoing necrosis or apoptosis. Followed by Karyorrhexis or fragmentation of nucleus
What is coagulative necrosis
Cell death due to ischaemia or infarction leaving a ghost outline before complete phagocytosis of the cell
When is risk of cardiac rupture the greatest
3-7 days
What replaces macrophage after MI
Fibroblasts; finish laying collagen 6 weeks
What cells have a central role in matrix formation after an injury
Myofibroblasts
When is necrosis physiological
Never
What kind of necrosis is found in the brain
Liquefactive necrosis
What kind of necrosis is found in TB
Caseous necrosis
Example of physiological apoptosis
Removal of self reactive lymphocytes
Embryological growth
Hormonal induced involution
Causes of pathological apoptosis
Injury, radiation, chemotherapy, cancer, graft vs host disease, viral infection
What is the extrinsic pathway for apoptosis
Death receptor initiated pathway: Tumour Necrosis Factor, Fas
What is Fas ligand
Fas ligand belongs to the Tumour Necrosis Factor family. It’s binding with receptor induces apoptosis
What is intrinsic pathway of apoptosis
Mitochondrial pathway
What is the BAX protein
Functions as an anti or pro apoptotic regulator. Increases permeability of mitochondria and release of cytochrome C
What ligands are involved in extrinsic and intrinsic pathway
Fas and Bax ligand
What protein is a checkpoint in cell cycle
p53, can induce apoptosis
What is lipofuscin
Fine yellow-brown pigment granules composed of lipid-containing residues of lysosomal digestion. Sign of wear and tear and ageing
What is cancer
Uncontrolled cell proliferation and growth that can invade other tissues
What is neoplasia
New and abnormal growth of tissue in body
Benign or malignant
If the cancerous cells chew up the basement membrane
What is metaplasia
Change in form, reversible substitution of a kind of cell with another mature cell of another differentiated kind
What causes metaplasia
Change in signals delivered to stem cells causing them to differentiate down a different line, due to cytokines, growth factors or chemicals in cells
What metaplastic change can occur in the lungs due to thermal/chemical injury
Squamous metaplasia - Usual bronchial epithelium turns to squamous epithelium
What metaplastic change can occur in the bladder due to catheter inflammation
Usual transitional epithelium changes to squamous epithelium
How is metaplastic tissue at risk of cancer development
No squamous cells in lungs but thermal/chemical injury can cause squamous metaplasia. This can become cancerous leading to lung squamous cell cancer
What is dysplasia
Bad form, cell maturation is hindered in tissue and not in response to a stimuli, basement membrane intact
What is cervical screening based on
Catching dysplasia before it becomes cancerous
What is carcinoma in situ
Means cancer in place, dysplasia affecting entire non-glandular epithelium, localized and not past basement membrane
Most potent cancer in men and women
Lung cancer
Causes of cancer
Smoking,genes,alcohol,radiation,drugs,infection,weight
What are BRCA 1 and BRCA 2 genes
Produce tumour suppressor proteins that help repair DNA. When these genes are mutated, there is genetic instability causing lack of DNA repair
Example of autosomal dominant cancer causing genes
Retinoblastoma mutation
Familial Adenomatous Polyposis
What is the double hit hypothesis
Knudson hypothesis states that mutation in both alleles of tumour suppressor genes is required to have a phenotypical problem. Those with one inherited faulty copy are at increased risk
Two steps towards chemical carcinogenesis
Initiaters - Cause long lasting genetic damage
Promoter - Require initiator to have caused damage
What is Ames test
Biological assay to assess the mutagenic potential of chemical compounds
What can Aflatoxin (fungus on peanuts) cause
p53 mutation
What cancers can Human Papillomavirus cause
Cervical cancer
What cancer can Beta Naphthylamine cause
Bladder cancer. Liver deactivates Naphthylamine to Glucuronic acid. This is re-activated by glucuronidase leading to bladder cancer
How does radiation affect the body
Radiation causes formation of pyrimidine dimers in DNA. Nucleotide excision repair helps remove DNA damage induced by UV light, however this is eventually overwhelmed.
What is Xeroderma pigmentosa
Genetic defect in nucleotide excision repair (NER) and suffer from numerous skin cancers
Example of not direct genetic mutation
Oncogenic virus - During viral replication, certains virus DNA/RNA can affect host cells genes causing it to become cancerous. Indirectly affects protein translation. HPV has E7 as an oncogenic product which binds to Rb gene. When free of Rb, E2F (initially attached to Rb) promotes transcription
What is Schistosomiasis
Snail fever caused by parasitic flatworm called Schistosomes. Cause UTI which may develop into liver damage, kidney failure or bladder cancer
Common forgotten condition predisposing to malignancy
Persistent chronic inflammation, tissue is replicating very often, prone to errors in production
Common mutation in Lymphoma, neuroblastoma, small cell carcinoma of lung
Myc - Nuclear transcription factor that promotes cell growth
Most commonly mutated kinase in cancer
PI3K, common target for haematological malignancies
Earliest mutations in colorectal cancer
APC gene, tumour suppressor gene. Ensures chromosome number through cell division is correct
Steps to malignancy
Sustained growth signalling Loss of growth inhibition Unlimited replicative potential Resisting apoptosis Inducing angiogenesis Disordered repair mechanisms Evasion of immune system Activating invasion and metastasis
What are cyclins
Cyclins are a family of proteins that control progression through the cell cycle by activating cyclin-dependant kinase enzymes
Most commonly mutated protein across all cancer
p53
von Hippel-Lindau Tumour suppressor
Known as VHL, codes for pVHL. Loss of this increases angiogenesis, can be a syndrome
Function of PTEN
PTEN increases transcription of p27. p27 blocks CDK and cell cycle progression. Mutation and deletion of PTEN leads to uncontrolled cell division
What can cause unlimited replicative potential
Mutation that reactivates telomerase, this can renew length of telomeres
What is upregulated in cancerous cells for angiogenesis
Vascular Endothelial Growth Factor
Mechanisms for mutation repair (DNA repair)
p53, NER, BRCA, mismatch repair proteins
Syndrome associated with frequent mismatched microsatellites
Lynch Syndrome
PD-L1
Programmed death - ligand 1. Inhibits T-cell proliferation. Over expressed by malignant cells to avoid apoptosis.
What ligand is tested for in all lung cancers
PD-L1, Programmed Death Ligand 1
Physiological function of PD-L1
In pregnancy to suppress immune response
What do metastatic cells overexpress to chew up surrounding tissue
Matrix Metalloproteinases (MMP)
Is cancer clonal?
No, individual cells aren’t identical
What is cancer recurrence
Clonal cells may have a survival advantage over specific treatment. These can remain in the body after treatment, multiply over time and grow large enough to cause symptoms. Some cancers have expected recurrence
4 things wanted from a pathologist
Is it out, what is it, how far has it gone, how bad is it
N:C Ratio
Ratio of the size of nucleus of cell to the size of cytoplasm. Nucleus generally decreases as cell matures, increased ratio associated with precancerous dysplasia
What is Pleomorphism
Change in size, shape and staining of cells/nuclei. Characteristic of malignant neoplasms/dysplasia
What is hyperchromasia
Increase in chromatin in cell nuclei leading to excessive pigmentation due to increased staining capacity of nuclei for hematoxylin
What kind of mitosis is seen in malignant cells
Abnormal and lots of mitosis
What are epithelial cancers called
Carcinomas
What are glandular cancers called
Adenoma vs Adenocarcinoma
What are squamous cancers called
Papilloma vs Squamous Cell Carcinoma
What are bladder cancers called
Transitional cell carcinoma or Urothelial cell carcinoma
What is Desmoplasia
Growth of fibrous or connective tissue. May occur around a neoplasm cause fibrosis around tumour
Malignant messenchymal lesions
Sarcoma
What are fat cell cancers called
Lipoma vs Liposarcoma (rare, deep soft tissue)
What are bone cell cancers called
Osteoma vs Osteosarcoma (rare, more in growing child)
What are cartilage cell cancers called
Enchondroma vs Chondrosarcoma
What are skeletal muscle cell cancers called
Rhabdomyoma (Rare) vs Rhabdomyosarcoma (Rare, eye, bild duct, gynae tract)
What are smooth muscle cell cancers called
Leiomyoma (Common, uterine fibroids) vs Leiomyosarcoma (Uncommon)
What are nerve cell cancers called
Neurofibroma, schwannoma vs Malignant peripheral nerve sheath tumour
What are blood vessel cancers called
Haemangioma vs Angiosarcoma, Kaposi’s sarcoma
What is Kaposi’s Sarcoma
Cancer causing patches of abnormal tissue growth under skin and other organs. They are made up of cancer cells, blood vessels and blood cells
What are melanocyte cancers called
Melanoma - Malignant type
What are blood cell cancers called
Leukaemia and Lymphoma, always metastatic
What is karyotyping
Culturing cells to find full chromosome complement
How can tumours be classfied
TNM classification
T - Tumour size
N - Number of lymph nodes affected
M - Metastasis
What is tumour staging
High stage - Well differentiated tumour, grows slowly but been there for long, hasn’t spread
Low stage - Aggressively growing, poorly differentiated
Tumour grading
Low grade - Well differentiated, grows slowly and unlikely to spread
High grade - Poorly differentiated, likely to spread
Lower grade tumours have better outlook
Early presentation in vocal cord cancer
Change in voice
What is Cachexia
Loss of weight in someone not actively trying to lose weight
What can cause increase metabolism by tumour cells
Release of Tumour Necrosis Factor (TNF)
What is haemorrhage within tumours a sign of
Malignancy
What is paraneoplastic syndrome
Due to cancer in body but not local presence of cancerous cells. These are mediated by humoral factors (hormones and cytokines) excreted by tumour cells. Can lead to osteoarthropathy, neurological symptoms, rash
Which has better prognosis, tumours that stimulate a strong or weak immune response
Strong immune response. Cancer cells want to avoid the body’s immune system (immunosuppression) and this makes patient prone to infection
Blood clot vs thrombus
Blood clot may be extra or intravascular. Blood clot consists of RBCs, fibrin, platelets etc. When the blood clot occurs inside a blood vessel, is it a thrombus. This is static and becomes an embolus when dislodged.
Where do the intrinsic and extrinsic coagulation cascades meet
Intrinsic - Factor IXa, Extrinsic - Factor VIIa
These factors help in formation of XIa which converts Prothrombin to Thrombin. Thrombin helps form fibrin from fibrinogen
What does the intrinsic factor start with
Factor XII
What does the extrinsic factor start with
Tissue factor
What is meant by a long Activated Partial Thromboplastin Time (APTT)
Something wrong with extrinsic pathway. If Prothrombin Time (PT) is long, something wrong with intrinsic
What favours thrombosis
Virchows Triad -
Endothelial injury, stasis/turbulent blood flow and Hypercoaguable blood
Why are athletes prone to thrombosis
Due to low heart rate, more stasis of blood
What can air embolism result in
Decompression sickness, breathing at high pressure results in more dissolved gas in blood. Upon depressurization, gas comes out in bubbles inside the body. This can embolize and cause an obstruction to blood flow
Cause of amniotic fluid embolism
Tear in placenta or uterine vessels with secondary infusion of amniotic fluid or fetal material. This can be diagnosed by identifying foetal skin (squamous cells) and hair in pulmonary vessels
When can fat embolise in the body
After a large skeletal injury where the marrow contents are released (mostly adipose cells)
What is septic emboli
Thrombus forms in association with an infectious agent
What can cause septic emboli
Mycotic Aneurysm, Infective Endocarditis
Are Atheroma and Atherosclerosis the same?
Yes
Aetiology of Atheroma
Smoking, hypertension, hyperlipidemia, diabetes, age, sex, genetics
Which vessels commonly affected by Atherosclerosis
Branching sites of vessels
How does Diabetes cause Atheroma
Tissues lose their elasticity in diabetes, become more rigid and prone to endothelial injury
Pathogenesis of Atheroma
Primary endothelial injury. Accumulation of LDL and macrophage in Tunica Intima. Migration of smooth muscles form Tunica Media. Formation of foam cells (fat laden macrophage). Collagenous fibrous cap increases in size decreasing size of lumen
Why causes macrophages to migrate vessel wall
Endothelial injury leads to increase permeability which leads to increase VCAM-1. Monocytes attach and migrate into wall
Uncomplicated vs complicated plaque
Uncomplicated plaque is static whereas complicated plaque has embolized.
Progression of atheromatous plaque
Fatty streak - Fibrofatty plaque - Complicated plaque
Complications of Atheroma
Stenosis, aneurysm, dissection, thrombosis/embolism
How can arterial stenosis affect Carotids
Transient Ischaemic Attack, Stroke, Vascular dementia
How can arterial stenosis affect renal arteries
Hypertension, renal failure
How can arterial stenosis affect peripheral arteries
Claudication and foot/leg ischaemia
What is an aneurysm
Abnormal and persistent dilation of vessel wall due to dilation of an artery due to weakness in its wall
What is arterial dissection
Splitting of Tunica media by flowing blood
