Session 1 Flashcards
1
Q
What is pathology?
A
Pathology is a bridging discipline betweens cience and clinical practice.
- investigates the changes (structural and functional) in cells, tissues and organs that are seen in disease.
- study of disease and cellular malfunction
- the ultimate abnormality always lies in the cell
2
Q
What did Rudolf Virchow do that has helped study pathology so much?
A
- he discredited the theory of 4 humours
- he said that all cells come from cells, and that the body is a society of living cells, a tiny well-ordered state, with all the accessories - high officials and underlings, servants and masters…
- “pathology is histology with obstacles”
3
Q
Why are cells called cells and who named them?
A
Robert Hooke named them cells, as when he looked down his primitive microscope at a slice of cork, he thought the compartments looked like monk cells.
4
Q
In all physical disease, the … is considered the central player.
A
cell
5
Q
Disease can be considered to be a consequence of failed …
A
homeostasis
6
Q
What is pathology?
A
The study of suffering
ie the study of disease and cellular dysfunction (as opposed to biology that studies life and cellular function)
7
Q
Which are the disciplines of pathology? (5)
A
- Chemical pathology (clinical biochemistry)
- Haematology - diseases of blood, blood clotting, blood transfusion, bonen marrow transplant
- Cellular pathology (histopathology and cytopathology) - examines organs, tissues and cells for diagnosis and to guide treatment, often cancer work.
- Immunology - diseases of the immune system
- Medical microbiology - disease-causing microbes including advice on antibiotic usage
8
Q
What is cellular pathology and what are its 2 main subdivisions?
A
Cellular pathology is the examination of organs, tissues and cells for diagnosis and to guide treatment, often cancer work.
Also conduct autopsies.
The 2 main subdivisions are
1. Histopathology - examines diseased tissues
2. Cytopathology - examines diseased individual CELLS, not tissues
9
Q
What is the difference between histopathology and cytopathology?
A
Histopathology investigates and diagnoses disease from the examination of TISSUES, whereas cytopathology investigates and diagnoses from the examination of ISOLATED CELLS
10
Q
What is the importance of a microscopic diagnosis?
A
Actually know whats going on! Ie. gives a definitive diagnosis.
It can be essential before major surgery to remove a lesion, as it wil lguide the type and extent of intervention.
11
Q
Give 4 examples of histology specimen
A
- Core biopsies
- Cancer resection specimens
- Excised skin lesions
- Endoscopic biopsies
12
Q
Give 4 examples of cytology specimen.
A
- Fine needle aspiration of breast, thyroid, salivary glands or lung
- Effusions
- Cervical smears
- Sputum
- Urine
13
Q
What are the advantages of cytology?
A
- fast and cheap
- can look at cells in a fluid
- non-invasive, or minimally, so very safe
- used as a preliminary test
14
Q
What are the disadvantages of cytology compared to histology?
A
- cytology has higher orror rates becasue it can’t see the architecture of the tissue, only individual cells.
15
Q
What sort of question does cytoloy provide the answer to as opposed to histology?
A
- Cytology ansers questions such as “is it cancer or not?”, so it is used to CONFIRM/EXCLUDE cancer/dysplasia; not to diagnose any other condition with accuracy
- Histology provides answers to questions such as “What kind of inflammatory condition is it?”
16
Q
What sort of information does histology provide?
A
- information on tissue architecture
- information of completeness of excision
- ## information on grading and staging
17
Q
Peritoneal fluid analysis falls into which subdivision of cellualar pathology?
A
- cytology (individual cells that can be found in fluids)
18
Q
Which organs could be affected by serous carcinoma and causing abdominal distension in a 63 year old female presenting with bilateral pelvic adnexal masses and ascites?
A
- Ovary
- Fallopian tubes
- Uterus
- Cervix
- Peritoneum
19
Q
What does neoplastic mean?
A
- tissue that shows abnormal growth (often forms a mass)
20
Q
What is the difference between a primary tumour and a metastasis?
A
A primary tumour is when the abnormality is at its origin still, whereas a emtastasis is when the abnormality has moved,, it comes from somewhere else
21
Q
What does coeliac disease look like in histology?
A
The villi have thikened and flattened and there are a lot more cells within the lamina propria.
22
Q
What can histopathologists tell us?
A
- Type of cancer
- Grade of cancer
- Stage of cancer
- Completeness of excision and if margins are involved which ones
- Likely efficacy or further treatments
23
Q
What is adenoma?
A
It is a type of cancer that forms in mucus-secreting glands throughout the body.
Eg. Lung, prostate, pancreatic, oesophageal, colorectal (doesn’t mean that lung cancer is necessarily adenoma, just that it can be!)
24
Q
What is lymphoma?
A
Lymphoma is a type of cancer affecting the lymphatic system. There are 2 main types,
- Hodgkin lymphoma
- Non-hodgkin lymphoma
25
What is Hodgkin lymphoma?
It is a type of lymphoma (cancer of lymphatic system). Lymphocytes are the cells that become abnormal.
- caracterised by presence of giant neoplastic cells called REED STERNBERG cells
- spreads slowly to sdjacent lymph nodes, but rarely metastasizes to distsnt site
- responsive to chemotherapy and radiation therapy
26
What is non-Hodgkin lymphoma?
It is a type of lymphoma (cancer affecting lymphatic system).
Do not contain Reed-Sternberg cells.
27
What is Mohs surgery?
It is performed by excising layer of diseased tissue, and then asking histopathologist if they have taken enough away. If pathologist sees diseased cell close to margin, then will suggest taking some more away.
= progressive removal till only cancer-free tissue remains.
28
What are ER and Her2 receptors and why are they relevant to histopathologists?
ER = estrogen receptor
- if breast cancer is positive to ER receptors (70%), then it will respond well to hormonal therapies
Her2 = human epidermal growth factor 2
- if breast cancer is Her2 positive, then Trastuzumab (Herceptin) is an effective ttt for this type of breast cancer.
=> so by testing for these receptors, the pathologist can orientate the treatment!
29
Tissue autolysis is a problem for pathologists preparing their specimen. What is autolysis, and what is the answer to this problem?
Autolysis is self-digeston of the cell which begins when the blood supply is cut off.
It destroys cells and tissue architecture, both of which we need for diagnosis!
We can block the biochemical process of autolysis with FIXATIVES.
1. Fixatives inactivate tissue enzymes and denature proteins
2. prevent bacterial growth
3. Harden tissue
30
What are fixatives and what are their 3 main functions?
Fixatives are the solution to stop cell autolysis before we observe it under the microscope.
Fixatives:
1. Prevent bacterial growth
2. Harden tissue - important for the cutting stage
3. Inactivate tissue enzymes and denature proteins
31
What is the fixation agent most comonly used?
Formalin
32
How do we get tissue hard enough to cut and observe?
1. Need to dehydrate the tissue using alcohol
2. Replace alcohol with xylene which mixes with wax
3. Replace xylene with molten paraffin wax, which will even be inside the cells.
33
What is the machine that cuts the very thin slices for microscopy observation called?
a Microtome
34
What does haematoxylin stain and what colour?
haematoxylin stains nuclei purple
35
What does eosin stain and what colour?
Eosin staisn cytoplasm and connective tissue pink.
36
What is immunohistochemistry?
- is an additinal test to viewing of routinely stained slides
- demonstrates the presence in or on cells of specific substances, usually proteins by LABELLING THEM WITH ANTIBODIES.
- usually the anitbodies are noined to an enzyme that catalyses a colour-producing reaction
- most often substances are demonstrated by a brown colour.
37
What are cytokeratins and why are they useful in immunohistochemistry?
Cytokeratins are fibrous proteins exclusively found in almost all epithelia. Their presence demonstrates epithelial differentiation and the different cytokeratins (20 diff sorts) show tissue-specific distribution.
=> they can therefore be used to give information about the primary site of a carcinoma.
38
What does immunohistochemistry result CK7+/CK20- indicate?
CK7 positive, so primary site of carcinoma could be lung, breast, endometrium, ovary, thyroid
39
What does immunohistochemistry result CK7-/CK20+ indicate?
It indicates that the primary site of carcinoma could be large bowel, some gastric carcinomas
40
What is molecular pathology?
Studies how diseases are caused by alterations in normal cellular molecular biology.
Can be due to altered DNA, RNA, or protein.
In situ molecular tests show how DNA is altered in tissues prepared for microscopy:
Eg. FISH, to test gains of additional copies of Her2 gene in breast cancer.
41
What are frozen sections?
- urgent histopathology
- method of hardening tissue quickly
- less good that paraffin sections
- intra-operative! performed during surgery
- takes about 10 minutes from receiving specimen in lab to result
- the aim is to establish presence and nature of a lesion and influence the course of the operation
- accuracy not very good, about 96%
42
How does cell soze change with apoptosis?
Cell shrinks
43
How does cell size change with necrosis (oncosis)
Swelling
44
Does necrosis (oncosis) trigger inflammatory response?
yes
45
Does apoptosis trigger inflammatory response?
no
46
Can apoptosis be pathological?
yes
47
Can necrosis be physiological?
no
48
Give 5 causes of cell injury.
1. Hypoxia
2. Toxins
3. Physical agents
4. Radiation
5. Micro-organisms
6. Immune mechanisms
7. Dietary insufficiency and deficiencies, dietary excess
49
What are heat shock protein?
They are a defense mechanism of cells against injury of any type.
Heat shock response aims to MEND mis-folded proteins and msintain viability.
Every living organism has heat shock proteins.
Heat shock protein are unfoldases or chaperonins, or which an example is ubiquitin.
50
What is ubiquitin?
Ubiquitin is a heat shock protein that, ie. mends mis-folded proteins occuring from cell injury.
51
What do dead injured cells look like under the microscope. Name 3 processes that affect the cells.
When the damage become irreversible, and cell is dead, then the cytoplasm goes deep pink and the follwing 3 processes are seen:
1. Pyknosis - proteins are denatured and clump
2. Karyorrhexis - nucleus breaks up into fragments
3. Karyolysis - nucleus disappears
As well as this, lysosomes release all their enzymes, and plasma membrane actually now has holes in it.
52
What dies one observe in a cell with reversible injury (under eelctron micoscope)?
- blebbing at membrane surface (cytoskeleton is degraded)
- generalised swelling
- clumping of nuclear chromatin
- autophagy by lysosomes
- ribosome detachment
- ER and mitochondrial swelling
53
What is the difference between oncosis and necrosis?
Oncosis is cell death with swelling, the spectrum of changes that occur in injured cells PRIOR to death.
But Necrosis is actually the morphologic changes that occur AFTER a cell has been dead for 12-24 hours!
54
Which are the 4 types of necrosis?
1. Liquefactive
2. Coagulative
3. Caseous
4. Fat necrosis
55
What is coagulative necrosis?
- Concerns solid organs; ie. have ++ connective tissue
- It is governed essentially by protein denaturation
- Cellular architecture is preserved - see ghost outline of cell
- less neutrophils as in liquefactive
Eg. Kidney
56
What is liquefactive necrosis?
- seen in loose tissue ischemia
- presence of many neutrophils
- important enzyme release and digestion of cellular elements
= degradation > denaturation
- no clumping
- can't see ghost outline of cell, everything is degraded.
Eg. Brain necrosis
57
What is caseous necrosis?
- contains amorphous (structureless) debris, but no ghost outline
- particularly associated with infections, TUBERCULOSIS +++
58
Which type of necrosis is typical of tuberculosis?
Caseous!
Can see cellular debris, but no clear ghot outline of cells.
Looks like cottage cheese.
59
What is fat necrosis?
It is a type of necrosis.
- typical of pancreatitis
- digestive enzymes leaks into GI tract and dogest enzymes in lumen,
- fatty acids from lipid digestion will combine with calcium forming calcium salts.
- fat necrosis form HARD LUMPS in chest.
=> think of cancer but actually just been hit by squash ball
60
What type of necrosis is caracterised by formation of hard lumps?
fat necrosis
61
Which type of necrosis is caracterised by protein clumping and observation of ghost outline of cells?
Coagulative necrosis
62
Which type of necrosis is caracterised by the absence of ghost outline and hig enzymatic digestion?
liquefactive
63
What is gangrene?
necrosis visible to the naked eye, it is an appearance of necrosis.
64
What is infarcation?
Necrosis caused by reduction in arterial blood flow.
It is a CAUSE of necrosis.
Can RESULT in gangrene.
65
What is infarct?
It is an AREA of necrotic tissue which is the result of loss of arterial blood supply.
An area ischemic necrosis.
66
Which 2 types of gangrene can be observed?
Dry and wet
67
What is dry gangrene?
- Necrosis modified by exposure to air (coagulative necrosis)
68
What is wet gangrene?
Necrosis modified by infection (liquefactive necrosis)
69
What is gas gangrene?
Is is a subtype of wet gangrene where the infection is by anaerobic bacteria that produce gas.
70
What are the most common causes of infarction? (2)
1. Thrombosis
| 2. Embolism
71
What does infarcted tissue look like?
It can be red or white.
1. White: it will look white in solid organs where and end artery is occluded and no blood is getting to the tissue. The infact is often wedge shaped. It is coagulative necrosis.
2. Red: Loose tissue infacts, dual blood supply (colateral). Not enough for tissue to finction, but there is blood getting to downstream tissues.
72
What is ischaemia-reperfusion injury?
If blood flow is returned to a damaged but not yet. ecrotic tissue, damage sustained can be worse than if blood flow hadn't been returned.
Causes?
-increased prod of oxygen free radicals
- increased no of neutrophils, so more inflammation, so increased tissue injury
- delivery of complement proteins and activstion of compl pathway
73
How is potassium dangerous in case of membrane damage?
Potassium is used to to put heart into cardiac arrest. So we don't want potassium to get around the heart.
1. If there is important MI, then potassium could be released very close to heart and cause arrest.
2. In severe burns, cells break down and release potassium, so infarction could occur post-burn.
3. During chemo treatment, if very effective, then many cells may die, release potassium and cause infarction,
74
Which molecule do we use to diagnose MI.
Troponin
75
Myoglobin can be release from injured skeletal muscle cells, why is this clinically important?
Myoglobin released can block kidney glomeruli and cause kidney failure.
76
Wat is caracteristic of DNA breakdown in apoptosis?
- non-random
| - internucleosomal cleavage of DNA (in oncosis, DNA is chopped into random length segments)
77
Which type of cell death involves lysosomal enzymes?
Oncosis (necrosis)
78
When does apoptosis occur physiologically? (3)
1. Embryogenesis
2. Hormone-controlled involution
3. In order to maintain a steady state
79
When does apoptosis occur pathologically? (3)
1. Cytotoxic T cell killing of virus infected or neoplastic cells
2. Cell are damaged, particularly DNA damage
3. Gradt vs. host disease (typically bone marrow transplant)
80
What are the 3 phases of apoptosis?
1. Initiation
2. Execution
3. Degradation and phagocytosis
81
Apoptosis can be triggered by 2 pathways, these are:
1. intrinsic pathway
| 2. extrinsic pathway
82
The result of extrinsic and intrinsic pathways of apoptosis initiation both result in ... activation
caspase
83
What are caspases?
- central players of apoptosis
- enzymes that control and mediate apoptosis
- cause cleavage of DNA and proteins of the cytoskeleton
- they are activated by both intrinsic and exteinsic pathway
84
How is the intrinsic pathway of apoptosis initiated and carried out?
- initiation comes from within the cell
- triggers:
a) irreparable DNA damage
b) withdrawal of growth factors or hormones
- p53 is activated and this results in the outer mitochondrial membrane becoming leaky
- cytochrome C is released from the mitochondria and this causes activation of caspases
85
How is the extrinsic pathway of apoptosis triggered and carried out?
- initiated by EXTRACELLULAR signals
- triggers: cells that are in danger such as tumour cells, virus-infected cells
- one of the signals is TNFa, it is secreted by T killer cells. TNFa binds to membrane receptor "death receptor"
- the binding results in caspase activation
86
Why are apoptotic bodies phagocytosed?
Both intrinsic and extrinsic pathways cause cells to SHRINK and BREAK UP into apoptotic bodies.
The apoptotic bodies express prpteins at their surface.
They can now be recognized by phagocytes or neighbouring cells.
Finally, degradation takes place within the phagocyte/neighbour.
87
What kind of things can accumulate in cells? (5)
1. Lipids
2. Carbohydrates
3. Water and electrolytes
4. Proteins
5. Pigments
88
When do lipids accumulate in cells?
Steatosis (= accumulation of triglycerides)
Often seen in the liver (major organ of fat metabolism)
Causes:
- alcohol
- diabetes mellitus
- obesity
- toxins
Steatosis can occur when cellular injury means that the ribosomes detach from ER, and protein synthesis is stopped. Liver no longer has necessary enzymes for fat metabolism.
89
What sort of accumulation does one see in hyperlipidaemias and which cells contain the accumulation?
Hyperlipidaemias are diseases with accumulations of cholesterol in macrophages of skin and tendons.
90
What are foam cells and in which common disease are they seen?
Foam cells are macrophages in atherosclerotic plaques that have accumulated cholesterol giving them a foamy appearance.
91
In what conditions do proteins accumulate in cells? (2)
1. Alcoholic liver disease; Mallory's hyaline - damaged keratin filaments by alcohol toxicity that clump together.
2. a1-antitrypsin deficiency - liver produces incorrectly folded a1-antitrypsin that cannot be packaged by ER, and so accumulates. This causes fibrosis and eventually cirrhosis. 2nd problem, normally a1-AT degades proteases, but if its lacking then these proteases will be active all the time and will degrade lung tissue and emphysema.
92
When do pigments accumulate in cells?
- carbon/coal dust/soot
- inhaled and phagocytosed by alveolar macrophages
- anthracosis and blackened peribronchial lymph nodes
93
What is the difference between ischemia and hypoxia?
Hypoxia is a lack of oxygen supply to the tissue, whereas ischemia is a lack of blood supply, and so not only lack of oxygen but also nutrients, etc.
94
Which cell components are most susceptible to injury?
1. Cell membranes (incl. organellar)
2. Nucleus
3. Proteins
4. Mitochondria
95
What happens at a molecular level in hypoxia?
The process of oxidative phosphorylation in mitochondria decreases as it needs O2. Consequently, less ATP is produced.
=> Lack of ATP for Na/K-ATPase so influx of Ca, water and Na, causing cellular swelling, blebs, etc.
=> Lack of ATP induces glycolysis, which lowers the pH inducing chromatin clumping..
=> Lack of ATP also causes ribosomes to detach from ER, so decrease in protein synthesis, and this will cause fat deposition in the liver for example, as it no longer has the necessary enzymes for lipid degradation.
96
What happens at a molecular level in prolonged hypoxia?
```
Massive influx of calcium (++ metabolically active) will activate
- ATPases
- Phospholipases
- Proteases
- Endocnucleases
The damage is now irreversible
```
97
At which point does cell damage become irreversible?
When there is massive influx of calcium into the cell activating ATPases, proteases, phospholipases and endonucleases.
98
What are free radicals?
Free radicals are not friends. They are reactive oxygen species. They have a single unpaired electron and so an unstable configuration. The makes these molecules strongly reactive as they want to pair the single electron. The damage membranes primarily.
99
Name 3 important free radicals in medicine-
1. OH° (the most dangerous)
2. O2- (superoxide)
3. H2O2 (hydrogen peroxide)
100
How are free radicals produced? Name 3
1. Normal metbaolic reactions (such as oxidative phosphorylation)
2. Inflammation
3. Radiation
4. Contact with unbound metals within the body: iron and copper!
5. Drugs and chemicals (eg. in the over during metabolism of paracetamol or carbon tetrachloride (cleaning) by P450 system)
101
Free radical damage occurs in which disease presenting with skin coloration?
Haemachromatosis
102
How does the body control free radicals?
1. Anti-oxydants, these are molecules willing to give an electron to free radicals to stabilise them.
Eg. vitamins A, C, E
2. Metal carrier and storage proteins that sequester iron and copper, hence disabling them to react.
3. Enzymes that neutralise free radicals
103
Which atoms are at risk of producing free radicals?
iron and copper
104
How do free radical injure cells?
1. Attack the membrane and steal its electrons = lipid peroxidation
2. Oxidise proteins, carbohydrates and DNA
105
What sorts of protection do cells have against injury?
1. Antioxydants
| 2. Heat shock proteins! They mend misfolded proteins
106
What is haemochromatosis?
It is a genetically inherited disorder that results in an increased intestinal absorption of dietary iron.
Iron deposits in skin, liver, pancreas, heart and endocrine organs.
Affected patins have a tanned complexion.
Often associated with diabetes as leads to pancreatic failure.
TTT = Regular bleeding
107
What is jaundice and what accumulates in this disease?
Jaundice is accumulation of BILIRUBIN in the blood. Bilirubin is a bright yellow molecule.
- product of heme breakdown
- FORMED IN ALL CELLS of the body, it must be eliminated by bile
- taken from tissues by albumin to the liver, then excreted in bile.
- if bile flow is obstructed or overwhelmed, bilirubin in blood rises and jaundice results
- deposited in tissues extracellulary or in macrophages.
108
What sorts of tissue calcification can occur form abnormal deposition of calcium salts? (2)
1. Localised - Dystrophic, it occurs in an area of dying tissue, atherosclerotic plaques, ageing or damaged heart valves, ...
2. Generalised - Metastatic (rare)
109
Why does dystrophic calcification occur?
- NO abnormality in calcium metabolism, serum calcium or phopshate concentrations
- local change favours nucleation of hydroxyapatite crystals
- can cause organ dysfunction eg. atherosclerosis, calcified heart valves.
110
Why does metastatic calcification occur?
- due to HYPERCALCAEMIA secondary to disturbances in calcium metabolism
- hydroxyapatite crystals are deposited in normal tissues throughout the body
- usually asymptomatic but can be lethal
- can regress if the cause of hypercalcaemia is corrected
111
Why go germ and stem cells have the ability to live for a very long time and through many replications without shortening?
The have the enzyme telomerase!
112
what is hemiplegia?
- lifelong condition caused by injury to the brain
- affects movement on one side of the body to a varying degree
- can cause epilepsy, learning difficulties, anxiety, challenging behaviour
- dont actually understand the causes. 80% of cases are congenital
