Pathology Flashcards
Steps of acute inflammation
Increased vessel calibre - inflammation cytokines (bradykinin, prostacyclin, NO) mediate vasodilation
- Fluid exudate - vessels become leaky, fluid forced out of vessel
- Cellular exudate - abundant in neutrophils
5 cardinal signs of acute inflammation
- Rubor (redness due to dilation of small vessels)
- Dolor (pain)
- Calor (heat)
- Tumor (swelling from oedema or a physical mass)
- Loss of function
Causes of acute inflammation
- Microbial infections
- Hypersensitivity reactions
- Physical agents
- Chemicals
- Bacterial toxins
- Tissue necrosis
Outcomes of acute inflammation
- Resolution - normal
- Supporation - pus formation
- Organisation - granulation tissue + fibrosis
- Progression - excessive recurrent inflammation -> becomes chronic and fibrotic tissue
Neutrophil action at the site of inflammation
- Phagocytosis
- Phagolysosome + bacterial killing
- Macrophages clear debris
Neutrophil action in acute inflammation
Margination - migrate to edge of blood vessel (plasmatic zone) due to increase in plasma viscocity and slow flow
- Adhesion - selectins bind to neutrophil, cause rolling along the blood vessel margin
- Emigration + diapedesis - movement out of blood vessel through or inbetween endothelium onto basal lamina and then vessel wall
- Chemotaxis - site of inflammation
Chronic inflammation
Subsequent and prolonged response to tissue injury
- Lymphocytes, macrophages and plasma cells
- Longer onset, long lasting effects
- Autoimmune diseases
Macroscopic appearance of chronic inflammation
- Chronic ulcer
- Chronic abscess cavity
- Granulomatous inflammation
- Fibrosis
Causes of chronic inflammation
- Resistance of infective agent
- Endogenous + materials
- Autoimmune conditions
- Primary granulomatous diseases
- Transplant rejection
Microscopic appearance of chronic inflammation
- Lymphocytes, plasma cells and macrophages
- Exudate is not a common feature
- Evidence of continuing destruction
- Possible tissue necrosis
Cellular cooperation in chronic inflammation
-B lymphocytes - transform into plasma cells and produce antibodies
- T lymphocytes - responsible for cell-mediated immunity
- Macrophages - respond to chemotactic stimuli, produce cytokines (interferon alpha and beta, IL1, IL6, IL8, TNF-alpha)
Types of granulomas
- Central necrosis - TB (identified by Ziel-Neelsen stain)
- No central necrosis - sarcoidosis, leprosy, vasculitis, Crohn’s disease
What are granulomas?
- An aggregate of epithelioid histocytes (macrophages)
- Granuloma + eosinophil -> parasite
- Secrete ACE as a blood marker
Platelets
- No nucleus, arise from megakaryocytes
- Contain alpha granules (adhesion) and dense granules (aggregation)
- Contain lysosomes
- Activated, releasing their granules when they come into contact with collagen
- Activation forms thrombus in intact vessels
What is thrombosis?
Solidification of blood constituents (mostly platelets) forming in vessels
Thrombosis formation (primary platelet plug)
- Platelet aggregation, starts the coagulation cascade
- Positive feedback loops
Causes of thrombosis (Virchow’s triangle, typically 2 out of these 3)
- Endothelial injury (trauma, surgery, MI, smoking)
- Hypercoagulability (sepsis, atherosclerosis, COCP, preggomalignancy)
- Decreased blood flow (AF, immobility)
Arterial thrombosis
- By atherogenesis and plaque rupture
- High pressure, low pulse
- Thin cool skin, intermittent claudication
- Mainly made of platelets - so treat with antiplatelet (aspirin)
Venous thrombosis
- Caused by venous stasis
- Low pressure, high pulse
- Rubor, tumour and pain
- Mainly fibrin - so treated by anticoagulants (DOACs, warfarin)
Fate of thrombi
- Resolution (dissolves and clears, normal/best case scenario)
- Organisation (leaves scar tissue, slight narrowing of vessel lumen)
- Recanalisation (intimal cells may proliferate, capillaries may grow into the thrombus and fuse to form larger vessels)
- Embolism (fragments of the thrombus break off into circulation)
Formation of the secondary platelet plug (coagulation cascade)
Prothrombin -> thrombin
Fibrinogen -> fibrin
Intrinsic - 12, 11, 9, 8, 10, 1(5), 2, 1
Extrinsic - 3, 7, 10, 1(5), 2, 1
What is an embolism
A mass of material in the vascular system able to block in a vessel and block its lumen
Arterial vs venous embolism
Arterial
- Lodges in systemic circulation (from left heart)
- eg: AF thrombus lodges in carotid artery -> ischaemic stroke
Venous
- Lodges in pulmonary circulation (from right heart)
- eg: DVT thrombus embolises and lodges in pulmonary artery -> pulmonary embolism
Ischaemia
The reduction in blood flow to a tissue or part of the body caused by constriction or blockage of the blood vessels supplying it
- Effects can be reversible
- Brief attack
- Cardiomyocytes and cerebral neurons are most vulnerable
Infarction
The necrosis of part of the whole of an organ that occurs when the artery supplying it becomes obstructed
- Usually macroscopic
- Reperfusion injury = damage to tissue during reoxygenation
What organs are susceptible to infarcts?
- Most organs as they only have a single artery supplying them
- Liver, brain and lungs are less susceptible as they have a dual supply
What is atherosclerosis?
- Fibrolipid plaques forming in the intima and media of systemic arteries
- More in high pressure arteries, eg: aorta and bifurcations
What is in an atherosclerotic plaque?
Lipids (cholesterol)
- Smooth muscle
- Macrophages (+foam cells)
- Platelets
- Fibroblasts
What are foam cells?
Macrophages that phagocytose LDLs (form fatty streaks in plaque)
Atherosclerosis formation
- Macrophages form foam cells from lipids in arterial wall - fatty streak formation (platelets) > intermediate lesion
- Plaque protrudes into artery lumen and disrupts laminar flow - medial thinning and platelet aggregation
- Secondary platelet plug forms fibrin mesh over itself and traps red blood cells
- Fibroblasts form smooth muscle ‘fibrous cap’ over this
- Continuous formation of secondary platelet plug, this is a stable atheroma - plaque stabilisation/( fibrous cap formation)
Risk factors for atherosclerosis
- Smoking
- High bp
- Hyperlipidemia
- Increasing age
- Male
- Poorly controlled diabetes mellitus
(all risk factors for MI!!)
Complications of atherosclerosis
- Cerebral infarction
- Carotid atheroma, leading to TIAs and cerebral infarcts
- MI
- Aortic aneurysm
- Peripheral vascular disease
- Gangrene
- Cardiac failure
- Ischaemic collitis in colon
Preventative measures for atherosclerosis
- Smoking cessation
- Blood pressure control
- Weight reduction
- Low dose aspirin
- Statins
- Control diabetes
What is apoptosis?
Non-inflammatory, controlled cell death in single cells
- Cells shrink, organelles retained, CSM intact
- Chromatin unaltered, fragmented for easy phagocytosis
What is necrosis?
Induces inflammation and repair, traumatic cell death
- Cells burst, organelles splurge, CSM damaged
- Chromatin altered, cell is f*cked
Intrinsic apoptosis mechanism
- Bax is a protein, inhibited by BCl-2 gene
- It acts on mitochondrial membrane to promote cytochrome C reusase
- This activates caspases
Extrinsic apoptosis mechanism
Fas-L or TNF-L binds to CSM receptors which activate caspases
Cytotoxic apopstosis mechanism
- CD8+ binding releases Granzyme B from CD8+ cells
- Granzyme B -> Perforin -> Caspases
Types of necrosis
Coagulative, liquifactive, caseous and gangrene
Coagulative necrosis
- Most common type
- Can occur in most organs
- Caused by ischaemia
Liquefactive necrosis
Occurs in the brain due to its lack of substantial supporting stroma
Gangrene necrosis
- Necrosis from rotting of the tissue
- Affected tissue appears black due to deposition of iron sulphide from degraded haemoglobin
Caseous necrosis
Causes a cheese pattern
- eg: TB
What is inflammation?
Acute/chronic tissue injury response
What is hypertrophy?
- Increase in cell size without cell division
- eg: skeletal muscle
What are polymorphs?
- What neutrophils are referred to as sometimes
- Because they have a varying number of lobulated nuclei
What is hyperplasia?
- Increase in cell number by mitosis
- eg: bone marrow at high alititudes, prostate at older age
What is atrophy?
- Decrease in tissue/organ size caused by a decrease in the number or size of constituent cells
- eg: brain in Alzheimer’s, muscular atrophy in ALS
What is metaplasia?
-The change in differentiation of a cell from one fully-differentiated cell type to another
- eg: GORD (squamous -> columnar epithelia)
What is dysplasia?
Morphological changes seen in cells in the progression to becoming cancer
What is carcinogenesis?
Transformation of normal cells to neoplastic (malignant) cells through permanent genetic alterations or mutations
What is a neoplasm?
An autonomous, abnormal and persistent growth
What is a tumour?
Any abnormal swelling; neoplasm, inflammation, hypertrophy, hyperplasm
What can a neoplasm arise from?
- Nucleated cells
- So can’t arise from erythrocytes but can arise from their precursor
Properties of benign tumours
Non-invasive
- Localised
- Slow growth rate, low mitotic activity
- Close resemblance to normal tissue
- Well circumscribed
- Rare necrosis and ulceration
- Growth on mucosal surfaces
- Often exophytic (outward growth)
Properties of malignant tumours
- Invasive
- Rapid growth rate, high mitotic activity
- Poorly defined + irregular border
- Hyperchromatic and pleomorphic nuclei
- Common necrosis and ulceration
- Growth on mucosal surfaces and skin
- Often endophytic (inward growth)
Complications of benign tumours
- Hormone secreting (eg: prolactinoma)
- Pressure on local structures (eg: pituitary -> optic chiasm)
- Obstruct flow
- Transformation to malignant neoplasm
- Anxiety
Complications of malignant tumours
- All of the issues of benign tumours +
- Destroy surrounding tissue
- Metastasise (spread around the body)
- Blood loss from ulcers
- Pain
- Paraneoplastic (eg: SCLC, SIADH)
- Form secondary tumours
Benign epithelial neoplasms
- Papilloma - non-glandular, non-secretory, eg: squamous cell papilloma
- Adenoma - glandular, secretory, eg: colonic adenoma
Malignant epithelial neoplasms (carcinomas)
glandular epithelium -> adenocarcinoma
eg: urothelial carcinoma
Malignant connective tissue neoplasms
- Lipoma - adipocytes
- Chondroma - cartilage
- Osteoma - bone
- Angioma - vascular
- Rhabdomyoma - striated muscle (rare)
- Leiomyoma - smooth muscle (more common)
- Neuroma - nerves
Same as benign ones, but followed by ‘sarcoma’ instead of ‘myoma’
adipocytes
cartilage
bone
vascular
- striated muscle (rare)
- smooth muscle (more common)
- nerves
- Lipoma - adipocytes
- Chondroma - cartilage
- Osteoma - bone
- Angioma - vascular
- Rhabdomyoma - striated muscle (rare)
- Leiomyoma - smooth muscle (more common)
- Neuroma - nerves
Host factors for cancer
- Race
- Diet
- Age
- Gender
- Inheritance
- Premalignant lesions
- Transplacental exposure
What is a tumour called where the cell origin is unknown?
Anaplastic
Metastasis pathway
- Detachment of tumour cell
- Invasion of surrounding connective tissue
- Intravasation into blood vessels
- Evasion of host defence mechanisms
- Adherance to endothelium at a remote location
- Extravasation to distant site
- Angiogenesis - growth of own blood supply
Benign connective tissue neoplasm
- Lipoma - adipocytes
- Chondroma - cartilage
- Osteoma - bone
- Angioma - vascular
- Rhabdomyoma - striated muscle (rare)
- Leiomyoma - smooth muscle (more common)
- Neuroma - nerves
Tumour differentiation grading
- Graded based on similarity to parent cell
1. >75% cells resemble parent - well differentiated
2. 10-75%
3. <10% cells resemble parent - poorly differentiated
Other tumours
- Melanoma (melanocyte malignancy)
- Mesothelioma (mesothelial malignancy - typically pleural)
- Teratoma - cancer of all 3 embryonic germ layers
- Blastoma - embryonal tumours
Lymphoid tumours (always malignant)
- Leukemia, lymphoma
- Need to be treated by systemic chemotherapy
Eponymously named tumours (people names)
- Burkitt’s lymphoma (B cell malignany cause by EBV)
- Kaposi sarcoma (vascular endothelial malignancy, HIV associated)
- Ewing’s sarcoma (bone malignancy)
Characteristics of the neoplastic cell
Autocrine growth stimulation (overexpression of GF and mutation of tumour suppressor genes, eg: p53, and underexpression of growth inhibitors)
- Evasion of apoptosis
- Telomerase - prevents shortening of telomeres with each replication
Classes of carcinogens
- Chemical - eg: paints, dyes, rubber, soot
- Viruses - eg: EBV, HPV
- Ionising and non-ionising radiation - eg: UVA and UVB, ionising radiation
- Hormones, parasites, mycotoxics - eg: high oestrogen, anabolic steroids
- Misc - eg: asbestos, arsenic
Methods of cancer spread
- Haematogenous - via blood, bone, breast, lung, liver
- Lymphatic - secondary formation in lymph nodes
- Transcolemic - via exudative fluid accumulation, spread through pleural, pericardial, peritoneal effusions
Method of spread for sarcomas (mesenchymal cells)
Mostly haematogenous
Method of spread for carcinomas (epithelial cells)
- Mostly lymphatic
- Exceptions: follicular thyroid, choriocarcinoma, RCC, HCC
Tumour staging
- Spread determined by histopthological and clinical examination
- TNM: primary tumour, lymph node, metastases
- Different for leukemias, lymphomas and CNS cancers
Screening in the UK
- Cervical cancer (cervical swab test)
- Breast cancer (mammogram)
- Colorectal cancer (fecal occult)
- Heel prick test at birth for sickle cell, CF and hypothyroid
Mutation involved in colorectal cancer
- FAP (familial adenamatous polyposis)
- HNPCC (lynch syndrome)
Which tumours are most likely to metastasise via bone?
Breast
Lung/lymphoma
Thyroid
Kidney
Prostate
…and multiple myeloma
FAP (mutation in colorectal cancer)
- Autosomal dominant
- Mutated APC (adenomatous polyposis coli) gene, millions of colorectal adenomas inevitable
- Adenocarcinoma by 35 years old
- Overexpression of x-MYC and point mutation in KRAS
HNPCC (mutation in colorectal cancer)
- Autosomal dominant
- Mutated MSH gene
- Involved in DNA mismatch repair
Lifespan of neutrophil polymorphs
2-3 days
Cellular sequence of acute inflammation
- Injury or infection
- Neutrophils arrive and phagocytose and release enzymes
- Marophages arrive and phagocytose
- Either resolution with clearance of inflammation or progression to chronic inflammation
Examples of acute inflammation
- Acute appendicitis
- Frostbite
- Streptococcal sore throat
- Lobar pneumonia
Treating inflammation
- Ice/cold
- Antihistamines
- Aspirin/ibuprofen - inhibit prostaglandins
- Corticosteroids - upregulate inhibitors of inflammation and downregulate chemical mediators of inflammation
What is the acute mediator of inflammation?
Histamine
Ischaemia vs infarction
Ischaemia - reduction in blood flow
Infarction - reduction in blood flow with subsequent cell death
Endothelial damage theory for atherosclerosis
Endothelial cells are delicate
- Easily damaged by cigarette smoke, shesring forces as arterial divisions, hyperlipidemia, glycosylation products
p53 DNA damage pathway
Resting cell. Is there DNA damage?
Yes- apoptose
No- divide
Apoptosis in HIV
- Can induce apoptosis in CD4 helper cells
- Reduces their numbers enormously to produce an immunodeficient state
Examples of necrosis-
Infarction due to lack of blood supply
- Frostbite
- Toxic venom from reptiles and insects
- Pancreatitis
- Avascular necrosis of bone- cuts off blood supply
Why do we get deafer as we get older?
Hair cells in cochlea can’t divide
Basal cell carcinoma
- The skin only invades locally
- Can be cured by complete local excision
What is adjuvant therapy?
Extra treatment given after surgical excision
Eg: radiotherapy in breast cancer
Example of chronic inflammatory process from the start
Infectous mononucleosis
Metaplasia in smoking
Cilliated bronchial epithelium with mucocillary escalator -> squamous epithelium
What is oncogenesis?
What is oncogenesis?
The transformation of normal cells to benign or malignant tumours through permanent genetic alterations or mutations
Carcinogen definitions
Carcinogenic = cancer causing
Oncogenesis = tumour causing
Mutagenic = act on DNA
Types of carcinoma
In situ and invasive
Angiogenesis promoters (new blood vessels)
- Vascular endothelial growth factor
- Basic fibroblast growth factor
Angiogenesis inhibitors
- Angiostatin
- Endostatin
- Vasculoatatin
Tumours that are most likely to metastasise to the lung
Sarcomas, any common cancers
Tumours that are most likely to metastasise to the liver
- GI tract tumours
- Carcinoid tumours lf intestine
- Pancreatic
- Breast
- Bronchial
Cons of conventional chemotherapy
- Not selective for tumour cells
- Targets other cells, causing hair loss, diarrhoea and myelosuppresion
What tumours is chemotherapy good for?
Fast dividing ones:
- Germ cell tumours of testis
- Acute leukemia
- Lymphomas
- Embryonal paediatric tumours
- Choriocarcinoma
What is targeted chemotherapy?
- Exploits some difference between cancer cells and normal cells to target drugs to the cancer cells
- More effective
- Less side effects
Arterial ulcers
- Punched out holes
- Little exudate
- Tips of toes + lateral maleolus
- Pale cool skin
- Low distal pulse
- Peripheral vascular disease
Venous ulcers
- Less demarcated
- Lots of exudate
- Medial malleolus + inner calf
- Warm erythematous skin
- Deep vein thrombosis
Stages of atherogenesis
- Endothelial demage
- Fatty streaks
- Intermediate lesions
- Fibrous plaques/advanced lesions
- Plaque erosion
- Plaque rupture
Cell wall and nucleic acid synthesis (MEMORISE)
antibiotics picture thing
Risk factors for developing tuberculosis
- HIV
- Born in high prevalance area
- Close contact with TB positive person
- Children under 5
- History of TB
- Immunosippression
- Homelessness
- Prison
- Excessive alcohol
- IVDU
- Smokers
- Co-morbidities
- Diabetes
- End stage CKD receiving RRT
- Malignancy
Which cell type is the primary receptor for HIV?
CD4+
Retroviral therapy targets within this cell type:
- Fusion/entry inhibitors
- Reverse transcriptase inhibitors
- Integrase inhibitors
- Protease inhibitors
What blood markers are secreted in sarcoidosis?
ACE and calcium
When does apoptosis take place?
- Development - removal of cells during development, eg: interdigital webs
- Cell turnover - removal of cells during normal turnover, eg: cells in the intestinal villi at the tips are replaces by cells from below
Cells that regenerate
- Hepatocytes
- Pneumocytes
- All blood cells
- Gut epithelium
- Skin epithelium
- Osteocytes
