general Flashcards
what is azathioprine used for?
DMARD; used for Crohns
what are the 3 MC types of skin cancer and how do they typically present?
- BCC
- MC type of skin cancer
- very slow growing
- almost always localised to the skin
- malignant tumour of the epidermal keratinocytes
- good chance of getting another BCC after having one
- earliest it is treated, the less destructive Tx is
- intermittently bleeding
- can be weepy - SCC
- second MC
- usually grow a little more quickly
- slightly more serious if left untreated
- locally invasive malignant tumour of the epidermal keratinocytes or its appendages, which has the potential to metastasise
- 2-10% risk of spread to other parts of the body, which could be fatal
- early Tx is less destructive and reduces the risk of spread
- red, sore
- increased risk in the immunosuppressed - melanoma
- 3rd MC
- most dangerous
- malignant tumour of the epidermal melanocytes, which has the potential to metastasise
- can be seen in younger individuals but if caught early the outlook is generally good
- develop from existing skin mole or appear as new mole-like marks on normal skin
using the ABCDE approach, identify the red flag features of pigmented lesions
A - asymmetry**
B - border irregularity
C - colour: 2 or more OR chaotic appearance**
D - diameter>6mm… OR….dark or different (not like any other moles - ‘ugly-duckling’)
E - evolving, especially quickly over weeks to months
**major suspicious features
(nodular melanoma can sometimes present as a rapidly growing nodule which is not pigmented and instead pink, red or flesh coloured often raw or ulcerated)
what is important in any skin lesion Hx and examination?
take a thorough history focussing on RFs and behaviour of skin lesion
examine the whole pt - allow comparison of index lesion to other naevi
what technique is used to remove a mole to confirm diagnosis of a malignant melanoma? if diagnosis is confirmed what procedure follows?
elliptical excision under LA of the lesion with 2mm margins. defect repaired with direct, side-to-side closure
a wide local excision (probably with split-thickness skin grafting) is performed to reduce the risk of local recurrence of the melanoma. referral to plastics. sentinel lymph node biopsy, in view of the working stage of melanoma
what are the possible risks of skin surgery which should be explained to the pt during consent process?
scarring infection bleeding pain incomplete excision delayed healing non-diagnostic biopsy
as there is a risk of recurrence with malignant melanoma, including in local lymph nodes and other organs what time period of follow up is required for pt’s?
5 years
what is Breslow thickness used for?
measurement of the depth of the melanoma from the surface of the skin through to the deepest point of the tumour. used for staging and prognosis
what are the risk factors of skin cancer?
- fair skin that burns easily
- light coloured eyes
- naturally blonde or red hair
- numerous freckles
- outdoor occupation and/or had intense sun exposure without se of sunscreen
- frequent use of sun lamps and beds
- Hx of skin cancer
how is DNA damaged?
constantly being damaged by…
- free radicals (associated with disease; Ca, atherosclerosis, Alzheimer D, Parkinsons D etc)
- radiation
- mutagenic chemicals
- errors in dan replication
what is Werner’s syndrome?
- autosomal recessive syndrome
- average life expectancy of 48yrs. problem with DNA unwinding mechanism responsible for DNA repair and replication.
- results in premature ageing
describe 3 dna repair mechanism and the type of damage
- dna mismatch repair - specifically recognises when base is mismatched e.g. c->t
- >damage = base mismatches, especially after DNA replication - base excision repair - responsible primarily for removing small, non-helix-distorting base lesions from the genome 🧬
- > damage = oxidation, deamination, alkylation, single strand dna breaks - non-homologous recombination re - repairing dna double strand breaks. relatively fast and slightly more error prone compared to homologous
- > damage = dna double strand breaks
how does UV damage DNA?
if there is 2 thymine residues on the same strand of dna, they can become covalently bonded.
this distorts the helix and if it is not repaired can result in mutation when that strand is duplicated
-> important that our bodies can recognise and repair damage. or stop happening in the first place
how does UV induce the expression of melanin?
melanocytes -> melanin that reside in the basal layer of the skin. following UV exposure, there is dramatic increase in the synthesis and they actively absorb the UVR and protect the skin from further damage
- in response to UV the melanocortin 1 receptor is activated to stimulate synthesis of eumelanin (Tyrosine —tyrosinase—> Dopa -> Dopaquinone -> Eu-melanin)
- in albinisms, there is a defect in tyrosinase which leads to production of pheo-melanin
- eumelanin is present in the skin and hair of dark-coloured persons and pheo-melanin is present in the skin and hair of light coloured persons
repair systems recognise UVR damage and prevent it from becoming worse. what defect occurs if there is a defect in this repair pathway?
Xeroderma Pigmentosum
- genetic disorder in which there is a decreased ability to repair DNA damage caused by UV light
- mutation is in the nucleotide excision repair mechanism (involved in repairing larger single stranded lesions and more acutely distort shape of helix e.g. thymine dimers)
- symptoms include severe sunburn after only a few minutes in the sun, freckling in sun exposed areas, dry skin and changes in skin pigmentation
- increased risk of skin cancer
Lynch syndrome is an inherited cancer syndrome: pt at high risk for colon cancer. what dna defect is it?
defect in the dna mismatch repair mechanism
autosomal dominant
tendency to develop tumours at an early age
use breast Ca as another example to compare the consequences of inherited defects in a dna repair pathway
- some people (5-10% of breast Ca is familial/inherited) have developed defects to repair double strand break –> susceptible to breast and ovarian Ca
- two main gene defects identified: BRACA 1 and BRACA 2
BRACA 1:
- AD
- not got full penatrance
- therefore, increases lifetime risk to 50-80%
- lots of mutation found (via sequencing) distributed throughout gene. hard to disguise pathogenic and normal variant, but pathogenetic is usually truncated protein
- BRACA 1 usually involved in dna damage response.
BRACA2:
- again, lots of mutations found. most pathogenic result in truncated protein
- founder effect
- role in dna damage response
- > normally BRACA1 is involved in recognising the dna double strand break and initiating cutting back in order to reveal the single stranded section where BRACA 2 (+RAD51) can then bind and promote homologous recombination repair that BACA 1 and 2 are involved in
- > damage to these genes causes double strand breaks as homologous recombination is faulty.
why does inherited defect of one copy predispose to Ca?
Nudson hypothesis ->in order for Ca to develop there needs to be mutations in both copies of tumour suppressor gene.
Concept is that in someone who develops a mutation in every cell of their body, if by chance there is a mutation in one copy of the other tumour suppressor gene that will leave them with no working gene and tendency to develop cancer
describe how the relationship between different dna repair pathways can be exploited therapeutically
PARP:
- involved in recognising DNA damage in single dna breaks in base excision repair pathway
- > problem here is that if a single stranded break is not prepared, it will go on to cause a double stranded break, this is where we need BRACA1 and 2 pathway in older to resolve
- > the PARP and BRACA pathways are an example of synthetic lethality
- > potential PARP inhibitor drug that would kill mutated cells if BRACA2 -/-. sounds good, but cell lines become resistant over time
- > resistant cells lines can actually develop into reverse mutations and start working again
describe the concept of synthetic lethality
where 2 genetic mutations, independently are compatible with life. But expression of both together –> mortality
name 4 functions of the skin
- homeostasis - thermoregulation (vasodilation, sweating, hairs)
- sensation (pain, temp, touch, pressure, vibration)
- protection (UV, organisms, chemicals, water, mechanical)
what embryonic layer are the layers of the skin derived from?
epidermis = ectoderm
dermis and hypodermis = mesoderm
melanocytes = neural crest cells
*the appendages of the epidermis are derived from ectoderm but extend downwards into the dermis
list the 4(5) layers of the epidermis deep to superficial
- stratum basale - 1 cell thick, active, epidermal stem cells with melanin
- stratum spinous - spikes of processes linking cell to cell
- stratum granulosum - cells containing deeply staining keratohyalin granules
**4. stratum lucidum - only in ‘thick’ skin
- stratum corneum - surface laters of flat, keratinised cells, stuck together, but no longer having nuclei; water barrier
list 4 cells of the epidermis
- keratinocytes - continuous migration from basal to corneum
- melanocytes - cell bodies in basal layer; processes extending into spinous layer. secrete melanin
- Langerhan’s cells - dendritic cells scattered in the epidermis; part of the macrophage system. protection, but also involved in delayed hypersensitivity reactions like contact dermatitis
- Merkel’s cells - sense organ. with afferent n. fibres immediately below, they form Merkel’s Capsules, a mechanoreceptor
the dermis is CT with n. endings, blood vessels and epidermal appendages. what are the 2 main layers of the dermis?
- papillary layer
2. reticular layer (deep). Langer’s lines are in this layer
list the sense organs of the skin
- free nerve endings - fine touch, temp, pain
- merkels cells - steady pressure
- pacinian corpuscle - pressure and vibration
- Krause end bulbs - touch and pressure
- meissners corpuscle - light touch i.e lips, palms, soles
- Ruffini corpuscle - skin stretch and torque, sustained pressure
list epidermal appendages and their function
- hair follicles and hair - thermoregulation
- sweat glands (eccrine and apocrine) - thermoregulation and pheromones
- sebaceous glands - sebum protection
- nails
- reservoir of epidermal cells for skin repair
classify burn depth
1st degree, superficial - epidermis (painful)
2nd degree, superficial partial thickness - papillary layer (very painful)
2nd degree, deep partial thickness - reticular later (pressure and discomfort)
3rd degree, full thickness - through entires dermis (painless)
4th degree, through entire skin and underlying tissue, fat, muscle and bone (painless): amputation
*depth affects the healing. 1st and superficial 2nd can re-epithelialize. deep 2nd is borderline. 3rd and 4th require skin graft
what causes hairs to stand up
erector pili muscle. it is smooth muscle, stimulated by SNS
- contraction also aids sebaceous gland secretion - their ducts open into infundibulum of the follicle
- sebum is a holocrine secretion. protects the hair and augments the water barrier of the stratum corneum
list 3 normal skin microbiota
- staphylococcus epidermidis and aureus (Gram +ve)
- streptococcus pyrogens (G+ve)
- propionibacterium acnes (G+ve)
provide an example of infections that occur at different sites/layer of skin
keratinised epithelium -> ringworm
epidermis -> impetigo
hair follicles -> folliculitis
dermis -> erysipelas (superficial cellulitis)
subcutaneous layers -> cellulitis
multi-layer -> necrotising fasciitis
muscle -> gangrene
how can bacteria, virus’ and fungi cause infection?
skin - pores, hair follicles
wounds - scratches, cuts, burns
bites - insects, animals
