clinical oncology 3: skin cancer Flashcards
epidemiology of skin cancer:
- commonest cancer to affect man
- incidence is rising
- main aetiological agent is sunlight
what are the important factors for development of skin cancer?
- sunlight
- ionising radiation
- viruses
- tissue scarring
what are the most common types of skin cancer?
- basal cell carcinoma (most common, least deadly)
- squamous cell carcinoma
- melanoma (least common, most deadly)
what is basal cell carcinoma?
tumours arise from pluripotent stem cells in epidermis
- almost always found on sun-exposed body parts
- locally destructive but rarely metastatic
what is squamous cell carcinoma?
tumours arise from basal keratinocytes
- usually tumours of elderly on sun-exposed areas
- often metastatic -> spread to lymph nodes + other organs, particularly lungs
- can arise from other lesions eg solar keratoses
what is melanoma?
tumours arise from epidermal melanocytes (or sometimes dermal)
- tumour of young age
- associated with intermittent, intense sun exposure
- unusually found in sun-exposed areas
- associated with systemic immunosuppression
- highly metastatic
what are the risk factors for melanoma?
- family history
- presence of dysplastic naevae (abnormal moles) or >50 naevae
- childhood radiotherapy
- higher socioeconomic background (sunny holidays)
- occupational hazards eg ionising radiation of airline pilots
- frequent tanning beds
- other cancer
- transplants
- certain melanocortin-1 receptor variant alleles
what are the 4 clinical subtypes of melanoma?
superficial spreading: horizontal growth phase through epidermis followed by vertical invasion
nodular: more aggressive, no horizontal growth phase
lentigo maligna: from precusor lesion of same name
acrolentigenous: start on feet/hands, tent to be due to trauma not sun exposure
what are the 4 types of precursor lesion for melanoma?
- junctional / compound-acquired melanocytic naevae
- dysplastic naevae
- dermal naevae
- ginat bathin trunk naevae
what are the types of UV light and how do they contribute to skin cancer?
UVA: main cause of skin agein
UVB: can’t penetrate glass -> more important than UVA
UVC: very little penetrates atmosphere so is less relevant even tho is strongest
what interactions happen between UVB & DNA?
DNA acts as a chromophore for UVB -> photoproducts eg cyclobutane butane pyrimidine dimers + thymine dimers
- thymine dimers can be repaired via base excision but if damage is irreparable cell apoptoses -> sunburn (mediated by Bax protein)
how does UVA damage DNA?
mainly causes indirect DNA damage by formation of xinglet oxygens + free radicals
what are Langerhans cells?
specialised dendritic cells that have migrated to superbasilar layer of skin
- recognise tumour-associated antigens on skin -> present to T cells -> mutatnts killed before cancer develops
how does Langerhans cell function change with UV exposure?
function decreases proportionally
what is the Fitzpatrick classification of skin types?
I: always burns, never tans II: usually burns, sometimes tans III: sometimes burns, usually tans IV: never burns, always tans V: moderate constitutive pigmentation VI: marked constitutive pigmentation
what does melanin do?
responsible for skin pigmentation
- acts as crhomophore for UV light -> absorbs UV -> provides protection for more sensitive layers of skin underneath
- also traps electrons & free radicals
how is melanin produced?
from tyrosine via DOPA
what are the types of melanin?
eumelanin: black/brown, insoluble, useful
phaeomelanin: yellowish-reddish brown, soluble in alkalis, useless
neuromelanin: present only in the substantia nigra of brain, function unknown
- number of melanocytes relatively constant in everyone so colour is determined by amount & type of melanin
what are melanocortins?
group of peptides derived from pro-opiomelanocortin (POMC) MSH (melanocyte stimulating hormone)
- ACTH
- endorphins
- liptrophins
what does MCIR do?
highly polymorphic melanocortin-1 receptor
- regulates skin & hair pigmentation phenotype
- promotes a switch from phaeomelanin to eumelanin production -> therefore alleles which don’t work as well are associated with ginger hair and hence skin cancer
what are the 2 ways in which tanning occurs?
immediate: UVA -> alteration & redistribution of melanin -> making you look tanned but affording you no extra protection eg tanning booth, first day at beach
delayed: UVB increases production of melanin but effects depend on MCIR variant
what is another effect of sun exposure?
epidermal thickening
what is an epidermal melanin unit?
each melanocyte is associated with 36 keratinocytes
- melanocytes pass melanosomes via dendrites to keratinocytes -> phagocytose melanosome
what is Gorlin’s syndrome?
development of hundreds of basal cell carcinomas on face and trunk age 10-20
- autosomal dominant
- casued by mutation of both alleles of Patched gene -> loss of suppression of Smoothened gene -> production of transcription factor that casues cell proliferation
- Patched & Smoothed gene part of sonic hedgehog pathway
what is Xeroderma pigmentosum?
defective base excision repair mechanisms -> very early solar ageing & get BCCs, SCCs & melanomas before age 10
- autosomal/sex-linked recessive
- usually death age 10-30
what is epidermodysplasia verruciformis?
mild immunodeficiency -> skin gets infected by opportunistic HPV -> thousands of warts beofre age 10 -> develop into SCCs on UV exposure
- autosomal recessive
- HPV’s E6 protein disrupts DNA repair following UV exposure and inactivates p53
what is FAMM syndrome?
famial atypical mole/melanoma syndrome - patients have multiple dysplastic naevae -> multiple melanomas
- 40-50% have CDKN2A mutation -> less p16 (a cyclin-dependent kinase inhibitor) produced -> cell proliferation
which type of skin cancer are transplant patients more likely to get and why?
10x more likely to get SCC than BCC due to EV-causing HPV strains
60% of melanomas have a ____ mutation
BRAF mutation
- BRAF is part of Raf family of protein kinases in MAPK pathway downstream of Ras
- mutation resulst in constitutive activation of BRAF without need for Ras stimulation -> cell proliferation
- 90% of mutations are replacement of valine by glutamate at position 600 (BRAF V600E mutation)
what is vemurafenib?
small molecule inhibitor selective for BRAV V600E mutants
- taken orally
- reversible
- ATP-competitive
how can immunotherapy be used to treat melanoma?
CTLA-4 receptor on T cells is negative regulator, important in self-tolerance to prevent autoimmunity
- ipilimumab (IgG mAb to CTLA-4 receptor) removes inhibition -> T cells react better
how can skin cancer be prevented?
- sun-block
- sun-protective clothing
- increasing public awareness of UV exposure dangers -> protective behaviour
- increasing public awareness of skin cancer identification -> early diagnosis
what does SPF mean?
sun protection factor = time needed in sun with sun-block before skin redness develops after 24h / time needed in sun without sun-block before skin redness develops 24h later
