Melanoma: Mechanisms, Management, Research Flashcards
Melanomas vs moles, clark scale (4 classes)
- benign naevus (mole, harmless)
- dysplastic naevus (atypical mole) 3 of these features : ill-defined or blurred borders, irregular margin/unusual shape, varying shades of colour, flat and bumpy components
- radial growth phase (RGP, thin) melanoma
- vertical growth phase (VGP, thicker) capable of metastasis
What are the 2 layers of the dermis?
- papillary dermis - dermal papillae and just below. fine collagen fibres, very few cells (fibroblasts, blood vessels)
- reticular dermis - coarse collagen fibres
Define RGP and VGP
- RGP (thin, early) - in epidermis and papillary dermis only. Typically no lymphatic spread
- VGP (thick, advanced) - cells proliferating in reticular dermis. Typically lymphatic spread
What is the Breslow thickness?
= height from granular layer of epidermis to base of melanoma
- easier in practice then clark system
- strong association with prognosis
What is epidemiology?
- study of the distribution, patterns and correlates of disease conditions in defined populations.
Skin colour related to melanoma risk factor
- fitzpatrick skin type 1 (never tans) relative melanoma risk = x2
- red/fair vs dark hair (europeans) relative melanoma risk = x3
- ever had severe sunburn (blistering) relative melanoma risk = x3
What are the established associations between sunlight/UV and melanoma
- skin type is important - incidence higher in white-skinned races
- incidence varies with latitude. For a given skin type, the nearer the equator one lives, the higher the incidence
- sun exposure habits affect risk. Sunburn, esp in children, is a risk factor
- melanomas rare on body areas rarely/never exposed to sunlight (scalp, bikini area)
main carcinogen = UV radiation
What are the 3 wavebands of UV?
- UVA = longest - passes through epidermis. some damage to dermis, some DNA effects
- UVB - harmful to DNA but most absorbed by atmosphere and epidermis
- UVC = shortest - harmful, but absorbed by ozone
- ozone blocks some UVA and UVB
Why is there an increasing incidence of melanoma?
- evidence links melanoma with sun exposure
- ozone changes? - not whole explanation - earlier rises in skin cancer incidence preceded falls in ozone. But now likely to be contributing
- changes in behaviour - more sunbathing, sunny holidays, correlation as already mentioned, also incidence rise levelled off following sun safety campaigns
What are the risks of UVA and UVB?
- UVA and UVB can induce DNA damage (breaks, adducts, intrastrand crosslinks) in cultured human cells. DNA damage increases chances of mutations and cancer
- induction of melanoma in susceptible mice by UV. only UVB in white mice, but UVA can induce melanoma in pigmented mice
- UVA can interact with melanin to release reactive oxygen species especially with phenomelanin. ROS can cause DNA damage
- UVA may also cause human melanoma, indicating by this more indirect rout of generating ROS from melanin
UV sunscreen
- sunscreen has been shown definitely to protect against non-melanoma skin cancer
- at present it it strongly advised for those with pale skin, when in the sun, to use a sunscreen with good UVB protection and good UVA protection
- those at highest risk should use shade, hats and t-shirts
- need to get some vitamin D
Which genes are involved in determining pigement?
- MC1R variants (give red or fair hair, pale skin) melanocortin-1 receptor also called MSH receptor. required in suntanning, variants are proven risk factors
- several other skin/hair colour genes show smaller effects on risk eg variants of TYR = tyrosinase, key enzyme in pigment synthesis
Dyplastic moles and melanoma
- major risk factor for melanoma is dysplastic naevi and family history of melanoma
- FAMMM (familial atypical moles and malignant melanoma) biggest known risk factor, 100-400x
How does p16 play a role?
- product of the commonest known mutated gene in familial melanoma, CDKN2A
- and one of the most commonly defective/silences gene in sporadic melanoma
What does p16 do?
causes cell senescence
How does senescence stop melanoma developing?
- normal melanocyte - UV causes oncogene activation, usually BRAF = proliferation
- forms benign, static, clonal lesion (proliferation but become senescent and arrests, expresses p16)
- leads to mutations in 1 cell that inactivates normal senescence - p16 pathway again amplified
- causes early (RGP) melanoma (mutation in cell reactivating TERT expression)
- through more mutations = repress apoptosis
= results in advances metastatic melanoma (immortal)
What is the ABCDE checklist for suspected melanoma?
a) asymmetry
b) border is irregular
c) colour - areas of varying colour
d) diameter >6mm
e) expansion - key feature in adults
What is the management for melanoma?
primary melanoma (stage 0-II) - surgical excision with wide margins and sometimes lymph nodes
- if invasive = further investigation
- sentinel (specific draining) lymph node biopsy used increasingly. if found to contain melanoma cells, remove local nodes
local/lymph node metastasis (stage III)
- surgery (laser/ablation) where possible
- further investigation for distant metastasis
What is the management for stage IV melanoma?
- no systemic therapy has yet been shown to prolong significantly the survival of patients with metastatic melanoma
- palliative treatment only - surgery where possible
- dacarbazine - only standard adjuvant treatment
What are the new advances for stage V melanoma?
- targeted therapies
- antibody to CTLA4 = ipilimumab
- CTLA4 involved in tolerance, where immune response to the cancer falls
- vemurafenib - inhibits oncogenic BRAF
- useful only for patients with oncogenic BRAF
- 99% eventual relapse
- dabrafenib and trametinib - another BRAF inhibitor and MEK inhibitor - MEK is downstream of BRAF signalling pathway = approach seems to delay the appearance of resistance
- many trials in progress - molecular understanding of cancer biology and genetics is informing and improving
- next hurdle is cost
