Melanomas Flashcards
what is the definition of a melanoma?
a malignant tumor of melanocyctes
where are the potential sites of a melanoma?
- skin; cutaneous (common)
- eye; ocular melaona (rare)
- melanoma of mucous membranes (rare)
lifetime risk of melanoma in the UK
- females 1 in 47
- males 1 in 36
what does the melanocyte do?
in epidermis
- transfer of melanosomes, mainly to basal keratinocytes
types of melanomas and moles
- benign naevus; harmless mole
- dyplastic naevus; atypical mole
- radial growth phase (RGP); melanoma
- vertical growth face (VGP); capable of metastasis
what makes a mole atypical?
3 or more of these features
- size >5mm diameter
- ill defined or blurred borders
- irregular margin/unusual shape
- varying shades of colour
- flat and bumpy components
what are the two layers of the dermis?
- papillary dermis; dermal papillae and below, fine collagen fibres, very few cells (fibroblasts, blood vessels)
- reticular dermis; coarse collagen fibres
- in healthy dermis; no clusers of cells, just single fibroblasts, leucocytes and blood vessels.
RGP characteristics
- thin ‘early’
- in epidermis and papillary dermis only
- typically no lymphatic spread
VGP characteristics
- thick ‘advanced’
- cell proliferating in reticular dermis
- typically lymphatic spread
what is clark level?
staging system that describes the depth of melanoma as it grows in the skin
breslow thickness
- height from granular layer of epidermis to base of melanoma
- easier in practice than the clark system
- strong association with prognosis
melaonma; rapid progression
- early detection is important
- a melanoma of >1mm thick may have already spread and potentially fatal
what is epidemiology?
study of the distribution, patterns and correlates of disease conditions in defined populations
whatis aetiology?
study of the causes and mechanisms of disease
- epidemiology provides evidence about aetiology
what is unusual about melanoma cases?
longstanding rise in incidence
sun-related risk factors
- fitzpatrick skin type (never tans) vs
what skin type has the heighest risk of melanoma?
- FItzpatrick skin type (never tans)
what is the association between sunlight/ UV and melanoma?
- skin type
- sun exposure habits
- melanomas are rare in areas rarely or never exposed to sunlight
AETIOLOGY: the main carcinogen appears to be UV radiation
three wavebands of solar UV
UVA= longest wavelength
UVB
UVC
ozone blocks all UVC, some UVB and UVA
why is there increasing incidences of melanomas?
- ozone changes
- changes in behaviour; more sunbanthing and sunny holidays
which waveband is more worrying?
both UVB and UVA;
- epidermis absorbs more UVB than UVA. UVB is more carcinogenic per photon but nearly all UV that reaches melanocytes is UVA
experimental data on UVA and UVB
- UVA can induce DNA damage as well as UVB
- DNA damage can kill cells (large amounts), induce cell senescence (medium) or be repaired (small).
- UVA can interact with melanin to relase ROS especially with pheomelanin. ROS can cause DNA damage.
why is sunscreen important?
- definitely protects against non-melanoma skin cancer but evidence is weaker for melanomas
what is the MC1R gene variant?
present in those with red or fair hair
- encodes the melanocortin 1-receptor (MSH receptor).
- required in suntanning
- variants are proven risk factors
how do benign naevi (moles) happen?
- partly genetic and partly reflecting UV exposure
dyplastic moles and melanoma
major risk factor for melanoma
- dyplastic naevi and family history of melanoma = 100-400x relative risk
what is FAMMM syndrome?
familial atypical moles and malignant melanoma.
- melanoma susceptibility genes
- most often CDKN2A gene mutation
- biggest known risk factor
what does CDKN2A encode for?
encodes the senescence effector p16
TSGs involved in sporadic human cutaneous melanomas
- CDKN2A (p16, ARF)
- APAF1
- CDKN28 (p15)
- PTE
- APC
- TP53 (p53)
types of changes; deletion, methylation, mutation
oncogenes involved in sporadic human cutaneous melanomas
- TERT
- BRAF
- TBX2
- MYC
- PTPRD
- NRAS
- PREX2
types of changes; amplification, activating mutations, promoting overexpression
what is p16?
aka; INK4A. CDKN2A, MTS1
- product of the most common mutated gene in familial melanoma ; CDKN2A
- most commonly defective/ silenced in sporadic melanoma
what does p16 do?
cause cell senescence
moles contain senescent melanocytes
- p16
- b-galactosidase
what are some other senescence markers?
- DNA damage markers
- histone H2AFY
- PML
- H3K9Me
- large nucleoli, multinucleacy
how do melanomas escape cell senescence?
- lack of p16
- reactivation of TERT expression (catalytic subunit of telomerase)
ABCDE checklist for suspected melanoma
- Asymmetry
- Border; is irregular
- Colour; areas of varying colour
- Diameter; >6mm
- Expansion
Primary melanoma (stage 0-2)
- surgical excision with wide margins and sometimes lymph nodes
- if invasive; further investigation
- sentinel (specific draining) lymph node biopsy used increasingle. If found to contain melanoma cells, remove lovcal nodes.
- cure frequent for thin lesions
Local/lymph node metstasis (Stage 3)
- surgery (/laser ablation) where possible
- further investigation for distant metastasis (x-ray, liver scan)
metastatic melanoma (stage 6)
- no adjuvant therapies of proven benefit
- palliative treatment only
- dacarbazine (UK)
- interferon a2b (USA)
Ipilimumab
antibody to CTLA4 (cytotoxic T-lymphocyte associated antigen 4).
- CTLA4 involved in tolerance where immune response to the cancer fails
Vemurafenib
inhibits oncogene BRAF(V600E) = VE mutant RAF inhibitor.
- oncogenic BRAF mutation found in 50% melanomas
- only useful for patients with oncogenic BRAF mutation
- 99% relapse
Dabrafenib and Trametinib
BRAF inhibitor + MEK inhibtor
- MEK is downstream of BRAF in signalling pathway.
- helps delay the appearance of resistance
Nivolumab
antibody to PD-1 (programmed death-1)
- PD-1 expressed on lymphocytes and involved in tolerance to cancers
Prospects of treatment
- many trials in progress
- molecular understanding of cancer biology and genetics.
- cost still a problem
