Melanoma Flashcards
Aetiology of Melanoma
UV exposure from UVA and UVB
Risk factors of Melanoma
>10 dysplastic naevi >100 common aquired naevi Fair skin Red hair High intermittent sun exposure Age
Prevention of Melanoma
Prevent skin exposure
Screening for skin cancer
Regular skin examination
Melanomas <0.76mm deep have 10yr survival >95%
Diagnosis of skin cancer
Asymmetry Border - uneven Colour - uneven Diameter >6mm Enlargement or evolution
Poor prognostic findings
Breslow depth
Bleeding and ulceration
Nodular melanoma
Melanoma subtypes
Superficial spreading
Lentigo malinga
Acral lentiginous
Nodular
Features of superficial spending melanoma
70% of melanomas
Intermittent sun exposure
Mid 40yrs
Trunk and limb location
Features of lentigo maligna melanoma
10-15% of melanomas
Cumulative sun exposure
Elderly
Face and neck
Long in-situ phase
Acral Lentiginous melanoma
2% of melanomas
Asian and dark skinned people
Palms, soles of feet under nails
Not caused by UV light
Nodular melanoma
10-15% of melanomas
50% of melanoma deaths
Vertical growth from outset - rapid growth
Symmetrical, dome shaped, firm amelanotic nodule
Not associated with high mole counts
Immunohistochem diagnosis of Melanoma
S100
Melan-A
Melanoma Staging
1 = small primary 2 = Large primary 3 = local disease in lymph nodes 4 = distant mets
Ulceration upstages disease
Poor prognostic factors by stage
Stage 1 and 2 = ulceration
Stage 3 = macroscopic disease, >2 lymph nodes, ulceration
Stage 4 = visceral mets except lung and high serum LDH
Staging Melanoma
For stage 3 and 4 Melanoma
MRI brain
CT chest, abdomen and pelvis
PET
Treatment of stage 1 disease
Local wide excision
Treatment of stage 2 disease
Local wide excision
Sentinel lymph node biopsy
MRI brain, CT CAP and PET
Treatment of stage 3 disease
Local wide excision
Total lymph node dissection
Nil other treatment currently recommended
Requires ongoing surveillence imaging
Treatment of stage 4 disease
Excision of primary
Curative if oligometastatic disease - 1-2 sites only
Common mets sites - skin, lung, brain and bone
Late relapses common
Treatment options:
- Chemo
- BRAF
- BRAF + MEK
- cKIT
- CTLA-4 inhibitors
- PD-1 inhibitors
BRAF inhibitors
BRAF = signal in the RAS-RAf pathway
Activating mutation of BRAF at V600
–> excessive cell proliferation and survival
50% of melanomas
Related to intermittent sun exposure
Drugs:
- Vemurafenib
- -> V600E mutation only
- -> No CNS activity
- Dabrafenib
- -> All V600 mutations
- -> CNS activity
Side effects:
- SCCs
- Arthralgias and fatigue
- Rash
- Photosensitivity
BRAF + MEK inhibitors
MEK is the downstream signal from BRAF in the RAS-AF pathway
Dabrafenib + Trametinib
Improves survival over BRAF alone
Reduces side effects of BRAF inhibition alone
cKIT inhibitors
KIT = extracellular part of the RAS-RAF pathway
cKIT mutations –> cell proliferation and survival
Acral melanomas
Drug = Imatinib
CTLA-4 Inhibition
CTLA-4 = a naturally occurring negative regulator of T cell function
Blocks co-stimulatory signalling of CD-28–> inhibits T cell activation and proliferation
Ipilimumab
Monoclonal antibody to CTLA-4 –> blocks CTLA-4 binding –> upregulation of T cell response
Causes psuedo-progression in the first 8 weeks –> regression which is often prolonged
Side effects of Ipilimumab
Rash Colitis Hepatitis Neuropathy Hypopituatarism Hypo and hyperthyroidism Adrenal crisis Pneumonitis
Surrogate for response to treatment
Treatment of ipilimumab side effects
Anti-inflammatory agents
Prednisone
Severe colitis may require prolonged steroids, TNF inhibition or prolonged bowel rest
PD-1 and PD-1 ligand inhibition
PD-1 activation –> down regulation of T cell effector functions
PD-1 ligand is selectivity expressed on many tumours
PD-1 blockade –> T cells maintain antitumour activity –> tumour cell death
Pembrolizumab and nivolumab
Same side effects as ipilimumab but at lower rates
Combination ipilimumab and nivolumab?
Better survival with combination
BUT higher rates of side effects especially higher grade side effects
