18 - Melanoma Flashcards
Melanoma
- A malignant tumour derived from melanocytes
- 3rd most commonly diagnosed cancer in aus
Melanocytes
Cells responsible for melanin production
Melanoma risk factors
- Fair complexion
- UV radiation
- Large numbers of naevi
- Family history
- Previous melanoma
- Immunosuppression
- Exposure to harmful chemicals
Clinical features of benign naevus
- Small
- Well circumscribed
- Even colourisation
Histological features of benign naevus
- Symmetrical
- Cells predominantly in nests
- Round to oval, even nuclei
- “maturation” as the cells get deeper
Spitz naevus
- Occurs in children and young adults
- Can be histologically mistaken for melanoma
Blue naevus
Appears darker as pigmented cells are in the dermis
Dysplastic naevus
- Larger than benign (>6mm))
- Irregular borders
- Variable colouration
- Some patients develop large numbers of dysplastic naevi (dysplastic naevus syndrome)
Dysplastic naevus syndrome
Increased risk of developing melanoma, especially if there is also a family history
Histological features of dysplastic naevus
- Broader and less symmetrical
- More single cell growth
- Some larger, darker nuclei
- Fibrosis in the upper dermis
Melanoma diagnosis
- Asymmetrical
- Border irregularity
- Colour variability
- Diameter (>6mm)
- Evolving
Microscopic features of melanoma
- Asymmetrical
- Poorly circumscribed
- Single cells predominate over nests
- Very disorganised growth
- Extension into the upper levels of the epidermis
- Cytological atypia
Extension into the upper levels of the epidermis
Pagetoid spread or “buckshot” scatter
Cytological atypia
- Nuclear enlargement, hyperchromasia, irregularity
- Prominent nucleoli
- Mitotic figures
Radial growth phase
- Refers to growth within epidermis (“melanoma in situ”), as well as “microinvasion” into superficial dermis
- The microinvasive component is limited to single cells and small
nests - Lacks metastatic potential
Vertical growth phase
- Invasive melanoma within the dermis which is expansile
- Larger than the epidermal nests
- Mitotic figures
- Implies a capacity for
metastatic spread
Prognostic indicators of melanoma
- Breslow thickness
- Clark level of invasion
- Ulceration
- Mitotic rate
- Lymphovascular or perineural invasion
- Satellite lesions
Important mutations in melanoma
- Mutations that activate pro growth signalling pathways
- Mutations that disrupt cell cycle control genes
- Mutations that activate telomerase
Mutations that activate pro growth signalling pathways
- BRAF
- NRAS
- KIT
Mutations that disrupts cell control genes
CDKN2A
Mutations that activate telomerase
TERT promoter mutations
BRAF
- Serine-threonine kinase
- Mutations found in 66% of melanomas
- Most mutations located in highly conserved kinase domain
- 80% are accounted for by a point mutation leading to V600E substitution
BRAF mutations in naevi
- Common in naevi
- Thus mutation of BRAF and activation of MAPK pathway is important in melanocytic neoplasia
- But not sufficient for development of melanoma (other mutations required)
MAPK
The mitogen-activated protein kinase signaling cascade
Why do we test for BRAF mutations if not sufficient for melanoma
- Driver mutation
- Specific BRAF inhibiting drugs have been developed which are selective for the V600E mutation
- Valuable treatment for metastatic melanoma
- Testing for the presence of the mutation allows for selection of patients which may benefit from the drug
Examples of BRAF inhibiting drugs
- Vemurafenib
- Dacarbazine
RAS mutations in melanoma
- NRAS mutations found in 15% in melanomas
- HRAS and KRAS mutations are rare
- KRAS more common in other cancers
KIT mutations and melanoma
- Cause increased migration of melanocytes
- Found in melanomas arising in skin without hair, nails, mucosa, skin with chronic sun exposure
- BRAF mutations uncommon
- Incidence increases with age
- Lentiginous growth pattern
CDKN2A
- Located on chromosome 9p21
- Encodes 2 genes
- Mutated in up to 40% of familial cases
2 genes encoded for by CDKN2A
- p16^INK4a
- p14^ARF
p16^INK4a
Inhibits CDK4 and CDK6, reinforcing the ability of RB to block cells in the G1 phase of the cell cycle
p14^ARF
Enhances the activity of p53 by inhibiting MDM2, which normally stimulates p53 degradation
TERT promotor mutations
- TERT encodes the catalytic subunit of telomerase
- Mutations in the promoter region of TERT have been identified in approximately 70% of melanomas
- These mutations increase TERT expression, thus acting as an antidote to senescence
- The promoter mutations create new binding sites for Ets family transcription factors (which are upregulated by BRAF signalling)
Telomerase
Enzyme which preserves telomeres and thus protects cells from senescence
Hallmarks of cancer displayed by melanomas
- Sustaining proliferative signalling
- Evading growth suppressors
- Enabling replicative immortality
