18 - Melanoma

Question 1

Melanoma

Answer 1

• A malignant tumour derived from melanocytes
• 3rd most commonly diagnosed cancer in aus

Question 2

Melanocytes

Answer 2

Cells responsible for melanin production

Question 3

Melanoma risk factors

Answer 3

• Fair complexion
• UV radiation
• Large numbers of naevi
• Family history
• Previous melanoma
• Immunosuppression
• Exposure to harmful chemicals

Question 4

Clinical features of benign naevus

Answer 4

• Small
• Well circumscribed
• Even colourisation

Question 5

Histological features of benign naevus

Answer 5

• Symmetrical
• Cells predominantly in nests
• Round to oval, even nuclei
• “maturation” as the cells get deeper

Question 6

Spitz naevus

Answer 6

• Occurs in children and young adults
• Can be histologically mistaken for melanoma

Question 7

Blue naevus

Answer 7

Appears darker as pigmented cells are in the dermis

Question 8

Dysplastic naevus

Answer 8

• Larger than benign (>6mm))
• Irregular borders
• Variable colouration
• Some patients develop large numbers of dysplastic naevi (dysplastic naevus syndrome)

Question 9

Dysplastic naevus syndrome

Answer 9

Increased risk of developing melanoma, especially if there is also a family history

Question 10

Histological features of dysplastic naevus

Answer 10

• Broader and less symmetrical
• More single cell growth
• Some larger, darker nuclei
• Fibrosis in the upper dermis

Question 11

Melanoma diagnosis

Answer 11

• Asymmetrical
• Border irregularity
• Colour variability
• Diameter (>6mm)
• Evolving

Question 12

Microscopic features of melanoma

Answer 12

• Asymmetrical
• Poorly circumscribed
• Single cells predominate over nests
• Very disorganised growth
• Extension into the upper levels of the epidermis
• Cytological atypia

Question 13

Extension into the upper levels of the epidermis

Answer 13

Pagetoid spread or “buckshot” scatter

Question 14

Cytological atypia

Answer 14

• Nuclear enlargement, hyperchromasia, irregularity
• Prominent nucleoli
• Mitotic figures

Question 15

Radial growth phase

Answer 15

• 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

Question 16

Vertical growth phase

Answer 16

• Invasive melanoma within the dermis which is expansile
• Larger than the epidermal nests
• Mitotic figures
• Implies a capacity for
  metastatic spread

Question 17

Prognostic indicators of melanoma

Answer 17

• Breslow thickness
• Clark level of invasion
• Ulceration
• Mitotic rate
• Lymphovascular or perineural invasion
• Satellite lesions

Question 18

Important mutations in melanoma

Answer 18

• Mutations that activate pro growth signalling pathways
• Mutations that disrupt cell cycle control genes
• Mutations that activate telomerase

Question 19

Mutations that activate pro growth signalling pathways

Answer 19

• BRAF
• NRAS
• KIT

Question 20

Mutations that disrupts cell control genes

Answer 20

CDKN2A

Question 21

Mutations that activate telomerase

Answer 21

TERT promoter mutations

Question 22

BRAF

Answer 22

• 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

Question 23

BRAF mutations in naevi

Answer 23

• 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)

Question 24

MAPK

Answer 24

The mitogen-activated protein kinase signaling cascade

Question 25

Why do we test for BRAF mutations if not sufficient for melanoma

Answer 25

- 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

Question 26

Examples of BRAF inhibiting drugs

Answer 26

- Vemurafenib - Dacarbazine

Question 27

RAS mutations in melanoma

Answer 27

- NRAS mutations found in 15% in melanomas - HRAS and KRAS mutations are rare - KRAS more common in other cancers

Question 28

KIT mutations and melanoma

Answer 28

- 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

Question 29

CDKN2A

Answer 29

- Located on chromosome 9p21 - Encodes 2 genes - Mutated in up to 40% of familial cases

Question 30

2 genes encoded for by CDKN2A

Answer 30

- p16^INK4a - p14^ARF

Question 31

p16^INK4a

Answer 31

Inhibits CDK4 and CDK6, reinforcing the ability of RB to block cells in the G1 phase of the cell cycle

Question 33

p14^ARF

Answer 33

Enhances the activity of p53 by inhibiting MDM2, which normally stimulates p53 degradation

Question 34

TERT promotor mutations

Answer 34

- 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)

Question 35

Telomerase

Answer 35

Enzyme which preserves telomeres and thus protects cells from senescence

Question 36

Hallmarks of cancer displayed by melanomas

Answer 36

- Sustaining proliferative signalling - Evading growth suppressors - Enabling replicative immortality