Melanomas

Question 1

what is the definition of a melanoma?

Answer 1

a malignant tumor of melanocyctes

Question 2

where are the potential sites of a melanoma?

Answer 2

• skin; cutaneous (common)
• eye; ocular melaona (rare)
• melanoma of mucous membranes (rare)

Question 3

lifetime risk of melanoma in the UK

Answer 3

• females 1 in 47
• males 1 in 36

Question 4

what does the melanocyte do?

Answer 4

in epidermis
- transfer of melanosomes, mainly to basal keratinocytes

Question 5

types of melanomas and moles

Answer 5

1. benign naevus; harmless mole
2. dyplastic naevus; atypical mole
3. radial growth phase (RGP); melanoma
4. vertical growth face (VGP); capable of metastasis

Question 6

what makes a mole atypical?

Answer 6

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

Question 7

what are the two layers of the dermis?

Answer 7

• 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.

Question 8

RGP characteristics

Answer 8

• thin ‘early’
• in epidermis and papillary dermis only
• typically no lymphatic spread

Question 9

VGP characteristics

Answer 9

• thick ‘advanced’
• cell proliferating in reticular dermis
• typically lymphatic spread

Question 10

what is clark level?

Answer 10

staging system that describes the depth of melanoma as it grows in the skin

Question 11

breslow thickness

Answer 11

• height from granular layer of epidermis to base of melanoma
• easier in practice than the clark system
• strong association with prognosis

Question 12

melaonma; rapid progression

Answer 12

• early detection is important
• a melanoma of >1mm thick may have already spread and potentially fatal

Question 13

what is epidemiology?

Answer 13

study of the distribution, patterns and correlates of disease conditions in defined populations

Question 14

whatis aetiology?

Answer 14

study of the causes and mechanisms of disease
- epidemiology provides evidence about aetiology

Question 15

what is unusual about melanoma cases?

Answer 15

longstanding rise in incidence

Question 16

sun-related risk factors

Answer 16

• fitzpatrick skin type (never tans) vs

Question 17

what skin type has the heighest risk of melanoma?

Answer 17

• FItzpatrick skin type (never tans)

Question 18

what is the association between sunlight/ UV and melanoma?

Answer 18

• 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

Question 19

three wavebands of solar UV

Answer 19

UVA= longest wavelength
UVB
UVC
ozone blocks all UVC, some UVB and UVA

Question 20

why is there increasing incidences of melanomas?

Answer 20

• ozone changes
• changes in behaviour; more sunbanthing and sunny holidays

Question 21

which waveband is more worrying?

Answer 21

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

Question 22

experimental data on UVA and UVB

Answer 22

• 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.

Question 23

why is sunscreen important?

Answer 23

• definitely protects against non-melanoma skin cancer but evidence is weaker for melanomas

Question 24

what is the MC1R gene variant?

Answer 24

present in those with red or fair hair
- encodes the melanocortin 1-receptor (MSH receptor).
- required in suntanning
- variants are proven risk factors

Question 24

how do benign naevi (moles) happen?

Answer 24

- partly genetic and partly reflecting UV exposure

Question 25

dyplastic moles and melanoma

Answer 25

major risk factor for melanoma - dyplastic naevi and family history of melanoma = 100-400x relative risk

Question 26

what is FAMMM syndrome?

Answer 26

familial atypical moles and malignant melanoma. - melanoma susceptibility genes - most often CDKN2A gene mutation - biggest known risk factor

Question 27

what does CDKN2A encode for?

Answer 27

encodes the senescence effector p16

Question 28

TSGs involved in sporadic human cutaneous melanomas

Answer 28

- CDKN2A (p16, ARF) - APAF1 - CDKN28 (p15) - PTE - APC - TP53 (p53) types of changes; deletion, methylation, mutation

Question 29

oncogenes involved in sporadic human cutaneous melanomas

Answer 29

- TERT - BRAF - TBX2 - MYC - PTPRD - NRAS - PREX2 types of changes; amplification, activating mutations, promoting overexpression

Question 30

what is p16?

Answer 30

aka; INK4A. CDKN2A, MTS1 - product of the most common mutated gene in familial melanoma ; CDKN2A - most commonly defective/ silenced in sporadic melanoma

Question 31

what does p16 do?

Answer 31

cause cell senescence

Question 32

moles contain senescent melanocytes

Answer 32

- p16 - b-galactosidase

Question 33

what are some other senescence markers?

Answer 33

- DNA damage markers - histone H2AFY - PML - H3K9Me - large nucleoli, multinucleacy

Question 34

how do melanomas escape cell senescence?

Answer 34

- lack of p16 - reactivation of TERT expression (catalytic subunit of telomerase)

Question 35

ABCDE checklist for suspected melanoma

Answer 35

- Asymmetry - Border; is irregular - Colour; areas of varying colour - Diameter; >6mm - Expansion

Question 36

Primary melanoma (stage 0-2)

Answer 36

- 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

Question 37

Local/lymph node metstasis (Stage 3)

Answer 37

- surgery (/laser ablation) where possible - further investigation for distant metastasis (x-ray, liver scan)

Question 38

metastatic melanoma (stage 6)

Answer 38

- no adjuvant therapies of proven benefit - palliative treatment only - dacarbazine (UK) - interferon a2b (USA)

Question 39

Ipilimumab

Answer 39

antibody to CTLA4 (cytotoxic T-lymphocyte associated antigen 4). - CTLA4 involved in tolerance where immune response to the cancer fails

Question 40

Vemurafenib

Answer 40

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

Question 41

Dabrafenib and Trametinib

Answer 41

BRAF inhibitor + MEK inhibtor - MEK is downstream of BRAF in signalling pathway. - helps delay the appearance of resistance

Question 43

Nivolumab

Answer 43

antibody to PD-1 (programmed death-1) - PD-1 expressed on lymphocytes and involved in tolerance to cancers

Question 45

Prospects of treatment

Answer 45

- many trials in progress - molecular understanding of cancer biology and genetics. - cost still a problem