Melanoma: Mechanisms, Management, Research

Question 1

Melanomas vs moles, clark scale (4 classes)

Answer 1

1. benign naevus (mole, harmless)
2. dysplastic naevus (atypical mole) 3 of these features : ill-defined or blurred borders, irregular margin/unusual shape, varying shades of colour, flat and bumpy components
3. radial growth phase (RGP, thin) melanoma
4. vertical growth phase (VGP, thicker) capable of metastasis

Question 2

What are the 2 layers of the dermis?

Answer 2

• papillary dermis - dermal papillae and just below. fine collagen fibres, very few cells (fibroblasts, blood vessels)
• reticular dermis - coarse collagen fibres

Question 3

Define RGP and VGP

Answer 3

• RGP (thin, early) - in epidermis and papillary dermis only. Typically no lymphatic spread
• VGP (thick, advanced) - cells proliferating in reticular dermis. Typically lymphatic spread

Question 4

What is the Breslow thickness?

Answer 4

= height from granular layer of epidermis to base of melanoma

• easier in practice then clark system
• strong association with prognosis

Question 5

What is epidemiology?

Answer 5

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

Question 6

Skin colour related to melanoma risk factor

Answer 6

• fitzpatrick skin type 1 (never tans) relative melanoma risk = x2
• red/fair vs dark hair (europeans) relative melanoma risk = x3
• ever had severe sunburn (blistering) relative melanoma risk = x3

Question 7

What are the established associations between sunlight/UV and melanoma

Answer 7

1. skin type is important - incidence higher in white-skinned races
2. incidence varies with latitude. For a given skin type, the nearer the equator one lives, the higher the incidence
3. sun exposure habits affect risk. Sunburn, esp in children, is a risk factor
4. melanomas rare on body areas rarely/never exposed to sunlight (scalp, bikini area)
   main carcinogen = UV radiation

Question 8

What are the 3 wavebands of UV?

Answer 8

• UVA = longest - passes through epidermis. some damage to dermis, some DNA effects
• UVB - harmful to DNA but most absorbed by atmosphere and epidermis
• UVC = shortest - harmful, but absorbed by ozone
• ozone blocks some UVA and UVB

Question 9

Why is there an increasing incidence of melanoma?

Answer 9

• evidence links melanoma with sun exposure
• ozone changes? - not whole explanation - earlier rises in skin cancer incidence preceded falls in ozone. But now likely to be contributing
• changes in behaviour - more sunbathing, sunny holidays, correlation as already mentioned, also incidence rise levelled off following sun safety campaigns

Question 10

What are the risks of UVA and UVB?

Answer 10

• UVA and UVB can induce DNA damage (breaks, adducts, intrastrand crosslinks) in cultured human cells. DNA damage increases chances of mutations and cancer
• induction of melanoma in susceptible mice by UV. only UVB in white mice, but UVA can induce melanoma in pigmented mice
• UVA can interact with melanin to release reactive oxygen species especially with phenomelanin. ROS can cause DNA damage
• UVA may also cause human melanoma, indicating by this more indirect rout of generating ROS from melanin

Question 11

UV sunscreen

Answer 11

• sunscreen has been shown definitely to protect against non-melanoma skin cancer
• at present it it strongly advised for those with pale skin, when in the sun, to use a sunscreen with good UVB protection and good UVA protection
• those at highest risk should use shade, hats and t-shirts
• need to get some vitamin D

Question 12

Which genes are involved in determining pigement?

Answer 12

• MC1R variants (give red or fair hair, pale skin) melanocortin-1 receptor also called MSH receptor. required in suntanning, variants are proven risk factors
• several other skin/hair colour genes show smaller effects on risk eg variants of TYR = tyrosinase, key enzyme in pigment synthesis

Question 13

Dyplastic moles and melanoma

Answer 13

• major risk factor for melanoma is dysplastic naevi and family history of melanoma
• FAMMM (familial atypical moles and malignant melanoma) biggest known risk factor, 100-400x

Question 14

How does p16 play a role?

Answer 14

• product of the commonest known mutated gene in familial melanoma, CDKN2A
• and one of the most commonly defective/silences gene in sporadic melanoma

Question 15

What does p16 do?

Answer 15

causes cell senescence

Question 16

How does senescence stop melanoma developing?

Answer 16

• normal melanocyte - UV causes oncogene activation, usually BRAF = proliferation
• forms benign, static, clonal lesion (proliferation but become senescent and arrests, expresses p16)
• leads to mutations in 1 cell that inactivates normal senescence - p16 pathway again amplified
• causes early (RGP) melanoma (mutation in cell reactivating TERT expression)
• through more mutations = repress apoptosis
  = results in advances metastatic melanoma (immortal)

Question 17

What is the ABCDE checklist for suspected melanoma?

Answer 17

a) asymmetry
b) border is irregular
c) colour - areas of varying colour
d) diameter >6mm
e) expansion - key feature in adults

Question 18

What is the management for melanoma?

Answer 18

primary melanoma (stage 0-II) - surgical excision with wide margins and sometimes lymph nodes
- if invasive = further investigation
- sentinel (specific draining) lymph node biopsy used increasingly. if found to contain melanoma cells, remove local nodes
local/lymph node metastasis (stage III)
- surgery (laser/ablation) where possible
- further investigation for distant metastasis

Question 19

What is the management for stage IV melanoma?

Answer 19

• no systemic therapy has yet been shown to prolong significantly the survival of patients with metastatic melanoma
• palliative treatment only - surgery where possible
• dacarbazine - only standard adjuvant treatment

Question 20

What are the new advances for stage V melanoma?

Answer 20

• targeted therapies
• antibody to CTLA4 = ipilimumab
• CTLA4 involved in tolerance, where immune response to the cancer falls
• vemurafenib - inhibits oncogenic BRAF
• useful only for patients with oncogenic BRAF
• 99% eventual relapse
• dabrafenib and trametinib - another BRAF inhibitor and MEK inhibitor - MEK is downstream of BRAF signalling pathway = approach seems to delay the appearance of resistance
• many trials in progress - molecular understanding of cancer biology and genetics is informing and improving
• next hurdle is cost