Session 5 - Melanoma

Question 1

What are the five hallmarks of cancer?

Answer 1

Self-sufficient growth 
Blood vessel production (angiogenesis)
Resistant to anti-growth 
Grow indefinitely
Invasion and metastases
Reject apoptosis

Question 2

What are melanocytes?

Answer 2

Pigment producing cells that arise embryologically from the neural crest

Question 3

Where are melanocytes most commonly found? (2)

Answer 3

Epidermis and hair follicles

Question 4

Give three not so common sites of melanocytic migration

Answer 4

Unveal tract of the eye
Meninges
Cochlea

Question 5

Does the number of melanocytes differ between people of different skin colour?

Answer 5

No, but the quantity and quality of melanin does.

Question 6

What is melanoma?

Answer 6

A malignant tumour of melanocytes which can occur anywhere that melanocytes are found.

Question 7

What is a benign melanoma called?

Answer 7

A melanocytic naevus (mole)

Question 8

Where do the majority of melanomas arise from?

Answer 8

Non-moled skin

Question 9

How common is melanoma?

Answer 9

6th commonest cancer

Question 10

Why is malignant melanoma so worrisome, despite it’s relative rarity?

Answer 10

Disproportionately more common in younger people. 1/3rd occurs in people under 50.

Question 11

How has incidence of melanoma changed over time?

Answer 11

Quadrupled

Question 12

Why has incidence of melanoma in britain changed over time?

Answer 12

UV exposure

Question 13

Why is melanoma dangerous?

Answer 13

Aggressive, as it has a tendency to metastasise very early during its evolution.

Question 14

How is the metastatic potential of melanoma different from that of standard cancers?

Answer 14

Most tumours typically of the order of centimeters in size and are still often cured.

Question 15

What are three ways in which melanoma can present clinically?

Answer 15

Primary tumour
Regional lymph node disease
Disseminated disease

Question 16

How are primary melanomas treated?

Answer 16

Usually treated by surgical excision with a wide margin of normal skin (this is determined by breslow depth)

Question 17

How is lymph nodal melanoma treated?

Answer 17

Local and regional lymph bode excision.

Question 18

What is sentinel lymph node biopsy?

Answer 18

A biopsy used to determine presence of regional melanoma metastasis before they are clinically palpable, using radioactive particles/coloured dyes injected into melanoma site (spreads to sentinal node).

Question 19

How is disseminated melanoma treated?

Answer 19

Chemotherapy and palliative therapy usually used - biological therapies becoming more important.

Question 20

What does the likelyhood of treatment being effective depend on, and how is this measured?

Answer 20

Breslow depth, measured from thickest part of the tumour on the skin surface down.

Question 21

Give overall staging of melanoma

Answer 21

2mm thick - stage II - 70%
>2mm + local lymph nodes - III - 45%
Distant spread - IV - 10%

Question 22

Give the risk factors for melanoma

Answer 22

MM RISK
M = > 100 moles
 M = > 5 dysplastic moles (moles which are larger than normal with an irregular outline)
 R = red hair/freckles/blue eyes
 I = inability to tan i.e. skin that burns very easily
 S = several episodes of sunburn
 K = kindred, i.e. any family history

Question 23

Which are the strongest risk factors for melanoma?

Answer 23

Ordinary or dysplastic moles are the strongest risk factors, giving a relative risk of 5-10 fold over pop.

Others 2-4 fold.

Question 24

How is family history related to development of melanoma?

Answer 24

If many close family members have developed melanoma AND have dysplastic naevi, risk increase dramatically.

Question 25

Outline the ABCDE criteria for assesing moles

Answer 25

 A = asymmetry
 B = border is irregular
 C = colour is variable (black/brown/red/white)
 D = diameter > 6 mm (approximately the size of the blunt end of a pencil)
- E = Evolving

Question 26

What is the UK seven point check list?

Answer 26

Major features: change in size, shape or colour.

 Minor features: inflammation, bleeding or crusting, sensory change and a lesion of 7 mm or greater.

Question 27

In the UK criteria, what constitutes a danger melanoma?

Answer 27

Any one major feature or two minor features would merit consideration for excision.

Question 28

How can a melanocyte achieve self-sufficiency in growth signalling?

Answer 28

Mutation of the NRAS/BRAF (protein kinase) gene, which forms part of the MAPK pathway involved in cell signallling.

NRAS OR BRAF mutation -> MAPK pathway permanently ON -> Cell cycle entry -> Proliferation

Question 29

How can a melanocyte develop insensitiity to anti-growth signals?

Answer 29

Mutation in CDKN2A tumour supressor gene, which prevents production of p16INK4A (cyclin dependent kinase inhibitor which supresses cell progression) and p14ARF (similar mech, but via p53).

Question 30

How can a melanocyte evade apoptosis?

Answer 30

CDKN2A increases p53 activity via P14ARF, which can induce apoptosis. Mutation and loss of CDKN2A means this pathway not available.

Activation of AKT signalling also important in evasion of apoptosis (AKT is path which supresses apoptosis). AKT sig activated by MAP kinase path - inappropriate activation of path OR deleation of PTEN gene (AKT supressor) activates this path.

Question 31

How do melanocytes stimulate angiogenesis?

Answer 31

Rapid growth -> Hypoxia -> HIF (hypoxia inducible factor) -> VEGF expression

Question 32

What two ways does angiogenesis facilitate fatal cancer?

Answer 32

Increased growth

Increased chance of metastases.

Question 33

Outline process of invasion and mets

Answer 33

1.Invasion - detachment of either small groups or individual cells from the main tumour mass; these cells must then
travel through adjacent tissues.
2. Transport to distant sites by entering blood vessels, lymphatic vessels or body cavities.
3. Thriving in a new site - cancer cells must escape from blood or lymphatic vessels (this is called extravasation) or, if they
invaded a body cavity, grow within it at a distant site or escape into surrounding distant tissues, where they form a
secondary tumour.
4. Escape immune destruction at each step

Question 34

What genetic changes are required for melanoma mets?

Answer 34

Changes in cell adhesion molecules 
as cells break away from the main tumour mass, such as switching from a type of cadherin called E-cadherin, which 
promotes binding of melanoma cells to each other, to a different type of cadherin called N cadherin, which mediates 
binding between melanocytes and fibroblasts. This switch in cadherin class enables melanoma cells to detach from each 
other and to interact with fibroblasts as they invade into the stroma. 

many different types of matrix
metalloproteinase enzymes have been found to be altered in melanoma

Question 35

How do melanomas achieve limitless replicative potential?

Answer 35

melanocytes that lack key cyclin dependant kinase inhibitors such as p21 (induced by p53)
and p16, the cells proliferate until they reach what is called crisis. In crisis, the telomeres have become eroded because
the absence of cyclin-dependant kinases means that relicative senescence cannot occur. There is therefore massive cell
death due to chromosomal fusions. However, a tiny number of cell clones emerge and these have become immortal.

This is achieved by re-activation of the enzyme telomerase, which is capable
of synthesizing new telomeres. Telomerase has a catalytic part called hTERT and an RNA part that primes synthesis of
new telomeres. It is hTERT that becomes expressed. Once the telomeres can be maintained, indefinite proliferation is
possible.

Question 36

What three pieces of information are clinicians and patiuents interested in when discussing cancer?

Answer 36

• accurate diagnosis
• Understanding of tumour natural history, and thus prognosis
• What therapeutic agents it will respond to

Question 37

READ “How to make a melanoma: what do we know of the primary clonal events?” Pigment Cell Melanoma
Res. 2008;21(1):27-38.

Answer 37

“How to make a melanoma: what do we know of the primary clonal events?” Pigment Cell Melanoma
Res. 2008;21(1):27-38.