Melanoma

Question 1

What is melanoma?

Answer 1

• Melanoma is a malignant tumour arising from melanocytes. It is among the most common forms of cancer in young adults and typically presents as a new or changing deeply pigmented skin lesion.

Question 2

What is the overall survival rate of early stage melanoma?

Answer 2

• Early-stage melanoma has an overall survival rate of nearly 100%, while metastatic melanoma can be rapidly fatal.
• Up to 20% of patients develop metastatic disease.

Question 3

What is the cause of melanoma?

Answer 3

• Melanoma arises from melanocytes, the pigment-producing cells found in the skin, eye, and CNS. Aetiology relates to both genetic and environmental factors.

Genetic factors include the inheritance of sun-sensitive skin (fair skin type and susceptibility to sunburn) and specific melanoma-related genes. The major susceptibility gene associated with familial melanoma is CDKN2A, which encodes the P16 and p14ARF proteins.

Environmental factors include excessive exposure to solar and artificial UV radiation (e.g., tanning beds) and proximity to the equator.

History of sunburns and intermittent high-intensity sun exposure are more strongly associated with melanoma development than cumulative chronic sun exposure.

Question 4

What regulates melanogenesis?

Answer 4

Melanocytes produce pigment: either brown or black eumelanin or red phaeomelanin within skin, hair and eyes through a process called melanogenesis.

Melanogenesis is hormonally regulated by Melanocyte Stimulating Hormone (MSH) and a number of other factors.

Question 5

What are the environmental factors that influences the development of melanoma?

Answer 5

• Environmental factors include excessive exposure to solar and artificial UV radiation (e.g., tanning beds) and proximity to the equator.
• History of sunburns and intermittent high-intensity sun exposure are more strongly associated with melanoma development than cumulative chronic sun exposure.

Question 6

Which gene mutations are seen in 40-50% melanomas?

Answer 6

• BRAF mutations are present in approximately 40% to 50% of melanomas.

Question 7

What are the different types of melanoma?

Answer 7

• Superficial spreading melanoma
• Nodular melanoma

• Lentingo maligna melanoma
o Frequency 5% to 15%
o Most commonly diagnosed in older people (>60 years of age) on sun-damaged skin, particularly the head and neck
o Tendency towards slow growth.

• Acral lentiginous melanoma:
o Frequency 5% to 10% but most common in people with darker skin types
o Arises on the palms, soles, and nail apparatus
o Commonly diagnosed at advanced stage

Question 8

Which type of melanoma is the most common?

Answer 8

• Superficial spreading melanoma:

o Most common (frequency 60% to 70%)

Question 9

Which body part is superficial spreading melanoma commonly seen?

Answer 9

o Any site, but preference for torso in men or legs in women

o Most commonly diagnosed between ages 30 and 50 years.

Question 10

Which type of melanoma is the second most common?

Answer 10

Modular melanoma
o Second most common (frequency 15% to 30%)
o Any site
o Most frequently diagnosed in the sixth decade of life
o Rapid vertical growth and later stage at diagnosis.

Question 11

Which type of melanoma has the tendency towards slow growth?

Answer 11

• Lentingo maligna melanoma:
o Frequency 5% to 15%
o Tendency towards slow growth.

Question 12

Who is more likely to be diagnosed with lentingo maligna melanoma?

Answer 12

o Most commonly diagnosed in older people (>60 years of age) on sun-damaged skin, particularly the head and neck

Question 13

Which type of melanoma is more likely to arise on the palms, soles and nail apparatus?

Answer 13

• Acral lentiginous melanoma:
o Frequency 5% to 10% but most common in people with darker skin types
o Arises on the palms, soles, and nail apparatus
o Commonly diagnosed at advanced stage

Question 14

How does melanoma present?

Answer 14

• Altered pigmented lesion:
o A melanocytic lesion that is changing with regard to size, shape, or colour is of concern.

• > 50 benign melanocytic mole
• Atypical mole
• Melanocytic mole that does not resemble surrounding moles.
• Spontaneous bleeding or ulceration of a pigmented lesion

• Constitutional symptoms:
o Late symptoms such as weight loss, fatigue, night sweats, headache, or cough may be symptoms of systemic metastasis in a patient with a history of melanoma.

• Fixed lymphadenopathy (uncommon):
o Fixed lymphadenopathy in a patient with a history of melanoma, especially in lymph node basins draining the site of melanoma excision, are concerning for metastasis.

• Hutchinson’s sign (uncommon)
• Bluish white veil (uncommon)

Question 15

What is the Hutchinson’s sign?

Answer 15

o In the setting of pigmented bands in the nail bed and matrix (melanonychia striata), this sign shows extension of pigment into the proximal or lateral nail fold.

Question 16

What is the bluish white veil?

Answer 16

o A bluish-white veiled appearance within a melanocytic lesion corresponds to dermal fibrosis, with pigmented melanophages in the dermis on histological examination of the pigmented lesion. These features represent regression and are common features of melanoma.

Question 17

What is the 7-point checklist referral?

Answer 17

• Weighted 7-point checklist referral:

o Major features of the lesion (2 points each): change in size, irregular shape or border, irregular colour.
o Minor features of the lesion (1 point each): largest diameter 7 mm or more, inflammation, oozing or crusting of the lesion, change in sensation (including itch).
o Suspicion is greater for lesions scoring 3 points or more.

However, if there are strong concerns about cancer, any one feature is adequate to prompt urgent referral under the 2-week rule.

Question 18

What are the risk factors of melanoma?

Answer 18

• FHx of melanoma
• Personal Hx of melanoma
• Personal hx of skin cancer
• Hx of atypical mole
• Fitzpatrick skin type 1 or 2( light-coloured skin)- pale skin with poor tanning ability.
• Red or blond hair colour
• Sun exposure or sun bed use
• High freckle density
• Increased numbers of moles
• Light eye colour like blue or green
• Large congenital mole
• Immunosuppression
• Increasing age
• Xeroderma pigmentosum- genetic syndrome with skin cancer predisposition.

Question 19

What are the investigations for melanoma?

Answer 19

Dermatoscopy 
• Skin biopsy
• Sentinel lymph node biopsy
• LDH- used to assess metastases of melanoma but it doesn’t detect early metastases so should not be used as part of routine investigation and staging.
• Further investigations include CXR and liver ultrasound, or CT scan of the chest, abdomen and pelvis.
• Ultrasound of lymph nodes
• Brain MRI for detection of metastases
• BRAF analysis

Question 20

Why do you do a dermatoscopy as part of the investigations for melanoma?

Answer 20

o The criteria evaluated in dermatoscopy include the presence or absence and regularity of pigment networks, dots/globules, streaks, blue-white veils, blotches, comedo-openings, leaf-like pigmentation, red-blue lacunas, and pattern of vascular structures within pigmented lesions.

o The procedure is performed to determine whether a pigmented lesion should be biopsied.

Question 21

Why do you do a BRAF analysis?

Answer 21

o Should be performed in patients with unresectable stage IIIC and stage IV melanoma.

o Approximately 40% of melanomas contain an activating mutation in the BRAF most commonly at position V600.

Question 22

What are the staging investigations done for melanoma?

Answer 22

o Imaging or SLNB should not be offered to people who have stage IA melanoma or those who have stage IB melanoma with a Breslow thickness of 1 mm or less.

o SLNB should be considered as a staging rather than a therapeutic procedure for people with stage IB-IIC melanoma with a Breslow thickness of more than 1 mm.

o Imaging:
CT staging should be offered to people with stage IIC melanoma who have not had sentinel lymph node biopsy, and to people with stage III or suspected stage IV melanoma.
The brain should be included as part of imaging for people with suspected stage IV melanoma.
Whole-body MRI should be considered for children and young people (from birth to 24 years) with stage III or suspected stage IV melanoma.

Question 23

What are the differentials of melanoma?

Answer 23

• Benign mole
• Seborrheic keratosis
• Pigmented BCC
• Pigmented actinic keratosis
• Dermatofibroma
• Subungual haematoma

Question 24

What is the management of melanoma?

Answer 24

MDT

• All patients with a suspicious pigmented skin lesion or a malignant melanoma, or where the diagnosis is uncertain, should be referred to a doctor trained in the specialist diagnosis of skin malignancy

• Stages 0-2 melanoma:
o Excision with a clinical margin
o Imiquimod for stage 0 melanoma

• Stage 3 melanoma:
o Completion lymphadenectomy if SLNC shows micro-metastases.
o Lymph node dissection with palpable stage 3 melanoma or nodal disease detected by imaging,
o Adjuvant radiotherapy offered to stage3b-3c melanoma
o Palliative treatment for in-transit metastases

• Stage 4 melanoma:
o Surgery or other ablative treatments (including stereotactic radiotherapy or radioembolisation) should be considered to prevent and control symptoms of oligometastatic stage IV melanoma in consultation with site-specific multidisciplinary teams (eg, for the brain or for bones).

Question 25

What are the systemic anti-cancer treatment available for melanoma?

Answer 25

o Small molecule treatments:
Dabrafenib and vemurafenib are recommended as options for treating unresectable or metastatic BRAF V600 mutation-positive melanoma.

o Immunotherapy:
Ipilimumab is recommended as an option for treating advanced (unresectable or metastatic) melanoma in people who have received prior therapy.

o Cytotoxic chemotherapy:
Dacarbazine can be considered for people with stage IV metastatic melanoma if immunotherapy or targeted therapy are not suitable.
Further cytotoxic chemotherapy should not be offered for stage IV metastatic melanoma to people previously treated with dacarbazine.

Question 26

Prevention of melanoma

Answer 26

• Avoiding sunburn and excessive sun exposure without protection seems to be the most important message in skin cancer prevention without advocating keeping away from the sun altogether.
• Sunbed use: current recommendations are that sunbeds should be avoided, especially in relation to premature skin ageing. Individuals with red hair and freckles, or multiple atypical naevi, should avoid sunbeds since their risks of developing both melanoma and non-melanoma skin cancer are already significantly increased.
• Secondary prevention with early detection of melanoma saves lives. Educating the public and health professionals to recognise melanoma early is crucial. Rapid referral for surgery and further management are imperative to improve outcomes.

Question 27

What are the side effects of immunotherapy?

Answer 27

Immunotherapy agents can cause immune-mediated toxicities due to activation of the immune system to target cancer cells.

These can include worsening of autoimmune conditions as well as itchy skin rashes, diarrhoea, endocrinopathy, pneumonitis, nephritis, hepatitis, uveitis, paresthesia and neuropathy.

The mainstay of toxicity management is immunosuppression with corticosteroids.

Important to ask a patient about autoimmune conditions before commencing treatment.

Question 28

Why is diarrhoea caused by immunotherapy treated differently to the one caused by chemotherapy?

Answer 28

• Chemotherapy side-effects are largely caused by damage to rapidly dividing cells. Within the GI tract this can result in malabsorption of fluid and increased secretions.
• Usually a break from chemotherapy and loperamide is sufficient to get this under control. Patients may require admission for hydration and management of electrolyte disturbance.
• With immunotherapy drugs diarrhoea is due to an inflammatory colitis and can progress without immunosuppression. With severe colitis patients are at risk of perforation and peritonitis. Influximab is used under the supervision of an oncologist if there’s no response to steroids.

Question 29

Which immunotherapy drugs are used in melanoma?

Answer 29

Ipilimumab
Nivolumab
Pembroluzimab

Question 30

What is the MoA of pembrolizumab and nivolumab?

Answer 30

• Pembrolizumab and Nivolumab act by binding to the PD1 protein on T lymphocytes. PD1 stands for Programmed cell Death Protein 1 and activation of it by the ligand PD-L1 leads to apoptosis of the T-cell. PD-L1 is over-expressed on the surface of several types of cancer cell including melanoma and lung cancer.
• The presence of PD1 inhibitors such as Nivolumab prevents the interaction of PD-L1 with PD1, so the T-cell cannot be triggered to self-destruct (apoptosis).
• The immune system is therefore more active, and the cancer cell can be destroyed. This increased immune system activity is also the main cause of the side effects.

Question 31

What is the MoA of ipilimumab?

Answer 31

• Ipilimumab is another monoclonal antibody which acts as a checkpoint inhibitor.

CTLA-4 is a molecule found on the surface of T-cells which switches them off. Ipilimumab blocks CTLA-4 so that the T-cells stay switched on and active and can attack the cancer cells. Ipilimumab can be used in combination with Nivolumab, but patients can also be treated with single-agent immunotherapy with either Nivolumab or Pembrolizumab.

Question 32

What is grade toxicity?

Answer 32

• Oncologists grade toxicity according to the Common Terminology Criteria (CTC) for Adverse Events. This allows us to communicate severity clearly and consistently. There are detailed definitions for each toxicity, but the basic principle is that

o Grade 1 = asymptomatic or mild symptoms
o Grade 2 = moderate symptoms limiting age appropriate instrumental ADL
o Grade 3 = Severe or medically significant but not immediately life-threatening. Usually requiring hospital admission
o Grade 4 = 4 Life-threatening consequences; urgent intervention indicated
o Grade 5 = Death caused by treatment toxicity

Question 33

What is the BRAF protein?

Answer 33

• The normal BRAF protein, when activated, signals the cell nucleus and causes it to divide and grow.

o The abnormal BRAF protein produced by the mutated gene is constantly in the activated state meaning that the cancer cells are constantly being stimulated to divide.

Question 34

What is the MoA of dabrafenib?

Answer 34

• Dabrafenib is a small molecule that targets the mutated BRAF protein in the Mitogen-activated protein kinase (MAPK) molecular pathway and blocks it, leading to death of the cancer cell.
o Unlike the monoclonal antibodies this drug is active within the cell and can be taken orally.

Often used together with trametinib

Question 35

What is the MoA of trametinib?

Answer 35

Trametinib which targets another protein in the SAME MOLECULAR PATHWAY as dabrafenib ALSO CALLED MEK iINHIBITOR (because it inhibits MEK1 and MEK 2 in the MAPk pathway downstream).

o The two drugs in combination can have a rapid effect on melanoma, but this is often relatively short-lived and patients may require another treatment after a number of months.

o In contrast immunotherapy responses can be long lasting

Question 36

What Is the management of stage 3/4 melanoma that is completely resected?

Answer 36

• High risk patients (stage 3 or 4 completely resected) are offered systemic adjuvant treatment with curative intent.

o Adjuvant treatment with either immunotherapy (pembrolizumab or nivolumab) or targeted therapy (dabrafenib and trametinib) is given for 1 year and it significantly reduces the risk of recurrence.

o If patients develop metastatic disease can now be treated with targeted therapy such as BRAF or MEK inhibitors, or with immunotherapy such as Nivolumab, Ipilimumab or Pembrolizumab.

o The response rate to combination treatment is good, around 80% respond to BRAF targeted therapy – although this may not be maintained beyond a year – and around 60% to combination immunotherapy, with some patients having a prolonged response to this therapy.

Question 37

What is a mole?

Answer 37

The clinical appearance of a naevus is dependent on the pattern of melanocyte distribution within the epidermis and dermis.

The scientific term for a mole is a melanocytic naevus. It is composed of melanocytes, cells that lie in the basal layer of the epidermis and within the dermis.

Question 38

Types of mole?

Answer 38

Junctional naevus:
o Melanocytes present at dermo-epidermal junction therefore the mole is flat and has a brown colour.

Intradermal naevus:
o Melanocytes present in dermis therefore the mole is raised and it is skin coloured.

Compound naevus:
o Melanocytes are present at dermo-epidermal junction and within dermis therefore the mole is brown and raised.