Malignant melanoma

Melanoma is a malignant tumour of melanocytes - the melanin producing cells of the body. It may be in-situ if it remains in the epidermis and it may be considered invasive once it spreads to the dermis. It is the 5th most common cancer in the UK, making up 4% of all cancer cases. This number is projected to increase significantly within the next 10 years. It is the skin cancer with the highest mortality rate (more than all other forms of skin cancer combined).

Pathophysiology

As with most cancers, melanoma’s pathogenesis involves an interplay of both environmental factors and genetics:

• Environmental factors - the biggest risk factor for melanoma is ultraviolet (UV) radiation (especially from sunlight). UV-B specifically is more likely to induce cell damage which increases the risk of mutagenesis that drives carcinogenesis.
• Genetic factors - genetic mutations are crucial in the transformation of melanocytes into malignant cells. The BRAF gene is most commonly affected (40%-50% of cases), especially with a V600E mutation. This is a point mutation where valine (V) is replaced by glutamic acid (E). The number 600 refers to it being the 600th amino acid inside the BRAF protein. BRAF plays a role in cell growth and promotes cell division. There are other V600 mutations such as V600K (valine to lysine) and V600D/R (valine to aspartic acid/arginine). Other important mutations include NRAS and KIT. They all result in activation of the MAPK pathway

These mutations lead to dysregulated growth of melanocytes and melanoma formation. The melanoma may grow vertically or radially. Vertical growth is more likely to lead to metastasis.

⚠️ Risk factors

• UV radiation exposure - history of sunburn, use of sun beds and tanning beds.
• Outdoor occupation
• Increasing age
• Fitzpatrick I and II skin types
• Family history/personal history of malignant melanoma
• BRAF, NRAS, KIT mutations
• Xeroderma pigmentosum - an autosomal recessive disorder that increases sensitivity of the skin to UV radiation.
• Familial atypical multiple mole melanoma (FAMMM) syndrome - a rare autosomal dominant condition characterised by the presence of >50 melanocytic naevi and early melanoma development. It is also associated with increased risk of pancreatic cancer.
• Immunosuppression - anti-TNF drugs also increase the risk of melanoma. This may be due to disruption of apoptosis, impaired UV-induced DNA damage repair and impaired detection/destruction of emerging malignant cells.
• Dysplastic naevi and giant congenital naevi

🔢 😷 Classification and presentation

There are 4 common subtypes of melanoma:

1. Superficial spreading melanoma
2. Nodular melanoma
3. Lentigo maligna melanoma
4. Acral lentiginous melanoma

Lets’ discuss these 4 subtypes in more detail and compare them all:

💡 Lentigo maligna, also known as Hutchinson’s melanotic freckle, differs from lentigo maligna melanoma. The former is a precursor to lentigo maligna melanoma as it remains in-situ. Once it invades the dermis then it is referred to as lentigo maligna melanoma (an invasive tumour).

• Amelanotic melanomas are rarer forms of melanoma with little to no pigment. They may present as macular lesions that are pink/red. There may be faint pigmentation at the edges. All the subtypes of melanoma may be amelanotic.

🦆

Ugly duckling sign:

This is a clinical guideline that is used to differentiate malignant melanomas from otherwise benign moles. The concept is based on the observation that most moles that are benign on an individual’s body look similar to one another. Melanoma’s on the other hand often appear different due to differences in colour, size, shape or texture.

We can use the ABCDEs of melanoma to highlight characteristics of the concerning lesions:

• Asymmetry
• Border - irregular border with indistinct margins.
• Colour - variegated (multicoloured) pigmentation within the same lesion.
• Diameter - >6mm.
• Evolving - lesion changes size, shape and colour over time.

Melanomas may also occur in non-cutaneous sites (although much rarer):

• Mucosal surfaces - mouth, nose, respiratory tract and oesophagus, as well as genitourinary melanoma (anorectal and vulvovaginal melanomas).
• Uveal melanoma
• Subungal melanoma

🔍 Investigations

• 🥇 Dermoscopy - allows us to examine skin lesions more accurately. It may be useful in distinguishing between benign and malignant lesions.
• 🏆 Full thickness excisional biopsy - this is sent for histopathological analysis. A 1-3mm peripheral margin should be obtained along with a cuff of subcutaneous fat. The biopsy may be obtained through punch biopsy, deep shave biopsy (saucerisation) or incisional biopsy.

The features to assess for in histological analysis include:

1. Breslow thickness - this is the distance between the stratum granulosum and the deepest point of the melanoma (measured in mm).
2. Degree of ulceration
3. Histological subtype
4. Immunohystocytochemistry - to identify the genetic markers present (such as BRAF).
5. Mitotic rate

💡 NICE does not recommend biopsy in primary care. If a melanoma is suspected or the diagnosis is not certain then the person should be referred urgently using the suspected cancer pathway.

Once a diagnosis has been confirmed, additional tests include:

• Sentinel lymph node biopsy - this should be done for all melanomas that have a Breslow thickness of >1mm.
• PET scan/CT scan of the chest, abdomen and pelvis and brain MRI - this allows us to stage the disease appropriately.
• Imaging needs to be done in the following patients:
• Stage IIc melanoma who have not had sentinel lymph node biopsy.
• Stage III and stage IV melanoma.

✍️ Referral

Weighted 7-point checklist:

NICE recommends using the weighted 7-point checklist to determine the need for referral:

• Major features of the lesion - worth 2 points each.
• Change in size
• Irregular shape
• Irregular colour
• Minor features of the lesion - worth 1 point each.
• Largest diameter ≥7mm
• Inflammation
• Oozing
• Change in sensation (including itching)

Individuals who should be referred urgently using the suspected cancer pathway include:

1. Individuals with a suspicious pigmented lesion + weighted 7-point checklist score of ≥3
2. Dermoscopy suggests melanoma
3. Nail changes (suggestive of subungal melanoma)
4. New persistent skin condition especially if growing, pigmented or vascular in appearance.
5. Uncertainty about the lesion and its history
6. Biopsy has confirmed the diagnosis.

📊 Staging

Melanoma is staged using the TNM staging system:

🧰 Management

🔮 Prognosis

Melanoma survival is strongly correlated with histopathological and individual features. Other determinants of prognosis include:

• Ulceration
• Mitotic index
• Spread to local lymphatics

Approximate 5-year survival based on the stage are:

• Stage 1 - 100%.
• Stage 2 - 80%.
• Stage 3 - 70%.
• Stage 4 - 30%.