Lucan · Conditions

Cutaneous melanoma

Australian guidance: Cancer Council Australia Clinical Practice Guidelines for Melanoma

1. Definition and epidemiology

Cutaneous melanoma is a malignant tumour arising from melanocytes within the epidermis that carries significant metastatic potential even when the primary lesion appears small. In Australia, melanoma was estimated to be the third most commonly diagnosed cancer in 2020, with Australian men estimated to have a one in 14 lifetime risk and women a one in 21 risk of being diagnosed before the age of 85. Australia's high UV index, outdoor lifestyle, and predominantly fair-skinned population combine to produce one of the highest melanoma incidence rates in the world.

2. Pathophysiology

Melanocytes are neural crest-derived dendritic cells responsible for melanin synthesis. In the skin they normally reside at the dermoepidermal junction. Melanoma arises from accumulated mutations in these cells, most commonly driven by UV radiation-induced DNA damage, particularly the formation of cyclobutane pyrimidine dimers in BRAF and other proto-oncogenes. The most prevalent oncogenic driver is the BRAF V600E substitution, present in approximately 50% of cutaneous melanomas, which constitutively activates the RAS-RAF-MEK-ERK mitogen-activated protein kinase pathway and drives uncontrolled proliferation. CDKN2A (encoding p16 and p14ARF) is the primary tumour suppressor gene lost in melanoma, removing both the pRb and p53 braking mechanisms simultaneously. Histologically, Robbins describes the radial growth phase (intraepidermal lateral spread, low metastatic potential) preceding the vertical growth phase (dermal invasion, high metastatic risk), with Breslow thickness measured in millimetres from the granular layer to the deepest invasive tumour cell being the dominant prognostic variable. Ulceration, mitotic rate, and microsatellitosis are additional adverse histological features that upstage the tumour.

3. Clinical presentation and diagnostic criteria

The ABCDE criteria anchor clinical detection: Asymmetry, Border irregularity, Colour variation, Diameter exceeding 6 mm, and Evolution (change over time). Additional concerning features include itching, scaling, bleeding, oozing, swelling or pain in a skin lesion, new or changing lesions that do not heal, a rapidly growing skin lesion persisting after one month, and spread of pigment from a lesion to the surrounding tissue. A minority of melanomas present as amelanotic lesions, typically nodular subtype, which grow rapidly as elevated, firm, non-pigmented nodules (the EFG pattern: elevated, firm, growing progressively) and carry a disproportionately high mortality due to delayed recognition. Nodular melanoma must be actively considered when any rapidly enlarging skin lesion is encountered, because watchful waiting for colour change is inappropriate.

4. Investigations and AU-specific cutoffs

GP assessment: Systematic lesion history (duration, rate of change, associated symptoms) with dermoscopy under good lighting. Observation is only appropriate for low-suspicion macular lesions using dermoscopic imaging; a review interval must not exceed three months.

Biopsy: When suspicion is high, complete excisional biopsy with a 2 mm clinical margin is the standard. Partial biopsy (shave or punch) is reserved for large lesions in cosmetically sensitive sites. All biopsies must be submitted for histopathological examination. If melanoma is suspected, biopsy or excision should occur within two weeks of the initial GP consultation and results provided within one week.

Staging investigations: Performed within two weeks of specialist assessment. Melanomas less than 0.8 mm thick with adequate margins do not require further investigation. Sentinel lymph node biopsy (SLNB) is considered for tumours greater than 1 mm thick, and for tumours greater than 0.75 mm with high-risk features such as ulceration, to provide staging and prognostic information. If sentinel nodes are positive, further staging with CT or PET-CT is required. Node-negative melanoma does not require imaging staging.

Performance status: Document using the ECOG or Karnofsky scale prior to systemic therapy planning.

Genetic testing: Refer to a dermatologist for clinical risk assessment when more than one first-degree relative has melanoma. Refer to a familial cancer service for genetic risk assessment when three or more relatives have melanoma and/or pancreatic cancer. Tumour BRAF mutation testing is required before initiating targeted therapy.

5. Management

Surgical excision is the cornerstone of treatment. For melanoma in situ, excision margins of 5 to 10 mm are standard; for invasive melanoma, margins of 10 mm or 20 mm are applied depending on Breslow thickness and subtype. Surgery in primary care should occur within two weeks of the decision that it is necessary. Sentinel lymph node biopsy and regional lymphadenectomy require a specialist surgeon. Completion lymph node dissection (CLND) does not offer survival benefit over observation with ultrasound review following a positive sentinel node.

Radiation therapy is used as definitive treatment for in situ melanoma where surgery is medically contraindicated, as adjuvant therapy after resection of high-risk invasive melanoma when systemic therapy is not available, and for palliation including stereotactic radiotherapy for oligometastatic and brain or spinal disease. If not urgent, radiation therapy should begin within four weeks of the multidisciplinary meeting (MDM).

Systemic therapy: Stage IIIB/C/D and all stage IV patients should be considered for systemic therapy. All patients with unresectable stage III or stage IV disease should be offered enrolment in clinical trials where available. MDM discussion for all stage III and IV patients must occur within four weeks of diagnosis. Adjuvant systemic therapy should start within 12 weeks of definitive surgery; for stage IV disease, treatment should begin as soon as clinically relevant, ideally within four weeks.

Multidisciplinary care: Patients with advanced stage primary melanoma, lymph node involvement, or melanoma in unusual sites are best managed by a specialist or melanoma multidisciplinary team.

6. Pharmacology and AU PBS notes

Immunotherapy (checkpoint inhibitors): - Pembrolizumab (Keytruda, anti-PD-1) or nivolumab (Opdivo, anti-PD-1) as monotherapy are first-line options for metastatic melanoma regardless of BRAF status. - Nivolumab combined with ipilimumab (Yervoy, anti-CTLA-4) delivers higher response rates and longer progression-free survival at the cost of significantly greater toxicity; this combination requires careful patient selection. - Immunotherapy continues until disease progression, unacceptable toxicity, or completion of two years of treatment. - Immune-related adverse events (irAEs) are a distinct toxicity profile including rash, pruritus, thyroid dysfunction, hypophysitis, hepatitis, colitis, arthritis and pneumonitis; clinically significant irAEs require immunotherapy interruption and immunosuppressive doses of corticosteroids. - PBS listing exists for pembrolizumab and nivolumab in unresectable stage III and stage IV melanoma; consult the current PBS schedule for streamlined authority codes as these are updated regularly.

Targeted therapy (for BRAF V600 mutant melanoma): - Combination of a BRAF inhibitor plus a MEK inhibitor is preferred over single-agent BRAF inhibition. Current PBS-listed doublets include dabrafenib (Tafinlar) plus trametinib (Mekinist), and vemurafenib (Zelboraf) plus cobimetinib (Cotellic). - Stage IIIB/C/D with BRAF V600 mutation: adjuvant BRAF plus MEK inhibitor combination or single-agent anti-PD-1 immunotherapy can both be recommended; stage IIIA adjuvant therapy is not indicated. - Targeted therapy continues until disease progression or intolerable toxicity; there is no established superior sequencing relative to immunotherapy for metastatic disease.

Sequencing note: The decision on sequencing targeted versus immune therapy for BRAF-mutant metastatic disease should be made by an experienced oncologist after considering individual patient factors.

7. Complications and monitoring

Treatment-related complications: - Surgical: wound complications, lymphoedema (upper and lower limb) following lymph node dissection, nerve injury and scarring. - Immunotherapy irAEs: any organ system can be affected; most common are skin, gastrointestinal, endocrine and pulmonary. Endocrinopathies (hypothyroidism, adrenal insufficiency, hypophysitis) are often permanent and require long-term hormone replacement. - Targeted therapy: pyrexia, rash, arthralgia, and secondary cutaneous malignancies including squamous cell carcinoma.

Surveillance schedule: - Tumours less than 1 mm thick: four- to six-monthly follow-up for two years, then annually at minimum; high-risk patients (numerous naevi, dysplastic naevi, family history) require indefinite periodic review. - Tumours greater than 1 mm thick: three- to four-monthly for the first two years, six-monthly review to five years, then lifelong annual review. - Stage III disease: three- to four-monthly for the first two years, six-monthly for the next two to three years, then as clinically necessary. - Follow-up includes full skin examination, lymph node palpation, and assessment for distant metastases. Imaging is ordered according to clinical indication and stage. - All patients must be educated about skin self-examination and ongoing sun protection, including SPF 30 or higher broad-spectrum sunscreen, protective clothing, and avoidance of solariums.

Written for Australian practice and grounded in the guidance named above. Study material only — not medical advice. Always check against current guidelines.