Melanoma: Clinical Presentation and Treatment
Clinical Recognition and Diagnosis
Melanoma presents as a new, changing, or irregularly pigmented skin lesion that requires immediate evaluation with excisional biopsy when suspected. 1
Key Clinical Features to Identify
Use the ABCDE criteria to assess suspicious lesions 2, 3:
- Asymmetry of the lesion
- Border irregularity
- Color variation (non-uniform pigmentation)
- Diameter greater than 6 mm
- Evolution over time (any change in size, shape, or color)
The "ugly duckling" sign is an alternative approach: identify pigmented lesions that appear different from other moles on the patient 2
Melanoma Subtypes and Distribution 1
- Superficial spreading (≈70% of cases)
- Lentigo maligna (≈15%)
- Nodular (≈5%)
- Desmoplastic (≈4%)
- Amelanotic (2-8%) - lacks pigmentation, easily missed
- Acral (≈1%) - occurs on palms, soles, or under nails; most common type in Black populations 2
Diagnostic Approach
Perform excisional biopsy with a small side margin for any suspicious lesion to ensure full-thickness removal and accurate Breslow depth measurement 2, 4. Deep scoop shave, saucerization, or punch biopsy are acceptable alternatives if excisional biopsy is not feasible 4.
Critical pitfall: Incisional or superficial shave biopsies may miss the true depth of invasion, leading to understaging 4.
Staging and Initial Workup
Essential Histopathology Elements 2
- Melanoma subtype
- Breslow thickness (maximum depth in millimeters) - most critical prognostic factor
- Presence of ulceration
- Mitotic rate (for thin melanomas)
- Surgical margin clearance
Staging Workup by Breslow Depth
For thin melanomas (≤0.8 mm, stage IA): No additional imaging required after wide local excision 2, 4
For melanomas ≥0.8 mm or ulcerated lesions: 1, 4
- Physical examination focusing on lymph nodes and distant metastases
- Sentinel lymph node biopsy (SLNB) is recommended 2
- Consider imaging (CT, PET/CT) for higher stages to detect regional or distant disease 2
For stage III-IV disease: 2
- BRAF V600 mutation testing is mandatory before treatment planning 2
- Consider expanded molecular profiling for treatment selection 5
Treatment by Stage
Stage 0 (Melanoma in situ)
Wide local excision with 0.5 cm margins 2
Stage IA-IIA (Localized Disease, Breslow ≤4 mm)
Wide local excision with margins based on Breslow depth 2, 1:
- 1 cm margins for tumors ≤2 mm thick
- 2 cm margins for tumors >2 mm thick
No adjuvant therapy recommended for stage IA-IIA 2
Stage IIB-IIC (High-Risk Localized Disease)
After wide local excision, offer adjuvant anti-PD-1 immunotherapy 2, 1:
- Nivolumab 480 mg IV every 4 weeks for 1 year (HR for recurrence 0.42) 2, 6
- Pembrolizumab 200 mg IV every 3 weeks for 1 year (HR for recurrence 0.62) 2, 1
Both agents significantly improve recurrence-free survival compared to observation 1.
Stage IIIA/B/C/D (Resected Regional Disease)
After complete resection with negative margins, offer one of the following adjuvant therapies (in no particular order) 2:
For BRAF wild-type melanoma:
For BRAF V600-mutant melanoma, add this option:
- Dabrafenib 150 mg PO twice daily + trametinib 2 mg PO daily for 1 year 2
All three regimens have strong evidence with hazard ratios for recurrence ranging from 0.52-0.72 1, 4.
Critical consideration: Patients with stage IIIA disease with sentinel node metastasis <1 mm were not included in pivotal trials; individualize treatment after discussing risk-benefit ratio 2.
Complete lymph node dissection is NOT recommended for sentinel node-positive patients 2. For clinically detectable (macroscopic) lymph node metastases, complete lymph node dissection is indicated 2.
Treatment of Unresectable/Metastatic Disease (Stage IV)
First-Line Treatment for BRAF Wild-Type Melanoma
Offer one of the following immunotherapy regimens 2, 5:
- Nivolumab 3 mg/kg IV every 2 weeks + ipilimumab 1 mg/kg IV every 3 weeks for 4 doses, then nivolumab 480 mg IV every 4 weeks (highest response rate ~70%, 10-year OS 43%) 2, 6, 1
- Nivolumab 480 mg IV every 4 weeks + relatlimab 2
- Nivolumab 480 mg IV every 4 weeks alone 2
- Pembrolizumab 200 mg IV every 3 weeks alone 2
Treatment selection algorithm 5:
- For symptomatic, bulky, or rapidly progressive disease: Prefer ipilimumab + nivolumab combination for fastest disease control 5
- For elderly patients or multiple comorbidities: Prefer single-agent anti-PD-1 (nivolumab or pembrolizumab) due to lower toxicity 5
- For low-volume, asymptomatic disease: Single-agent anti-PD-1 allows time for immune response to develop 2
First-Line Treatment for BRAF V600-Mutant Melanoma
Offer any of the immunotherapy options above, OR one of these BRAF/MEK inhibitor combinations 2:
- Dabrafenib 150 mg PO twice daily + trametinib 2 mg PO daily 2
- Encorafenib 450 mg PO daily + binimetinib 45 mg PO twice daily 2
- Vemurafenib 960 mg PO twice daily + cobimetinib 60 mg PO daily (21 days on, 7 days off) 2
Treatment selection for BRAF-mutant disease 2:
- For symptomatic or rapidly progressive disease: Consider BRAF/MEK inhibitors for rapid response 2
- For asymptomatic disease with time for immune response: Consider immunotherapy first for potential durable benefit 2
Treatment Duration 2, 5
- Anti-PD-1 monotherapy: Continue for up to 2 years or until progression/toxicity 2
- BRAF/MEK inhibitors: Continue until progression or unacceptable toxicity 2
- Consider stopping after 2 years if complete or partial response achieved 5
Monitoring During Treatment 5
- CT chest/abdomen/pelvis every 2-3 months initially to assess response 5
- Brain MRI at baseline and during follow-up due to melanoma's propensity for CNS metastases 5
Second-Line Treatment After Progression
After Anti-PD-1 Failure in BRAF Wild-Type Disease 2
- Ipilimumab or ipilimumab + nivolumab combination (ORR 21%, 12-month OS 55%) 2, 5
- Consider clinical trial enrollment 2
After Anti-PD-1 Failure in BRAF-Mutant Disease 2
- Switch to BRAF/MEK inhibitor combination (if not previously used) 2
- OR switch to ipilimumab-containing regimen 2
After BRAF/MEK Inhibitor Failure 2
Important caveat: Switching between different BRAF/MEK combinations after failure has no efficacy data 2. Retest for BRAF mutations if disease progresses, as false-negatives can rarely occur 5.
Special Situations
Brain Metastases 2
For asymptomatic brain metastases: Ipilimumab + nivolumab combination is the preferred first-line treatment, even in BRAF-mutant patients 2
For small number of metastases (<5-10 lesions, <3 cm): Stereotactic radiosurgery (SRS) upfront is an option 2
For symptomatic or bulky brain metastases: Treat CNS disease first with surgery/radiation, then systemic therapy 2
Avoid high-dose interleukin-2 in patients with untreated brain metastases (may worsen edema) 2
Injectable Cutaneous/Subcutaneous Lesions 2
For patients with unresectable injectable lesions who decline or are ineligible for systemic therapy: Talimogene laherparepvec (T-VEC) may be offered as primary therapy 2
For unresectable stage IIIB/C or IVM1a with injectable lesions: T-VEC is an option 2
Uveal Melanoma 2
For HLA-A*02:01-positive patients with metastatic uveal melanoma: Tebentafusp 20 mg on day 1,30 mg on day 8, then 68 mg weekly until progression 2
For all other uveal melanoma patients: No specific systemic therapy can be recommended; enroll in clinical trials 2
Mucosal Melanoma 2
Treat with the same therapies recommended for cutaneous melanoma (immunotherapy or BRAF/MEK inhibitors if BRAF-mutant) 2
Critical Safety Considerations
Immunotherapy Toxicity 2
Close monitoring for immune-related adverse events is essential, particularly:
- Colitis, hepatitis, pneumonitis, endocrinopathies, dermatitis
- Ipilimumab + nivolumab has higher toxicity than single-agent anti-PD-1 5
- Participation in risk evaluation programs during ipilimumab treatment is strongly recommended 2
BRAF Inhibitor Monitoring 2
Regular dermatologic evaluation is required to monitor for secondary skin cancers (squamous cell carcinoma, keratoacanthomas) 2
Follow-Up and Surveillance
Skin Surveillance 2
- Lifelong annual skin examinations for all patients with melanoma (stage IA-IV) 3
- Patient education on self-examination of skin and lymph nodes 2
- Counsel on sun protection: avoid sunburns, limit UV exposure, use sunscreen and protective clothing 2
- Family members have increased melanoma risk and should be screened 2
Imaging Surveillance 2
For thin melanomas (stage IA-IIA): Routine imaging is not recommended 2
For high-risk patients (thick primaries, stage III-IV): Consider ultrasound of lymph nodes, CT, or PET/CT for earlier detection of recurrence 2
Serum S-100 protein has higher specificity than LDH for disease progression if blood monitoring is performed 2
Follow-Up Schedule 2
Recommendations vary, but a reasonable approach is:
- Every 3 months for the first 3 years
- Every 6-12 months thereafter 2
Sentinel node-positive patients should undergo regular ultrasound examinations of the nodal basin 2
Prevention and Screening
Primary Prevention 2, 1
- Avoid direct sunlight and indoor tanning beds 2
- Use photoprotection: sunscreen and sun-protective clothing 2
- Counsel patients aged 6 months to 24 years on minimizing UV exposure 4
Screening 2
The USPSTF concludes that evidence is insufficient to recommend for or against routine visual skin examination by clinicians for asymptomatic adults 2. However, patients with risk factors (fair skin, history of sunburns, multiple/atypical nevi, family history) warrant heightened surveillance 2, 1.
Prognosis
5-Year Survival by Stage (2017 data) 1
- Stage IA-B: 98-94%
- Stage IIA-C: 88-75%
- Stage IIIA: 88%
- Stage IIIB-C: 77-60%
- Stage IIID: 24%
10-Year Survival 1
- Metastatic melanoma treated with ipilimumab + nivolumab: 43% (2024 data)
The introduction of checkpoint immunotherapy and targeted therapy from 2011 onward has dramatically improved survival in advanced melanoma 1, 7.