Melanoma

Melanoma is a cancer of pigment-producing cells. Most cases start in skin, but acral melanoma can arise on palms, soles or nail units, mucosal melanoma in internal lining tissues, and uveal melanoma in the eye. A pink or unpigmented lesion can also be melanoma. Suspicious changes need clinical assessment rather than diagnosis from a photograph alone.

For suspected skin melanoma, the initial biopsy should allow reliable assessment of invasion and depth; a full-thickness excision is preferred when practical. Large lesions or difficult sites may need a planned partial biopsy. Uveal melanoma is different: specialist eye examination and imaging often establish the diagnosis, with tissue sampling used selectively for uncertainty or prognostic testing.

For cutaneous melanoma, key pathology details include Breslow thickness, ulceration, margins and whether satellite deposits are present. Stage also considers regional lymph nodes and distant spread. A stage based only on the first skin biopsy may change after sentinel-node assessment or other investigations.

Imaging is selected by risk and symptoms rather than ordered identically for every early lesion. For higher-risk or advanced disease, body imaging and brain MRI can affect treatment planning. BRAF V600 testing matters when targeted treatment is a realistic option; a negative V600E-only test may require broader testing. Other testing is selected by the subtype and clinical question.

Wide local excision removes the biopsy site and an appropriate surrounding margin. The margin depends on the tumor’s features and anatomy. A sentinel lymph node biopsy looks for microscopic spread in clinically normal nodes; it is a staging procedure, not the same operation as clearing all regional nodes.

ESMO recommends discussing sentinel-node biopsy for 0.8–1.0 mm tumors or thinner ulcerated tumors, and generally recommends it above 1.0 mm when nodes are clinically negative. Individual risk and local guidance matter. A positive sentinel node does not automatically require completion dissection: ultrasound surveillance is often appropriate when reliable follow-up is possible.

After complete surgery for stage IIB–IIC or selected stage III melanoma, adjuvant anti-PD-1 treatment can reduce recurrence risk. The discussion should include the baseline risk, the expected benefit and the possibility of serious or permanent immune effects. For stage IIB–IIC, recurrence-free benefit should not be presented as established mature overall-survival benefit.

For resectable disease with clinically apparent nodal involvement, neoadjuvant immunotherapy may improve the treatment pathway. NADINA showed better event-free survival with preoperative ipilimumab plus nivolumab and response-adapted postoperative treatment than surgery followed by nivolumab. S1801 supports a perioperative pembrolizumab strategy in its eligible population. These findings are not a reason to give preoperative drugs to every small primary melanoma.

The surgical and medical teams should agree the sequence before treatment starts, including how pathological response will affect later therapy. Guideline support, drug labeling and reimbursement are separate questions. For BRAF-mutant disease, an adjuvant BRAF–MEK combination may also be discussed, with attention to the exact variant rather than treating every BRAF change as equivalent.

Systemic options include anti-PD-1 treatment, nivolumab with ipilimumab, and nivolumab with relatlimab where appropriate and available. Combination treatment can improve disease control in selected settings but has its own toxicity trade-offs. The choice accounts for speed of progression, disease burden, prior treatment, autoimmune conditions and the patient’s priorities.

A BRAF V600 alteration can make combined BRAF–MEK inhibition an option. In DREAMseq, starting with nivolumab–ipilimumab produced better survival than starting with dabrafenib–trametinib in the studied fit, treatment-naive population. Rapidly threatening disease, contraindications and individual circumstances still matter; a mutation alone does not dictate that targeted treatment must come first.

Brain metastases require a coordinated plan for local and systemic control. Size, symptoms, bleeding risk, steroid requirement and disease outside the brain influence the use of surgery, stereotactic radiation and medicines. New seizures, weakness or severe neurological symptoms need prompt medical assessment.

Nivolumab–ipilimumab has demonstrated intracranial activity in selected patients with untreated, asymptomatic brain metastases. That evidence should not be assumed to predict the same result in a patient needing high-dose steroids or urgent decompression. If only one or a few sites progress while the rest remain controlled, a team may assess local treatment rather than automatically abandoning every effective systemic option.

In the United States, lifileucel (Amtagvi) has accelerated approval for adults with unresectable or metastatic melanoma previously treated with anti-PD-1 and, for BRAF V600-positive disease, a BRAF inhibitor with or without a MEK inhibitor. It uses the patient’s tumor-infiltrating lymphocytes (TILs), expanded from removed tumor tissue. It is not CAR-T therapy and is not simply a routine blood collection and infusion.

The treatment course includes tumor procurement, manufacturing, lymphodepleting treatment and subsequent IL-2 support. It requires an experienced inpatient center because severe blood-count suppression, infection, organ impairment and treatment-related death can occur. Disease pace and fitness during the manufacturing interval are part of eligibility.

Tudriqev (vusolimogene oderparepvec-wtpg) is a separate oncolytic viral treatment, approved in the United States in combination with nivolumab for adults with unresectable advanced cutaneous melanoma progressing after a PD-1-based regimen. It is injected into suitable tumors, not into a vein. Its accelerated approval is based on response and response duration, with confirmatory benefit still required.

Viral treatment needs assessment of injectable lesions and precautions for herpes infection, injection complications and exposure of close contacts. Neither option should be described as a universal rescue treatment, and the U.S. approval does not establish approval or availability in every country.

Acral melanoma involves palms, soles or nail units; mucosal melanoma may arise in the head and neck, anorectal or genital tract. Their biology and mutation patterns differ from common sun-related skin melanoma. Specialist pathology review and site-specific surgical planning are important, especially where removal may affect walking, continence or other function.

Immunotherapy may still be used, but response expectations should come from the relevant subtype. Molecular testing can identify BRAF or selected actionable KIT alterations; KIT protein staining or amplification alone is not interchangeable with a sensitive activating mutation. Evidence for many uncommon-subtype combinations remains limited, making an appropriate clinical trial a meaningful option.

Localized uveal melanoma may be managed with plaque brachytherapy, proton radiotherapy or surgery according to size, location and visual potential. Its molecular biology differs from skin melanoma, and surveillance often gives particular attention to the liver. A molecular prognostic result estimates risk; it does not by itself establish an effective adjuvant drug.

For unresectable or metastatic disease, tebentafusp is an important option for eligible HLA-A*02:01-positive adults. This requires HLA testing, not merely a general tumor panel, and treatment includes monitoring for cytokine-release syndrome and other reactions. Skin-melanoma immunotherapy results should not be assumed to apply unchanged to uveal disease.

Selected liver-dominant cases may also be assessed for liver-directed treatment. The U.S. Hepzato Kit indication has specific limits: unresectable liver metastases involving less than half the liver, and no extrahepatic disease or only specified treatable extrahepatic sites. It requires a specialist procedure with risks of bleeding, liver injury and severe marrow suppression, rather than being an ordinary intravenous chemotherapy substitute.

Immune treatment can inflame the bowel, lungs, liver, endocrine glands or other organs, including after treatment ends. Persistent diarrhea, breathlessness, marked weakness, severe headache or other new symptoms should be reported promptly. Some hormone problems require long-term replacement. Keep a treatment record available when seeing another clinician.

Follow-up is adapted to stage, recurrence risk and the treatment received. It includes examination of the skin and relevant lymph nodes, with imaging where indicated. Check for new or changing lesions, including nails and soles, and use sun protection. Follow-up also supports recovery from surgery, swelling, anxiety and the practical effects of repeated treatment.

Bring the original pathology report and slides, primary-site details, sentinel-node or nodal surgery results, BRAF and other molecular results, current body and brain imaging, and a treatment timeline showing best response and why each treatment stopped. Include autoimmune disease, organ transplantation, steroid use and previous serious immune toxicity.

Ask whether the immediate goal is cure, recurrence prevention, rapid symptom relief or longer control; whether treatment should precede surgery; and what remains possible if this option fails. For cell or viral treatment, establish the exact eligibility, preparation time, center requirements and local availability before making travel plans.