Maximizing survival for patients with primary cutaneous melanomas depends on early diagnosis and appropriate management. Despite well-documented guidelines, many patients still do not receive optimal care, particularly when patient age is not adequately considered in treatment planning. Several new drugs have improved survival in high-risk melanoma patients, yet gaps remain between evidence-based recommendations and clinical practice.
This comprehensive review covers melanoma management from the initial decision to biopsy a suspicious skin lesion through to long-term follow-up. The authors reviewed melanoma-management research published between 2018 and 2023 using PubMed, Google Scholar, Ovid, and the Cochrane Library, identifying 81 publications since 2017 that have changed melanoma management practices.
The two key steps in maximizing survival remain early diagnosis followed by excision with a wide margin. However, the review also highlights often-neglected aspects of management, including the evolving role of sentinel lymph node biopsy (SLNB), adjuvant drug therapy for high-risk patients, and the importance of lifelong skin surveillance. The emergence of the BAUSSS biomarker represents a paradigm shift in how mortality risk is assessed.
The appropriate diagnostic technique for a suspected melanoma is the excision of the entire apparent lesion with a narrow margin, typically 1 to 3 mm. The accuracy of initial diagnosis is significantly better with excisional biopsy than with partial shave or punch biopsy, as inaccurate assessment of melanoma depth and subtype from partial biopsies may increase mortality risk.
Partial biopsies should be reserved for circumstances where a complete excisional biopsy is impracticable, such as large lesions on the head, neck, hands, feet, anterior legs, or genitalia. In these cases, saucerization is an ideal alternative provided the specimen includes the entire lesion and its full depth. Other options include a deep shave biopsy for broad thin tumors or a 6 mm or larger punch biopsy for thicker tumors.
An accurate and detailed pathology report is crucial for planning further management. Key microscopic parameters include Breslow thickness (the single most important prognostic factor), ulceration status, melanoma subtype, margins, growth phase, perineural invasion, lymphovascular invasion, tumor-infiltrating lymphocytes, regression, and mitotic index. Standardized reporting recommendations from the Royal College of Pathologists help ensure consistency.
Nine features from pathology reports and patient history have traditionally been considered important for survival prediction. A landmark study by El Sharouni et al. categorized these into four groups based on their predictive power using the c-statistic. Group A (Breslow thickness, Age, Ulceration) represents the three most important factors with c-scores above 0.59. Group B (Subtype, Sex, Site) has moderate impact with c-scores between 0.54 and 0.59.
Notably, mitotic activity and regression (Group C) have minimal impact on survival prediction when analyzed on multivariate analysis, with c-statistics close to 0.5 (essentially random). Clark levels (Group D) provide no statistical difference to outcome on multivariate analysis and are no longer considered a meaningful feature in pathology reports.
Combining the Group A and Group B factors yields the BAUSSS biomarker (Breslow thickness, Age, Ulceration, Subtype, Sex, and Site), which has emerged as a key staging process for determining melanoma mortality risk. The BAUSSS provides a more accurate method than older approaches, including SLNB, without subjecting patients to added costs, hospitalization, anesthesia, and the approximately 11% complication rate associated with SLNB.
Excision margins for wide local excision (WLE) are determined by Breslow thickness. Current guidelines recommend: melanoma in situ receives 5 to 10 mm margins; invasive melanomas under 1 mm Breslow get 10 mm margins; 1 to 2 mm Breslow receives 10 to 20 mm margins; and Breslow over 2 mm receives 20 mm margins. The depth of excision extends to but does not include the deep fascia, and radial margins greater than 20 mm do not improve survival.
Mohs micrographic surgery may be used to obtain clear margins and reduce recurrence for melanoma in situ, and is particularly considered for anatomically challenging locations such as the eyelid, ear, lips, face, hands, and feet. A recent systematic review found Mohs outcomes comparable to WLE, though further evidence is needed to confirm its precise role.
Concerning findings from Australian data show that many melanoma patients are not excised with appropriate margins, particularly for facial tumors. Only about one third of patients in New South Wales and Victoria with facial melanomas received margins consistent with national guidelines. Meanwhile, patients with non-facial tumors were more likely to be overtreated with margins beyond those required for optimal outcomes.
SLNB became a common part of melanoma management in the 1990s, but current evidence suggests it is no longer a routine requirement. The two most important prospective RCTs (MSLT1 and MSLT2) demonstrated that SLNB and subsequent completion lymphadenectomy does not improve overall survival or ten-year melanoma-specific survival. Even in patients with positive sentinel lymph nodes, completion lymphadenectomy provides no survival benefit compared to observation alone.
While SLNB status provides some prognostic information, it is markedly inferior to BAUSSS. When SLNB status is added to BAUSSS, the difference in predictive accuracy is only about 3%, with confidence limits often overlapping. Breslow thickness and Age are more powerful risk factors for mortality than SLNB positivity, with Breslow having a c-stat of 0.68-0.70 compared to SLNB's c-score of 0.60-0.63.
The SLNB is a particularly poor prognostic indicator for patients under 40 and over 60 years of age. In young patients, SLNB has high false-positive rates relative to actual mortality risk, potentially leading to unnecessary adjuvant drug therapy. In older patients, SLNB sensitivity is poor, with low positivity rates despite high actual mortality risk. The authors argue that age-dependent limitations of SLNB make BAUSSS a more reliable alternative for guiding adjuvant therapy decisions.
Several main drug groups have been shown to prolong survival in melanoma patients. BRAF inhibitors (dabrafenib, vemurafenib, encorafenib) target melanomas with the BRAF V600E mutation, occurring in about half of melanoma patients. These are typically combined with MEK inhibitors (trametinib, cobimetinib, binimetinib) for synergistic effect and reduced adverse events. The combination of dabrafenib and trametinib achieved 72% twelve-month survival and 28% five-year survival in unresectable stage 3 or 4 disease.
Immune checkpoint inhibitors represent perhaps the most encouraging drug class. PD-1 inhibitors (pembrolizumab, nivolumab, toripalimab, atezolizumab) block cancer cells from suppressing T-cell immune responses. Pembrolizumab achieved 55% two-year survival in unresectable or metastatic melanoma and was FDA-approved for high-risk primary melanoma following the Keynote-716 study. Nivolumab showed 52% three-year survival with a more favorable adverse event profile.
Adjuvant drug therapy is now considered for three main categories: nodal spread (Stage 3), distant metastases (Stage 4), and increasingly for high-risk primary melanomas even without identifiable metastatic disease and negative SLNB status. The Keynote-716 study demonstrated improved distant-metastasis-free survival for patients with Breslow greater than 2 mm with ulceration or Breslow over 4 mm regardless of ulceration.
Ipilimumab (anti-CTLA4) has shown benefit in combination with nivolumab, particularly for brain metastases, but severe adverse events occur in over half of patients. Combination therapy with nivolumab achieved 58% three-year survival but 59% grade 3 or greater adverse events. Shared decision-making with patients regarding the balance of potential survival benefit against significant side effects is essential.
Total body photography (TBP) is increasingly used in melanoma follow-up, particularly for higher-risk patients who stand to benefit the most. Second melanomas are found at earlier Breslow thickness when TBP is employed. The risk of developing a second melanoma ranges from 4.6% to 7.9% and does not decline after 10 years, supporting the argument for lifelong skin surveillance rather than discharge at 5 or 10 years.
Melanoma management must include advice on lifelong sun protection and UV minimization. Cumulative sun exposure is a risk factor for further melanoma. Occupational therapy has an important role in assessing workplace and home UV exposure, potentially rescheduling outdoor activities to avoid peak UV hours between 11:00 a.m. and 3:00 p.m. Wearable UV-exposure monitoring devices are also recommended.
Vitamin D supplementation should be considered for melanoma patients, as improved melanoma outcomes may be achievable through non-solar vitamin D sources. The role of nicotinamide supplements remains unclear for melanoma specifically, though they have been shown to reduce squamous and basal cell carcinomas in skin cancer patients. Psychosocial support services should also be offered, as a melanoma diagnosis brings significant psychological and social difficulties for patients and their families.
When a cutaneous melanoma is suspected, an excision biopsy with a narrow margin should be undertaken in most circumstances, followed by wide excision after diagnosis. For melanomas likely in situ or invasive but under 1 mm Breslow, a single diagnostic-plus-therapeutic procedure may be appropriate when the clinician is confident in their clinical assessment.
The BAUSSS biomarker incorporating Breslow thickness, Age, Ulceration, Subtype, Sex, and Site provides a more accurate method of assessing high-risk melanoma patients than SLNB-based approaches. It avoids the added costs, hospitalization, anesthesia, and complications of sentinel node surgery while being integral to the future selection of patients for adjunctive drug therapy.
The authors emphasize that future clinical trials should not require SLNB positivity for enrollment in adjuvant drug therapy studies, as this erroneously restricts access to potentially life-saving treatments. Patients who decline or are not offered SLNB must not be denied access to drugs that can treat their disease, particularly those with clearly high mortality risk on the BAUSSS biomarker. ADT trials should increasingly use BAUSSS-based risk thresholds for enrollment eligibility.