Journal of Clinical and Aesthetic Dermatology • Hot Topics in Melanoma November 2024 • Meeting Highlights

The European Academy of Dermatology and Venerology (EADV) held its 33rd Congress on September 25–28, 2024, in Amsterdam, Netherlands. The conference gave researchers, physicians, and members of industry the opportunity to share and learn about the latest research in dermatology, including melanoma. The event included speaker presentations on various clinical topics in skin cancer, as well as posters reporting the latest data assessing surgical interventions and outcomes in melanoma. Summaries of key abstracts from the meeting are included here.

Microwave therapy for the treatment of cutaneous melanoma metastases. In this study, researchers evaluated the efficacy of nonablative microwave therapy in the treatment of nine patients with cutaneous melanoma metastases. Three metastases were measured, two of which (T1 and T2) received microwave therapy and one of which (T3) served as a control. Microwave therapy was well tolerated, though there were reports of short-term pain. Complete response at the T1 lesion occurred in three patients. After three weeks, T1 lesions showed a significant mean reduction of 67.6 percent, and T2 demonstrated a significant mean reduction of 38.7 percent. The volume of T3 lesions did not significantly change at three weeks, compared to baseline. There was a decrease in melanoma marker expression following microwave therapy, compared to pretreatment levels. Microwave therapy was associated with immune pathway induction, with more active induction observed in complete responders versus partial responders.

Vitiligo-like depigmentation as a predictor of prolonged response to immune checkpoint inhibitors in patients with advanced melanoma - single center experience. In this retrospective analysis, Popovic et al studied the impact of vitiligo-like depigmentation on survival outcomes among 109 patients with unresectable Stage III/IV melanoma. All patients were treated with immune checkpoint inhibitors (ICIs). Vitiligolike depigmentation occurred in 22 patients (20.2%), with a median time to onset of 10.44 months. Vitiligo-like depigmentation incidence was not associated with evaluated clinical or demographic factors, such as sex, Eastern Cooperative Oncology Group Performance Status (ECOG PS), and BRAF mutation status. Patients with vitiligo-like depigmentation had a superior overall response rate (ORR) of 72.7 percent, compared to patients without vitiligo-like depigmentation (ORR: 29.9%). The complete response rate was 31.8 percent in the vitiligo-like depigmentation group, compared to 13.8 percent of the non-vitiligo-like depigmentation group. Median progressionfree survival (PFS) and overall survival (OS) were significantly greater in patients with vitiligo-like depigmentation, compared to those without vitiligo-like depigmentation.

Examining melanoma Breslow thickness in relation to age, sex, and body site. Here, Eghlileb et al analyzed the potential association between Breslow thickness and anatomical location, age, and sex in primary melanoma. Data from 1,730 patients diagnosed between 2012 to 2022 were analyzed; cases of melanoma in situ, metastatic melanoma, atypical nevi, and lentigo maligna were excluded. Melanoma most frequently occurred on the posterior trunk of male patients and lower limbs of female patients. Compared to melanoma of the posterior thorax and limbs, head and neck melanoma had significantly greater Breslow thickness. Overall, male patients presented with thicker melanoma, compared to female patients. However, among patients over the age of 80 years, Breslow thickness was greater in female patients, compared to male patients. Breslow thickness was significantly greater among patients aged 60 to 80 years, compared to patients in other age groups. Further analysis showed that the peak incidence of lower limb melanoma occurred in patients aged 40 to 80 years, and head and neck melanoma was most common in patients over the age of 80 years.

Outcomes in patients with resected Stage III/IV melanoma treated with adjuvant targeted therapy or anti-PD-1 agents: a four-year analysis. Researchers assessed real-world outcomes and safety of adjuvant therapy among 163 patients with resected Stage III/IV melanoma. Patients were treated with targeted therapy (TT, dabrafenib+trametinib; n=82) or antiprogrammed cell death protein 1 therapy (IT; n=81); in the IT group, 63 patients received nivolumab and 18 received pembrolizumab. Over 48 months, the overall recurrence-free survival (RFS) rate was 54.9 percent, and the distant metastasis-free survival (DMFS) rate was 58.4 percent. RFS and DMFS did not significantly differ between the TT and IT groups. The 48-month OS rate was 66.5 percent, and as with RFS and DMFS, there were no significant differences in OS between the TT and IT groups. Additionally, there were no differences in RFS, DMFS, or OS in comparisons based on receipt of dabrafenib+trametinib, nivolumab, or pembrolizumab. The one-year adjuvant therapy cycle was completed by 75.7 percent of patients; 12.9 and 10.4 percent experienced treatment disruptions due to adverse events (AEs) and disease progression, respectively. A total of 68.3 percent of patients in the TT group experienced temporary disruption of adjuvant therapy, which was significantly greater than in the IT group (13.6%). Both groups had a similar rate of treatment discontinuation due to AEs (TT: 11.1%, IT: 14.8%). Mitoses, lymphovascular invasion, ulceration, and positive sentinel lymph nodes (SLNs) were identified as predictive factors for disease recurrence.

A comparison of the dermoscopic features of blue nevi and melanomas: a single-center retrospective study. Here, researchers utilized dermoscopy to assess and compare melanoma and blue nevus lesions (n=82) in 79 patients diagnosed between 2017 and 2024. Four patients with blue nevi had a prior history of skin cancer (basal cell carcinoma, n=3; melanoma, n=1). Mean lesion size was significantly larger for melanoma lesions (1.70cm), compared to blue nevi (0.62cm). A total of 25.8 and 62.7 percent of blue nevi and melanoma lesions, respectively, were skin-level, while 74.2 and 37.3 percent, respectively, were raised. Patient sex and location of lesion were not significantly different between melanoma and blue nevi. A total of 25.1 percent of melanoma lesions presented with atypical peripheral globules, compared to only 6.5 percent of blue nevi. There was a similar frequency of white and blue-gray structureless areas in both groups. Melanoma lesions with blue colored areas more commonly had irregular blue color borders and blue color borders that did not reach the peripheral extension, compared to blue nevi. In both groups, the minority of lesions contained vascular findings. Atypical network and ring structures were observed in 41.2 and 27.5 percent of melanoma lesions versus 3.2 and zero percent of blue nevi, which was a significant difference. All blue nevi lacked homogenous milky-red areas, compared to 78.4 percent of melanoma lesions.

Pembrolizumab cutaneous toxicities in 131 patients with metastatic melanoma: incidence, management, clinical implications and relationship with survival. In this retrospective review, researchers analyzed cutaneous toxicities among patients with metastatic melanoma who received pembrolizumab treatment between March 2016 and August 2020. Seventy-one cutaneous toxicities occurred in 57 of 131 patients (44%). The most common cutaneous toxicity was rash (n=52), followed by vitiligo (n=13), pruritus (n=3), xerostomia (n=2), and brittle nails (n=1). The vast majority of cutaneous toxicities were mild, with only two cases above Grade 2. However, only 28.2 percent of toxicities resolved. The most commonly prescribed treatments for cutaneous toxicities included emollients, hydrocortisone 0.5% to 1%, and antihistamines. Pembrolizumab was discontinued due to rash in two patients. PFS and OS were significantly superior in patients with rash or vitiligo, compared to patients without these toxicities.

Aquaporin 1, 8, and 9 expression: possible correlation with prognosis and clinical outcome on malignant melanoma. Analyzing formalin-fixed paraffin-embedded samples from 58 patients with malignant melanoma (nodular melanoma, n=14; superficial spreading melanoma, n=44) for aquaporin (AQP) 1, 8, and 9, researchers found that all nodular melanoma samples lacked AQP1. AQP8 and AQP9 were expressed in seven (50%) and eight (5.71%) nodular melanoma tissues, respectively. For superficial spreading melanoma samples, 11 (25%) expressed AQP1, 34 (77.3%) expressed AQP8, and 36 (83.7%) expressed AQP9. The differences in AQP expression between groups were not statistically significant. Further analysis indicated associations between the expression of AQPs and improved outcomes. AQP1 expression was significantly associated with low mitotic index, and there was a significant correlation between negative SLN and AQP8 expression. AQP9 expression showed a significant relationship with decreased Breslow thickness and absence of ulceration. Additionally, a nonsignificant improvement in OS with AQP expression was observed.

Mechanical force promotes the progression of acral melanoma via PIEZO1**.** Cao et al aimed to assess the relationship between mechanical force and acral melanoma progression, as well as characterize PIEZO1 expression in tumor tissues. Data from 279 patients with acral melanoma treated between January 2011 and December 2021 were analyzed. Acral melanoma lesions were frequently observed at high-pressure areas of the body, including thumbs, heels, and lesser toes, and in 105 patients, Breslow depth was observed in these areas. Among 64 patients with plantar acral melanoma, lesions and Breslow depth of the lesions were largely concentrated in the highpressure area. Further analysis of this patient subgroup illustrated that the center of mass of lesions fit well with the trajectory of the plantar center of pressure, and the number of center of mass showed a significant correlation with peak plantar pressure. Acral melanoma lesions had significantly greater PIEZO1 expression, compared to non-acral melanoma lesions and nevi. Patients with elevated PIEZO1 expression had significantly inferior OS, compared to those with low expression.

The role of miR-146a-5p and miR-21-5p in cutaneous melanoma as diagnostic and prognostic biomarkers. Here, researchers evaluated miR-146a-5p and miR-21-5p expression in superficial spreading melanoma (n=116), lentigo maligna melanoma (n=28), and nodular melanoma (n=26). Expression of both microribonucleic acids (miRNAs) was significantly elevated in nodular melanoma, compared to superficial spreading and lentigo maligna melanoma. Among all cutaneous melanomas and in superficial spreading melanoma, there was a significant difference in miRNA expression based on Breslow thickness (≥0.8 mm vs. <0.8mm). Cases of cutaneous melanoma with ulceration showed increased expression of miR-21-5p. Ulceration and mitotic rate of 1/mm2 or greater were significantly associated with increased expression of both miR-146a-5p and miR- 21-5p. Cases of lentigo maligna melanoma without regression showed significantly lower expression of both miRNAs, compared to cases of lentigo maligna melanoma with regression. According to univariate analysis, miRNA expression could better stratify patients with a Breslow thickness of 0.8mm or greater without ulceration into prognostic groups.

New insight in dermoscopy of lentigo maligna/lentigo maligna melanoma. In this retrospective analysis, researchers analyzed data from 153 patients with lentigo maligna/lentigo maligna melanoma to better characterize their dermoscopic features. Patients were diagnosed between January 2011 and March 2023. Mean age was 72 years, and 56.2 percent of patients were male. Most patients (n=112; 73.2%) had lentigo maligna, and 41 (26.8%) had lentigo maligna melanoma. Mean Breslow thickness was 0.7mm for the lentigo maligna group and 2.1mm for the lentigo maligna melanoma group. Several subtypes of lentigo maligna/lentigo maligna melanoma were identified, the first meeting the classical criteria of lentigo maligna. Other subtypes included solar lentigo/seborrheic keratosislike lesions with homogenous brown coloring and a well-defined border; nevus-like, small, dark, well-defined lesions; gray macules; and hypopigmented/amelanotic lesions. The latter two subtypes appeared similar to pigmented actinic keratosis/lichen planuslike keratosis and actinic keratosis/Bowen’s disease, respectively. Dermoscopy revealed a prevalence of irregularly distributed pseudonetwork, identified in 84.3 percent of cases, and dots, identified in 77.8 percent of cases. The most common classical features of lentigo maligna were hyperpigmented follicular opening (67.3%) and short streaks (59.5%). Other classical criteria, including obliterated hair follicles, annular-granular pattern, and pigmented rhomboidal structures, were observed in less than half of all cases.

Integrating RNA tape stripping and dermoscopy for comprehensive melanoma diagnosis. Here, researchers assessed the utility of RNA tape stripping, alongside dermoscopy (7-point checklist), in the diagnosis of melanoma. Seventy-five suspicious lesions underwent RNA tape stripping prior to surgical excision, 18 of which were histopathologically proven to be malignant melanoma. Two lesions were identified as basal cell carcinoma, and 53 lesions were nonmalignant. RNA tape stripping demonstrated 100-percent sensitivity for malignant lesions. It detected 25 percent of nonmalignant lesions, giving it a specificity of 25 percent. The 7-point checklist failed to identify four malignant melanoma lesions, and it had a sensitivity and specificity of 78 and 58 percent, respectively. Lesions with atypical network or regression structures identified via dermoscopy demonstrated significant variations in RNA profiles.

Efficacy and safety of nivolumab and ipilimumab combination versus ipilimumab alone for skin melanoma: a systematic review and meta-analysis. In this review and meta-analysis of three studies, researchers found that combination nivolumb and ipilimumab showed significantly inferior OS compared to ipilimumab monotherapy. Ipilimumab monotherapy also demonstrated significantly improved PFS over combination nivolumab and ipilimumab. Further analysis revealed that ipilimumab monotherapy was associated with better rates of objective response, complete response, and partial response, compared to combination therapy. Only one significant difference in safety outcomes was reported; ipilimumab monotherapy was associated with a greater risk of fatigue, compared to combination nivolumab and ipilimumab.

Melanoma metastases to the scalp: a case series. In this study, researchers assessed cases of melanoma with scalp metastases diagnosed between 2012 to 2022 to identify clinical features, prognosis, and treatment patterns. Among 13 patients, eight (61.5%) were women, and the median age at diagnosis was 65 years. Nine patients (69.2%) had primary melanoma of the head and neck. The median Breslow thickness of primary tumors was 1.2mm. The most common primary melanoma subtype was superficial spreading melanoma (30.7%), followed by lentigo maligna melanoma (23%). Among tumors with staging information, Stage T3a was the most common (23%), followed by T1a and T2a (both 15.4%) and T1b and T4a (both 7.7%). Four patients had c-KIT mutations, and two patients each had BRAF, GNA11, and NRAS mutations. One patient had deletions at several genes, including BRCA1. Patients experienced a 16-month median time to scalp metastasis. Ten primary melanomas and three scalp metastases were treated with local excision. Five patients underwent chemotherapy for scalp metastases. Median time from diagnosis of scalp metastasis to death was 24 months.

Beta-blockers and cutaneous melanoma outcomes: a systematic review and meta-analysis. Beta-blockers have shown promise in improving outcomes in melanoma, but more research is required on this subject. As such, Muller et al evaluated 12 articles including 21,582 patients with melanoma, 4,904 who used beta-blockers and 16,678 who did not use beta-blockers, to determine the impact of beta-blocker use on cutaneous melanoma outcomes. Melanomaspecific survival (MSS) was not associated with beta-blocker use, and interstudy heterogeneity was low. Additionally, there was no association between OS and beta-blocker use, but interstudy heterogeneity was high. Studies showed nonsignificant trends toward increased MSS and OS with beta-blocker use. It should be noted that most patients use cardioselective beta-blockers, rather than nonselective beta-blockers, which might have influenced the results. For instance, some studies showed trends toward improved MSS and OS among patients who used nonselective beta-blockers, compared to patients who did not use beta-blockers, whereas cardioselective beta-blocker use showed no trends toward improved survival outcomes. There was a significant association between beta-blocker use and disease-free survival (DFS); however, all studies on DFS were conducted by one group, and as such, this finding is limited in its generalizability. RFS was evaluated in one study, and no significant association between beta-blocker use and RFS was found.

RESEARCH BITE—31-gene expression profile testing in cutaneous melanoma and survival outcomes in a population-based analysis: a SEER collaboration

Bailey et al evaluated the real-world utility of 31-gene expression profile (31-GEP) testing to stratify risk of melanoma-specific survival (MSS) and overall survival (OS) in patients with Stage I to III cutaneous malignant melanoma (n=4,687). Three-year MSS was significantly higher in patients with a Class 1A result (low risk; 99.7%), compared to those with Class 1B/2A (intermediate risk; 97.1%) and Class 2B (high risk; 89.6%) results. Similarly, patients with a Class 1A result had a three-year OS of 96.6 percent, which was significantly greater than the OS of patients with Class 1B/2A (90.2%) and Class 2B (79.4%) results. Multivariable analysis identified 31-GEP Class 1B/2A and Class 2B results as independent predictors of MSS and OS.

Source: Bailey CN, Martin BJ, Petkov VI, et al. 31-gene expression profile testing in cutaneous melanoma and survival outcomes in a population-based analysis: a SEER collaboration. JCO Precis Oncol. 2023;7:e2300044.

RESEARCH BITE—The roles of genetic mutation and cytokines/ chemokines in immune response and their association with uveal melanoma patient outcome

Among 188 patients with uveal melanoma, the most common genetic mutation was GNAQ (46.8%), followed by GNA11 (46.3%), BAP1 (26.6%), and SF3B1 (20.7%). Univariate analysis showed an association between GNAQ mutation and improved progression-free survival (PFS) and disease-specific survival (DSS); SF3B1 mutation was also linked to longer DSS. There was an association between BAP1 mutation and inferior PFS and DSS, and multivariable analysis demonstrated that BAP1 mutation was significantly associated with worse overall survival (OS). Increased expression of PDCD1, CXCL9, CXCL10, tumor-necrosis factor, and interleukin-6 were predictive of worse OS. Additionally, greater CD8+ T cell expression was significantly associated with inferior OS.

Source: Yong Liu, Huang Y, Zhao C, Zhou X, Lu J, Fang S. The roles of genetic mutation and cytokines/chemokines in immune response and their association with uveal melanoma patient outcome. Heliyon. 2024;10(18):e37852.

RESEARCH BITE—Social vulnerabilities in head-neck melanoma care: a retrospective cohort study in the United States

Here, researchers analyzed data from the Surveillance, Epidemiology, and End Results (SEER) database to determine the impact of social determinants of health (SDH) on patients with head and neck melanoma. In various melanoma subtypes (e.g., amelanotic, lentigo maligna, nodular), increasing vulnerability, measured by the Centers for Disease Control and Prevention-Social Vulnerability Index (CDC-SVI), was associated with lower likelihood of undergoing surgery. Patients with epithelioid cell melanoma, malignant melanoma not otherwise specified, and nodular melanoma who had higher total CDC-SVI vulnerability experienced higher odds of undergoing radiation therapy. Additionally, the likelihood of advanced disease stage at presentation was linked to increased with incresing total CDC-SVI vulnerability in cases of nodular melanoma, malignant melanoma not otherwise specified, and acral lentiginous melanoma malignant.

Source: McCampbell L, Fei-Zhang DJ, Chelius D, et al. Social vulnerabilities in head-neck melanoma care: a retrospective cohort study in the United States. JAAD Int. 2024;17:37–47.