The limited value of sentinel lymph node biopsy in lentigo maligna melanoma: A nomogram based on the results of 29 years of the nationwide dutch pathology registry (PALGA).

BACKGROUND: Lentigo maligna melanoma (LMM) predominantly presents in the head and neck of the elderly. The value of sentinel lymph node biopsy (SLNB) for LMM patients remains to be determined, as the reported average yield of positive lymph nodes is less than 10%. In this nationwide cohort study, we wanted to identify LMM patients with an increased risk of SLNB-positivity. METHODS: LMM with an SLNB indication according to the 8th AJCC melanoma guidelines were retrospectively identified from the nationwide network and registry of histo- and cytopathology in the Netherlands (PALGA). A penalized (LASSO) logistic regression analysis was performed to determine the optimal combination of clinicopathological factors to predict a positive SLNB. RESULTS: Between 1991 and 2020, 1989 LMM patients met our inclusion criteria. SLNB was performed in 16.7% (n = 333) and was positive in 7.5% (25/333). The false-negative rate was 21.9%. Clinically detectable regional lymph node (LN) metastases were found in 1.3% (n = 25). Clinicopathological characteristics best predictive for SLNB-positivity (Odds ratio; 95% CI) were age (0.95; 0.91-0.99), ulceration 1.59 (0.44-4.83), T4-stage (1.81; 0.43-6.2), male sex (1.97; 0.79-5.27), (lymph)angioinvasion (5.07; 0.94-23.31), and microsatellites (7.23; 1.56-32.7) (C-statistic 0.75). During follow-up, regional LN recurrences were detected in 4.2% (83/1989) of patients, of which the majority (74/83) had no evidence of regional LN metastases at baseline. CONCLUSION: Our findings confirm the limited SLNB-positivity in LMM patients. Based on the identified high-risk clinicopathological features, a nomogram was developed to predict the risk of a positive SLNB.

IFN-γ signature enables selection of neoadjuvant treatment in patients with stage III melanoma.

Neoadjuvant ipilimumab + nivolumab has demonstrated high pathologic response rates in stage III melanoma. Patients with low intra-tumoral interferon-γ (IFN-γ) signatures are less likely to benefit. We show that domatinostat (a class I histone deacetylase inhibitor) addition to anti-PD-1 + anti-CTLA-4 increased the IFN-γ response and reduced tumor growth in our murine melanoma model, rationalizing evaluation in patients. To stratify patients into IFN-γ high and low cohorts, we developed a baseline IFN-γ signature expression algorithm, which was prospectively tested in the DONIMI trial. Patients with stage III melanoma and high intra-tumoral IFN-γ scores were randomized to neoadjuvant nivolumab or nivolumab + domatinostat, while patients with low IFN-γ scores received nivolumab + domatinostat or ipilimumab + nivolumab + domatinostat. Domatinostat addition to neoadjuvant nivolumab ± ipilimumab did not delay surgery but induced unexpected severe skin toxicity, hampering domatinostat dose escalation. At studied dose levels, domatinostat addition did not increase treatment efficacy. The baseline IFN-γ score adequately differentiated patients who were likely to benefit from nivolumab alone versus patients who require other therapies.

A cohort analysis of surgically treated primary head and neck lentigo maligna (melanoma): Prognostic value of melanoma subtype and new insights in the clinical value of guideline adherence.

BACKGROUND: Knowledge about lentigo maligna (melanoma) (LM/LMM) and its associated prognostic clinicopathological characteristics are limited compared to that of non-LM/LMM subtypes. The current study aimed to determine the clinical relevance of the LM/LMM subtype and its influence on recurrence and survival outcomes. METHODS: All consecutive cases of primary cutaneous head and neck LM/LMM treated by wide local excision over a ten-year period were retrospectively reviewed and compared to non-LM/LMM. Clinical outcome and prognostic factors were assessed by cumulative incidence and competing risk analyses. RESULTS: A total of 345 patients were identified. Specific clinicopathological characteristics such as lower median Breslow thickness (1.6 mm versus 2.1 mm; P = 0.013), association with diagnostic sampling errors (17.3% versus 5.2%; P = 0.01), and increased risk of local recurrences due to incomplete resection (18.7% versus 2.3%; P < 0.001), were significantly associated with LM/LMM. Guideline adherence was similar between the two study groups. The positive nodal status at baseline for LMM was low compared to non-LM/LMM (4.2% vs 17.9%; P = 0.037). The LMM subtype, facial localization, and reduced surgical margins (i.e., guideline non-adherence) were not shown to be independent prognostic factors for disease-free, melanoma-specific, or overall survival after correction for competing risks such as patient age and Breslow thickness. CONCLUSIONS: The LMM subtype was not shown to be prognostically different from non-LM/LMM when corrected for other variables of influence such as patient age and Breslow thickness. Reduced resection margins did not seem to affect disease-free, and melanoma-specific survival and warrant LM/LMM-specific guidelines. Further research is needed to evaluate the value of SLNB in LMM patients.

Severe blistering eruptions induced by immune checkpoint inhibitors: a multicentre international study of 32 cases.

Among dermatologic adverse events induced by immune checkpoint inhibitors (ICI), bullous life-threatening reactions are rare. To better define the clinical and histological features, treatment, and prognosis of ICI-related severe blistering cutaneous eruptions. This retrospective case series was conducted between 2014/05/15 and 2021/04/15 by the dermatology departments of four international registries involved in drug reactions. Inclusion criteria were age ≥18 years old, skin eruption with blisters with detachment covering ≥1% body surface area and at least one mucous membrane involved, available pictures, and ICI as suspect drug. Autoimmune bullous disorders were excluded. Each participant medical team gave his own diagnosis conclusion: epidermal necrolysis (EN), severe lichenoid dermatosis (LD), or unclassified dermatosis (UD). After a standardized review of pictures, cases were reclassified by four experts in EN or LD/UD. Skin biopsies were blindly reviewed. Thirty-two patients were included. Median time to onset was 52 days (3-420 days). Cases were originally diagnosed as EN in 21 cases and LD/UD in 11 cases. After review by experts, 10/21 EN were reclassified as LD/UD. The following manifestations were more frequent or severe in EN: fever, purpuric macules, blisters, ocular involvement, and maximal detachment. Most patients were treated with topical with or without systemic corticosteroids. Eight patients (25%) died in the acute phase. The culprit ICI was not resumed in 92% of cases. In three patients, another ICI was given with a good tolerance. Histology did not reveal significant differences between groups. Severe blistering cutaneous drug reactions induced by ICI are often overdiagnosed as EN. Consensus for management is pending.

Merkel Cell Carcinoma, the Impact of Clinical Excision Margins and Mohs Micrographic Surgery on Recurrence and Survival: A Systematic Review.

BACKGROUND: When treating Merkel cell carcinoma (MCC), the relation between wide local excision (WLE) margin and recurrence or survival is unclear. Mohs micrographic surgery (MMS) is an alternative surgical option for MCC, but it is unknown whether the local recurrence rate differs between MMS and WLE. OBJECTIVE: To systematically assess the available literature to determine the recurrence and survival rates when treating MCC with MMS and different clinical excision margins. MATERIALS AND METHODS: The MEDLINE, EMBASE, and CENTRAL databases were searched. Two independent reviewers selected studies that defined clear excision margins and either recurrence or survival. When possible, individual cases were extracted from case series and included in the analyses. Other studies were reviewed narratively. RESULTS: Overall, 1108 studies were identified; of which, 19 case series (168 cases) and 12 cohort studies were eligible. None of the cohort studies showed significant differences in recurrence or survival for either excision margins or MMS. Equally, logistic and Cox regression analyses of the case series revealed no significant differences in recurrence or survival between different excision margins and MMS. CONCLUSION: Synthesis of the available data does not indicate differences in recurrence and/or survival rates for MCC between different clinical excision margins and MMS.

Handheld reflectance confocal microscopy: Personalized and accurate presurgical delineation of lentigo maligna (melanoma).

BACKGROUND: The surgical treatment of lentigo maligna melanoma is associated with high rates of local recurrence. Handheld reflectance confocal microscopy (HH-RCM) allows for in vivo presurgical detection of subclinical lentigo maligna (melanoma) (LM/LMM). METHODS: A single-center retrospective study from December 2015 to July 2017. Frequency and extent of negative surgical margins, and the diagnostic accuracy of presurgical mapping by HH-RCM was determined. RESULTS: Twenty-six consecutive patients with LM/LMM were included. In 45.8%, HH-RCM detected subclinical LM with a sensitivity of 0.90 and specificity of 0.86. The management was changed in two (7.7%) patients. Of the 24 remaining lesions, 95.8% were excised with negative margins with a mean histological margin of 3.1 and 5.3 mm for LM and LMM, respectively. At a mean follow-up of 36.7 months, there was one (4.8%) confirmed recurrence. CONCLUSIONS: Our method of presurgical delineation by HH-RCM appears to provide a reliable method for the surgical treatment of LM/LMM with a limited rate of overtreatment.

Management of cytotoxic chemotherapy-induced hand-foot syndrome.

Improvements in systemic cancer treatments have resulted in more patients surviving for prolonged periods of time on treatment. This has made treatment-related toxicity and quality of life concerns increasingly relevant. Hand-foot syndrome (HFS) is a common skin reaction to systemic therapy that should be anticipated with chemotherapeutic treatments such as pegylated liposomal doxorubicin, docetaxel, and fluoropyrimidines. In this review we discuss current knowledge of the diagnosis, incidence, pathogenesis, and management of hand-foot syndrome (HFS). Although HFS is not life threatening, it can cause significant discomfort and impairment of function, especially in elderly patients, and may seriously impact quality of life. The incidence of HFS is dependent on the chemotherapeutic drug used, the treatment schedule, and the median duration of treatment. Effective measures for prevention and treatment of HFS include systemic and topical treatments, dose reductions, and switching to other drugs in the same class that are associated with lower rates of HFS. These approaches allow patients to continue cancer treatment while reducing negative impacts on quality of life. Awareness and early recognition are important to ensure timely treatment and avoidance of dose reductions or treatment discontinuation. We provide useful recommendations to guide the management of HFS in clinical practice.

Oncodermatology of the Head and Neck.

The European Academy of Facial Plastic Surgery celebrates its 40th anniversary. We aimed to describe innovations in the diagnostics and treatment in head and neck skin cancer over the past 40 years as well as future perspectives. Landmark events, developments, and highlights over the past decades for basal cell carcinoma, cutaneous squamous cell carcinoma, and melanoma are discussed.