Targeted therapy or immunotherapy in BRAF-mutated metastatic melanoma: a Spanish center's decade of experience.

Background: Targeted therapies and immunotherapy are currently considered the mainstay first-line treatment for advanced BRAF-mutated melanoma. However, the impact of treatment (targeted therapy and immunotherapy) and the prognostic factors are still not clear. Material and methods: Medical records of 140 patients diagnosed with advanced melanoma between 2011 and 2021 were retrospectively reviewed to extract demographic, BRAF status, treatment, performance status, and survival data. ORR, PFS, and OS were compared between patients diagnosed with advanced melanoma and treated with first-line IT or BRAF/MEKi. The prognostic factors were assessed using Cox regression models. Results: In all patients and those treated with immunotherapy, we did not find any effect of BRAF status on ORR, PFS, or OS. In patients with BRAF-mutated melanoma, ORR was 43.8% vs. 70% (P=0.04), PFS was 19.2 vs. 11.5 months (p=0.22), and OS was 33.4 vs. 16.4 months for the immunotherapy and targeted therapy groups, respectively (P=0.04). ECOG, presence of brain metastases, and high LDH level from initiation of first-line treatment were all associated with differences in PFS and OS. Conclusion: Patients with advanced BRAF-mutated melanoma treated with first-line immunotherapy had a significantly longer PFS and OS than those treated with first-line BRAF/MEKi; however, first-line BRAF/MEKi treatment had a significantly higher ORR than first-line immunotherapy.

Melanoma-specific survival is worse in the elderly: a multicentric cohort study.

We aimed to characterise cutaneous melanoma in the elderly and determine its association with poorer prognosis. We studied a prospective cohort of the melanoma population in Catalonia between 2012 and 2016. We compared young patient group (<75 years old) with elderly patient group (≥75 years old). We included 3009 patients (52.5% women) from 14 centres, with a mean age at diagnosis of 61.1 years. In the ≥75-year-old group there was a predominance of men (53.9% vs. 45.5%, P  < 0.001), melanoma was more frequently located in the head and neck area (37.7% vs. 15.5%, P  < 0.001) and lentigo maligna melanoma subtype was significantly more frequent (31.4% vs. 11.6%, P  < 0.001), as were nodular melanoma and acral lentiginous melanoma ( P  < 0.001). In older people, Breslow index, the presence of ulceration and mitotic rate were higher than in younger people. Kaplan-Meier survival curves showed longer melanoma-specific survival (MSS) and melanoma-free survival (MFS) in <75-year-old group compared to the elderly group. Cox regression models demonstrated reduced MSS in patients ≥75 years regardless of gender, location, IB, ulceration and lymph node status at diagnosis (HR 1.54, P  = 0.013) whereas MFS was not independently associated with elderly when head and neck location was considered. Age appears to be an independent risk factor for MSS but not for MFS. Worse melanoma prognosis in elderly could be explained by factors unrelated to the tumour, such as age-related frailty and comorbidities that limit the access to systemic treatments and, eventually, age-related immune dysfunction.

Spaghetti Technique Versus Wide Local Excision for Lentigo Maligna Affecting the Head and Neck Regions: Surgical Outcome and Descriptive Analysis of 79 Cases from a Single Practice Cohort.

INTRODUCTION: Lentigo maligna is a subtype of melanoma in situ that typically affects the head and neck region with an increasing incidence. Margin-controlled techniques, such as spaghetti technique (ST), have gained popularity over wide local excision (WLE) with a margin of 5 mm. OBJECTIVES: To evaluate the outcomes of lentigo maligna cases in the head and neck area treated by either WLE or ST in a tertiary referral hospital. The secondary goal was to describe the demographic and clinical characteristics of our series. METHODS: Cohort study of patients diagnosed with lentigo maligna on the head and neck region between January 2014 and February 2022 in a tertiary hospital. RESULTS: In total, 79 lentigo maligna were studied, corresponding to 77 patients. Fifty-three lesions (67%) were treated with WLE and 26 (33%) with ST. The mean age of the patients was 73 years and 58% were men. Most of the tumors were located on the cheek (50%) and mean lesion diameter was 2.2 cm for the ST group and 1.2 cm for the WLE group. Mean duration follow-up was 44 months. There were two local recurrences in the WLE group (2/53; 3.7%) and none in the ST group. CONCLUSIONS: Both WLE and ST are appropriate surgical approaches for lentigo maligna. ST offers an efficient alternative to Mohs surgery for treating lentigo maligna in the head and neck area, especially when guided by reflectance confocal microscopy.

Challenges for New Adopters in Pre-Surgical Margin Assessment by Handheld Reflectance Confocal Microscope of Basal Cell Carcinoma; A Prospective Single-center Study.

Introduction: In vivo reflectance confocal microscopy (RCM) is a useful tool for assessing pre-surgical skin tumor margins when performed by a skilled, experienced user. The technique, however, poses significant challenges to novice users, particularly when a handheld RCM (HRCM) device is used. Objectives: To evaluate the performance of an HRCM device operated by a novice user to delineate basal cell carcinoma (BCC) margins before Mohs micrographic surgery (MMS). Methods: Prospective study of 17 consecutive patients with a BCC in a high-risk facial area (the H zone) in whom tumor margins were assessed by HRCM and dermoscopy before MMS. Predicted surgical defect areas (cm2) were calculated using standardized photographic digital documentation and compared to final defect areas after staged excision. Results: No significant differences were observed between median HRCM-predicted and observed surgical defect areas (2.95 cm2 [range: 0.83-17.52] versus 2.52 cm2 [range 0.71-14.42]; P = 0.586). Dermoscopy, by contrast, produced significantly underestimated values (median area of 1.34 cm2 [0.41-4.64] versus 2.52 cm2 [range 0.71-14.42]; P < 0.001). Confounders leading to poor agreement between predicted and observed areas were previous treatment (N = 5), a purely infiltrative subtype (N = 1), and abundant sebaceous hyperplasia (N = 1). Conclusions: Even in the hands of a novice user, HRCM is more accurate than dermoscopy for delineating lateral BCCs margins in high-risk areas and performs well at predicting final surgical defects.

Sentinel Lymph Node Biopsy vs. Observation in Thin Melanoma: A Multicenter Propensity Score Matching Study.

The therapeutic value of sentinel lymph node biopsy (SLNB) in thin melanoma remains controversial. The aim of this study is to determine the role of SLNB in the survival of thin melanomas (≤1 mm). A multicenter retrospective observational study was designed. A propensity score matching was performed to compare patients who underwent SLNB vs. observation. A multivariate Cox regression was used. A total of 1438 patients were matched by propensity score. There were no significant differences in melanoma-specific survival (MSS) between the SLNB and observation groups. Predictors of MSS in the multivariate model were age, tumor thickness, ulceration, and interferon treatment. Results were similar for disease-free survival and overall survival. The 5- and 10-year MSS rates for SLN-negative and -positive patients were 98.5% vs. 77.3% (p < 0.001) and 97.3% vs. 68.7% (p < 0.001), respectively. SLNB does not improve MSS in patients with thin melanoma. It also had no impact on DSF or OS. However, a considerable difference in MSS, DFS, and OS between SLN-positive and -negative patients exists, confirming its value as a prognostic procedure and therefore we recommend discussing the option of SLNB with patients.

Differences in cutaneous melanoma survival between the 7th and 8th edition of the American Joint Committee on Cancer (AJCC). A multicentric population-based study.

BACKGROUND: The 8th edition of the AJCC manual for melanoma includes many changes leading to major substage migrations, which could lead to important clinical reassessments. OBJECTIVES: To evaluate the differences and prognostic value of the 8th AJCC classification in comparison with the 7th edition. METHODS: Clinical and histopathological data were retrieved from five melanoma referral centers including 7815 melanoma patients diagnosed between January 1998 and December 2018. All patients were reclassified and compared using the 7th and 8th classifications of the AJCC. Sankey plots were used to evaluate the migration of patients between the different versions. The primary outcome was overall survival (OS), and curves based on the Kaplan-Meier method were used to investigate survival differences between the 7th and 8th editions. RESULTS: The number of patients classified as stages IB, IIIA, and IIIB decreased while the patients classified as stages IA and IIIC increased notably. Migration analysis showed that many patients in group I were understaged whereas a significant percentage of patients in group III were upstaged. Indirect OS analysis showed a loss in the linearity in the AJCC 8th edition and the groups tended to overlap. Direct OS analysis between groups and versions of the AJCC showed a better prognosis within the new stage III patients, with no effect on those in stages I and II. CONCLUSION: The 8th AJCC edition represents an important change in the classification of patients. We observe that the main migratory changes occur in stage I and III, that severity linearity is lost and groups overlap, and that a more advanced stage does not mean a worse prognosis.

Incidence of Melanoma in Catalonia, Spain, Is Rapidly Increasing in the Elderly Population. A Multicentric Cohort Study.

The incidence of melanoma has been increasing worldwide during recent decades. The objective of the study was to analyse the trends in incidence for in situ and invasive melanoma in the Spanish region of Catalonia during the period of 2008-2017. We designed a cross-sectional study with an age-period-cohort analysis of melanoma patient data from the Network of Melanoma Centres in Catalonia. Our database covered a population of over seven million and included a total of 8626 patients with incident melanoma. The main outcome measures were crude and age-standardised incidence rates to the European 2013 standard population. Joinpoint regression models were used to evaluate the population trends. We observed an increase in the age-standardised incidence rate (per 100,000 population) of all melanoma subtypes from 11.56 in 2008 to 13.78 in 2017 with an average annual percent change (AAPC) of 3.5%. This incidence increase was seen exclusively in the older population. Moreover, the stratified analysis showed a statistically significant increase in the age-standardised incidence rate for invasive (AAPC 2.1%) and in situ melanoma (AAPC 6.5%). In conclusion, the incidence of melanoma has continued to increase in the elderly population over recent decades, with a rapidly increasing trend of in situ melanomas and the lentigo maligna subtype.

Vemurafenib-induced histiocytoid neutrophilic panniculitis simulating myeloid leukaemia cutis.

Neutrophilic panniculitis is an infrequent but characteristic adverse event under therapy with BRAF inhibitors (BRAFi). Since the approval of vemurafenib for treatment of metastatic melanoma in 2011, only two cases of neutrophilic panniculitis in malignancies other than melanoma have been published. Histiocytoid infiltrates of immature neutrophils resembling histiocytes or myelocytes have been reported in Sweet's syndrome and rarely in other neutrophilic dermatoses. We describe a novel variant of neutrophilic panniculitis with histiocytoid myeloid cells in an early lesion from a patient treated with vemurafenib in combination with an anti-EGFR (epidermal growth factor receptor) agent for metastatic colon carcinoma, three weeks after initiation of therapy. Recognizing this variant of panniculitis associated to BRAFi can avoid misinterpretation of the atypical subcutaneous infiltrate as myeloid leukaemia cutis.

PDL1 expression in desmoplastic melanoma is associated with tumor aggressiveness and progression.

BACKGROUND: The prognostic role of programmed death ligand 1 (PDL1), CD8, and forkhead box p3 (FoxP3) expression in desmoplastic melanomas is unclear. METHODS: We correlated PDL1, p53, and Ki-67 expression with CD8+ and FoxP3+ immune infiltrates with clinicopathologic variables and patient outcomes in a series of 66 desmoplastic melanomas. RESULTS: Tumoral PDL1 expression (≥25%), which was seen in 21% of patients (14 of 66), significantly correlated with mixed histology, tumor thickness, mitoses, recurrence, and metastasis. According to linear regression analysis, tumoral PDL1 expression correlated with thickness (P = .0041); p53 expression (P = .019); Ki-67 proliferation index (P = .0018); and tumoral CD8 (P = .0084), stromal CD8 (P < .0001), and FoxP3 (P < .0001) T-cell counts. According to univariate analyses, PDL1 expression of 25% or higher correlated with shorter progression-free survival (P < .0001) and melanoma-specific survival (P = .034). According to multivariate analyses, PDL1 expression of 25% or more (P = .026) and mixed histology (P = .039) independently predicted shorter progression-free survival, and presence of lymphovascular invasion predicted shorter overall survival (P = .018). LIMITATIONS: Small study size. CONCLUSION: Tumoral and stromal CD8+ and FoxP3+ lymphocyte counts correlated with tumoral PDL1 expression, which is supportive of an adaptive immune response. PDL1 expression in desmoplastic melanoma was associated with tumor aggressiveness and progression. Although PDL1 expression is typically low in melanoma, its frequency and level of expression in desmoplastic melanoma may identify a subset of melanomas that are likely to respond to immunotherapy.