Double Immunohistochemical Labelling of PRAME and Melan A in Slow Mohs Biopsy Margin Assessment of Lentigo Maligna and Lentigo Maligna Melanoma.

Introduction: Lentigo maligna (LM) and lentigo maligna melanoma (LMM) predominantly affect the head and neck areas in elderly patients, presenting as challenging ill-defined pigmented lesions with indistinct borders. Surgical margin determination for complete removal remains intricate due to these characteristics. Morphological examination of surgical margins is the key form of determining successful treatment in LM/LMM and underpin the greater margin control provided through the Slow Mohs micrographic surgery (SMMS) approach. Recent assessments have explored the use of immunohistochemistry (IHC) markers, such as Preferentially Expressed Antigen in Melanoma (PRAME), to aid in LM/LMM and margin evaluation, leveraging the selectivity of PRAME labelling in malignant melanocytic neoplasms. Methods: A Novel double-labelling (DL) method incorporating both PRAME and MelanA IHC was employed to further maximise the clinical applicability of PRAME in the assessment of LM/LMM in SMMS biopsies. The evaluation involved 51 samples, comparing the results of the novel DL with respective single-labelling (SL) IHC slides. Results: The findings demonstrated a significant agreement of 96.1% between the DL method and SL slides across the tested samples. The benchmark PRAME SL exhibited a sensitivity of 91.3% in the SMMS specimens and 67.9% in histologically confirmed positive margins. Discussion: This study highlights the utility of PRAME IHC and by extension PRAME DL as an adjunctive tool in the assessment of melanocytic tumours within staged excision margins in SMMS samples.

Nevus-associated Lentigo Maligna and Lentigo Maligna Melanoma, Clinicopathological Features.

Nevus-associated lentigo maligna and lentigo maligna melanoma (NALMM) are rarely described in the literature and are considered an incidental finding. This study aimed to evaluate the frequency of NALMM and its clinicopathological features. A total of 201 histopathology reports were reviewed and among them 20% of the samples corresponded to NALMM, with females overrepresented in this group (p = 0.02). A significant association was also observed between NALMM with the presence of multiple nevi (p = 0.01), and dysplastic nevi (p = 0.04). Moreover, the risk of developing a second melanoma of nevus-associated type was 4.3 times higher in patients with NALMM. These results indicate that NALMM is more frequent than previously reported, suggesting that the associated nevus could interact or even act as a precursor for LM/LMM. Future studies with larger samples allied to techniques like confocal microscopy and molecular analysis are essential to determine this biological link between nevus and LM/LMM.

Melanocyte Density in the Diagnosis of Melanoma In Situ in Sun-Damaged Skin.

ABSTRACT: Histologic differentiation between melanoma in situ in chronically sun-damaged skin (CSDS) [lentigo maligna (LM)] and CSDS without malignancy is difficult because signs of melanocyte activation and proliferation are found in both. A potentially reliable and quantifiable criterion is melanocyte density (MD). Here, we evaluated whether and to what extent MD allows the distinction between LM and CSDS, which is particularly relevant for the evaluation of borderline cases and surgical margins.Articles assessing MD in LM and/or CSDS were evaluated in a systematic review. The results were categorized and compared according to staining. Cutoff values were included whenever stated.Twenty articles matched the selection criteria. Six hundred forty-four samples of CSDS and 227 samples of LM were considered. In each individual study, mean MD scores were higher for LM than for CSDS. However, looking at the overall study situation, it becomes clear that the data are very heterogeneous and show overlaps. Therefore, no reliable orientation value can be derived. Only 1 article defined a cutoff value.The data of MD in LM in contrast to CSDS were sparse, and a defined cutoff value was only mentioned in 1 article for microphthalmia-associated transcription factor, which cannot yet be generalized. Especially regarding the importance for the definition of surgical resection margins, this unsatisfactory data set highlights the need for further studies. More precise diagnostic criteria could spare some patients extensive and possibly disfiguring surgery.

Incidence trends of lentigo maligna and lentigo maligna melanoma in the United States from 2000 to 2019.

BACKGROUND: Information on lentigo maligna (LM) and lentigo maligna melanoma (LMM) in the 21st century is scarce. We aimed to elucidate the incidence of LM and LMM using the Surveillance, Epidemiology, and End Results (SEER) 17 Registries. METHODS: The data of patients diagnosed between 2000 and 2019 were extracted from the SEER database. The percentage of LM/LMM cases among all melanoma patients, age-standardized incidence rates, estimated annual percentage changes, and the cumulative incidence of LMM after LM were calculated. RESULTS: The SEER data yielded 95,175 patients with LM/LMM between 2000 and 2019. Cases of LM/LMM accounted for 15.7% of all melanomas. The age-standardized incidence per 100,000 person-years for LM increased from 4.16 to 5.61 and for LMM from 1.33 to 2.35 between 2000 and 2019. The annual increase in incidence of LM was 2.42%, and that of LMM was 3.32%. The cumulative incidence of LMM after a primary LM after 10-year follow-up was 0.94%. CONCLUSIONS: This study provides the first comprehensive analysis of the epidemiological status of LM/LMM in the United States in the 21st century using the population-based SEER data.

The combination of dermoscopy and reflectance confocal microscopy increases the diagnostic confidence of amelanotic/hypomelanotic lentigo maligna.

The dermoscopic diagnosis of amelanotic/hypomelanotic lentigo maligna/lentigo maligna melanoma (AHLM/LMM) may be very difficult in its early stages because of lack of pigment. Reflectance confocal microscopy (RCM) is an imaging technique that is especially helpful for the diagnosis of lentigo maligna. To determine the diagnostic performances of dermoscopy and RCM in the diagnosis of AHLM/LMMs we evaluated dermoscopic and RCM images of consecutive cases of histopathologically confirmed AHLM/LMMs, amelanotic/hypomelanotic basal cell carcinoma and squamous cell carcinoma (AHBCCs/AHSCCs), amelanotic/hypomelanotic benign lesions (AHBLs), and actinic keratoses (AKs) from five participating centers. Sensitivity, specificity, accuracy, predictive values, and level of diagnosis confidence were calculated for both diagnostic procedures. Both dermoscopy and RCM showed diagnostic performance >97% in the diagnosis of AHLM/LMMs versus AHBCC/AHSCCs and their combination slightly improved diagnostic performance, with accuracy increasing from 98.0% to 99.1%. Similarly, RCM in combination with dermoscopy showed a tiny increase in the diagnostic performance in the diagnosis of AHLM/LMMs versus AHBLs (accuracy increased from 87.2% to 88.8%) and versus AKs (accuracy increased from 91.4% to 93.4%). Although the increase in diagnostic performance due to RCM was modest, the combination of dermoscopy and RCM greatly increased the level of confidence; high confidence in the diagnosis of AHLM/LMMs versus AHBLs increased from 36.2% with dermoscopy alone to 76.6% with dermoscopy plus RMC. Based on our results, dermoscopy and RCM should be complementary to improve not only diagnostic accuracy but also the level of diagnostic certainty in the diagnosis of AHLM/LMMs.

Lentigo maligna and lentigo maligna melanoma in patients younger than 50†years: a multicentre international clinical-dermoscopic study.

BACKGROUND: Lentigo maligna/lentigo maligna melanoma (LM/LMM) is usually diagnosed in older patients, when lesions are larger. However, it is important to detect it at an earlier stage to minimize the area for surgical procedure. OBJECTIVES: To determine and define clinical, dermoscopic and reflectance confocal microscopy (RCM) features of LM/LMM in patients < 50 years old. METHODS: This was a multicentre study involving tertiary referral centres for skin cancer management. The study included cases of consecutively excised LM/LMM arising in patients < 50 years of age with a histopathological diagnosis of LM/LMM and a complete set of clinical and dermoscopic images; RCM images were considered when present. RESULTS: In total, 85 LM/LMM of the face from 85 patients < 50 years were included in the study. A regression model showed a direct association with the size of the lesion (R2 = 0.08; P = 0.01) and with the number of dermoscopic features at diagnosis (R2 = 0.12; P < 0.01). In a multivariable analysis, an increasing number of dermoscopic features correlated with increased patient age (P < 0.01), while the presence of grey colour was a predictor of younger age at diagnosis (P = 0.03). RCM revealed the presence of melanoma diagnostic features in all cases (pagetoid cells and atypical nesting). CONCLUSIONS: LM is not a disease limited to older people as previously thought. LM presenting in young adults tends to be smaller and with fewer dermoscopic features, making its diagnosis challenging. Careful evaluation of facial pigmented lesions prior to cosmetic procedures is imperative to avoid incorrectly treating early LM as a benign lesion.

Lentigo maligna: a review.

Lentigo maligna (LM) is a melanoma in situ with distinct clinical features and histology. It commonly affects men after the sixth decade of life. Incidence rates of LM have increased based on early 21st century data from different countries; however, data are suboptimal. Data from England show a plateauing crude incidence between 2013 and 2019. By comparison, invasive melanoma and other types of melanoma in situ commonly appears in younger age groups (median age 58 and 67 years old, respectively) and incidence is rising. The most important risk factors for LM include fair skin and cumulative ultraviolet solar radiation exposure. Although LM is limited to the epidermis and connected skin adnexa, it may progress to invasive LM melanoma. The reported rate of malignant progression varies, reflecting a challenge for LM epidemiology research as often lesions are removed on diagnosis. LM poses a challenge in diagnosis and management. Although it can be diagnosed clinically or dermoscopically, histopathological assessment of biopsied skin tissue remains the gold standard. Reflectance confocal microscopy allows for better appreciation of the complexity of LM at a cellular level, often progressing beyond clinical margins. Management of LM may involve Mohs micrographic surgery or excision, although recurrence may occur even with 5 mm clinical margins. Imiquimod cream may be effective, but incomplete treatment and recurrence has been reported. Conservative management with observation or radiotherapy may be used in selected patients' cases. Five-year net survival rates are excellent. This paper reviews the natural history, epidemiology, aetiology, pathogenesis, diagnosis and management of LM.

Sentinel lymph node biopsy for lentigo maligna melanoma under local anaesthesia.

BACKGROUND: Lentigo maligna melanoma is mainly localized in the head and neck region in elderly patients. Due to its slow horizontal growth, it has a good prognosis compared to other melanoma subtypes, but specific data are rare. OBJECTIVES: The aim of this study was to investigate sentinel lymph node biopsy in lentigo maligna melanoma under local anaesthesia and to discuss the benefit. METHODS: Investigation of patients with lentigo maligna melanoma and tumour thickness ≥1 mm treated at the Department of Dermatology, University Medical Centre Tuebingen, between January 2008 and October 2019. RESULTS: In total, 204 patients (126 SLNB, 78 non-SLNB) with a median age of 75.7 years (SLNB: 73.3 years, non-SLNB: 79.7 years) could be included. Sixteen of 126 (12.7%) sentinel lymph nodes were positive. Five-year overall survival was 87.9% (88.5% SLNB; 87.4% non-SLNB) and 5-year distant metastasis-free survival was 85.8% (85.4% SLNB; 86.7% non-SLNB). There was no significant difference for distant metastasis-free survival (p = 0.861) and overall survival (p = 0.247) between patients with and without sentinel lymph node biopsy. CONCLUSIONS: Sentinel lymph node biopsy in lentigo maligna melanoma under local anaesthesia is a safe and simple method, even in very old patients. However, LMM has a very good 5-year overall survival. In high-risk patients with high tumour thickness and/or ulceration, adjuvant immunotherapy can now be offered without the need to perform this procedure.

Dermoscopy of Lentiginous Melanomas and Equivocal Benign Pigmented Macules of the Scalp: A Case-Control Multicentric Study.

INTRODUCTION: Although the dermoscopic features of facial lentiginous melanomas (LM), including lentigo maligna and lentigo maligna melanoma, have been extensively studied, the literature about those located on the scalp is scarce. This study aims to describe the dermoscopic features of scalp LM and assess the diagnostic accuracy of dermoscopy to discriminate them from equivocal benign pigmented macules. METHODS: Consecutive cases of scalp LM and histopathology-proven benign but clinically equivocal pigmented macules (actinic keratoses, solar lentigos, seborrhoeic keratoses, and lichen planus-like keratoses) from four referral centres were included. Dermoscopic features were analysed by two blinded experts. The diagnostic performance of a predictive model was assessed. RESULTS: 56 LM and 44 controls were included. Multiple features previously described for facial and extrafacial LM were frequently identified in both groups. Expert's sensitivity to diagnose scalp LM was 76.8% (63.6-87.0) and 78.6% (65.6-88.4), with specificity of 54.5% (38.9-69.6) and 56.8% (41.0-71.7), and fair agreement (kappa coefficient 0.248). The strongest independent predictors of malignancy were (OR, 95% CI) chaos of colour (15.43, 1.48-160.3), pigmented reticular lines (14.96, 1.68-132.9), increased density of vascular network (3.45, 1.09-10.92), and perifollicular grey circles (2.89, 0.96-8.67). The predictive model achieved 85.7% (73.8-93.6) sensitivity, 61.4% (45.5-75.6) specificity, and 81.5 (73.0-90.0) area under curve to discriminate benign and malignant lesions. A diagnostic flowchart was proposed, which should improve the diagnostic performance of dermoscopy. CONCLUSION: Both facial and extrafacial dermoscopic patterns can be identified in scalp LM, with considerable overlap with benign pigmented macules, leading to low specificity and interobserver agreement on dermoscopy.

Is sentinel lymph node biopsy needed for lentigo maligna melanoma?

BACKGROUND AND OBJECTIVES: Sentinel lymph node biopsy (SLNB) is an area of debate in the management of lentigo maligna melanoma (LMM). The utility of SLNB and its prognostic value in LMM have not yet been studied with large databases. METHODS: We performed a retrospective review of the National Cancer Database (2012-2020) and the Surveillance, Epidemiology, and End Results (2010-2019) database for patients with cutaneous nonmetastatic LMM with Breslow thickness >1.0 mm. Multivariable logistic regression identified factors associated with SLNB performance and sentinel lymph node (SLN) positivity. Univariable and multivariable analyses assessed overall survival (OS) and melanoma-specific survival (MSS) based on SLNB performance and SLN status. RESULTS: Compared to other melanoma subtypes, LMM had lower rates of SLNB (66.6% vs. 80.0%-84.0%) and SLN positivity (11.3% vs. 18.6%-34.2%). Compared to patients who did not undergo SLNB, SLN status was significantly associated with improved OS in patients with SLN positive (HR = 0.64 [0.55-0.76]) and SLN negative (HR = 0.68 [0.49-0.94]), and worse MSS only in patients with positive SLN (HR = 3.93, p < 0.05). CONCLUSION: The improved OS associated with SLNB likely implies surgical selection bias. Analysis of MSS confirms appropriate patient selection and suggests important prognostic value associated with SLN status. These results support continued SLNB for LMM patients according to standard guidelines.

Melanoma clinicopathological groups characterized and compared with dermoscopy and reflectance confocal microscopy.

BACKGROUND: Dermoscopic and reflectance confocal microscopy (RCM) correlations between morphologic groups of melanoma have not yet been described. OBJECTIVE: Describe and compare dermoscopic and RCM features of cutaneous melanomas with histopathological confirmation. METHODS: Single center, retrospective analysis of consecutive melanomas evaluated with RCM (2015-2019). Lesions were clinically classified as typical, nevus-like, amelanotic/nonmelanoma skin cancer (NMSC)-like, seborrheic keratosis (SK)-like and lentigo/lentigo maligna (LM)-like. Presence or absence of common facial and nonfacial melanoma dermoscopic and RCM patterns were recorded. Clusters were compared with typical lesions by multivariate logistic regression. RESULTS: Among 583 melanoma lesions, significant differences between clusters were evident (compared to typical lesions). Observation of dermoscopic features (>50% of lesions) in amelanotic/NMSC-like lesions consistently displayed 3 patterns (atypical network, atypical vascular pattern + regression structures), and nevus-like and SK-like lesions and lentigo/LM-like lesions consistently displayed 2 patterns (atypical network + regression structures, and nonevident follicles + heavy pigmentation intensity). Differences were less evident with RCM, as almost all lesions were consistent with melanoma diagnosis. LIMITATIONS: Small SK-like lesions sample, single RCM analyses (no reproduction of outcome). CONCLUSION: RCM has the potential to augment our ability to consistently and accurately diagnose melanoma independently of clinical and dermoscopic features.

Perifollicular linear projections: A dermatoscopic criterion for the diagnosis of lentigo maligna on the face.

BACKGROUND: Lentigo maligna (LM) can mimic benign, flat, pigmented lesions and can be challenging to diagnose. OBJECTIVE: To describe a new dermatoscopic feature termed "perifollicular linear projections (PLP)" as a diagnostic criterion for LM on the face. METHODS: Retrospective study on reflectance confocal microscopy and dermatoscopy images of flat facial pigmented lesions originating from 2 databases. PLP were defined as short, linear, pigmented projections emanating from hair follicles. Dermatoscopy readers were blinded to the final histopathologic diagnosis. RESULTS: From 83 consecutive LMs, 21/83 (25.3%) displayed "bulging of hair follicles" on reflectance confocal microscopy and 18 of these 21 (85.7%), displayed PLP on dermatoscopy. From a database of 2873 consecutively imaged and biopsied lesions, 252 flat-pigmented facial lesions were included. PLP was seen in 47/76 melanomas (61.8%), compared with 7/176 lesions (3.9%) with other diagnosis (P < .001). The sensitivity was 61.8% (95% CI, 49.9%-72.7%), specificity 96.0% (95% CI, 92.9%-98.4%). PLP was independently associated with LM diagnosis on multivariate analysis (OR 26.1 [95% CI, 9.6%-71.0]). LIMITATIONS: Retrospective study. CONCLUSION: PLP is a newly described dermatoscopic criterion that may add specificity and sensitivity to the early diagnosis of LM located on the face. We postulate that PLP constitutes an intermediary step in the LM progression model.

Racial-Ethnic, Education, and Socioeconomic Differences in the Treatment of Head and Neck Melanoma in situ: A Surveillance Epidemiology and End Results Population-Based Analysis.

BACKGROUND: Incidence and treatment disparities for cutaneous melanomas have been documented among racial and sociodemographic minorities. However, the association between treatment types, race, and socioeconomic status remains unknown. OBJECTIVE: To characterize treatment differences for head and neck melanoma in situ (MIS) and lentigo maligna (LM) based on race and sociodemographic variables. MATERIALS AND METHODS: A population-based retrospective cohort study of the Surveillance Epidemiology and End Results database (1998-2016) was performed. Univariate and multivariate logistic regression modeling evaluated the association of race and US census-reported sociodemographic factors with Mohs micrographic surgery (MMS) utilization. RESULTS: A total of 76,328 adult patients with head and neck MIS/LM were included. MMS accounted for 11.8% of total cases, with increased utilization observed since 1998-2002. Compared with areas with greater percentages of individuals completing high school (first quartile), patients living in the second (Odds ratio [OR] 0.71; 95% confidence interval [CI] 0.64-0.80; p < .001), third (OR 0.74; 95% CI 0.63-0.86; p < .001), and fourth quartiles (OR 0.44; 95% CI 0.35-0.55; p < .001) were less likely to undergo MMS for their MIS/LM. CONCLUSION: Educational efforts and awareness can bridge the knowledge gaps of appropriate treatment in patients with head and neck MIS/LM.

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.

Dermoscopy of atypical pigmented lesions of the face: Variation according to facial areas.

Atypical pigmented facial lesions (aPFLs)-including lentigo maligna (LM) and lentigo maligna melanoma (LMM), solar lentigo (SL), pigmented actinic keratosis (PAK), atypical nevi (AN), seborrheic keratosis (SK) and lichen planus-like keratosis (LPLK)-can exhibit clinical and dermoscopic overlapping features. We aimed to investigate if and how 14 dermoscopic features suggestive for the aforementioned aPFLs vary according to six facial sites among 1197 aPFLs cases (excised to rule out malignancy) along with lesion and patients' metadata. According to distribution and association analysis, aPFLs on the forehead of a male patient aged > 69 years displaying the obliterated follicular openings pattern, appear to be more at risk of malignancy. Of converse, aPFLs of the orbital/cheek/nose area with evident and regular follicular openings with diameter < 10 mm in a female aged below 68 are probably benign. The obliterated follicular openings, keratin plugs, evident and regular follicular openings and target-like pattern features differed significantly among six facial areas in all aPFLs cases. Lesion of the nose may show both features suggestive of malignancy and benignity (e.g. many SL and PAK may display target-like pattern and some LM/LMM cases display keratin plugs and evident and follicular openings), making these features less specific.

Prognosis in stage II melanoma of the head and neck depends on the histological subtype.

BACKGROUND AND OBJECTIVES: The melanoma guideline is mainly based on the AJCC stage. There is no difference according to histological subtypes such as superficial spreading melanoma (SSM), lentigo maligna melanoma (LMM) or nodular malignant melanoma (NM). We aimed to evaluate whether patients with LMM have a different clinical course from patients with SSM/NM. This is particularly important as adjuvant anti-PD-1 therapy is approved for stage IIB and IIC melanoma. PATIENTS AND METHODS: Data were extracted from the Central Registry of Malignant Melanoma. Only patients with LMM, SSM, and NM of the head and neck with primary diagnosis between 01/01/2000 and 12/31/2019 were included. Progression-free survival (PFS), melanoma-specific survival (MSS), and pattern of metastases were analyzed for the LMM group compared to SSM/NM. RESULTS: The LMM cohort (n = 902) had significantly better MSS than the SSM/NM cohort (n = 604). There was no difference in PFS. The 5-year MSS of the stage II LMM cohort was 88.5% (95% CI 81.4-95.6) compared to 79.7% (95% CI 72.8-86.6) in the stage II SSM/NM cohort. CONCLUSION: It does not appear appropriate to use adjuvant therapy in stage II LMM patients to the same extent as in patients with SSM/NM.