Lentigo Maligna Research Articles

Histopathologic classification and prognostic factors of melanoma: a 2021 update.

Despite the rapid recent advances in molecular analysis of tumors, which allow large-scale and high-resolution genomics, the "gold standard" for melanoma diagnosis continues to be histopathology, in conjunction with clinical characteristics and sometimes with important support of immunohistochemistry. Observations, where postulated that cutaneous melanomas may arise through two distinct pathways, discoveries such as that BRAFV600E mutations were mostly common in melanomas on sun-exposed skin with little solar elastosis and seminal works for melanoma progression and evolution set the groundwork for the new WHO Classification of Melanoma: a classification of melanoma that not only encompasses histologic but also clinical, epidemiologic, and genetic characteristics. The melanomas were divided into those etiologically related to sun exposure and those that are not, based on their mutational signatures, anatomic site, and epidemiology. On the basis of degree of associated solar elastosis melanomas on the sun exposed skin were further divided by the histopathologic degree of cumulative solar damage (CSD) of the surrounding skin, into low and high CSD. On the low-CSD group of melanomas are included superficial spreading melanomas, while the high-CSD melanomas encompasses lentigo maligna and desmoplastic melanomas. The "non-CSD" classification includes acral melanomas, some melanomas in congenital nevi, melanomas in blue nevi, Spitz melanomas, mucosal melanomas, and uveal melanomas. Nodular and nevoid melanoma may occur in any pathway. A group of intermediate tumors termed melanocytoma is proposed for tumors that in addition to mutations that activate the MAPK pathway, harbor multiple driver mutations, and they are either low-grade or high-grade, to indicate that they may carry a higher risk of malignant transformation. In this review a summary of the most recent WHO classification of melanoma is provided. A short analysis of essential histopathologic prognostic parameters is also provided. The new classification of melanoma discriminates distinct types of melanoma based on their clinicopathologic, and genomic characteristics. Undoubtedly, melanoma research will continue to evolve as new clinical, pathological, molecular data accumulates. The challenge of the forthcoming years is to better characterize the intermediate category of melanocytic lesions.

DP06: Assessment of skin shave biopsies in the diagnosis of lentigo maligna: a 12‐year study

DP06: Assessment of skin shave biopsies in the diagnosis of lentigo maligna: a 12‐year study

Morphological diagnosis of skin melanoma

The morphological diagnosis of melanoma is difficult and requires knowledge and evaluation of a large number of histological parameters and often immunohistochemical analysis proving the origin of the tumor. According to the latest WHO classification of skin tumors, melanoma is presented in its full variety of forms, with extensive characteristics of each, based on several key indicators: growth pattern, ultraviolet exposure/solar trauma and genetic disorders. Based on the presence or absence of radial growth, melanomas are divided into nodular, superficially progressive (pagetoid), and lentigo maligna melanoma. Depending on the involvement of solar trauma, they are divided into melanomas occurring in skin exposed to sunlight and cumulative solar trauma and those whose genesis does not involve solar trauma. The first group, developing in solar-exposed skin, includes melanomas associated with sun exposure in predisposed individuals. Clinically and histologically, they are associated with varying degrees of cumulative solar trauma. The second group, whose genesis does not involve solar trauma and ultraviolet radiation, are Spitz melanoma, acral melanoma, mucosal melanoma, melanoma arising on the basis of congenital nevus, melanoma arising on the basis of blue nevus, and uveal melanoma.

Lentigo maligna: defining margins and predictors of recurrence utilizing clinical, dermoscopic, confocal microscopy and histopathology features.

Lentigo maligna (LM) is a subtype of melanoma insitu with poorly defined margins and a high recurrence rate. The biological behaviour of LM appears to differ widely between cases, from biologically indolent to biologically active variants, with some patients experiencing multiple recurrences. It is not known whether this is secondary to inadequate margins, field cancerization or the innate biology of the lesion itself. (a) Describe the margins of LM in detail by analysing LM in three zones, that is centre, edge and surround using reflectance confocal microscopy (RCM) and histopathology; (b) ascertain association of histological distance of LM and atypical melanocytic hyperplasia from the surgical margin with multi-recurrent (MR) disease and (c) identify features (clinical, dermoscopy, RCM and histopathology) associated with MR LM. (1) Descriptive observational study comparing the centre, edge and surround of LM on histopathology and RCM; (2) retrospective cohort study comparing parameters associated with MR and non-recurrent (NR) LM. 30 patients (median follow-up time 6.2years) were included. On histopathology, confluent or near confluent lentiginous proliferation, melanocyte density >15 per 0.5mm and adnexal spread were best for distinguishing surround from edge of LM. On RCM, predominant melanocytes, lentiginous proliferation and pleomorphism distinguished surround from centre/edge. MR patients had a median histological distance of LM from the surgical margin of 2mm (versus NR patients with an average distance of 4mm). MR patients had a greater proportion of more florid features, compared with NR on histopathology at both the centre and the edge but were similar in the surround. These data may help pathologists and confocalists better define margins of LM. More florid features in MR patients, despite a similar background of sun-damaged skin, suggest the innate biology of the lesion rather than the field of cancerization may explain MR LM.

Prospective observational study of the efficacy of nivolumab in Japanese patients with advanced melanoma (CREATIVE study).

BackgroundNivolumab, the anti-programmed cell death protein 1 antibody, has been approved for advanced melanoma, mainly based on evidence from Western countries. The profile of melanoma differs between Caucasian and Asian patients. This study was performed to obtain post-marketing data of nivolumab in Japanese patients with advanced melanoma.MethodsThis prospective, observational study involved patients with unresectable or metastatic melanoma treated with nivolumab at dosages of 2 mg/kg every 3 weeks or 3 mg/kg every 2 weeks. The primary endpoints were objective response rate and overall survival. The secondary endpoints were progression-free survival and the objective response rate according to immune-related Response Evaluation Criteria in Solid Tumours.ResultAmong 124 patients analysed, mucosal melanoma was the most common subtype, followed by acral lentiginous, nodular, superficial spreading and lentigo maligna melanoma. Response Evaluation Criteria in Solid Tumours evaluation showed an objective response rate of 17.7%. The median survival time was 15.93 months, and the 1-year overall survival rate was 66%. Outcomes were not significantly different among melanoma subtypes. Better overall survival and/or progression-free survival but not objective response rate were associated with performance status 0, lower levels of lactate dehydrogenase, C-reactive protein and neutrophil-to-lymphocyte ratio. Patients with immune-related adverse events showed a better objective response rate, 3-month landmark overall survival and progression-free survival than patients without immune-related adverse events.ConclusionThe objective response rate and median survival time in Japanese patients treated with nivolumab were lower in daily practice than the >30% and >30 months, respectively, seen in global phase III trials. The occurrence of immune-related adverse events may be a predictor for survival and response to treatment with nivolumab.

Volume tumor impact on melanoma survival assessed using Breslow density

Volume tumor impact on melanoma survival assessed using Breslow density

Melanoma In Situ: A Critical Review and Re-Evaluation of Current Excision Margin Recommendations.

Most international clinical guidelines recommend 5–10 mm clinical margins for excision of melanoma in situ (MIS). While the evidence supporting this is weak, these guidelines are generally consistent. However, as a result of the high incidence of subclinical extension of MIS, especially of the lentigo maligna (LM) subtype, wider margins will often be needed to achieve complete histologic clearance. In this review, we assessed all available contemporary evidence on clearance margins for MIS. No randomized trials were identified and the 31 non-randomized studies were largely retrospective reviews of single-surgeon or single-institution experiences using Mohs micrographic surgery (MMS) for LM or staged excision (SE) for treatment of MIS on the head/neck and/or LM specifically. The available data challenge the adequacy of current international guidelines as they consistently demonstrate the need for clinical margins > 5 mm and often > 10 mm. For LM, any MIS on the head/neck, and/or ≥ 3 cm in diameter, all may require wider clinical margins because of the higher likelihood of subclinical spread. Histologic clearance should be confirmed prior to undertaking complex reconstruction. However, it is not clear whether wider margins are necessary for all MIS subtypes. Indeed, it seems that this is unlikely to be the case. Until optimal surgical margins can be better defined in a randomized trial setting, ideally controlling for MIS subtype and including correlation with histologic excision margins, techniques such as preliminary border mapping of large, ill-defined lesions and, most importantly, sound clinical judgement will be needed when planning surgical clearance margins for the treatment of MIS.

Flat scalp melanoma dermoscopic and reflectance confocal microscopy features correspond to histopathologic type and lesion location.

BackgroundDermoscopy and Reflectance Confocal Microscopy (RCM) features of scalp melanoma according to lesion location and histopathology have not been fully investigated.ObjectivesTo reveal dermoscopic and RCM features of scalp melanoma according to lesion location and histopathology.MethodsWe retrospectively retrieved images of suspicious, atypical excised, flat melanocytic lesions of the scalp, assessed on dermoscopy and RCM at five centres, from June 2007 to April 2020. Lesions were classified according to histopathological diagnoses of nevi, lentigo maligna melanoma (LM/LMM) or superficial spreading melanoma (SSM). Clinical, dermoscopic and RCM images were evaluated; LM/LMM and SSM subtypes were compared through multivariate analysis.ResultsTwo hundred forty‐seven lesions were included. In situ melanomas were mostly LM (81.3%), while invasive melanomas were mostly SSM (75.8%). Male sex, baldness and chronic sun‐damaged skin were associated with all types of melanomas and in particular with LM/LMM. LMs were mostly located in the vertex area and SSM in the frontal (OR: 8.8; P < 0.05, CI 95%) and temporal (OR: 16.7; P < 0.005, CI 95%) areas. The dermoscopy presence of pseudo‐network, pigmented rhomboidal structures, obliterated hair follicles and annular–granular pattern were associated with LM diagnoses, whereas bluish‐white veil was more typical of SSM. Observations on RCM of atypical roundish and dendritic cells in the epidermis were associated with SSM (42.4%) and dendritic cells with LM (62.5%) diagnoses. Folliculotropism on RCM was confirmed as a typical sign of LM.ConclusionsFlat scalp melanomas reveal specific dermoscopic and RCM features according to histopathologic type and scalp location.

Effect of reflectance confocal microscopy compared to dermoscopy in the diagnostic accuracy of lentigo maligna: A meta-analysis.

Many concerns were raised aboutthe sensitivity and specificity outcome of reflectance confocal microscopy compared to dermoscopy for the diagnosis of lentigo maligna. However, the reported relationships between their sensitivity and specificity were variable. Our meta-analysis was performed to clarify this relationship. A systematic literature search up to July 2020 was performed and six included studies had 479 subjects at the baseline with 294 undergoing lentigo maligna diagnoses. They were reporting relationships between sensitivity and specificity outcome of reflectance confocal microscopy compared to dermoscopy for the diagnosis of lentigo maligna. Mean difference (MD) with 95% confidence intervals (CIs) was calculated to evaluate the prognostic role of the sensitivity and specificity of reflectance confocal microscopy compared to dermoscopy for the diagnosis of lentigo maligna using the continuous method with a random or fixed-effect model. Reflectance confocal microscopy was significantly related to higher specificity (MD, 19.10; 95% CI, 0.93-37.28, P=.04) compared to dermoscopy in lentigo maligna diagnosis. However, reflectance confocal microscopy was only relatively but not significantly related to higher sensitivity (MD, 14.56; 95% CI, 0.29-28.83, P=.05) compared to dermoscopy in lentigo maligna diagnosis. Based on this meta-analysis, the reflectance confocal microscopy compared to dermoscopy in lentigo maligna diagnosis had a significantly higher specificity and relatively higher sensitivity. This relationship forces us to recommend reflectance confocal microscopy in lentigo maligna diagnosis for better outcomes and to avoid any possible false-negative results. Further studies are required.

Langerhans Cells as Morphologic Mimickers of Atypical Melanocytes on Reflectance Confocal Microscopy: A Case Report and Review of the Literature.

Pagetoid spread of melanocytes in the epidermis is a common indicator of melanocytic atypia, both histopathologically and with reflectance confocal microscopy (RCM). Specifically on RCM, large, bright, atypical dendritic and/or roundish cells are characteristic of melanoma. However, intraepidermal Langerhans cells (ILC) create the potential for diagnostic ambiguity on RCM. We describe one case of a pigmented facial lesion that was initially diagnosed as lentigo maligna (LM) due to numerous atypical perifollicular dendritic cells on RCM. Additionally, we present the findings of a literature review for similar reported cases conducted by searching the following terms on PubMed: reflectance confocal microscopy, RCM, lentigo maligna, melanoma, Langerhans cells, dendritic cells, and atypical cells. In our case, the lesion was determined to be a solar lentigo on histopathology. Immunohistochemistry (IHC) with CD1a identified the atypical-appearing cells as ILC, as it did in 54 reported cases of benign lesions (benign melanocytic nevus, Sutton/halo nevus, labial melanotic macule, and solar lentigo) misdiagnosed as malignant on RCM (melanoma, lip melanoma, lentigo maligna, and LM melanoma). According to our case and the literature, both ILC and atypical melanocytes can present with atypical-appearing dendritic and/or roundish cells under RCM. Currently, there is no method to distinguish the two without IHC. Therefore, the presence of pagetoid cells should continue to alert the confocalist of a potential neoplastic process, prompting biopsy, histopathologic diagnosis, and IHC differentiation.

Risk factors for cardiovascular mortality and melanoma-specific mortality among patients with melanoma: a SEER based study.

This study aims to identify the risk factors for cardiovascular mortality in melanoma patients. Data of melanoma patients were obtained from the Surveillance, Epidemiology, and End Results database. We used Person's chi-square test to assess the relationships between categorical variables. We used Kaplan-Meier test in the univariate analysis and Cox regression test for the multivariate analysis. Analyses were conducted using the SPSS software. We analyzed data of 194 503 melanoma patients. Among them, 28 818 (14.8 %) died due to cardiovascular diseases. Cardiovascular-specific survival was higher in younger patients, women, married, localized disease, superficial spreading melanoma and in patients who had surgery. It was lower in patients who received chemotherapy or radiotherapy. The multivariate analysis revealed a higher risk of cardiovascular mortality in patients aged 50-64 years [hazard ratio (HR), 7.297; 95% confidence interval (CI), 6.68-7.97], patients aged ≥65 years (HR, 43.309; 95% CI, 39.706-47.240), men (HR, 1.535; 95% CI, 1.475-1.597), Blacks (HR, 1.29; 95% CI, 1.044-1.594), separated (HR, 1.286; 95% CI, 1.058-1.562), widowed (HR, 1.829; 95% CI, 1.706-1.961), patients with no or unknown history of chemotherapy (HR, 1.302; 95% CI, 1.071-1.583) or radiotherapy (HR, 1.477; 95% CI, 1.217-1.793) and patients with no surgery (HR, 1.468; 95% CI, 1.264-1.706). In patients with melanoma, the risk of cardiovascular death is higher in older patients, men, Blacks, separated, widowed and patients with nodular or lentigo maligna melanoma. The risk is lower in married, patients with superficial spreading or acral lentiginous melanoma, and patients who had chemotherapy, radiotherapy or surgery.

Comparing the characteristics and predicting the survival of patients with head and neck melanoma versus body melanoma: a population-based study

BackgroundPrevious studies reported cutaneous melanoma in head and neck (HNM) differed from those in other regions (body melanoma, BM). Individualized tools to predict the survival of patients with HNM or BM remain insufficient. We aimed at comparing the characteristics of HNM and BM, developing and validating nomograms for predicting the survival of patients with HNM or BM.MethodsThe information of patients with HNM or BM from 2004 to 2015 was obtained from the Surveillance, Epidemiology, and End Results (SEER) database. The HNM group and BM group were randomly divided into training and validation cohorts. We used the Kaplan-Meier method and multivariate Cox models to identify independent prognostic factors. Nomograms were developed via the rms and dynnom packages, and were measured by the concordance index (C-index), the area under the curve (AUC) of the receiver operating characteristic (ROC) curve and calibration plots.ResultsOf 70,605 patients acquired, 21% had HNM and 79% had BM. The HNM group contained more older patients, male sex and lentigo maligna melanoma, and more frequently had thicker tumors and metastases than the BM group. The 5-year cancer-specific survival (CSS) and overall survival (OS) rates were 88.1 ± 0.3% and 74.4 ± 0.4% in the HNM group and 92.5 ± 0.1% and 85.8 ± 0.2% in the BM group, respectively. Eight variables (age, sex, histology, thickness, ulceration, stage, metastases, and surgery) were identified to construct nomograms of CSS and OS for patients with HNM or BM. Additionally, four dynamic nomograms were available on web. The internal and external validation of each nomogram showed high C-index values (0.785–0.896) and AUC values (0.81–0.925), and the calibration plots showed great consistency.ConclusionsThe characteristics of HNM and BM are heterogeneous. We constructed and validated four nomograms for predicting the 3-, 5- and 10-year CSS and OS probabilities of patients with HNM or BM. These nomograms can serve as practical clinical tools for survival prediction and individual health management.

Lesion-based radiotherapy of the ears, lips and eyelids for skin cancer

Purpose: This study is a retrospective audit of radiotherapy (RT) for skin cancer of the ear, eyelid, and lip in Sydney, Australia. The growth of referrals to a tertiary radiation oncology service over a specific time period were also assessed. Materials and Methods: The records of patients who received RT to the external ear, eyelid or lip between January 1 2007 and April 30 2020 were reviewed. Patient, tumour, treatment and outcome factors were recorded. Results: 147 patients with a mean age of 73 years (range: 33-96) were identified as eligible for inclusion. 165 lesions were treated and 18 patients had multiple treatment events. Of all the treated lesions, 81 were basal cell carcinoma (49.2%), 65 cutaneous squamous cell carcinoma (39.4%), 7 lentigo maligna (LM) (4.2%), 2 sebaceous carcinoma (1.2%), 2 merkel cell carcinoma (1.2%), 4 Bowen’s disease (2.4%), 2 actinic change (1.2%) and 2 keloid treatments (1.2%). The mean follow-up was 42 weeks. Definitive RT, that is, RT given as primary treatment rather than post operatively, was given in 108 cases. There were five cases of BCC recurrence and three cases of cSCC recurrence within 3 - 61 months. These were successfully salvaged in six cases (75%). Late side effects were seen in 26 patients with abnormal cosmetic results being the most common late effect (6/26; 23.1%). Conclusion: Lesion-based RT for skin cancer of the ear, eyelid, and lip can be delivered safely and is effective. Definitive RT may be preferable to surgery especially when tissue loss may lead to poor functional and cosmetic outcomes.

PRAME immunohistochemistry as an adjunct for diagnosis and histological margin assessment in lentigo maligna.

Lentigo maligna (LM), the most common type of melanoma in situ, is a diagnostically challenging lesion for pathologists due to abundant background melanocytic hyperplasia in sun-damaged skin. Currently, no laboratory methods reliably distinguish benign from malignant melanocytes. However, preferentially expressed antigen in melanoma (PRAME) has shown promise in this regard, and could potentially be applied to diagnosis and margin assessment in difficult cases of LM. Ninety-six cases with a diagnosis of LM (n=77) or no residual LM (n=19) following initial biopsy were identified and stained with an antibody directed towards PRAME. Immunohistochemistry (IHC) was scored as positive or negative, and measurement of histological margins by PRAME was performed and compared to the measurement of histological margins using conventional methods [haematoxylin and eosin (H&E) and/or sex-determining region Y-box 10 (SOX10) and/or Melan-A]. Of cases with LM, 93.5% (72 of 77) were PRAME+ and 94.7% (18 of 19) of cases with no residual LM were PRAME- . Of the 35cases with no margin involvement by PRAME or conventional assessment, 14cases (40.0%) had no difference in measurement, 17(48.6%) had a difference of 1mm or less and four (11.4%) differed by between 1 and 3.5mm. There was a high correlation between margin assessment methods (r=0.97, P<0.0001). PRAME IHC is a sensitive (93.5%) and specific (94.7%) method for diagnosing LM on biopsy and excision, and measurement of histological margins by PRAME shows a high correlation with conventional methods for margin assessment. Furthermore, the nuclear expression of PRAME makes it a good target for use in dual-colour IHC stains.

Desmoplastic Melanoma: A Clinicopathological Analysis of Three Cases in the Chinese Population.

PurposeTo investigate the clinicopathological characteristics and immunophenotype of desmoplastic melanoma (DM) in the Chinese population.Patients and MethodsWe report three cases of DM diagnosed by the Pathology Department of Shanghai Dermatology Hospital. We describe the clinical and pathological characteristics of the three cases and examine molecular markers used in the diagnosis of DM. Finally, we summarize the current literature in the DM field.ResultsClinically, lesions in the three DM patients were characterized by non-pigmented nodules or papules. Microscopically, we observed an abundance of fibrous interstitium mixed with spindle cells exhibiting various degrees of atypia. Occasionally, these structures exhibited changes in lentigo maligna at the epidermal junction, accompanied by the presence of lymphoid follicular structures and neurophilic behavior. Diagnosis of DM was confirmed by immunohistochemical staining, which revealed high expression levels of S-100 and SOX-10. Melanocyte markers were focally positive or negative. Unlike DMs from other populations, our three patients were negative for WT-1 and P53. All three cases received surgical resection, which is the preferred treatment for DM, and none of the patients experienced recurrence.ConclusionDM in these Chinese patients was similar to that observed in other DM populations in terms of immunophenotype and clinical and histological features. A notable absence in p53 staining was observed in the three cases reported here, suggesting that p53 negativity should not exclude the diagnosis of DM in the Chinese population.

Malignant Melanoma Metastasis to the Appendix as the First Presentation of Lentigo Maligna Melanoma

Malignant melanoma is a malignant neoplasm of the skin and mucosal tissues, and its behavior is not predictable. Thus, it could metastasize via mysterious routes. Here, we report a rare case of acute abdomen and acute appendicitis which involved metastatic malignant melanoma in a 63-year-old man without a history of previously treated malignant melanoma.

Change in lentigo maligna score assessed by in vivo reflectance confocal microscopy after 1 month of imiquimod treatment for lentigo maligna management

Treatment of lentigo maligna (LM) is challenging because of the potential functional and esthetic surgical sequelae. Imiquimod has been proposed as a treatment for LM. Reflectance confocal microscopy (RCM) is a noninvasive method for the diagnosis of LM and margin assessment. To compare the overall LM score (LMS) assessed by RCM before and 1month after the start of imiquimod treatment compared to placebo and to define the immunohistochemical (IHC) profile of responders to imiquimod. A controlled randomized study was conducted. Forty patients underwent RCM examination with calculation of the LMS at baseline and after 1month of treatment. An IHC analysis of excised tissues was performed. The 1-month LMS was significantly lower in patients treated with imiquimod compared to those treated with placebo (P<.001). The criteria in the imiquimod-treated patients that demonstrated significant decrease were nonedged papillae; large, round pagetoid cells; atypical cells at the dermoepidermal junction; and follicular location of atypical cells. IHC analysis showed a higher level of interferon gamma in the resected specimens of patients responding to imiquimod (P=.04). Sample size was small. Assessing the LMS by RCM was useful to monitor LM response to imiquimod accurately.

Lentiginous melanoma (lentigo maligna and lentigo maligna melanoma) in Australia: clinicopathological characteristics, management and recurrence rates after 10-year follow-up at a tertiary centre.

Lentiginous melanoma or lentigo maligna is a slow-growing type of melanoma frequently arising in sun-damaged skin and often first diagnosed in the elderly. Few studies report long-term follow-up. To define characteristics of lentiginous melanoma in situ (LM) and invasive lentiginous melanoma (LMM) in Australian patients managed at a tertiary centre and describe local recurrence or treatment failure rates after long-term follow-up. Retrospective single-centre study of LM/LMM patients evaluated between January 2005 and March 2007. Medical and photographic records were reviewed. One hundred two patients were included, with a total of 117 lesions (70 LM and 47 LMM). Seventy-nine were new primary LM/LMM, and 38 were recurrences. Primary cases were mostly pigmented (71%), while 77% of recurrent cases were partially pigmented/light brown or amelanotic. The margins were clinically ill-defined in the majority of cases (64% of primary cases and 94% of recurrent cases). Dermoscopy of the primary LM/LMM showed either classic 'common' melanoma features (33%) or classic LM/LMM features (41%), while 95% of recurrent cases had no features for melanoma or LM/LMM. Primary cases that were initially excised (113, 97%) had mean histopathological clear margins of 4.9mm (range 0.1-22mm). The median follow-up time was 7.5years (95% CI 5.2-10.0) with more than 10-year follow-up in 32% and 5-10years in 24% of patients. There were 44 (38%) recurrences over the entire follow-up period. Half of the patients who recurred did so within the first 3.8years after the first treatment. LM/LMM often recur late and are clinically subtle; therefore, careful monitoring and long-term follow-up are required.

Treatment of lentigo maligna (Review)

Lentigo maligna (LM) is the most common type of <em>in situ</em> melanoma, usually appearing on chronically sun‑exposed skin (mostly the head and neck) of elderly patients. It manifests clinically as a macule with a heterogeneous pigmentation and irregular contours. LM grows gradually over the years in a radial pattern and may eventually progress with a vertical growth phase, thereby transforming into an invasive melanoma (LM melanoma) that has potential for metastasis and a lethal outcome; accordingly, LM is currently regarded as an authentic melanoma <em>in situ</em>, rather than a premalignant condition. To the best of my knowledge, no prospective, randomized controlled studies evaluating the efficacy of the various treatment modalities applied for the treatment of LM exist to date. Surgical excision with tumour‑free margins is regarded as the most effective treatment, achieving optimal rates of tumour clearance. Excision can be performed as traditional, one‑step tumour ablation with predefined safety margins or, preferably, with margin‑controlled techniques, such as staged excision or Mohs micrographic surgery, the latter methods achieving the highest cure rates. In the case of surgically‑unresectable tumours or in frail patients with severe comorbidities, alternative non‑surgical (off‑label) therapies can be applied, including namely radiotherapy and imiquimod, as monotherapy or in various combinations.

Clinical Applications of In Vivo and Ex Vivo Confocal Microscopy

Confocal laser scanning microscopy (CLSM) has been introduced in clinical settings as a tool enabling a quasi-histologic view of a given tissue, without performing a biopsy. It has been applied to many fields of medicine mainly to the skin and to the analysis of skin cancers for both in vivo and ex vivo CLSM. In vivo CLSM involves reflectance mode, which is based on refractive index of cell structures serving as endogenous chromophores, reaching a depth of exploration of 200 μm. It has been proven to increase the diagnostic accuracy of skin cancers, both melanoma and non-melanoma. While histopathologic examination is the gold standard for diagnosis, in vivo CLSM alone and in addition to dermoscopy, contributes to the reduction of the number of excised lesions to exclude a melanoma, and to improve margin recognition in lentigo maligna, enabling tissue sparing for excisions. Ex vivo CLSM can be performed in reflectance and fluorescent mode. Fluorescence confocal microscopy is applied for “real-time” pathological examination of freshly excised specimens for diagnostic purposes and for the evaluation of margin clearance after excision in Mohs surgery. Further prospective interventional studies using CLSM might contribute to increase the knowledge about its application, reproducing real-life settings.