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

BACKGROUND: Lentigo maligna (LM) is a subtype of melanoma in situ 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. OBJECTIVES: (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. METHODS: (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. RESULTS: 30 patients (median follow-up time 6.2 years) were included. On histopathology, confluent or near confluent lentiginous proliferation, melanocyte density >15 per 0.5 mm 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. CONCLUSION: 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.

Cutaneous sarcoidosis due to immune-checkpoint inhibition and exacerbated by a novel BRAF dimerization inhibitor.

Sarcoidosis is a non-infective granulomatous disorder of unknown aetiology, with cutaneous involvement affecting up to 30% of patients. Drug-induced sarcoidosis has been reported secondary to modern melanoma therapies including immune-checkpoint inhibitors and first generation BRAF inhibitors such as vemurafenib and dabrafenib. Herein, we report a case of cutaneous micropapular sarcoidosis that first developed on immune-checkpoint inhibition with ipilimumab and nivolumab for metastatic melanoma, which was exacerbated and further complicated by pityriasis rubra pilaris-like palmar plaques upon transition to a next-generation BRAF-dimerisation inhibitor. Both the micropapular eruption and palmar plaques rapidly resolved after cessation of the novel BRAF-inhibitor and concurrent commencement of hydroxychloroquine. It is unclear how inhibition of BRAF-dimerisation results in granuloma formation, though upregulation of TH1/TH17 T-cells and impairment of T-reg cells may be responsible. Clinicians should be aware of the potential for exacerbation of sarcoidosis when transitioning from immune-checkpoint inhibitors to these novel BRAF-dimerisation inhibitors, particularly as their uptake in treating cancers increases beyond clinical trials. Further studies are required to assess whether these next-generation agents can trigger sarcoidosis de-novo, or simply exacerbate pre-existing sarcoidosis.

The smart approach: feasibility of lentigo maligna superficial margin assessment with hand-held reflectance confocal microscopy technology.

BACKGROUND: Lentigo maligna may be challenging to clear surgically. OBJECTIVE: To evaluate feasibility of using superficial skin cuts as RCM imaging anchors for attaining negative surgical margins in lentigo maligna. METHODS: Included patients presented with lentigo maligna near cosmetically sensitive facial structures. We evaluated, with hand-held-RCM, microscopic clearance of melanoma beyond its dermoscopically detected edges. Evaluated margins were annotated using shallow skin cuts. If a margin was positive at 'first-step' RCM evaluation, we sequentially advanced the margin radially outward at that segment by 2-mm intervals until an RCM-negative margin was identified. Prior to final surgical excision, we placed sutures at the outmost skin cuts to allow comparison of RCM and histopathological margin assessments. Primary outcome measure was histopathological verification that RCM-negative margins were clear of melanoma. RESULTS: The study included 126 first-step margin evaluations in 23 patients, median age 70 years (range: 43-91). Seventeen patients (74%) had primary in-situ melanoma and six (26%) invasive melanoma, mean thickness 0.3 mm (range 0.2-0.4 mm). Six cases (26%) showed complete negative RCM margins on 'first-step', 11 (48%) were negative at 'second-step', and four (17%) at 'third-step'. In two additional cases (9%), margins clearance could not be determined via RCM due to widespread dendritic cells proliferation. The RCM-negative margins in all 21 cases proved clear of melanoma on histopathology. Of the 15 cases that returned at 1-year follow-up, none showed any residual melanoma on dermoscopic and RCM examinations. Interobserver reproducibility showed fair agreement between bedside RCM reader and blinded remote-site reader, with Spearman's rho of 0.48 and Cohen's kappa of 0.43; using bedside reader as reference, the remote reader's sensitivity was 92% and specificity 57% in positive margin detection. CONCLUSIONS: Margin mapping of lentigo maligna with hand-held-RCM, using superficial skin cuts, appears feasible. This approach needs validation by larger studies.