Histologic Features Associated With an Invasive Component in Lentigo Maligna Lesions

Abstract

IMPORTANCE Lentigo maligna (LM) presents an invasive component in up to 20% of biopsied cases, but to date the histologic features useful in detecting this invasive component have not been described. Some histologic characteristics are hypothesized to contribute to the progression of LM invasion. OBJECTIVE To identify the histologic characteristics associated with lentigo maligna melanoma (LMM) in patients with LM diagnosed by a partial diagnostic biopsy. DESIGN, SETTING, AND PARTICIPANTSA retrospective cross-sectional study of patients treated between January 1, 2000, and December 31, 2017, was conducted in a referral oncology center in València, Spain. Data and specimens of patients (n = 96) with a diagnosis of primary cutaneous melanoma in the form of either LM or LMM who had undergone surgical treatment, a complete histologic examination of the whole tumor, and an initial diagnostic partial biopsy of LM were included in the study. Histologic assessment was blinded to the presence of an invasive component.INTERVENTIONS All biopsy specimens were evaluated for the presence of certain histologic characteristics.MAIN OUTCOMES AND MEASURES Comparisons between invasive samples and samples without an invasive component were performed. The differences in the distribution of variables between the groups were assessed using the χ 2 and Fisher exact tests, and the degree of association of the relevant variables was quantified by logistic regression models. A classification and regression tree analysis was performed to rank the variables by importance. RESULTSIn total, 96 patients had sufficient histologic material that could be evaluated. The patients were predominantly male (56 [58.3%]) and had a mean (SD) age at diagnosis of 72 (12) years. Of these patients, 63 (65.6%) had an LM diagnosis and 33 (34.4%) had an LMM diagnosis (an invasive component). The histologic variables associated with the presence of an invasive component were melanocytes forming rows (odds ratio [OR], 11.5; 95% CI, 1.4-94.1; P = .02), subepidermal clefts (OR, 2.8; 95% CI, 1.0-7.9; P = .049), nests (OR, 3.0; 95% CI, 1.1-8.6; P = .04), and a lesser degree of solar elastosis (OR, 0.4; 95% CI, 0.1-1.1; P = .07). A classification and regression tree analysis of the relevant histologic features was able to accurately identify lentigo maligna with an invasive component (LMM) in more than 60% of patients.CONCLUSIONS AND RELEVANCE These findings may be useful in classifying early LM specimens at higher risk of invasion, which may eventually be relevant in identifying the most appropriate management for LM.

A Review of Key Biological and Molecular Events Underpinning Transformation of Melanocytes to Primary and Metastatic Melanoma

“…The loss of contact inhibition has been shown to be an important event in vitro for controlling cell density and is postulated to be critical in vivo to facilitate the radial growth phase of the junctional components of melanocytic lesions, particularly early melanomas ( Figure 8A) [25,66,67]. As previously noted, normal melanocytes have dendritic handles that regulate equidistant melanocyte distribution within the basal epidermis.…”

“…Melanoma in situ has been conceptualized as an early melanoma confined by the epidermal basement membrane and, as such, does not have the biological potential to metastasize once it has been completely excised ( Figure 8A) [46]. In their study of lentigo maligna cases with and without invasive components, Moreno et al showed that early lesions had sparse inflammation, while advanced forms of lentigo maligna melanoma had dense lymphocytic infiltrates, suggesting the immunogenicity of melanoma in situ is lower than that of invasive forms of this melanoma subtype [67].…”

“…Loss of contact inhibition manifests histologically as lentiginous ("back-to-back") growth and melanocyte nests. To varying degrees, these features are present in both benign nevi and melanoma in situ, however they are more pronounced in melanoma, manifesting histologically as confluent lentiginous growth, variably sized nests, pagetoid spread and subepidermal clefts [66,67]. The vertical growth phase of melanoma requires the accumulation of mutations that promote tissue invasion, tumor cell survival, mesenchymal interactions and host immune system evasion.…”

“…Progression to invasive melanoma requires the accumulation of mutations that continue to allow dysregulated tumor cell proliferation, promote the acquisition of tumor cell survival characteristics and activate advantageous mesenchymal interactions, all while tumor cells evade host immune control ( Figure 8B,C) [67][68][69][70][71][72][73][74][75][76].…”

“…Melanoma is one of the most immunogenic tumors and immunogenicity has been observed to occur prior to the development of invasion [67]. In circumstances of optimal host immunosurveillance, melanoma encounters an early innate immune response that is mediated by interplay of macrophages, granulocytes, dendritic cells and natural killer cells [91,92].…”