Naevus-associated Melanomas Research Articles

Melanoma arising on a naevus is different from melanoma arising de novo

British Journal of DermatologyVolume 185, Issue 1 p. e12-e12 Plain Language Summary Melanoma arising on a naevus is different from melanoma arising de novo First published: 02 July 2021 https://doi.org/10.1111/bjd.20450AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onEmailFacebookTwitterLinked InRedditWechat Abstract Linked Article: Dessinioti et al. Br J Dermatol 2021; 185:101–109. Skin melanoma usually arises on healthy-looking skin and this is called de novo melanoma (70% of melanoma). When melanoma arises on a pre-existing naevus (skin mole) it is called naevus-associated melanoma (NAM, 30% of melanoma). The differences between de novo and NAM are not clear because de novo melanoma are thicker tumours and there may have been a naevus component that was later replaced by tumour growth. To investigate if de novo melanoma is distinctly different from NAM, we conducted a multicentre study (in Europe, Australia and the USA) focusing on thin melanoma (Breslow thickness ≤1 mm). We found that in a total of 9474 localized melanoma (i.e. ones that have not spread to other parts of the body), de novo melanoma compared with NAM were associated with thicker tumours and there were body-site clinical differences and histological differences (changes seen under the microscope). When looking at a subset of 5307 thin melanoma, we observed similar body-site differences: de novo melanoma compared with NAM was more likely to affect older individuals (≥70 years) when located on the head/neck, trunk or the upper extremity; to affect females when located on the lower extremities; to be of the nodular melanoma subtype when located on the trunk; and this type of melanoma was less likely to have histological regression present (a focal decrease in the number of melanoma cells, with changes similar to those observed in a scar). We did not find a difference in survival between patients with de novo melanoma compared with NAM, but our study had an average follow-up time of 3 years. In conclusion, these differences suggest that de novo melanomas are different from NAM and point to different mechanisms of development that depend on the body site. Volume185, Issue1July 2021Pages e12-e12 RelatedInformation

A multicentre study of naevus-associated melanoma vs. de novo melanoma, tumour thickness and body site differences.

Whether melanoma in histological contiguity with a naevus [naevus-associated melanoma (NAM)] is distinctly different from melanoma arising de novo remains unclear. To determine whether the characteristics of de novo melanoma differ from NAM and are not due to naevus obliteration in thicker tumours. We conducted a multicentre retrospective study of de novo melanoma and NAM in seven referral centres in Europe, Australia and the USA between 2006 and 2015. In a total of 9474 localized melanomas, de novo melanoma was associated with thicker tumours and body site differences compared with NAM. In the subset of T1 melanomas (n=5307), similar body site differences were found in multivariate analysis by body site. When compared with NAM, de novo melanoma was more likely to affect older individuals (≥ 70years) when located on the head/neck [odds ratio (OR) 4·65, 95% confidence interval (CI) 2·55-8·46], the trunk (OR 1·82, 95% CI 1·40-2·36) or the upper extremity (OR 1·69, 95% CI 1·14-2·50), was more likely to affect female patients when located on the lower extremities (OR 1·36, 95% CI 1·03-1·80), and was more likely to be of the nodular melanoma subtype (OR 2·23, 95% CI 1·14-4·35) when located on the trunk. De novo melanoma was less likely to have regression present compared with NAM. Clinicopathological and body site differences between de novo melanoma and NAM support the divergent pathway model of development. These differences were also found in thin melanomas, suggesting that de novo melanomas are different from NAM and their differences are not due to the obliteration of naevus remnants in thicker tumours.

Clinicopathological, Genetic and Survival Advantages of Naevus-associated Melanomas: A Cohort Study.

Several studies have suggested that naevus-associated melanomas differ from de novo melanomas, being thinner and with less ulceration; however, the prognostic implication is unclear. The objective of this study was to describe clinicopathological, genetic and survival characteristics of de novo and naevus-associated melanomas in a cohort of primary invasive cutaneous melanomas over a 20-year period. Of the 2,227 patients included in the study, 509 (22.86%) had naevus-associated melanomas. Compared with patients with de novo melanoma, they were younger, with a fairer phototype and a higher naevus count, tumours were predominantly the superficial spreading subtype, American Joint Committee on Cancer stage I, located on the trunk, and there were fewer signs of invasiveness (thinner Breslow index, less ulceration, lower mitotic index and less satellitosis). Germline mutational status did not show any significant association. As determined through univariate analysis, overall survival was significantly better in patients with naevus-associated melanoma (hazard ratio 0.64; 95% confidence interval 0.51–0.80, p < 0.001), but multivariate analysis did not support this prognostic indication (hazard ratio 0.94; 95% confidence interval 0.75–1.18, p < 0.606). Despite this, we conclude that naevus-associated and de novo melanomas should be considered as different subtypes of melanoma.

Nodular melanoma is less likely than superficial spreading melanoma to be histologically associated with a naevus.

To determine the frequency of naevus-associated melanoma among superficial spreading and nodular subtypes; and to investigate associations between naevus-associated melanoma and other clinico-pathological characteristics. Cross-sectional study of all patients with nodular and superficial spreading melanomas diagnosed between 1994 and 2015 at the Victorian Melanoma Service, Melbourne. Clinical and pathological characteristics of naevus-associated and de novo melanomas were assessed in univariable and multivariable logistic regression analyses. Of 3678 primary melanomas, 1360 (37.0%) were histologically associated with a naevus and 2318 (63.0%) were de novo melanomas; 71 of 621 nodular (11.4%) and 1289 of 3057 superficial spreading melanomas (42.2%) were histologically associated with a naevus. In multivariable analyses, the odds of being associated with a naevus were higher for melanomas located on the trunk (v head and neck: adjusted odds ratio [OR], 2.27; 95% CI, 1.73-2.96; P < 0.001), while the odds were lower for thicker tumours (adjusted OR, 0.75 per millimetre increase in Breslow thickness; 95% CI, 0.69-0.81; P < 0.001), amelanotic/hypomelanotic melanomas (adjusted OR, 0.68; 95% CI, 0.48-0.97; P = 0.035), and older age (patients 70 years or older v patients under 30 at diagnosis: adjusted OR, 0.28; 95% CI, 0.20-0.40; P < 0.001). After adjusting for confounders, the odds of an associated naevus was three times as high for superficial spreading melanomas as for nodular melanomas (adjusted OR, 3.05; 95% CI, 2.24-4.17; P < 0.001). Melanomas are most likely to arise in the absence of a pre-existing naevus, particularly nodular melanomas. Public health campaigns should therefore emphasise the detection of suspicious de novo lesions, as well as of changing lesions.

Mutational status of naevus-associated melanomas.

The origin of melanoma has always been a debated subject, as well as the role of adjacent melanocytic naevi. Epidemiological and histopathological studies point to melanomas arising either de novo or from a naevus. To evaluate the presence of mutations in genes from well-known melanomagenesis pathways in a large series of naevus-associated melanomas. Sixty-one melanomas found in association with a pre-existing naevus were microdissected, after careful selection of cell subpopulations, and submitted to Sanger sequencing of the BRAF, NRAS, c-KIT, PPP6C, STK19 and RAC1 genes. Each gene was evaluated twice in all samples by sequencing or by sequencing and another confirmation method, allele-specific fluorescent polymerase chain reaction (PCR) and capillary electrophoresis detection or by SNaPshot analysis. Only mutations confirmed via two different molecular methods or twice by sequencing were considered positive. The majority of cases presented concordance of mutational status between melanoma and the associated naevus for all six genes (40 of 60; 66.7%). Nine cases presented concomitant BRAF and NRAS mutations, including one case in which both the melanoma and the adjacent naevus harboured V600E and Q61K double mutations. In two cases, both melanoma and associated naevus located on acral sites were BRAF mutated, including an acral lentiginous melanoma. To our knowledge this is the largest naevus-associated melanoma series evaluated molecularly. The majority of melanomas and adjacent naevi in our sample share the same mutational profile, corroborating the theory that the adjacent naevus and melanoma are clonally related and that the melanoma originated within a naevus.

Observational study on the mitotic rate and other prognostic factors in cutaneous primary melanoma arising from naevi and from melanoma de novo

Melanomas can arise from naevi or appear de novo. The frequency or the effect of their origin on prognosis is still debated. Mitotic rate (MR) and ulceration of melanomas have been proposed as further new prognostic indexes. To determine the different prognostic factors in melanomas de novo and melanomas from pre-existing naevi and whether these two melanoma groups have different MR or presence of ulceration. All patients with confirmed primary melanomas observed in our clinic from 1996 to July 2013 were included. The distinction between the two groups of melanomas was histologically based. We compared Breslow's thickness, the number of mitosis/mm(2) and the presence of ulceration between the naevus-associated melanoma and de novo melanoma group. Of the 873 melanomas, 626 (71.8%) have a de novo melanoma, 247 (28.2%) a naevus-associated melanoma. Breslow's thickness was not significantly different in the two groups (0.77 ± 1.47 mm vs. 0.59 ± 1.35 mm). The number of patients with presence of ulceration and MR ≥1 mitosis/mm(2) was not significantly different in the two groups (19.6% vs. 16.3%). In thicker melanomas (Breslow's thickness ≥ 1 mm), the number of patients with ≥6 mitosis/mm(2) was significantly higher (26.6% vs. 7.9%; P < 0.05) in the de novo melanoma group. When mitosis ≥ 1 mm/mm(2) , the results obtained do not show a better or worse prognosis based on Breslow's thickness, ulceration and MR in melanomas associated with naevus vs. melanomas de novo. When ≥6 mitosis/mm(2) are considered, the number of patients in the de novo melanoma group with thick melanoma is highly more represented. The debate about the cut-off value of mitosis ≥1 mm(2) is open.

Cytoplasmic β-catenin is lacking in a subset of melanoma-associated naevi, but is detectable in naevus-associated melanomas: potential implications for melanoma tumorigenesis?

An excess of intracellular beta-catenin protein is triggered by various genetic alterations in melanoma cell lines, and has been suggested to play a role in melanoma tumorigenesis. To investigate the role played in vivo by beta-catenin in melanoma tumorigenesis, we compared the cytoplasmic detection of beta-catenin in benign melanocytic cells vs. malignant melanoma cells presumably generated from these benign melanocytic cells. For this purpose, melanocytic naevi occurring in association with melanoma, which were suggested to be melanoma precursors, were compared with their associated melanoma for beta-catenin cytoplasmic immunoreactivity. Fifty-seven consecutive cases of primary cutaneous melanoma were considered, and 15 of them were found to be associated with a melanocytic naevus portion. The naevus portion showed features of acquired melanocytic naevus (total 12 cases: five dysplastic, seven intradermal) or congenital growth pattern naevus (total three cases: one superficial, two deep). All specimens were immunohistochemically investigated for beta-catenin. Virtually all primary cutaneous melanomas, including those associated with a naevus portion, showed cytoplasmic beta-catenin positivity. However, the intradermal naevus portion was consistently cytoplasmic beta-catenin negative, while both the dysplastic and the congenital naevus portions were cytoplasmic beta-catenin positive. Beta-catenin excess may play a role in melanoma tumorigenesis, because beta-catenin cytoplasmic reactivity was found in primary cutaneous melanoma but not in its associated intradermal naevus precursor. As, however, beta-catenin cytoplasmic reactivity was detected not only in primary cutaneous melanoma but also in its associated dysplastic/congenital naevus precursors, beta-catenin stabilization alone is not sufficient to play a decisive role for melanoma onset.

Fluorescence in situ hybridization (FISH) evaluation of chromosomes 6, 7, 9 and 10 throughout human melanocytic tumorigenesis

Loss of the 9p21 region, 6q and 10q and gain of chromosome 7 are the most frequent chromosomal abnormalities found in human melanomas, but very few cytogenetic data are available regarding dysplastic and common naevi. To study the occurrence of the most consistent chromosomal changes during melanocytic tumorigenesis, archival samples from 30 common naevi and 30 naevus-associated melanomas were analysed by interphase fluorescence in situ hybridization (FISH) using centromeric probes for chromosomes 9 and 7 and locus-specific probes for 9p21, 6q11.1, 6q24.1, 10p15.3 and 10q23.1 regions. In naevus-associated melanomas, separate evaluations were made for sectors corresponding to residual naevus, dysplastic naevus, radial growth phase melanoma and vertical growth phase melanoma. No chromosomal aberrations were found in common naevi, but monosomy 7 was observed in one case. In naevus-associated melanomas, loss of the entire chromosome 9 or of the 9p21 region was observed in 56% of common and 54% of dysplastic naevus sectors, in 64% of radial growth phase melanoma and in 82% of vertical growth phase melanoma. Loss of the long arm of chromosome 6, monosomy 10 and deletion 10q were exclusively confined to radial (18% for both chromosomes) and vertical (29 and 59%, respectively) growth phase melanomas. Polysomy of chromosome 7 was detected only in melanoma sectors (radial growth phase, 14%; vertical growth phase, 59%). The high incidence of 9p21 loss in melanoma-associated naevi, which is maintained in all evolutionary phases of melanocytic tumorigenesis, and the complete absence of chromosomal aberrations in common naevi, strongly suggest that 9p21 loss may be regarded as a cytogenetic marker of melanocytic naevi with a high potential for progression.

Dermoscopic features of naevus-associated melanoma.

Little is currently known about the relationship between melanocytic naevi and melanoma in terms of neoplastic progression. At histological examination, remnants of a pre-existing melanocytic naevus adjoining a melanoma are seen in 20-30% of cases. This study investigated dermoscopic features of 108 naevus-associated melanomas, identified on the basis of histological classification, consecutively observed at a University Department. Because of the risk of misclassification due to destruction of naevus remnants in thick tumours, only lesions of < 1 mm Breslow thickness were considered. We found naevus-associated melanomas showing atypical pigment networks and regression patterns more frequently than de novo melanomas, while irregular blotches and atypical vascular patterns were found less frequently. Dermatologists should be aware that dermoscopic features of melanoma differ according to the histogenesis of the lesion. Atypical pigment networks and regression patterns are the most useful dermoscopic criteria suggested to make a diagnosis of naevus-associated melanoma.

Lack of clinical-pathological correlation in the diagnosis of congenital naevi.

Congenital naevocellular naevi (CNN) have classical histological criteria that are thought to allow distinction from acquired naevi. These criteria are mainly the horizontal distribution of melanocytes, forming 'Indian files', and a prominent adnexotropism. In order to check whether the previously described criteria were reliable, we analysed 1349 unselected consecutive cases of naevocellular naevi excised in children under 16 years, during a 54-month period. The slides were analysed in order to determine by histological analysis only if they could be classified as CNN. These results were then compared with the clinical files, in which only the most reliable data from parental and/or medical observations were included. Of the 1349 naevi, 659 had the typical histological criteria of CNN, 32 of them being deep CNN, characterized by massive involvement of the lower dermis and hypodermis. The comparison with clinical data showed that 32 naevi with the histological criteria of congenital naevi were actually acquired, and that 179 naevi present at birth did not fulfil these criteria. This study shows that the classic histological criteria are not absolutely specific and are poorly sensitive as 36% of naevi present at birth lacked the classic criteria. The most specific criteria of true CNN were the involvement of eccrine glands and presence of melanocytes in the septae. In the case of deep CNN which corresponded to large or very large naevi, the clinicopathological correlation was 100%. Deep CNN could easily be distinguished from superficial CNN and often exhibited many histological changes consistent with a complex hamartoma, such as presence of brown fat tissue, abnormal vessels and numerous large terminal follicles. In conclusion, our study suggests that it is not possible to predict, by histological analysis alone, that a naevus was present at birth, except in deep CNN which are likely to be a separate entity among all congenital naevi. Studies dealing with congenital naevus-associated melanoma should take into account the lack of sensitivity of these criteria.