Proliferating tests for proliferative nodules of congenital melanocytic nevi
By Warren R. Heymann, MDOct. 19, 2016
Proliferative nodules (PN) arising in congenital melanocytic nevi (CMN) require differentiation from melanoma. These are disconcerting, if not frightening, lesions to contend with. Do new techniques help in differential process?
The standard assessment involves clinical-pathologic correlation. PNs far more commonly arise from the dermis of a GCN than lethal melanomas during childhood. Clinically, multiple nodules favor a diagnosis of PN, whereas ulceration is infrequent in PN compared to melanomas. Histologically, PNs commonly show expansile nodules of epithelioid melanocytes with mean mitotic counts significantly lower than in the melanomas. However, high mitotic counts can be found in PNs within the small round blue cell pattern, complex pattern, or morphologies other than that of expansile nodules of highly atypical epithelioid melanocytes. The prognosis of PNs within GCN is excellent. The presence of expansile nodular growth of severely atypical epithelioid-shaped melanocytes with high mitotic count, such as > 5 mitoses/mm with ulceration and partial chromosomal copy number changes by molecular studies are the features that raise greatest concern for the possibility of melanoma (1).
Vergier et al studied 13 children with PNs arising in CMN in childhood and 5 children with melanomas arising in CMN in childhood. Five patients with giant CMN with no nodules were included as negative controls, and 6 patients with melanomas arising in CMN in adulthood were included as positive controls. Follow-up ranged from 3 to 21 years in all children (mean, 9.9 years) and from 3 months to 7 years in adults. Specimens were selected for immunohistochemistry and FISH. Of the 13 patients (5 boys and 8 girls) with PNs present at birth, all PNs were stable (mean follow-up, 9 years). Eight patients with PNs and 4 of 5 patients with childhood-onset melanoma showed homogeneous staining for HMB45, while heterogeneous staining for HMB45 was seen in 3 of 6 patients with adult-onset melanoma. Expression of p16 was strongly positive in most patients with childhood-onset PNs (10 of 11 patients) and melanoma (all patients) but negative in 4 patients with adult-onset melanoma. Patients with PNs and the 5 patients with childhood-onset melanoma had numerical chromosomal aberrations never observed in the adjacent CMN. The 2 children with FISH-positive PNs are melanoma free after 7 and 4 years. Only 1 patient with childhood-onset melanoma had a FISH aberration compared with 4 patients with adult-onset melanoma. The authors concluded that immunohistochemistry and the 4-probe FISH melanoma analysis are not useful for distinguishing PN from childhood-onset melanoma as opposed to adult-onset melanoma. Numerical anomalies seen in PNs but not in the adjacent CMN could be the result of a chromosomal segregation malfunction resulting in the development of nodules (2).
Despite the fact that we cannot rely on molecular techniques to differentiate PNs from melanoma yet, I have no doubt that we will be able to soon. After you read the following abstract by Pavlova et al (3), I think you will reach the same conclusion:
Differentiation of proliferative nodules in giant congenital nevi from melanoma arising within such nevi is an important diagnostic challenge. DNA methylation is a well-established epigenetic modification already observed in the earliest stages of carcinogenesis, which increases during melanoma progression. The ten-eleven translocation enzymes catalyze the oxidation of 5-methylcytosine to 5-hydroxymethylcytosine (5-hmC), which has recently been reported as an epigenetic hallmark associated with tumor aggressiveness and poor prognosis in a wide variety of cancers. In this study, we analyzed 12 proliferative nodules and 13 melanomas both arising in giant congenital nevi and matched results with a control group including 67 benign and malignant melanocytic lesions. Proliferative nodules displayed high 5-hmC expression levels (90.65%) compared with melanomas with almost complete loss of this marker (7.87%). We showed that low 5-hmC levels in melanomas correlate with downregulation of isocitrate dehydrogenase and ten-eleven translocation families of enzymes implicated in the cytosine methylation cycle. Simultaneously, these enzymes were overexpressed in proliferative nodules leading to strong 5-hmC expression. We emphasize the significance of 5-hmC loss for discrimination of melanomas from benign proliferative nodules arising within giant congenital nevi, and for establishing the correct diagnosis in ambiguous cases when histological and immunohistochemical characteristics are not sufficiently specific.
1. Yélamos O, et al. A comparative study of proliferative nodules and lethal melanomas in congenital nevi from children. Am J Surg Pathol 2015; 39: 405-15.
2. Vergier B, et al. Proliferative nodules vs melanoma arising in congenital melanocytic nevi during childhood. JAMA Dermatol 2016; 152: 1147-51.
3. Pavlova O, et al. 5-hydroxymethylcytosine expression in proliferative nodules arising within congenital nevi allows differentiation from malignant melanoma. J Invest Dermatol; 2016; July 22 [Epub ahead of print].
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