Proliferative Nodules in Congenital Melanocytic Nevi

Abstract

Congenital melanocytic nevi (CMN) occur in 1% to 2% of newborns, and the risk of malignant melanoma is increased in patients with large CMN. Appearance at birth or later of a nodular or hyperpigmented area within a CMN simulates malignant melanoma and prompts biopsy. Although their clinical and pathologic features seem ominous, proliferative nodules (PNs) typically are benign and may regress, although atypical features cause greater concern. Here we report clinical and pathologic findings with outcome in 10 children who had multiple biopsies of large CMN with PNs. We reviewed 78 separate samples from the 10 patients and classified the 60 PNs according to published criteria. A subset of 30 samples containing both the CMN and a PNs was analyzed for immunohistochemical reactivity for melanocytic (S-100 protein, HMB45, melan-A), lymphocytic (CD45), cell-cycle/proliferative (Mib-1, p16, p21, p27, c-Myc), apoptotic (p53, Bax, c-kit, CD95), and anti-apoptotic (bcl-2) markers. Both CMN and PNs had similar expression of melanocytic, lymphocytic, and most cell-cycle/proliferative and apoptotic markers, including Mib-1, p16, p21, p27, c-Myc, Bax, CD95, and bcl-2. A greater proportion of PNs than CMN were reactive for p53 (67% vs. 30%, P < 0.0098) and c-kit (97% vs. 3%, P < 0.0001). p53 and p21 expression in CMN and all types of PNs were inversely correlated. When ordinary and atypical PNs were compared, the atypical PNs more frequently expressed p53, Mib-1, Bax, and bcl-2, but less frequently expressed p21. The c-kit expression in nearly all PNs and its absence in nearly all CMN is potentially useful for recognition of PN, suggests a delayed melanocytic maturation process in proliferative nodules, and may be likely indicative of their benign nature. p53 reactivity in concert with a lack of p21 up-regulation by immunohistochemistry suggests that a p53 mutation may be present in PN, although the immunohistochemical findings alone cannot exclude possible overexpression of wild-type p53. Regressive, involutional, or maturational changes were observed in sequential samples from 4 patients. No patient developed malignant melanoma or another melanocytic nevus-associated malignancy during the follow-up period. These findings underscore the similarities between PNs and the underlying CMN and suggest that maturational, proliferative, and apoptotic processes are involved in their clinical evolution.

G1 cell cycle regulators in congenital melanocytic nevi. Comparison with acquired nevi and melanomas

“…In agreement with our results, Rudolph et al 5 and Li et al 6 detected < 1% immunoreactivity in the junctional and upper dermal parts of congenital nevi. Other investigators have also found low Ki‐67 labeling only in a subset of congenital nevi examined 7 . Bergman et al 8 found a marked reduction of Ki‐67 staining in the dermal component of ordinary melanocytic nevi in contrast to melanomas, which displayed only a slight and insignificant decrease.…”

“…Moreover, they observed only rare (< 5%) reactivity in all melanomas. Herron et al 7 found p‐53 staining ranging from < 10% to > 50% in 9 of 30 (30%) specimens of congenital nevi. The increased detection of p‐53 in the study of Herron et al 7 may be explained by the selected sample, which included only congenital nevi with atypical proliferative nodules.…”

“…Herron et al 7 found p‐53 staining ranging from < 10% to > 50% in 9 of 30 (30%) specimens of congenital nevi. The increased detection of p‐53 in the study of Herron et al 7 may be explained by the selected sample, which included only congenital nevi with atypical proliferative nodules. Generally, increased wild‐type p‐53 expression is accompanied by p‐21 upregulation, which was not the case in the study of Herron et al Increased p‐53 expression without a parallel p‐21 expression in a subset of nevi might be because of p‐53 mutation and might reflect a clonal process increasing their susceptibility to malignant transformation.…”

Cell cycle and apoptosis regulators in Spitz nevi: Comparison with melanomas and common nevi

“…Although high and broad expression has been observed by other investigators in various types of nevi including Spitz nevi, 39,40 others have demonstrated lower rates of bcl-2 expression ranging from 23% to 40% in acquired and congenital nevi. 37,41 In conclusion the interesting subset of Spitz nevi differ from melanomas in their immunohistochemical pattern of expression and demonstrate a distinct pattern, which may help in the correct diagnosis.…”

Giant congenital melanocytic nevus

“…40 The expression of c-kit was observed even in proliferative nodules which appear in CMN. 41 Although there are reports of familial cases of CMN, most of these lesions occur in at random. 7,42 …”