The immunohistochemical profile of Spitz nevi and conventional (non-Spitzoid) melanomas: a baseline study

Abstract

Several isolated markers have been proposed to aid in differential diagnostic of difficult melanocytic lesions, albeit none has been shown to be definitive in differentiating Spitz nevus from melanoma. This study proposes a wide panel of 22 markers having important functions in different biological functions (cell cycle, apoptosis, DNA repair proteins and membranous receptors) to provide a combination of proteins associated with either benign or malignant phenotype. Using tissue microarrays, we compared protein expression profiles in 28 typical Spitz nevi and 62 primary vertical growth phase non-spitzoid melanomas. Most of the significant differences were linked to cell-cycle deregulation such as overexpression of cyclin D1 and p21 in Spitz nevi compared with non-spitzoid melanomas (74 vs 16% and 91 vs 27%, respectively) and mitotic rate including Ki-67, highly expressed in deep areas of non-spitzoid melanomas (37%), whereas it is not expressed in Spitz nevi (0%), topoisomerase IIa (79% in non-spitzoid melanomas vs 15% in Spitz nevi) and nuclear survivin (69% in melanomas vs 0% in Spitz nevi). A combination of biological markers differentially expressed in Spitz nevi from non-spitzoid melanomas is defined, thus providing a potential tool for histopathological differential diagnostic between Spitz nevus and melanoma. Nevertheless, more studies including atypical Spitz nevi and spitzoid melanomas are necessary to further establish a reliable panel to differentiate among difficult cases.

Differential diagnosis of Spitzoid melanocytic neoplasms

“…CD99 has shown a diffuse expression in 56% of SMM, whereas only focal staining in 5% of SN . Carrido‐Ruiz et al . showed overexpression of p‐21 and cyclin D1 in SN, whereas low expression in non‐Spitzoid MM.…”

Enhanced Detection of Spitzoid Melanomas Using Fluorescence In Situ Hybridization With 9p21 as an Adjunctive Probe

“…3 We focused on 9p21 because there is growing evidence that copy number aberrations at the 9p21 chromosomal locus containing p16 INK4a and p14 ARF may be overrepresented in lesions with spitzoid morphology. 10,11,17 The 9p21 locus where the CDKN2A gene is located has long been recognized as a key player in melanoma. The CDKN2A gene by means of an alternative reading frame encodes for 2 critical tumor suppressor proteins, p16 INK4a and p14 ARF .…”

Pigmented Spindle Cell Nevus

“…Although a high expression of cyclin D1 has been related to malignant transformation in melanocytic tumors, a variable or even a high expression of cyclin D1 has been observed in some nevus subtypes, such as Spitz and dysplastic nevi, in contrast to common acquired or congenital nevi, which usually show a low expression of this marker. 2,14,25 Both p16INK4 and p27KIP1 are CDK inhibitors and suppress cell cycle progression. Familial melanomas and a subset of sporadic melanomas show deletion or mutation of the CDKN2A gene.…”

“…22 A nuclear higher expression of survivin in malignant melanomas has been previously reported, in contrast with benign nevi. 10,14,26 Moreover, this expression has been assessed as a prognostic factor and as a potentially important therapeutic target in melanomas. 19 In our study, nevi did not express this protein, whereas melanomas showed a low but significantly higher expression of it, in accordance with previously published studies.…”

“…19 In our study, nevi did not express this protein, whereas melanomas showed a low but significantly higher expression of it, in accordance with previously published studies. 10,14,26 However, nuclear staining for survivin was very low in all positive cases, which renders the assessment of this marker difficult and limits its usefulness for differential diagnosis purposes.…”