Cyclin D1 Overexpression in Spitz Nevi: An Immunohistochemical Study

Abstract

The morphologic distinction between Spitz nevus and malignant melanoma can be difficult. Because cyclin D1 has been reported to be overexpressed in malignant melanomas, but not in common acquired nevi, we hypothesized that cyclin D1 might be a useful marker to distinguish Spitz nevi from malignant melanoma. Thus, we assessed for cyclin D1 expression in 11 Spitz nevi (10 compound and 1 intradermal) and 9 malignant melanomas (4 Clark stages I-III and 5 Clark stages IV-V) using an immunohistochemical method and routinely fixed and processed tissues. The cyclin D1 results were arbitrarily divided into three groups: 0% to 10%, >10% to 25%, and >25%. We confirmed the observations reported previously by others that cyclin D1 is expressed in malignant melanomas but not in common acquired nevi. Unexpectedly, a relatively high number of cyclin D1-positive cells (i.e., >10%) was also found in all cases of Spitz nevus. However, unlike malignant melanoma, the cyclin D1 positivity in Spitz nevi was present in a zonal pattern. In other words, the number of cyclin D1-positive cells decreased as the lesion extended more deeply, with the number of positive cells in the reticular dermis being less than that in the papillary dermis. Fluorescence in situ hybridization methods were used to assess amplification of 11q13, the locus harboring the cyclin D1 gene, in four cases of Spitz nevus; all were disomic. Using the antibody MIB-1, we compared cyclin D1 expression to the proliferation rate in Spitz nevi. Despite the high cyclin D1 positivity, all Spitz nevi had a relatively low number of MIB-1-positive cells (mean=3.2%), which was significantly lower than that of malignant melanomas (mean=15.3%) (p < 0.001). Thus, unlike malignant melanoma, there appears to be a dissociation between cyclin D1 overexpression and cell proliferation in Spitz nevi.

Immunohistochemical Expression of p16, p21, p27 and Cyclin D1 in Oral Nevi and Melanoma

“…These data are in accord with literature reports of negative or weak expression of cyclin D1 in benign melanocytic lesions and high levels in cutaneous melanomas [22][23][24][25]. Besides cutaneous melanomas, increased expression of cyclin D1 has been reported in uveal melanomas, and now we also confirm in oral melanomas, suggesting that it has an oncogenic role in the pathogenesis of this aggressive neoplasm [13,24,26].…”

Spitz nevi and atypical Spitz nevi/tumors: a histologic and immunohistochemical analysis

“…16,17,22,41 Nagasaka et al 16 found that all Spitz nevi had a relatively low MIB-1 index (mean 3.2%), which was significantly lower than that of malignant melanoma (mean 15.3%). Similarly, Kanter-Lewensohn et al 17 found an average MIB-1 index of 4% in Spitz nevi and 29.7% in malignant melanoma and Bergman et al 22 reported 1.5% for Spitz nevi vs 14.9% for malignant melanoma.…”

“…40 Spitz nevi also display evidence of cell cycle deregulation such as increased cyclin D1, p21, p16, p27, and phospho-ERK expression, which may partly account for the overlapping immunoprofile seen in Spitz nevi and malignant melanoma. 16,36 The adverse biologic effect of p21 and cyclin D1 overexpression in Spitz nevi might be mitigated by other properly functioning G1 regulatory mechanisms still present in Spitz nevi, but lost in malignant melanoma.…”

“…10,11 Similar results are observed for DNA ploidy analysis, cyclin D1, c-myc, c-fos, telomerase, and Bcl-2. [12][13][14][15][16][17] Negligible levels of p53 expression are seen in Spitz nevi in contrast with higher expression in malignant melanoma. 18 However, a negative result does not exclude malignant melanoma since positive p53 staining is reported in only 35% of malignant melanomas.…”

“…21 Several studies have shown that the MIB-1 index is a helpful marker for distinguishing between melanocytic nevi and malignant melanoma. 8,16,17,20,22 Tumor suppressor p21 WAF1/CIP1 is the main downstream effector gene mediating p53-induced cell cycle arrest and has different expression in nevi and malignant melanoma. 20 Fatty acid synthase, the key enzyme responsible for the synthesis of fatty acids, was weakly expressed in some normal human tissues.…”