The Mechanism of Epidermal Hyperpigmentation in Dermatofibroma is Associated with Stem Cell Factor and Hepatocyte Growth Factor Expression

Abstract

Dermatofibromas have an increased brownish color due to hyperpigmentation of the overlying skin. To determine paracrine factors involved in the epidermal hyperpigmentation, we have studied the expression of cytokines in lesional and nonlesional dermatofibroma skin at the transcriptional and protein levels using reverse transcription polymerase chain reaction and immunohistochemistry, respectively. The number of tyrosinase immuno-positive melanocytes in the pigmented dermatofibroma epidermis is significantly increased (2-fold) compared with nonlesional normal epidermis. Reverse transcription polymerase chain reaction analysis of mRNAs encoding stem cell factor and hepatocyte growth factor demonstrated that there is an accentuated expression of stem cell factor and hepatocyte growth factor transcripts in the lesional dermatofibroma dermis compared with the nonlesional dermis, although there is no difference in their expression between the lesional and nonlesional epidermis. In contrast, mRNA transcripts encoding endothelin-1, growth-related oncogene alpha, and basic fibroblast growth factor are not increased in lesional epidermis or in dermis relative to nonlesional skin. In parallel, immunohistochemical analysis using antibodies to stem cell factor and hepatocyte growth factor reveal a marked immunostaining in growing fibroblastic tumor cells in the dermatofibroma lesions with no detectable staining in the nonlesional dermis, but there is no difference in their immunostaining between the lesional and nonlesional epidermis. Interestingly, and consistent with the increased expression of stem cell factor in lesional dermatofibroma dermis, toluidine blue staining in the dermis revealed a 5-fold increase in the number of mast cells, an indication of their longevity or accumulation induced by stem cell factor. These findings suggest an important role of fibroblastic tumor cell-derived stem cell factor in the mechanism involved in the hyperpigmentation of the dermatofibroma epidermis.

Melanocytic lesions associated with dermatofibromas: a spectrum of lesions ranging from junctional nevus to malignant melanoma in situ

“…[20][21] Furthermore, fibroblastic tumor cell-derived stem cell factor may play an important role in melanocyte hyperplasia and hyperpigmentation in dermatofibromas. 13 Utilizing c-kit (CD 117) immunostaining we did note significant staining of dermatofibromas vs the adjacent nonlesional dermis, similar to a previous study. However, in our control group, similar findings were noted, and there were no quantitative differences in immunostaining in the dermatofibromas with and without melanocytic lesions.…”

“…Along similar lines, it has been demonstrated that the number of tyrosinase immunopositive melanocytes in the pigmented dermatofibroma epidermis is increased up to two-fold when compared with the adjacent, nonlesional normal epidermis, and this may account for the hyperpigmentation seen clinically. 13 To the best of our knowledge, there has been no report of melanocytic neoplasms arising in association with a dermatofibroma.…”

Biphasic Expression of Two Paracrine Melanogenic Cytokines, Stem Cell Factor and Endothelin-1, in Ultraviolet B-Induced Human Melanogenesis

“…49,50 Furthermore, type IV Waardenburg syndrome (Shah-Waardenburg syndrome with Hirschsprung disease) is caused by mutations in the genes encoding ET-3 or ET B R. 48 In addition to their significance during the development of melanocytes, ET-1 and/or SCF are involved in melanocyte activation in several human pigmentary disorders such as lentigo senilis, dermatofibroma, café -aulait macules, and seborrehoic keratosis. [51][52][53][54][55] Especially in lentigo senilis, which is similar in histological aspects to UVB-melanosis, the enhanced expression of SCF and ET-1 occurs concomitantly with an increased expression of ET B R in the lesional pigmented epidermis.…”

Modulation of the expression of the FGFR2-IIIb and FGFR2-IIIc molecules in dermatofibroma

“…DF lesions are characterized by proliferating fibroblasts, young and mature collagen, capillaries and histiocytes, accompanied by hyperplasia of the overlying epidermis [1,2]. Several studies have suggested the involvement of growth factors and their receptors in the epidermal changes occurring in DF, since overexpression of hepatocyte growth factor [3], transforming growth factor b receptor-I and -II [4] and epidermal growth factor receptor [5] have been reported in DF lesions. Anyway, the etiology of DF has not been established yet.…”