BackgroundMelanomas, highly malignant tumors arise from the melanocytes which originate as multipotent neural crest cells during neural tube genesis. The purpose of this study is to assess the pattern of neural differentiation in relation to angiogenesis in VGP melanomas using the tumor as a three dimensional system.MethodsTumor-vascular complexes [TVC] are formed at the tumor-stroma interphase, by tumor cells ensheathing angiogenic vessels to proliferate into a mantle of 5 to 6 layers [L1 to L5] forming a perivascular mantle zone [PMZ]. The pattern of neural differentiation is assessed by immunopositivity for HMB45, GFAP, NFP and synaptophysin has been compared in: [a] the general tumor [b] tumor-vascular complexes and [c] perimantle zone [PC] on serial frozen and paraffin sections. Statistical Analysis: ANOVA: Kruskal-Wallis One Way Analysis of Variance; All Pairwise Multiple Comparison Procedures [Tukey Test].ResultsThe cells abutting on the basement membrane acquire GFAP positivity and extend processes. New layers of tumor cells show a transition between L2 to L3 followed by NFP and Syn positivity in L4&L5. The level of GFAP+vity in L1&L2 directly proportionate to the percentage of NFP/Syn+vity in L4&L5, on comparing pigmented PMZ with poorly pigmented PMZ. Tumor cells in the perimantle zone show high NFP [65%] and Syn [35.4%] positivity with very low GFAP [6.9%] correlating with the positivity in the outer layers.DiscussionFrom this study it is seen that melanoma cells revert to the embryonic pattern of differentiation, with radial glial like cells [GFAP+ve] which further differentiate into neuronal positive cells [NFP&Syn+ve] during angiogenic tumor-vascular interaction, as seen during neurogenesis, to populate the tumor substance.
The relationship of vasculogenic mimicry to pigment in nodular vertical growth phase [VGP] cutaneous melanomas is assessed in this study. 10 nodules each from 27 tumors, 15 pigmented and 12 amelanotic were sampled in proportion to the pigment level. Serial frozen and paraffin sections subjected to HE, Reticulin, PAS to assess the vascular pattern; Dopa Oxidase and Immunopositivity for HMB45, LN5 [laminin 5] & integrin[α(5)β(1)], and EM [electron microscopy] to identify Weibel-Palade bodies within endothelial cells. The vascular pattern, pigment and the immunopositivity was mapped to assess the percentage VM [vasculogenic sinusoids] vs INC [incorporated microvasculature]. In pigmented melanomas, INC from pre-existing stromal vessels is predominant. Amelanotic melanomas show embryonic vasculogenic mimicry, a self-propagating system of spaces within the sheets of tumors cells. Both INC and VM co-exist in tumors with both amelanotic and melanotic nodules. In areas with VM, loci of LN5 and α(5)β(1) integrin positive cells appear within the proliferating columns, positivity in these cells suggesting a switch to a more aggressive form. Irregular spaces appear lined by tumor cells, with initial hemopoeitic activity, coalesce and interlink into tubular networks. Spaces lined by tumor cells extend into an intricate network which then connects with the angiogenetic system. The tumor cells lining the vasculogenic spaces are positive for LN5, α(5)β(1) integrin. Statistically, INC is significantly higher in pigmented melanomas, whereas amelanotic melanomas show significantly higher VM. Pigmentation is correlated positively with INC and negatively with VM. INC and VM are negatively correlated with each other.
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