CD31 and CD34 Expression as Immunohistochemical Markers of Endothelial Transdifferentiation in Human Cutaneous Melanoma

A M Pisacane,M Risio,F Picciotto

doi:10.1155/2007/486579

Abstract

Introduction: Vasculogenic mimicry, as previously described in aggressive melanoma, is characterized by the de novo generation of intratumoral patterned vascular channels, composed of PAS-positive basement membrane in the absence of endothelial cells, providing additional microcirculation, in support to the classic tumoral angiogenesis. Methods: We investigated the immunohistochemical expression of two endothelial markers, CD31 and CD34, in tumoral cells of 60 melanomas (45 primary cutaneous and 15 metastatic) as possible evidence of vasculogenic mimicry. In addition we investigated the relationship between CD31 and CD34 expression and three pathological markers such as Clark’s level, and skin ulceration, predictive of melanoma’s aggressive behaviour, and mitotic index. Results: No cases of common melanocytic nevi immunoreacted with CD31 or CD34. Random CD31 immunoreactivity was present in 6% of Clark’s level I/II, 50% of Clark's level III and 80% Clark's level IV/V. CD34 was negative in Clark's level I/II but randomly stained the 20% and 55% of level III and IV/V respectively. 66% (10/15) of metastatic melanomas were CD31 positive showing a canalicular immunostaining pattern, conversely CD34 expression was never found. 7/8 cutaneous ulcerated melanomas immunostained for CD31 and 4/8 for CD34. CD31 immunostained 88% high/intermediate MI, and 53% of low MI melanomas. CD34 decorated the 29% of high/intermediate and 38% of low MI melanomas. Conclusions: CD31 and CD34 immunoreactivity closely parallel both the different morphologic steps of melanocytic tumor progression and the presence of histological parameters related to the aggressive behaviour. Their expression could be related to endothelial transdifferentiation of melanoma cells although a consequent functional role has not been demonstrated yet.

Highlights

Vasculogenic mimicry, as previously described in aggressive melanoma, is characterized by the de novo generation of intratumoral patterned vascular channels, composed of periodic acid-Schiff (PAS)-positive basement membrane in the absence of endothelial cells, providing additional microcirculation, in support to the classic tumoral angiogenesis
It is assumed that vasculogenic mimicry is a complex process characterized by (i) the ability of aggressive melanoma cells to form extracellular matrix (ECM)-rich vasculogenic-like networks surrounding clusters of tumoral cells, when seeded on threedimensional matrix of collagen I; (ii) the upregulation, as revealed by the gene-expression profiling in aggressive melanoma-cells, of genes involved in angiogenesis and vasculogenesis, such as the genes en
Our final goal was to investigate the possible relationship between CD31 and/or CD34 expression and the presence of three histopathological markers related to aggressive behaviour in cutaneous melanomas such as Clark’s level, skin ulceration and mitotic index [1,4,9]

Summary

Introduction

It is well known that in aggressive primary and metastatic melanomas, tumor cells generate, and subsequently line, acellular, microcirculatory patterned channels delimited by PAS-positive extracellular matrix. In 1999 Maniotis et al in their pivotal article [20] described the CD31 immunohistochemical staining of uveal melanoma cells proximal to the patterned matrixassociated intratumoral channels whereas CD34 immunostaining was limited to the lumen contents around red blood cells Both the CD31 and CD34 over expression has been detected by molecular methods in aggressive breast, ovarian and prostatic tumor cells [15,28,30] associated with deregulation of the genes involved in vasculogenic mimicry. The present work was aimed at evaluating the immunohistochemical expression of CD31 and CD34 in common melanocytic nevi and malignant primary and metastatic melanoma cells We assumed that these two molecules could be related to the acquisition of an endothelial phenotype in tumor cells, occurring during the vasculogenic-mimicry as expression of tumor cell plasticity. Our final goal was to investigate the possible relationship between CD31 and/or CD34 expression and the presence of three histopathological markers related to aggressive behaviour in cutaneous melanomas such as Clark’s level, skin ulceration and mitotic index [1,4,9]

Tissue specimens

Histology and immunohistochemistry

CD31 and CD34 immunohistochemical evaluation and scoring:

Statistical analysis

Results

Discussion