Simple SummaryIn comparison with other species, a large knowledge gap remains in Equine melanocytic tumors regarding their uncommon benign behavior, since invasion and metastasis are rarely present. Melanocytic tumors invasion and metastization have been associated with Epithelial-Mesenchymal Transition, where the disruption of cell-adhesion molecules has a crucial role. E-cadherin is one of the most prominent adhesion molecules, and the loss of its expression is observed in malignant tumors being associated with aggressive behavior. This study aimed to evaluate E-cadherin immunostaining in equine melanocytic tumors. There was high immunolabeling of E-cadherin in most tumors, with 70.7% of melanomas remaining with high immunostaining. The typical loss of immunostaining in malignant tumors was not observed, and there were no differences between malignant and benign tumors. The high E-cadherin expression is well correlated with the benign biological behavior of equine melanocytic tumors being in accordance with the genetic development factors associated with this neoplastic disease in horses.AbstractMelanocytic tumors are an important neoplastic disease in human and veterinary medicine, presenting large differences regarding tumor behavior between species. In horses, these tumors present a prolonged benign behavior, with rare invasiveness and metastases. In humans and small animals, invasion and metastasis have been associated with an Epithelial-Mesenchymal Transition, where the loss of E-cadherin expression plays a key role in tumor progression. This process and the role of E-cadherin have not yet been evaluated in equine melanocytic tumors. This study aimed to assess the immunolabeling of E-cadherin in equine melanocytic tumors and relate this with clinicopathological variables. A total of 72 equine melanocytic tumors were classified as benign and malignant and evaluated by immunohistochemistry for E-cadherin expression. A different pattern of immunostaining was found, contrasting with other species. A total of 69.4% of tumors presented raised immunolabeling of E-cadherin, with 70.7% of melanomas remaining with high expression. The typical loss of immunostaining was not seen in malignant melanomas and no differences were found between benign and malignant melanomas regarding E-cadherin immunostaining. The high immunolabeling of E-cadherin may contribute to the low invasiveness of these tumors, and it is in accordance with the benign behavior of equine melanoma and with the genetic factors associated with its development.