Diagnosing skin rejection in vascularized composite allotransplantation: advances and challenges

Refinements in microsurgical techniques coupled with advances in immunosuppressive and immunomodulatory protocols have enabled broader clinical application of vascularized composite allotransplantation (VCA) with encouraging immunological, functional, and esthetic results. However, skin rejection remains a significant obstacle and a serious complication for VCA recipients. Clinical and histopathological features of rejection in VCA have been described in a number of studies, which led to the development of an international consensus on the classification guidelines of rejection in the context of VCA. Nevertheless, currently available diagnostic modalities still have several limitations and shortcomings that can pose a significant diagnostic challenge, particularly when signs of rejection are found to be equivocal. In this review, we provide a critical analysis of these advances and challenges in diagnosing skin rejection. Specifically, we highlight the gaps in understanding of rejection mechanisms, the shortfalls in correlating cellular, molecular, and clinicopathologic markers with rejection grades, deficiencies in defining chronic rejection, and antibody-mediated rejection after VCA, as well as providing an outlook on novel concepts, such as the utilization of advanced computational analyses and cross-disciplinary diagnostic approaches.