Face vascularized composite allografts (FVCAs) have helped patients with severe facial disfigurement, with acute rejection now largely controlled through iatrogenic immunosuppression. However, little is known regarding the incidence and mechanism(s) of more long‐term pathologic alterations in FVCAs that may affect function and graft durability. Protocol surveillance biopsy specimens for up to an 8‐year interval in 7 patients who received FVCAs at our institution revealed histopathologic evidence of chronic rejection. Clinical manifestations included features of premature aging, mottled leukoderma accentuating suture lines, telangiectasia, and dryness of nasal mucosa. Pathologic changes consisted of epidermal thinning accompanied by discrete foci of lymphocyte‐mediated cytotoxicity, hyperkeratosis, follicular plugging, vascular ectasia, and sclerosis beneath the epidermal layer associated with collagen type I deposition. Genomic interrogation and immunohistochemistry of sclerotic zones revealed upregulation of the AP‐1 pathway components, JunB and c‐Fos, previously implicated in overproduction of type I dermal collagen in the setting of systemic sclerosis. We conclude that some patients develop chronic rejection in FVCAs with striking similarities to alterations seen in certain autoimmune cutaneous disorders (lupus erythematosus and scleroderma/chronic sclerodermoid graft‐versus‐host disease). Identification of relevant pathways and genes, such as JunB and c‐Fos, may provide new targets for preventative therapies for chronic immune‐mediated changes in vascularized composite allografts.

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More than thirty-five facial allograft transplantations (FAT) have been reported worldwide since the pioneering case performed in France in the year 2005. FAT has received tremendous interest by the medical field and the general public while gaining strong support from multiple disciplines as a solution for reconstructing complex facial defects not amenable/responsive to conventional methods. FAT has expanded the frontiers of reconstructive microsurgery, immunology and transplantation, and established its place in the cross section of multiple disciplines. The procedure introduces complex scientific, ethical, and societal issues. Patients and physicians are called to deal with a variety of-sometimes everlasting-challenges, such as immunosuppression management and psychosocial hurdles. This review reflects on the surgical and scientific advancements in FAT and milestones reached in the last 12 years. It aims to encourage active discussion regarding the current practices and techniques used in FAT and suggest future directions that may allow transitioning into the next phase of FAT, which we describe as safe, reliable, and accessible standard operation for selected patients.