Clinicopathologic Observations of the Skin in Seven (5 Hand, 2 Face) Composite Tissue Allograft Recipients

Abstract

Composite tissue allotransplantation has emerged as a new reconstructive surgical technique aiming at restoring non-vital parts of the body, such as limbs and face. It involves transplantation of various tissues including the skin, vessels, nerves, cartilage, bones and immune cells. Among these, the skin is of special importance since it is the most visible and the most antigenic tissue in a composite tissue allograft (CTA), therefore its macroscopic and microscopic observation provides information on the viability of the CTA and on the presence or absence of rejection, possibly requiring adjustments of the immunosuppressive treatment. We report here our clinicopathological observations of the allografted skin of seven CTA recipients (five hands, two face) followed regularly in our hospital. The patients (five men, two women) received a triple immunosuppressive regimen (steroids, tacrolimus (or sirolimus) and mycophenolate mofetil); they were monitored clinically and protocol biopsies were taken at least twice yearly, and whenever rejection was suspected. All of them developed at various times post-graft one or more episodes of rejection, reversed by increasing the dosages of immunosuppressants and by local applications of steroids and tacrolimus. The longest individual clinicopathologic follow-up of the skin varied from 2 to 11.8 years. At the follow-up endpoint (11.8, 8, 4.8 and 3 years respectively), 4 hand-graft recipients had neither clinical nor pathological signs of rejection (Banff grade 0), while the latest one (2 years) showed clinically slight erythema of the forearms and pathologically mild rejection (grade I). The first face-transplant recipient showed microscopically mild and moderate signs of rejection (grades I and II, respectively) on the skin from the face and the sentinel allograft skin, although no obvious macroscopic changes were seen. The second face-grafted recipient had developed over the preceding months fluctuating signs of rejection because of immunosuppressive treatment tapering during courses of chemotherapy for an EBV+ lymphoma. At the latest follow-up (2 years postgraft) his facial skin was erythematous, pigmented and somewhat indurated. Microscopically, signs consistent with grade III rejection were found both on the facial and the sentinel-graft skin, despite an absence of significant dermal inflammation. In all patients, apart from changes related to rejection, the skin showed microscopically a normal structure and contained all main cell types, including cycling keratinocytes, Langerhans cells (of recipient's origin), melanocytes, endothelial cells and axons. Occasional FoxP3+ T-reg and TiA1+ cytotoxic T-cells were found in the skin, even in the absence of obvious rejection. No C4d deposits were found, suggesting that humoral rejection does not occur in CTA. Apart from rejection, cutaneous transplantation-related side-effects were mild (tinea versicolor, molluscum contagiosum, warts), although one basal-cell carcinoma developed 6 years post-graft on the (self) cheek of the female face-transplant recipient. Close clinicopathologic monitoring of the skin seems to be important for the assessment of the quality of the CTA as a whole, and for the detection of signs of rejection. In the majority of cases, the structure of the skin remains normal with a conventional triple immunosuppressive protocol that seems adequate to prevent CTA rejection in the majority of cases.