Graft vasculopathy in the skin of a human hand allograft: implications for diagnosis of rejection of vascularized composite allografts

Abstract

SummaryWhereas vascularized composite allografts often undergo acute rejections early in the postgraft period, rejection manifesting with severe vascular changes (graft vasculopathy) has only been observed on three occasions in humans. We report a hand-allografted patient who developed severe rejection following discontinuation of the immunosuppressive treatment. It manifested clinically with erythematous maculopapules on the skin and pathologically with graft vasculopathy that affected both large vessels and smaller cutaneous ones. The observation that graft vasculopathy can affect skin vessels shows that it is amenable to diagnosis with usual skin biopsy as recommended for the follow-up of these allografts. Graft vasculopathy developing in the setting of vascularized composite allografts likely represents chronic rejection due to under-immunosuppression and, if confirmed, should be included in a future update of the Banff classification of vascularized composite allograft rejection.

Chronic Rejection in Human Vascularized Composite Allotransplantation (Hand and Face Recipients)

“…5 In all of these patients, GV led to amputation of the respective allografts. We have observed GV in medium-sized vessels of the skin in 2 hand-grafted patients, one who discontinued voluntarily his treatment 25 and in another who developed, despite an initial 10-year favorable course with only 2 AR episodes, 35 pain, decrease of graft motor function and persistent necrotic skin lesions over several fingers ( Figures 1C-D), leading to amputation of several fingers and eventually the whole graft (unpublished data). Circulating anticlass II DSA were detected in this patient transiently and in low titers from the sixth posttransplant year.…”

“…28 Pathologically, one of the commonest and certainly the most severe feature of CR in VCA is vascular damage, manifesting, as in animal models and in SOT, with myointimal proliferation of arteries, resulting in luminal narrowing and obstruction, producing ischemic-necrotic damage to the graft. These changes, referred to as GV, have been documented pathologically in deep (radial and ulnar) donor arteries, 24,25 in the sentinel skin graft (SSG) and synovial vessels in the setting of knee transplantation. 26 Another patient diagnosed with GV on postoperative day 771 has been reported in the International Registry of Hand and Composite Tissue Transplantation.…”

“…They include scaly psoriasiform plaques, 23 bruise-like or purpuric skin lesions, 24,25 necrotic ulcerations 25 (Figures 1A-B and 2B), sclerodermoid induration of the skin with dyschromic (hyperpigmented and hypopigmented) lesions reminiscent of graft-versus-host disease 27 (Figures 3A-B), finger thinning, and nail loss. 28 Pathologically, one of the commonest and certainly the most severe feature of CR in VCA is vascular damage, manifesting, as in animal models and in SOT, with myointimal proliferation of arteries, resulting in luminal narrowing and obstruction, producing ischemic-necrotic damage to the graft.…”

“…Insufficient IST can lead to CR; this may happen because of minimization (steroid sparing) protocols, 24 patient nonadherence, 23,25,38 or IST weaning because of intercurring complications of immunosuppression. 27 In experimental VCA, CR may develop after repeated episodes of AR, 29 and it seems likely that this scenario is also valid in some cases of human VCA.…”

“…36,37 Despite these facts, with an increasing number of VCA and a longer follow-up time, it could be expected that cases of CR would be observed, and indeed, some patients with hand, and more recently with facial, allografts showing clinicopathological features suggestive of CR (as observed in SOT and animal VCA models) were recently reported. Chronic rejection has resulted in most cases from a decrease or discontinuation of the IST, either due to patient nonadherence 23,25,38 or from programmed IST reduction due to complications of the treatment. 27 Other cases developed in apparently adhering patients who were receiving a standard triple IST regimen including MMF (or rapamycin), tacrolimus (trough levels around 10 ng/mL), and steroids.…”