Graft Vasculopathy May Affect the Skin of Vascularized Composite Allografts Undergoing Rejection.

Abstract

Acute rejection (AR) episodes often occur in the early post-graft period in Vascularized Composite Allografts (VCA) and manifest mainly with perivascular lymphocytic infiltration and epidermal changes but no severe vascular damage. More recently changes of graft vasculopathy (GV) similar to the ones developing in chronic rejection in kidney and heart were observed in three cases of VCA (2 hands, one knee) undergoing rejection. These affected deep arteries of the graft and manifested with myo-intimal proliferation and fibrosis of medium and large-sized blood vessels resulting in luminal narrowing/occlusion. We recently observed typical changes of GV in the skin of a hand allograft undergoing rejection following weaning of the immunosuppresive treatment. The patient received an allograft of the right hand in 2000. The induction immunosuppression included basiliximab, MMF, tacrolimus and steroids; the maintenance regimen included tacrolimus, MMF and steroids. The patient developed several episodes of AR (on days 76, 2653, 4400, 4500 and 4600). He was intermittently adhering to the treatment, developed rejection manifesting linically with diffuse erythemato-violaceous cutaneous macules, and was eventually amputated on day 4680 post-graft. Pathological examination of the radial artery showed GV, characterized by myo-intimal proliferation, fibrosis, lumen narrowing/obstruction, lymphocytic infiltration, calcification and fibrinoid necrosis of vessel wall. Remarkably, changes of GV, consisting namely of myo-intimal hyperplasia resulting in luminal occlusion, were observed in the skin in medium and small-sized vessels of the mid- and deep dermis and the dermal-hypodermal junction. Several medium-sized vessels were extensively infiltrated with CD4+ lymphocytes, and dermal capillaries were thickened. C4d deposits were seen in vascular endothelial cells but their presence was unrelated to the severity of pathological changes. This is the first observation of GV occurring in the skin of a VCA, and shows that even superficial (punch) skin biopsies are adequate to reveal GV. This specific alteration remains an exceptional finding in VCA, and apparently reflects chronic rejection, as it is not seen in the commonly-observed episodes of AR.