Journal of Plastic, Reconstructive & Aesthetic Surgery (2008) 61, 1512e1515
Allogeneic split-skin grafting in stem cell transplanted patients* J.O. Berg a,*, L. Vindeløv b, G. Schmidt a, K.T. Drzewiecki a a b
Department of Plastic Surgery and Burn Unit, Copenhagen University Hospital, Rigshospitalet, Denmark Department of Haematology, Copenhagen University Hospital, Rigshospitalet, Denmark
Received 2 September 2006; accepted 17 July 2007
KEYWORDS Allogeneic; Split thickness skin graft; Bone marrow transplant; GvHD
Summary We present a unique case of a bone marrow stem cell transplanted (BMT) patient with cutaneous chronic Graft versus Host Disease (cGvHD) who underwent successful allogeneic split-thickness skin graft (STSG) transplantation. BMT had previously been carried out due to myelodysplasia and non-Hodgkin’s lymphoma of the patient. Pre-BMT human leucocyte antigen (HLA)-typing had revealed identity between the donor and the recipient, who were siblings (not twins). Complete donor chimaerism was achieved. The recipient developed severe cGvHD with ichthyosis-like dryness and scleroderma. A folliculitis evolved to a full thickness ulceration on the entire scalp. From the femoral region of the donating sister a STSG was harvested under local analgesia and transplanted without analgesia to the prepared scalp ulcer of the recipient. The result was full and permanent take of the allogeneic STSG (follow up: three years). Allogeneic skin grafts are known to be acutely rejected. Successful allogeneic STSG has only been reported in sporadic cases of identical twins (isotransplantation). This case is the first to demonstrate what works in theory: the immune system of a stem cell transplanted patient with 100% or mixed stable donor chimaerism will not recognise skin from the stem cell donor as foreign. Due to advances in haematology, the number of BMT patients and their long-term survival is expected to increase. cGvHD, predisposing to skin problems and ulcerations, complicates up to 70% of cases of BMT. In BMT patients with cGvHD and large skin defects, allogeneic STSC from the BMT donor seems to be a safe alternative for permanent coverage. ª 2008 British Association of Plastic, Reconstructive and Aesthetic Surgeons. Published by Elsevier Ltd. All rights reserved.
*
Presented at the XXXI Meeting of the Nordic Society of Plastic Surgery, May 11e13 2006 in Malmo ¨, Sweden. * Corresponding author. Address: Department of Plastic Surgery and Burn Unit, Copenhagen University Hospital, Rigshospitalet, Section 2102, Blegdamsvej 9, DK-2100 Copenhagen, Denmark. Tel.: þ45 3545 2916; fax: þ45 3545 2102. E-mail address:
[email protected] (J.O. Berg). 1748-6815/$ - see front matter ª 2008 British Association of Plastic, Reconstructive and Aesthetic Surgeons. Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.bjps.2007.11.015
Allogeneic split-skin grafting in stem cell transplanted patients Allogeneic skin grafts are rejected. The only exception is a few sporadic reports of successful skin transplantation between identical twins (i.e. isotransplantation).1 We present a ‘new’ exception with a case of an allogeneic haematopoietic bone marrow stem cell transplanted (BMT) woman with a severe chronic scalp ulcer who was treated successfully with a split-thickness skin graft (STSG) donated from her stem cell donor, a human leucocyte antigen (HLA)-identical younger sister (not twin). To our knowledge, this has never been reported before, but more cases are likely to appear in the future.
Case report A 49-year-old woman was referred for plastic surgery of a chronic ulcer secondary to a massive folliculitis on the entire scalp (Figure 1). At age 41, the patient was diagnosed with malignant nonHodgkin’s lymphoma (NHL) of follicular/mixed type (Ann Arbor Stage II B). The patient had been treated with combined chemo- and radiotherapy and had had several relapse treatments. Autologous BMT at age 44 was complicated by therapy-induced myelodysplasia, thrombocytopenia and recurrence of NHL. At age 46, the patient underwent allogeneic BMT (allo-BMT) with peripheral stem cells donated by her younger HLA-identical sister (Table 1). Before the allo-BMT, the patient received non-myeloablative conditioning with fludarabin and whole body irradiation of 2 Gy. Post-transplant immunosuppression was conducted with cyclosporin and mycophenolate mofetil. The allo-BMT
Figure 1 At the time of referral for plastic surgery a chronic ulcer from GvHD-related folliculitis on the scalp was found. It measured approximately 12 15 cm and the ulcer bed consisted of exposed periosteum and only sparse and partially dried-out granulation tissue.
1513 resulted in 100% donor cell chimaerism with regard to granulocytes, CD4- and CD8-T-cells within 12 months. The course was complicated by acute Graft versus Host Disease (GvHD). This evolved into extensive chronic GvHD (cGvHD) with universal cutaneous alterations resembling ichthyosis-like dryness and exfoliation, especially on the lower abdomen and in the flanks, and with irregular hypoand hyperpigmentation on the trunk and extremities. The cGvHD evolved into a scleroderma-like condition with thickening and fibrosis of the skin. The face was relatively unaffected, but the skin on the scalp exfoliated and itched. At age 49, the patient developed a chronic ulcer from a severe folliculitis with methicilline-sensitive Staphylococcus aureus, which primarily had been treated with antibiotics and surgical debridements. When referred for plastic surgery, the ulcer had been persistent for six months. Since there were no signs of re-epithelialisation and no hair follicle-bearing skin remaining in the ulcer area, a STSG was planned to cover the defect. However, the patient had a lack of suitable donor sites due to her universal cutaneous cGvHD. With informed consent, it was planned instead to harvest the donor skin from the healthy sister, who had donated blood stem cells three years earlier. Due to the experimental setting and an uncertain outcome, it was planned only to harvest a single lane of donor skin leaving the rest of the scalp defects to heal by conservative means. A granulating ulcer bed was produced in two months by interim moist wound healing by topical cod liver ointment and petroleum gauze with change of dressing every other day. At the time of skin transplantation the patient received immunosuppressive therapy (prednisolone, cyclosporin and mycophenolate mofetil), antimicrobial therapy (dicloxacillin, fluconazol, prophylactic aciclovir and dapsone), and anticoagulant therapy (warfarin) due to prior deep venous thrombosis in the lower extremities. The allogeneic STSG procedure was carried out as follows: under local analgesia by topical lidocaineprilocaine 5.0% cream (EMLA) combined with infiltrative lidocaine-epinephrine 1%, the donor skin was harvested with an air-dermatome (Zimmer, Germany) from the femoral region of the donating sister. The graft was meshed to 1:1.5. With no delay and without analgesia, the graft was applied to the ulcer of the recipient patient. The central 80% of the defect was covered and islets of STSG were dispersed in the remaining peripheral parts of the ulcer. Dressings inside out were nitrofurazone gauze, petroleum gauze and a dry sterile head dressing. At six days postoperatively, the dressings were removed and the graft had taken completely. Since there was an unexpectedly very slow and insufficient epithelialisation from the edges, the remaining defects had not closed after three weeks. In the meantime, additional treatment with infliximab was given for cGvHD, which was suspected to inhibit the migration and proliferation of host keratinocytes. With renewed consent, a re-transplantation to these defects was performed in the same manner 25 days after the primary operation and dicloxacilline was administered for 14 days postoperatively. Complete graft take was obtained except minor defects, which healed conservatively. The donor sites of the sister healed without complications or scarring.
1514 Table 1
J.O. Berg et al. Perfect match in AB0-type and class I and II MHC between patient and donor Year of birth
AB0
HLA class I A
Patient/recipient Donor
1954 1956
0 0
3 3
HLA class II B
24 24
The patient did not tolerate a synthetic wig because of local hyperthermia and skin problems such as maceration and minor wounds (Figure 2). Instead she uncomplicatedly wore a wig of human hair attached to the remnants of her own hair. The patient experienced marked improvement in life quality and was able to return to her work in a leading position. She continuously received immunosuppressive therapy with a low daily dose of prednisolone (5 mg/day) against cGvHD. At follow up after 36 months there was still a complete remission of the NHL and the allografts were still intact and stable.
Discussion Allo-BMT plays a key role in the curative treatment of NHL and other haematological diseases. The development of reduced (non-myeloablative) conditioning and improvements in supportive care have been able to minimise the toxic effects of conventional conditioning, in which treatment-related mortality may be as high as 34e44%.2 The dramatic and significant reduction in procedural morbidity and mortality makes it possible that there will be a great increase in the number of allogeneic haematopoietic stem cell transplantations performed in the future.3 Complications are prevalent in this category of transplant patients, especially GvHD, thrombocytopenia and risk of severe infections. GvHD is one of the most common and serious complications to allo-BMT and remains an important problem following reduced conditioning allo-BMT. Chronic GvHD, predisposing to skin problems and ulcerations, complicates up to 70% of cases of allo-BMT. The incidence
7 7
Cw 13 13
6 6
DR 7 7
7 7
DRB1 8 8
0701 0701
0801 0801
of acute GvHD following allo-BMT between HLA-identical siblings is 30e80%.4 In resurfacing of large and deep skin defects, autogeneic STSGs represent the best treatment. Alternatives of synthetic, bio-synthetic and tissue engineered skin substitutes are all inferior in their ability to provide immediate and permanent wound closure regardless of (vascularised) wound bed and in aspects of stability, contracture, availability, procedural simplicity and cost effectiveness.5e7 In immunocompetent patients, skin allografts from histoincompatible donors are acutely rejected. Obvious clinicopathologic signs of rejection appear within two weeks.5 The rejection is antigen specific, the epidermis being the most antigenic component of the skin.6 Both cellular and humoral immune responses are involved in allo-skin graft rejection, but it is primarily T-cell mediated. T-cells detect allo-antigen either directly by encountering intact allo-MHC (major histocompatibility complex) molecules on the surface of donor cells or indirectly by processed allogeneic donor antigens which are presented by self-MHC molecules on antigen presenting cells (APCs) of the recipient. The Langerhans cells, comprising up to 4% of the epidermal cell population, play an important role in the rejection, since they are the most prominent APCs of the skin and express the important class II antigen HLA-DR.5,6 Allogeneic skin grafting does practically not exist today apart from temporary wound coverage with allogeneic cadaver skin grafts in various burn centres. In this situation it is shown that allograft survival may be prolonged by immunosuppression of the recipient, by techniques of combined auto- and allograft transplantation and/or by preoperative preparation of the donor skin in terms of depletion of the Langerhans cells and adnexae, but eventually and without immunosuppressants, allo-STSGs will be rejected.8,9 In conclusion, this is the first report of a ‘new’ exception of skin allotolerance, demonstrating what is working in theory: allo-BMT induces tolerance to skin grafts from the stem cell donor, since the immune system of a stem cell transplanted with full or mixed stable donor chimaerism will not recognise skin from the stem cell donor as foreign. Due to advances in haematology, the number of allo-BMT patients and their long-term survival is expected to increase. In case of the need for skin transplantation for this category of patients (e.g. burns, trauma or cancer surgery), allogeneic skin transplantation from the stem cell donor (who is often a 1st degree relative) seems to be a simple and safe alternative for permanent coverage.
References Figure 2 Status five months postoperatively. Complete closure with stable grafts. A synthetic wig had caused new minor ulcerations.
1. Westerveld AW, Sauer EW, Klasen HJ. Successful treatment of a severely burned elderly patient with homografts from her identical twin sister. Br J Plast Surg 1986;36:136e8.
Allogeneic split-skin grafting in stem cell transplanted patients 2. Vindeløv L. Allogeneic bone marrow transplantation with reduced conditioning (RC-BMT). Eur J Haematol 2001;66:73e82. 3. Peggs KS, Mackinnon S, Linch DC. The role of allogeneic transplantation in non-Hodgkin’s lymphoma. Br J Haematol 2005;128:153e68. 4. Barrett AJ, Rezvani K, Solomon S, et al. New developments in allotransplant immunology. Hematology Am Soc Hematol Educ Program; 2003;350e71. 5. Nakano M, Yoshida T, Ohura T, et al. Clinocopathologic studies on human epithelial autografts and allografts. Plast Reconstr Surg 1992;90:899e909.
1515 6. Nanchalal J, Ward CM. New grafts for old? A review of alternatives to autologous skin. Br J Plast Surg 1992;45:354e63. 7. Bannasch H, Fo ¨hn M, Unterberg T, et al. Skin tissue engineering. Clin Plast Surg 2003;30:573e9. 8. Alsbjørn BF. Clinical results of grafting burns with epidermal Langerhans’ cell depleted allograft overlay. Scand J Plast Reconstr Surg Hand Surg 1991;25:35e9. 9. Wendt JR, Ulich T, Rao PN. Long-term survival of human skin allografts in patients with immunosuppression. Plast Reconstr Surg 2004;113:1347e54.
SURGICAL TIP Modified square flap method The square flap method was first introduced by Hyakusoku in 1987.1 It is a very useful method for the correction of scar contracture, various clefts and cryptotia. The flaps are referred to as the S-flap, T-flap and U-flap, respectively, as named by the authors of that manuscript. It is easy to move each flap if the skin around the incision line is soft. On the contrary, if the skin around them is hard, it is difficult to transpose the U-flap for the estimated position without tension. This modification is effective for these cases, and it is easy to transpose it without tension because of the short neck width of the Uflap. Moreover, it is useful for making an oblique line by changing the shape of the S-flap ‘square’ to trapezoid. The fundamental designs of classical and modified square flap are shown in Figure 1. Case report: A 2-year-old girl had an inter-digital web after steam burn. Full-thickness skin graft to the second finger and third finger was performed at 1. For the second inter-digital web, we selected the modified square flap method. The appropriate oblique web line from the third finger to the second finger was created (Figure 2). Figure 2 A case of inter-digital web: preoperative view (upper), preoperative design (middle), postoperative view (lower).
T S
T
S
U
Reference U 1. Hyakusoku H, Fumiiri M. The square flap method. Br J Plast Surg 1987;40:40e6.
T. Chin H. Hyakusoku K. Kubo Y. Ohmori Nippon Medical School Hospital, Tokyo, Japan E-mail address:
[email protected]
T S
T U
S U
ª 2008 British Association of Plastic, Reconstructive and Aesthetic Surgeons. Published by Elsevier Ltd. All rights reserved.
Figure 1 Basic design of classical (upper) and modified (lower) square method before and after transposing flaps.
doi:10.1016/j.bjps.2008.05.037