Cultured Epithelial Autografts in the Treatment of Extensive Recalcitrant Keloids

THE CUTTING EDGE

SECTION EDITOR: GEORGE J. HRUZA, MD; ASSISTANT SECTION EDITORS: LYNN A. CORNELIUS, MD; JOHN STARR, MD Cultured Epithelial Autografts in the Treatment of Extensive Recalcitrant Keloids

Ann F. Haas, MD, Department of Dermatology; Debra A. Reilly, MD, Division of Plastic Surgery; University of California, Davis, Sacramento

The Cutting Edge: Challenges in Medical and Surgical Therapeutics

REPORT OF A CASE the clavicle to the inframammary crease (Figure 1). The inferior portion of the keloid, which was the thickest por- A 42-year-old black man presented with an extensive ke- tion, had curled under itself and had completely en- loid on the anterior section of his chest wall. He had acne cased the patient’s areolae, which were not visible. In ad- as a child and developed a number of significant ke- dition, the patient had a number of keloids located on loids, the most symptomatic being the keloid on his chest his back and upper extremities. He had hypertrophic, but wall. This keloid had been treated with excision approxi- not keloidal, scars on his thighs at the donor sites from mately 10 years previously in another city, followed by his previous STSGs. placement of a number of mesh split-thickness skin grafts (STSGs) obtained from his thighs. According to the pa- THERAPEUTIC CHALLENGE tient, the superior edge of the keloid had also been irra- diated some time after surgery. The entire keloid located on his chest wall had regrown significantly, causing Provide treatment with minimal surgical trauma to un- the patient problems with bending at the waist and with involved areas for an extensive recalcitrant keloid lo- full range of motion in his shoulders. The recurrence had cated in an area at high risk for keloid re-formation. been treated with intralesional corticosteroids and cryotherapy (separately and combined), as well as silicone SOLUTION gel and flurandrenolide (Cordran tape, Lilly, Eli and Co, Indianapolis, Ind) without significant improvement. In Using local anesthesia, a 1-cm2 piece of the patient’s epi- addition, a smaller keloid had been excised on his back dermis was removed from the lateral section of his right and the epidermis removed from the keloid and re- thigh with a Weck blade. This skin specimen was cul- placed over the wound, with significant regrowth of that tured at the Epithelial Autograft Facility, University of keloid as well. California, Davis, in Sacramento. Sheets of keratino- On physical examination the patient had an exten- cytes were cultured and were ready for grafting approxi- sive keloid encompassing the surface area extending from mately 2 weeks after receiving the skin biopsy sample. Extra cells were frozen for future grafting. With the patient under general anesthesia in the operating room, the entire keloid, measuring 300 cm2, was removed with a carbon dioxide laser. The areolae were found to be em- bedded in the keloidal tissue and were dissected from the surrounding keloid with the laser. The keloid measured 4 cm at its thickest point. The autografts were then placed onto the defect (Figure 2), secured at the wound edge with a fine net, and his chest was wrapped with a bulky dressing. Dressing changes down to, but not including, the fine net were performed daily, and the grafts were irrigated using a cell culture medium. The complete dressing was removed at 1 week, after which the patient used hydrocolloid dressings to help speed reepithelialization and prevent friction. Figure 1. Patient with extensive recurrent keloid on his chest years after Because of the size and location of the wound (an- placement of split-thickness skin grafts and radiation treatment. terior portion of the chest, which tends to be suscep-

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©1998 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 10/02/2021 Figure 2. Cultured epithelial autografts being applied immediately after Figure 3. Patient’s chest area 2 years after placement of cultured epithelial keloid excision. autografts with considerable repigmentation of the cultured epithelial autografts.

Figure 4. A patient with extensive facial keloids following burn injury. Figure 5. Same patient in Figure 4, 6 months after keloid excision and placement of cultured epithelial autografts. tible to friction), the decision was made to perform more following excision and autografting of those keloids grafts approximately 2 months following the initial graft- (Figure 4 and Figure 5). ing session to correct for shearing of the neoepidermis. Stored frozen cells were thawed, grown into confluent COMMENT sheets, and his chest area was regrafted. The patient has been followed up for more than 2 Keloids are an overgrowth of fibrous tissue following heal- years, with development of a hypertrophic, soft, and ing of a skin injury. Surgery, vaccinations, skin infec- asymptomatic scar (Figure 3). He has not had a signifi- tions, and burns are probably the most common causes cant scar develop at the autograft biopsy donor site. To- of keloid formation in individuals who are predisposed to tal reepithelialization of his chest took almost 1 year. How- develop such formations. The fibrous tissue tends to ex- ever, the patient has had no other problems. He was so tend beyond the borders of the original skin injury, recur encouraged by the dramatic improvement and the lack after excision, and not regress spontaneously. Symptoms of morbidity from the procedure that at his request, we can include cosmetic disfigurement, pruritus, pain, ten- went on to remove and place cultured epithelial auto- derness, skin discoloration, and restricted movement. grafts (CEAs) on an extensive keloid located on his el- One of the first descriptions of keloids has been found bow. He is now able to bend comfortably at the waist and in a papyrus describing surgical techniques used in Egypt has considerably more range of motion of his elbow fol- about 1700 BC.1 In addition to the nonsurgical modalities lowing CEA grafting of both areas. This patient’s re- commonly used to treat smaller keloids, there have been sponse has been similar to that in some patients with burns a number of newer nonsurgical therapies proposed.

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©1998 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 10/02/2021 These have been recently thoroughly reviewed,2 and in- semble normal skin histopathologically.24 Not only have clude such modalities as interferon, anti–transforming CEAs been shown to be able to regenerate a stable, nor- growth factor ␤ (wounds treated with anti–transforming mal epidermis and induce dermal regeneration from growth factor ␤ healed with minimal scar formation and wound bed connective tissue, but the application of skin normal tensile strength),3,4 and others. Although pro- autografts may also provide a stimulus for healing.24,33 posed to treat keloids and hypertrophic scars, these newer The advantages of this technique are numerous for agents may actually be more useful either for preventing the treatment of extensive keloids. At any time, more epi- recurrences or for treatment of smaller keloids. dermal sheets can be grown from the patient’s keratino- The treatment of larger keloids is still primarily sur- cytes, which are in frozen storage. The initial small bi- gical, and since excisional surgery alone is associated with opsy specimen permits an almost infinite quantity of the a high rate of recurrence,5 surgical treatment of keloids is patient’s own epidermis to be placed on numerous or ex- generally followed by one of the more familiar treatments tensive postkeloid excision defects and reapplied at any used adjunctively,6,7 such as pressure,8 radiation therapy,9-12 time in the postoperative course. There is no harvesting intralesional steroid injections,13,14 cryosurgery,15,16 zinc ox- of multiple skin grafts, no additional trauma from full- ide tape,17,18 silicone gel sheeting,19,20 and others. thickness skin grafts, and since these are autografts, com- Following excisional surgery, excised areas have been plete take can be expected. In addition, placement of CEAs allowed to heal by secondary intention,21 closed prima- can easily be done in the clinic. rily or covered with either STSGs or full-thickness skin The disadvantages of this technique are related to grafts. As for our patient, treating a traumatically in- the length of time necessary for CEAs to develop nor- duced problem with a procedure that can cause addi- mal anchoring fiber attachments to the dermal layer. Con- tional skin trauma is problematic. In addition, in indi- sequently, late graft loss due to mechanical trauma has viduals with large keloids, full-thickness skin grafts would been reported in the burn literature,25,34 and these grafts not even be feasible. Grafting of the wound with the epi- are less likely to be successful if placed on dependent ar- dermis from the keloid has also been reported to be suc- eas that are susceptible to shear forces. One solution would cessful.9,22 This is somewhat impractical for extensive ke- be to grow and apply additional grafts as needed. It also loids and was not successful as an initial procedure in has been suggested that some form of dermal matrix re- our patient. placement be placed before the surface application of the Historically, CEAs have been used more extensively CEA as epidermis.24,35,36 In addition, development of a in patients with burns. However, CEAs also have been used composite graft using a dermal substitute combined with to treat leg ulcers and other chronic wounds, such as those the autograft is being explored. The other limitation of in epidermolysis bullosa, as donor site coverage for STSGs, this procedure is that the ability to grow CEAs is gener- to cover large postexcisional skin defects in giant congen- ally limited to university settings, large burn centers, and ital nevi, and for other nonburn indications.23-30 commercial manufacturers. Consequently, shipping and The initial skin specimen for preparation of the au- manufacturing, depending on the facility, would tend to tografts can be either a superficial shave biopsy sample increase the cost of the grafts. or a 1-cm2 full-thickness biopsy sample (depending on Although cost and other factors may not make ap- the requirements of the laboratory growing the grafts). plication of CEAs the initial therapy of choice for smaller The method of preparing cultured skin in the labora- keloids for which a number of treatment alternatives al- tory was originally described by Green et al,31 in which ready exist, we have found CEAs useful in the treatment human keratinocytes were grown in culture media. The of extensive recalcitrant keloids. cultured cells form colonies that ultimately coalesce to form the epithelial sheets used for grafting. The cul- Presented at the 23rd annual meeting of the American Soci- tured cells are transferred to petrolatum gauze sheets and ety of Dermatologic Surgery, Palm Desert, Calif, May 19, 1996. transported in sterile containers prior to grafting. The We wish to acknowledge the clinical contributions of backing is necessary because the cultured skin is only a Seth Thaller, MD. few cells thick and therefore friable. The grafts are draped over the wound, secured in place with fine net mesh, then REFERENCES dressed with bulky dressings, which are changed daily. The wound is irrigated with a cell culture medium with each dressing change. 1. Brested J. The Edwin Smith Surgical Papyrus, vol 1: Hieroglyphic Translation and Commentary. Chicago, Ill: University of Chicago Press; 1930:403-406. Healing CEAs undergo evolutionary changes over 2. Berman B, Bieley H. Adjunct therapies to surgical management of keloids. Der- 24,32 time. On application, CEAs are undifferentiated and matol Surg. 1996;22:126-130. have no granular or cornified cell layer. After 1week, all 3. Shaw M, Foreman DM, Ferguson MW. Control of scarring in adult wounds by neu- the normal epidermal layers are present, but there are no tralising antibody to transforming growth factor B. Lancet. 1992;339:213-214. 4. Border WA, Nobel NA. Transforming growth factor B in tissue fibrosis. N Engl J rete ridges. After 1 month, a confluent basal lamina and Med. 1994;331:1286-1292. mature hemidesmosomes are formed. Anchoring fibrils 5. Lawrence W. In search of the optimal treatment of keloids: report of a series and are immature until 6 to 12 months, when rete ridges and a review of the literature. Ann Plast Surg. 1991;27:164-178. a neodermis with normal stroma and vascular organiza- 6. Munro KJG. Treatment of hypertrophic and keloid scars. J Wound Care. 1995; tion can be seen. Elastin expression is seen in the CEA 4:243-245. 7. Datubo-Brown DD. Keloids: a review of the literature. Br J Plast Surg. 1990;43: neodermis at 4 to 5 years. The skin that results from CEA 70-77. application is comparable with mesh STSGs over time. 8. Linares HA, Larson DL, Willis-Galstaun A. Historical notes on the use of pres- However, on long-term follow-up CEAs more closely re- sure in the treatment of hypertrophic scars or keloids. Burns. 1993;19:17-21.

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©1998 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 10/02/2021 9. Norris JEC. Superficial X-ray therapy in keloid management: a retrospective study 29. Premachandra DJ, Woodward BM, Milton CM, Sergeant BJ, Sabre JW. Treat- of 24 cases and literature review. Plast Reconstr Surg. 1995;95:1051-1055. ment of postoperative otorrhea by grafting of mastoid cavities with cultured au- 10. Klumpar DJ, Murray JC, Anscher M. Keloids treated with excision followed by tologous epidermal cells. Lancet. 1990;335:365-367. radiation therapy. J Am Acad Dermatol. 1994;31:225-231. 30. Nakano M, Yoshida T, Ohura T, Azami K, Sennoo A, Fuse Y. Clinicopathologic 11. Babin RW, Ceilley RI. Combined modalities in the management of hypertrophic studies on human epithelial autografts and allografts. Plast Reconstr Surg. 1992; scars and keloids. J Otolaryngol. 1979;87:457-459. 90:899-909. 12. Ollstein RN, Siegel HW, Gillooley JF, Barsa JM. Treatment of keloids by com- 31. Green H, Kehinde O, Thomas J. Growth of cultured human epidermal cells into bined surgical excision and immediate post-operative X-ray therapy. Ann Plast multiple epithelia suitable for grafting. Proc Natl Acad SciUSA.1976;76:5665- Surg. 1981;7:281-285. 5668. 13. Griffith GH. Treatment of keloids with triamcinolone acetonide. Plast Reconstr 32. Petersen MJ, Lessane B, Woodley DT. Characterization of cellular elements in Surg. 1966;38:202-208. healed cultured keratinocyte autografts used to cover burn wounds. Arch Der- 14. Larson DL, Abston S, Evans B, Dobrokovsky M, Linares HA. Techniques for de- matol. 1990;126:175-180. creasing scar formation and contractures in the burned patient. J Trauma. 1971; 33. Kirsner RS, Falanga V, Eaglstein WH. The biology of skin grafts. Arch Dermatol. 11:807-823. 1993;129:481-483. 15. Rusciana L, Rossi G, Bono R. Use of cryotherapy in the treatment of keloids. 34. Law EJ, Orlet HK, Still JM. Experience with cultured skin in a Georgia regional J Dermatol Surg Oncol. 1993;19:529-534. burn unit. J Med Assoc Ga. 1992;81:185-188. 16. Zouboulis CC, Blume U, Buttner P, Orfanos CE. Outcomes of cryosurgery in ke- 35. Odessey R. Addendum: multicenter experience with cultured epithelial autograft loids and hypertrophic scars: a prospective consecutive trial of case series. Arch for treatment of burns. J Burn Care Rehabil. 1992;13:174-180. Dermatol. 1993;129:1146-1151. 36. Cuono C, Langdon R, McGuire J. Use of cultured epidermal autografts and der- 17. Soderberg T, Hallmans G, Bartholdson L. Treatment of keloids and hypertrophic mal allografts as skin replacement after burn injury. Lancet. 1986;1:1123-1124. scars with adhesive zinc tapes. Scand J Plast Reconstr Surg Hand Surg. 1982; 16:261-266. 18. Perkins K, Davey RB, Wallis KA. Current materials and techniques used in a burn scar management programme. Burns. 1987;13:406-410. Submissions 19. Perkins K, Davey RB, Wallis KA. Silicone gel: a new treatment for burn scars and contractures. Burns. 1983;9:201-204. 20. Quinn KJ. Silicone gel in scar treatment. Burns. 1987;13:533-540. Clinicians, local and regional societies, residents, and fel- 21. Stucker FJ, Shaw GY. An approach to management of keloids. Arch Otolaryngol lows are invited to submit cases of challenges in man- Head Neck Surg. 1992;118:63-67. agement and therapeutics to this section. Cases should 22. Apfelberg DB, Maser MR, Lash H. The use of epidermis over a keloid as an au- follow the established pattern. Submit 4 double-spaced tograft after resection of the keloid. J Dermatol Surg Oncol. 1976;2:409-411. copies of the manuscript with right margins nonjusti- 23. Carter DM, Lin A, Varghese MC, Caldwell D, Pratt LA, Eisinger M. Treatment of fied and 4 sets of the illustrations. Photomicrographs and junctional epidermolysis bullosa with epidermal autografts. J Am Acad Derma- illustrations must be clear and submitted as positive color tol. 1987;17:246-250. transparencies (35-mm slides) or black-and-white prints. 24. Compton CC. The biology of cultured epithelial autografts: an eight-year study Do not submit color prints unless accompanied by origi- in pediatric burn patients. Eur J Pediatr Surg. 1992;2:216-222. 25. Still JM, Orlet HK, Law EJ. Use of cultured epidermal autografts in the treatment nal transparencies. Material should be accompanied by of large burns. Burns. 1994;20:539-541. the required copyright transfer statement, as noted in “In- 26. Gallico GG, O’Connor NE, Compton CC. Cultured epithelial autografts for giant structions for Authors.” Material for this section should congenital nevi. Plast Reconstr Surg. 1989;84:1-9. be submitted to George J. Hruza, MD, Cutaneous Sur- 27. Hefton JM, Caldwell D, Biozes DG, Balin AK, Carter DM. Grafting of skin ulcer s gery Center, Suite 16411, 1 Barnes Hospital Plaza, St with cultured autologous epidermal cells. J Am Acad Dermatol. 1986;14:399-405. Louis, MO 63110. Reprints are not available. 28. Leigh IM, Purkis PE. Cultured grafted leg ulcers. Clin Exp Dermatol. 1986;11: 650-652.

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