British Journal of Plastic Surgery ( 1990), 43, 7C-77 0 1990 The Trustees of British Association of Plastic Surgeons
Keloids: a review of the literature D. D. DATUBO-BROWN Burns and Plastic Surgery Unit, Birmingham Accident Hospital, Birmingham
Summary-A review of the literature on keloids, a complex and poorly understood subject, is presented. Keloid is a disease principally of the human dermis, and occasionally the cornea, appearing as thick scar tissue invading normal skin or cornea and produced by the deposition of excessive amounts of collagen over prolonged periods. The African negro is particularly susceptible. Available methods of treatment include surgical excision, external superficial radiotherapy, interstitial irradiation, intralesional steroid injections, cryotherapy, ultrasound, systemic chemotherapy, zinc tape strapping, pressure and silicone gel. Any of these could be used alone or in combination with other forms of treatment. The lesions are notoriously recurrent and their management frustrating. The risk of late tumour induction following radiotherapy and systemic complications of depot steroids are underlined. There is still the need for a better understanding of the behaviour of keloids. This should form the biological basis on which to plan more effective prevention and treatment, with minimal complications.
ever, saw them as benign dermal tumours that form during an abnormal wound healing process in genetically susceptible individuals. Keloids are not limited to the skin. Though uncommon, keloids of the cornea have been described (Shukla et al., 1975; LeMasters and Notz, 1986). There is no indication, however, that keloids occur in every ectodermally derived tissue and no amount of dense scarring in endodermally derived tissue could be referred to as a keloid. Keloids, therefore, are thick scar tissuesof human skin or cornea which have escaped the boundaries of the original wound to invade surrounding normal skin or cornea and are produced by deposition of excessive amounts of collagen over prolonged periods.
Keloids affect only homo sapiens, and the African, especially the negro race, is particularly susceptible. It is therefore not surprising that the story of keloids is rooted in African folklore and their behaviour well described in African proverbs and folk medicine. Although this lesion was said to have been first described by Retz in the 18th century (Retz, 1790), and later by Alibert, the Yorubas of Western Nigeria had depicted keloids in sculpture as early as the 13th century (Oluwasanmi, 1979). The search for the cause and satisfactory cure for keloids has proved to be one of the perplexing puzzles of medicine in Africa and modern medical research in the developed world. Perhaps part of the obstacle is the lack of an animal experimental model in the study of keloids. An understanding and assessment of the work done so far is, however, necessary to be able to expose the gaps in our knowledge and enable more to be learned.
Epidemiology Keloids occur in all races, with a preponderance of the disease in Africans (Oluwasanmi, 1979). It would seem that the more darkly pigmented tribes are more prone to keloid formation. Caucasians and albinos are least affected. The disease appears to run in families (Omo-Dare, 1975) but the mode of inheritance is not clear although autosomal dominance has been suggested (Oluwasanmi, 1979). Both sexes form keloids equally within the same age group. Keloid scars are uncommon in injuries sustained at the extremes of life; in fact, the
Definition Various authors have defined or described keloids differently. Peacock et al. (1970) defined keloid as a healed human skin wound which extends beyond the confines of the original wound and is characterised by overabundant collagen deposition. According to McCoy and Cohen (198 l), keloids are clinically vexatious scars characterised by excessive collagen accumulation. Russell et al. (1988), how70
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71
OF THE LITERATURE
Yorubas of Western Nigeria, who are noted for their facial tribal marks, have a proverb which says that “tribal marks made in early childhood never form keloids”. Regional susceptibility to keloids is also recognised (Davey, 1968). The presternal area, the back and the posterior neck are the most susceptible regions of the body and these form severe keloids. The ears, deltoid areas, anterior chest, beard areas of the face and rest of the neck are moderately susceptible while the abdominal skin, forearms and rest of the face are mildly susceptible. Hospital figures, however, tend to suggest a preponderance of lesions on the face (Oluwasanmi, 1979). The explanation for this may be found in the fact that facial keloids are exposed and disfiguring hence patients with such lesions tend to seek hospital help more than patients with hidden keloids. On the other hand, keloids on the palms of the hands and soles of the feet are virtually unknown. Similarly, keloids on very lax skin like the upper eyelids, penis, scrotum and areola of the breast are very rare, if not unknown. Clinical features Keloids develop secondary to skin wounds (Oluwasanmi, 1974; Selezneva, 1976; Ruiz-Maldonaldo and Baker, 1977; Oluwasanmi, 1979). Although some patients claim that their keloids arose spontaneously, it is believed that in most of these the skin wounds that gave rise to them might have been forgotten. Minor skin lesions like acne, septic spots or insect bites may be complicated by keloid formation. The onset is gradual and pruritus as a symptom is invariable. Pain is not a common complaint. It is the ugliness of the scars that bothers the sufferers, appearing as thick mounds of scar tissue which may remain actively growing for many years. Sometimes they grow to gigantic sizes that can be crippling (Raje, 1980). In the presternal area, they tend to grow aggressively in a crab-like manner and are often known as butterfly keloids (Abdel-Fattah, 1976; Stott, 1977). Characteristically they spread to invade normal skin beyond the boundaries of the original wound. The time lag between injury and keloid formation is very variable. For example, BCG vaccination given in infancy may form keloid scars in adult life (Mullikenetal., 1976; Ruiz-Maldonaldoand Baker, 1977; Lotte etal., 1984). On the other hand, shaving injuries or earlobe piercing in adulthood may cause beard area or earlobe keloids respectively within a few weeks of injury. The assessment of this lag
phase is therefore usually unreliable. Keloids may present as any of their recognised complications which include pseudomelanomata (Hiss and Shafir, 1978; Ronnen et al., 1986), suppuration (Onwukwe, 1978; Novick et al., 1986) and Rubinstein-Taybi syndrome (Kurwa, 1979). Although keloids are clinically different from hypertrophic scars, there is often a grey area between both pathologies where the differential diagnosis becomes difficult. The difference between them is quantitative rather than qualitative (Peacock, 1984). Khan (1988) has outlined the following distinguishing features : The differential
diagnosis
Keloid scars Not confined to wound Thick glassy collagen Mucoid matrix tRemains elevated (tauthor)
of keloid and hypertrophic
scars
Hypertrophic scars Limited to area of injury Fewer thick collagen fibres Scanty mucoid matrix Flattens spontaneously with time
This distinction between keloid and hypertrophic scars is important especially in the assessment of results of treatment because the natural history of hypertrophic scars is that of spontaneous softening and flattening with time while keloids remain raised and thick over many years. Histopathology Although keloids of the cornea have been described (Shukla er al., 1975; LeMasters and Notz, 1986), keloids are principally lesions of the dermis. They consist of thick “glassy” or hyalinised bands of intensely eosinophilic collagen wound in a nodular configuration with a few fibroblasts and often a mucoid matrix between the fibres (Khan, 1988). The early lesions tend to be vascular at the periphery and are less conspicuously hyalinised. Long-standing keloids may calcify and undergo osseous metaplasia. Comparative studies using the transmission electron microscope showed that most microvessels in keloid and hypertrophic scars are either partially or completely occluded due to an excess of endothelial cells when compared with normal skin (Kischer et al., 1982a). This microvascular occlusion produces a measurable tissue hypoxia with lower pOz. and higher pCOZ in keloid and hypertrophic scars compared with normal skin (Kischer et al., 1982b). Kischer and Brody (1981) postulated that it is this microvascular occlusion and the resultant hypoxia that leads to what they have described as a “revascularisation process” which is
72 responsible for the formation of the “collagen nodule” that is histologically so characteristic of keloids and less so of hypertrophic scars, but never found in other mature scars. Immunology There is a suspicion that keloids arise as a result of an immune reaction mounted by the body against cutaneous antigens (Mukherjee er al., 1982), sebum (Abdalla-Osman et al., 1978; Yagi et al., 1979), melanin (Oluwasanmi, 1979) and blood products (haematoporphyrins) (Nunzi et al., 1983) that leak into the dermis. Some workers have demonstrated delayed type hypersensitivity reaction to cutaneous antigens (Mukherjee er al., 1982) while others have demonstrated antinuclear antibodies (Janssen de Limpens and Cormane, 1982a and b) directed against fibroblasts in keloid formers by means of acid elution technique and immunofluorescence studies. Kischer et al. (1983) using the immunofluorescent antibody method found increased levels of immunoglobulin IgA, IgG and IgM localised in keloid tissues compared to normal skin. No single immunoglobulin appeared significantly raised more than others in keloid tissues when compared with each other. The following year, however, Bloch et al. (1984) examined the general immune reactivity in keloid patients and found significantly higher serum levels of IgM and complement C3 in healthy keloid formers than in healthy non-keloid formers, but IgA and complement C4 were significantly higher in healthy non-keloid formers compared with healthy keloid formers. Serum IgG levels were similar in both groups. Mitogenic stimulation was significantly lower in the keloid population for both phytohaemagglutinin (PHA) and concavalin A (con-A) while pokeweed mitogen (PWM) stimulation showed no differences. These findings contradict in part the observation by Cohen et al. (1979) who found normal serum levels of IgG and IgM in keloid patients and significantly raised levels of extractable IgG from keloid tissues compared with normal controls. In addition Cohen er al. (1979) analysed the human lymphocyte antigen (HLA) profiles of keloid and non-keloid formers and found no significant differences in the incidence of HLAA and B antigens. They concluded that there must be a localised immune response involved in keloid pathogenesis, one which is not related to either the HLA-A or B histocompatibility loci. Kischer and Hendrix (1983) demonstrated a high concentration of fibronectin, a high molecular
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weight glycoprotein, in keloid tissues compared with normal dermis. Fibronectin is usually very abundant in wounds between the first 24 and 48 hours of injury and then gradually disappears (Peacock, 1984). The persistence of fibronectin in keloid scars may be regarded as “prolonged wound healing process” which in turn may account for the prolonged activity of fibroblasts by way of synthesis and deposition of excessive amounts of collagen which is so characteristic of keloid scars. Tissue culture studies Tissue culture studies have allowed medical science some insight into the behaviour of keloid cells compared with normal dermal fibroblasts. Fibroblasts from normal skin, normal scar and keloid scar grown for four passages showed similar growth kinetics (Diegelmann er al., 1979). By altering the culture conditions, Russell et al. (1988) found that keloid cells were less demanding than normal cells and grew to higher densities in media with reduced growth factors. They then postulated that this reduced growth factor requirement may explain the exuberant growth of keloids into tumour-like masses. In mature normal scar there is an equilibrium between collagen synthesis, via the activity of prolyl hydroxylase, and collagen degradation by collagenase (Peacock, 1984). In keloid scars there is an imbalance in this equilibrium in favour of increased collagen synthesis while collagen degradation remains normal (Diegelmann et a(., 1979; McCoy and Cohen, 1982). The production of this collagenase seems to be controlled by the presence of intact epidermis (Ehrlich and Buttle, 1984) and the types of collagen (types I and III collagen) synthesised in keloid scars are similar to those produced by normal dermis (Clore et al., 1979). It is not known why keloid fibroblasts synthesise and lay down increased amounts of collagen. The suspicion that there might be a systemic factor that stimulates them led to the trial of the effects of various sera from keloid formers on normal skin and keloid derived fibroblasts. McCoy and Cohen (198 1) demonstrated that both cell types showed no significant difference in both their growth kinetics and collagen synthesis and thus concluded that sera from keloid patients do not contain factor(s) that significantly modify the in vitro gr0wt.h kinetics or collagen synthesis of keloid-derived or normal fibroblasts. The addition of hydrocortisone or triamcinolone acetonide to fibroblast cultures has been shown to retard the
KELOIDS: A REVIEW OF THE LITERATURE
growth of fibroblasts, inhibit the activity of prolyl hydroxylase and reduce the synthesis of collagen (Russell et al., 1978, 1982; McCoy et al., 1980; Trupin er al,, 1983). When keloid-derived fibroblasts were compared with normal dermal fibroblasts, collagen synthesis was less inhibited by hydrocortisone in the keloidderived fibroblast line. This suggests that the defect in wound healing that results in keloid formation is associated with a change in a regulatory mechanism that controls the rate of collagen synthesis and is sensitive to physiological levels of hydrocortisone. Unlike the effect of hydrocortisone, growth of fibroblasts in ascorbate-enhanced medium increased the rate of collagen synthesis affecting the keloid and normal dermal fibroblasts equally (Trupin et al., 1983). It has been suggested that the steroids act by binding on to the receptor sites on human fibroblasts (Oikarinen et al., 1987). Retinoic acid has also been shown to reduce the growth of fibroblasts and their synthesis of collagen in vivo (Janssen de Limpens, 1980) and in tissue culture (Abergel et al., 1985; Oikarinen et al., 1985; Daly and Weston, 1986). Dextran sulphate similarly seems to have inhibitory effects on fibroblasts in vitro (Chiu et al., 1987). Top01 et al. (1981) have demonstrated that fibroblasts from normal skin, scar tissue and keloid scar are stimulated to grow to higher densities when cultured in the presence of histamine. They were able to suppress this stimulation by the addition of pharmacological levels of the antihistamine diphenhydramine hydrochloride. This finding, which suggests an allergic background to the formation of keloids, is supported by Smith et al. (1987) who believe that the allergy may be mediated by mast cells. Management Keloids have remained an enigma of plastic surgery (Pierce, 1979). There is yet no sound biological basis on which to plan their management because they are still poorly understood. The variety of treatments suggests that none is very satisfactory as the lesion is notoriously recurrent. From the present state of knowledge, however, any effective management of keloids should aim at removal of the existing growth and prevention of recurrence by inhibiting the proliferation of the fibroblasts and their synthesis of collagen. Although the degradation of collagen is normal in keloid tissues, localised enhancement of accelerated collagenase activity might also help reduce the tumour bulk. Surgical
73 excision (Salasche and Grabski, 1983) therefore seems a logical form of treatment since keloids are benign dermal growths. The high recurrence rate following excision alone unsupported by a suppressive measure makes this form of management unpopular. The intralesional surgical excision as recommended by many authors (Sharma, 1980; HarveyKemble, 1988) may be supported by perioperative radiotherapy (Ollstein et al., 1981; Enhamre and Hammar, 1983) or depot steroid (triamcinolone) injections (Shons and Press, 1983). When pedunculated (Raje, 1980) or on the earlobes (Shons and Press, 1983), they are easier to excise, but in “crablike” lesions on the presternal region (Stott, 1977) surgery is unrewarding and other forms of treatment are preferred (Sharma, 1980). In such situations radiotherapy or steroid injections alone or combined modalities (Babin and Ceilley, 1979a and b) of non-operative procedures yield better results. The management of keloids could be broadly subdivided into two major groups, namely, physical and pharmacological methods. Radiotherapy in the form of superficial X-ray therapy (Hoffman, 1982) or treatment with strontium 90 beta rays (Deka et al., 1987) are examples of physical forms of treatment. Other physical forms of management include ultrasound (Walker, 1983), cryotherapy (Muti and Ponzio, 1983; Cirne de Castro et al., 1986), pressure (Brent, 1978; Mercer and Studd, 1983; Ng et al., 1983) and laser (Abergel et al., 1984; Henderson et al., 1984; Kantor et al., 1985). Varying degrees of success have been claimed by different authors. While some claim “promising” and “encouraging” results from the use of new techniques and devices, others, perhaps seeking to confirm these claims, report poor results (Shepherd and Dawber, 1982). Keloids have been known to be active for many years, sometimes decades, so it is necessary to follow up patients for very long periods after any form of treatment, for proper evaluation of the efficacy of that mode of therapy. Among the physical methods of management, radiotherapy may be inappropriate because malignant tumours are known to have been caused as a consequence (Hoffman, 1982). Steroids, whether used alone (Sharma, 1980) or in combination with other modes of treatment (Ceilley and Babin, 1979), are good examples of pharmacological agents used in the management of keloids. Other pharmacological agents such as penicillamine (Mayou, 1981), retinoic acid (Janssen de Limpens, 1980), dextran sulphate (Chiu et al.,
74
1987) and madecasol (Bosse er al., 1979) have also been used with varying degrees of success. Even systemic chemotherapy (Murray et al., 1981) has been used in this benign condition. Unfortunately, these drugs are not without their complications. In addition to causing local atrophy of tissues (Jemec, 1988), triamcinolone acetonide injected intralesionally as a depot steroid has been shown to produce a systemic response (Dziewulski ef a/., 1988) for example reactivation of quiescent pulmonary tuberculosis (Amene, 1983). Adhesive zinc tapes (Soderberg et al., 1982) and silicone gels (Perkins et al., 1983, 1987; Quinn et al., 1985) have also been claimed to reduce keloid and hypertrophic scars or prevent their recurrence. Acrylic splints or stents (Hurtado and Crowther, 1985; Pierce, 1986) are thought to exert a pressure effect, but it is not clear how zinc tapes and silicone gels produce their effects. Some details of a few of these methods and the results obtained over given periods are necessary for their assessment. Enhamre and Hammar (1983) treated 62 keloids in 47 patients with surgical excision followed by postoperative radiotherapy and followed them up for 6 months to 9 years. They recorded 88% cure rate and had hyperpigmentation as a side-effect in 16 patients. Smaller keloids gave better results and the time lag between excision and irradiation made no difference to the outcome of treatment. Ollstein et al. (198 1) practised immediate post-excision radiotherapy on 68 histopathologitally confirmed keloids on 40 patients over 10 years. Excision was intralesional and all patients received X-ray therapy totalling 1,500 rads delivered in three equal doses, the first within several hours after surgery and the rest at 2-3 day intervals. Minimum follow-up was one year with a mean of 2 years. They recorded 21% recurrence rate per lesion and 28% per patient; 75% of the recurrences were evident within one year of treatment. A method of interstitial postoperative irradiation of scar edges using flexible radioactive iridium-192 wires buried in the wounds was described by Malaker et al. (1976). Although they recorded no complications directly attributable to radiation in 31 treated patients after 2 years’ follow-up, they had a lower and pleasing 16% recurrence rate by 6 months. As they and other authors acknowledge, however, quite long latent periods may at times elapse between treatment and recurrence. Also the risk of late tumour induction must be borne in mind while treating such benign conditions in young patients with long life expectancy.
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Shons and Press (1983) practised complete surgical excision of 3 1 earlobe keloids in 20 patients followed by three postoperative injections of O.l0.2 ml of 40 mg/ml of triamcinolone at 4-weekly intervals beginning 3 weeks after surgery. They had only one recurrence in a 12-62 months follow-up. Salasche and Grabski (1983) tried “core” (intralesional) excision of dumbbell-shaped earlobe keloids combined with intralesional depot steroids in 6 patients followed up for one year. They believed the patients were cured, with good cosmetic results. These results are encouraging but the fear of systemic effects of the steroids, as already highlighted, limits their use to small size keloids. Shepherd and Dawber (1982), using portable liquid nitrogen spray, treated 17 patients with keloid scars. Only two scars exhibited marked reduction in volume. They concluded that keloid response to cryotherapy was poor. Soderberg et al. (1982) treated both keloid and hypertrophic scars with ordinary zinc tapes. Among the 41 patients treated, 23 had their scars reduced to the level of the surrounding skin in 6 months, pruritus was decreased in all 37 who complained of itching, and disappeared completely in 20 of them. Redness decreased in all. This result must be assessed cautiously as it has not distinguished between keloids and hypertrophic scars whose natural history is that of spontaneous regression. The pathogenesis of keloid scarring is only partly understood at present. We know how they are formed but not why they form. It is hoped that when this aspect of the pathogenesis of keloids is better understood, a sound biological basis will have been laid on which to plan more effective prevention and treatment of keloids with minimal complications.
References AbdaIIa-Osman, A. A., Gumma, K. A. and Satir, A. A. (1978). Highlights on the etiology of keloid. Znternationaf Surgery, 63, 33. Abdel-Fattah, A. M. (1976). The evolution of pre-sternal British Journal of Plastic Surgery, 29, 56.
keloids.
Abergel, R. P., Dwyer, R. M., Meeker, C. A., Lask, G., Kelly, A. P. and Uitto, J. (1984). Laser treatment of keloids: a clinical trial and an in vitro study with Nd:YAG laser. Lasers in Surgery and Medicine. 4,291. Abergel, R. P., Meeker, C. A., Oikarinen, H., Oikarinen, A. I. and Uitto, J. of connective in keloid Amene, P. C. (1983). Activation
of pulmonary
tuberculosis
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OF THE LITERATURE
following intralesional corticosteroids. Archives of Dermatology, 119,361. Babin, R. W. aad Ceilley, R. I. (1979a). Combined modalities in the management of hypertrophic scars and keloids. Journal of Otolaryngology, 8,457. Babin, R. W. and CeiUey, R. I. (1979b). The freeze-injection method of hypertrophic scar and keloid reduction. Otolaryngolog.v-Head and Neck Surgery, 81.91 I. Bloch, E. F., HaII, M. G., Jr., Denson, M. J. and Slay-Solomon, V. (1984). General immune reactivity in keloid patients. Plastic and Reconstructive Surgery, 13,448. Bosw, J. P., PapiIlon, J., Frenette, G., Dansereau, J., Cadotte, M. and Le Lorier, J. (1979). Clinical study of a new antikeloid agent. Annals of Plastic Surgery, 3, 13. Brent, B. (1978). The role of pressure therapy in management of earlobe keloids: preliminary report of a controlled study. Annals of Plastic Surgery, 1,579. CeiRey, R. I. and Babm, R. W. (1979). The combined use of cryosurgery and intralesional injection of fluorinated adrenocorticoids for reducing keloids and hypertrophic scars. Journal of Dermatologic Surgery and Oncology, 5, 54. Chiu, H. C., Wu, Y. C. and Lu, Y. C. (1987). Effects of dextran sulphate on the growth of cultured fibroblasts derived from normal human skin and keloid lesions. Journal of the Formosan Medical Association, 86,264. Cime de Castro, J. L., dos Santos, A. P., Cardoso, J. P. and Ribeiro, R. (1986). Cryosurgical treatment of a large keloid. Journal of Dermatologic Surgery and Oncology, 12,740. Clore, J. N., Cohen, I. K. and Diegehnann, R. F. (1979). Quantitative assay of types I and III collagen synthesis by keloid biopsies and fibroblasts. Biochemica et Biophysics Acta. 586,384. Cohen, I. K., McCoy, B. J., Mohanakumar, T. and Diegehnann, R. F. (1979). Immunoglobulin, complement, and histocompatibility antigen studies in keloid patients. Plastic and Reconstructive Surgery, 63,689. Daly, T. J. and Weston, W. L. (1986). Retinoid effects on fibroblast proliferation and collagen synthesis in vitro and on fibrotic disease in vivo. Journal of the American Academ.v of Dermatology, 15,900. Davey, W. W. (1968). In Companion to Surgery in Africa. Edinburgh: Churchill Livingstone. Deka, B. C., Deka, A. C., Avadhard, J. S., Sathiyanarayan, V. K., Kalghatgi, R. R., Pat& A. C. andsupe, S. J. (1987). Treatment of keloids with strontium 90 beta rays. Indian Journal of Cancer, 24, I 5. Diegehnann, R. F., Cohen, I. K. and McCoy, B. J. (1979). Growth kinetics and collagen synthesis of normal skin, normal scar and keloid fibrobasts in vitro. Journal of Cellular Physiology, 98,341. Dtiewulski, P., Gaul& D. T. and Davies, P. K. (1988). Systemic response to intralesional therapy (letter). British Medical Journal, 2%, 137. EhrIicb, H. P. and Buttle, D. J. (1984). Epidermis promotion of collagenase in hypertrophic scar organ culture. Experimental and Molecular Pathology. 40,223. Enhamre, A. and Hammar, H. (1983). Treatment of keloid with excision and postoperative X-ray irradiation. Dermatologica, 167,90. Harvey-Kemble, J. V. (1988). The management of scars, hypertrophic scars and keloids. Surgery. 54, 1286. Henderson, D. L., Cromwell, T. A. and Mes, L. G. (1984). Argon and carbon dioxide laser treatment of hypertrophic and keloid scars. Losers in Surgery and Medicine. 3, 27 1.
75 Hiss, Y. and Shafir, R. (1978). “Pseudomelanoma” in a keloid. Journal of Dermatologic Surgery and Oncology, 4,938. Hoffman, S. (1982). Radiotherapy for keloids (letter). Annals of Plastic Surgery, 9, 262. Hurtado, A. J. and Crowther, D. S. (1985). Methyl methacrylate stent for prevention of postexcisional recurrent ear keloid. Journal of Prosthetic Dentistry, 54,245. Janssen de Limpens, A. M. (1980). The local treatment of hypertrophic scars and keloids with topical retinoic acid. British Journalof Dermatology, 103,319. Janssen de Liipens, A. M. and Connane, R. H. (1982a). Keloids and hypertrophic scars-immunological aspects. Aesthetic Plastic Surgery, 6. 149. Janssen de Limpens, A. M. and Cormane, R. H. (1982b). Studies on immunologic aspects of keloids and hypertrophic scars. Archives of Dermatology, 274,259. Jemec, G. B. (1988). Linear atrophy following intralesional steroid injections. Journal of Dermatologic Surgery and Oncology, 14, 88. Kantor, G. R., Wheeland, R. G., Bailin, P. L., Walker, N. P. and Ratz, J. L. (1985). Treatment of earlobe keloid with carbon dioxide laser excision: a report of 16 cases. Journal of Dermatologic Surgery and Oncology, 11, 1063. Khan, S. (1988). The pathology of keloid scars. Surgery, 54, 1299b. Kiseher, C. W. and Brody, G. S. (1981). Structure of the collagen nodule from hypertrophic scars and keloids. Scanning Electron Microscopy, part 3, 371. K&her, C. W. and Hendrix, M. J. (1983). Fibronectin (FN) in hypertrophic scars and keloids. Cell and Tissue Research, 231, 29. Kischer, C. W., Shetlar, M. R. and ChvapiI, M. (1982a). Hypertrophic scars and keloids: a review and new concept concerning their origin. Scanning Electron Microscop.v, part 4, 1699. K&her, C. W., Thies, A. C. and Chvapil, M. (1982b). Perivascular myofibroblasts and microvascular occlusion in hypertrophic scars and keloids. Human Pathology, 13,819. K&her, C. W., Shetlar, M. R., Shetlar, C. L. and ChvapiI, M. (1983). Immunoglobulins in hypertrophic scars and keloids. Plastic and Reconstructive Surgery, 71,821. Kurwa, A. R. (1979). Rubinstein-Taybi syndrome and spontaneous keloids. Clinical and Experimental Dermatology, 4,251. LeMasters, W. C. and No&, R. G. (1986). Comeal keloids. Transactions-Pennsylvania Academy of Ophthalmology and Otolaryngology, 38, 286. Lotte, A., Wasz-Hockert, D., Poisson, N., Dumitrescu, N., Verron, M. and Couvet, E. (1984). BCG complications. Estimates of the risk among vaccinated subjects and statistical analysis of their main characteristics. Advances in Tuberculosis Research, 21, 107. McCoy, B. J. and Cohen, I. K. (1981). Effects of various sera on growth kinetics and collagen synthesis by keloid and normal dermal fibroblasts. Plastic and Reconstructive Surgery, 67,505. McCoy, B. J. and Cohen, 1. K. (1982). Collagenase in keloid biopsies and fibroblasts. Connective Tissue Research, 9, 181, McCoy, B. J., Diegebnann, R. F. and Cohen, I. K. (1980). In vitro inhibition of cell growth, collagen synthesis, and prolyl hydroxylase activity by triamcinolone acetonide. Proceedings of the Society for Experimental Biology and Medicine. 163,216. Malaker, K., Ellis, F. and Paine, C. (1976). Keloid scars : a new method of treatment combining surgery with interstitial radiotherapy. Clinical Radiology, 27, 179.
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Mayou, B. J. (1981). D-Penicillamine in the treatment of keloids. British Journalof Dermatology, 105,87. Mercer, D. M. and Studd, D. M. (1983). “Oyster splints”: a new compression device for the treatment of keloid scars of the ear. British Journal of Plastic Surgery, 36, 75. Mukherjee, A., Mukhejee, A. and Saha, K. C. (1982). Delayed type hypersensitivity reaction to cutaneous antigen in keloid. Indian Journal of Dermatology, 27, 125. Mulliken, J. B., Gifford, G. H. Jr. and Goldwyn, R. M. (1976). Vaccination caveat. The off-the-shoulder look. American Journal ofDiseases of Children, 130, 1094. Murray, J. C., Pollack, S. V. and Pinnell, S. R. (1981). Keloids: a review. Journal of the American Academy of Dermatology, 4, 461. Muti, E. and Ponzio, E. (1983). Cryotherapy in the treatment keloids. Annals of Plastic Surgery, 11, 227.
of
Ng, C. L., Lee, S. T. and Wong, K. L. (1983). Pressure garments in the prevention and treatment of keloids. Annals of the Academy of Medicine, Singapore, 12 (suppl), 430. Novick,N. L.,Lawson, W.andSchwartz,I.S.(1986). Suppurative keloidosis in a black woman. Journalof the American Academ.v of Dermatology, 15, 1090. Nunzi, E., Par&, A. and Rehora, A. (1983). Immunofluorescence findings in haematoporphyrin-induced keloid. British Journal of Dermatology, 108,263. Oikarinen, A., Oikarinen, H., Meeker, C. A., Tan, E. M. and Uitto, J. (1987). Glucocorticoid receptors in cultured human skin fibroblasts: evidence for down regulation of receptor by glucocorticoid hormone. Acta Dermato- Venereologica (Stockholm), 67,461. Oikarinen, H., Oikarinen, A. I., Tan, E. M., Abergel, R. P., Meeker, C. A., Chu, M. L., Proekop, D. J. and U&o, J. (1985). Modulation of procollagen gene expression by retinoids. Inhibition of collagen production by retinoic acid accompanied by reduced type I procollagen messenger ribonucleic acid levels in human skin fibroblast cultures. Journalof Clinical Invesiigation, 75. 1545. Ollstein, R. N., Siegel, H. W., Gillocdey, J. F. and Barsa, J. M. (1981). Treatment of keloids by combined surgical excision and immediate postoperative X-ray therapy. Annals of Plastic Surgery, 7,28 1. Oluwasanmi, J. 0. (1974). Keloids in the African. Clinics in Plastic Surgery, 1, 179. Oluwasanmi, J. 0. (1979). In Plastic Surgery in the Tropics. London and Basingstoke: The MacMillan Press Ltd. Omo-Dare, P. (1975). Genetic studies on keloids. Journal of the National Medical Association, 67,428. Onwukwe, M. F. (1978). The suppurative keloid. Journal of Dermatologic Surgery and Oncology, 4, 333. Peacock, E. E. Jr. (1984). Inflammation and cellular response to injury. In Wound Healing. Third edition. Philadelphia: W. B. Saunders. Peacock, E. E. Jr., Madden, J. W. and Trier, W. C. (1970). Biological basis for treatment of keloids and hypertrophic scars, Southern Medical Journal, 63,755. Perkins, K., Davey, R. B. and Wallis, K. A. (1983). Silicone gel: a new treatment for burns scars and contractures. Burns, 9, 201. Perkins, K., Davey, R. B. and Wallis, K. A. (1987). Current materials and techniques used in a burn scar management programme. Burns, 13,406. Pierce, H. E. (1979). Keloids: enigma of the Plastic Surgeon. Journalof the National Medical Association, 71, I 177.
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Pierce, H. E. (1986). Postsurgical acrylic ear splints for keloids. Journal of Dermatologic Surgery and Oncology, 12,583. Quinn, K. J., Evans, J. H., Courtney, J. M. and Caylor, J. D. S. (1985). Non-pressure treatment of hypertrophic scars, Burns, 12, 102. Raje, D. (1980). Crippling giant keloid. British Journalof Surgery, 67, 452. Retz, N. (1790). Traite des Maladies de la peau et de celles de l&wit. Paris. Ronnen, M., Sokol, M. S., Huszar, M., Kahana, M. and Sehewach-Millet, M. (1986).Pseudomelanoma following treatment with surgical excision and intralesional triamcinolone acetonide to prevent keloid formation. International Journalof Dermatology, 25, 533. Ruiz-Maldonaldo, R. and Baker, J. (1977). Site of BCG vaccine administration and development of hypertrophic scar. Boletin Medico Del Hospital Infantil De Mexico, 34, I8 1. Russell,J. D.,Russell,S. B.andTrupin,K. M.(1978). Differential effects of hydrocortisone on both growth and collagen metabolism of human fibroblasts from normal and keloid tissue. Journal of Cellular Physiology, 97, 221. Russell, S. B., Russell, J. D. and Trupin, J. S. (1982). Alteration of amino acid transport by hydrocortisone. Different effects in human fibroblasts derived from normal skin and keloid. Journalof Biological Chemistry, 257,9525. Russell, S. B., Trupin, K. M., Rodriguez-Eaton, S. and Russell, J. D. (1988). Reduced growth-factor requirement of keloidderived fibroblasts may account for tumour growth. Proceedings of the National Academy of Sciences of the United States of America, 85, 587. Salasche, S. J. and Grabski, W. J. (1983). Keloids of the earlobes: a surgical technique. Journal of Dermatologic Surgery and Oncology, 9, 552. Selezueva, L. G. (1976). Keloid scars after burns. Acta Chirurgiae Plasticae. 18, 106. Sharma, B. C. (1980). Keloids: a prospective study of 57 cases. Medical Journal of Zambia, 14,66. Shepherd, J. P. and Dawber, R. P. (1982). The response of keloid scars to cryosurgery. Plastic and Reconstructive Surgery, 70, 677. Shons, A. R. and Press, B. H. (1983). The treatment of earlobe keloids by surgical excision and postoperative triamcinolone injection. Annals of Plastic Surgery, 10,480. Shukla, I. M., Arora, N. P. and Arora, M. M. (1975). Cornea1 keloids. Indian Journal of Ophthalmology, 23, 18. Smith, C. J., Smith, J. C. and Finn, M. C. (1987). The possible role of mast cells (allergy) in the production of keloid and hypertrophic scarring. Journalof Burn Care and Rehabilitation, 8, 126. Soderberg, T., Hallmans, G. and Bartholdson, L. (1982). Treatment of keloids and hypertrophic scars with adhesive zinc tapes. Scandinavian Journal of Plastic and Reconstructive Surgery, 16, 26 1. Stott, W. (1977). Butterfly keloids elsewhere than presternal. British Journal of Plastic Surgery, 30,243. Topol, B. M., Lewis, V. L., Jr. and Benveniste, K. (1981). The use of antihistamine to retard the growth of fibroblasts derived from human skin, scar, and keloid. Plastic and Reconstructive Surgery, 68, 227. Trupin, J. S., RusselI, S. B. and Russell, J. D. (1983). Variation in prolyl hydroxylase activity of keloid-derived and normal human fibroblasts in response to hydrocortisone and ascorbic acid. Collagen and Related Research, 3, 13.
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OF THE LITERATURE
Walker, J. J. (1983). Ultrasound therapy for keloids (letter). South African Medical Journal, 64,270. Yagi, K. I., Dafalla, A. A. and Oman, A. A. (1979). Does an immune reaction to sebum in wounds cause keloid scars? British Journalof Plastic Surgery. 32, 223.
The Author D. D. Datubo-Brown, FRCSEd, FRCSEng, FWACS, Lecturer, Department of Surgery, University of Port Harcourt, and Consultant Plastic Surgeon and Head of the Plastic Surgery
Unit, University of Port Harcourt Teaching Hospital; currently the recipient of a Commonwealth Medical Fellowship researching on keloids at the Birmingham Accident Hospital. Requests for reprints to: Mr D. D. Datubo-Brown, College of Health Sciences, University of Port Harcourt, PO Box 164. Choba, Port Harcourt, Nigeria. Paper received 24 November 1988 Accepted 30 June 1989 after revision
Keloids: a review of the literature D. D. DATUBO-BROWN Burns and Plastic Surgery Unit, Birmingham Accident Hospital, Birmingham
Summary-A review of the literature on keloids, a complex and poorly understood subject, is presented. Keloid is a disease principally of the human dermis, and occasionally the cornea, appearing as thick scar tissue invading normal skin or cornea and produced by the deposition of excessive amounts of collagen over prolonged periods. The African negro is particularly susceptible. Available methods of treatment include surgical excision, external superficial radiotherapy, interstitial irradiation, intralesional steroid injections, cryotherapy, ultrasound, systemic chemotherapy, zinc tape strapping, pressure and silicone gel. Any of these could be used alone or in combination with other forms of treatment. The lesions are notoriously recurrent and their management frustrating. The risk of late tumour induction following radiotherapy and systemic complications of depot steroids are underlined. There is still the need for a better understanding of the behaviour of keloids. This should form the biological basis on which to plan more effective prevention and treatment, with minimal complications.
ever, saw them as benign dermal tumours that form during an abnormal wound healing process in genetically susceptible individuals. Keloids are not limited to the skin. Though uncommon, keloids of the cornea have been described (Shukla et al., 1975; LeMasters and Notz, 1986). There is no indication, however, that keloids occur in every ectodermally derived tissue and no amount of dense scarring in endodermally derived tissue could be referred to as a keloid. Keloids, therefore, are thick scar tissuesof human skin or cornea which have escaped the boundaries of the original wound to invade surrounding normal skin or cornea and are produced by deposition of excessive amounts of collagen over prolonged periods.
Keloids affect only homo sapiens, and the African, especially the negro race, is particularly susceptible. It is therefore not surprising that the story of keloids is rooted in African folklore and their behaviour well described in African proverbs and folk medicine. Although this lesion was said to have been first described by Retz in the 18th century (Retz, 1790), and later by Alibert, the Yorubas of Western Nigeria had depicted keloids in sculpture as early as the 13th century (Oluwasanmi, 1979). The search for the cause and satisfactory cure for keloids has proved to be one of the perplexing puzzles of medicine in Africa and modern medical research in the developed world. Perhaps part of the obstacle is the lack of an animal experimental model in the study of keloids. An understanding and assessment of the work done so far is, however, necessary to be able to expose the gaps in our knowledge and enable more to be learned.
Epidemiology Keloids occur in all races, with a preponderance of the disease in Africans (Oluwasanmi, 1979). It would seem that the more darkly pigmented tribes are more prone to keloid formation. Caucasians and albinos are least affected. The disease appears to run in families (Omo-Dare, 1975) but the mode of inheritance is not clear although autosomal dominance has been suggested (Oluwasanmi, 1979). Both sexes form keloids equally within the same age group. Keloid scars are uncommon in injuries sustained at the extremes of life; in fact, the
Definition Various authors have defined or described keloids differently. Peacock et al. (1970) defined keloid as a healed human skin wound which extends beyond the confines of the original wound and is characterised by overabundant collagen deposition. According to McCoy and Cohen (198 l), keloids are clinically vexatious scars characterised by excessive collagen accumulation. Russell et al. (1988), how70
KELOIDS:
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71
OF THE LITERATURE
Yorubas of Western Nigeria, who are noted for their facial tribal marks, have a proverb which says that “tribal marks made in early childhood never form keloids”. Regional susceptibility to keloids is also recognised (Davey, 1968). The presternal area, the back and the posterior neck are the most susceptible regions of the body and these form severe keloids. The ears, deltoid areas, anterior chest, beard areas of the face and rest of the neck are moderately susceptible while the abdominal skin, forearms and rest of the face are mildly susceptible. Hospital figures, however, tend to suggest a preponderance of lesions on the face (Oluwasanmi, 1979). The explanation for this may be found in the fact that facial keloids are exposed and disfiguring hence patients with such lesions tend to seek hospital help more than patients with hidden keloids. On the other hand, keloids on the palms of the hands and soles of the feet are virtually unknown. Similarly, keloids on very lax skin like the upper eyelids, penis, scrotum and areola of the breast are very rare, if not unknown. Clinical features Keloids develop secondary to skin wounds (Oluwasanmi, 1974; Selezneva, 1976; Ruiz-Maldonaldo and Baker, 1977; Oluwasanmi, 1979). Although some patients claim that their keloids arose spontaneously, it is believed that in most of these the skin wounds that gave rise to them might have been forgotten. Minor skin lesions like acne, septic spots or insect bites may be complicated by keloid formation. The onset is gradual and pruritus as a symptom is invariable. Pain is not a common complaint. It is the ugliness of the scars that bothers the sufferers, appearing as thick mounds of scar tissue which may remain actively growing for many years. Sometimes they grow to gigantic sizes that can be crippling (Raje, 1980). In the presternal area, they tend to grow aggressively in a crab-like manner and are often known as butterfly keloids (Abdel-Fattah, 1976; Stott, 1977). Characteristically they spread to invade normal skin beyond the boundaries of the original wound. The time lag between injury and keloid formation is very variable. For example, BCG vaccination given in infancy may form keloid scars in adult life (Mullikenetal., 1976; Ruiz-Maldonaldoand Baker, 1977; Lotte etal., 1984). On the other hand, shaving injuries or earlobe piercing in adulthood may cause beard area or earlobe keloids respectively within a few weeks of injury. The assessment of this lag
phase is therefore usually unreliable. Keloids may present as any of their recognised complications which include pseudomelanomata (Hiss and Shafir, 1978; Ronnen et al., 1986), suppuration (Onwukwe, 1978; Novick et al., 1986) and Rubinstein-Taybi syndrome (Kurwa, 1979). Although keloids are clinically different from hypertrophic scars, there is often a grey area between both pathologies where the differential diagnosis becomes difficult. The difference between them is quantitative rather than qualitative (Peacock, 1984). Khan (1988) has outlined the following distinguishing features : The differential
diagnosis
Keloid scars Not confined to wound Thick glassy collagen Mucoid matrix tRemains elevated (tauthor)
of keloid and hypertrophic
scars
Hypertrophic scars Limited to area of injury Fewer thick collagen fibres Scanty mucoid matrix Flattens spontaneously with time
This distinction between keloid and hypertrophic scars is important especially in the assessment of results of treatment because the natural history of hypertrophic scars is that of spontaneous softening and flattening with time while keloids remain raised and thick over many years. Histopathology Although keloids of the cornea have been described (Shukla er al., 1975; LeMasters and Notz, 1986), keloids are principally lesions of the dermis. They consist of thick “glassy” or hyalinised bands of intensely eosinophilic collagen wound in a nodular configuration with a few fibroblasts and often a mucoid matrix between the fibres (Khan, 1988). The early lesions tend to be vascular at the periphery and are less conspicuously hyalinised. Long-standing keloids may calcify and undergo osseous metaplasia. Comparative studies using the transmission electron microscope showed that most microvessels in keloid and hypertrophic scars are either partially or completely occluded due to an excess of endothelial cells when compared with normal skin (Kischer et al., 1982a). This microvascular occlusion produces a measurable tissue hypoxia with lower pOz. and higher pCOZ in keloid and hypertrophic scars compared with normal skin (Kischer et al., 1982b). Kischer and Brody (1981) postulated that it is this microvascular occlusion and the resultant hypoxia that leads to what they have described as a “revascularisation process” which is
72 responsible for the formation of the “collagen nodule” that is histologically so characteristic of keloids and less so of hypertrophic scars, but never found in other mature scars. Immunology There is a suspicion that keloids arise as a result of an immune reaction mounted by the body against cutaneous antigens (Mukherjee er al., 1982), sebum (Abdalla-Osman et al., 1978; Yagi et al., 1979), melanin (Oluwasanmi, 1979) and blood products (haematoporphyrins) (Nunzi et al., 1983) that leak into the dermis. Some workers have demonstrated delayed type hypersensitivity reaction to cutaneous antigens (Mukherjee er al., 1982) while others have demonstrated antinuclear antibodies (Janssen de Limpens and Cormane, 1982a and b) directed against fibroblasts in keloid formers by means of acid elution technique and immunofluorescence studies. Kischer et al. (1983) using the immunofluorescent antibody method found increased levels of immunoglobulin IgA, IgG and IgM localised in keloid tissues compared to normal skin. No single immunoglobulin appeared significantly raised more than others in keloid tissues when compared with each other. The following year, however, Bloch et al. (1984) examined the general immune reactivity in keloid patients and found significantly higher serum levels of IgM and complement C3 in healthy keloid formers than in healthy non-keloid formers, but IgA and complement C4 were significantly higher in healthy non-keloid formers compared with healthy keloid formers. Serum IgG levels were similar in both groups. Mitogenic stimulation was significantly lower in the keloid population for both phytohaemagglutinin (PHA) and concavalin A (con-A) while pokeweed mitogen (PWM) stimulation showed no differences. These findings contradict in part the observation by Cohen et al. (1979) who found normal serum levels of IgG and IgM in keloid patients and significantly raised levels of extractable IgG from keloid tissues compared with normal controls. In addition Cohen er al. (1979) analysed the human lymphocyte antigen (HLA) profiles of keloid and non-keloid formers and found no significant differences in the incidence of HLAA and B antigens. They concluded that there must be a localised immune response involved in keloid pathogenesis, one which is not related to either the HLA-A or B histocompatibility loci. Kischer and Hendrix (1983) demonstrated a high concentration of fibronectin, a high molecular
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weight glycoprotein, in keloid tissues compared with normal dermis. Fibronectin is usually very abundant in wounds between the first 24 and 48 hours of injury and then gradually disappears (Peacock, 1984). The persistence of fibronectin in keloid scars may be regarded as “prolonged wound healing process” which in turn may account for the prolonged activity of fibroblasts by way of synthesis and deposition of excessive amounts of collagen which is so characteristic of keloid scars. Tissue culture studies Tissue culture studies have allowed medical science some insight into the behaviour of keloid cells compared with normal dermal fibroblasts. Fibroblasts from normal skin, normal scar and keloid scar grown for four passages showed similar growth kinetics (Diegelmann er al., 1979). By altering the culture conditions, Russell et al. (1988) found that keloid cells were less demanding than normal cells and grew to higher densities in media with reduced growth factors. They then postulated that this reduced growth factor requirement may explain the exuberant growth of keloids into tumour-like masses. In mature normal scar there is an equilibrium between collagen synthesis, via the activity of prolyl hydroxylase, and collagen degradation by collagenase (Peacock, 1984). In keloid scars there is an imbalance in this equilibrium in favour of increased collagen synthesis while collagen degradation remains normal (Diegelmann et a(., 1979; McCoy and Cohen, 1982). The production of this collagenase seems to be controlled by the presence of intact epidermis (Ehrlich and Buttle, 1984) and the types of collagen (types I and III collagen) synthesised in keloid scars are similar to those produced by normal dermis (Clore et al., 1979). It is not known why keloid fibroblasts synthesise and lay down increased amounts of collagen. The suspicion that there might be a systemic factor that stimulates them led to the trial of the effects of various sera from keloid formers on normal skin and keloid derived fibroblasts. McCoy and Cohen (198 1) demonstrated that both cell types showed no significant difference in both their growth kinetics and collagen synthesis and thus concluded that sera from keloid patients do not contain factor(s) that significantly modify the in vitro gr0wt.h kinetics or collagen synthesis of keloid-derived or normal fibroblasts. The addition of hydrocortisone or triamcinolone acetonide to fibroblast cultures has been shown to retard the
KELOIDS: A REVIEW OF THE LITERATURE
growth of fibroblasts, inhibit the activity of prolyl hydroxylase and reduce the synthesis of collagen (Russell et al., 1978, 1982; McCoy et al., 1980; Trupin er al,, 1983). When keloid-derived fibroblasts were compared with normal dermal fibroblasts, collagen synthesis was less inhibited by hydrocortisone in the keloidderived fibroblast line. This suggests that the defect in wound healing that results in keloid formation is associated with a change in a regulatory mechanism that controls the rate of collagen synthesis and is sensitive to physiological levels of hydrocortisone. Unlike the effect of hydrocortisone, growth of fibroblasts in ascorbate-enhanced medium increased the rate of collagen synthesis affecting the keloid and normal dermal fibroblasts equally (Trupin et al., 1983). It has been suggested that the steroids act by binding on to the receptor sites on human fibroblasts (Oikarinen et al., 1987). Retinoic acid has also been shown to reduce the growth of fibroblasts and their synthesis of collagen in vivo (Janssen de Limpens, 1980) and in tissue culture (Abergel et al., 1985; Oikarinen et al., 1985; Daly and Weston, 1986). Dextran sulphate similarly seems to have inhibitory effects on fibroblasts in vitro (Chiu et al., 1987). Top01 et al. (1981) have demonstrated that fibroblasts from normal skin, scar tissue and keloid scar are stimulated to grow to higher densities when cultured in the presence of histamine. They were able to suppress this stimulation by the addition of pharmacological levels of the antihistamine diphenhydramine hydrochloride. This finding, which suggests an allergic background to the formation of keloids, is supported by Smith et al. (1987) who believe that the allergy may be mediated by mast cells. Management Keloids have remained an enigma of plastic surgery (Pierce, 1979). There is yet no sound biological basis on which to plan their management because they are still poorly understood. The variety of treatments suggests that none is very satisfactory as the lesion is notoriously recurrent. From the present state of knowledge, however, any effective management of keloids should aim at removal of the existing growth and prevention of recurrence by inhibiting the proliferation of the fibroblasts and their synthesis of collagen. Although the degradation of collagen is normal in keloid tissues, localised enhancement of accelerated collagenase activity might also help reduce the tumour bulk. Surgical
73 excision (Salasche and Grabski, 1983) therefore seems a logical form of treatment since keloids are benign dermal growths. The high recurrence rate following excision alone unsupported by a suppressive measure makes this form of management unpopular. The intralesional surgical excision as recommended by many authors (Sharma, 1980; HarveyKemble, 1988) may be supported by perioperative radiotherapy (Ollstein et al., 1981; Enhamre and Hammar, 1983) or depot steroid (triamcinolone) injections (Shons and Press, 1983). When pedunculated (Raje, 1980) or on the earlobes (Shons and Press, 1983), they are easier to excise, but in “crablike” lesions on the presternal region (Stott, 1977) surgery is unrewarding and other forms of treatment are preferred (Sharma, 1980). In such situations radiotherapy or steroid injections alone or combined modalities (Babin and Ceilley, 1979a and b) of non-operative procedures yield better results. The management of keloids could be broadly subdivided into two major groups, namely, physical and pharmacological methods. Radiotherapy in the form of superficial X-ray therapy (Hoffman, 1982) or treatment with strontium 90 beta rays (Deka et al., 1987) are examples of physical forms of treatment. Other physical forms of management include ultrasound (Walker, 1983), cryotherapy (Muti and Ponzio, 1983; Cirne de Castro et al., 1986), pressure (Brent, 1978; Mercer and Studd, 1983; Ng et al., 1983) and laser (Abergel et al., 1984; Henderson et al., 1984; Kantor et al., 1985). Varying degrees of success have been claimed by different authors. While some claim “promising” and “encouraging” results from the use of new techniques and devices, others, perhaps seeking to confirm these claims, report poor results (Shepherd and Dawber, 1982). Keloids have been known to be active for many years, sometimes decades, so it is necessary to follow up patients for very long periods after any form of treatment, for proper evaluation of the efficacy of that mode of therapy. Among the physical methods of management, radiotherapy may be inappropriate because malignant tumours are known to have been caused as a consequence (Hoffman, 1982). Steroids, whether used alone (Sharma, 1980) or in combination with other modes of treatment (Ceilley and Babin, 1979), are good examples of pharmacological agents used in the management of keloids. Other pharmacological agents such as penicillamine (Mayou, 1981), retinoic acid (Janssen de Limpens, 1980), dextran sulphate (Chiu et al.,
74
1987) and madecasol (Bosse er al., 1979) have also been used with varying degrees of success. Even systemic chemotherapy (Murray et al., 1981) has been used in this benign condition. Unfortunately, these drugs are not without their complications. In addition to causing local atrophy of tissues (Jemec, 1988), triamcinolone acetonide injected intralesionally as a depot steroid has been shown to produce a systemic response (Dziewulski ef a/., 1988) for example reactivation of quiescent pulmonary tuberculosis (Amene, 1983). Adhesive zinc tapes (Soderberg et al., 1982) and silicone gels (Perkins et al., 1983, 1987; Quinn et al., 1985) have also been claimed to reduce keloid and hypertrophic scars or prevent their recurrence. Acrylic splints or stents (Hurtado and Crowther, 1985; Pierce, 1986) are thought to exert a pressure effect, but it is not clear how zinc tapes and silicone gels produce their effects. Some details of a few of these methods and the results obtained over given periods are necessary for their assessment. Enhamre and Hammar (1983) treated 62 keloids in 47 patients with surgical excision followed by postoperative radiotherapy and followed them up for 6 months to 9 years. They recorded 88% cure rate and had hyperpigmentation as a side-effect in 16 patients. Smaller keloids gave better results and the time lag between excision and irradiation made no difference to the outcome of treatment. Ollstein et al. (198 1) practised immediate post-excision radiotherapy on 68 histopathologitally confirmed keloids on 40 patients over 10 years. Excision was intralesional and all patients received X-ray therapy totalling 1,500 rads delivered in three equal doses, the first within several hours after surgery and the rest at 2-3 day intervals. Minimum follow-up was one year with a mean of 2 years. They recorded 21% recurrence rate per lesion and 28% per patient; 75% of the recurrences were evident within one year of treatment. A method of interstitial postoperative irradiation of scar edges using flexible radioactive iridium-192 wires buried in the wounds was described by Malaker et al. (1976). Although they recorded no complications directly attributable to radiation in 31 treated patients after 2 years’ follow-up, they had a lower and pleasing 16% recurrence rate by 6 months. As they and other authors acknowledge, however, quite long latent periods may at times elapse between treatment and recurrence. Also the risk of late tumour induction must be borne in mind while treating such benign conditions in young patients with long life expectancy.
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Shons and Press (1983) practised complete surgical excision of 3 1 earlobe keloids in 20 patients followed by three postoperative injections of O.l0.2 ml of 40 mg/ml of triamcinolone at 4-weekly intervals beginning 3 weeks after surgery. They had only one recurrence in a 12-62 months follow-up. Salasche and Grabski (1983) tried “core” (intralesional) excision of dumbbell-shaped earlobe keloids combined with intralesional depot steroids in 6 patients followed up for one year. They believed the patients were cured, with good cosmetic results. These results are encouraging but the fear of systemic effects of the steroids, as already highlighted, limits their use to small size keloids. Shepherd and Dawber (1982), using portable liquid nitrogen spray, treated 17 patients with keloid scars. Only two scars exhibited marked reduction in volume. They concluded that keloid response to cryotherapy was poor. Soderberg et al. (1982) treated both keloid and hypertrophic scars with ordinary zinc tapes. Among the 41 patients treated, 23 had their scars reduced to the level of the surrounding skin in 6 months, pruritus was decreased in all 37 who complained of itching, and disappeared completely in 20 of them. Redness decreased in all. This result must be assessed cautiously as it has not distinguished between keloids and hypertrophic scars whose natural history is that of spontaneous regression. The pathogenesis of keloid scarring is only partly understood at present. We know how they are formed but not why they form. It is hoped that when this aspect of the pathogenesis of keloids is better understood, a sound biological basis will have been laid on which to plan more effective prevention and treatment of keloids with minimal complications.
References AbdaIIa-Osman, A. A., Gumma, K. A. and Satir, A. A. (1978). Highlights on the etiology of keloid. Znternationaf Surgery, 63, 33. Abdel-Fattah, A. M. (1976). The evolution of pre-sternal British Journal of Plastic Surgery, 29, 56.
keloids.
Abergel, R. P., Dwyer, R. M., Meeker, C. A., Lask, G., Kelly, A. P. and Uitto, J. (1984). Laser treatment of keloids: a clinical trial and an in vitro study with Nd:YAG laser. Lasers in Surgery and Medicine. 4,291. Abergel, R. P., Meeker, C. A., Oikarinen, H., Oikarinen, A. I. and Uitto, J. of connective in keloid Amene, P. C. (1983). Activation
of pulmonary
tuberculosis
KELOIDS:
A REVIEW
OF THE LITERATURE
following intralesional corticosteroids. Archives of Dermatology, 119,361. Babin, R. W. aad Ceilley, R. I. (1979a). Combined modalities in the management of hypertrophic scars and keloids. Journal of Otolaryngology, 8,457. Babin, R. W. and CeiUey, R. I. (1979b). The freeze-injection method of hypertrophic scar and keloid reduction. Otolaryngolog.v-Head and Neck Surgery, 81.91 I. Bloch, E. F., HaII, M. G., Jr., Denson, M. J. and Slay-Solomon, V. (1984). General immune reactivity in keloid patients. Plastic and Reconstructive Surgery, 13,448. Bosw, J. P., PapiIlon, J., Frenette, G., Dansereau, J., Cadotte, M. and Le Lorier, J. (1979). Clinical study of a new antikeloid agent. Annals of Plastic Surgery, 3, 13. Brent, B. (1978). The role of pressure therapy in management of earlobe keloids: preliminary report of a controlled study. Annals of Plastic Surgery, 1,579. CeiRey, R. I. and Babm, R. W. (1979). The combined use of cryosurgery and intralesional injection of fluorinated adrenocorticoids for reducing keloids and hypertrophic scars. Journal of Dermatologic Surgery and Oncology, 5, 54. Chiu, H. C., Wu, Y. C. and Lu, Y. C. (1987). Effects of dextran sulphate on the growth of cultured fibroblasts derived from normal human skin and keloid lesions. Journal of the Formosan Medical Association, 86,264. Cime de Castro, J. L., dos Santos, A. P., Cardoso, J. P. and Ribeiro, R. (1986). Cryosurgical treatment of a large keloid. Journal of Dermatologic Surgery and Oncology, 12,740. Clore, J. N., Cohen, I. K. and Diegehnann, R. F. (1979). Quantitative assay of types I and III collagen synthesis by keloid biopsies and fibroblasts. Biochemica et Biophysics Acta. 586,384. Cohen, I. K., McCoy, B. J., Mohanakumar, T. and Diegehnann, R. F. (1979). Immunoglobulin, complement, and histocompatibility antigen studies in keloid patients. Plastic and Reconstructive Surgery, 63,689. Daly, T. J. and Weston, W. L. (1986). Retinoid effects on fibroblast proliferation and collagen synthesis in vitro and on fibrotic disease in vivo. Journal of the American Academ.v of Dermatology, 15,900. Davey, W. W. (1968). In Companion to Surgery in Africa. Edinburgh: Churchill Livingstone. Deka, B. C., Deka, A. C., Avadhard, J. S., Sathiyanarayan, V. K., Kalghatgi, R. R., Pat& A. C. andsupe, S. J. (1987). Treatment of keloids with strontium 90 beta rays. Indian Journal of Cancer, 24, I 5. Diegehnann, R. F., Cohen, I. K. and McCoy, B. J. (1979). Growth kinetics and collagen synthesis of normal skin, normal scar and keloid fibrobasts in vitro. Journal of Cellular Physiology, 98,341. Dtiewulski, P., Gaul& D. T. and Davies, P. K. (1988). Systemic response to intralesional therapy (letter). British Medical Journal, 2%, 137. EhrIicb, H. P. and Buttle, D. J. (1984). Epidermis promotion of collagenase in hypertrophic scar organ culture. Experimental and Molecular Pathology. 40,223. Enhamre, A. and Hammar, H. (1983). Treatment of keloid with excision and postoperative X-ray irradiation. Dermatologica, 167,90. Harvey-Kemble, J. V. (1988). The management of scars, hypertrophic scars and keloids. Surgery. 54, 1286. Henderson, D. L., Cromwell, T. A. and Mes, L. G. (1984). Argon and carbon dioxide laser treatment of hypertrophic and keloid scars. Losers in Surgery and Medicine. 3, 27 1.
75 Hiss, Y. and Shafir, R. (1978). “Pseudomelanoma” in a keloid. Journal of Dermatologic Surgery and Oncology, 4,938. Hoffman, S. (1982). Radiotherapy for keloids (letter). Annals of Plastic Surgery, 9, 262. Hurtado, A. J. and Crowther, D. S. (1985). Methyl methacrylate stent for prevention of postexcisional recurrent ear keloid. Journal of Prosthetic Dentistry, 54,245. Janssen de Limpens, A. M. (1980). The local treatment of hypertrophic scars and keloids with topical retinoic acid. British Journalof Dermatology, 103,319. Janssen de Liipens, A. M. and Connane, R. H. (1982a). Keloids and hypertrophic scars-immunological aspects. Aesthetic Plastic Surgery, 6. 149. Janssen de Limpens, A. M. and Cormane, R. H. (1982b). Studies on immunologic aspects of keloids and hypertrophic scars. Archives of Dermatology, 274,259. Jemec, G. B. (1988). Linear atrophy following intralesional steroid injections. Journal of Dermatologic Surgery and Oncology, 14, 88. Kantor, G. R., Wheeland, R. G., Bailin, P. L., Walker, N. P. and Ratz, J. L. (1985). Treatment of earlobe keloid with carbon dioxide laser excision: a report of 16 cases. Journal of Dermatologic Surgery and Oncology, 11, 1063. Khan, S. (1988). The pathology of keloid scars. Surgery, 54, 1299b. Kiseher, C. W. and Brody, G. S. (1981). Structure of the collagen nodule from hypertrophic scars and keloids. Scanning Electron Microscopy, part 3, 371. K&her, C. W. and Hendrix, M. J. (1983). Fibronectin (FN) in hypertrophic scars and keloids. Cell and Tissue Research, 231, 29. Kischer, C. W., Shetlar, M. R. and ChvapiI, M. (1982a). Hypertrophic scars and keloids: a review and new concept concerning their origin. Scanning Electron Microscop.v, part 4, 1699. K&her, C. W., Thies, A. C. and Chvapil, M. (1982b). Perivascular myofibroblasts and microvascular occlusion in hypertrophic scars and keloids. Human Pathology, 13,819. K&her, C. W., Shetlar, M. R., Shetlar, C. L. and ChvapiI, M. (1983). Immunoglobulins in hypertrophic scars and keloids. Plastic and Reconstructive Surgery, 71,821. Kurwa, A. R. (1979). Rubinstein-Taybi syndrome and spontaneous keloids. Clinical and Experimental Dermatology, 4,251. LeMasters, W. C. and No&, R. G. (1986). Comeal keloids. Transactions-Pennsylvania Academy of Ophthalmology and Otolaryngology, 38, 286. Lotte, A., Wasz-Hockert, D., Poisson, N., Dumitrescu, N., Verron, M. and Couvet, E. (1984). BCG complications. Estimates of the risk among vaccinated subjects and statistical analysis of their main characteristics. Advances in Tuberculosis Research, 21, 107. McCoy, B. J. and Cohen, I. K. (1981). Effects of various sera on growth kinetics and collagen synthesis by keloid and normal dermal fibroblasts. Plastic and Reconstructive Surgery, 67,505. McCoy, B. J. and Cohen, 1. K. (1982). Collagenase in keloid biopsies and fibroblasts. Connective Tissue Research, 9, 181, McCoy, B. J., Diegebnann, R. F. and Cohen, I. K. (1980). In vitro inhibition of cell growth, collagen synthesis, and prolyl hydroxylase activity by triamcinolone acetonide. Proceedings of the Society for Experimental Biology and Medicine. 163,216. Malaker, K., Ellis, F. and Paine, C. (1976). Keloid scars : a new method of treatment combining surgery with interstitial radiotherapy. Clinical Radiology, 27, 179.
76
BRITISH JOURNAL
Mayou, B. J. (1981). D-Penicillamine in the treatment of keloids. British Journalof Dermatology, 105,87. Mercer, D. M. and Studd, D. M. (1983). “Oyster splints”: a new compression device for the treatment of keloid scars of the ear. British Journal of Plastic Surgery, 36, 75. Mukherjee, A., Mukhejee, A. and Saha, K. C. (1982). Delayed type hypersensitivity reaction to cutaneous antigen in keloid. Indian Journal of Dermatology, 27, 125. Mulliken, J. B., Gifford, G. H. Jr. and Goldwyn, R. M. (1976). Vaccination caveat. The off-the-shoulder look. American Journal ofDiseases of Children, 130, 1094. Murray, J. C., Pollack, S. V. and Pinnell, S. R. (1981). Keloids: a review. Journal of the American Academy of Dermatology, 4, 461. Muti, E. and Ponzio, E. (1983). Cryotherapy in the treatment keloids. Annals of Plastic Surgery, 11, 227.
of
Ng, C. L., Lee, S. T. and Wong, K. L. (1983). Pressure garments in the prevention and treatment of keloids. Annals of the Academy of Medicine, Singapore, 12 (suppl), 430. Novick,N. L.,Lawson, W.andSchwartz,I.S.(1986). Suppurative keloidosis in a black woman. Journalof the American Academ.v of Dermatology, 15, 1090. Nunzi, E., Par&, A. and Rehora, A. (1983). Immunofluorescence findings in haematoporphyrin-induced keloid. British Journal of Dermatology, 108,263. Oikarinen, A., Oikarinen, H., Meeker, C. A., Tan, E. M. and Uitto, J. (1987). Glucocorticoid receptors in cultured human skin fibroblasts: evidence for down regulation of receptor by glucocorticoid hormone. Acta Dermato- Venereologica (Stockholm), 67,461. Oikarinen, H., Oikarinen, A. I., Tan, E. M., Abergel, R. P., Meeker, C. A., Chu, M. L., Proekop, D. J. and U&o, J. (1985). Modulation of procollagen gene expression by retinoids. Inhibition of collagen production by retinoic acid accompanied by reduced type I procollagen messenger ribonucleic acid levels in human skin fibroblast cultures. Journalof Clinical Invesiigation, 75. 1545. Ollstein, R. N., Siegel, H. W., Gillocdey, J. F. and Barsa, J. M. (1981). Treatment of keloids by combined surgical excision and immediate postoperative X-ray therapy. Annals of Plastic Surgery, 7,28 1. Oluwasanmi, J. 0. (1974). Keloids in the African. Clinics in Plastic Surgery, 1, 179. Oluwasanmi, J. 0. (1979). In Plastic Surgery in the Tropics. London and Basingstoke: The MacMillan Press Ltd. Omo-Dare, P. (1975). Genetic studies on keloids. Journal of the National Medical Association, 67,428. Onwukwe, M. F. (1978). The suppurative keloid. Journal of Dermatologic Surgery and Oncology, 4, 333. Peacock, E. E. Jr. (1984). Inflammation and cellular response to injury. In Wound Healing. Third edition. Philadelphia: W. B. Saunders. Peacock, E. E. Jr., Madden, J. W. and Trier, W. C. (1970). Biological basis for treatment of keloids and hypertrophic scars, Southern Medical Journal, 63,755. Perkins, K., Davey, R. B. and Wallis, K. A. (1983). Silicone gel: a new treatment for burns scars and contractures. Burns, 9, 201. Perkins, K., Davey, R. B. and Wallis, K. A. (1987). Current materials and techniques used in a burn scar management programme. Burns, 13,406. Pierce, H. E. (1979). Keloids: enigma of the Plastic Surgeon. Journalof the National Medical Association, 71, I 177.
OF PLASTIC SURGERY
Pierce, H. E. (1986). Postsurgical acrylic ear splints for keloids. Journal of Dermatologic Surgery and Oncology, 12,583. Quinn, K. J., Evans, J. H., Courtney, J. M. and Caylor, J. D. S. (1985). Non-pressure treatment of hypertrophic scars, Burns, 12, 102. Raje, D. (1980). Crippling giant keloid. British Journalof Surgery, 67, 452. Retz, N. (1790). Traite des Maladies de la peau et de celles de l&wit. Paris. Ronnen, M., Sokol, M. S., Huszar, M., Kahana, M. and Sehewach-Millet, M. (1986).Pseudomelanoma following treatment with surgical excision and intralesional triamcinolone acetonide to prevent keloid formation. International Journalof Dermatology, 25, 533. Ruiz-Maldonaldo, R. and Baker, J. (1977). Site of BCG vaccine administration and development of hypertrophic scar. Boletin Medico Del Hospital Infantil De Mexico, 34, I8 1. Russell,J. D.,Russell,S. B.andTrupin,K. M.(1978). Differential effects of hydrocortisone on both growth and collagen metabolism of human fibroblasts from normal and keloid tissue. Journal of Cellular Physiology, 97, 221. Russell, S. B., Russell, J. D. and Trupin, J. S. (1982). Alteration of amino acid transport by hydrocortisone. Different effects in human fibroblasts derived from normal skin and keloid. Journalof Biological Chemistry, 257,9525. Russell, S. B., Trupin, K. M., Rodriguez-Eaton, S. and Russell, J. D. (1988). Reduced growth-factor requirement of keloidderived fibroblasts may account for tumour growth. Proceedings of the National Academy of Sciences of the United States of America, 85, 587. Salasche, S. J. and Grabski, W. J. (1983). Keloids of the earlobes: a surgical technique. Journal of Dermatologic Surgery and Oncology, 9, 552. Selezueva, L. G. (1976). Keloid scars after burns. Acta Chirurgiae Plasticae. 18, 106. Sharma, B. C. (1980). Keloids: a prospective study of 57 cases. Medical Journal of Zambia, 14,66. Shepherd, J. P. and Dawber, R. P. (1982). The response of keloid scars to cryosurgery. Plastic and Reconstructive Surgery, 70, 677. Shons, A. R. and Press, B. H. (1983). The treatment of earlobe keloids by surgical excision and postoperative triamcinolone injection. Annals of Plastic Surgery, 10,480. Shukla, I. M., Arora, N. P. and Arora, M. M. (1975). Cornea1 keloids. Indian Journal of Ophthalmology, 23, 18. Smith, C. J., Smith, J. C. and Finn, M. C. (1987). The possible role of mast cells (allergy) in the production of keloid and hypertrophic scarring. Journalof Burn Care and Rehabilitation, 8, 126. Soderberg, T., Hallmans, G. and Bartholdson, L. (1982). Treatment of keloids and hypertrophic scars with adhesive zinc tapes. Scandinavian Journal of Plastic and Reconstructive Surgery, 16, 26 1. Stott, W. (1977). Butterfly keloids elsewhere than presternal. British Journal of Plastic Surgery, 30,243. Topol, B. M., Lewis, V. L., Jr. and Benveniste, K. (1981). The use of antihistamine to retard the growth of fibroblasts derived from human skin, scar, and keloid. Plastic and Reconstructive Surgery, 68, 227. Trupin, J. S., RusselI, S. B. and Russell, J. D. (1983). Variation in prolyl hydroxylase activity of keloid-derived and normal human fibroblasts in response to hydrocortisone and ascorbic acid. Collagen and Related Research, 3, 13.
KELOIDS:
A REVIEW
77
OF THE LITERATURE
Walker, J. J. (1983). Ultrasound therapy for keloids (letter). South African Medical Journal, 64,270. Yagi, K. I., Dafalla, A. A. and Oman, A. A. (1979). Does an immune reaction to sebum in wounds cause keloid scars? British Journalof Plastic Surgery. 32, 223.
The Author D. D. Datubo-Brown, FRCSEd, FRCSEng, FWACS, Lecturer, Department of Surgery, University of Port Harcourt, and Consultant Plastic Surgeon and Head of the Plastic Surgery
Unit, University of Port Harcourt Teaching Hospital; currently the recipient of a Commonwealth Medical Fellowship researching on keloids at the Birmingham Accident Hospital. Requests for reprints to: Mr D. D. Datubo-Brown, College of Health Sciences, University of Port Harcourt, PO Box 164. Choba, Port Harcourt, Nigeria. Paper received 24 November 1988 Accepted 30 June 1989 after revision
