―Review― Keloids and Hypertrophic Scars Can Now Be Cured Completely: Recent Progress in Our Understanding of the Pathogenesis of Keloids and Hypertrophic Scars and the Most Promising Current Therapeutic Strategy Rei Ogawa1, Satoshi Akaishi1, Shigehiko Kuribayashi2 and Tsuguhiro Miyashita2 1Department of Plastic, Reconstructive and Aesthetic Surgery, Nippon Medical School, Tokyo, Japan 2Department of Radiation Oncology, Nippon Medical School, Tokyo, Japan Keloids and hypertrophic scars are fibroproliferative disorders of the skin that are caused by abnormal healing of injured or irritated skin. It is possible that they are both manifestations of the same fibropro- liferative skin disorder and just differ in terms of the intensity and duration of inflammation. These fea- tures may in turn be influenced by genetic, systemic, and local risk factors. Genetic factors may include single nucleotide polymorphisms, while systemic factors may include hypertension, pregnancy, hor- mones, and cytokines. The most important local factor is tension on the scar. Over the past 10 years, our understanding of the pathogenesis of keloids and hypertrophic scars has improved markedly. As a result, these previously intractable scars are now regarded as being treatable. There are many therapeu- tic options, including surgery, radiation, corticosteroids, 5-fluorouracil, cryotherapy, laser therapy, anti- allergy agents, anti-inflammatory agents, bleaching creams and make-up therapies. However, at present, we believe that the following combination of three therapies most reliably achieves a complete cure: surgery, followed by radiation and the use of steroid tape/plaster. (J Nippon Med Sch 2016; 83: 46―53) Key words: keloid, hypertrophic scar, radiation, steroid, steroid tape Introduction that more superficial damage would not elicit keloids Keloids and hypertrophic scars are fibroproliferative dis- and hypertrophic scars. Indeed, a clinical study on hu- orders of the skin that are caused by abnormal healing of man volunteers showed that cutaneous injury must reach injured or irritated skin1. Common causes of injury and the reticular layer before it results in inflammatory scar irritation are trauma, burn, surgery, vaccination, skin formation3. piercing, acne, and herpes zoster. The scars are red and Many classical textbooks consider keloids and hy- elevated, and have an unappealing appearance. More- pertrophic scars to be completely different types of scar. over, they associate with intermittent pain, persistent Clinicians define hypertrophic scars as scars that do not itching, and a sensation of contraction. Some keloids can grow beyond the boundaries of the original wound, discharge due to the presence of infected inclusion cysts whereas keloids are defined as scars that spread into the that arise because the follicles are obliterated by the surrounding normal skin. By contrast, pathologists make scars. The inflammation in the scars is continuous and lo- a histological distinction between keloids and hy- cal, being mainly found in the reticular layer of the der- pertrophic scars on the basis of thick eosinophilic (hya- mis of the skin2. In this reticular layer, there is also accel- linizing) collagen bundles called“keloidal collagen”: these erated angiogenesis and collagen accumulation. These are present in the former scar type but fewer in the latter. features suggest that the cause of keloids and hy- However, there are many cases in which the scar bears pertrophic scars is an aberrant wound healing process in the growth and histological features of both hypertrophic the damaged reticular layer of the dermis. This implies scars and keloids4. Indeed, it is possible that hypertrophic Correspondence to Rei Ogawa, MD, Department of Plastic, Reconstructive and Aesthetic Surgery, Nippon Medical School, 1―1―5 Sendagi, Bunkyo-ku, Tokyo 113―8603, Japan E-mail: [email protected] Journal Website (http://www.nms.ac.jp/jnms/) 46 J Nippon Med Sch 2016; 83 (2) Keloids and Hypertrophic Scars Can Now Be Cured Completely scars and keloids are manifestations of the same fibropro- regions) but seldom in areas where stretching/contrac- liferative skin disorder4 and just differ in the intensity tion of the skin is rare (such as the parietal region or an- and duration of inflammation. These features may in terior lower leg). This is true even for patients with mul- turn be influenced by genetic, systemic, and local risk tiple/large keloids. Moreover, keloids are rare on the up- factors2. per eyelid. This reflects the fact that eyelid skin is always relaxed regardless of whether the eyes are open or Pathogenesis of Keloids and Hypertrophic Scars closed. An exception may be earlobe keloids: the contri- A number of genetic, systemic, and local factors that in- bution of mechanical factors to the development of these fluence the characteristics and quantity of keloids and keloids may be minor (although friction from the pillow hypertrophic scars have been identified. The genetic and the weight of the keloid itself can increase the risk of causes of pathological scar development may involve sin- keloid development and progression). The most likely lo- gle nucleotide polymorphisms (SNPs): a genome-wide cal cause of these keloids is the repeated attaching and association study5 showed that four SNP loci in three detaching of the piercing, which may lead to repeated in- chromosomal regions associate significantly with keloid jury and infection. Both are triggers of inflammation. development in the Japanese population. Moreover, our At present, physicians cannot (or at least find it very study showed that one SNP associates with the clinical difficult to) control genetic and systemic factors. How- severity of keloids6. There are probably many other ge- ever, they can reduce the mechanical forces around netic factors that have not yet been identified. keloids and hypertrophic scars by using various surgical In terms of systemic factors, adolescence and preg- techniques (including z-plasties). Moreover, anti- nancy appear to associate with a higher risk of develop- inflammatory treatments such as corticosteroids or anti- ing pathological scars7. It may be that sex hormones such angiogenesis agents (which reduce the number of blood as estrogens and androgens have vasodilatory effects8 vessels) are viable clinical strategies for the treatment of that intensify inflammation, thereby worsening keloids these scars. and hypertrophic scars. This is supported by our unpub- lished data, which suggest that the incidence of keloids Prevention of Keloids and Hypertrophic Scars that are not caused by trauma suddenly increases at A burn wound that heals in less than 10 days has a 4% around 10 years of age. This implies that the increases in risk of developing into a hypertrophic scar, whereas a sex steroid levels at the start of adolescence, not a higher burn wound that takes 21 days or more to heal has a likelihood of trauma, are responsible for the greater risk 70% or greater risk of developing into a hypertrophic of pathological scar development in adolescents. More- scar14. This means that a deep skin injury that extends to over, our recent study showed that hypertension associ- the reticular layer of dermis needs time to heal; however, ates with the development of severe keloids9,10. This asso- if inflammation continues for a long period, then the risk ciation may reflect the fact that hypertension damages of developing a pathological scar increases. Histopa- blood vessels, thereby increasing inflammation in scar tis- thological examination of pathological scars reveals that sue9,10. the epidermis and papillary layer of the dermis are al- Of the many factors that contribute to pathological scar most normal apart from minor inflammation, but the re- development, however, we believe that local mechanical ticular layer shows strong inflammation with more blood forces play a particularly important role11―13. Several lines vessels and greater collagen accumulation2,4. Thus, to pre- of evidence support this notion. First, keloids commonly vent the formation of pathological scars, it is essential to adopt distinct site-specific shapes, namely, the typical ensure speedy wound healing. Since keloids can arise butterfly, crab’s claw, and dumbbell shapes on the shoul- from very small injuries or from irritated skin (e.g., acne, der, anterior chest, and upper arm, respectively. This, to- herpes zoster, insect bites, and skin injections), special gether with our visual analysis using the finite element care should be taken to ensure fast healing of such small method, suggests that keloids are largely determined by wounds when treating patients with a history of keloids. the direction of the tension that is applied to the skin Since stretching wounds can evoke inflammation of the around the wound site13. Second, keloids show a marked dermis, wounds should be stabilized as soon as the exu- preference for particular locations on the body: they usu- date from the wound surface has stopped. The wound ally occur at sites that are constantly or frequently sub- healing of the epidermis and dermis differ completely. In jected to tension (such as the anterior chest and scapular the case of sutured wounds, the epidermis can regenerate J Nippon Med Sch 2016; 83 (2) 47 R. Ogawa, et al within 7―10 days, leading both the patient and the physi- carefully. To reduce the risk of recurrence, it is also advis- cian to believe that the wound has healed completely. In able to use particular surgical techniques, namely,