Abstract
Scar formation is a consequence of the wound healing process that occurs when body tissues are damaged by a physical injury. Hypertrophic scars and keloids are pathological scars resulting from abnormal responses to trauma and can be itchy and painful, causing serious functional and cosmetic disability. The current review will focus on the definition of hypertrophic scars, distinguishing them from keloids and on the various methods for treating hypertrophic scarring that have been described in the literature, including treatments with clearly proven efficiency and therapies with doubtful benefits. Numerous methods have been described for the treatment of abnormal scars, but to date, the optimal treatment method has not been established. This review will explore the differences between different types of nonsurgical management of hypertrophic scars, focusing on the indications, uses, mechanisms of action, associations and efficacies of the following therapies: silicone, pressure garments, onion extract, intralesional corticoid injections and bleomycin.
Hypertrophic Scar; Review; Pathological Scars; Update
INTRODUCTION
Hypertrophic scars (HTSs) are defined as visible and elevated scars that do not
spread into surrounding tissues and that often regress spontaneously (11. English RS, Shenefelt PD. Keloids and hypertrophic scars.
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). These scars are characterized by
proliferation of the dermal tissue, with excessive deposition of fibroblast-derived
extracellular matrix (ECM) proteins and especially collagen, over long periods and
by persistent inflammation and fibrosis (22. Atiyeh BS. Nonsurgical management of hypertrophic scars:
evidence-based therapies, standard practices, and emerging methods. Aesthetic
Plast Surg. 2007;31(5):468-92,
http://dx.doi.org/10.1007/s00266-006-0253-y.
http://dx.doi.org/10.1007/s00266-006-025...
).
Numerous methods have been described for the treatment of abnormal scars, but to
date, the optimal treatment method has not been established. A wide variety of
treatments have been advocated for HTSs. Among these treatments are surgical
excision with or without grafting (11. English RS, Shenefelt PD. Keloids and hypertrophic scars.
Dermatol Surg. 1999;25(8):631-8,
http://dx.doi.org/10.1046/j.1524-4725.1999.98257.x.
http://dx.doi.org/10.1046/j.1524-4725.19...
),
pressure therapy (33. Anzarut A, Olson J, Singh P, Rowe BH, Tredget EE. The
effectiveness of pressure garment therapy for the prevention of abnormal
scarring after burn injury: a meta-analysis. J Plast Reconstr Aesthet Surg
2009;62:77-84, http://dx.doi.org/10.1016/j.bjps.2007.10.052.
http://dx.doi.org/10.1016/j.bjps.2007.10...
), intralesional
interferon (44. Leventhal D, Furr M, Reiter D. Treatment of keloids and
hypertrophic scars: a meta-analysis and review of the literature. Arch Facial
Plast Surg. 2006;8(6):362-8.), topical and intralesional
corticosteroids (55. Jalali M, Bayat A. Current use of steroids in management of
abnormal raised skin scars. Surgeon. 2007;5(3):175-80,
http://dx.doi.org/10.1016/S1479-666X(07)80045-X.
http://dx.doi.org/10.1016/S1479-666X(07)...
), intralesional bleomycin
(66. Naeini FF, Najafian J, Ahmadpour K. Bleomycin tattooing as
apromising therapeutic modality in large keloids and hypertrophicscars. Dermatol
Surg. 2006;32(8):1023-9; discussion 1029-30,
http://dx.doi.org/10.1111/j.1524-4725.2006.32225.x.
http://dx.doi.org/10.1111/j.1524-4725.20...
), laser therapy (77. Leclàre FM, Mordon SR. Twenty-five years of active laser
prevention of scars: what have we learned? J Cosmet Laser Ther
2010;12:227-34, http://dx.doi.org/10.3109/14764172.2010.514923.
http://dx.doi.org/10.3109/14764172.2010....
), silicone gel sheeting (88. O′Brien L, Pandit A. Silicon gel sheeting for preventing
and treating hypertrophic and keloid scars. Cochrane Database Syst Rev
2013;9:CD003826.), onion extract gel and other therapies directed at collagen synthesis
(99. Shih R, Waltzman J, Evans GR. Plastic Surgery Educational
Foundation Technology Assessment Committee Review of over-the-counter topical
scar treatment products. Plast Reconstr Surg. 2007;119(3):1091-5,
http://dx.doi.org/10.1097/01.prs.0000255814.75012.35.
http://dx.doi.org/10.1097/01.prs.0000255...
).
Distinguishing hypertrophic scars from keloids
When faced with patients seeking treatment for pathological scars, many physicians have difficulty in differentiating HTSs from keloids; therefore, it is crucial to establish criteria to distinguish them.
HTSs are usually raised, although rarely elevated more than 4 mm above the skin; red or pink in color; hard; and pruritic. Additionally, these scars do not extend beyond the general geographic margins of the wound and tend to regress over time (1010. Ehrlich HP, Desmouliere A, Diegelmann RF, Cohen IK, Compton CC, Garner WL, et al. Morphological and immunochemical differences between keloid and hypertrophic scar. Am J Pathol. 1994;145(1):105-13.) (Figure 1). HTSs primarily contain type III collagen, oriented parallel to the epidermal surface and with abundant nodules and large extracellular collagen filaments (1111. Gauglitz GG, Korting HC, Pavicic T, Ruzicka T, Jeschke MG. Hypertrophic Scarring and Keloids: Pathomechanisms and Current and Emerging Treatment Strategies. Mol Med. 2011;17(1-2):113-25.).
Hypertrophic scar regression in a burned child after four years (A and B). Hypertrophic scars are usually raised, although rarely elevated more than 4 mm above the skin; red or pink in color; hard; and pruritic. Additionally, these scars do not extend beyond the general geographic margins of the wound and tend to regress over time.
In contrast, keloids continue to evolve over time, without a quiescent or
regressive phase and do infiltrate the surrounding tissue (Figure 2). Keloids appear as firm, mildly tender,
bosselated tumors with a shiny surface and occasional telangiectasia. The
epithelium is thinned and there may be focal areas of ulceration. The color is
pink to purple and may be accompanied by hyperpigmentation (1212. Al-Attar A, Mess S, Thomassen JM, Kauffman CL, Davison SP.
Keloid pathogenesis and treatment. Plast Reconstr Surg. 2006;117:286-300,
http://dx.doi.org/10.1097/01.prs.0000195073.73580.46.
http://dx.doi.org/10.1097/01.prs.0000195...
). The initial lesions are erythematous
and become brownish red, followed by paling as they age. The lesions
preferentially develop on the earlobes, shoulders and presternal skin; are void
of hair follicles and other glands; and usually project above the level of the
surrounding skin (1313. Burd A, Huang L. Hypertrophic response and keloid diathesis: two
very different forms of scar. Plast Reconstr Surg. 2005;116(7):150e-57e,
http://dx.doi.org/10.1097/01.prs.0000191977.51206.43.
http://dx.doi.org/10.1097/01.prs.0000191...
). Keloids are
primarily composed of abnormally thick, irregularly branched and septal
disorganized type I and III collagen bundles without nodules and with excess
myofibroblasts (1111. Gauglitz GG, Korting HC, Pavicic T, Ruzicka T, Jeschke MG.
Hypertrophic Scarring and Keloids: Pathomechanisms and Current and Emerging
Treatment Strategies. Mol Med. 2011;17(1-2):113-25.) and overproduction of
multiple fibroblast proteins, indicating the persistence of wound healing or
even a failure to downregulate wound-healing cells. In addition, keloids are not
triggered to enter the final phase of wound healing, or the
“remodeling” phase, whereas HTSs will eventually do so (1414. Lane JE, Waller JL, Davis LS. Relationship between age of ear
piercing and keloid formation. Pediatrics. 2005;115(5):1312-4,
http://dx.doi.org/10.1542/peds.2004-1085.
http://dx.doi.org/10.1542/peds.2004-1085...
).
Keloid evolution after seven years (A and B). Keloids continue to evolve over time, without a quiescent or regressive phase, and infiltrate the surrounding tissue.
Distinguishing HTSs from keloids histopathologically is occasionally difficult because thickened hyalinized collagen (keloidal collagen), the hallmark of keloids, is not always detectable and because α-smooth muscle actin (α-SMA), a differentiating marker of HTSs, is variably expressed in both types of scars (1515. Lee JY, Yang CC, Chao SC, Wong TW. Histopathological differential diagnosis of keloid and hypertrophic scar. Am J Dermatopathol. 2004;26(5):379-84.).
The histopathological findings most commonly observed in HTSs are flattening of the epidermis and replacement of the papillary and reticular dermis by scar tissue with prominent vertically oriented blood vessels (Figure 3). In keloids, there is no flattening of the overlying epidermis, no scarring of the papillary dermis, the presence of a significant amount of keloidal collagen, an absence of prominent vertically oriented blood vessels and the presence of a significant disarray of fibrocollagenous fascicles (Figure 4) (1515. Lee JY, Yang CC, Chao SC, Wong TW. Histopathological differential diagnosis of keloid and hypertrophic scar. Am J Dermatopathol. 2004;26(5):379-84.).
The histology of hypertrophic scars is characterized by replacement of the papillary and reticular dermis by scar tissue with prominent vertically oriented blood vessels. The fibrous bundles are parallel and horizontal in the upper dermis. (Masson's trichrome, 100X).
The histology of keloids is characterized by well-demarcated and disorganized fibrous tissue usually involving the upper half or two-thirds of the dermis. The collagen fibers are noticeably thicker (Masson's trichrome, 100X).
Differential and exclusive diagnosis
The differential and exclusive diagnosis of diseases that are similar to keloids
and HTSs is important because various types of malignant tumors resemble these
scars (1616. Sabater-Marco V, Perez-Valles A, Berzal-Cantalejo F,
Rodriguez-Serna M, Martinez-Diaz F, Martorell-Cebollada M. Sclerosing
dermatofibrosarcoma protuberans (DFSP): an unusual variant with focus on the
histopathologic differential diagnosis. Int J Dermatol.
2006;45:59-62.
17. D′Andrea F, Vozza A, Brongo S, Di Girolamo F, Vozza G.
Dermatofibrosarcoma protuberans: experience with 14 cases. J Eur Acad
Dermatol Venereol. 2001;15(5):427-9,
http://dx.doi.org/10.1046/j.0926-9959.2001.00307.x.
http://dx.doi.org/10.1046/j.0926-9959.20...
18. Kanitakis J, Euvrard S, Sebbag L, Claudy A. Trichilemmal
carcinoma of the skin mimicking a keloid in a heart transplant recipient.
J Heart Lung Transplant. 2007;26(6):649-51,
http://dx.doi.org/10.1016/j.healun.2007.03.001.
http://dx.doi.org/10.1016/j.healun.2007....
-1919. Misago N, Ogusu Y, Narisawa Y. Keloidal basal cell carcinoma
after radiation therapy. Eur J Dermatol.
2004;14(3):182-5.). For example, malignant dermatofibrosarcoma protuberans (DFSP)
tumors have been mistaken for keloids or HTSs (1616. Sabater-Marco V, Perez-Valles A, Berzal-Cantalejo F,
Rodriguez-Serna M, Martinez-Diaz F, Martorell-Cebollada M. Sclerosing
dermatofibrosarcoma protuberans (DFSP): an unusual variant with focus on the
histopathologic differential diagnosis. Int J Dermatol.
2006;45:59-62.,1717. D′Andrea F, Vozza A, Brongo S, Di Girolamo F, Vozza G.
Dermatofibrosarcoma protuberans: experience with 14 cases. J Eur Acad
Dermatol Venereol. 2001;15(5):427-9,
http://dx.doi.org/10.1046/j.0926-9959.2001.00307.x.
http://dx.doi.org/10.1046/j.0926-9959.20...
).
Nodular scleroderma and keloidal scleroderma are rare benign tumors with lesions that clinically resemble keloids (2020. Cannick L III, Douglas G, Crater S, Silver R. Nodular scleroderma: case report and literature review. J Rheumatol. 2003;30(11):2500-02.). The skin lesions are characteristically nodules or plaques, hard in consistency, and nontender, with a predilection for the superior portions of the thorax and sparing of the face and hands (2121. Santiago M1, de Castro DO Jr, Costa CA, Passos ES, Paixão A. Keloidal scleroderma. Clin Rheumatol. 2004;23(1):50-1.).
Gonzalez-Vela et al. (2222. Gonzalez-Vela MC, Val-Bernal JF, Gonzalez-Lopez MA, Drake M,
Fernández-Llaca JH. Sclerotic neurofibroma: a neurofibroma mimicking
sclerotic fibroma. J Cutan Pathol. 2006;33(1):47-50,
http://dx.doi.org/10.1111/j.0303-6987.2006.00392.x.
http://dx.doi.org/10.1111/j.0303-6987.20...
) described
keloids and HTSs as differential diagnoses of sclerotic neurofibroma. Sclerotic
neurofibroma is differentiated from a keloid by an absence of previous surgical
excision and by the positivity of the sclerotic neurofibroma cells for the
protein S100 (2222. Gonzalez-Vela MC, Val-Bernal JF, Gonzalez-Lopez MA, Drake M,
Fernández-Llaca JH. Sclerotic neurofibroma: a neurofibroma mimicking
sclerotic fibroma. J Cutan Pathol. 2006;33(1):47-50,
http://dx.doi.org/10.1111/j.0303-6987.2006.00392.x.
http://dx.doi.org/10.1111/j.0303-6987.20...
).
Other rare, benign keloid and HTS-like diseases include keloidal granuloma (2323. Verma R, Das AL, Vaishampayan SS, Vaidya S. Keloidal granuloma
faciale with extrafacial lesions. Indian J Dermatol Venereol Leprol.
2005;71(5):345-7, http://dx.doi.org/10.4103/0378-6323.16787.
http://dx.doi.org/10.4103/0378-6323.1678...
), erythema elevatum diutinum (2424. Krishnan RS, Hwang LY, Tschen JA, Subrt P, Hsu S. Erythema
elevatum diutinum mimicking extensive keloids; quiz 386. Cutis.
2001;67(5):381-5.), infantile digital fibromatosis (2525. Chirayil PT, Jayaraj J, Kumar P. Infantile digital
fibromatosis-a case report. Burns. 2001;27(1):89-90,
http://dx.doi.org/10.1016/S0305-4179(00)00074-7.
http://dx.doi.org/10.1016/S0305-4179(00)...
), dermatofibroma,(2626. Zelger BG, Sidoroff A, Zelger B. Combined dermatofibroma:
co-existence of two or more variant patterns in a single lesion. Histopathology.
2002;36(6):529-39.) penile edema (2727. Bang RL. Penile oedema induced by continuous condom catheter use
and mimicking keloid scar. Scand J Urol Nephrol.
1994;28(3):333-5.), pseudoangiomatous hyperplasia (2828. Ibrahim RE, Sciotto CG, Weidner N. Pseudoangiomatous hyperplasia
of mammary stroma. Some observations regarding its clinicopathologic spectrum.
Cancer. 1989;63(6):1154-60.) and lichen sclerosus (2929. Allan A, Andersen W, Rosenbaum M. Histologic features of lichen
sclerosus et atrophicus in a surgical scar. Am J Dermatopathol.
1999;21(4):387-91.).
Hair folliculitis occasionally leads to hypertrophic scarring (3030. Luz-Ramos M, Munoz-Perez MA, Pons A, Ortega M, Camacho F. Acne
keloidalis nuchae and tufted hair folliculitis. Dermatology.
1997;194(1):71-3.) but more often leads to progressive
folliculitis caused by bacterial or fungal infection. The nape is an area of
predilection for hair folliculitis. Treatment of any infection should be primary
and steroid injection is contraindicated for infection. Moreover, a fungus may
cause a skin nodule that mimics a keloid (3131. Hecker MS, Weinberg JM. Cutaneous cryptococcosis mimicking
keloid. Dermatology. 2001;202(1):78-9,
http://dx.doi.org/10.1159/000051597.
http://dx.doi.org/10.1159/000051597...
). Thus, examination for fungal infection should be conducted in
cases of nape hair folliculitis, even if the nodule appears to be a keloid or
HTS.
In conclusion, the following issues are considered important in the examination
of a keloid or HTS: a biopsy should be conducted in anomalous cases because
malignant disease may be the original or secondary problem, steroid injection
should be performed only after careful consideration because malignancy or
infections may be present, making a careful differential diagnosis is
particularly challenging in African-Americans because the skin and the tumor
colors are often similar and the presence of bacterial or fungal infection
should be investigated (3232. Ogawa R, Akaishi S, Hyakusoku H. Differential and exclusive
diagnosis of diseases that resemble keloids and hypertrophic scars. Ann Plast
Surg. 2009;62(6):660-4,
http://dx.doi.org/10.1097/SAP.0b013e31817e9d67.
http://dx.doi.org/10.1097/SAP.0b013e3181...
).
Demographics
The majority of individuals who develop HTSs and keloids are young, with ages
ranging from 10 to 30 years old. The elderly rarely develop these lesions (3333. Rockwell WB, Cohen IK, Ehrlich HP. Keloids and hypertrophic
scars: a comprehensive review. Plast Reconstr Surg. 1989;84(5):827-37,
http://dx.doi.org/10.1097/00006534-198911000-00021.
http://dx.doi.org/10.1097/00006534-19891...
). This observation is partly attributed
to the following facts: young individuals are more prone to trauma; their skin
generally possesses more elastic fibers, resulting in greater tension; and the
rate of collagen synthesis is greater in younger individuals (3434. Aarabi S, Longaker MT, Gurtner GC. Hypertrophic scar formation
following burns and trauma: new approaches to treatment. PLoS Med.
2007;4(9):e234, http://dx.doi.org/10.1371/journal.pmed.0040234.
http://dx.doi.org/10.1371/journal.pmed.0...
). Keloids are more common in patients
with darker skin, with an incidence of 4.5% to 16% in the black and Hispanic
populations (3434. Aarabi S, Longaker MT, Gurtner GC. Hypertrophic scar formation
following burns and trauma: new approaches to treatment. PLoS Med.
2007;4(9):e234, http://dx.doi.org/10.1371/journal.pmed.0040234.
http://dx.doi.org/10.1371/journal.pmed.0...
).
HTSs are a common complication of burn injury. In the developed world,
approximately four million patients acquire scars due to burns each year and the
incidence is even greater in developing countries (44. Leventhal D, Furr M, Reiter D. Treatment of keloids and
hypertrophic scars: a meta-analysis and review of the literature. Arch Facial
Plast Surg. 2006;8(6):362-8.). Previous studies have reported diverging incidences of
hypertrophic scarring, with incidence rates varying from 40% to 94% following
surgery and from 30% to 91% following burns (3535. Bombaro KM, Engrav LH, Carrougher GJ, Wiechman SA, Faucher L,
Costa BA, et al. What is the prevalence of hypertrophic scarring following
burns? Burns. 2003;29(4):299-302,
http://dx.doi.org/10.1016/S0305-4179(03)00067-6.
http://dx.doi.org/10.1016/S0305-4179(03)...
,3636. Miller MC, Nanchahal J. Advances in the modulation of cutaneous
wound healing and scarring. BioDrugs. 2005;19(6):363-81,
http://dx.doi.org/10.2165/00063030-200519060-00004.
http://dx.doi.org/10.2165/00063030-20051...
).
Etiology
Wound healing is classically divided into four stages: hemostasis, inflammation, proliferation and tissue remodeling. In these four stages, there are complicated interactions within a complex network of profibrotic and antifibrotic molecules, such as growth factors, proteolytic enzymes and ECM proteins (3737. Tredget EE. Pathophysiology and treatment of fibroproliferative disorders following thermal injury. Ann N Y Acad Sci. 1999;888:165-82.). Each molecule has its own function in the different phases of the wound healing process. As soon as an injury occurs, the process of hemostasis begins and the bleeding is controlled by the aggregation of platelets at the site of injury. The subsequent formation of a fibrin clot helps to stop the bleeding and provides a scaffold for the attachment and proliferation of cells. Growth factors and cytokines are mainly secreted by inflammatory cells and contribute to the initiation of the proliferative phase of wound healing. Later, angiogenesis and collagen synthesis, followed by tissue remodeling complete the stages of the wound healing process.
The delicate balance of the deposition and degradation of ECM proteins is
disrupted when either excessive production of collagen, proteoglycans and
fibronectin by fibroblasts or deficient degradation and remodeling of the ECM
occur (3838. Wang J, Ding J, Jiao H, Honardoust D, Momtazi M, Shankowsky HA,
et al. Human hypertrophic scar-like nude mouse model: characterization of the
molecular and cellular biology of the scar process. Wound Repair Regen.
2011;19(2):274-85,
http://dx.doi.org/10.1111/j.1524-475X.2011.00672.x.
http://dx.doi.org/10.1111/j.1524-475X.20...
). HTSs occur when the
inflammatory response to injury is prolonged, leading to the pathological
characteristics of HTSs, including increased vascularization, hypercellularity,
excessive collagen deposition and a decrease in small leucine-rich proteoglycans
(SLRPs) (3939. Honardoust D, Varkey M, Hori K, Ding J, Shankowsky HA, Tredget
EE. Small leucine-rich proteoglycans, decorin and fibromodulin, are reduced in
postburn hypertrophic scar. Wound Repair Regen. 2011;19(3):368-78,
http://dx.doi.org/10.1111/j.1524-475X.2011.00677.x.
http://dx.doi.org/10.1111/j.1524-475X.20...
,4040. Scott PG, Dodd CM, Tredget EE, Ghahary A, Rahemtulla F.
Immunohistochemical localization of the proteoglycans decorin, biglycan and
versican and transforming growth factor-beta in human post-burn hypertrophic and
mature scars. Histopathology. 1995;26(5):423-31.).
HTS tissue contains enhanced amounts of fibroblasts that exhibit an altered
phenotype and higher expression of transforming growth factor beta-1
(TGF-β1) than normal fibroblasts do (4141. Shah M, Foreman DM, Ferguson MW. Neutralisation of TGF-beta 1
and TGF-beta 2 or exogenous addition of TGF-beta 3 to cutaneous rat wounds
reduces scarring. J Cell Sci. 1995;108(Pt 3):985-1002.). An increase in or prolonged activity of TGF-β1 leads to
overproduction and excess deposition of collagen by fibroblasts, often resulting
in HTS formation (4242. Nedelec B, Shankowsky H, Scott PG, Ghahary A, Tredget EE.
Myofibroblasts and apoptosis in human hypertrophic scars: the effect of
interferon-alpha2b. Surgery. 2001;130(5):798-808,
http://dx.doi.org/10.1067/msy.2001.116453.
http://dx.doi.org/10.1067/msy.2001.11645...
). Fibroblasts in
HTSs may differentiate into myofibroblasts and account for increased ECM
synthesis and contraction of tissue. These cells have a particular phenotype
that differs from that of fibroblasts based on their expression of α-SMA
(4343. Moulin V, Larochelle S, Langlois C, Thibault I, Lopez-Vallé
CA, Roy M. Normal skin wound and hypertrophic scar myofibroblasts have
differential responses to apoptotic inductors. J Cell Physiol.
2004;198(3):350-8, http://dx.doi.org/10.1002/jcp.10415.
http://dx.doi.org/10.1002/jcp.10415...
). Myofibroblasts in HTSs are less
sensitive to apoptotic signals, coupled with an ability to produce more collagen
and play an important role in HTS formation (4343. Moulin V, Larochelle S, Langlois C, Thibault I, Lopez-Vallé
CA, Roy M. Normal skin wound and hypertrophic scar myofibroblasts have
differential responses to apoptotic inductors. J Cell Physiol.
2004;198(3):350-8, http://dx.doi.org/10.1002/jcp.10415.
http://dx.doi.org/10.1002/jcp.10415...
).
Clinical manifestations
The clinical manifestations of HTSs are variable and correlate with a variety of
causes that initiate HTS formation. HTSs can develop anywhere on the body. In
contrast, keloids preferentially develop on the earlobes, shoulders and
presternal skin; are void of hair follicles and other glands; and usually
project above the level of the surrounding skin (1313. Burd A, Huang L. Hypertrophic response and keloid diathesis: two
very different forms of scar. Plast Reconstr Surg. 2005;116(7):150e-57e,
http://dx.doi.org/10.1097/01.prs.0000191977.51206.43.
http://dx.doi.org/10.1097/01.prs.0000191...
). Curiously, pathological scars are rare on the scalp. Farina Jr
et al. recently described a casuistic study of 413 surgical procedures involving
collection of thin skin grafts from the scalp, without development of HTSs or
keloids among 295 cases over a period of ten years (4444. Farina JA Jr, Freitas FA, Ungarelli LF, Rodrigues JM, Rossi LA.
Absence of pathological scarring in the donor site of the scalp in burns: an
analysis of 295 cases. Burns. 2010;36(6):883-90,
http://dx.doi.org/10.1016/j.burns.2009.11.015.
http://dx.doi.org/10.1016/j.burns.2009.1...
).
Hypertrophic scarring following surgical procedures, trauma and especially burns
is a significant concern for patients and a challenging problem for clinicians
because it can be painful, pruritic, erythematous, raised and cosmetically
unacceptable. A previous study reported that the most common and distressing
complications in burn patients who developed HTSs were abnormal appearance
(75.2%), pruritus (73.3%) and pain (67.6%) (4545. Forbes-Duchart L, Cooper J, Nedelec B, Ross L, Quanbury A. Burn
therapists' opinion on the application and essential characteristics of a
burn scar outcome measure. J Burn Care Res. 2009;30(5):792-800,
http://dx.doi.org/10.1097/BCR.0b013e3181b47cc2.
http://dx.doi.org/10.1097/BCR.0b013e3181...
). The cause of pruritus in HTSs and keloid scars is not yet well
characterized, but recent studies have indicated the probable involvement of
direct activation of opioid receptors identified in the skin (4646. Biao Cheng, MD, PhD,* Hong-Wei Liu, MD,† Xiao-Bing Fu.
Update on pruritic mechanisms of hypertrophic scars in postburn patients: the
potential role of opioids and their receptors. J of Burn Care & Res.
2011;32(4):e118-25.).
Prevention and non-surgical treatment
There is evidence suggesting that increased mechanical tension can initiate HTS
formation (4747. Aarabi S, Bhatt KA, Shi Y, Paterno J, Chang EI, Loh SA, et al.
Mechanical load initiates hypertrophic scar formation through decreased cellular
apoptosis. FASEB J. 2007;21(12):3250-61,
http://dx.doi.org/10.1096/fj.07-8218com.
http://dx.doi.org/10.1096/fj.07-8218com...
). Based on this hypothesis,
it makes sense to minimize mechanical forces after surgery. Surgical excision
scars should be positioned along, rather than across, relaxed skin tension lines
whenever possible. An appropriate strength, depth and number of sutures should
ensure that the risk of dehiscence is minimized.
Inflammation is also known to contribute to hypertrophic scarring, (4949. Wang J, Hori K, Ding J, Huang Y, Kwan P, Ladak A, et al.
Toll-like receptors expressed by dermal fibroblasts contribute to hypertrophic
scarring. J Cell Physiol. 2011;226(5):1265-73,
http://dx.doi.org/10.1002/jcp.22454.
http://dx.doi.org/10.1002/jcp.22454...
) and every attempt to minimize the
inflammatory response should be made by ascertaining clean surgery and good
wound care to prevent infection thereafter. Using inert suture materials is also
important in this context (4848. Jaad 2012: Tziotzios C, Profyris C, Sterling J. Cutaneous
scarring: pathophysiology, molecular mechanisms and scar reduction therapeutics
Part II. Strategies to reduce scar formation after dermatologic procedures.
J Am Acad Dermatol. 2012;66(1):13-24.).
In patient candidates for skin grafts, the donor site must be well chosen by the surgeon in consultation with the patient to try to hide or avoid HTSs or keloids. In burn patients, the corresponding author believes that using the scalp as a source of thin skin grafts can reduce the level of visible aesthetic deformities at donor sites in patients who have already suffered the immense trauma that being a burn victim entails.
Conceptually and practically, treatment and prevention regimens can be similar
and the following section presents the clinical data for both. Early diagnosis
can considerably affect the outcome. There is evidence that the most successful
non-surgical treatment of an HTS or keloid is achieved when the scar is immature
and the overlying epithelium is intact, although further studies are necessary
to confirm this concept (5050. Mustoe TA, Cooter RD, Gold MH, Hobbs FD, Ramelet AA, Shakespeare
PG, et al. International clinical recommendations on scar management. Plast
Reconstr Surg. 2002;110(2):560-7,
http://dx.doi.org/10.1097/00006534-200208000-00031.
http://dx.doi.org/10.1097/00006534-20020...
).
Silicone
Silicone gel sheeting (SGS) has been widely used in clinical practice for the
treatment of HTSs since the early 1980s. There is good evidence of the efficacy
of the SGS, which has become standard practice among plastic surgeons (5151. Signorini M, Clementoni MT. Clinical evaluation of a new
self-drying silicone gel in the treatment of scars: a preliminary report.
Aesthetic Plast Surg. 2007;31(2):183-7,
http://dx.doi.org/10.1007/s00266-005-0122-0.
http://dx.doi.org/10.1007/s00266-005-012...
).
Although gel sheeting is effective for HTS treatment, patient compliance may not
be satisfactory for the following reasons: skin reaction to the tape used for
fixation; excessive sweating; difficulty in its application; and the visibility
of the treatment in the case of scars located in visible areas, such as the face
(5252. Karagoz H, Yuksel F, Ulkur E, Evinc R. Comparison of efficacy of
silicone gel, silicone gel sheeting, and topical onion extract including heparin
and allantoin for the treatment of postburn hypertrophic scars. Burns.
2009;35(8):1097-103,
http://dx.doi.org/10.1016/j.burns.2009.06.206.
http://dx.doi.org/10.1016/j.burns.2009.0...
).
In contrast, silicone gel does not require fixation and is nearly invisible when
dry, suggesting that it could be especially useful in visible areas (5252. Karagoz H, Yuksel F, Ulkur E, Evinc R. Comparison of efficacy of
silicone gel, silicone gel sheeting, and topical onion extract including heparin
and allantoin for the treatment of postburn hypertrophic scars. Burns.
2009;35(8):1097-103,
http://dx.doi.org/10.1016/j.burns.2009.06.206.
http://dx.doi.org/10.1016/j.burns.2009.0...
). However, there are certain problems in
its application. For example, silicone gel requires multiple applications in a
day and one must wait long enough for drying because the dressing may be
smudged. Friction by clothes may also contribute to early removal of the
silicone film (5151. Signorini M, Clementoni MT. Clinical evaluation of a new
self-drying silicone gel in the treatment of scars: a preliminary report.
Aesthetic Plast Surg. 2007;31(2):183-7,
http://dx.doi.org/10.1007/s00266-005-0122-0.
http://dx.doi.org/10.1007/s00266-005-012...
). Because of these
problems, silicone gel use may not always be practical.
Karagoz et al. found no statistically significant difference between silicone gel
and silicone gel sheet groups when their scores on the Vancouver Scar Scale
after treatment were compared. This finding suggests that silicone gel is most
likely as effective as SGS for the treatment of HTSs (5252. Karagoz H, Yuksel F, Ulkur E, Evinc R. Comparison of efficacy of
silicone gel, silicone gel sheeting, and topical onion extract including heparin
and allantoin for the treatment of postburn hypertrophic scars. Burns.
2009;35(8):1097-103,
http://dx.doi.org/10.1016/j.burns.2009.06.206.
http://dx.doi.org/10.1016/j.burns.2009.0...
).
The mechanism of action of topical silicone materials in the treatment of HTSs is
not well understood and various mechanisms of action have been proposed. It has
been suggested that the materials' therapeutic effect is not due to
pressure, but rather to decreased scarring via wound hydration. There is
evidence that SGS affects the hydration status of the scar by decreasing the
water vapor transmission rate to nearly half that of normal skin, causing a
buildup of moisture on the skin surface under the silicone sheet (5353. Gilman TH. Silicone sheet for treatment and prevention of
hypertrophic scar: A new proposal for the mechanism of efficacy. Wound Rep Reg.
2003;11(3):235-6,
http://dx.doi.org/10.1046/j.1524-475X.2003.11313.x.
http://dx.doi.org/10.1046/j.1524-475X.20...
). This evidence suggests that the
stratum corneum acts as a water reservoir, with fluid accumulating below the
gel, although when visualized directly, this phenomenon is not evident (5454. Musgrave MA, Umraw N, Fish JS, Gomez M, Cartotto RC. The effect
of silicone gel sheets on perfusion of hypertrophic burn scars. J Burn Care
Rehab. 2002;23(3):208-14,
http://dx.doi.org/10.1097/00004630-200205000-00010.
http://dx.doi.org/10.1097/00004630-20020...
). Hydration and occlusion therefore seem
to be the principal modes of SGS action and increased skin hydration is most
likely responsible for decreased capillary activity, reduced hyperemia and
reduced collagen deposition (5555. Niessen FB, Spauwen PH, Robinson PH, Fidler V, Kon M. The use of
silicone occlusive sheeting (Sil-K) and silicone occlusive gel (Epiderm) in the
prevention of hypertrophic scar formation. Plast Reconstr Surg.
1998;102(6):1962-72,
http://dx.doi.org/10.1097/00006534-199811000-00023.
http://dx.doi.org/10.1097/00006534-19981...
).
Furthermore, altered hydration is thought to cause electrostatic changes that
influence collagen deposition and remodeling within the scar (5656. Hirshowitz B, Ullmann Y, Har-Shai Y, Vilenski A, Peled IJ.
Silicone occlusive sheeting (SOS) in the management of hypertrophic scarring,
including the possible mode of action of silicone, by static electricity.
Eur J Plast Surg. 1993;16(1):5-9.). The static electricity generated by
friction has also been proposed as a plausible reason for silicone's
anti-scarring effects (5757. Har-Shai Y, Lindenbaum E, Tendler M, Gamliel-Lazarovich A,
Feitelberg L, Hirshowitz B. Negatively charged static electricity stimulation as
a possible mechanism for enhancing the involution of hypertrophic and keloid
scars. Isr Med Assoc J. 1999;1(3):203-5.).
The lower water vapor transmission rate and the accumulation of water below the
material can cause skin maceration (5858. Chan KY, Lau CL, Adeeb SM, Somasundaram S, Nasir-Zahari M. A
randomized, placebo-controlled, double-blind, prospective clinical trial of
silicone gel in prevention of hypertrophic scar development in median sternotomy
wound. Plast Reconstr Surg. 2005;116(4):1013-20,
http://dx.doi.org/10.1097/01.prs.0000178397.05852.ce.
http://dx.doi.org/10.1097/01.prs.0000178...
).
Other common side effects associated with gel sheeting include persistent
pruritus, skin breakdown, skin rash, foul smell from the gel, poor durability of
the sheet, failure of the sheet to improve the hydration of dry scars, a poor
response of the scar to treatment and poor patient compliance (5959. Van den Kerckhove E, Stappaerts K, Boeckx W, Van den Hof B,
Monstrey S, Van der Kelen A. Silicones in the rehabilitation of burns: A review
and overview. Burns. 2001;27(3):205-14,
http://dx.doi.org/10.1016/S0305-4179(00)00102-9.
http://dx.doi.org/10.1016/S0305-4179(00)...
,6060. So K, Umraw N, Scott J, Campbell K, Musgrave M, Cartotto R.
Effects of enhanced patient education on compliance with silicone gel sheeting
and burn scar outcome: A randomized prospective study. J Burn Care Rehabil.
2003;24(6):411-7,
http://dx.doi.org/10.1097/01.BCR.0000095516.98523.04.
http://dx.doi.org/10.1097/01.BCR.0000095...
). Similar to pressure therapy, detailed multimedia-based patient
education improves compliance with SGS, resulting in a better scar outcome
(6060. So K, Umraw N, Scott J, Campbell K, Musgrave M, Cartotto R.
Effects of enhanced patient education on compliance with silicone gel sheeting
and burn scar outcome: A randomized prospective study. J Burn Care Rehabil.
2003;24(6):411-7,
http://dx.doi.org/10.1097/01.BCR.0000095516.98523.04.
http://dx.doi.org/10.1097/01.BCR.0000095...
). Obviously, the key to the
success of this therapy is to ensure that hygienic precautions are taken,
particularly when it is used in combination with pressure in children or in warm
weather or climates (6060. So K, Umraw N, Scott J, Campbell K, Musgrave M, Cartotto R.
Effects of enhanced patient education on compliance with silicone gel sheeting
and burn scar outcome: A randomized prospective study. J Burn Care Rehabil.
2003;24(6):411-7,
http://dx.doi.org/10.1097/01.BCR.0000095516.98523.04.
http://dx.doi.org/10.1097/01.BCR.0000095...
). It must be
noted, however, that complications increase with the use of combined pressure
and SGS therapy (6060. So K, Umraw N, Scott J, Campbell K, Musgrave M, Cartotto R.
Effects of enhanced patient education on compliance with silicone gel sheeting
and burn scar outcome: A randomized prospective study. J Burn Care Rehabil.
2003;24(6):411-7,
http://dx.doi.org/10.1097/01.BCR.0000095516.98523.04.
http://dx.doi.org/10.1097/01.BCR.0000095...
).
Applying silicone gel twice daily or wearing SGS 12 to 24 h per day for 6 to 12
months, with temporary interruption when adverse effects appear, is recommended
(6161. Bloemen MCT, Van der Veer WM, Ulrich MW, van Zuijlen PP, Niessen
FB, Middelkoop E. Prevention and curative management of hypertrophic scar
formation. Burns. 2009;35(4):463-75,
http://dx.doi.org/10.1016/j.burns.2008.07.016.
http://dx.doi.org/10.1016/j.burns.2008.0...
).
Pressure garments
Using mechanical compressive force exerted by pressure garments to treat HTSs in
burn patients was first described in 1860 (6262. Linares HA, Larson DL, Willis-Galstaun BA. Historical notes on
the use of pressure in the treatment of hypertrophic scars or keloids. Burns.
1993;19(1):17-21,
http://dx.doi.org/10.1016/0305-4179(93)90095-P.
http://dx.doi.org/10.1016/0305-4179(93)9...
). It was only in the 1960s that this treatment became standard in
several burn centers to accelerate the remodeling phase of wound healing (6262. Linares HA, Larson DL, Willis-Galstaun BA. Historical notes on
the use of pressure in the treatment of hypertrophic scars or keloids. Burns.
1993;19(1):17-21,
http://dx.doi.org/10.1016/0305-4179(93)90095-P.
http://dx.doi.org/10.1016/0305-4179(93)9...
). Prophylactic pressure is recommended
in burn patients if spontaneous closure of the wound takes longer than 10 to 14
days and in those requiring grafting (22. Atiyeh BS. Nonsurgical management of hypertrophic scars:
evidence-based therapies, standard practices, and emerging methods. Aesthetic
Plast Surg. 2007;31(5):468-92,
http://dx.doi.org/10.1007/s00266-006-0253-y.
http://dx.doi.org/10.1007/s00266-006-025...
).
Currently, elastic compression using elastic garments is the predominant means of
both prophylaxis and treatment for HTSs (6362. Linares HA, Larson DL, Willis-Galstaun BA. Historical notes on
the use of pressure in the treatment of hypertrophic scars or keloids. Burns.
1993;19(1):17-21,
http://dx.doi.org/10.1016/0305-4179(93)90095-P.
http://dx.doi.org/10.1016/0305-4179(93)9...
), despite controversial evidence-based data about their value in
reducing the prevalence or magnitude of scarring (6363. Esselman PC, Thombs BD, Magyar-Russell G, Fauerbach JA. Burn
rehabilitation: State of the science. Am J Phys Med Rehabil.
2006;85(4):383-413,
http://dx.doi.org/10.1097/01.phm.0000202095.51037.a3.
http://dx.doi.org/10.1097/01.phm.0000202...
). In fact, studies investigating pressure garments have
found no significant difference between treatments involving the use of
high-pressure garments, lower-pressure garments, or no pressure at all (6464. Macintyre L, Baird M. Pressure garments for use in the treatment
of hypertrophic scars: A review of the problems associated with their use.
Burns. 2006;32(1):10-5,
http://dx.doi.org/10.1016/j.burns.2004.06.018.
http://dx.doi.org/10.1016/j.burns.2004.0...
). Others, however, claim that pressure
therapy achieves HTS regression success rates of 60% to 85% (6363. Esselman PC, Thombs BD, Magyar-Russell G, Fauerbach JA. Burn
rehabilitation: State of the science. Am J Phys Med Rehabil.
2006;85(4):383-413,
http://dx.doi.org/10.1097/01.phm.0000202095.51037.a3.
http://dx.doi.org/10.1097/01.phm.0000202...
), without any conclusive evidence.
To date, the working mechanism of pressure and the way that pressure positively
influences the development and maturation of HTSs are not fully understood and
explanations remain hypothetical. However, many studies have been performed to
try to explain the possible mechanisms of action, exploring theories based on
hypoxia, biochemical changes, and cellular and collagenous influences. Certain
valuable evidence suggests that pressure controls collagen synthesis by limiting
the supply of blood, oxygen, and nutrients to the scar tissue (6565. Puzey G. The use of pressure garments on hypertrophic scars.
J Tissue Viability. 2002;12(1):11-5.); reduces collagen production to the
levels found in normal scar tissue more rapidly than the natural maturation
process does; encourages the realignment of collagen bundles that are already
present (6666. Costa AM, Peyrol S, Porto LC, Comparin JP, Foyatier JL,
Desmouliere A. Mechanical forces induce scar remodeling. Study in non-pressure-
treated versus pressure-treated hypertrophic scars. Am J Pathol.
1999;155(5):1671-9.); partly restores the ECM
organization observed in normal scarring; and induces the disappearance of
fibrogenic α-SMA-expressing myofibroblasts and vascular cells, most likely
by apoptosis (6767. Reno F, Sabbatini M, Lombardi F, Stella M, Pezzuto C, Magliacani
G, et al. In vitro mechanical compression induces apoptosis and regulates
cytokines release in hypertrophic scars. Wound Rep Reg. 2003;11(5):331-6,
http://dx.doi.org/10.1046/j.1524-475X.2003.11504.x.
http://dx.doi.org/10.1046/j.1524-475X.20...
).
Additionally, certain studies have demonstrated that mechanical compression
directly modulates the remodeling phase of wound healing, altering the release
and activity of matrix metalloproteinase (MMP)-28 in HTSs and inducing a
significant reduction in the protein's presence in keratinocytes in HTSs
(6868. Reno F, Sabbatini M, Stella M, Magliacani G, Cannas M. Effect of
in vitro mechanical compression on Epilysin (matrix metalloproteinase-28)
expression in hypertrophic scars. Wound Repair Regen. 2005;13(3):255-61,
http://dx.doi.org/10.1111/j.1067-1927.2005.130307.x.
http://dx.doi.org/10.1111/j.1067-1927.20...
). Moreover, it has been suggested
that pressure acts by accelerating the remission phase of the postburn
reparative process (6666. Costa AM, Peyrol S, Porto LC, Comparin JP, Foyatier JL,
Desmouliere A. Mechanical forces induce scar remodeling. Study in non-pressure-
treated versus pressure-treated hypertrophic scars. Am J Pathol.
1999;155(5):1671-9.).
Currently, the recommendations for the clinical use of pressure garments are
restricted to deep dermal wounds that have healed spontaneously over weeks,
grafted wounds surrounded by a deep dermal wound that was permitted to heal
spontaneously over weeks, wounds in children and young adults, wounds in
individuals with dark skin and wounds in body locations where compression can be
applied (6971. Cho JW, Cho SY, Lee SR, Lee KS. Onion extract and quercetin
induce matrix metalloproteinase-1 in vitro and in vivo. Int J of Mol
Med. 2010;25(3):347-52.). The amount of effective
pressure generated by a given pressure garment is also still unknown and remains
controversial (7070. Van den Kerckhove E, Stappaerts K, Fieuws S, Laperre J, Massage
P, Flour M. The assessment of erythema and thickness on burn related scars
during pressure garment therapy as a preventive measure for hypertrophic
scarring. Burns. 2005;31(6):696-702,
http://dx.doi.org/10.1016/j.burns.2005.04.014.
http://dx.doi.org/10.1016/j.burns.2005.0...
). Problems with
pressure loss from the garments over time and problems with the compliance of
the patients using the garments are yet other factors complicating the issue
(6969. Engrav LH, Heimbach DM, Rivara FP, Moore ML, Wang J, Carrougher
GJ, et al. 12-Year within-wound study of the effectiveness of custom pressure
garment therapy. Burns. 2010;36(7)975-83,
http://dx.doi.org/10.1016/j.burns.2010.04.014.
http://dx.doi.org/10.1016/j.burns.2010.0...
,7070. Van den Kerckhove E, Stappaerts K, Fieuws S, Laperre J, Massage
P, Flour M. The assessment of erythema and thickness on burn related scars
during pressure garment therapy as a preventive measure for hypertrophic
scarring. Burns. 2005;31(6):696-702,
http://dx.doi.org/10.1016/j.burns.2005.04.014.
http://dx.doi.org/10.1016/j.burns.2005.0...
).
Onion extract and heparin gel
Onion extract possesses fibroblast-inhibiting properties that reduce both
fibroproliferative activity and the production of ECM, increasing the expression
of MMP-1 (7171. Cho JW, Cho SY, Lee SR, Lee KS. Onion extract and quercetin
induce matrix metalloproteinase-1 in vitro and in vivo. Int J of Mol
Med. 2010;25(3):347-52.). Heparin strongly interacts
with collagen molecules, inducing the formation of the thicker fibrils typical
of a mature tissue and also promoting intermolecular bonding in collagen (7272. Ho WS, Ying SY, Chan PC, Chan HH. Use of onion extract, heparin,
allantoin gel in prevention of scarring in Chinese patients having laser removal
of tattoos: A prospective randomized controlled trial. Dermatol Surg.
2006;32(7):891-6,
http://dx.doi.org/10.1111/j.1524-4725.2006.32192.x.
http://dx.doi.org/10.1111/j.1524-4725.20...
). Therefore, heparin and onion extract
affect scar development via their inhibitory effects on inflammatory processes,
fibroblast proliferation and the synthesizing capacity of fibroblasts (7272. Ho WS, Ying SY, Chan PC, Chan HH. Use of onion extract, heparin,
allantoin gel in prevention of scarring in Chinese patients having laser removal
of tattoos: A prospective randomized controlled trial. Dermatol Surg.
2006;32(7):891-6,
http://dx.doi.org/10.1111/j.1524-4725.2006.32192.x.
http://dx.doi.org/10.1111/j.1524-4725.20...
). Onion extract and heparin exert
similar antiproliferative effects that depress fibroblast proliferation and
reduce scar size in the case of excessive scar formation in HTSs and keloid
scars (7375. Chanprapaph K, Tanrattanakorn S, Wattanakrai P, Wongkitisophon
P, Vachiramon V. Effectiveness of onion extract gel on surgical scars in Asians.
Dermatol Res Pract. 2012;2012:212945.).
The topical gel preparation includes 10% aqueous onion extract, 50 U heparin per
gram of gel, and 1% allantoin gel, and this formulation has been used for many
years to treat wounds. Despite the gel's popularity, data demonstrating its
efficacy are lacking. Certain clinical studies of the efficacy and tolerability
of this topical preparation have been conducted. Ho et al. found onion extract,
heparin and allantoin gel to be effective, safe and simple to apply for the
prevention of scarring in 120 Chinese patients undergoing laser removal of
tattoos. The researchers found that the topical gel preparation reduced the risk
of scarring significantly, from 23.5% to 11.5% (7272. Ho WS, Ying SY, Chan PC, Chan HH. Use of onion extract, heparin,
allantoin gel in prevention of scarring in Chinese patients having laser removal
of tattoos: A prospective randomized controlled trial. Dermatol Surg.
2006;32(7):891-6,
http://dx.doi.org/10.1111/j.1524-4725.2006.32192.x.
http://dx.doi.org/10.1111/j.1524-4725.20...
). Willital and Heine studied the effect of the same topical gel
preparation on fresh scars after thoracic surgery in children and adolescents.
The authors randomly assigned 45 young patients with fresh scars after thoracic
surgery to the treatment and found that the scars in the treated group were
narrower than those in the untreated group after 1 year of the treatment (7474. Willital GH, Heine H. Efficacy of contractubex gel in the
treatment of fresh scars after thoracic surgery in children and adolescents.
Int J Clin Pharm Res. 1994;14(5-6):193-202.). In this study, the benefit of the gel
for the treatment of physiologic scars as well as for the treatment of HTSs and
keloid scars were described. In a more recent study, the early use of onion
extract gel in surgical scars resulted in the improvement of scar height and
symptoms, but there was no statistically significant difference in the
scars' redness, pliability or overall cosmetic appearance (7575. Chanprapaph K, Tanrattanakorn S, Wattanakrai P, Wongkitisophon
P, Vachiramon V. Effectiveness of onion extract gel on surgical scars in Asians.
Dermatol Res Pract. 2012;2012:212945.). Nevertheless, we have observed that
many patients who use a topical preparation containing onion extract, heparin
and allantoin gel or another onion extract gel do not notice any significant
improvement in their HTSs.
Intralesional corticosteroid injections
Intralesional corticosteroid injections, used for the treatment of pathological
scars since the mid-1960s, continue to play a major role in the regression of
HTSs and keloids (7676. Chen MA, Davidson TM. Scar management: Prevention and treatment
strategies. Curr Opinion Otolaryngol Head Neck Surg. 2005;13(4):242-7,
http://dx.doi.org/10.1097/01.moo.0000170525.74264.f8.
http://dx.doi.org/10.1097/01.moo.0000170...
). Steroid injections
have been shown to cause HTS and keloid regression in vivo,
mainly by decreasing collagen and glycosaminoglycan synthesis, by reducing the
inflammatory process in the wound, by decreasing fibroblast proliferation and by
increasing hypoxia (7777. Niessen FB, Spauwen P, Schalkwijk J, Kon M. On the nature of
hypertrophic scars and keloids: A review. Plast Reconstr Surg.
1999;104(5):1435-58,
http://dx.doi.org/10.1097/00006534-199910000-00031.
http://dx.doi.org/10.1097/00006534-19991...
). Insoluble
triamcinolone acetonide (TAC; 10 to 40 mg/ml), the most common corticosteroid
used for the treatment of scars, may be administered alone or in combination
with lidocaine to reduce the pain associated with the injection and several
treatments administered once or twice per month are usually required to achieve
the desired results (7878. Manuskiatti W, Fitzpatrick RE. Treatment response of keloidal
and hypertrophic sternotomy scars: Comparison among intralesional
corticosteroid, 5-fluorouracil, and 585-nm flashlamp- pumped pulsed-dye laser
treatments. Arch Dermatol. 2002;138(9):1149-55,
http://dx.doi.org/10.1001/archderm.138.9.1149.
http://dx.doi.org/10.1001/archderm.138.9...
).
Despite few randomized, prospective studies, there is broad consensus that
injected TAC is efficacious and it is the first-line therapy for the treatment
of keloids and the second-line therapy for the treatment of HTSs if other,
easier treatments have not been efficacious. Response rates vary from 50% to
100%, with a recurrence rate of 9% to 50% (7373. Koc E, Arca E, Surucu B, Kurumlu Z. An open, randomized,
controlled, comparative study of the effect of intralesional triamcinolone
acetonide and onion extract gel and intralesional triamcinolone acetonide alone
in the treatment of hypertrophic scars and keloids. Dermatol Surg.
2008;34(11):1507-14,
http://dx.doi.org/10.1111/j.1524-4725.2008.34314.x.
http://dx.doi.org/10.1111/j.1524-4725.20...
).
Manuskiatti and Fitzpatrick found clinical improvement of HTSs and keloid scars
after treatment with an intralesional injection of TAC combined with
Contractubex¯ gel, which appears to be superior to intralesional TAC
administered alone in the treatment of keloids and HTSs, with no significant
side effects (7878. Manuskiatti W, Fitzpatrick RE. Treatment response of keloidal
and hypertrophic sternotomy scars: Comparison among intralesional
corticosteroid, 5-fluorouracil, and 585-nm flashlamp- pumped pulsed-dye laser
treatments. Arch Dermatol. 2002;138(9):1149-55,
http://dx.doi.org/10.1001/archderm.138.9.1149.
http://dx.doi.org/10.1001/archderm.138.9...
).
Although the use of corticosteroids to suppress abnormal scar formation has been relatively effective for most patients, it has also been a troublesome therapy. Intralesional corticosteroid injection is associated with significant injection pain, even using standard doses of triamcinolone (40 mg/ml), with up to 63% of patients experiencing certain side effects, including hypopigmentation, skin and subcutaneous fat atrophy, telangiectasias, rebound effects and ineffectiveness (7981. Bodokh I, P Brun. Traitement des chéloïdes par infiltrations de bléomycine. Ann Dermatol Venereol. 1996;123(12):791-4.). After intralesional injection, linear hypopigmentation also may develop secondary to lymphogenous uptake of the corticosteroid crystals (8080. George WM. Linear lymphatic hypopigmentation after intralesional corticosteroid injection: Report of two cases. Cutis. 1999;64(1):61-4.).
Bleomycin
Bleomycin sulfate was introduced by Bodokh and Brun in 1996 as an alternative
therapy for keloids and HTSs, based on its action as an inhibitor of the
synthesis of deoxyribonucleic acid (DNA) (8181. Bodokh I, P Brun. Traitement des chéloïdes par
infiltrations de bléomycine. Ann Dermatol Venereol.
1996;123(12):791-4.). Bleomycin is a secondary metabolite of a strain of
Streptomyces obtained from soil and has antitumor,
antiviral and antibacterial activity. This compound acts by binding to DNA,
whether double stranded and single stranded, causing strand scissions (8282. Bennett JM., Reich SD. Bleomycin. Ann Intern Med.
1979;90(6):945-8, http://dx.doi.org/10.7326/0003-4819-90-6-945.
http://dx.doi.org/10.7326/0003-4819-90-6...
). The use of intralesional bleomycin has
been documented for the treatment of keloids and HTSs, with promising results
(8383. Espana A, Solano T, Quintanilla E. Bleomycin in the treatment of
keloids and hypertrophic scars by multiple needle punctures. Dermatol Surg.
2001;27(1):23-7,
http://dx.doi.org/10.1111/j.1524-4725.2001.99315.x.
http://dx.doi.org/10.1111/j.1524-4725.20...
). Certain studies have
investigated the effects of intradermal bleomycin administration into the skin
of healthy individuals (8484. Templeton SF, Solomon AR, Swerlick RA. Intradermal bleomycin
injections into normal human skin. A histopathologic and immunopathologic
study. Arch Dermatol. 1994;130(5):577-83,
http://dx.doi.org/10.1001/archderm.1994.01690050045006.
http://dx.doi.org/10.1001/archderm.1994....
). From a
histologic point of view, bleomycin has been found to cause necrosis of
keratinocytes and this treatment can also induce inflammatory infiltration,
along with expression of various adhesion molecules (8484. Templeton SF, Solomon AR, Swerlick RA. Intradermal bleomycin
injections into normal human skin. A histopathologic and immunopathologic
study. Arch Dermatol. 1994;130(5):577-83,
http://dx.doi.org/10.1001/archderm.1994.01690050045006.
http://dx.doi.org/10.1001/archderm.1994....
). Furthermore, the presence of apoptotic cells has been
noted in common warts treated with bleomycin (8585. James MP, Collier PM, Aherne W, Hardcastle A, Lovegrove S.
Histologic, pharmacologic, and immunocytochemical effects of injection of
bleomycin into viral warts. J Am Acad Dermatol. 1993;28(6):933-7,
http://dx.doi.org/10.1016/0190-9622(93)70133-E.
http://dx.doi.org/10.1016/0190-9622(93)7...
). Despite these findings, the exact mechanism by which bleomycin
induces keloid and HTS regression is not entirely clear.
Concerning the side effects of intralesional administration of bleomycin, hyperpigmentation and dermal atrophy have developed in the healthy skin surrounding the lesion in only a few cases (8686. Saray Y, Gulec AT. Treatment of keloids and hypertrophic scars with dermojet injections of bleomycin: a preliminary study. Int J Dermatol. 2005;44:777-84.). The systemic side effects of bleomycin with intradermal/intralesional administration alone are not of concern because the concentration and dosage are not sufficient to incite systemic problems such as hepatotoxicity and pulmonary fibrosis (8787. Crooke ST, Bradner WT. Bleomycin, a review. J Med. 1976;7(5):333-428.).
Certain findings have revealed that bleomycin not only improves cosmetic
appearance but also relieves patients' pruritus and pain, symptoms often
associated with pathological scars. Although intralesional bleomycin is a
promising treatment option for keloids and HTSs, further investigation and
efficacy trials are needed before this agent can be included in future treatment
protocols (8888. Shridharani SM, Magarakis M, Manson PN, Singh NK, Basak B,
Rosson GD. The emerging role of antineoplastic agents in the treatment of
keloids and hypertrophic scars. Annals of Plastic Surgery. 2010;64(3):355-61,
http://dx.doi.org/10.1097/SAP.0b013e3181afaab0.
http://dx.doi.org/10.1097/SAP.0b013e3181...
).
Emerging alternative treatments
The use of interferon alpha, beta and gamma increases collagen lysis. In
particular, alpha and gamma inhibit the synthesis of collagen types I and III,
acting on mRNA in the cell and reducing the levels of TGF-β. However,
interferon application is very painful and it is a costly drug (8888. Shridharani SM, Magarakis M, Manson PN, Singh NK, Basak B,
Rosson GD. The emerging role of antineoplastic agents in the treatment of
keloids and hypertrophic scars. Annals of Plastic Surgery. 2010;64(3):355-61,
http://dx.doi.org/10.1097/SAP.0b013e3181afaab0.
http://dx.doi.org/10.1097/SAP.0b013e3181...
).
The drug 5-fluorouracil may be used alone or in combination with corticosteroid
injections and achieves better results when combined with triamcinolone because
monotherapy has limited use due to pain on application (5050. Mustoe TA, Cooter RD, Gold MH, Hobbs FD, Ramelet AA, Shakespeare
PG, et al. International clinical recommendations on scar management. Plast
Reconstr Surg. 2002;110(2):560-7,
http://dx.doi.org/10.1097/00006534-200208000-00031.
http://dx.doi.org/10.1097/00006534-20020...
). The use of a carbon dioxide laser and an argon laser
is ineffective due to recurrences, which are treated with steroids. Intense
pulsed light therapy has shown satisfactory results, although further studies
are needed, especially with later assessment of cases (5050. Mustoe TA, Cooter RD, Gold MH, Hobbs FD, Ramelet AA, Shakespeare
PG, et al. International clinical recommendations on scar management. Plast
Reconstr Surg. 2002;110(2):560-7,
http://dx.doi.org/10.1097/00006534-200208000-00031.
http://dx.doi.org/10.1097/00006534-20020...
).
Drugs such as imiquimod, flurandrenolide, clobetasol, tacrolimus, methotrexate and pentoxifylline are several of the tested agents that have shown a clinical response, an increase in the local production of interferon in particular. However, the results must be considered with skepticism until further studies are conducted (8989. Kelly AP. Medical and surgical therapies for keloids. DermatolTher. 2004;17(2):212-8.).
Cryotherapy with liquid nitrogen combined with corticosteroids showed a satisfactory response in the treatment of keloid scars, although its use in HTSs has not been assessed (9090. Zoubollis CC, Blume U, Büttner P, Orfanos CE. Outcomes of cryosurgery in keloids and hypertrophic scars: a prospective consecutive trial of case series. Arch Dermatol. 1993;129(9):1146-51.).
Botulinum toxin type A stimulates collagen formation and hyperbaric oxygen
provides pure oxygen at a pressure slightly higher than atmospheric pressure,
leading to decreased growth of atypical fibroblasts and restoration of tissue
regeneration. In both cases, use of the treatment does not occur in isolation
but rather as a complementary therapy. Still, further studies are necessary
(9191. Freshwater MF. Botulinum toxin for scars: can it work, does it
work, is it worth it? J Plast Reconstr Aesthet Surg. 2013;66(3):e92-3,
http://dx.doi.org/10.1016/j.bjps.2012.11.034.
http://dx.doi.org/10.1016/j.bjps.2012.11...
,9292. Romero-Valdovinos M, Cárdenas-Mejía A,
Gutiérrez-Gómez C, Flisser A, Kawa-Karasik S, Ortiz-Monasterio F.
Keloid skin scars: the influence of hyperbaric oxygenation on fibroblast growth
and on the expression of messenger RNA for insulin like growth factor and for
transforming growth factor. In Vitro Cell Dev Biol Anim. 2011;47(7):421-4,
http://dx.doi.org/10.1007/s11626-011-9418-3
http://dx.doi.org/10.1007/s11626-011-941...
).
Dermal radiofrequency can be another therapeutic option for the treatment of HTSs. This treatment's mechanism of action is based on a slight increase in the temperature of the skin, increasing the extensibility and reducing the density of collagen (by a lifting effect due to the radio frequency) (9393. Carvalho GF, Silva RMV, Mesquita-Filho Joaquim JT, Meyer PF, Ronzio OA, Medeiros JO, et al. Avaliação dos efeitos da radiofrequência no tecido. RBM - Rev Bras Med. Edição Especial Dermatologia&Cosmiatria 2011;68:10-25.).
Surgery
HTSs rapidly increase in size for 3 to 6 months. Then, after a static phase, they
begin to regress. The scars mature during a period of at least 1 year and can
show decreased contractures, along with flattening, softening and repigmentation
without any physical manipulation. For this reason, surgery is usually not
necessary. However, surgery is indicated for those cases of HTSs with scar
contractures (and especially joint contractures) that could result in loss of
function (5050. Mustoe TA, Cooter RD, Gold MH, Hobbs FD, Ramelet AA, Shakespeare
PG, et al. International clinical recommendations on scar management. Plast
Reconstr Surg. 2002;110(2):560-7,
http://dx.doi.org/10.1097/00006534-200208000-00031.
http://dx.doi.org/10.1097/00006534-20020...
).
HTSs may impair movement when they cross joints or exert abnormal forces on
surrounding tissues. The shoulder, elbow, and knee are the most common joints
affected by contractures after burn injury (9494. Hudson DA, Renshaw A. An algorithm for the release of burn
contractures of the extremities. Burns. 2006;32(6):663-8,
http://dx.doi.org/10.1016/j.burns.2006.02.009.
http://dx.doi.org/10.1016/j.burns.2006.0...
). Certain burn scars can cause enough impairment of function to
require surgical intervention. The techniques of releasing burn scar
contractures vary significantly, depending on the individual characteristics of
the scar in question. In general, local, linear or small planar scars that
impair movement may be lengthened by Z or V-Y plasty procedures and skin grafts
may be necessary after major contracture release (9494. Hudson DA, Renshaw A. An algorithm for the release of burn
contractures of the extremities. Burns. 2006;32(6):663-8,
http://dx.doi.org/10.1016/j.burns.2006.02.009.
http://dx.doi.org/10.1016/j.burns.2006.0...
). Additionally, the use of a dermal matrix and negative
pressure therapy to generate higher-quality skin grafts for the treatment of
sequelae and contractures in burns is more and more common (9595. Aldunate JLCB, Fontana LPMVC, Ferreira MC. Use of dermal matrix
and negative pressure dressings for the treatment of contractures in burn
patients. Rev Bras Cir Plást. 2012;27(3):369-73,
http://dx.doi.org/10.1590/S1983-51752012000300006.
http://dx.doi.org/10.1590/S1983-51752012...
).
Mental status
It is important to investigate a patient's current mental status to exclude the possibility of any psychiatric disorder before initiating treatment planning. Patients presenting a history of severe sadness or other depressive symptoms should be diagnosed and followed by a psychologist and psychiatrist and should start treatment only after discharge by the expert. Psychological stress also seems to be related to the recurrence of fibroproliferative scarring (9696. Silva MMA, Furtado FMGP, Hochman B, Ferreira ML. Recidiva de quelóides: o estresse psicológico como fator de risco. Rev Bras Cir Plást. 2012;27(supl):1-102.).
Patients who are dissatisfied with the treatment of their HTSs often cite a pre-existing psychopathological condition in lawsuits filed against their doctors, claiming that they did not have the mental faculties to understand the outcomes and limitations of the proposed treatment. It is necessary to present reports by expert professionals to provide a legal protection measure when prompted in court.
The doctor-patient relationship must include transparency, empathy and trust to reduce the patient's anxiety (9797. Jaimovich CA, Neto MK, Almeida AHT, Pinheiro AG, Loma DC. Consentimento informado e cirurgia plástica. Rev Bras Cir Plást. 2007;22(3):188-93.).
CONCLUSIONS
In this review, the authors sought to emphasize the actual need for the correct diagnosis of HTSs, which differ from keloid scarring, the latter being much more difficult to treat. The development of more reliable and objective methods for the diagnosis and the measurement of the severity of HTSs is also essential for further research in the area of prevention and treatment. In the last few years, increased understanding of the molecular and biologic mechanisms involved in HTS formation has allowed the development of more therapeutic options for these lesions. HTSs remain difficult to manage and there is no universally accepted treatment regimen or evidence-based literature to guide their management.
Treatment begins by educating the patient about the etiology of the scarring process and must be individualized, depending on the distribution, size, thickness and consistency of the lesions and the associated inflammation. The physician should select the most appropriate agent according to the patient's needs and the guidelines for these signs. Nonsurgical treatment seems to be the best option most of the time. Currently, silicone gel or a silicone sheet remains the most accepted modality for the treatment and prevention of HTSs, but in many cases, there are specific indications for different types of approaches, such as the use of pressure garments; combinations of corticosteroid injections and onion extract gel; bleomycin and even surgery in cases of contractures associated with the scar, mainly in burns.
Disputes concerning this topic are very far from over. Fibroproliferative disorders represent one of the greatest puzzles in medicine and although there is no consensus, combination therapy has proven to be more effective than monotherapy. It is essential that the physician be aware of the different therapeutic options available and be able to individualize treatment because certain patients may not respond to any single treatment modality. Finally, guidance for patients whose hypertrophic scarring usually regresses completely after six months to three years would appear to be fundamental.
Thanks to the Department of Pathology and Forensic Medicine of FMRP-USP for providing the histopathological photographs.
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No potential conflict of interest was reported.
Publication Dates
-
Publication in this collection
Aug 2014
History
-
Received
13 Sept 2013 -
Reviewed
2 Dec 2013 -
Accepted
10 Feb 2014