2Doctor at department of dermatology, Tishreen Hospital, lattakia. Syria
Keywords: Keloids; Pathogenesis; Risk factors; Diagnosis; Different diagnosis; Histopathology; Treatment; Prevention;
PDGF: Platelet-derived growth factor
TGF: Transforming growth factor
VEGF: Vascular endothelial growth factor
CTGF: Connective tissue growth factor
IFN-g: Interferon-g
IGF-IR: Insulin-like growth factor-1 receptor
Hemostasis is the process that responds to injury to stop blood loss by vascular and cellular responses. Immediately the injured vessels undergo vasoconstriction (10-15 min) is followed by vasodilation due to activation of mast cells, which is important for the chemotaxis of neutrophils, macrophages, and lymphocytes. The increased blood flow, triggering the signs of inflammation, such as heat, edema and redness. Platelets aggregate at the site of injury, leading to blood clot (the coagulation system). Blood clot is temporarily seal the bleeding, and acts as a reservoir for growth factors and cytokines, and cell migration. Blood clots predominantly consist of fibrin, but other Extracellular Matrix (ECM) proteins, such as fibronectin, vitronectin, and thrombospondin, are also present. Possible involvements of fibrin and fibronectin in keloid pathogenesis have been suggested [6,8].
After injury, resident mast cells degranulate and release histamine, bradykinins, and leukotrienes, which lead to the recruitment of immune cells. The first inflammatory cells arriving to the injury site are Neutrophils, which kill microbes, and provide a source of proinflammatory cytokines. Monocytes enter the wound bed and develop into activated macrophages, which secrete numerous growth factors and cytokines that act on fibroblast, endothelial cells, and keratinocytes, such as: Platelet- Derived Growth Factor (PDGF), transforming growth factor TGF-a, TGF-b, and vascular endothelial growth factor VEGF. In addition to their involvements in the inflammatory phase, some of these growth factors and cytokines are also involved in the proliferative phase and have also been implicated to be abnormal in keloids [6,8].
Reepithelialization is the first visible event of the proliferative phase, which is characterized by the migration and proliferation of keratinocytes from the epidermis at the wound edge that occurs 1-2 days post-wounding. Although keloids are defined as a dermal disease involving fibroblasts, there is suggestion for keratinocyte involvements [6,8].
Neovascularization is the process of new blood vessel formation (granulation tissue) in response to tissue malnutrition. New vessels are formed from solid endothelial sprouts that migrate from the wound edges to the central area. Chemical mediators like bradykinin and prostaglandin, from macrophages induce migration and mitosis of endothelial cells. Neoangiogenesis increases the recruitment of cells, such as macrophages and fibroblasts, to the wound site. Active neovascularization has been implicated in keloid disease. Vascular endothelial growth factors VEGF plays a significant role in neovascularization and have been linked to keloids disease. Platelet Derived Growth Factor (PDGF) and Connective Tissue Growth Factor (CTGF) are other growth factors that play an important role in the proliferative phase. These factors have been implicated in keloid formation [6,8].
Fibroplasia; after injury, fibroblasts in normal tissue are attracted to the inflammation site, where they divide and produce the extracellular matrix molecules ECM. Fibroblasts only appear at the lesion site from the third day onwards, after leukocytes have cleansed the injured area. The primary role of fibroblasts is to synthesize collagen. Collagen is the substance responsible for the support and tensile strength of the scar. The rate of collagen synthesis declines approximately after 4 weeks and balances with the rate of degradation, after which the collagen maturation phase begins that, continues for months or even years. TGF-b has a significant role in wound healing. It stimulates type I collagen transcription and inhibits collagenase transcription in fibroblasts. TGF-b is overproduced by keloid tissue, so the excess collagen present in keloid scars may result from overexpression of TGF-b and decreased collagen degradation [6,8].
The process by which keloid develop is poorly understood, but it is known to be induced by abnormal wound healing in predisposed individuals. There are several theories of keloid etiology, most of them are related to fibroblast dysfunction. Keloid fibroblasts, when compared with fibroblasts isolated from a normal wound, excessive deposition of extracellular matrix components, especially collagen, fibronectin, elastin, proteoglycans. In addition, these cells have higher rates of mitosis, and lower rates of apoptosis. [6,9,10,11] There are several theories of keloid formation according to induced factor. Some of them implicate certain cytokines, other implicate keratinocyte. In contrast, some theories suggest that fibroblasts have the initial disorder.
Vascular Endothelial Growth Factor (VEGF) and Connective Tissue Growth Factor (CTGF) are overexpressed in keloid tissue and may have a potential role in its evolution [14].
Platelet-Derived Growth Factor (PDGF) is known to stimulate the proliferation of connective tissue. High expression of PDGFreceptor in fibroblasts derived from keloid, maybe contribute to the formation of keloid [15]. Also, insulin-like growth factor-1 receptor (IGF-IR) may be involved in the pathogenesis of keloid [16].
Some authors indicated that the excessive scar formation in keloids may be a result of reduced apoptosis of fibroblasts, which may lead to an imbalance between collagen synthesis and degradation. Keloid lesions were found to have lower rates of apoptosis than normal skin, because downregulation of apoptosis-related genes, including p53 [6,9,11,17].
Expression of connexins and other constituent proteins of gap junctions along with gap junctional intercellular communication are involved in cellular development and differentiation processes. Some studies suggest that the loss of gap junctional intercellular communication and connexin expression may affect intercellular recognition and thus break the proliferation and apoptosis balance in fibroblasts derived from keloid tissue [18,19].
However, some studies suggest that keloid fibroblasts may be normal, but they receive abnormal signals from neighboring cells: (a) Maybe there is a role of keratinocyte of keloid formation; some studies suggested that keratinocytes contribute to keloid scarring by regulating extracellular matrix production in fibroblasts [20]. Others showed fundamental abnormalities in keloid keratinocytes, suggesting they have a profoundly more direct role in keloid scarring than previously appreciated [21]. The present of red cell antigens on the membrane surface of red blood cells and certain epithelial cells maybe contribute to keloid formation [22]. (b) Mast cells enhance scar formation, and that these cells may mediate the transition from scar less to fibrotic healing during fetal development [23]. (c)-Recent evidence has indicated the role of type of immune response in keloid formation. Th-1 is stimulated in normal wound healing, while Th-2 is stimulated in keloid formation. INF-y and IL-12, which produced from Th- 1, inhibit proliferation of fibroblasts, while IL-4, IL-5, IL-10 and IL-13, which produce from Th-2 has strongly link to fibrogenesis [23-25].
Proposed inheritance patterns include autosomal recessive, autosomal dominant with incomplete penetrance, and variable expression [4,26]. Several genes are considered responsible for keloid disease, but no single gene mutation has thus far been found to be responsible [32]. Genome wide association studies in Japanese population have shown that four SNP (single nucleotide polymorphism) loci in three chromosomal regions (1q41, 3q22.3-23 and 15q21.3) exhibit significant associations with keloids [33]. Marneros and colleagues studied two families with an autosomal dominant inheritance pattern of keloids (Japanese family and African American one). they identified linkage to chromosome 2q23 (maximal two-point LOD score of 3.01) for the Japanese family. The African-American family showed evidence for a keloid susceptibility locus on chromosome 7p11 (maximal two-point LOD score of 3.16) [34]. Brown and colleagues found a genetic association between HLA-DRB1*15 statuses and the risk of developing keloid scarring in white individuals [35]. Also, carriers of HLA-DQA1*0104, DQB1*0501 and DQB1*0503 have been reported to be have an increased risk of developing keloid scarring [5].
There is importance of the cause and anatomical site in heredity of keloid. 76 % of patients with family history have keloids located in the same anatomical sites of the relative, and 66 % of them have keloids caused by the same cause [27]. Also, there is predisposition to heredity spontaneous keloids, which usually appears in the second decade, and for heredity presternal and shoulder keloids [27]. In addition, family history is strongly associated with the formation of keloid scars in multiple sites as opposed to a single anatomical site [4,28,36,37].
The relationship between melanin and keloid formation have been assumed by several theories: (a) During wound healing, melanocytes from the stratum basal contact or interact with fibroblasts from the dermal layers after the basal membrane is damaged, which in turn facilitates fibroblast proliferation and the secretion and deposition of collagen [38]. (b) High levels of melanin cause decreasing of histologic PH, which inhibit collagenase, that disrupts collagen degradation process [41].
Anterior chest, shoulders, earlobes, upper arms and cheeks have a higher predilection for keloid formation. Eyelids, cornea, palms, mucous membranes, genitalia and soles are generally less affected [5]. The most common anatomical site for developing keloids differs according to race, traditions and conditions of study's society. Shaheen indicated that upper limb 20% followed by sternum 19.17 % were the most common sites for developing keloids in Syrian patients [27]. Similarly, Abas Mouhari Toure noted that sternum 28.95 %, upper limb 15.8 % and head 16.7 % were the most common sites in dark skin patients [43]. Conversely, ear 23% was the most common one in Bayat's study [27]. On other hand, most of studies agree that genitalia, buttock, palm and sole are the rarest sites for developing keloids [27- 29,43].
keloids could develop at any anatomical sites, but there is association between type of skin injury and specific anatomical sites. Syrian study found that 80% of spontaneous keloids were located on sternum and shoulders, these agree partly with a previous study, which demonstrated that sternum was the most common site for spontaneous keloids [27,44]. Also, 45% of burn keloids were located on extremities (lower and upper) in that study, while a Japanese study found that all burn keloids were located on chest wall and lower limbs [27,45]. About 40% of sharp wound keloids were located on upper limbs, and 50% of surgical keloids were located on sternum and abdominal wall [27,45]. Sternum and shoulder are the most common site for acne keloids. Syrian study found that about half of acne keloids were located in these sites, while most acne keloids were located in these sites in the Japanese study [27,45]. 37% of trauma keloids were located on face and upper limb in Syrian patients, which agree partly with the Japanese study, which found that most trauma keloids were located on extremities (upper and lower) [27,45].
Few studies discussed the development of keloids in single versus multiple anatomical sites and its correlation with patient's clinical feature and prognosis [28,37]. Shaheen found that 19.3 % of patients had keloids in multiple anatomical sites, where upper limb was the most common site for developing keloids in them 46 %, and burn was the most common cause 38.2%. Bayat demonstrated that 42.2% of patients had keloids in multiple anatomical sites, where earlobe was the most common site in multiple 24 % sites, and ear piercing was the most common cause [27,28]. Although all causes tend to develop keloids in multiple sites, only burn and acne have association with developing keloid in multiple sites in Syrian patients (p = 0.029) (p = 0.0002) respectively, which means there is high probability to develop acne or burn keloids in another anatomical site in a patient who had a previous acne or burn keloid respectively, because both acne and burn could affect multiple sites more than other causes, which is more located [27]. Female sex, younger age at presentation and the presence of a positive family history are associated with the development of keloid scars in multiple anatomical sites in Afro Caribbean individuals [28].
The most common cause of keloid differs according to conditions of study's society. Syrian and Iranian studies found that keloids could follow any form of skin injury, but burn was the most common [27,46]. Bayat found that laceration was the most common cause in Afro Caribbean patients [28]. Causes have almost coordinated distribution in males and females, but males have higher predisposition to develop acne keloids compared to female, because only males have acne keloidalis nuchae, and the severity of acne is higher in them [27].
Spontaneous keloid is a rare condition, and it is controversial whether it is in fact spontaneous. The scar tissue may form after an insignificant inflammatory reaction or injury which the patient has no recollection of [47]. Syrian study found 13.4 % of spontaneous keloids, which was similar to Togo study 13.13%, but lesser than an Iraqi one 34% [27,43,48]. As we said before, some patients have hereditary of spontaneous keloids, while others have association with blood group A [27]. There is confirmed evidence of the association between spontaneous keloid formation and different diseases such as Dubowitz syndrome, Rubenstein-Taybi syndrome, and Noonan syndrome [36]. In addition, Spontaneous keloid has been reported in siblings and in people with allergic disease [49]. There are very few patients have keloids caused by two different causes [27]. They are only 2.32% of patients in Syrian study, 83.3% of them had surgical keloids, so we have to be careful when performing surgery for a patient who had a previous keloid [27]. On other hand, this percentage is higher in dark skin patients 15.9%, maybe because developing keloid is more common in Blacks than in Whites [43].
keloids could follow any skin insults, but there is association between anatomical sites and specific injuries. Shaheen found that burn was the most common cause of keloid formation in uncovered sites (face (35%), neck (50%), upper limbs (44.29%, lower limbs (66.66%), and chest wall (27.59%)),) and less affected sites (lower back (37.5%), button (50%), genitalia (50%), palm and sole (66.66%)), which disagree partly with the Japanese study, found that trauma was the most common cause of extremities keloids [27,45]. Ear piercing is the most common cause for earlobe keloid [27,28,45]. Acne is the most common cause for scalp keloids [27,28]. More than quarter of shoulder keloids were caused by acne [27,45]. The Syrian study found that Most sternum keloids were spontaneous (35.82%), or followed surgery (37,13%), while most sternum keloids were caused by trauma in Jamaican study, or acne in Japanese study [27,28,45]. At last, abdominal keloids followed by surgery in several study, more than half of abdominal keloids followed surgery in the Syrian study, while all abdominal keloids followed surgery in the Japanese study [27,45].
A previous study reported that 1.93% of patients have keloids caused by two different causes, and distributed on multiple anatomical sites. This maybe indicates that very few people have a high predisposition to develop keloids, but this finding needs more research [27].
Note: the above risk factors are unmodifiable factors, but there are modifiable factors like delayed healing, and hypertension [51,52].
|
Keloid |
Hypertrophic scar |
Heredity |
Some patients have positive family history |
No family history |
Race |
Blacks more than Whites |
No predisposed race |
Sex |
Equal |
Equal |
Age |
Second and third decades |
Second and third decades |
Extension |
Spreads beyond the margin of the original wound |
Remained within the boundaries of the original lesion |
Anatomical site |
Any anatomical sites, especially with high tension (joints), such as knees and ankles. |
Anterior chest, shoulders, earlobes, upper arms and cheeks |
Causes |
The exact cause is unknown |
Related to tension on the wound. |
Incidence |
6% to 16% in African populations. |
Vary from 40% to 70% following surgery to up to 91% following burn injury, depending on the depth of the wound. |
Evolution |
May develop up to several years after minor injuries, persist usually for long periods of time, and do not regress spontaneously. |
Usually occurs within 4 to 8 weeks following wound, has a rapid growth phase for up to 6 months, and then gradually regresses over a period of a few years. |
Response to surgery |
Poor, with possible worsening |
Good, especially with adjuvant therapy. |
Contractures |
Not present |
Present |
Appearance |
Have clawlike configurations |
No clawlike configurations |
Itch - Erythema |
Yes |
Yes, but rare |
Occlusive dressings include silicone gel sheets and dressings, nonsilicone occlusive sheets, and cordran tape. These measures have been used with varied success. Antikeloidal effects appear to result from a combination of occlusion and hydration, rather than from an effect of the silicone. More than 60 products have been marketed, including silicone sheets (Figure 17,18), strips, gels, sprays, and foams. To be effective, sheets must be worn over the scar for 12 to 24 hours per day for two to three months. The sheet and the scar should be washed daily with mild soap and water. The sheets can be reused until they start to disintegrate. There is variation in the success rate of these treatments; a previous study has shown that in patients treated with silicone occlusive sheeting with pressure worn 24 h/d for up to 12 months, 34% showed excellent improvement, 37.5% showed moderate improvement, and 28% demonstrated no or slight improvement. Another study has shown that in patients treated with semipermeable, semiocclusive, nonsilicone-based dressings for 8 weeks, 60% experienced flattening of keloids, 71% had reduced pain, 78% had reduced tenderness, 80% had reduced pruritus, 87.5% had reduced erythema, and 90% were satisfied with the treatment. Cordran tape is a clear surgical tape that contains flurandrenolide, a steroid that is uniformly distributed on each square centimeter of the tape, and it has been shown to soften and flatten keloids over time [53,56,57].
Compression treatments include button compression, pressure earrings (Figure 19,20), ACE bandages, elastic adhesive bandages, compression wraps, spandex or elastane (Lycra) bandages, and support bandages. In one study, button compression (2 buttons sandwiching the earlobe applied after keloid excision) prevented recurrence during 8 months to 4 years of follow-up observation [53,58].
Newer methods of application of liquid nitrogen include the insertion of a lumbar puncture needle through the long axis of the keloid, from one side to the other, passing the liquid nitrogen with an intravenous drip set for 2 freeze thaw cycles of 20-30 seconds each for 5-10 sessions. Flattening was achieved in 75% of the patients. A single treatment with an intralesional cryoprobe was used to treat 10 earlobe keloids in 10 white patients, obtaining a statistically significant reduction in the scar volume of 67.4% after 18 months of follow up compared with baseline measurements. Zero recurrences were reported. Other scar parameters also improved [53].
The authors have studied the effects of topically applied imiquimod 5% cream (Aldara) on the postexcision recurrence rates of 13 keloids excised surgically from 12 patients. Starting the night of surgery, imiquimod 5% cream was applied for 8 weeks. Patients were examined at weeks 4, 8, 16, and 24 for local erythema, edema, erosions, pigment alteration, and/or recurrence of the keloid. Of the 11 keloids evaluated at 24 weeks, none (0%) recurred. Both patients completed the 8 weeks of topical therapy and the final 24-week assessment. At 24 weeks, the recurrence rate of excised keloids treated with postoperative imiquimod 5% cream was lower than recurrence rates previously reported in the literature. Side effects are hyperpigmentation, irritation and superficial erosion [53].
Recurrence is not uncommon, and this technique is unsuitable for young patients as late side effects of radiotherapy may develop. When excisional surgery is followed by postoperative radiation treatment, the total fractionated dose should be a minimum of 12Gy, according to a comparative study showing a higher recurrence rate for patients treated with total doses less than 12Gy [51,59].
Erbium: Yttrium aluminum garnet laser (Er: YAG) (1064 nm): Er: YAG laser showed a decrease of 51.3% in redness, 50% in elevation, and 48.9% in hardness of keloids in one study after treating 21 keloids. The recurrence rate was not reported [53].
Argon 488-nm laser: Similar to the carbon dioxide laser, the argon 488-nm laser can induce collagen shrinkage via generation of excessive localized heat. The argon laser has demonstrated recurrence rates of 45-93% [53].
Note: a previous study found that 8% of keloids resolved spontaneously after 5 years [60].
T0 |
T7 |
T15 |
T21 |
T30 |
T45 |
T60 |
|
Cortisone |
40 mg |
40 mg |
30 mg |
30 mg |
|||
HA |
0.8 ml |
0.8 ml |
0.8 ml |
consistency, was reduced by 40% and the skin synechia became smaller.
He repeated the previous treatment with the following order (table 3).
Synechia disappeared and the keloid was reabsorbed at 15 days after the last cortisone infiltration. The patient did not show any recurrence of the lesion at the 6- month and 12- month follow-up visits [61].
T0 |
T15 |
T20 |
T45 |
T50 |
|
Cortisone |
40 mg |
30 mg |
20 mg |
||
HA |
0.8 ml |
0.8 ml |
2-Avoid skin insults like tattoo and piercing.
3-Proper and effective treatment for acne and other inflammatory lesions.
2-Wear appropriate clothing.
3-Avoid direct friction on the wound, use silicone gel sheets and micropore over it.
4-For patients with wounds on the earlobes, choose adequate pillows and covers to avoid rubbing the wound while lying.
5-Female patients with wounds on the anterior chest should wear surgical bra and appropriate clothing to prevent increase in tensile strength by the weight of the breasts (Figure 24).
6-Patients with suprapubic scars should use post-operative braces and foam compression.
7-After surgery or injury, apply aseptic precautions and always keep the wound clean.
2-Guide skin incisions following skin tension forces.
3-Manipulate the skin atraumatically with delicate instruments, fine suture threads and small diameter needles.
4-Avoid or reduce the use of electrocautery.
5-Suture edges making them well coapted with the least possible tension.
6-Clean the wound thoroughly, removing foreign bodies, performing adequate debridement, etc.
7-Take all available measures to prevent surgical infection.
8-Indicate compression treatment in high-risk scars.
9-Indicate intralesional corticosteroids or use betatherapy in selected patients.
10-Control and periodic follow up of the evolution of the scar and the patient.
Some pictures of keloids, which located in different sites and caused by different forms of skin injury [27]: (Figure 25,26,27,28,29,30,31,32).
- Burrows NP, Lovell CR. Rook textbook of dermatology. 8th edition. Volume 3. Chapter 45.54. keloids and hypertrophic scars.
- Burton CS, Vaishali E. Bolognia text book. Second edition. Volume 2. Section 15. Chapter 98. Dermal Hypertrophies.
- Naylor MC, Brissett AE. Current concepts in the etiology and treatment of keloids. Facial Plast Surg. 2012;28(5):504-512. doi: 10.1055/s-0032-1325644
- Clark JA, Turner ML, Howard L, Stanescu H, Kleta R, Kopp JB. Description of familial keloids in five pedigrees: Evidence for autosomal dominant inheritance and phenotypic heterogeneity. BMC Dermatol. 2009;9:8. doi: 10.1186/1471-5945-9-8
- 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):113-125. doi: 10.2119/molmed.2009.00153
- Shih B, Garside E, McGrouther DA, Bayat A. Molecular dissection of abnormal wound healing processes resulting in keloid disease. Wound Repair Regen. 2010;18(2):139-153. doi: 10.1111/j.1524-475X.2009.00553.x
- Michael O. The Search for the Genetic Basis of African Keloids. Annals of Ibadan Postgraduate Medicine. 2012;10(2):53-55.
- Henriquez CB, Costa F. Resident's Thesis Systematization of treatment of keloid at the Plastic Surgery Unit of the 38th Infirmary of Santa Casa de Misericórdia do Rio de Janeiro. 2003.
- Muthusubramaniam L, Zaitseva T, Paukshto M, Martin G, Desai T. Effect of collagen nanotopography on keloid fibroblast proliferation and matrix synthesis: implications for dermal wound healing. Tissue Eng Part A. 2014;20(19-20):2728-2736. doi: 10.1089/ten.TEA.2013.0539
- Zulato E, Favaretto F, Veronese C, Campanaro S, Marshall JD, Romano S, et al. ALMS1-deficient fibroblasts over-express extra-cellular matrix components, display cell cycle delay and are resistant to apoptosis. PLoS One. 2011;6(4):e19081. doi: 10.1371/journal.pone.0019081
- He S, Liu X, Yang Y, Huang W, Xu S, Yang S, et al. Mechanisms of transforming growth factor β1/Smad signalling mediated by mitogen-activated protein kinase pathways in keloid fibroblasts. Br J Dermatol. 2010;162(3):538-546. doi: 10.1111/j.1365-2133.2009.09511.x
- Li J, Cao J, Li M, Yu Y, Yang Y, Xiao X, et al. Collagen triple helix repeat containing-1 inhibits transforming growth factor‐β1‐induced collagen type I expression in keloid. Br J Dermatol. 2011;164(5):1030-1036.
- Robles DT, Moore E, Draznin M, Berg D. Keloids: Pathophysiology and management. Dermatol Online J. 2007;13(3):9.
- Shang QX, Yuan R, Wang W. Expression of platelet derived growth factor receptor-beta in fibroblasts of keloid. Zhongguo Xiu Fu Chong Jian Wai Ke Za Zhi. 2000;14(5):278-282.
- Hu ZC, Tang B, Guo D, Zhang J, Liang YY, Ma D, et al. Expression of insulin-like growth factor-1 receptor in keloid and hypertrophic scar. Clin Exp Dermatol. 2014;39(7):822-828. doi: 10.1111/ced.12407
- De Felice B, Ciarmiello LF, Mondola P, Damiano S, Seru R, Argenziano C, et al. Differential p63 and p53 expression in human keloid fibroblasts and hypertrophic scar fibroblasts. DNA Cell Biol. 2007;26(8):541-547.
- Lu F, Gao J, Ogawa R, Hyakusoku H. Variations in gap junctional intercellular communication and connexin expression in fibroblasts derived from keloid and hypertrophic scars. Plast Reconstr Surg. 2007;119(3):844-851.
- Vinken M. Role of Connexin-related Signalling in Hepatic Homeostasis and its Relevance for Liver-based in vitro Modelling. World J Gastrointest Pathophysiol. 2011;2(5):82-87. doi:10.4291/wjgp.v2.i5.82
- Sidgwick GP, Bayat A. Extracellular matrix molecules implicated in hypertrophic and keloid scarring. J Eur Acad Dermatol Venereol. 2012;26(2):141-152. doi: 10.1111/j.1468-3083.2011.04200.x
- Hahn JM, Glaser K, McFarland KL, Aronow BJ, Boyce ST, Supp DM. Keloid-derived keratinocytes exhibit an abnormal gene expression profile consistent with a distinct causal role in keloid pathology. Wound Repair Regen. 2013;21(4):530-544. doi: 10.1111/wrr.12060
- Ravn V, Dabelsteen E. Tissue distribution of histo-blood group antigens. APMIS. 2000;108(1):1-28.
- Wulff BC, Parent AE, Meleski MA, DiPietro LA, Schrementi ME, Wilgus TA. Mast cells contribute to scar formation during fetal wound healing. J Invest Dermatol. 2010;132(2):458-465. doi: 10.1038/jid.2011.324
- Hunasgi S, Koneru A, Vanishree M, Shamala R. Keloid: A case report and review of pathophysiology and differences between keloid and hypertrophic scars. J Oral Maxillofac Pathol. 2013;17(1):116-120. doi: 10.4103/0973-029X.110701
- XIONG Li-xia, LI Wen-lin, CAI Zhen-yu, ZHOU Ying, XIONG Jun-ping, ZHAO Lin, et al. Suppressive effect of interferon γ on IL-13-induced fibrosis in fibroblasts. Chinese Journal of Pathophysiology. 2013;3(2013):022.
- Halim A, Emami A, Salahshourifar I, Kannan T. Keloid scarring: understanding the genetic basis, advances, and prospects. Arch Plast Surg. 2012;39(3):184-189. doi: 10.5999/aps.2012.39.3.184
- Shaheen A, Khaddam J, Kesh F. Risk factors of keloids in Syrians. BMC Dermatol. 2016;16(1):13. doi: 10.1186/s12895-016-0050-5
- Bayat A, Arscott G, Ollier WE, McGrouther DA, Ferguson MW. Keloid disease: clinical relevance of single versus multiple site scare. Br J Plast Surg. 2005;58(1):28-37.
- Olaitan P.B, Olabanji J.K, Oladele A.O, Oseni G.A. Symptomatology of keloids in Africans. Sierra Leone Journal of Biomedical Research. 2013;5(1):29-33.
- Ramakrishnan KM, Thomas KP, Sundararajan CR. Study of 1,000 patients with keloids in south India. Plast Reconstr Surg. 1974;53(3):276-280.
- Sun LM, Wang KH, Lee YC. Keloid incidence in Asian people and its comorbidity with other fibrosis-related diseases: a nationwide population-based study. Arch Dermatol Res. 2014;306(9):803-808. doi: 10.1007/s00403-014-1491-5
- Shih B, Bayat A. Genetics of keloid scarring. Arch Dermatol Res. 2010;302(5):319-339. doi: 10.1007/s00403-009-1014-y
- Nakashima M, Chung S, Takahashi A, Kamatani N, Kawaguchi T, Tsunoda T, et al. A genome-wide association study identifies four susceptibility loci for keloid in the Japanese population. Nat Genet. 2010;42(9):768-771. doi: 10.1038/ng.645
- Marneros AG, Norris JE, Watanabe S, Reichenberger E, Olsen BR. Genome scans provide evidence for keloid susceptibility loci on chromosomes 2q23 and 7p11. J Invest Dermatol. 2004;122(5):1126-1132.
- Brown JJ, Ollier WE, Thomson W, Bayat A. Positive association of HLA-DRB1*15 with keloid disease in Caucasians. Int J Immunogenet. 2008;35(4-5):303-307. doi: 10.1111/j.1744-313X.2008.00780.x
- Mandal A, Imran D, Rao GS. Spontaneous keloids in siblings. Ir Med J. 2004;97(8):250-251.
- Park TH, Park JH, Tirgan MH, Halim AS, Chang CH. Clinical Implications of Single Versus Multiple-Site Keloid Disorder: A Retrospective Study in an Asian population. Ann Plast Surg. 2015;74(2):248-251. doi: 10.1097/SAP.0b013e3182a2b537
- Gao FL, Jin R, Zhang L, Zhang YG. The contribution of melanocytes to pathological scar formation during wound healing. Int J Clin Exp Med. 2013;6(7):609-613.
- Goyal S, Saini I, Goyal S. Familial Keloid in Indian Scenario: Case Report and Review of Literature. OALibJ. 2015;2(7):1-4.
- Wolfram D, Tzankov A, Pülzl P, Piza-Katzer H. Hypertrophic scars and keloids -a review of their pathophysiology, risk factors, and therapeutic management. Dermatol Surg. 2009;35(2):171-181. doi: 10.1111/j.1524-4725.2008.34406.x
- Perdanakusuma DS. The effect of melanin concentration on collagen accumulation in keloid. Folia Medica Indonesiana. 2006;42(4):218-227.
- Ogawa R, Okai K, Tokumura F, Mori K, Ohmori Y, Huang C, et al. The relationship between skin stretching/contraction and pathologic scarring: The important role of mechanical forces in keloid generation. Wound Repair Regen. 2012;20(2):149-157. doi: 10.1111/j.1524-475X.2012.00766.x
- Mouhari-Toure A, Saka B, Kombaté K, Akakpo S, Egbohou P, Tchangaï-Walla K, et al. Is There an Association between Keloids and Blood Groups? ISRN Dermatol. 2012;2012:750908. doi: 10.5402/2012/750908
- Kelly AP. Update on the Management of Keloids. Semin Cutan Med Surg. 2009;28(2):71-76. doi: 10.1016/j.sder.2009.04.002
- Ogawa R, Mitsuhashi K, Hyakusoku H, Miyashita T. Postoperative Electron-Beam Irradiation Therapy for Keloids and Hypertrophic Scars: Retrospective Study of 147 Cases Followed for More Than 18 Months. Plast Reconstr Surg. 2003;111(2):547-553.
- Jannati P, Aref S, Jannati A A, Jannati F, Moravvej H. Comparison of Therapeutic Response of Keloids to Cryotherapy Plus Intralesional Triamcinolone Acetonide or Verapamil Hydrochloride. Journal of Skin and Stem Cell. 2015;2(1):e29284.
- Monarca C, Maruccia M, Palumbo F, Parisi P, Scuderi N. A rare case of Postauricular Spontaneous Keloid in an Elderly Patient. In Vivo. 2012;26(1):173-175.
- Sharquie KE, Al-Dhalimi MA. Keloid in Iraqi Patients. A Clinicohistopathologic Study. Dermatol Surg. 2003;29(8):847-851.
- Oittinen HA, O'Shaughnessy M. Multiple nonsyndromic spontaneous keloids in allergic disease. Plast Reconstr Surg. 2007;119(2):762-763.
- Philandrianos C, Kerfant N, Jaloux C Jr, Martinet L, Bertrand B, Casanova D. Keloid scars (part I): Clinical presentation, epidemiology, histology and pathogenesis. Ann Chir Plast Esthet. 2016;61(2):128-135. doi: 10.1016/j.anplas.2015.09.005
- Weledji EP, Ngwane S. The Management of Keloids and Hypertrophic Scars. Darlington and County Durham Medical Journal. 2012;6(2):39-45.
- Ogawa R. Keloid and Hypertrophic Scars Are the Result of Chronic Inflammation in the Reticular Dermis. Int J Mol Sci. 2017;18(3). pii: E606. doi: 10.3390/ijms18030606
- Berman B, Elston DM. Keloid and Hypertrophic Scar Clinical Presentation. Medscape. 2016.
- Ogawa R, Akaishi S, Hyakusoku H. Differential and Exclusive Diagnosis of Diseases That Resemble Keloids and Hypertrophic Scars. Ann Plast Surg. 2009;62(6):660-664. doi: 10.1097/SAP.0b013e31817e9d67
- Moshref SS, Mufti ST. Keloid and Hypertrophic Scars: Comparative Histopathological and Immunohistochemical Study. JKAU: Med Sci. 2010;17(3):3-22. doi: 10.4197/Med. 17-3.1
- Juckett G, Adams HH. Management of Keloids and Hypertrophic Scars. Am Fam Physician. 2009;80(3):253-260.
- O'Brien L, Jones DJ. Silicone gel sheeting for preventing and treating hypertrophic and keloid scars. Cochrane Database Syst Rev. 2013;(9):CD003826. doi: 10.1002/14651858.CD003826.pub3
- Viera MH, Amini S, Valins W, Berman B. Innovative therapies in the treatment of keloids and hypertrophic scars. J Clin Aesthet Dermatol. 2010;3(5):20-26.
- Shejbal D, Bedekoviæ V, Ivkiæ M, Kalogjera L, Aleriæ Z, Drvis P. Strategies in the Treatment of Keloid and Hypertrophic Scars. Acta clin Croat. 2004;43:417-422.
- Smith OJ, McGrouther DA. The natural history and spontaneous resolution of keloid scars. J Plast Reconstr Aesthet Surg. 2014;67(1):87-92. doi: 10.1016/j.bjps.2013.10.014
- ARIANNA DI STADIO. Ear Keloid Treated with Infiltrated Non-cross-linked Hyaluronic Acid and Cortisone Therapy. In vivo. 2016;30(5):695-700.