A keloid is a lump formed by abnormal proliferation of connective tissue during the repair process of skin tissue after a burn or minor injury, characterized by scarring that extends beyond the original lesion area and infiltrates into the surrounding normal tissue, often accompanied by a distinct inflammatory infiltrative zone in the early stages, hence the name keloid. Its treatment has always been a difficult clinical problem.
1. History
The term “keloid” was coined by Alibert in 1806, borrowing the image of the Greek “crab claw”, and was first systematically reviewed by Cosman et al. in 1961. In 1961, Cosman et al. first systematically reviewed the information on keloids, describing the presenting features and treatment of keloids. Since then, Mancini and Peacock et al. have described in detail the differences between keloids and hyperplastic keloids.
2. Keloids and hyperplastic keloids
The clinical presentation and histochemical characteristics of keloid (K) and hypertrophic scar (HS) are different; HS lesions are confined to the original injury area, whereas K can invade the surrounding normal dermis. In contrast, K may first exhibit HS-like characteristics and then present as a keloid. Although both have dense fibroblast (FB), keloid fibroblasts (KFB) have a higher proliferation rate and their collagen fibers are thicker and thicker, and are distinctly wavy and disorganized, whereas HS collagen fibers are relatively parallel to the skin surface.
3.Pathogenesis
3.1 Changes in growth factors: The development of keloids is thought to be associated with enhanced growth factor activity (transfer growth factor-β, TGF-β
; platelet-derived growth factor, PDGF) and alterations in the extracellular matrix (fibronectin, hyaluronic acid, dimeric glycans).
3.2 Differences in growth factors:Transfer growth factor-β (TGF-β ) and platelet-derived growth factor (PDGF) are both produced during wound healing, but both expressions are abnormally increased in K The keloid fibroblasts (KFB) were sensitive to TGF-β response, and the amount of TGF-β was significantly elevated in the proliferative and collagen deposition zones of K. Moreover, the synergistic effect of PDGF receptor and TGF-β was 4- to 5-fold enhanced in KFB.
3.3
Differences in the extracellular matrix:The extracellular matrix regulates the biological activity of growth factors.In K, the extracellular matrix showed abnormalities, with increased amounts of fibronectin (FN) and dimeric glycans and decreased amounts of hyaluronic acid.FN and hyaluronic acid are normal proteins expressed in wound healing. In K, their dysfunctional regulation is attributed to an abnormal fibrillar phenotype. Biglycan and decorin are proteoglycans that bind to collagen fibrils and affect the structure of collagen, and these abnormal proteoglycans produced by K cause abnormal changes in the structure of the extracellular matrix and collagen.
As to why the growth factors of K are abnormal, there are three explanations for this: (i) the epithelial-stromal interrelationship may be related to K occurrence; (ii) the proliferation channels that make adult inactivated embryonic cells are activated in keloids; and (iii) in keloids, hypoxia can trigger the release of vascular growth factors, promote endothelial cell proliferation, and cause fibroblasts to produce more collagen.
3.4
Collagen renewal theory:The dysregulation of collagen metabolism results in a large amount of collagen deposition in K Light and electron microscopy showed that there was a large amount of collagen in K with disorganized arrangement, thick collagen bundles, a distinct wavy shape, and the signature “collagen nodules”. In K, the ratio of type I and III collagen was significantly higher. Collagen was mainly produced by fibroblasts and endothelial cells, while KFB had a stronger capacity for pro-collagen production, collagenase inhibitor.
α-globulin (α-globuling) and inhibitor of fibrinolytic enzyme (plasminogen) activity -1, were both elevated in K, while enzymes that degrade collagen were reduced.
3.5
Tension is said to affect fibroblast proliferation and promote collagen synthesis. In vitro and in vivo studies have confirmed that tension not only promotes collagen production, but also affects collagen structure and alignment and influences dermal remodeling. It has been shown that incisions parallel to the dermal striae rarely trigger scarring, and incisions at the joints often have keloid hyperplasia. The less frequent occurrence of scarring in the elderly is due to the low tension of their relaxed skin. Tension plays a more pronounced role in proliferative scar formation than keloid scarring.
3.6 Hereditary abnormalities of immune function theory:
K predisposes to dark-skinned individuals with a family history and is polygenic. Several studies have shown that in K persons, there is often an A blood type and the presence of human leukocyte antigens B14, B21, BW35, DR5 and DQW3. Patients with keloids often have a history of hypoallergy and elevated immunoglobulin E in the blood.
3.7 Cortical gland reaction theory:After dermal damage, the hair follicle sebaceous gland units come into contact with the body circulation, whereupon an immune response to T lymphocytes is triggered. The cytokines interleukin and TGF-β are released, stimulating mast cell chemotaxis and promoting collagen production in the FB. With the expansion of K, the boundaries of the follicular sebaceous gland units are disrupted and the condition worsens.
Keloid occurs in areas with many sebaceous glands, such as the chest, shoulders and suprapubic area. In contrast, areas lacking sebaceous glands, such as the palms of the hands and the plantar areas of the feet, rarely develop K. Similarly, this may explain why keloids do not occur in animals but only in humans. The former is associated with a reduction in sebaceous gland secretions, whereas the latter is associated with inhibition of sebaceous gland function. Accordingly, it is possible to prevent the occurrence of keloids if the follicular sebaceous gland units are removed prior to surgery.
4. Treatment
4.1 Corticosteroids:Intra-lesion injection of deferensone-A is currently the most effective therapy and has been widely used in the treatment of keloids. 10 mg/ml of deferensone-A injected into K
The effect is to inhibit both normal and keloidal lesions. It works by inhibiting the proliferation of normal and keloid fibroblasts, inhibiting collagen synthesis, increasing collagenase production, decreasing collagenase inhibitor production, causing changes in collagen ultrastructure and ordering the collagen fibers, and also degrading the characteristic collagen nodules in K.
4.2 Surgical excision:
The recurrence rate of keloid resection alone is as high as 40% to 100%. using the subexcision method (within the keloid) together with subcutaneous latent detachment method reduces the recurrence rate due to less manipulation of stimulated collagen. the recurrence rate can be reduced if subcutaneous sutures can be performed after K resection to reduce the tension of skin sutures. using single-stranded silk thread, the same as reducing the inflammatory response, can reduce recurrence. Early postoperative suture removal can also reduce the recurrence rate.
4.3
Radiation therapy: Radiation therapy as an adjuvant therapy after surgical resection, its efficiency can reach 65% to 99%. Radiation therapy can directly damage fibroblasts and affect the structure of collagen and the arrangement of collagen fibers. In vitro studies have identified that radiotherapy can induce apoptosis of KFB. Early postoperative initiation of radiation therapy does not cause wound dehiscence, although it is not recommended for children and pregnant women, and should be used with caution if there are important internal organs on the deep side of the lesion.
4.4
Silicone gel: Silicone gel film is effective for keloid scars and can be applied alone or for wounds after excision of K. The use requires continuous application for more than 12h per day, preferably 24h continuous application, and the treatment should last for 4-6 months after surgery, in addition to the time for daily local cleaning. The mechanism of action of silicone gel is to act as an impermeable membrane that keeps the skin in a hydrated state and performs a function similar to that of the normal skin stratum corneum. The use of silicone gel film can cause local changes such as dampness, rash and erythema, which can subside and be reapplied as long as the use is suspended for a few days.
4.5
Compression therapy:Compression therapy used after excision of keloids can show its effect in reducing the recurrence rate. Up to 80% of K excisions in the earlobes without recurrence were achieved using compression, and the mechanism of action may be a change in the tension of the wound. It is also possible that pressure induces tissue ischemia, promotes collagen degradation and alters the biological activity of fibroblasts.
4.6
Laser treatment:The efficacy of laser on keloid scars is not obvious. There is a 50% recurrence rate after excisional K with CO2 laser alone. Some studies have shown that keloids are more than 75% effective for treatment with 585 nm flash-pumped pulsed dye laser.
4.7 5-Fluorouracil:5-FU is a class of antimetabolic drugs that inhibit the proliferation of fibroblasts and affect the proliferation of keloid scars. There is data on 1000 cases where 5-FU was used for injection of K. Initially, there was some inhibitory effect, but then there was a relapse, requiring continuous injection. The method of administration is 50 mg/ml of 5-FU injected into K every 3 weeks up to 10 times. 5-FU injection was added after surgical resection of K. It was followed up for 6 months with good results. There is also the method of soaking the wound with 5-FU for 5 min after excision of K before closing the wound, which is also said to be effective.
4.8
Interferon:It is a cytokine secreted mainly by T lymphocytes and has an inhibitory effect on fibrosis. IFN-γ and IFN-α2b have been used to treat keloids. IFN-α2b has a broader enzymatic effect and can adjust the level of collagen, and injection into K
can be softened and reduced in size, but there are three reports that it does not work. In contrast, laser excision of K followed by IFN-α2b injection resulted in a 66% cure rate after 3 years of follow-up. One set of comparative studies, in which resection of K
After removal of K, the recurrence rate was 46% with IFN-α2b and only 15% with defensone-A. Interferon application can produce flu-like syndromes such as fever, headache, and muscle pain.
4.9
Other therapies: There are many other treatments for keloids, such as retinoids, calcium channel blockers, cryotherapy, penicillamine, colchicine, bleomycin, imiquimod, cyclosporine, etc. Combination therapy: surgical excision + hormone injection, laser therapy + hormone injection, surgical excision + radiation therapy, surgical excision + compression therapy, surgical excision + silicone gel film and surgical excision + 5-FU, etc.
Example 1: Right auricular scar
Example 1: right auricular keloid excision + tretinoin injection
Example 2: keloid left after abdominal cesarean section