Keloids and Hypertrophic Scars

A keloid is a benign, well-demarcated area of fibrous tissue overgrowth that extends beyond the original defect.

A hypertrophic scar is similar but remains confined to the initial defect and tends to resolve with time. An imbalance of matrix degradation and collagen biosynthesis resulting in excess accumulation of collagen in the wound has been postulated to be the primary biochemical features of this skin lesion.

Keloid and hypertrophic scars derived fibroblasts produce increased amount of collagen per cell compared with normal fibroblasts. Treatment has to be individualized depending upon the distribution size, thickness and consistency of the of the lesion and association of inflammation. Prevention is the key, but therapeutic treatment of hypertrophic scars and keloids includes a large number of options and among these options the most commonly used corticosteroid is triamcinolone acetonide. Studies have shown that up to 50% of the cases showed significant improvement with respect to scar color itching and scar elevation.

Introduction

Throughout our lives, we all have experiences that injure our skin, leaving behind scar. Scars are unsightly and painful reminders of previous injury, trauma or certain disease. Ability of scar depends upon many factors: the depth and size of wound, age, heredity, sex, and ethnicity. Not all scars are the same. They vary from normal skin scars to distinct types of abnormal scars, such as hypertrophic and disfiguring keloids. Patients with scars often face aesthetic, physical, psychological and social consequences that result in substantial emotional and financial costs.¹

The first description of abnormal scar formation in the form of keloid was given in the Smith papyrus in approximately 1700 BC. Later in 1806, the term cheloide was used by Alibert (which was derived from the Greek ‘chele’ meaning “crab’s claw”) to describe the condition.

Both these conditions (Keloids and hypertrophic scar) represent an excessive connective tissue response to injury, which may be trivial. A keloid is a benign, well-demarcated area of fibrous tissue overgrowth that extends beyond the original defect. A hypertrophic scar is similar, but remains confined to the initial defect and tend to resolve with time.²

Etiopathogenesis

Although the basis for keloid and hypertrophic scar formation has not been fully delineated, an imbalance of matrix degradation and collagen biosynthesis resulting in excess accumulation of collagen in the wound have been postulated to be the primary biochemical features of these skin lesions.^{3, 4} Fibroblast construct new extra cellular matrix components initiate collagen synthesis and provide wound edge tension through contractile proteins, actin and desmin.

Keloid and hypertrophic scar derived fibroblasts produce increased amount of collagen per cell compared with normal fibroblasts.⁵ Experimental evidence implicates the importance of member’s of the transforming growth factor β (TGF-β) family in cutaneuos scaring, as well as scaring in other organs.⁶Although TGF-β is essential for wound healing, overproduction of TGF-β can result in excessive deposition of scar tissue and fibrosis.

Both local and constitutional factors are involved in influencing their development. Burns or scalds and infected lesions predispose to hypertrophy. Another risk factor is the presence of foreign material, either exogenous (e.g. suture material) or endogenous (e.g. embedded hair). Isotretinoin, has been reported to delay would healing and induce keloids in patients who received argon laser or dermabrasion for acne or rosacea.²

Some races, notably Afro-Caribbean’s, are more prone to develop keloids than others. A positive family history is obtained in 5-10% or Europeans with keloids, particularly severe lesions. Family studies suggest an autosomal dominant inheritance with incomplete penetrance keloids from readily in acromegalics, and after thyroidectomy in young patients. Linear keloids have been reported to occur in athletes taking anabolic steroids.²

Histopathology

In the early stages, keloids and hypertrophic scars have similar pathologic feathers: an increase in fibroblasts, bundles of thick, glassy, acidophilic, haphazardly arranged collagen fibers and increased vascularity. The collagen is different from normal skin and non- hypertrophic scars. Mast cells are increased in number.

Hypertrophic scars have less glassy collagen and less mucin as compared to keloids: in addition, the contraction of myofibroblasts present in hypertrophic scars is responsible for the flattening of the lesion after an initial growth phase. Hyalinization is seen in the later stages of both these tumors.

Clinical Features

Keloids are rare in infancy and old age, occurring chiefly between puberty and the age of30 years. Women have a greater predisposition, and keloids may occur or enlarge during pregnancy. The common sites are the presternal area, deltoid region and upper back. Although they can appear anywhere, they are rare on the palms, soles, eyelids and genitalia.⁷

Both keloids and hypertrophic scars begin as soft, erythematous, well circumscribed, round, oval or linear elevation. They may be asymptomatic, pruritic, painful or tender. With time they are become white and indurated.⁷A keloid extends beyond the borders of the original wound, does not regress spontaneously, grows in pseudotumor fashion with distortion of the lesion and tends to recur after excision. Whereas hypertrophic scars remain confined to the borders of the original wound and most of the times retain their shape.⁸

Differential Diagnosis of Keloids and Hypertrophic Scars

They need to differentiated from:

·Each other

·Lobomycosis

·Collagenoma

Treatment of Keloids and Hypertrophic Scars

Keloid and hypertrophic scars have affected patients and frustrated physicians for centuries. Over the past four decades, there has been considerable clinical and experimental research looking at the biological nature and therapeutic response of keloid and hypertrophic scarring.⁹

There seems to be no absolutely effective treatment for hypertrophic scars and keloids and the number of treatment modalities illustrate the lack of understanding concerning this kind of pathologic scar healing. Most studies have not been well controlled and have produced conflicting results.

Table 1. Prevention

There are no set guidelines for the treatment of keloid. Treatment has to be individualized depending upon the distribution, size, thickness, and consistency of the of the lesion and association of inflammation.⁸ Prevention is the key, but therapeutic treatment of hypertrophic scars and keloids includes a large number of options.

Brissett and Sherris state that all treatment protocols are individualized, but the standard approach to keloids and hypertrophic scars begins with corticosteroid injection followed by surgical excision, pressure dressing and long term follow up.¹¹

Table2. Treatment options for keloids and hypertrophic scars

1.Pressure garments

2.Radiation

a.Superficial X- rays

b.Electron beam therapy

c.Interstitial radiotherapy

3.Excision

4.Intralesional injectons

a.Triamcinolone

b.5-Fluorouracil

c.Bleomycin

d.Interferon-alpha

5.Cryotherapy

6.Silicon gel dressings

7.Lasers

a.Carbon dioxide laser

b.Erbium-YAG laser

c.Pulsed dye laser

Pressure Garments

Prolonged pressure on the hypertrophic collagen has been reported to be effective in preventing recurrence of keloid after surgical treatment.¹² Garments made up of elasticized material are available for different anatomical areas of the body. Such garments are advised immediately after wound healing.

Radiation

Superficial x-ray, electron beam therapy and interstitial radiotherapy have been used in the past for effectively treating keloids. There has been controversy in using potentially harmful radiation therapy to treat benign lesions like keloids. But it has been found that good clinical response can be achieved without harmful effects.¹²

Excision

Keloids can be excised with scalpel or electro surgery or laser surgery, but almost 100 per cent keloids are known to recur after surgical treatment. Keloids over areas like ear lobes are less likely to recur after surgical treatment provided proper precautions and post-op treatment is followed. Ideally surgical excision of keloid should be avoided as far as possible, because the failure rate is significantly high. Surgical excision of hypertrophic scars may be efficacious in selected cases but requires meticulous adherence to the surgical principles and adjunctive measures like radiation, intralesional interferon or topical imiquimod.¹³

Intralesional Injections

Triamcinolone

Intralesional injection of corticosteroid (triamcinolone acetonide 10 mg / 40 mg) has always remained the first line treatment for keloids. Steroids are known to inhibit collagen synthesis and possess anti-inflammatory properties. Atrophy, one of the side effects of steroids, is utilized to achieve therapeutic effect in keloids. Multiple injections in the keloid bulk at intervals of 4 to 6 weeks are required to achieve desirable effect. Very often it is difficult to force the injection into the hard mass of keloid. This problem could be overcome by softening the lesion either with cryotherapy, or pulsed dye laser or by addition of hyaluronidase, or topical application of immuno-modulator like imiquimod.¹⁴ Adverse sequelae like hypo or depigmentation, telangiectasia and atrophy are seen in about 20% of cases injected with triamcinolone as reported by Manuskiatti and Fitzpatrick.¹⁵ Berman et al evaluated 13 keloids after surgical excision followed by imiquimod application initiated the night of surgery and continued for 8 weeks. Of the 11 keloids evaluated at the 24 weeks follow – up visit, there were no recurrences observed.¹⁶

Fluorouracil

Fitzpatrick has also reported his 9 years experience of using a pyrimidine analog with antimetabolite activity, 5-flurouracil (FFU) 50 mg/ml with or without triamcinolone acetonide, in the treatment of keloids and hypertrophic scars.¹⁷ FFU has been shown to inhibit fibroblast proliferation in tissue culture, and is believed to reduce post-operative scarring by decreasing fibroblast proliferation. Frequent initial injections (once to thrice weekly), followed by injections at intervals of 4 to 6 weeks was found to be effective in reducing the size of the lesions substantially. Interval between 2 injections should be decided by judging the induration and inflammation of the lesions. FFU injections are quite painful. This pain can be alleviated either by addition of triamcinolone acetonide or by giving a field block anesthesia. Addition of 0.1 ml of triamcinolone acetonide (10 mg/ml) to 0.9 ml of FFU (50 mg/ml) helps to reduce the pain and also the inflammation. This mixture should be injected only in the indurated portions until slight blanching is observed. On an average 5 to 10 injection sessions are required to achieve complete flattening of the lesions. Subjective improvement in the form of decrease in pain, pruritus, stretching or pulling sensation, and discomfort is first noted followed by softening and then flattening of the lesion a and b. The only side effects seen with FFU injection are pain and stinging, blackish discoloration, purpura at injection site, and occasionally superficial ulceration.

Bleomycin

Bleomycin in the dose of 1.5 IU/ml injected intralesionally through multiple pricks resulted in flattening of lesions in 6 out of 13 cases.¹⁸ Similarly bleomycin has also been tried by Badokh and Brun intralesionally (0.1 to 1ml at monthly interval) to treat keloids¹⁹ but its use is restricted due to its side effects and the cost. Antiarrhythmic agent verapamil, which has a property of inhibiting endothelial growth factor and interleukin-6, has been reported in few sporadic trials, to be effective in the treatment of keloids when administered intralesionally.²⁰

Interferons

Interferon α-2b, which has antiproliferative properties, was tried by Berman and Duncan.²¹ They injected a keloid intralesionally with 1.5 million IU IFN α-2b, twice over 4 days. The area of the keloid was found to be reduced to 50% of its size by day 9. IFN α-2b, when used post-operatively, reduced the rate of recurrence to 19% as compared with that of intralesional steroid, where the rate of recurrence was 51%.²²

Role of intralesional corticosteroids

Corticosteroids, specifically intralesional corticosteroid injections have been the mainstay of treatment. The most commonly used corticosteroid is Triamcinolone acetonide (TAC). The dosage and treatment interval have arbitrarily varied from 10 to 40 mg/mL administrated at intervals of 4 to 6 weeks for several months or until the scar is flattened.

Intralesional TAC administration has shown clinical efficacy.^{23, 24} The problem of finding it difficult to force the injection into the hard mass of keloid could be overcome easily by softening the lesion either with cryotherapy or pulsed dye laser or by addition of hyaluronidase or topical application of immuno-modulator like imiquimod.²⁵

Evidence for triamicinolone

E Zanon et al in a study involving 57 patients with hypertrophic scars or keloids, who received high pressure injections of triamicinolone acetonide found that 50% of the cases showed significant improvement with respect to scar color, itching and scar elevation.²⁶ Intralesional steroids decrease the connective tissue components and scar volume. Post-operative steroid injections reduce keloid recurrence to less than 50%. ²⁷

Triamicinolone in combination With cryotherapy

Yosipovitch et al conducted a controlled study, to evaluate the combined effect of intralesional corticosteroids injection with cryotherapy. Ten patients completed the study; eight patients had at least three keloids and two had two keloids. Patients were treated for at least three sessions 4 weeks apart. The outcome of the lesion was compared between the treatments regarding the thickness of the lesion using a caliper and photographic assessment and the presence of itch and pain before and after treatment using a visual analogue scale.

Pain intensity was significantly lowered with all treatment modalities. No significant side effects were noted with any of the treatment and no reoccurrence of keloids was noted with the combined therapy.²⁸

With 5-FU

Manuskiatti et al have concluded that clinical improvement of keloidal and hypertrophic scars after treatment with intralesional corticosteroid alone or combined with 5-FU, 5-FU alone and PDL seemed comparable.

With surgical excision

Chowdri et al treated 58% keloid and hypertrophic scars 58.62% of which were recurrent. Each lesion was subjected to surgical excision with intra-operative local injection of triamicinolone acetonide, followed by repeat injection of the same drug at weekly interval for 2-5 weeks depending on the symptomatic relief in all patient within 5 week of surgery. Objective response in terms of no recurrence was noted in 91.9% of patients with keloids, & 95.24% of patients with hypertrophic scars at amine follow up of 30.5 months. Local or systemic complications were insignificant.²⁹

In conclusion, intralesional triamicinolone, either alone or in combination with other modalities treatment is an effective and probably the treatment of choice for keloids and hypertropic scars.

Cryotherapy

Freezing the lesions of keloid with liquid nitrogen (LN), with 15-30 seconds freeze-thaw cycles resulted in flattening of those keloids < 6 mm in depth, and lesions over back showed better results as compared to those over chest.³⁰,³¹

Cryotherapy helps to soften the lesions, making the intralesional administration of medication easier. Cryotherapy is quite painful and demands infiltration of local anesthesia. As the freezing effect of spray technique does not reach the entire depth of thick keloids, intralesional cryotherapy has been tried and seems to be more effective. It is also devoid of residual depigmentation, commonly observed with spray technique, as the epidermis remains untouched. Because the depth of penetration of the probe technique is 2 cm while the spray technique is even less, lesions 2 cm or more in thickness are difficult to treat by either technique. A therapeutic effect at a depth of 2 cm or more is easy to achieve by the intralesional cryotherapy.³² Twelves cases of bulky keloids unresponsive to intralesional steroid injections were treated with intralesional LN cryotherapy. A wide bored spinal needle is inserted into the keloid parallel to the skin surface, and the nozzle of the cryo-gun is connected to this needle, for delivering LN. After this therapy seven cases out of 12 showed 75% flattening. For a wider lesion, multiple hypodermic needles are inserted at right angles to the length of the lesion, and LN is delivered through these needles to cover the entire lesion uniformly. Intralesional cryotherapy can cause extensive destruction of the tissue at the point of entry of the needle and its exit. It is a potential hazard if the needle remains in contact with the skin after its introduction into the lesion.³⁴ This can be avoided by using peripherally insulated needles.³³ It is advisable to restrict cryotherapy to only small keloids.³⁵

Lasers

Ample reports have documented the use of CO2 or Erbium YAG laser for ablating the keloid lesions, but similar to the excision modality, the failure rate is 100%, as the laser ablation actually burns the lesion.Lately pulsed dye laser (PDL) has been tried successfully for softening the lesions.As the target chromophore for PDL is hemoglobin, PDL also helps to destroy the blood vessels supplying the keloid, thereby reducing its size. It has been hypothesized that laser induced tissue hypoxia leads to decreased cellular function, laser induced heating leads to disulfide band disruption with subsequent re-modelling of the fibers, or collagenolysis occurs following cytokine stimulation. Sixteen adult patients with hypertrophic or keloidal median sternotomy scars after heart surgery treated with PDL every 6-8 weeks for 6 months, showed a significant improvement in erythema, scar height, skin surface texture, and pruritus in laser-treated scar areas; this improvement persisted for at least 6 months.^36,37

Silicon gel dressings

Silicon gel dressings kept in contact with the keloids, secured with micropore tape, for 12 hours a day, resulted in moderate improvement in 50% cases, within a span of 3 to 6 months.³⁸ This dressing can also be used as a preventive method immediate post-operatively, after the surgical wound has healed. Of all non-invasive treatment modalities the use of continuous pressure and occlusive contact media, e.g. silicones, seem to be generally accepted as the only ones that are able to manage hypertrophic scarring without significant side-effects.^39,40

Conclusion

Patient with scars often face aesthetic, physical, psychological, and social consequence that result in substantial emotional and financial cost. This can cause significant impact and morbidity on the affected person. Corticosteroids specifically intralesional Corticosteroid injections have been the mainstay of treatment.

Numerous clinical trials have shown that intralesional corticosteroid have significantly changed the outcome of keloids and hypertrophic scars. The most commonly used corticosteroid is triamicilone acetonide. Studies have shown that up to 50% of the cases showed significant improvement with respect to scar color itching other modalities treatment is effective. Post-operative steroid injection reduces keloid recurrence of choice for keloids and hypertrophic scars.

Future

Multiple treatments have been proposed, often backed by anecdotal evidence alone. Some treatments, such as topical vitamin E, have been widely promulgated as effective in the popular press, whereas others have been marketed directly to the consumer despite a lack of evidence.
A number of different approaches have been taken to modify activity of transforming growth factor β locally.⁴¹ The other principal strategy being followed up by pharmaceutical companies is to interfere with collagen synthesis locally, and this has been effective in an animal model.^42,43 Regardless of the technique employed, an observation period of at least 2 years is necessary to watch for a recurrence.^39,44 

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18. Espana A, Solano T, Quintanilla E. Bleomycin in the treatment of keloids and hypertrophic scars. Dermatol Surg 2001;27:23-7
19. Bodokh I, Brun P. The treatment of keloids with intralesional Bleomycin. Ann Dermatol Venereol 1996;123:791-4.
20. Giugliano G, Pasquali D, Notaro A, Brongo S, Nicoletti G, D'Andrea F, et al. Verapamil inhibits interleukin-6 and vascular endothelial growth factor production in primary cultures of keloid fibroblasts. Br J Plast Surg 2003;56:804-9.
21. Berman B, Dunan MR. Short-term keloid treatment in vivo with human interferon α 2b results in a selective and persistent normalization of keloid fibroblast collagen, glycosaminoglycan and collagenase production in vitro. J Am Acad Dermatol 1989;21:694-702
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About Authors:

Basant Kaushik , Ravindra Gendle, Shekhar Verma, Laxmi Verma and Roshan Patel

Basant Kaushik
B. Sc., M. Pharm. Pharmacognosy, Lecturer, Institute of Pharmacy, RITEE, Chatauna, Mandirhasoud, Raipur, Chhattisgarh, India, 492101
Mob. No. 09300655265, basantpharmacognosy@gmail.com
Basant is  working as a lecturer in Institute of Pharmacy, RITEE, Raipur, CG. He completed  graduation from Smt. SLT Institute of Pharmacy, GGDU Bilaspur, CG in 2005 and post graduation with Pharmacognosy stream from Padmavathi College of Pharmacy, The Tamilnadu Dr. MGR Medical University, Chennai in March 2008. He is life time member of APTI. He presented number of posters on different national seminar and symposium.

Ravindra Gendle
M. Pharm. Pharmaceutics, Lecturer, Institute of Pharmacy, RITEE Chatauna, Mandirhasoud, Raipur, Chhattisgarh, India, 492101
Mob. No. 09977177557, ravi18_k@rediffmail.com
Ravinda is working as a lecturer in Institute of Pharmacy, RITEE, Raipur, CG. He  completed  graduation from Smt. SLT Institute of Pharmacy, GGDU Bilaspur, CG in 2005 and post graduation with Pharmaceutics stream from Padmavathi College of Pharmacy, The Tamilnadu Dr. MGR Medical University, Chennai in March 2008. He is life time member of APTI. He presented number of posters on different national seminar and symposium.

Shekhar Verma
M. Pharm. Pharmaceutics, (Ph. D.), Sr. Lecturer, Institute of Pharmacy, RITEE Chatauna, Mandirhasoud, Raipur, Chhattisgarh, India, 492101
Mob. No. 09826225924, shekharpharma@gmail.com
Shekar is  working as senior lecturer cum research scholar in department of pharmaceutics in Institute of Pharmacy, RIT, Raipur India . He has published several Research Paper / Abstract in National and International journals. He has taken life memership of APTI and IPA. He delivered number of research paper and scientific lecture in different seminar and conferences.

Roshan Patel
M. Pharm. Pharmacognosy, Vels College of Pharmacy, Pallavaram, Chennai, TN Mob. No. 0975587285
roshan.cg@gmail.com
Roshan completed  graduation from Smt. SLT Institute of Pharmacy, GGDU Bilaspur, CG in 2005 and post graduation with Pharmacognosy stream from Vels College of Pharmacy, The Tamilnadu Dr. MGR Medical University, Chennai in March 2008. He is life time member of APTI. He presented number of poster on different national seminar and symposium.

Laxmi Verma
B. Pharm., VNS College of Pharmacy, Bhopal, MP. Mob. No. 09301969089
laxmiverma14sep@yahoo.co.in
Laxmi completed  graduation from Institute of Pharmacy, Pt. RSU, Raipur, CG in 2006 and pursuing M. Pharm. in Pharmacognosy branch from VNS College of Pharmacy, Bhopal, MP.